text
stringlengths 0
1.67M
|
|---|
<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with the present invention a transmit device which has further improved data transfer properties and is particularly suitable for channels having a quasi-static behavior is produced, in particular, by using a first encoding level, a transmit demultiplexer level, a second encoding level for performing a second encoding, a modulator level for performing a QAM modulation, a transmit multiplexer level, a multi-carrier modulator and a bit-loading device for performing a bit-loading algorithm and for controlling the transmit demultiplexer level and transmit multiplexer level. In particular, a receive device features a multi-carrier demodulator, a receive demultiplexer level, a first decoding level for performing a first decoding, a demodulator level for performing a QAM demodulation, a receive multiplexer level, a second decoding level and a bit-loading device for performing a bit-loading algorithm for controlling the receive demultiplexer level and the receive multiplexer level, whereby a more stable transfer or reduced failure susceptibility can be achieved on the receive side, particularly when transferring data on channels having quasi-static behavior. The transmit and receive devices optionally may feature an interleaver or de-interleaver in their first encoding level or decoding level, respectively, for performing or reversing interleaving, whereby the data transfer properties can be further improved. Furthermore, the first encoding level or decoding level may feature a puncturer or de-puncturer, respectively, for performing puncturing or de-puncturing depending on the bit-loading algorithm which is performed, thereby producing a more reliable transfer for the data values on either side of the punctured data value. The multi-carrier modulator or demodulator of the transmit and receive device, respectively, preferably performs an OFDM, MC-CDMA and/or CDMA modulation or demodulation (Orthogonal Frequency Division Multiplexing, Multi-Carrier Code Division Multiple Access, Code Division Multiple Access), whereby particularly stable data transfer conditions can be achieved when high interference levels are present. The modulator or demodulator level of the transmit and receive device, respectively, preferably includes a multiplicity of QAM modulators or demodulators with which different modulation or demodulation procedures can be performed. In this way, it is possible to adapt very precisely to the relevant transfer conditions or channel properties. In order to further improve the data transfer properties, the receive device can include a transmitter chain in a feedback path, the transmitter chain providing for the feeding back of output signals of the second decoding level, which preferably performs a Viterbi algorithm, wherein the transmitter chain reproduces the function blocks which are used in a transmit path. In this context, a resulting reproduced serial sequence of QAM symbols is analyzed, together with a received serial sequence of QAM symbols which was generated by the multi-carrier demodulator, in an analysis unit for generating a reliability information signal, and then forwarded to a selection device for selecting a relevant reliability information signal of a 1 st to k th iteration, which signal subsequently affects the first decoding level. However, as an alternative to the feedback described in the previous paragraph, it is also possible in the second decoding level to perform a so-called Soft-Output Viterbi Algorithm (SOVA) for outputting an additionally calculated reliability information signal, the signal then being forwarded in a selection device to the demultiplexer level and the first decoding level. If puncturing or interleaving is used, this feedback path also may include a puncture and an interleaver, again resulting in improved transfer properties. Additional features and advantages of the present invention are described in, and will be apparent from, the following Detailed Description of the Invention and the Figures. |
Parallel infinite element method calculation system |
The well known methods for a very large scaled structure problem, including domain decomposition method (DDM), DDM with Neumann preprocessing, BDD method and projected CG method, may involve problems that the divergence prevents from solving, and that the computation takes long time. The present invention provides a system of high potential computing performance for solving a very large scaled structure problem without divergence, with shorter computing time for a very large scaled structure problem of the degree of freedom of a million or more. The present invention comprises a parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, comprising: a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution, and a program for operating said system, and a computer readable recording medium having said program stored thereon. |
1. A parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, comprising: a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution. 2. A parallel finite element method computing system set forth in claim 1, in which said means for defining overlapped movement of entire subdomain may further comprise: a means for creating a projector for displaying all degree of freedom; a means for creating an overlapped movement matrix of entire subdomain; and a means for LU decomposing said overlapped movement matrix of entire subdomain. 3. A parallel finite element method computing system set forth in claim 1, in which said means for defining a default setting of projected CG method with preprocessing of all degree of freedom may further comprise: a means for setting initial displacement of all degree of freedom; a means for performing computation of initial residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; and a means for defining an initial vector value in the search direction of CG method with all degree of freedom. 4. A parallel finite element method computing system set forth in claim 1, in which said means for performing iterative computation of projected CG method with preprocessing of all degree of freedom may further comprise: a means for updating the displacement of all degree of freedom; a means for updating the residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; a means for updating vectors in the search direction of CG method of all degree of freedom; and a means of determining the convergence. 5. A parallel finite element method computing program used in a parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, characterized in that said program operates as a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution, 6. A parallel finite element method computing program set forth in claim 5, in which said means for defining overlapped movement of entire subdomain may further operate as a means for creating a projector for displaying all degree of freedom; a means for creating an overlapped movement matrix of entire subdomain; and a means for LU decomposing said overlapped movement matrix of entire subdomain; 7. A parallel finite element method computing program, set forth in claim 5, in which said means for defining a default setting of projected CG method with preprocessing of all degree of freedom may further operate as a means for setting initial displacement of all degree of freedom; a means for performing computation of initial residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; and a means for defining an initial vector value in the search direction of CG method with all degree of freedom; 8. A parallel finite element method computing program, set forth in claim 5, in which said means for performing iterative computation of projected CG method with preprocessing of all degree of freedom may further operate as a means for updating the displacement of all degree of freedom; a means for updating the residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; a means for updating vectors in the search direction of CG method of all degree of freedom; and a means of determining the convergence. 9. A computer readable recording medium having stored thereon a parallel finite element method computing program used in a parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, characterized in that said program operates as a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution. 10. A computer readable recording medium having stored thereon a parallel finite element method computing program set forth in claim 9, in which said means for defining overlapped movement of entire subdomain may further operate as a means for creating a projector for displaying all degree of freedom; a means for creating an overlapped movement matrix of entire subdomain; and a means for LU decomposing said overlapped movement matrix of entire subdomain. 11. A computer readable recording medium having stored thereon a parallel finite element method computing program set forth in claim 9, in which said means for defining a default setting of projected CG method with preprocessing of all degree of freedom may further operate as a means for setting initial displacement of all degree of freedom; a means for performing computation of initial residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; and a means for defining an initial vector value in the search direction of CG method with all degree of freedom. 12. A computer readable recording medium having stored thereon a parallel finite element method computing program, set forth in claim 9, in which said means for performing iterative computation of projected CG method with preprocessing of all degree of freedom may further operate as a means for updating the displacement of all degree of freedom; a means for updating the residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; a means for updating vectors in the search direction of CG method of all degree of freedom; and a means of determining the convergence. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a very large scale parallel finite element method solver algorithm, which may effectively solve a very large scale structure problem of the degree of freedom of more than a million (1,000,000). More particularly, the algorithm incorporates a conjugate projected gradient algorithm of the domain decomposition, based on a parallel CG algorithm. The algorithm may be referred to as a “CGCG method (coarse Grid CG method)”: A space of the degree of freedom of subdomain level by the domain decomposition is referred to as a coarse space, and the subspace perpendicular to K is referred to as a fine space, where a stiffness matrix of the given structure problem is defined as K. The CGCG method may perform in parallel the conjugate projected gradient algorithm, adopting the k-orthogonal projection to the fine space for the projection. 2. Description of the Prior Art The structural problem may be in general treated as follows: The objective structure in question is formulated as a continuum to define the dynamic equation of the continuum (equalizing equation in case of a static problem). It is almost impossible to solve this equation strictly. Rather the equation must be solved in such a manner as the numerical analysis. For this reason a reformulation of discrete proximity of the continuum problem is required. One of the solution proposed is the finite element method (computational dynamics handbook (I): finite element method for the structure, Japan Society of Mechanical Engineers, 1998) In the finite element method the space occupied by the continuum is at first decomposed to a plurality of elements (elements of the finite element method). Functions (form functions) having a domain with non-zero value localized to each element is then introduced to proximate to limit the continuum displacement field to expressions of the convolution of these functions. This may result in digitizing of the continuum displacement field and its motion equation (or equalizing equation). The digitizing allows the equation to decompose to a single linear equation (in case of a static linear problem) or a plurality of linear equations (for each incremental step in case of a non-linear problem; for each time step in case of dynamic problem). The degree of freedom (or dimension) treated by the linear equation is depending on the number of division of elemental decomposition of the continuous domain by the finite element method; the degree of freedom increases in general with the increase of the number of decomposition for better proximity, causing the difficulty of solving the corresponding linear equation. The static structural problem of micro deformation may be decomposed to a linear problem on a product vector space in a finite dimension V given by the following equation (1) in-line-formulae description="In-line Formulae" end="lead"? Ku=F eq 1 in-line-formulae description="In-line Formulae" end="tail"? where V designates to a space of permissible displacement field (vector field satisfying the boundary conditions of the displacement field), K to a stiffness matrix of the dimension dimV of V (symmetric when positive fixed set point), u to a variable vector of V, F to a constant vector of the KV≈V indicative of external force. The dimension dimV of V is equal to the number of the degree of freedom of the problem. The objective of the solver is to find a vector u, which satisfies the equation (1) above from within V. Now the conjugate projected gradient algorithm (CPG: Conjugate Projected Gradient Algorithm: C. Farhat, F. X. Roux: Implicit Parallel Processing in Structural Mechanics, Computational Mechanics Advances 2, 1-124, 1994) will be described, which constitutes the base of the present invention. Consider a generic liner equation (eq. 2) of an inner product vector space V in a finite dimension: in-line-formulae description="In-line Formulae" end="lead"? Ku=F, u, FεV eq 2 in-line-formulae description="In-line Formulae" end="tail"? where K is a linear transform of positive constant symmetry. One subspace Y of V is then selected. V is K-orthogonally projected to Y. A unique K-orthogonal projector P (Y) , KP (Y) =P (Y) T K is determined. P (Y) T is the transposition of P (Y) . At this point a K-orthogonal projector P (a) (auxiliary projector of P (Y) ), KP (a) =P (a) T K is uniquely determined, which satisfies the condition P (Y) +P (a) =1, the entire space V may be k-orthogonal direct sum decomposed to the image space Y, V (a) of the P (Y) and P (a) , as given by equation (3): V = Y ⊕ V ( a ) , Y ⊥ K V ( a ) , ( Y V ( a ) ) = ( p ( Y ) p ( a ) ) V eq 3 The K-orthogonality of P (Y) T P (Y) and P (a) can be summarized as equation (4): K ( P ( Y ) P ( a ) ) = ( P ( Y ) T P ( a ) T ) K eq 4 Therefore the linear equation eq. (2) can be decomposed to equation (5) K ( P ( Y ) P ( a ) ) u = ( P ( Y ) T P ( a ) T ) F eq 5 Now the KY-component of F, P (Y) T F and KV (a) -component, P (a) T F, or Y-component of u, P (Y) u and V (a) -component P (a) u maybe independently processed. In brief, equation (2) can be K-orthogonally direct sum decomposed to two independent equations (6) and (7) with equation (8). For the sake of convenience, Y is referred to as direct space, V (a) that is k-orthogonal auxiliary space of Y is referred to as iterative space. in-line-formulae description="In-line Formulae" end="lead"? Ku (Y) =F (Y) , u (Y) εY, F (Y) εKY eq 6 in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? Ku (a) =F (a) , u (a) εV (a) , F (a) εKV (a) eq 7 in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? u=u (a) +u (Y) , F=F (a) +F (Y) eq 8 in-line-formulae description="In-line Formulae" end="tail"? Now consider that a subspace W of the direct space Y is specially determined. This W is referred to as coarse space, herein below. The K-orthogonal auxiliary space of W is referred to as a fine space. When Y is K-orthogonal direct sum decomposed to W and W c , the K-orthogonal auxiliary space of W, equation (9) on W may be set in a manner similar to equation (6) as follows: in-line-formulae description="In-line Formulae" end="lead"? u (W) εW:Ku (W) =F (W) , F (W) ≡P (W) T FεP (W) T V=KW eq 9 in-line-formulae description="In-line Formulae" end="tail"? where P (W) designates to the k-orthogonal projector to W. This equation is referred to as the coarse grid problem. If W is defined by setting its base {e j (W) } j , equation 9 may be formulated to the following equation (10): in-line-formulae description="In-line Formulae" end="lead"? u (W) =e j (W) u j , K ij (W) u j =F i eq 10 in-line-formulae description="In-line Formulae" end="tail"? Now the following equation (11) is defined: in-line-formulae description="In-line Formulae" end="lead"? K ij (W) ≡e i (W) ·Ke j (W) , F i ≡e i (W) ·F=e i (W) ·F (W) eq 11 in-line-formulae description="In-line Formulae" end="tail"? where K ij (W) is referred to as a coarse grid matrix. The equal sign in the second equation is due to the orthogonality of W with the image space K(W c β K V (a) )) of fine space W c ⊕ K V (a) by K. Now consider to solve, among k-orthogonally direct sum decomposed equations, equation (6) by the direct method, and equation (7) by the iteration method. When applying the iteration method to equation (7), iterative equation of n-th step may be written as following equations (12) and (13): in-line-formulae description="In-line Formulae" end="lead"? Ku n (a) +r (a) n =F (a) , u n (a) εV (a) , F (a) εKV (a) eq 12 in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? r (a) n ≡F (a) −Ku n (a) , u n ≡u (Y) +u n (a) eq 13 in-line-formulae description="In-line Formulae" end="tail"? where r (a) n designates to the residual error. Note that r (a) n εKV (a) . For the iteration method, the CG method with preprocess, which includes P (a) GP (a) T (where G is symmetric) as the preprocess determinant: P (a) GP (a) T −CG method, equations (14) to (16) will be adopted: in-line-formulae description="In-line Formulae" end="lead"? p 0 =P (a) Gr (a) 0 εV (a) eq 14 in-line-formulae description="In-line Formulae" end="tail"? u n + 1 ( a ) = u n ( a ) + α n p n , r ( a ) n + 1 = r ( a ) n - α n Kp n , α n ≡ r ( a ) n · Gr ( a ) n p n · kp n eq 15 p n + 1 = P ( a ) Gr ( a ) n + 1 + β n p n , β n = r ( a ) n + 1 · Gr ( a ) n + 1 r ( a ) n · Gr ( a ) n eq 16 where p n designates a search direction vector of P (a) GP (a) T −CG method. Note that P (a) T r (a) n =r (a) n εKV (a) . As shown here, the method which solves one of equations k-orthogonally direct sum decomposed by the CG method with preprocess is referred to as conjugate projected gradient (CPG) method. In the discussion which follows, such method will be referred to as projected CG method, including solving the other of equations by direct method, for the sake of convenience. K-orthogonal projector to the subspace W⊕ K V (a) is designated to P (W+a) . Although it is impossible to directly compute P (a) itself, P (W+a) may be computable, and now consider a case that the base of W, {e j (W) } j is given. In such a case the preprocess computation of P (a) Gr (a) n in equations (14) and (16) may be conducted as follows: P (a) Gr (a) n may be rewritten as equation (17): in-line-formulae description="In-line Formulae" end="lead"? P (a) Gr (a) n =P (W+a) Gr (a) n −μ n (W) , Kμ n (W) =P (W) T KGr (a) n eq 17 in-line-formulae description="In-line Formulae" end="tail"? μ n (W) εW can be determined from equation (4). The preprocessing computation P (a) Gr (a) n can be reduced to the coarse grid problem of equation (18). in-line-formulae description="In-line Formulae" end="lead"? μ n (W) εW:Kμ n (W) =P (W) T KGr (a) n eq 18 in-line-formulae description="In-line Formulae" end="tail"? The coarse grid problem can be solved by following the procedure of equation (10). To characterizing the CGCG method, conventional finite element method parallel solver algorithm, DDM, BDD method, parallel CG method are now described herein below. As will be described, existent finite element method parallel solver algorithm, DDM, BDD method based on the domain decomposition may be considered to pertain a projected CG method based on the k-orthogonal direct sum decomposition method. In the following, V is defined as space of all degree of freedom in the structure problem determined according to the finite element method, and the linear equation to be solved is given as equation (19) by: in-line-formulae description="In-line Formulae" end="lead"? Ku=F, u, FεV eq 19 in-line-formulae description="In-line Formulae" end="tail"? where K designates to a stiffness matrix. There is a domain decomposition method (DDM) conceived as a method for efficiently solving (in particular in the parallel processing) a very large scale problem (a problem having the degree of freedom of or more than approximately 1,000,000). Elements decomposed according to the finite element method and adjoining each other are appropriately grouped. The spatial domain occupied by a group is referred to as a subdomain (see FIG. 1 ). The space is hierarchically decomposed and scattered such that the entire domain is at first decomposed to subdomains, then a subdomain is decomposed to finite elements, and soon. The process on the entire domain will be split into two levels, a process for intra-subdomain and a process for inter-subdomain. The process for intra-subdomain may be paralleled. The two step process as described above may be achieved by separately processing the displacement into the displacement within a subdomain in response to a stress applied to the inside of subdomain, and the remaining displacement in response to a stress applied to the boundary between subdomains (internal boundary). The latter displacement may be further separated into the displacement within the subdomain and the displacement on the internal boundary, the former one is the slave variable of the latter. The degree of freedom of the internal boundary, which is an independent variable, may be solved by the CG method. By solving the internal boundary, the displacement within a subdomain can be determined as the displacement of non-load with the boundary condition of the displacement on the boundary. More specifically, the entire domain {overscore (Ω)}occupied by the structure is decomposed to the boundary Γ, domain fused of entire contents of subdomains Ω i , and internal boundary Γ s . Γ and Γ s may be partly overlapped. The freedom space of the admissible displacement on the {overscore (Ω)} constitutes the total space of the degree of freedom V. By using a form function array {φ α } α as the standard orthogonal base, an inner product is defined to V. The inner product may depend on the {φ α } α , and may be set for the convenience of computation which may vary according to the digitizing method, thus may have neither objective nor physical meaning. The domain {overscore (Ω)}−Γ s include Ω i . The space V i of the degree of freedom of the admissible displacement on the {overscore (Ω)}−Γ s is perpendicular to the space Vs of the degree of freedom of the admissible displacement on the internal boundary Γ s , The entire space of the degree of freedom V may be orthogonally direct sum decomposed to V i and V s as given by equation (20): in-line-formulae description="In-line Formulae" end="lead"? V=V i ⊕V s , V i ⊥V s eq 20 in-line-formulae description="In-line Formulae" end="tail"? Based on this direct sum decomposition, linear transform of positive fixed set point may be block decomposed to K = ( K ii K is K si K ss ) , and diagonalized as given by equation (21): K = ( K ii K is K si K ss ) = ( 1 K si K ii - 1 1 ) ( K ii S ) ( 1 K ii - 1 K is 1 ) eq 21 where S is Schur's element. Projectors P (i) , P (s) may be defined as equation (22): P ( i ) ≡ ( 1 K ii - 1 K is 0 ) , P ( s ) ≡ 1 - P ( i ) = ( 0 - K ii - 1 K is 1 ) eq 22 where P (s) causes the displacement on the internal boundary Γ s to correspond to the displacement {overscore (Ω)}−Γ s that has this boundary condition and receives no stress. From the definition equations (23) and (24) can be derived: KP ( i ) = ( 1 K si K ii - 1 1 ) ( K ii 0 ) ( 1 K ii - 1 K is 1 ) = ( K ii K is K si K si K ii - 1 K is ) eq 23 KP ( s ) = ( 0 S ) eq 24 therefore can be written as equation (25): K ( P ( i ) P ( s ) ) = ( P ( i ) T P ( s ) T ) K eq 25 where P (i) and P (s) are k-orthogonal projectors, which satisfy the condition P (i) +P (s) =1. Note that =P (s) T KP (s) . Therefore, from these projectors, V may be k-orthogonal direct sum decomposed to equation (26) in-line-formulae description="In-line Formulae" end="lead"? V=V (i) ⊕V (s) , V (i) ⊥ K V (s) , V (i) ≡P (i) V, V (s) ≡P (s) V eq 26 in-line-formulae description="In-line Formulae" end="tail"? The relationship between (V i V s ) and (V (i) V (s) ) may be written as equation (27): V ( i ) = V i , KV ( s ) = ( 0 SV s ) , V ( s ) = P ( s ) V s = ( - K ii - 1 K is 1 ) V s eq 27 Following can be derived therefrom for V (s) : the second equation indicates that V (s) is a space of displacement where the reaction on {overscore (Ω)}−Γ s is zero. On the other hand the third equation indicates that V (s) is a space of displacement on {overscore (Ω)}, which has as geometric boundary condition the displacement on the Γ s . Therefore these two characteristics of V (s) are equal. Since the eigenspace belonging to the eigenvalue 0 of the projector P (s) , i.e., kerP (s) , may be kerP (s) =V (i) =V i , then V s and V (s) are linearly uniform. Thus the limitation of P (s) to V s , V s →V (s) , can be found to be linearly uniform. This indicates that when V (s) is a variable space, V s can be instead used for the variable space. The direct method space Y and iterative method space V (a) of k-orthogonal direct sum decomposed space and equation may be defined as following equation (28): in-line-formulae description="In-line Formulae" end="lead"? Y=V (i) , V (a) =V (s) eq 28 in-line-formulae description="In-line Formulae" end="tail"? and the projection CG method (J. Mandel, M. Brezina: Balancing Domain Decomposition: Theory and Performance in two and Three Dimensions, MGNet, http://casper.cs.yale.edu/mgnet/www/mgnet-papers.ht ml) is applied to the preprocessing determinant G of equation (14) to (16) with unit determinant G=1 to yield the Domain Decomposition Method (DDM). V (i) indicates a space of the degree of freedom on the admissible displacement of {overscore (Ω)}−Γ s , V s indicates a space of the degree of freedom of the displacement that does not receive any stress on the {overscore (Ω)}, with the admissible displacement on the Γ s and the boundary condition thereof (more exactly, displacement restriction condition). KV (s) is a space of the degree of freedom of the reaction force on the internal boundary corresponding to the displacement of V (s) . In the conventional DDM algorithm V s is used for the variable space instead of V (s) , according to the foregoing. By setting G other than the unit determinant, the DDM with preprocessing can be achieved. For the usual preprocessing determinant G, preprocess is valid when G ≅ S - ≡ ( 0 S - 1 ) = P ( s ) K - 1 P ( s ) T . Preprocess used in the CG method of the DDM, includes Neumann preprocess (P. Le. Tallec: Domain decomposition methods in computational mechanics, Computational Mechanics Advances 1 (2) (1994) 121-220). This preprocess uses Neumann preprocess determinant as the above preprocess determinant G, instead of unit determinant of 1. Neumann preprocess determinant may be defined as equation (29) below, as representation of block decomposition corresponding to equation (24) by using general inverse determinant S 1− of Schur auxiliary element S 1 (also referred to as local Schur auxiliary element) of the local stiffness matrix K 1 in each subdomain I: G = ( 0 ∑ I N I D I S I - D I T N I T ) eq 29 where I is the index of subdomain by domain decomposition, N I is 0-1 component determinant, which maps the degree of freedom of subdomain I to the degree of freedom of the entire domain, {D I } I is the set 1 = ∑ I N I D I N I T of decomposition determinant of 1 to each subdomain. This preprocess is likely not to satisfy the condition G≅S − , depending on the selected general inverse determinant S 1− . By applying Neumann preprocess to the DDM, undetermined rigid displacement for each subdomain may be interfused for each iteration, according to the arbitrary selection of S 1− . This may cause random floating movement in subdomains, and may be the cause of aggravation of the efficiency of iterative convergence. This may also be the cause of unsatisfying the condition G≅S − . The BDD method (Balancing Domain Decomposition method, J. Mandel: Balancing Domain Decomposition, Communications on Numerical Methods in Engineering 9 (1993) 233-341., J. Mandel, M. Brezina: Balancing Domain Decomposition: Theory and Performance in Two and Three Dimensions, MGNet, http://casper.cs.yale.edu/mgnet/www/mgnet-papers.html, ARASOL An Integrated Programming Environment for Parallel Sparse Matrix Solvers (Project No. 20160), Deliverable D 2.4e Final report Domain Decomposition Algorithms for Large Scale Industrial Finite Element Problems, Jul. 30, 1999) is a solution based on the DDM by using the CG method with preprocessing for the displacement on the internal boundary. Specifically for a static problem of micro deformation of linear material, this method divides the displacement responsive to the stress applied onto the internal boundary to the rigid displacement for each subdomain and residual distortional displacement to solve the former freedom by using the direct method prior to the latter freedom, which will be solved by the CG method with preprocessing. In other words, projection that avoids the interference of the freedom of rigid displacement for each subdomain already solved in advance is added to Neumann preprocessing for every iteration. More specifically, this projection is introduced in such a manner that it eliminates any stress which may cause random floating movement in the subdomain, or it is a correspondence F→F (a) in equations (7) and (8) of k-orthogonally direct sum decomposition, or the projection of residual error r→r (a) in the projected CG method algorithm. As can be seen from the foregoing, the projection as described above is referred to as balancing, which suppresses the floating movement in subdomains by improving the DDM with Neumann preprocessing. More specifically, subspace V (s) =P (s) V s in the DDM is further k-orthogonally direct sum decomposed as follows: by considering a movement that sum spaces across I of subspace including kerS 1 , for example every rigid displacement of a subdomain are summed for all of subdomains, the space of that degree of freedom is defined as a coarse space W. W is a subspace of V (s) V (s) is then k-orthogonally direct sum decomposed to W and k-orthogonal auxiliary space V (t) for V (s) . Now by defining a pair of k-orthogonal projectors P (W) and P (t) , equation (30) can be given: P ( s ) = P ( W ) + P ( t ) , K ( P ( W ) P ( t ) ) = ( P ( W ) T P ( t ) T ) K eq 30 The space of all freedom V may be k-orthogonal direct sum decomposed to equations (31) and (32): in-line-formulae description="In-line Formulae" end="lead"? V=V (i) ⊕W⊕V (i) , V (i) ⊥ K W, V (i) ⊥ K V (a) , W⊥ K V (t) eq 31 in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? W=P (W) V, V (t) ≡P (t) V eq 32 in-line-formulae description="In-line Formulae" end="tail"? Now define the direct method space and iterative method space of k-orthogonal direct sum decomposition of the space and equation as equation (33): in-line-formulae description="In-line Formulae" end="lead"? Y=V (i) ⊕ K W, V (a) =V (t) eq 33 in-line-formulae description="In-line Formulae" end="tail"? In the BDD method, the projection CG method (J. Mandel, M. Brezina: Balancing Domain Decomposition: Theory and Performance in Two and Three Dimensions, MGNet, http://casper.cs.yale.edu/mgnet/www/mgnet-papers.html) is applied thereto after having preprocessing determinant G of equations (14) to (16) substituted for Neumann preprocessing determinant. In particular, preprocessing corresponding to equations (17) and (18) may be rewritten as equations (34) and (35) as follows, since P (W+a) =P (s) : in-line-formulae description="In-line Formulae" end="lead"? P (a) Gr (a) n =P (s) Gr (a) n −μ n (W) eq 34 in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? μ n (W) εW:Kμ n (W) =P (W) T KGr (a) n eq 35 in-line-formulae description="In-line Formulae" end="tail"? The projection Gr (a) n ″P (s) Gr (a) n may be computed as stated in equation (22). The iterative space V (t) of the BDD method is also defined together with the later definition of W 1 of the local coarse space. This is also a balanced space. K −1 -orthogonal projection from a balanced space to an image space SV (a) , r (a) n εSV s →P (a) T r (a) n εεSV (a) is referred to as “balancing” (J. Mandel: Balancing Domain Decomposition, Communications on Numerical Methods in Engineering 9 (1993)233-341., J. Mandel, M. Brezina: Balancing Domain Decomposition: Theory and Performance in Two and Three Dimensions, MGNet, http://casper.cs.yale.edu/mgnet/www/mgnet-papers.html). Balancing may not appear directly in algorithm equations (14) to (16) of the projection CG method applied to the BDD method, however is corresponded to k-orthogonal projection Gr (a) n εV s ⊂V→P (a) Gr (a) n εV (a) equations (14) and (16). In contrast to the DDM, even when G of BDD method may be G≢S − , if P (a) GP (a) T ≅P (a) S − P (a) T =P (a) K −1 P (a) T then it is valid for the preprocessing. Neumann preprocessing determinant equation (29) satisfies this condition, which may solve the problem of the DDM with Neumann preprocessing, as stated above in the beginning of this section. In the parallel CG method no domain decomposition is conducted, rather all freedom space V is processed in the CG method. In addition k-orthogonal direct sum decomposition of V is not performed. This corresponds Y={0} for the direct method space. If the problem to be solved is large scaled, and the dimensions of vector space V is large, then the domain subject to be analyzed will be split into some spaces (referred to as “part”) the degree of freedom for every subspaces will be processed in different processors based on the V decomposition (decomposition that leaves boundary overlapped) along with the division. Interprocess communication is necessary only when some computations are conducted, which require information exchange between subspaces such as the inner product of vectors or matrix-vector product. As can be seen, solutions according to the DDM (Domain Decomposition Method), the DDM with Neumann preprocessing, the BDD (Balancing Domain Decomposition) method, and the parallel CG method have been described, for solving a very large scale structure problem. However, there has been pointed out the problems associated therewith that none of these methods may determine the solution because of divergence at the time of solving a very large scaled structure problem, and the computation is very time-consuming. The present invention has been made in view of the above circumstances and has an object to overcome the above problems and to provide a systematic CGCG method for solving a very large scaled structure problem having the degree of freedom of a million or more, which allows determining the solution without divergence of solutions, with less number of steps of iterative computation, and with less time-consuming computation. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a system for solving a very large scaled structure problem, a program for operating the system, and a computer readable recording medium having the program stored thereon. The CGCG method is a finite element method solver algorithm for a very large scaled structure problem, which uses the projection CG method with preprocessing, by performing domain decomposition, defining thereby coarse space without regarding the inside of subdomain and boundary, and adopting simple diagonal scaling for the preprocessing. The present invention provides a parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, characterized by a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution. Said means for defining overlapped movement of entire subdomain may further include a means for creating a projector for displaying all degree of freedom; a means for creating an overlapped movement matrix of entire subdomain; and a means for LU decomposing said overlapped movement matrix of entire subdomain. Said means for defining a default setting of projected CG method with preprocessing of all degree of freedom may further include a means for setting initial displacement of all degree of freedom; a means for performing computation of initial residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; and a means for defining an initial vector value in the search direction of CG method with all degree of freedom. Said means for performing iterative computation of projected CG method with preprocessing of all degree of freedom may further include a means for updating the displacement of all degree of freedom; a means for updating the residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; a means for updating vectors in the search direction of CG method of all degree of freedom; and a means of determining the convergence. The present invention may also provide a program for operating said system. More specifically, the present invention provides a parallel finite element method computing program used in a parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, characterized by operating as a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution, in which said means for defining overlapped movement of entire subdomain may further operate as a means for creating a projector for displaying all degree of freedom; a means for creating an overlapped movement matrix of entire subdomain; and a means for LU decomposing said overlapped movement matrix of entire subdomain; in which said means for defining a default setting of projected CG method with preprocessing of all degree of freedom may further operate as a means for setting initial displacement of all degree of freedom; a means for performing computation of initial residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; and a means for defining an initial vector value in the search direction of CG method with all degree of freedom; in which said means for performing iterative computation of projected CG method with preprocessing of all degree of freedom may further operate as a means for updating the displacement of all degree of freedom; a means for updating the residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; a means for updating vectors in the search direction of CG method of all degree of freedom; and a means of determining the convergence. The present invention provides a computer readable recording medium having the program stored thereon for operating said system. More specifically, the present invention provides a computer readable recording medium having stored thereon a parallel finite element method computing program used in a parallel finite element method computing system for solving a very large scaled structure problem having the degree of freedom of one million (1,000,000) or more, characterized by operating as a means for performing domain decomposition; a means for distributing a subdomain to a responsible part of each processor; a means for creating a rigid matrix; a means for defining overlapped movement of entire subdomain; a means for defining a default setting of projected CG method with preprocessing of all degree of freedom; a means for performing iterative computation of projected CG method with preprocessing of all degree of freedom; and a means for outputting a displacement solution, in which said means for defining overlapped movement of entire subdomain may further operate as a means for creating a projector for displaying all degree of freedom; a means for creating an overlapped movement matrix of entire subdomain; and a means for LU decomposing said overlapped movement matrix of entire subdomain; in which said means for defining a default setting of projected CG method with preprocessing of all degree of freedom may further operate as a means for setting initial displacement of all degree of freedom; a means for performing computation of initial residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; and a means for defining an initial vector value in the search direction of CG method with all degree of freedom; in which said means for performing iterative computation of projected CG method with preprocessing of all degree of freedom may further operate as a means for updating the displacement of all degree of freedom; a means for updating the residual error of all degree of freedom; a means for performing computation of diagonal scaling preprocessing; a means for performing computation of coarse grid preprocessing of all degree of freedom; a means for updating vectors in the search direction of CG method of all degree of freedom; and a means of determining the convergence. The above and further objects and novel features of the present invention will more fully appear from following detailed description of a preferred embodiment, when the same is read in connection with the accompanying drawings. It is to be expressly understood, however, tha the drawings are for the purpose of illustration only and not intended as a definition of the limits of the present invention. |
N-(heterocycle-methyl)alkylamine derivative, process for producing the same, and bactericide |
A N-heterocyclicmethyl-alkylamine derivative according to the present invention is a N-heterocyclicmethyl-alkylamine derivative represented by the following general formula (I): or an acid addition salt thereof. [in the formula, R1 represents a heterocycle which has at least one nitrogen atom as a hetero atom and may have a substituent on a ring; R2 represents a hydrogen or the like; R3 represents an alkyl group having a carbon number of 1 to 5 or the like; R4 represents an alkyl group having a carbon number of 1 to 5 or the like; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents a cycloalkyl group or the like described by the following formula (III): (in the formula, Y and Z each represents a hydrogen atom or the like, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] |
1. A N-heterocyclicmethyl-alkylamine derivative represented by the following general formula (I) or an acid addition salt thereof: [in the formula, R1 represents a heterocycle which has at least one nitrogen atom as a hetero atom and may have a substituent on a ring; R2 represents one kind selected from a group consisting of a hydrogen atom and an alkyl group having a carbon number of 1 to 5; R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6.) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] 2. A method of manufacturing a N-heterocyclicmethyl-alkylamine derivative including a process which obtains a N-heterocyclicmethyl-alkylamine derivative represented by the following formula (I): from an aldehyde derivative represented by the following formula (IV): and a heterocyclicmethylamine derivative represented by the following formula (V): by using a reductive amination reaction, [in the formula, R1 represents a heterocycle which has at least one nitrogen atom as a hetero atom and may have a substituent on a ring; R2 represents one kind selected from a group consisting of a hydrogen atom and an alkyl group having a carbon number of 1 to 5; R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6.) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] 3. A method of manufacturing a N-heterocyclicmethyl-alkylamine derivative including a process which obtains a N-heterocyclicmethyl-alkylamine derivative represented by the following formula (I): from an alkylamine derivative represented by the following formula (VI): and a heterocyclicmethylation agent represented by the following formula (VII): R1—CH2—W (VII) [in the formula, R1 represents a heterocycle which has at least one nitrogen atom as a hetero atom and may have a substituent on a ring; R2 represents one kind selected from a group consisting of a hydrogen atom and an alkyl group having a carbon number of 1 to 5; R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6.) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different.), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] 4. The method of manufacturing the N-heterocyclicmethyl-alkylamine derivative according to claim 2, wherein the aldehyde derivative represented by the following formula (IV): which is obtained from the aldehyde derivative represented by the following formula (VIII): and the alkylation agent represented by the following formula (IX): W—(CH2)m—R5 (X) is used, [in the formula, R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6.) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different.); and W represents a leaving group.] 5. The method of manufacturing the N-heterocyclicmethyl-alkylamine derivative according to claim 2, wherein the aldehyde derivative represented by the following formula (IV): which is obtained from the imine derivative represented by the following formula (X): and the alkylation agent represented by the following formula (IX): W—(CH2)m.R5 (IX) is used, [in the formula, R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6.) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different) when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III), R6 represents one kind selected from a group consisting of an alkyl group having a carbon number of 2 to 6 and a cycloalkyl group having a carbon number of 3 to 6.] 6. The method of manufacturing the N-heterocyclicmethyl-alkylamine derivative according to claim 2, wherein the aldehyde derivative represented by the following formula (IV): which is obtained by reducing the ester derivative represented by the following formula (XI): is used, [in the formula, R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III), R7 represents an alkyl group having a carbon number of 1 to 3.] 7. The method of manufacturing the N-heterocyclicmethyl-alkylamine derivative according to claim 3, wherein the alkylamine derivative represented by the following formula (VI): which is obtained from the aldehyde derivative represented by the following formula (IV): and the amination agent represented by the following formula (XII): R2—NH2 (XII) is used, by using a reductive amination reaction. [in the formula, R2 represents one kind selected from a group consisting of a hydrogen atom and an alkyl group having a carbon number of 1 to 5; R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] 8. The method of manufacturing the N-heterocyclicmethyl-alkylamine derivative according to claim 3, including a process which obtains the alkylamine derivative represented by the following formula (VI): by reducing the alkylamide derivative represented by the following formula (XIII): [in the formula, R2 represents one kind selected from a group consisting of a hydrogen atom and an alkyl group having a carbon number of 1 to 5; R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group, having a carbon number of 1 to 6) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] 9. A fungicide containing a N-heterocyclicmethyl-alkylamine derivative represented by the following general formula (I): and an acid addition salt thereof as effective ingredients, [in the formula, R1 represents a heterocycle which has at least one nitrogen atom as a hetero atom and may have a substituent on a ring; R2 represents one kind selected from a group consisting of a hydrogen atom and an alkyl group having a carbon number of 1 to 5; R3 represents one kind selected from a group consisting of an alkyl group having a carbon number of 1 to 5 and a halogenated alkyl group having a carbon number of 1 to 5; R4 represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 5, and a halogenated alkyl group having a carbon number of 1 to 5; when R4 is an alkyl group having a carbon number of 1 to 5 or a halogenated alkyl group having a carbon number of 1 to 5, carbon atoms in R3 and R4 may be bonded to form a ring structure; m represents an integer of 1 to 3; R5 represents one kind selected from a group consisting of a phenyl group and a cycloalkyl group described by the following formulae (II) and (III), respectively, the formula (II) is: (in the formula, X represents one kind selected from a group consisting of a hydrogen atom, a halogen atom, an alkyl group having a carbon number of 1 to 6, a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6, a halogenated alkoxy group having a carbon number of 1 to 6, a hydroxyalkyl group having a carbon number of 1 to 6, an alkoxyalkyl group (-AOB; A and B each represents an alkyl group having a carbon number of 1 to 6), a hydroxyiminoalkyl group having a carbon number of 1 to 6, an alkoxyiminoalkyl group (-A=N—OB; A and B each represents an alkyl group having a carbon number of 1 to 6), an acyl group, an ester group, a cyano group, a benzyl group optionally having a substituent on the ring, and a cycloalkyl group having a carbon number of 3 to 10; n represents an integer of 0 to 5; when n is 2 or more, X may be the same or different from each other and may be cross-linked to be condensed into a benzene ring forming a 5- or 6-membered ring; when R3 is methyl group, R4 is hydrogen atom and m is 1, n is not 0 and Xn (n represents an integer of 1 to 5) include a group other than one kind selected from a group consisting of a hydrogen atom, halogen atom, an alkyl group having a carbon number of 1 to 6 a halogenated alkyl group having a carbon number of 1 to 6, an alkoxy group having a carbon number of 1 to 6 and a halogenated alkoxy group having a carbon number of 1 to 6) and the formula (III) is: (in the formula, Y and Z may be the same or different from each other, and each represents one kind selected from a group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 6, and a halogenated alkyl group having a carbon number of 1 to 6, the letter p represents an integer of 2 to 5, and the groups described by CYZ may be each the same or different), when m is 1 and R4 is a hydrogen atom, R5 is a cycloalkyl group described by the foregoing formula (III).] |
<SOH> BACKGROUND ART <EOH>3-phenylpropylamines are commercialized as fungicides such as a compound of N-[3-p-t-butylphenyl-2-methyl-1-propyl]-cis-2,6-dimethylmorpholine (fenpropimorph) described in Japanese Unexamined Patent Publication No. SH053-77070 and a compound of N-[3-p-t-butylphenyl-2-methyl-1-propyl]piperidine (fenpropidine) described in Japanese Unexamined Patent Publication No. SHO 53-68785 and Japanese Unexamined Patent Publication No. SHO 53-68786. Although nitrogen atoms of the amino groups in the foregoing compounds form a part of the ring structures, certain compounds are known that nitrogen atoms of the amino groups do not form as part of the ring structures and a heterocyclicmethyl group is bonded to the nitrogen atom, whose examples are the compounds described in Japanese Unexamined Patent Publication No. SHO 63-258867, wherein the compounds have a heterocyclicmethyl group such as a tetrahydrofurfuryl group and a thenyl group containing oxygen and sulfur, respectively, and the following N-heterocyclicmethylpropylamine derivatives that are described in the literature Pestic. Sci., 35, 339 (1992)., N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine, N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine and N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine. Additionally, Publication No. WO99/12902 discloses the N-heterocyclicmethyl-propylamine derivatives, and it is described that the fungicide having the above derivatives as an effective ingredient has a control effect on plant diseases. However, even the conventional N-heterocyclicmethyl-propylamine derivatives described in the aforementioned Publication No. WO99/12902 are yet insufficient to obtain a fungicide that exhibits a sufficiently high control effect. Thus, the development of a compound which has a more powerful fungicidal activity on various kinds of deleterious organism has been required. |
Method for treating ocular hypertension and glaucoma |
A method for treating ocular hypertension and glaucoma, which comprises an administration of eye drops comprising a 15-keto-prostaglandin compound as an active ingredient to a subject in need of such treatment in a single administration volume of at least 20 μL/eye is disclosed. According to the present method, the intraocular pressure reducing effect of the compound is surprisingly augmented. |
1. A method for treating ocular hypertension and glaucoma, which comprises an administration of eye drops comprising a 15-keto-prostaglandin compound as an active ingredient to a subject in need of such treatment in a single administration volume of at least 20 μL/eye. 2. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a compound as shown by the following general formula (I). wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo, wherein at least one of the groups of L and M is a group other than hydrogen, and a five-membered ring may have at least one double bond; A is —CH2OH, —COCH2OH, —COOH or functional derivatives thereof; B is —CH2—CH2—, —CH═CH— or —C—C—; R1 is a saturated or unsaturated lower to medium bivalent aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or a heterocyclic group and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur atom. Ra is a saturated or unsaturated lower to medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; cyclo (lower) alkyl; cyclo (lower) alkyloxy; aryl; aryloxy; heterocyclic group; heterocyclic-oxy group. 3. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-prostaglandin compound. 4. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 15-keto-20-lower alkyl-prostaglandin compound. 5. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-lower alkyl-prostaglandin compound. 6. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 15-keto-20-ethyl-prostaglandin compound. 7. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin compound. 8. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 15-keto-prostaglandin F compound. 9. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α. 10. The method as described in claim 1 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α isopropyl ester. 11. The method as described in claim 1, wherein the single administration volume is at least 25 μL/eye. 12. The method as described in claim 1, wherein the single administration volume is at least 30 μL/eye. 13. An eye drop composition for treating ocular hypertension and glaucoma comprising a 15-keto-prostaglandin compound as an active ingredient, which is administrated to a subject in need of such treatment in a single administration volume of at least 20 μL/eye. 14. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a compound as shown by the following general formula (I). wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo, wherein at least one of the groups of L and M is a group other than hydrogen, and a five-membered ring may have at least one double bond; A is —CH2OH, —COCH2OH, —COOH or functional derivatives thereof; B is —CH2—CH2—, —CH═CH— or —C≡C—; R1 is a saturated or unsaturated lower to medium bivalent aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or a heterocyclic group and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur atom. Ra is a saturated or unsaturated lower to medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; cyclo (lower) alkyl; cyclo (lower) alkyloxy; aryl; aryloxy; heterocyclic group; heterocyclic-oxy group. 15. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-prostaglandin compound. 16. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 15-keto-20-lower alkyl-prostaglandin compound. 17. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-lower alkyl-prostaglandin compound. 18. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 15-keto-20-ethyl-prostaglandin compound. 19. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin compound. 20. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 15-keto-prostaglandin F compound. 21. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α. 22. The composition as described in claim 13 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α isopropyl ester. 23. The composition as described in claim 13, wherein the single administration volume is at least 25 μL/eye. 24. The composition as described in claim 13, wherein the single administration volume is at least 30 μL/eye. 25. An eye drop product comprising the composition as described in any of claims 13-24, wherein the composition is incorporated in an eye drop container of which single administration volume is at least 20 μL/eye. 26. Use of a 15-keto-prostaglandin compound for manufacturing an eye drop composition for treating ocular hypertension and glaucoma, wherein the eye drop composition is administrated to a subject in need of such treatment in a single administration volume of at least 20 μL/eye. 27. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a compound as shown by the following general formula (I). wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy (lower) alkyl or oxo, wherein at least one of the groups of L and M is a group other than hydrogen, and a five-membered ring may have at least one double bond; A is —CH2OH, —COCH2OH, —COOH or functional derivatives thereof; B is —CH2—CH2—, —CH═CH— or —C≡C—; R1 is a saturated or unsaturated lower to medium bivalent aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, alkyl, hydroxy, oxo, aryl or a heterocyclic group and at least one of carbon atom in the aliphatic hydrocarbon is optionally substituted by oxygen, nitrogen or sulfur atom. Ra is a saturated or unsaturated lower to medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo (lower) alkyl, cyclo (lower) alkyloxy, aryl, aryloxy, heterocyclic group or heterocyclic-oxy group; cyclo (lower) alkyl; cyclo (lower) alkyloxy; aryl; aryloxy; heterocyclic group; heterocyclic-oxy group. 28. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-prostaglandin compound. 29. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 15-keto-20-lower alkyl-prostaglandin compound. 30. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-lower alkyl-prostaglandin compound. 31. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 15-keto-20-ethyl-prostaglandin compound. 32. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin compound. 33. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 15-keto-prostaglandin F compound. 34. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α. 35. Use as described in claim 26 wherein the 15-keto-prostaglandin compound is a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F2α isopropyl ester. 36. Use as described in claim 26, wherein the single administration volume is at least 25 μL/eye. 37. Use as described in claim 26, wherein the single administration volume is at least 30 μL/eye. 38. Use as described in any one of claims 26-37, wherein the composition is provided as an eye drop product incorporated in an eye drop container of which single administration volume is at least 20 μL/eye. |
<SOH> TECHNICAL FIELD <EOH>The present invention relates to a method for treating ocular hypertension and glaucoma characterized by ocular administration of eye drops comprising a 15-keto-prostagladin compound as an active ingredient in a specified volume or more. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 . represents effect of isopropyl unoprostone eye drops on intraocular pressure (ΔIOP:mmHg) in albino rabbits (n=8) FIG. 2 . represents effect of timolol maleate eye drops on intraocular pressure (ΔIOP:mmHg) in albino rabbits (n=8) detailed-description description="Detailed Description" end="lead"? |
Method for forming a stable complex comprising a transcription product and translation product of a dna encoding a desired polypeptide, a nucleic acid construct used for the method, a complex formed by the method, and screening of a functional protein and mrna or dna encoding the protein using the method |
A stable linkage between a genotype and a phenotype in a cell-free system was successfully achieved by using interaction between a RNA-binding protein and RNA, between a DNA-binding protein and DNA, or by using a protein that inactivates a ribosome. Furthermore, it was found that functional proteins could be selected by using these stable linkages. |
1. A DNA construct comprising the DNAs of (i) and (ii), wherein the DNAs are bound so as to express the fused transcript and translation product: (i) a DNA encoding an arbitrary polypeptide; and (ii) a DNA encoding a polypeptide having the function of stabilizing a complex comprising the transcript and translation product of the DNA defined in (i). 2. The DNA construct according to claim 1, wherein the DNA defined in (ii) encodes a polypeptide having a ribozyme-inactivating function. 3. The DNA construct according to claim 2, wherein a DNA encoding a spacer peptide is linked downstream of the DNA encoding a polypeptide having the ribozyme-inactivating function. 4. The DNA construct according to claim 2, wherein a DNA encoding a linker peptide is inserted between the DNA encoding the arbitrary polypeptide and the DNA encoding the polypeptide having the ribozyme-inactivating function. 5. The DNA construct according to claim 1, wherein the DNA defined in (ii) is a combination of a DNA encoding an RNA binding protein, and a DNA encoding an RNA to which the RNA binding protein binds. 6. The DNA construct according to claim 5, wherein the fused transcript of the DNAs defined in (i) and (ii) is modified so as to lack the termination codon. 7. The DNA construct according to claim 5, wherein a plurality of DNAs encoding RNA binding proteins are tandemly arranged and wherein a plurality of DNAs encoding RNAs to which the RNA binding proteins bind are tandemly arranged. 8. The nucleic acid construct according to claim 7, wherein the plurality of tandemly arranged DNAs encoding RNA binding proteins are DNAs encoding a plurality of different RNA binding proteins, and wherein the plurality of tandemly arranged DNAs encoding RNAs to which the RNA binding proteins bind, are DNAs encoding RNAs to which a plurality of different RNA binding proteins bind. 9. A nucleic acid construct comprising a complex of an mRNA defined in (i) and a DNA defined in (ii): (i) a fusion mRNA of an RNA encoding a DNA binding protein, and an RNA encoding an arbitrary polypeptide; and (ii) a DNA comprising a DNA region to which the translation product of the fusion mRNA defined in (i) binds. 10. The nucleic acid construct according to claim 9, wherein the mRNA defined in (i) is hybridized with the DNA defined in (ii) to form a complex. 11. The nucleic acid construct according to claim 9, wherein the 3′-end region of the mRNA defined in (i) is hybridized with the 3′-end region of the DNA defined in (ii). 12. A DNA construct defined in the following (i) or (ii), which is used for preparing the DNA construct as set forth in claim 1: (i) a DNA construct comprising a DNA having a function of stabilizing a complex of the transcript and translation product of a DNA encoding an arbitrary polypeptide; and (ii) a DNA construct comprising a DNA having a function of stabilizing a complex of the transcript and translation product of a DNA encoding an arbitrary polypeptide, and a cloning site for the DNA encoding that arbitrary polypeptide. 13. A method for producing a complex comprising the transcript and translation product of the DNAs defined in (i) and (ii) in the DNA construct as set forth in claim 1, wherein the method comprises expressing the DNAs defined in (i) and (ii). 14. A method for producing a complex of the translation product obtained by translating the mRNA defined in (i) in the nucleic acid construct as set forth in claim 9, and the nucleic acid construct as set forth in claim 9, wherein the method comprises translating the mRNA defined in (i) and binding that translation product to the DNA defined in (ii), in the nucleic acid construct as set forth in claim 9. 15. The method according to claim 14, wherein the method uses a nucleic acid construct in which a complex is formed by hybridizing the mRNA defined in (i) and the DNA defined in (ii). 16. The method according to claim 14, wherein the method uses a nucleic acid construct in which the 3′-end region of the mRNA defined in (i) is hybridized with the 3′-end region of the DNA defined in (ii). 17. A method for elongating the 3′-end region of the DNA defined in (ii) in a complex produced by the method as set forth in claim 15, wherein the method comprises contacting the complex with reverse transcriptase and carrying out a reverse-transcription reaction using the mRNA defined in (i) as a template. 18. A method for elongating the DNA defined in (ii) in a complex produced by the method as set forth in claim 16, wherein the method comprises contacting the complex with reverse transcriptase and carrying out reverse-transcription reaction using the mRNA defined in (i) as a template and the DNA defined in (ii) as a primer. 19. The method according claim 13, wherein the method is used in a cell-free system. 20. A complex produced by the method as set forth in claim 13. 21. A complex produced by the method as set forth in claim 14. 22. A method of screening for a polypeptide binding to a particular target substance, or for an mRNA encoding that polypeptide, wherein the method comprises the steps of: (a) forming a complex comprising the transcript and translation product of the DNAs defined in (i) and (ii) in the DNA construct as set forth in claim 1, by expressing the DNAs defined in (i) and (ii); (b) contacting the particular target substance with the complex formed in step (a); and (c) collecting the complex bound to that target substance. 23. A method of screening for a polypeptide binding to a particular target substance, or for an mRNA encoding that polypeptide, wherein the method comprises the steps of: (a) translating the mRNA defined in (i) in the nucleic acid construct as set forth in claim 9, (a′) forming a complex comprising this translation product and the nucleic acid construct as set forth in claim 9, by binding the translation product to the DNA defined in (ii), in the nucleic acid construct as set forth in claim 9; (b) contacting the particular target substance with the complex formed in step (a); and (c) collecting the complex bound to that target substance. 24. A method of screening for a polypeptide binding to a particular target substance or for an mRNA or a DNA encoding the polypeptide, wherein the method comprises the steps of: (a) translating the mRNA defined in (i) in the nucleic acid construct as set forth in claim 10, (a′) forming a complex comprising that translation product and the nucleic acid construct as set forth in claim 10, by binding the translation product to the DNA defined in (ii), in the nucleic acid construct as set forth in claim 10; (b) elongating the DNA defined in (ii) in the complex formed in step (a), by contacting the complex with reverse transcriptase and carrying out a reverse-transcription reaction using, as a template, the mRNA defined in (i) in the complex; (c) contacting the particular target substance with the complex formed in step (b); and (d) collecting the complex bound to that target substance. 25. A method of screening for a polypeptide binding to a particular target substance or for an mRNA or DNA encoding that polypeptide, wherein the method comprises the steps of: (a) translating the mRNA defined in (i) in the nucleic acid construct as set forth in claim 11, (a′) forming a complex comprising the translation product and the nucleic acid construct as set forth in claim 11, by binding the translation product to the DNA defined in (ii) in the nucleic acid construct as set forth in claim 11; (b) elongating the 3′-end region of the DNA defined in (ii) in the complex formed in step (a), by contacting the complex with reverse transcriptase and carrying out a reverse-transcription reaction using as a template the mRNA defined in (i) in the complex, and as a primer the DNA defined in (ii) in the complex; (c) contacting the particular target substance with the complex formed in step (b); and (d) collecting the complex bound to that target substance.1 26. A method of screening for a polypeptide binding to a particular target substance or for an mRNA or DNA encoding that polypeptide, wherein the method comprises the steps of: (a) translating the mRNA defined in (i) in the nucleic acid construct as set forth in claim 10, (a′) forming a complex comprising the translation product and the nucleic acid construct as set forth in claim 10, by binding the translation product to the DNA defined in (ii) in the nucleic acid construct as set forth in claim 10; (b) contacting the particular target substance with the complex formed in step (a); (c) elongating the DNA defined in (ii) in the complex bound to the target substance, by contacting the complex with reverse transcriptase and carrying out reverse-transcription reaction using, as template, the mRNA defined in (i) in the complex; and (d) collecting the complex bound to the target substance. 27. A method of screening for a polypeptide binding to a particular target substance, or for an mRNA or a DNA encoding that polypeptide, wherein the method comprises the steps of: (a) translating the mRNA defined in (i) in the nucleic acid construct as set forth in claim 11, (a′) forming a complex comprising the translation product and the nucleic acid construct as set forth in claim 11, by binding the translation product to the DNA defined in (ii) in the nucleic acid construct as set forth in claim 11; (b) contacting the particular target substance with the complex formed in step (a); (c) elongating the 3′-end region of the DNA defined in (ii) in the complex bound to the target substance, by contacting the complex with reverse transcriptase and carrying out a reverse-transcription reaction using, as a template, the mRNA defined in (i) in the complex, and, as a primer, the DNA defined in (ii) in the complex; and (d) collecting the complex bound to the target substance. 28. The method according to claim 22, wherein the target substance is fixed on a carrier. 29. A kit used for the screening for a polypeptide binding to a particular target substance, or for an mRNA encoding that polypeptide, comprising the DNA construct as set forth in claim 1. 30. A kit used for the screening for a polypeptide binding to a particular target substance, or for an mRNA or a DNA encoding that polypeptide, comprising the nucleic acid construct as set forth in claim 9. 31. The method according to claim 14, wherein the method is used in a cell-free system. 32. The method according to claim 23, wherein the target substance is fixed on a carrier. |
<SOH> BACKGROUND ART <EOH>Recent years have seen an increase in the importance of a method for selecting and identifying a functional protein from a group of random amino acid sequences. Living cells are used in many screening systems, such as the phage display method and the two hybrid method, which can be used for efficient selection of specific functional proteins (Fields, S. et al., Nature, 1989, 340, 245-246; Harada, K. et al., Nature, 1996, 380, 175-179; Moore, J. C. et al., Nature Biotech., 1996, 14, 458-467; Schatz, P. J. et al., Methods Enzymol., 1996, 267, 171-191; Boder, E. T. et al., Nature Biotech., 1997, 15, 553-557; Smith, G. P. et al., Chem. Rev., 1997, 97, 391-410). In such selection systems, the sequence information (genotype) encoding a selected protein (phenotype) is obtained from a DNA that has been introduced into each cell displaying the appropriate phenotype. The connection between genotype and phenotype is an important factor in selecting a functional protein from a group of random sequences. However, as long as such methods depend on the use of living cells, sequence library variety will be limited. For example, library variety will be limited due to low transfection efficiency, restricted size of proteins displayed, and restriction of target protein properties as cytotoxic proteins cannot be selected. In order to overcome these problems, a number of methods comprising cell-free protein selection systems have been developed (Mattheakis, L. C. et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 9022-9026; Mattheakis, L. C. et al., Methods Enzymol., 1996, 267, 195-207; Hanes, J. et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 4937-4942; He, M. et al., Nucleic Acids Res., 1997, 25, 5132-5134; Nemoto, N. et al., FEES Lett., 1997, 414, 405-408; Roberts, R. W. et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 12297-12302; Hanes, J. et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 14130-14135; Tawfik, D. S. et al., Nature Biotech., 1998, 16, 652-656; Doi, N. et al., FEBS Lett., 1999, 457, 227-230; Hanes, J. et al., FEES Lett., 1999, 450, 105-110; Makeyev, E. V. et al., FEBS Lett., 1999, 444, 177-180; He, M. et al., J. Immunol. Methods, 1999, 231, 105-117; Schaffitzel, C. et al., J. Immunol. Methods, 1999, 231, 119-135; Hanes, J. et al., Nat. Biotechnol., 2000, 18, 1287-1292; Hanes, J. et al., Methods Enzymol., 2000, 328, 404-430). Specifically, such methods include ribosome-display methods, methods using covalently linked protein-mRNA fusion, and micelle methods. However, currently available cell-free systems comprise processes that reduce variety, and are thus generally difficult to practically apply. For example, when using a ribosome-display method, a ribosome is used to form a relatively stable complex between a translated protein and the mRNA encoding that protein. This stability results from a delay of protein release from the complex due to the lack of the termination codon. Under these conditions, termination factors cannot efficiently induce protein release from the ribosome complex. However, in this method, success of protein selection depends on the half life of the complex (in the absence of the termination codon, delay of protein release is limited), and therefore selection must be carried out in a short time. In practice, maintaining a perfectly intact mRNA-ribosome-protein complex is not easy. Ribosome display methods using Escherichia coli are described, for example, in the following references: Jermutus, L., et al., “Tailoring in vitro evolution for protein affinity or stability”, Proc. Natl. Acad. Sci. USA., 2001 Jan 2, 98(1) :75-80; Hanes, J. et al., “Picomolar affinity antibodies from a fully synthetic naive library selected and evolved by ribosome display”, Nat. Biotechnol., 2000 Dec. 18(12) :1287-92; Hanes, J. et al., “Selecting and evolving functional proteins in vitro by ribosome display”, Methods Enzymol., 2000, 328:404-30; and Schaffitzel, C. et al., ”Ribosome display: an in vitro method for selection and evolution of antibodies from libraries”, J. Immunol. Methods., Dec. 10, 1999; 231(1-2) :119-35. Ribosome display methods using rabbit reticulocyte system are described, for example, in the following references: He, M. et al., “Selection of a human anti-progesterone antibody fragment from a transgenic mouse library by ARM ribosome display. ”, J. Immunol. Methods., Dec. 10, 1999 231(1-2):105-17; and Bieberich, E. et al., “Protein-ribosome-mRNA display: affinity isolation of enzyme-ribosome-mRNA complexes and cDNA cloning in a single-tube reaction.”, Anal Biochem., Dec. 15, 2000 287(2):294-8. A ribosome display method using the wheat germ system is described, for example, in the following reference: Gersuk, G. M. et al., “High-affinity peptide ligands to prostate-specific antigen identified by polysome selection”, Biochem. Biophys. Res. Commun., Mar. 17, 1997 232(2):578-82. In mRNA display, a translated protein is covalently linked to its mRNA, whose 3′-end has been labeled with puromycin. This method typically requires chemical synthesis to link the mRNA and puromycin, a step which reduces the size of available libraries. Documents describing mRNA display include: Keefe, A. D. et al., “Functional proteins from a random-sequence library”, Nature., Apr. 5, 2001 410(6829) :715-8; Wilson, D. S. et al., “The use of mRNA display to select high-affinity protein-binding peptides”, Proc. Natl. Acad. Sci. USA., Mar. 27, 2001 98(7):3750-5; Liu, R. et al., “Optimized synthesis of RNA-protein fusions for in vitro protein selection”, Methods Enzymol., 2000, 318:268-93; and Cho, G. et al., “Constructing high complexity synthetic libraries of long ORFs using in vitro selection”, J. Mol. Biol., Mar. 24, 2000 297(2):309-19. In micelle methods, chemically modified DNA molecules are individually packaged into a colloidal micelle. Inside the micelle, the modified DNA is transcribed and translated, and then binds to the protein it encodes. However, because packaging is achieved by diluting the reaction mixture such that each micelle contains a single DNA molecule, the sequence variety of the library is reduced. Thus, cell-free systems have an advantage over systems that use living cells in that they can test more sequences. However, a considerable portion of the sequence pool remains -to be sufficiently searched using the currently available cell-free systems. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 depicts a schematic illustration of the purified DHFR-(RE) 1-3 fusion proteins and wild type (wt) DHFR, and a photograph showing the gel after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The purified recombinant proteins (about 100 μg) were fractionated with SDS-PAGE, and visualized using Coomassie Brilliant Blue staining. Lane 1, marker; lane 2, wild type DHFR; lane 3, DHFR-(RE) 1 ; lane 4, DHFR-(RE) 2 ; and lane 5, DHFR-(RE) 3 . The molecular weights of the marker proteins are indicated to the left. A poly-glycine linker was inserted between DHFR and the first RE peptide, and between RE peptides neighboring each other. A stretch of poly-histidine (His) was attached to the N-terminus of DHFR for the convenience of purification. FIG. 2 depicts diagrams and photographs showing experimental results for the dissociation constant (K d ). Lane C in each panel contains only the aptamer. Closed arrows indicate protein-RNA complexes, and open arrows indicate free RNAs. 32 P radioactivity was used to determine relative amounts of complex and free RNA. Equilibrium dissociation constants were determined from the theoretical curves provided by the least square method, in which the concentration of free RNA or complex is plotted against peptide concentration. Diamonds indicate the relative amounts of free RNA, and squares indicate the relative amounts of the complex. The closed narrow triangles in each panel indicate an increase in protein concentration. (A) is a photograph showing the loss of interaction between (Apt) 1-3 and wild-type DHFR. Lanes C contain 1 nM (Apt) 1-3 with wild-type DHFR added at concentrations of 20, 100, and 500 nM respectively, as indicated by the narrow triangles. (B) depicts a diagram and photograph showing binding between (Apt) 1 and DHFR-(RE) 1 . DHFR-(RE) 1 was mixed at concentrations of 0.25, 0.5, 1, 2, 4, 8, 16, or 32 nM with 30 pM (Apt) 1 (lane C), as indicated by the narrow triangles. (C and D) depict diagrams and photographs showing binding between (Apt) 2-3 and DHFR-(RE) 2-3 protein. The protein was mixed at a concentration of 0.03, 0.06, 0.12, 0.25, 0.5, 1, 2, 4, 8, or 16 nM with 30 pM (Apt) 2 or (Apt) 3 RNA (lane C), as indicated by the narrow triangles. FIG. 3 depicts diagrams and photographs showing models for the selection of functional proteins using the interaction between (Apt) 3 and (RE) 3 in vitro. (A) is a schematic illustration showing the interaction between translated proteins, transcribed RNAs, and methotrexate-immobilized agarose beads (MTX ligand). (B) depicts photographs showing the results of SDS-PAGE for DHFR-(RE) 3 protein and mRNA (wild type) enriched by MTX-beads. Each sample was fractionated using 15% SDS-PAGE. After the translation reaction, 1 μl of cell lysate was loaded onto each of lanes 1 to 3. 10 μl of elution solution containing mRNA and protein bound to MTX-beads was loaded onto each of lanes 4 to 6. Lanes 1 and 4 contain the wild-type protein. Lanes 2 and 5 contain the mutant protein. Lanes 3 and 6 contain a control sample. (C) consists of diagrams showing the results of quantitation of the protein and mRNA indicated in (B). FIG. 4 depicts diagrams and photographs showing in-vitro selection of streptavidin-encoding mRNA from the pool of mixed streptavidin and DHFR mRNAs. (A) is a schematic illustration showing the interaction between transcribed RNAs, translated proteins, and biotin-immobilized agarose beads (biotin ligand). (B) is a photograph showing the results of denaturing PAGE on streptavidin-(RE) 3 -(Apt) 3 mRNA enriched with biotin agarose beads. After translation and subsequent selection, each sample was fractionated using 4% denaturing PAGE. Lane 1: isolated streptavidin-(CQ) 3 -(Apt) 3 mRNA. mRNA (1.25 μg) encoding streptavidin was translated in cell lysate, and then selected using biotin beads. Lane 2: isolated DHFR-(CQ) 3 -(Apt) 3 mRNA. mRNA (1.25μg) encoding DHFR was translated in cell lysate, and then selected using biotin beads. Since DHFR is not expected to interact with biotin beads, the level of bound DHFR-(CQ) 3 -(Apt) 3 mRNA corresponds to the degree of non-specific (background) interaction. Lane 3: isolated streptavidin-(CQ) 3 -(Apt) 3 and DHFR mRNA (upper band, DHFR mRNA; and lower band, streptavidin). The respective mRNAs encoding streptavidin and DHFR were mixed at a ratio of 1:1. The mixture was translated in cell lysate, and then selected using biotin beads. FIG. 5 depicts diagrams and a photograph showing the comparison of intensities of the interaction between (RE) 3 -(Apt) 3 and ribosome-display system in the selection of functional DHFR in rabbit reticulocyte lysate. (A) is a schematic illustration showing the interaction among the transcribed RNAs, the translated proteins, and methotrexate-immobilized agarose beads (MTX ligand). (B) is a photograph showing the result of electrophoresis of RT-PCR products using 2% agarose for DHFR-(RE) 3 -(Apt) 3 , DRFR−Stop or DHFR+Stop mRNA enriched by MTX-beads. The PCR was carried out for 20 cycles. Each sample was fractionated using a 2% Sea Kem GTG agarose gel (FMC, Riceland, Me. USA). Lane 1, PCR product from DHFR-(RE) 3 -(Apt) 3 mRNA; lane 2, PCR product from DHFR+Stop mRNA; and lane 3, PCR product from DHFR−Stop mRNA. The PCR products were. analyzed once, however, the mRNA quantitation result shown in FIG. 5C is more reliable. (C) is a diagram showing the result of quantitation of enriched mRNA. The relative amount of selected mRNA was determined from the radioactivity of 32 P-labeled mRNA. The respective lane numbers correspond to those shown in FIG. 5B . The result is an average of independent experiments carried out in quadruplicate. FIG. 6 depicts diagrams and a photograph showing the increased stability of the complex between each mRNA and its product, using the (RE) 3 -(Apt) 3 interaction and ribosome-display system in combination, and in E. coli S30 strain cell extract. (A) is a schematic illustration for the interaction between transcribed RNAs, translated proteins, and methotrexate-immobilized agarose beads (MTX ligand). (B) is a photograph showing the result of electrophoresis of the RT-PCR products using 2% agarose-gel in the presence (lanes 1 and 3) or absence (lanes 2 and 4) of the polyclonal antibody IgGs against the termination factors (RF1, RF2, and RF3 from E. coli ), and DHFR−Stop mRNA (lanes 1 and 2) and (Apt) 3 -(RE) 3 -DHFR−Stop mRNA (lanes 3 and 4) enriched by MTX-beads. The selected mRNA was incubated with MTX-agarose beads under the same conditions as indicated in FIG. 5 . (C) is a diagram showing the result of quantitation of the RT-PCR products indicated in (B). The result was obtained as an average in independent experiments carried out in duplicate. FIG. 7A depicts a diagram showing the possibility of networking due to binding between RNA and protein. In principle, the tandemly arranged Tat (RE) peptide and aptamer can bind with each other not only intramolecularly but also intermolecularly. In the case of intermolecular binding, RNA-protein binding will result in networking. This intermolecular interaction can be minimized by linking different peptides and aptamers instead of linking the same peptides and aptamers in tandem. FIG. 7B depicts a diagram showing a schematic illustration for the first embodiment of the method for selecting functional proteins in vitro. The enrichment can be achieved via multiple cycles comprising production of the binding protein, transcription, translation, affinity selection, and PCR. In the step of translation, the tandemly arranged aptamer (Apt) 3 binds with tandemly arranged RE peptide (RE) 3 with exceedingly high affinity. This binding ensures binding between the protein and the mRNA. In Example 1, DHFR and streptavidin were used as targets in the selection step. However, an arbitrary protein can be used in combination with the tandemly arranged aptamer (Apt) 3 and tandemly arranged RE peptide (RE) 3 . FIG. 8 depicts a diagram showing a model for an in-vitro protein selection system using ricin. A random DNA library or cDNA library is used. The ricin and spacer sequences are attached to the 3′ end of this sequence. After transcription/translation of a protein from the library, the ricin is also translated. The ricin inactivates ribosomes by intramolecular reaction, thus terminating ribosome-mediated translation. As a result, an RNA-ribosome-protein complex is formed. The RNA in the complex encodes the genetic information on the protein, and thus selection of a particular functional protein results in recovery of an RNA comprising the genetic information of that protein. This RNA is amplified by reverse transcription/PCR, and the sequence of the selected protein can be determined by decrypting the genetic information. The above-described cycle can be repeated for higher selection pressure. FIG. 9A depicts a diagram showing the DNA sequence used in the model of the protein selection system. Genes for the T7 promoter, streptavidin or GST sequence, the linker sequence, the ricin A chain sequence or the inactive ricin A chain sequence (prepared by introducing mutations in a portion of the ricin A chain sequence), and the M13 Phage Gene III-derived spacer sequence (360 bp or 1212 bp) were inserted in this order from the 5′-end. The streptavidin and GST sequences are the target proteins for selection. The linker sequence encodes a peptide linker and was inserted to prevent steric hindrance between streptavidin or GST, and the ricin A chain. The spacer sequence was inserted to prevent the ribosome from inhibiting other proteins' activities, such as folding. FIG. 9B depicts schematic illustrations for the translation of SLmRS, SLRS, SLmRL, and SLRL genes. Ricin does not function in the SLmRS and SLmRL genes, and so the RNA-ribosome-protein complex does not form. The proteins thus dissociate from the ribosomes, and protein synthesis proceeds efficiently. FIG. 9C depicts a photograph showing proteins translated from SLmRS, SLRS, SLmRL, and SLRL genes. The proteins were labeled with 35 S-methionine, and detected by SDS-PAGE using 10% gel. The shorter the linker the more protein was produced. When ricin was inactive, a larger amount of protein was produced. Protein synthesis was negligible in the case of the SLRL gene. FIG. 10A is a schematic illustration of the selection of mRNA encoding streptavidin protein using biotin agarose (SLRS). mRNA encoding DHFR does not bind to biotin agarose (DLRS). In addition, when ricin is inactivated, mRNA encoding streptavidin protein does not bind to biotin agarose (SLmRS). FIG. 10B consists of diagrams showing the amount of streptavidin protein-encoding mRNA recovered using biotin agarose. After translation, mRNA was bound to biotin agarose, unbound mRNA was washed away, and residual RNA was quantified. After three washes, 30% of the SLRS mRNA used in the translation had bound to the biotin agarose. However, after three washes, hardly any DLRS and SLmRS mRNA had bound to the agarose. After three washes, SLRS mRNA had been enriched 100 times or more. FIG. 11A is a schematic illustration for the selection of mRNA encoding streptavidin protein using biotin agarose (SLRS). GST-encoding mRNA does not bind to biotin agarose (GLRS). In addition, mRNA encoding streptavidin protein does not bind to biotin agarose (SLmRS) when ricin has been inactivated. FIG. 11B consists of diagrams showing the amount of streptavidin protein-encoding mRNA recovered using biotin agarose. After translation, mRNA was bound with biotin agarose, unbound mRNA was washed away, and residual RNA was quantified. After four washes, 5% of SLRS mRNA used in the translation had bound to biotin agarose. However, after four washes, hardly any GLRS and SLmRS mRNA had bound to the agarose. SLRS mRNA was enriched 25 times or more after four washes. FIG. 12A is a schematic illustration for the selection of mRNA encoding GST protein by glutathione Sepharose (GLRS). Streptavidin-encoding mRNA does not bind to glutathione Sepharose (SLRS). In addition, when ricin has been inactivated, GST protein-encoding mRNA does not bind to glutathione Sepharose (GLmRS). FIG. 12B consists of diagrams showing the amount of GST protein-encoding mRNA recovered post-translation using glutathione Sepharose. After translation, mRNA was bound to glutathione Sepharose, unbound mRNA was washed away, and residual RNA was quantified. After four washes, 1.2% of GLRS mRNA used in the translation had bound to glutathione Sepharose. On the other hand, after four washes, hardly any SLRS and GLmRS mRNA had bound to the agarose (0.2% or less). GLRS mRNAwas enriched six times ormore after four washes. FIG. 13A is a schematic illustration of the selection of streptavidin protein-encoding mRNA using biotin agarose (SLRS and SLRL). DHFR-encoding mRNA does not bind to biotin agarose (DLRS, SLRL) The SLRS and DLRS spacers are shorter than the SLRL and DLRL spacers. FIG. 13B is a photograph showing the selection of mRNA encoding streptavidin proteins (SLRS and SLRL) from a pool of mixed mRNAs encoding streptavidin and DHFR proteins (SLRS+DLRS and SLRL+DLRL) with biotin agarose. Biotin agarose was added to this mRNA pool after its translation. RT-PCR was then carried out to amplify the bound mRNA. As a result, SLRS mRNA and SLRL mRNA were amplified. On the other hand, SLmRS(L) mRNA and DLRS(L) mRNA were not amplified by RT-PCR. A pool of 1:1 mixture of SLRS(L) mRNA and DLRS(L) mRNA was translated, and biotin agarose was added thereto. SLRS(L) mRNA was revealed to be selectively amplified by RT-PCR. A shorter spacer resulted in more efficient selection. FIG. 14A is a photograph showing the selection of mRNA encoding streptavidin protein (SLRS) from a pool of mixed mRNA encoding streptavidin and GST protein (SLRS+GLRS) with biotin agarose. After translation of SLRS mRNA, biotin agarose was added thereto. RT-PCR was carried out to amplify the bound mRNA. As a result, SLRS mRNA was amplified. On the other hand, SLmRS mRNA and GLRS mRNA were not amplified by RT-PCR. A 1:1 mixed pool of SLRS mRNA and GLRS mRNA was translated, and biotin agarose was added thereto. SLRS mRNA was revealed to be selectively amplified by RT-PCR. FIG. 14B is a photograph showing the selection of mRNA encoding GST protein (GLRS) from a mixed pool of mRNA encoding streptavidin and GST protein (SLRS+GLRS) with glutathione agarose. After translation of GLRS mRNA, glutathione agarose was added thereto. RT-PCR was carried out to amplify the bound mRNA. As a result, GLRS mRNA was amplified. On the other hand, GLmRS mRNA and SLRS mRNA were not amplified by RT-PCR. A 1:1 mixed pool of SLRS mRNA and GLRS mRNA was translated, and biotin agarose was added thereto. GLRS mRNA was revealed to be selectively amplified by RT-PCR. FIG. 15 is a predictive diagram of a circularized polysome display system. FIG. 16A is a diagram showing the constructs prepared as templates for in-vitro transcription to achieve the novel selection system of the present inventors. The following template DNAs were designed: dCvH(+)mM2D(+), (I); dCvH(−)mM2D(+), (II); dCvH(+)mM2D(−), (III); and dCvH(−)mM2D(−), (IV). While both dCvH(+)mM2D(+) and dCvH(−)mM2D(+) have the termination codon, dCvH(+)mM2D(−) and dCvH(−)mM2D(−) have no termination codon. The lengths expected were 1786 bp(I), 1723 bp(II), 1716 bp(III) and 1653 bp(IV). FIG. 16B is a photograph showing the confirmation of in-vitro translation. Lane 1, translation product for rCvH(+)mM2D(+) ; lane 2, translation product for rCvH(−)mM2D(+); lane 3, translation product for rCvH(+)mM2D(−); and lane 4, translation product for rCvH(−)mM2D (−). The predicted molecular weights were 55.7 kDa (lanes 1 and 3) and 53.5 kDa (lanes 2 and 4), respectively. FIG. 17 is a photograph showing the result of in-vitro selection to assess the efficiency of the novel system of the present inventors. Patterns of agarose gel electrophoresis for the RT-PCR products are indicated. Lanes 1 to 3 and lanes 5 to 7 contain RT-PCR products amplified from their respective mRNA pools after in-vitro selection. For lane 1, the initial mRNA pool contained only rCvH(+)mM2D(+); and for lane 5, the initial mRNA pool contained only rCvH(+)mM2D(−). The lanes indicated above are used as positive controls in the selection. For lane 2, the initial mRNA pool contained only rCvH(−)mM2D(+); and for lane 6, the initial mRNA pool contained only rCvH(−)mM2D(−). These two lanes are used as negative controls in the selection. For lane 3, the initial mRNA pool was a 1:1 mixture of rCvH(+)mM2D(+) and rCvH(−)mM2D(+); and for lane 7, the initial mRNA pool was a 1:1 mixture of rCvH(+)mM2D(−) and rCvH(−)mM2D(−). These two lanes were used for determining selection efficiency. Lane 4 contains RT-PCR products amplified from a 1:1 mixture of rCvH(+)mM2D(+) and rCvH(−)mM2D(+) prior to in-vitro selection; and lane 8 contains RT-PCR products amplified from a 1:1 mixture of rCvH(+)mM2D(−) and rCvH(−)mM2D(−) prior to in-vitro selection. FIG. 18 is a diagram showing the correlation between the involvement of mMS2p-Cv interaction in the system and in-vitro selection. The horizontal axis indicates the yield defined as a ratio between the radioactivity of Ni-NTA agarose pelleted prior to the elution step in the selection, and the radioactivity of the radio-labeled mRNA added. The yield of each mRNA is determined as an average of results obtained in two independent experiments. detailed-description description="Detailed Description" end="lead"? (I) Positive control having the histidine tag. (rCvH(+)D(+)) Contains a Cv but no MSp. (II) Positive control having the histidine tag. (rCvH(+)mM1D(+)) Contains a Cv and am MSp. (III) Positive control having the histidine tag. (rCvH(+)mM2D(+)) Contains a Cv and two MSps. (IV) Negative control having no histidine tag. (rCvH(−)mM2D(+)) Contains two Cvs and two MSps. |
Computing system |
A computing unit (42) executes a second computing in the middle of a first computing. At this time, the hardware structure of the computing unit (42) is switched in accordance with a computing which is a target of execution. A controller (46) stores the internal state of the computing unit (42) in a memory (44) when a computing to be executed by the computing unit (42) changes from the first computing to the second computing. And the controller (46) controls execution of the first computing to be continued by returning the internal state stored in the memory (44) to the computing unit (42), when a computing to be executed by the computing unit (42) returns from the second computing to the first computing. |
1. A computing system, comprising: a computing unit (42) which has a hardware structure corresponding to a computing which is a target of execution, and executes the computing which is the target of execution; a state memory (44) which stores an internal state of said computing unit; and a controller (46, 46′) which controls the internal state of said computing unit, wherein: said computing unit (42) executes a second computing in the middle of a first computing; and said controller (46, 46′) stores the internal state in said state memory (44) when a computing to be executed by said computing unit (42) switches from the first computing to the second computing, and controls said computing unit (42) to resume execution of the first computing by returning the internal state stored in said state memory (44) to said computing unit (42) when a computing to be executed by said computing unit (42) returns from the second computing to the first computing. 2. The computing system according to claim 1, wherein said state memory (44) stores the internal state in accordance with a First-In-Last-Out method. 3. The computing system according to claim 1, wherein: said computing unit (42) comprises a plurality of gate circuits; and connection between said plurality of gate circuits is switched in accordance with a computing which is a target of execution. 4. A computing system, comprising: a loader (3) which loads a plurality of data modules by each module, each of the plurality of data modules representing a hardware structure which is suitable for executing a predetermined computing; a computing unit (42) which has a hardware structure changeable in accordance with a hardware structure represented by a loaded data module, and executes a predetermined computing; and a result retaining unit (44) which retains an intermediate result of a computing executed by said computing unit (42) in a case where the hardware structure of said computing unit (42) changes, and returns the retained intermediate result to said computing unit (42) in a case where the hardware structure of said computing unit (42) returns to an original state. 5. The computing system according to claim 4, wherein: the plurality of data modules include a first data module which represents a first hardware structure for executing a first computing, and a second data module which represents a second hardware structure for executing a second computing which is executed during the first computing; the first data module contains call data for calling the second data module in the middle of the first computing; and said computing system further comprises: a detection unit (43) which detects the call data contained in the first data module which is loaded; and a controller (46) which stores an intermediate result of the first computing executed by said computing unit (42) in said result retaining unit (44), and controls said loader (3) to load the second data module, in a case where said detection unit (43) detects the call data. 6. The computing system according to claim 5, wherein in a case where said computing unit (42) completes the second computing, aid controller (46) controls said loader (3) to load the first data module, and controls said computing unit (42) to resume the first computing by returning the intermediate result stored in said result retaining unit (44) to said computing unit (42). 7. The computing system according to claim 6, further comprising an argument supply unit (45) which supplies a part of the intermediate result of the first computing to said computing unit (42) as an argument for executing the second computing, and supplies an execution result of the second computing to said computing unit (42) as an argument for resuming the first computing. 8. The computing system according to claim 7, wherein said result retaining unit (44) comprises a memory which stores an intermediate result in accordance with a First-In-Last-Out method. 9. The computing system according to claim 7, wherein: said computing unit (42) comprises a plurality of gate circuits; and connection between said plurality of gate circuits is switched in accordance with a loaded data module. 10. The computing system according to claim 5, wherein: said computing system is connectable to another computing system which has a hardware structure changeable in accordance with a hardware structure represented by a supplied data module, and executes a predetermined computing; and said computing system further comprises a result acquiring unit (7) which supplies the second data module which is loaded, to another computing system in order to control another computing system to execute the second computing, and acquires an execution result of the second computing from another computing system, in a case where said computing system is connected to another computing system. 11. The computing system according to claim 10, wherein: said computing unit (42) supplies the second data module which is loaded, to said result acquiring unit (7), and stops execution of the first computing, in a case where said computing system is connected to another computing system; and said result acquiring unit (7) controls said computing unit (42) to resume the first computing by supplying said computing unit with the acquired execution result of the second computing as an argument for resuming the first computing. 12. A computing system, comprising: a loader (3′) which loads a plurality of program modules by each module, each of the plurality of program modules representing a predetermined computing; an interpreter (47) which interprets an instruction included in a loaded program module, and outputs at least one signal for realizing a hardware structure which corresponds to a computing represented by the loaded program module in accordance with an interpretation result; a computing unit (42) which has a hardware structure changeable in accordance with the at least one signal output by said interpreter (47), and executes a predetermined computing; and a result retaining unit (44) which retains an intermediate result of a computing executed by said computing unit (42) in a case where the hardware structure of said computing unit (42) changes, and recovers said computing unit as it was before the hardware structure of said computing unit (42) changed, by returning the retained intermediate result to said computing unit (42), in a case where the hardware structure returns to an original structure. 13. The computing system according to claim 12, wherein: the plurality of program modules include a first program module representing a first computing, and a second program module representing a second computing which is executed during the first computing; the first program module contains a call instruction for calling the second program module in the middle of the first computing; and said computing system further comprises a controller (46′) which stores an intermediate result of the first computing executed by said computing unit (42) in said result retaining unit (44), and controls said loader (3′) to load the second program module, in a case where said interpreter (47) interprets the call instruction. 14. The computing system according to claim 13, wherein in a case where said computing unit (42) completes the second computing, said controller (46′) controls said loader (3′) to load the first program module, and controls said computing unit (42) to resume the first computing by returning the intermediate result stored in said result retaining unit (44) to said computing unit (42). 15. The computing system according to claim 14, further comprising an argument supply unit (45) which supplies a part of the intermediate result of the first computing to said computing unit (42) as an argument for executing the second computing, and supplies an execution result of the second computing to said computing unit (42) as an argument for resuming the first computing. 16. The computing system according to claim 15, wherein said result retaining unit (44) comprises a memory which stores an intermediate result in accordance with a First-In-Last-Out method. 17. The computing system according to claim 15, wherein: said computing unit (42) comprises a plurality of gate circuits; and connection between said plurality of gate circuits is switched in accordance with at least one signal supplied from said interpreter. 18. The computing system according to claim 13, wherein said computing system is connectable to another computing system which has a hardware structure changeable in accordance with a computing represented by a program module which is supplied, and executes the computing represented by the supplied program module; and said computing system further comprises a result acquiring unit (7) which supplies the second program module which is loaded, to another computing system in order to control another computing system to execute the second computing, and acquires an execution result of the second computing from another computing system, in a case where said computing system is connected to another computing system. 19. The computing system according to claim 18, wherein: said interpreter (47) supplies the second program module which is loaded, to said result acquiring unit (7), in a case where said computing system is connected to another computing system; and said result acquiring unit (7) controls said computing unit to continue the first computing, by supplying said computing unit (42) with the acquired execution result of the second computing as an argument for resuming the first computing. |
<SOH> BACKGROUND ART <EOH>In a current general-purpose computer, computing is progressed while a CPU (Central Processing Unit) sequentially interprets instructions in a program stored in a memory. A CPU is for executing a computing which is a target of execution, by means of software. Thus, the hardware structure of a CPU is not necessarily the most suitable for a computing which is a target of execution. As a result, there is incurred a lot of overhead until the final computing result is obtained. In contrast, as a technique for executing a computing represented by a program directly by hardware, a computing system utilizing a field programmable gate array (FPGA) has been known. National Publication No. H8-504285 (International Publication No. WO94/10627) and National Publication No. 2000-516418 (International Publication No. WO98/08306) disclose a computing system utilizing an FPGA. The hardware structure of an FPGA is changeable by logic data. By utilizing such an FPGA, hardware can directly execute a computing represented by a program. Therefore, a computing result can be obtained at higher speed than in a case where a CPU executes a computing. On the other hand, a large-scale program executed by a current general-purpose computer consists of a plurality of program modules. A computing represented by a large-scale program is progressed while a program module calls another program module. However, the above described conventional computing systems utilizing an FPGA can only execute a computing represented by a program consisting of substantially one program module. In other words, the conventional computing systems utilizing an FPGA cannot execute a large-scale computing represented by a large-scale program consisting of a plurality of program modules. Therefore, there is a problem that conventional computing systems utilizing an FPGA cannot be applied in various ways. The disclosures of National Publication No. H8-504285 (International Publication No. WO94/10627) and National Publication No. 2000-516418 (International Publication No. WO98/08306) are incorporated herein by reference. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a diagram showing a structure of a computing system according to a first embodiment. FIG. 2 is a diagram showing an example of a computing executed by the computing system shown in FIG. 1 . FIG. 3 is a diagram showing a structure of a computing system according to a second embodiment. FIG. 4 is a diagram showing another example of a structure of a computing system. FIG. 5 is a diagram showing an example in which another computing system is connected to the computing system shown in FIG. 4 . FIG. 6 is a diagram showing another example of a structure of a computing system. detailed-description description="Detailed Description" end="lead"? |
Method and system for optically performing an assay to determine a medical condition |
A method and system are disclosed for detecting a medical condition wherein a blood or plasma sample is combined with a metal such as cobalt and optically analyzed for an optical distinction that identifies the medical condition. The invention is useful for diagnosing medical conditions such as ischemia. Moreover, the diagnoses of patient samples according to the invention may be enhanced by developing a mathematical model based on signal processing techniques such as principal component analysis on the data obtained in patient studies. |
1. A method for detecting a medical condition comprising: providing a patient fluid sample divided into first and second portions, and combining a substance for providing free metal ions with the first portion of the sample; irradiating both the first and second portions of the sample with light; determining absorbance values for the first and second portions; obtaining a differential absorbance value from the first and second portions; analyzing the differential absorbance value for determining one or more characteristics that are indicative of whether the medical condition is present; wherein said analyzing step uses principal component analysis for reducing a dimension of the differential absorbance value. 2. The method of claim 1, wherein the medical condition is ischemia. 3. The method of claim 1, wherein the metal ion is cobalt ion. 4. A method of diagnosing an ischemic event comprising: a) providing a first and second patient sample comprising albumin; b) adding to the first patient sample a metal ion, whereby the metal ion binds to the albumin; c) conducting optical analyses of the first and second patient samples to generate signals or spectra, respectively; d) measuring the amount of metal bound to the albumin by comparing the signals or spectra of step (c) to generate a differential signal or spectra; and e) comparing the differential signal or spectra to a standard curve or mathematical model that correlates the differential signal or spectra to amount of metal bound to albumin, whereby an ischemic event may be diagnosed if the measured amount of metal bound to albumin is below a defined value. 5. The method of claim 4, wherein the patient samples are serum. 6. The method of claim 4, wherein the first and second patient samples are provided by dividing an original patient sample. 7. The method of claim 43, wherein the metal ion is cobalt ion. 8. The method of claim 4, wherein the metal ion binds to the N-terminus of the albumin. 9. The method of claim 4, wherein the optical analyses are absorbance spectroscopy and the analyses is conducted in the range of 300-450 nm. 10. The method of claim 4, wherein the optical analyses comprise fluorescence spectroscopy, said method further comprising: adding to the first patient sample a fluorescent dye in step (b), wherein the dye binds to said metal ion and wherein the fluorescence signal changes as a function of whether the metal ion is unbound or bound to the albumin. 11. The method of claim 4, further comprising: analyzing the differential signal or spectra of step (d) using principal component analysis. 12. A method for diagnosing an ischemic event, comprising: a) adding a metal ion and a fluorescent dye to a patient sample comprising albumin, whereby the dye binds to the metal ion which may bind to the albumin; b) measuring the metal bound to the albumin by measuring a fluorescent signal of the sample, wherein the fluorescent signal changes as a function of whether the metal ion is unbound or bound to the albumin; and c) comparing the fluorescent signal to a standard curve or mathematical model that correlates the fluorescent signal to an amount of metal ion bound to albumin, whereby the measurement of metal ion bound to albumin below a defined value may be diagnostic for an ischemic event. 13. The method of claim 12 wherein the metal ion and fluorescent dye are added as a conjugate. 14. The method of claim 12, wherein the fluorescent signal is quenched or shifts to a different wavelength when the dye is bound to a metal ion that is bound to the albumin. 15. The method of claim 12, wherein the metal ion is a cobalt ion. 16. The method of claim 12, wherein the fluorescent dye is selected from the group consisting of Cumarin, Rhodamine and Newport green. 17. A method of rapidly diagnosing an ischemic event comprising: a) providing a first and second patient sample comprising albumin; b) adding to the first patient sample a metal ion, whereby the metal ion binds to the albumin in a reaction that reaches equilibrium at a predetermined time; c) conducting, during a defined time interval prior to achievement of equilibrium, optical analyses of the first and second patient samples to generate first and second signals or spectra, respectively, for each sample at selected time points during the defined time interval; d) measuring the rate of change of amount of metal bound to the albumin over the defined time interval by comparing the first and second signals or spectra for each time point to generate differential signals or spectra for each time point in the time interval; e) calculating a rate of change in the differential signals or spectra over the time interval; f) and comparing the rate of change of signal or spectra to a standard curve or mathematical model that correlates rate of change with projected metal bound to albumin at equilibrium, whereby an ischemic event may be diagnosed if the projected amount of metal bound to albumin is below a defined value. 18. A method of rapidly diagnosing an ischemic event, comprising: a) adding a metal ion and a fluorescent dye to a patient sample comprising albumin, whereby the dye binds to the metal ion which binds to the albumin in a reaction that reaches equilibrium at a predetermined time, wherein the fluorescent dye's signal changes as a function of whether the metal ion is unbound or bound to the albumin; b) measuring the rate of change of metal bound to the albumin by measuring the fluorescent signal of the sample at selected time points over a time interval that is prior to achievement of equilibrium; c) calculating the rate of change of the fluorescent signal over the time interval; and d) comparing the rate of change of the fluorescent signal to a standard curve or mathematical model that correlates the rate of change in fluorescent signal to a projected amount of metal ion bound to albumin at equilibrium, whereby ischemia may be diagnosed if the measured rate of change of metal ion bound to albumin is below a defined value. 19. A method for diagnosing an ischemic event comprising: (a) providing a patient sample comprising albumin, a portion of which may be N-terminally modified; (b) measuring the N-terminally modified albumin by measuring absorbance of the sample, and comparing the absorbance to a standard curve or mathematical model that correlates the absorbance to a ratio of modified to unmodified albumin, wherein an ischemic event may be diagnosed if the ratio is below a defined value. 20. The method of claim 19, wherein the patient sample comprises whole blood, serum or plasma provided in a sample container and the absorbance is measured with a spectral probe placed in the sample. 21. The method of claim 19, wherein the patient sample comprises whole blood in the patient's blood vessel and the absorbance is measured with a spectral probe placed in the blood vessel. 22. An instrument for detecting a medical condition, comprising: a spectral probe having a tip for insertion into a patient fluid sample and receiving spectral light from the patient fluid sample; a spectrophotometer coupled to said spectral probe for quantifying each frequency of spectral light received by said spectral probe and outputting a signal representative of the quantity of each frequency of spectral light; a computing unit, comprising: an input coupled to receive the signal from said spectrophotometer; a memory for storing a model representing spectral light data obtained from a first set of patients known to have the medical condition and a second set of individuals known to not have the medical condition, whereby the model includes a value identified with a high probability of the presence of the medical condition; a processor programmed to execute instructions for: comparing the quantity of each frequency of spectral light from the patient with corresponding data in the stored model; and determining whether the quantity of each frequency of spectral light is indicative of the presence of the medical condition in the patient; and an output to provide the determination to a user. 23. A method for providing an instrument for diagnosing a medical condition in a patient, comprising: obtaining a control fluid sample from a first plurality of control individuals known to have the medical condition; obtaining a control fluid sample from a second plurality of control individuals known to not have the medical condition; dividing each control fluid sample into first and second portions; combining a substance for providing free metal ions with the first portion of each control fluid sample; irradiating both the first and second portions of each control fluid sample with light; determining absorbance values for the first and second portions of each control fluid sample; obtaining a differential absorbance value from the first and second portions of each control fluid sample; generating a principal component analysis model of the obtained differential absorbance values, the principal component analysis model including a value indicative of the presence of the medical condition; storing the generated principal component analysis model in a computer readable format; providing computer executable instructions for: providing a differential absorbance value, determined from first and second portions of a patient fluid sample obtained from a patient, said first portion having been combined with free metal ions, and comparing said differential value with the stored principal component analysis model; in response to the comparing step, determining whether the differential absorbance value of the patient fluid sample is indicative of the presence of the medical condition. |
<SOH> BACKGROUND <EOH>Ischemia is the leading cause of illness and disability in the world. Ischemia is the state of imbalance of oxygen supply and demand in a part of the body often due to a constriction or an obstruction in the blood vessel supplying that part. The two most common forms of ischemia are cardiovascular and cerebrovascular. Cardiovascular ischemia is generally a direct consequence of coronary artery disease, and is usually caused by rupture of an atherosclerotic plaque in a coronary artery, leading to formation of thrombus (blood clot), which can occlude or obstruct a coronary artery, thereby depriving the downstream heart muscle of oxygen. Prolonged ischemia can lead to cell death or necrosis, and the region of dead tissue is commonly called an infarct. Patients suffering an event of acute cardiac ischemia often present to a hospital emergency room with chest pain and other symptoms and signs (such as changes to the electrocardiogram of ECG) referred to as Acute Coronary Syndromes or ACS. A patient diagnosed with ACS requires immediate treatment to avoid irreversible damage to the heart muscle. Cerebral ischemia is often due to narrowing of the arteries leading to the brain, and early symptoms may be called Transient Ischemic Attack (TIA), which may include headache, dizziness, sensory changes, and temporary loss of certain motor function. TIAs are a precursor to cerebrovascular accident (CVA) or stroke which is the third leading cause of death in the United States. The continuum of ischemic disease includes five conditions: (1) elevated blood levels of cholesterol and other lipids; (2) buildup of atherosclerotic plaque and subsequent narrowing of the arteries; (3) reduced blood flow to a body organ (as a result of arterial narrowing or plaque rupture and subsequent thrombus formation); (4) cellular damage to an organ caused by a lack of oxygen; (5) death of organ tissue caused by sustained oxygen deprivation. Stages three through five are collectively referred to as “ischemic disease,” while stages one and two are considered its precursors. It is important to distinguish between the state of ischemia and the disease which leads to it. For example, a patient with coronary artery disease is not always in the state of cardiac ischemia, but a person in the state of cardiac ischemia almost invariably suffers from coronary artery disease. Together, cardiovascular and cerebrovascular disease accounted for 954,720 deaths in the U.S. in 1994. Furthermore, more than 20% of the population has some form of cardiovascular disease. It was estimated that in 1998, as many as 1.5 million Americans would have a new or recurrent heart attack, and about 33% of them would die. Additionally, as many as 3 to 4 million Americans suffer from what is referred to as “silent ischemia.” This is a condition where ischemic heart disease is present without the usual and classic symptoms of chest pain or angina. There is a pressing need for the development and utilization of blood tests able to detect injury to the heart muscle and coronary arteries. Successful treatment of cardiac events depends largely on detecting and reacting to the presence of cardiac ischemia in time to minimize damage. Cardiac enzymes, specifically the creatine kinase isoenzyme (CK-MB), and markers of cardiac necrosis, specifically myoglobin and the Troponin I and Troponin T biochemical markers, are utilized for diagnosing heart muscle injury. However, these enzymes and markers are only capable of detecting the existence of cell death or necrosis, and therefore have limited or no value in patients who have ischemia without necrosis, such as those in an ischemic state prior to myocardial infarction. Additionally, these enzymes and markers do not show a measurable increase until several hours after the onset of necrosis. For instance, the cardiac troponins do not show a measurable increase above normal in a person's blood test until about four to six hours after the beginning of a heart attack and do not reach peak blood level until about 18 hours after such an event. Thus, the primary shortcoming of using markers of cardiac necrosis for diagnosis of ischemic states is that these markers are only detectable after heart tissue has been irreversibly damaged. A pressing requirement for emergency medicine physicians who treat patients with chest pain and stroke symptoms is for a diagnostic test that would enable them to definitively “rule out” or “rule in” acute coronary syndrome (which may be acute myocardial infarction), stroke, and other emergent forms of ischemia. A need exists for a method for immediate and rapid distinction between ischemic and non-ischemic events, particularly in patients undergoing acute cardiac-type symptoms. While the ACB™ Test (Ischemia Technologies, Inc., Denver, Colo.) is such a test, the medical demand is such that additional diagnostic tests are desirable. A broad array of diagnostic tests is available for diagnosis of cardiac ischemia, particularly in the emergency room (see, for example, Selker, H P, Zalenski, R J et al An Evaluation of Technologies for Identifying Acute Cardiac Ischemia in the Emergency Department: A Report from a National Heart Attack Alert Working Group Annals Emergency Medicine 1997;29:13-87). The accepted standard of care is the 12 lead electrocardiogram (ECG or EKG) which, nevertheless, has a clinical sensitivity of less than 50%. Other diagnostic tests include echocardiography, and radionuclide myocardial perfusion imaging. Diagnosis of coronary artery disease is done either by imaging (e.g.: coronary angiography) or by provocative testing, where the intent is to deliberately induce cardiac ischemia and observe the effects. For example, in the ECG exercise stress test, the patient is exercised at an increasing rate to see if symptoms of ischemia are evoked, or if changes indicative of ischemia can be observed on the ECG. Stress ECG commonly used as an initial screen for coronary artery disease, but is limited by its accuracy rates of only 25-50%. Another commonly used diagnostic test is myocardial perfusion imaging in which a radioactively tagged chemical is injected during stress and is taken up by normally metabolizing cardiac tissue, and then imaged using conventional techniques (PET or SPECT scanning). The present invention, however, is believed to be advantageous over the known methods of diagnosis in that it is a simple blood test which will offer comparable accuracy at far lower costs and decreased risk and inconvenience to the patient. It is believed that the present invention provides specificity and sensitivity levels that are comparable in accuracy to current diagnostic standards. It is known that following an ischemic event leading to necrosis, proteins (enzymes, cytoplasmic proteins and structural proteins) are released into the blood. Well known proteins released after such an event include creatine kinase (CK), serum glutamic oxalacetic transaminase (SGOT—also known as ALT and AST—alanine amino transferase and aspartate amino transferase), lactic dehydrogenase (LDH), myoglobin and cardiac troponin (for myocardial necrosis). One well known method of evaluating the occurrence of past heart events is the detection of these proteins in a patient's blood, and in fact the standard of care for diagnosis of Acute Myocardial Infarction is the rise and fall of markers of cardiac necrosis (i.e.: troponin or CK-MB) in the presence of signs and symptoms of cardiac ischemia. The difficulty lies in the diagnosis of ischemia. U.S. Pat. No. 4,492,753 relates to a method of assessing the risk of future ischemic heart events. However, injured heart tissue releases proteins such as troponin to the bloodstream after both ischemic and non-ischemic events. For instance, patients undergoing non-cardiac surgery may experience perioperative ischemia. Electrocardiograms of these patients show ST-segment shifts with an ischemic cause which are highly correlated with the incidence of postoperative adverse cardiac events. However, ST-segment shifts also occur in the absence of ischemia; therefore, electrocardiogram testing does not distinguish ischemic from non-ischemic events. The present invention provides a means for distinguishing perioperative ischemia from ischemia caused by, among other things, myocardial infarctions and progressive coronary artery disease. It is an object of the subject invention to provide a diagnostic test that detects a change in a biological molecule by processing a signal produced or altered by the change in the biological molecule, wherein the change relates to the binding of a metal to a portion of the biological molecule. Another object is to provide a diagnostic test that determines a difference in absorbance and/or fluorescence spectra between plasma, serum, or whole blood samples from ischemic patients and non-ischemic individuals, wherein the samples are first combined with cobalt or another metal. It is another object of the subject invention to provide an optical assay for detecting a biological condition via detection of a metal binding with a biological sample, wherein there is an increased latitude in the amount of additives such as metal, dye or other reagents added to the biological sample. Another object of the subject invention is to use data processing techniques such as principal component analysis to identify the features of a spectral output data from an optical assay for differences between ischemic patients and non-ischemic individuals. It is a further object of the subject invention to reduce the time required to identify a biological condition of a patient, wherein the condition is indicated by an assay that tests for the binding of a metal (e.g., cobalt) to the albumin found in plasma, serum, whole blood or other patient fluid. It is also an object of the invention to provide a portable apparatus for combining an additive (e.g., a metal) with a sample from a patient and thereby detect/identify a condition related to the health of the patient, wherein the manufacture of the apparatus is reduced in cost due to the fact that additives to be combined with the patient sample need not be measured as precisely as in currently available comparable equipment for detecting or identifying the patient's condition. It is a further object of the invention to provide a biological assay platform wherein there are a plurality of assay containers with each container having a different metal (and for a fluorescence analysis, a corresponding dye) therein wherein each metal is different and varies according to the biological condition to be detected. It is an additional object of the invention to provide an apparatus for assaying a patient's condition at the patient's bedside. A further object of the invention is to measure the rate of change in an optical signal (e.g., absorbance or fluorescence) of an additive combined with a sample from a patient for determining ischemia. It is an additional object of the invention to continuously or periodically assay small samples of a patient for ischemia analysis, wherein a needle for doing such may have a fiber optic device therein for transmitting and/or receiving light to the sample to be assayed. |
<SOH> SUMMARY <EOH>The present invention is a method and system for detecting a change in a biological system or molecule by processing a signal produced or altered by the change in the biological system or molecule, wherein the change relates to a binding of a metal to portion of the biological system or molecule. In one embodiment, the present invention is a method and system for determining whether a protein has been altered or damaged by measuring its metal binding capacity. If a protein has the ability to bind metals (or another type of substrate) and the binding site is somehow altered, then it often occurs that the site will either bind less or more to a substrate or ligand. Accordingly, the present invention measures a difference in such binding capacities optically. In particular, any disease state that has an associated alteration of some protein that in turn causes a metal to bind differently than it would in a non-diseased state could be measured using an embodiment of the present invention. In one particular embodiment of the invention, an improved assay for detecting ischemia is provided, wherein a binding of cobalt ion to albumin is directly measured. In particular, it is believed that cobalt ion binds readily and/or strongly to human serum albumin from patients not having ischemia, and that cobalt ion binds less readily and/or strongly to albumin from patients experiencing ischemia due to an elevated amount damaged binding sites for cobalt on the albumin molecule. This damaged albumin is referred to as Ischemia Modified Albumin, or IMA. Accordingly, one embodiment of the present invention comprises a method for detecting the amount of cobalt bound to albumin directly via absorption spectroscopy in at least the range of 300-450 nm. Moreover, it is believed that spectroscopic signals indicative of the bound cobalt may also be distinguishable in a wider spectral range as well, and in particular, 200-450 nm. In one embodiment for detecting ischemia, a patient serum sample is measured via absorbance spectroscopy with and without cobalt ion, and then the results from the two measurements are subtracted thereby arriving at a difference or differential spectra. This difference spectrum is quantified by, e.g., either a ratio of wavelength intervals or an integration over some spectral interval. In performing various experiments for detecting ischemia in this manner, Applicants have obtained evidence that the spectral measurements and the analysis thereof are indicative of direct cobalt binding to albumin as opposed to detecting free (i.e., unbound) cobalt. Moreover, Applicants have determined that a major advantage of detecting direct cobalt binding to albumin, is that the test is far less sensitive to reagent (e.g., cobalt) concentration than the detection of free (unbound) cobalt. In fact, excess cobalt is believed to be somewhat advantageous in detecting albumin bound cobalt in that the excess cobalt substantially assures that all cobalt binding sites on the albumin will be used. More generally, it is an aspect of the present invention to combine cobalt or another metal with a sample of plasma, serum or whole blood and determine a difference in spectral absorption between ischemic and non-ischemic patients, wherein the measurements obtained are indicative of the amount of metal bound to albumin within the sample independently of the amount of unbound or free metal (or ions thereof) that may also be in the sample. Additionally, when whole blood is provided as the sample, then the sample can be centrifuged (spun) to obtain the plasma therein, and subsequently in one embodiment, this plasma may be diluted approximately 5 times or more with an appropriate buffer keeping the pH in the range 7.5-8.5, before being optically assayed. Further, when cobalt is the metal used, it has been determined that approximately 15 μL to 40 μL of 1% cobalt solution per approximately 150 μL to 250 μL of plasma is effective for detecting ischemia. More particularly, it has been determined that approximately 25 μL of 1% cobalt solution per approximately 200 μL plasma is effective for detecting ischemia. In at least some (if not most) embodiments of the invention, a metal compound may be added to the sample thereby causing free metal ions to be introduced into the sample. For example, a 1% cobalt chloride solution in 100 μL of plasma may be used for detecting ischemia, wherein the cobalt chloride provides cobalt ions to the sample. Accordingly, it is to be understood herein that when the term “free metal” or similar terms are used, these terms are intended to mean that unbound metal ions are introduced into a sample. In another embodiment of the present invention, fluorescence spectroscopy may be performed, wherein a fluorescent dye may be added to a sample of plasma or whole blood or a diluted sample thereof wherein the dye is relatively specific to a particular metal ion, and fluoresces differently in the presence of a free metal (e.g., cobalt, copper or nickel) than in the presence of the metal bound to albumin. In particular, the dyes can indicate the amount of free metal ions or bound metal ions residing in the sample. Moreover, since the dyes contemplated to be used in this embodiment of the invention fluoresce very differently in the presence of free and bound metal, Applicants have discovered that it is unnecessary to precisely calibrate the amount of such a dye to be added to the plasma or blood sample, and as with spectral absorption embodiment above, excess dye is believed to be somewhat advantageous in that this substantially assures that all possible metal bindings by the dye are achieved. Additionally, note that certain dyes to be used fluoresce strongly enough such that the fluorescence can be readily measured in whole blood. It is worth noting that in performing fluorescence spectroscopy according to the present invention, fluorescence signals for the dyes contemplated tend to be quite strong and are therefore quite sensitive to detecting such medical conditions as ischemia. In particular, the following dyes may be used in various embodiments of the invention: Rhodamine, Cumarin and Newport Green. Applicants have also discovered that it may take time (e.g., 20 minutes) to obtain a steady state (i.e., equilibrium) of bound and unbound metal (e.g., cobalt) within a plasma or whole blood sample. Accordingly, to perform faster assays and for operator convenience, it is an aspect of the present invention to provide the metal ion in the assay container prior to providing the plasma or blood (e.g., during container manufacture). Moreover, to further reduce the assay time, it is an aspect of the present invention to measure a rate of change in the amount of bound metal within a sample at a defined time interval prior to reaction equilibrium instead of the amount of bound metal at equilibrium. This defined time interval can be, for example, any 1-10 minute interval prior to the time of equilibrium. Preferably, the defined time interval is any 1-5 minute or 1-2 minute interval prior to the time of equilibrium. In one embodiment, the interval is selected at 5-15 minutes prior to equilibrium. The subject invention also comprises a method of optically detecting modifications to the albumin N-terminus using absorbance without the addition of reagents such as metal ions. As is described in the Examples, it has been observed that albumin that has been modified at its N-terminus, as happens during an ischemic event, has a different absorbance spectrum than full length albumin. In each of the foregoing methods, the optical data from the patient sample obtained is compared to a standard curve or other mathematical model that has been constructed from data collected during clinical trials or other patient studies. The standard curve or mathematical model is used to define the cut-off point between optical data that reflects an ischemic event and that which is indicative of normal or non-ischemic albumin. For example, a set of data from samples collected from non-ischemic people can be used to generate a “normal range”, and the 97 th percentile of the upper limit of normal can be defined as the cutoff—any value higher than this is regarded as “ischemic”, and any value lower than this is regarded as “non-ischemic”. Other techniques such as receiver operating characteristic (ROC) curves will be well known to one skilled in the art. Thus, in a further aspect of the present invention, various signal processing techniques may be used in the analysis of the resulting data obtained from an assay performed according to the present invention. In one embodiment, principal component analysis (PCA) is performed on this resulting data for both data dimension reduction and effectively identifying differences between ischemic and non-ischemic samples using the reduced dimension PCA data set. Principal component analysis (PCA) involves a mathematical procedure that transforms a number of (possibly) correlated variables into a (smaller) number of uncorrelated variables called principal components. The first principal component accounts for as much of the variability in the data as possible, and each succeeding component accounts for as much of the remaining variability as possible. A trivial example of principal component analysis is fitting a straight line to a large and noisy data set plotted in two dimensions. In this case, a large amount of data is reduced to the two variables required to describe the line, and therefore the number of mathematical dimensions required to describe the data set has been reduced enormously. For example, the absorption spectra (i.e., the resulting data) of a sample is obtained. Subsequently, the resulting data is converted to PCA space to reduce the number of dimensions of the data. In one embodiment, the resulting data may be acquired at a sample rate of approx. 2 measurements per nm, thus giving a spectrum with 300+ components. In PCA the 300+ components are converted to coefficients of basis elements that represent the directions of maximum variation in the resulting data. These basis elements (called principal components or factors) can be ordered from those that describe the most variation to the least. By utilizing only those principal components that describe the most variation, the efficiency of the analysis can be substantially enhanced. Moreover, note that there are several tests to determine how many principal components to include in this subset including the Kaiser Criterion and the Scree test as one skilled in the art will understand. By this conversion, “noise” in the form of the weak components is reduced, and the dimension of the resulting data is reduced as well as the degrees of freedom to be addressed when attempting to detect and/or diagnose a medical condition. Accordingly, the detection/diagnosis is based on this reduced space. Note that it is also within the scope of the present invention to utilize other signal processing techniques in addition to or as a substitute for PCA such as the following: a. wavelets (which are often more stable than PCA), b. Fourier analysis, c. general factor analysis techniques, and d. independent component analysis. There are many other classification techniques that may be used in embodiments of the present invention, including the following: a. Linear discriminant functions (including piecewise linear); b. Non-linear discriminant functions (including piecewise non-linear); c. Cluster techniques to find natural groupings: i. Hierarchical, ii. Non-hierarchical, iii. Density; d. Mahalanobis distance type metrics from known class means; e. Multi-dimensional Probability density functions; f. Neural networks; and g. Support vector machines. In yet a further aspect of the present invention, devices are provided for performing the foregoing assays. In one such embodiment, a measurement sample chamber, a reference sample chamber, and a spectrophotometer are provided for measuring spectra or signals in a patient control sample and a test patient sample (the latter containing metal ion and optionally fluorescent dye). These signals or spectra data are transmitted to a computer for determination of the differential spectra or signal, and/or further processing and analysis. In another embodiment, a device is provided for assaying a (plurality of) patient control(s) and a plurality of patient test samples. Specifically, an assay platform may be provided wherein there is a plurality of assay containers with each container having a different metal (and optionally a fluorescent dye) therein so that the metal may differentially bind with the assay sample depending upon whether the assay indicates one or more medical conditions such as ischemia or non-ischemia. Accordingly, such an optical platform may allow a plurality of such conditions to be diagnosed substantially simultaneously. Additionally, since certain patient treatments may affect the results of some such assays, the assay platform may include redundant assays for the same condition wherein any one of the redundant assays may detect an abnormal medical condition. Note that some embodiments of the present invention may be performed away from the traditional location of a central hospital laboratory, for example at a patient's bedside. In particular, the invention may be substantially provided in a portable unit that has great flexibility in location, such as adjacent to or attached to a patient's bed. Moreover, such a portable embodiment may include a hypodermic needle having a fiber optic device therein for transmitting and/or receiving light to a sample to be assayed. Thus, assays may be performed continuously or periodically on small samples from a patient. Other advantages and benefits of the present invention will become apparent from the accompanying drawings and Detailed Description herein below. All references cited are incorporated by reference herein in their entirety. |
Nets for bodies of water |
A net (10) for a body of water (12) that serves to collect flat objects (11), which are made of foamed plastic and which are saturated with contamination substances, is provided with a catching net part (13), which can be vertically placed in the body of water (12) by means of a longitudinally extending sink line (18) and of a longitudinally extending float line (21, 22). The aim of the invention is to be able to pull a net of the aforementioned type through the water while tensioned, whereby an upper area of the net always remains above the water surface even in rough water. To this end, the invention provides that the catching net part (13) is widened by a flexible net part (14) that, in the area of its free longitudinal edge, is fitted with a longitudinally extending sink line (32) and is fitted with at least one main float line (33) between said longitudinal edge and the upper float line (21, 22) of the catching net part (13). |
1. Net (10, 110) for waters (12, 112) to intercept, collect and/or recover flat products (11, 111), particularly of open-cell expanded plastic soaked with polluting substances, on or from the surface of water (12, 112), with a fixed net part (13, 113) which an be arranged in water (12, 112) mainly in upright position by means of a first longitudinal lower ballast unit (18, 118) and a first longitudinal upper float unit (21, 121), characterized by the fixed net part (13, 113) being widened by a flexible net part (14, 114) which, in the area of its longitudinal edge distant from the fixed net part (13, 113), is equipped with a second longitudinal ballast unit (32, 132) and, between the latter and the first upper float unit (21, 121) for the fixed net part (13, 113), with at least one second longitudinal main float unit (33, 133). 2. Net according to claim 1, characterized by the main float line (33) being at a shorter distance from the ballast line (32) of the flexible net part (14) than from the float line (21, 22) of the fixed net part (13). 3. Net according to claim 1, characterized by the distance between the main float line (33) and the ballast line (32) of the flexible net part (14) being considerably shorter than the distance between the float line (21, 22) and the ballast line (18) of the fixed net part (13). 4. Net according to claim 1, characterized by one or more ancillary float lines (36) being provided between the float line of the grid net part (14) and the main float line (33) of the flexible net part (14). 5. Net according to claim 4, characterized by the ancillary float lines (36) being evenly spaced between the float line (21, 22) of the fixed net part (13) and the main float line (33) of the flexible net part (14). 6. Net according to claim 1, characterized by at least a part of the flexible net part (14) being composed of two or more superimposed net layers (26-28). 7. Net according to claim 6, characterized by the net layers (27, 28) being superimposed in meanders. 8. Net according to claim 1, characterized by the flexible net part (14) being bending-elastic along its width. 9. Net (110) according to claim 1, characterized by, along the width of the net (110), a second fixed net part (120) being connected to the longitudinal edge, distant from the first fixed net part (113), of the net part (114) which is flexible along its width. 10. Net according to claim 9, characterized by the second fixed net part (120) being connected by its free longitudinal edge (124) to the first fixed net part (113). 11. Net according to claim 10, characterized by the second fixed net part (120) having a width corresponding to the width of the first fixed net part (113) and the free longitudinal edges (117, 124) of the two fixed net parts (113, 120) being connected to each other. 12. Net according to claim 11, characterized by the first lower ballast unit (118) being common to the two fixed net parts (113, 120) and by a pull line (125) being provided in this connection area of the two fixed net parts (113, 120). 13. Net according to claim 9, characterized by the width of the flexible net part (114) being equal to or somewhat less than the sum of the individual widths of the two fixed net parts (113, 120). 14. Net according to claim 9, characterized by the flexible net part (114) being manufactured in a slack net design connected to nonmetallic flexible bars (150) over its width. 15. Net according to claim 14, characterized by the flexible bars (150) being threaded through the net design. 16. Net according to claim 14, characterized by the flexible bars (150) being evenly spaced over the length of the flexible net part (114). 17. Net according to claim 9, characterized by the float units (121, 133) being composed of extended strips (151) preferably of closed-cell expanded plastic. 18. Net according to claim 17, characterized by the float strips (151) being threaded through the net design. 19. Net according to claim 17, characterized by several float strips (151) being provided in parallel side by side in each float unit (121, 133). 20. Net according to claim 9, characterized by the first fixed net part (113), the flexible net part (114), and the second fixed net part (120) being manufactured as an integral unit. 21. Net according to claim 1, characterized by its capability of being coiled in the flat state. 22. Net according to claim 1, characterized by its capability of being placed on the water (12, 112) in the flat state. 23. Net according to claim 1, characterized by a longitudinal pull rope (23, 125) being provided between fixed net part (13, 113) and flexible net part (14, 114). 24. Net according to claim 1, characterized by an extraction hollow section (44, 144) being provided between two nets (10, 110) in the connecting area of fixed net part (13, 113) and flexible net part (14, 114) and above and/or below this area. 25. Process to remove pollutant layers such as oily layers, e.g. oil patches, thin layers of oil or of liquid plastic, e.g. styrene, from surfaces of water using flat products or open-cell expanded plastic such as PP or PU or PE open-cell foam, the flat products being placed on the water surface and, when soaked with polluting substances, recovered by means of one or more nets according to claim 1, characterized by the net being uncoiled from a drum in the flat state and placed on the water surface, with two or more net sections being connected to each other by means of an extraction hollow section, and the free ends of the external net sections being connected to buoys or an anchor and/or ships by means of pull ropes. 26. Process according to claim 25, characterized by one or two ships circling around the polluted zone on the water surface. 27. Process according to claim 25, characterized by the net sections being placed off the coast in a zigzag manner. |
Method of separating suspension, in particular for waste water treatment, and an apparatus for performing the same |
A method of separating suspension, in particular for treatment of waste water, wherein the flocculating suspension is separated from the liquid by filtration in a fluidized layer in a sludge blanket wherein the flocks are created from the separated suspension and the fluidization is maintained by the rising stream of liquid, while the liquid with suspension enters the fluidized layer from the bottom and the liquid freed from suspension is discharged above the surface of the sludge blanket represented by the interface between the fluidized layer and the liquid without suspension. The thickened separated suspension in form of flocks from a sludge blanket is withdrawn from the zone of the fluidized layer, the velocity of upward flow in the fluidized layer essentially decreasing in the upward direction. The apparatus for performing this method contains an upward widening separator (1) provided by inlet (5, 38, 59) of treated suspension in its bottom part, and by means for withdrawing the liquid without suspension at its top. A separator (1) the inner space of which contains a separation space is provided with at least one withdrawal spot of the thickened suspension from separation space that is arranged above the inlet (5, 38, 59) into separator (1), predominantly at its outer wall (2) or outer walls (33, 34, 50, 51) and under the surface of the sludge blanket. |
1. Method of separating suspension, in particular for treatment of waste water, wherein the flocculating suspension is separated from the liquid by filtration in a fluidized layer of a sludge blanket wherein the flocks are created from the separated suspension and the fluidization is maintained by the rising stream of liquid, while the liquid with suspension enters the fluidized layer from the bottom and the liquid freed from suspension is discharged above the surface of the sludge blanket represented by the interface between the fluidized layer and the liquid without suspension, and the velocity of upward flow in the fluidized layer decreases essentially in the upward direction, characterised in getting an upper partially fluidized sludge blanket and bottom fully fluidized sludge blanket, where in a partially fluidized sludge blanket agglomerates of thickened suspension are established which drop down along its side boundary and then they are withdrawn, and in a fully fluidized sludge blanket the liquid flow is distributed into the partially fluidized sludge blanket, the thickened separated suspension being withdrawn from an side boundary of the fluidized layer at an interface of the partially fluidized sludge blanket and fully fluidized sludge blanket. 2. Method according to claim 1, characterised in that the separated thickened suspension removed from the fluidized layer is forcibly moved downward while getting further thickened. 3. Method according to claim 1, characterised in that if the concentration of inflowing suspension exceeds 1 kg of dry matter per cubic meter, the velocity of upward water flow immediately above the surface of sludge blanket is in the range of 1.6 to 2.2 meters per hour. 4. Method according to claim 1, characterised in that the water flow velocity at the entrance to the sludge blanket is within the range of 2 to 6 cm per second. 5. Method according to any of above claims, characterised in that the volume of withdrawn thickened suspension makes 1.5 multiple to 3 multiple of the volume of water without suspension withdrawn above the surface of sludge blanket. 6. Apparatus for separation of flocculating suspension by filtration in a fluidized layer of a sludge blanket, in particular for treatment of waste water, containing an essentially upward widening separator (1), the inner volume of which contains a separation space and is provided with the inlet (5, 38, 59) of liquid with suspension in its bottom part and means (4, 42, 43, 61, 62) for withdrawal of liquid without suspension in its upper part, in the separation space in operation being a fluidized layer of sludge blanket, above the level (14) of which purified water is located, characterised in that the separation space in the separator (1) at least in one place over the inlet (5, 38, 59) into the separator (1) and under the sludge blanket level (14) is upwards suddenly widened which in this place causes essentially a sudden decrease of the upwards flow velocity in the separation space, and at the level of this widening at least close to one of outer walls (2, 33, 34, 50, 51) of the separator (1) at least one withdrawal spot of the thickened suspension from the fluidized layer of sludge blanket is located inside the separation space in the separator (1). 7. Apparatus according to claim 6, characterised in that the separation space within the separator (1), in its bottom part, is limited at least by one, at least partially inclined inner wall (29, 52, 53), while the space between the bottom part of the outer wall (2, 50, 51) and the inner wall (29, 52, 53) creates a thickening space (31, 56), whereas the gap between the upper edge (30, 54, 55) of this inner wall (29, 52, 53) and the outer wall (2, 51, 52) represents the place of the sudden widening and also the withdrawal spot of thickened suspension from the separation space. 8. Apparatus according to claim 7, characterised in that the gap between the upper edge (30, 54, 55) of the inner wall (29, 52, 53) and the outer wall (2, 51, 52) also creates an inlet to the thickening space (31, 56) that is provided with a means (32, 57, 58) for withdrawing the thickened suspension in its bottom part. 9. Apparatus according to claim 7, characterised in that the inclined outer wall (50, 51) of the separator (1) includes an angle in the withdrawal zone of thickened suspension and its upper part above this level is more inclined than the bottom part of the same underneath. 10. Apparatus according to claim 6, characterised in that the means for withdrawing thickened suspension is created by a perforated collecting tube (3, 35, 36) and the sudden widening of the separation space in this place is performed by a shift of the outer wall (2, 33, 34), which both from beneath and from above is joined on the collecting tube (3, 35, 36), holes (7, 37) for withdrawing the thickened suspension being performed on the side of the collecting tube (3, 35, 36) turned to the upper part of the shifted inclined outer wall (2, 33, 34). 11. Apparatus according to claim 6, characterised in that the inlet area (5, 38, 59) to the separation space makes more than 3 percent and less than 6 percent of the surface of the separation space at the level of withdrawal of liquid without suspension. 12. Apparatus according to claim 6, characterised in that the area of the separation space immediately under the withdrawal level of thickened suspension makes more than 20 percent, and immediately above the level of thickened suspension removal it is less than 70 percent of the surface of the separation space at the withdrawal level of liquid without suspension. 13. Apparatus according to claim 6, characterised in that both the height of inlet (5, 38, 59) to the separation space and the height of withdrawing the liquid without suspension are at vertical distance of more than one meter from the withdrawal level of thickened suspension. 14. Apparatus according to claim 6, characterised in that the height of the withdrawal level of thickened suspension above the level of inlet (5, 38, 59) into the separation space is in the range from ¼ to ¾ of the height of withdrawing liquid without suspension above the inlet level (5, 38, 59) into the separation space. 15. Apparatus according to any of claims 6 to 14, characterised in that at least one functional tube from the group created by collecting tubes (3, 35, 36) of the thickened suspension, collecting tubes (32, 57, 58) for withdrawing the thickened suspension, collecting tubes (4, 42, 43, 61, 62) for withdrawing liquid without suspension, discharge tubes (11, 67), inlet pipes (25, 44, 45. 64, 65) of pressure air and the rinsing tubes (39, 40), creates also part of the supporting structure of the outer walls (2, 33, 34, 50, 51) of the separation space. 16. Apparatus according to claim 6 or 7, characterised in that the angle of the inclined outer wall (2, 33, 34, 50, 51) in its upper part is within the range of 52° to 60°. 17. Apparatus according to claim 9, characterised in that the angle of the inclined inner wall (29, 52, 53) is within the range of 52° to 60°, whereas the angle of the inclined outer wall (2, 50, 51) in its bottom part is within the range of 30° to 40°. 18. Apparatus according to claim 9, characterised in that the inclined outer wall (50, 51) of the separator (1) includes an angle in the withdrawal zone of thickened suspension and its upper part above this level is more inclined than the bottom part of the same underneath. 19. Apparatus according to claim 18, characterised in that at least one functional tube from the group created by collecting tubes (3, 35, 36) of the thickened suspension, collecting tubes (32, 57, 58) for withdrawing the thickened suspension, collecting tubes (4, 42, 43, 61, 62) for withdrawing liquid without suspension, discharge tubes (11, 67), inlet pipes (25, 44, 45. 64, 65) of pressure air and the rinsing tubes (39, 40), creates also part of the supporting structure of the outer walls (2, 33, 34, 50, 51) of the separation space. |
<SOH> FIELD OF THE INVENTION <EOH>The invention relates to a method of separating suspension, in particular for treatment of waste water, wherein the flocculating suspension is separated from the liquid by filtration in a fluidized layer in a sludge blanket wherein the flocks are created from the separated suspension and the fluidized state is maintained by the rising stream of liquid, while the liquid with suspension enters the fluidized layer from the bottom and the liquid freed from suspension is discharged above the surface of the sludge blanket represented by the interface between the fluidized layer and the liquid without suspension. Further it relates to an apparatus for performing this method containing an upward widening separator that is provided with the inlet of liquid with suspension in its bottom part, and a means for withdrawal of liquid without suspension in its upper part. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Four exemplifying embodiments of the invention will be described, where FIG. 1 shows the first example of embodiment of an apparatus according to the invention in side section, FIG. 2 shows the first example of embodiment of an apparatus according to the invention in axonometric representation, FIG. 3 is an integration of the first example of embodiment into an exemplary integrated reactor for activation treatment of waste water, FIG. 4 is a second exemplary embodiment of the apparatus in side section, FIG. 5 the second exemplary embodiment in axonometric representation, FIG. 6 a third exemplary embodiment of the apparatus in side section within an exemplary integrated biological reactor, FIG. 7 an axonometric representation of an exemplary embodiment according to FIG. 6 , FIG. 8 shows the fourth exemplary embodiment of the apparatus in side section and FIG. 9 the fourth exemplary embodiment in axonometric representation within an exemplary integrated biological reactor. detailed-description description="Detailed Description" end="lead"? |
Numerically controlled lath and method of machining work by this numerically controlled lath |
A numerically controlled machine tool that is capable of simultaneously effecting a variety of machining operations using work on a first main shaft and work on a second main shaft, with a high machining efficiency. A first tool post 300 is movable together with a second main shaft 210 in the direction of a main shaft axis C2 and in a direction X1 orthogonal thereto in a plane, while a second tool post 400 is movable at least in the same biaxial direction as the directions of movement of the first tool post 300. A control device superposes the uniaxial or biaxial movement required for the first tool post 300 to machine work W1 on the uniaxial or biaxial movement required for the second tool post 400 to machine work W2, and issues an instruction for movement to the first tool post 300 or second tool post 400, so that the machining operation of the work W1 by the tool on the first tool post 300 and the machining operation of the work W2 by the tool on the second tool post 400 are simultaneously effected. |
1. A numerically controlled lathe comprising: first and second main shafts which are disposed opposite to each other and which are movable with respect to each other; first and second tool posts to which a plurality of tools are attached so as to machine works held by the first and second main shafts; and a control device which controls movements of the first and second main shafts and the first and second tool posts, wherein the first tool post, integrally with the second main shaft, is movable in a main shaft axial direction of the second main shaft and in an axial direction crossing at right angles to the main shaft axial direction in a plane, and the second tool post is movable in a biaxial direction which is the same direction as that of the movement of at least the first tool post, the control device superposes the uniaxial or biaxial movement required for the first tool post to machine the work on the uniaxial or biaxial movement required for the second tool post to machine the work, and outputs an instruction for movement to the first or second tool post, and the machining operation of the work by the tool attached to the first tool post and that of the work by the tool attached to the second tool post are simultaneously effected. 2. The numerically controlled lathe according to claim 1, wherein the second tool post is movable in the biaxial direction including the main shaft axial direction of the first main shaft and the axial direction crossing at right angles to the main shaft axial direction in the plane, and is movable in the axial direction crossing at right angles to the biaxial direction. 3. The numerically controlled lathe according to claim 1, wherein the tools are linearly arranged and attached along the movement directions of the first and second tool posts, and the tool is indexed by the linear movement of the first and second tool posts in the uniaxial or biaxial direction. 4. The numerically controlled lathe according to claim 3, wherein an interval between the tools attached to the first or second tool post is determined based on an amount of the movement of the first or second tool post required for machining the work by one tool so as to minimize a distance between the tools such that the other tool disposed adjacent to this one tool does not interfere with the work or the first or second main shaft during the machining operation of the work by the one tool. 5. The numerically controlled lathe according to claim 1, wherein a time required for machining the work by one tool attached to the first tool post is compared with that required for machining the work by one tool attached to the second tool post, and the tool attached to the second tool post is changed to machine the work during the machining of the work by one tool attached to the first tool post, when the time required for machining the work by the one tool attached to the first tool post is longer. 6. The numerically controlled lathe according to claim 5, wherein the work held by the first main shaft is simultaneously machined with the tools attached to the first and second tool posts. 7. The numerically controlled lathe according to claim 1, wherein a time required for machining the work by one tool attached to the first tool post is compared with that required for machining the work by one tool attached to the second tool post, and the tool attached to the first tool post is changed to machine the work during the machining of the work by the one tool attached to the second tool post, when the time required for machining the work by the one tool attached to the second tool post is longer. 8. The numerically controlled lathe according to claim 1, wherein the machining of the work by the tool attached to the second tool post or that of the work by the tool attached to the first tool post is started behind a machining start timing of the work by the tool attached to the first tool post or that of the work by the tool attached to the second tool post. 9. The numerically controlled lathe according to claim 1, wherein the second tool post is disposed on a headstock which rotatably supports the first main shaft. 10. A method of machining a work using the numerically controlled lathe according to claim 1, comprising the steps of: superposing a uniaxial or biaxial movement required for the second tool post to machine the work held by the second main shaft on that required for the first tool post to machine the work held by the first main shaft to move the second tool post; and simultaneously effecting the machining of the work by the tool attached to the first tool post, and that of the work by the tool attached to the second tool post. 11. The method of machining the work according to claim 10, further comprising the steps of: changing the tool attached to the second tool post to machine the work during the machining operation performed on the work by one tool attached to the first tool post, when a time required for one tool attached to the first tool post to machine the work is longer than that required for one tool attached to the second tool post to machine the work. 12. The method of machining the work according to claim 11, further comprising the steps of: machining the work held by the first main shaft simultaneously with one tool attached to the first tool post and that attached to the second tool post. 13. The method of machining the work according to claim 10, further comprising the steps of: changing the tool attached to the first tool post to machine the work during the machining operation performed on the work by one tool attached to the second tool post, when the time required for one tool attached to the second tool post to machine the work is longer than that required for one tool attached to the first tool post to machine the work. 14. The method of machining the work according to claim 10, further comprising the steps of: starting the machining of the work by the tool attached to the second tool post or that of the work by the tool attached to the first tool post behind a machining start timing of the work by the tool attached to the first tool post or that of the work by the tool attached to the second tool post. 15. The method of machining the work according to claim 10, wherein the tool attached to the second tool post includes a tool for machining a hole inner peripheral surface or an outer peripheral surface of the work, and a cutting edge of the tool is directed in a direction crossing at right angles to a superposed movement direction of the second tool post with respect to the first tool post during the machining of the work. |
<SOH> BACKGROUND ART <EOH>A numerically controlled lathe (hereinafter referred to as the NC lathe) which includes two headstocks and tool posts disposed opposite to each other and which is capable of simultaneously machining two works attached to two main shafts with tools attached to the tool posts is known, for example, in Japanese Patent Publication No. 10-501758. FIG. 11 is a plan view showing a schematic constitution of the NC lathe disclosed in the Japanese Patent Publication No. 10-501758. A first headstock 520 and a second headstock 530 are disposed opposite to each other on a bed 510 of an NC lathe 5. The first headstock 520 and second headstock 530 rotatably support parallel main shafts 521 , 531 . These main shafts 521 , 531 are arranged so that axes of the main shafts 521 , 531 are eccentric. Chucks (not shown) are disposed on tip ends of the respective main shafts 521 , 531 , and works W 1 , W 2 are grasped by the chucks. The first headstock 520 is fixed to the bed 510 . In the bed 510 , guide rails 540 are disposed extending in a Z1-axis direction which is the same direction as that of the axis of the main shaft 531 . A carriage 550 is disposed on the guide rails 540 , and this carriage 550 is guided by the guide rails 540 by driving drive members such as a servo motor (not shown) to move forwards/backwards in a Z1-axis direction. Guide rails 570 are disposed in an X1-axis direction crossing at right angles to the Z1-axis on the carriage 550 . A carriage 555 is movably disposed in the X1-axis direction on the guide rails 570 , and a first tool post 560 and second headstock 530 are disposed on the carriage 555 . The second headstock 530 and the first tool post 560 are guided by the guide rails 540 , 570 by driving the driving members such as the servo motor (not shown), and are movable in the X1-axis and Z1-axis directions. The first tool post 560 includes a indexable/rotatable turret plane plate 561 on one side. Onto the turret plane plate 561 , a plurality of tools T 1 for machining work W 1 held by the main shaft 521 of the first headstock 520 are attached. Moreover, by a combination of movements of the carriages 550 , 555 in the Z1-axis and X1-axis directions, the tools T 1 are positioned with respect to the work W 1 to machine the work W 1 . A second tool post 580 is disposed opposite to the main shaft 531 of the second headstock 530 . An indexable/rotatable turret plane plate 581 is disposed on one side of the second tool post 580 . A plurality of tools T 2 for machining work W 2 attached to the main shaft 531 of the second headstock 530 are attached to the turret plane plate 581 . The second tool post 580 is movable along guide rails 582 disposed in parallel with the guide rails 570 in an X2-axis direction which is the same direction as that of the X1-axis. In this NC lathe 5, the first tool post 560 and the second headstock 530 are disposed on the common carriages 550 , 555 . Therefore, feed of the tools T 1 with respect to the work W 1 corresponds to that of the tools T 2 with respect to the work W 2 . Therefore, the same hole-making operation can simultaneously be effected with respect to two works W 1 , W 2 . Moreover, while the tools T 2 are moved in the X2-axis direction in synchronization with the movement of the tools T 1 in the X1-axis direction, the movement in the X2-axis direction required for machining the work W 2 by the tools T 2 is added. Accordingly, it is possible to simultaneously perform different machining operations with respect to the works W 1 , W 2 . The above-described NC lathe 5 is capable of simultaneously machining a plurality of works W 1 , W 2 in the same or different manners, and is therefore advantageously superior in a machining efficiency, but there are the following disadvantages. That is, since relative movement of the tools T 1 and T 2 with respect to the works W 1 , W 2 in the Z1-axis and Z2-axis directions is determined by the movement of the carriage 550 in the Z1-axis direction, there is a problem that machining modes of the simultaneously machinable works W 1 , W 2 are limited. Moreover, even when the machining of the work W 2 by either one tool, for example, the tool T 2 ends in a time shorter than that of the machining of the work W 1 by the tool T 1 , the second tool post 580 has to move following the movement of the first tool post 560 on standby until the machining of the work W 1 by the tools T 1 ends. This is because even when the tool T 2 is changed and the work W 2 is to be continuously machined with the next tool, the tool T 2 cannot be detached from the work W 2 , and the next tool cannot be indexed. Therefore, there is a problem that there is much waste of time such as standby and the machining efficiency is bad. Furthermore, for the NC lathe 5, the second tool post 580 can move only in an uniaxial direction of the X2-axis. Therefore, while the X1-axis is superposed on the X2-axis, machining operations such as a boring operation are carried out, and superposition error is caused. Then, there is a disadvantage that the superposition error appears as a machining quality as it is on the work. Therefore, when the superposition error is large, machining defect is easily generated, and a problem occurs that there is a possibility of a high defect ratio. An object of the present invention is to provide an NC lathe and a method of machining the work by this numerically controlled lathe in which a variety of machining operations can simultaneously be carried out with respect to the works on the first and second main shafts and in which waste of time such as a waiting time can be reduced as much as possible and in which the machining efficiency is high. Even when the superposition error is generated during the machining operations such as the boring operation, adverse influences by the superposition error can substantially be eliminated. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic plan view showing a constitution of an NC lathe of the present invention; FIG. 2 is a schematic front view of a first tool post seen from a I-I direction of FIG. 1 ; FIG. 3 is a schematic front view of a second tool post seen from a II-II direction of FIG. 1 ; FIG. 4 is a block diagram showing a constitution of a control device disposed in the NC lathe according to one embodiment of the present invention; FIG. 5 is a flowchart showing a procedure of superposition according to the control device of FIG. 4 ; FIG. 6 is a diagram showing a first embodiment of a method of machining a work by the NC lathe of the present invention; FIG. 7 is a diagram showing a second embodiment of the method of machining the work by the NC lathe of the present invention; FIG. 8 is a front view of a bore cutting tool seen from the II-II direction of FIG. 1 in a case where the bore cutting tool is attached to a rotary tool attaching section of the second tool post according to a third embodiment of the method of machining the work by the NC lathe of the present invention; FIG. 9 ( a ) is a partial enlarged view of FIG. 8 showing a function of the bore cutting tool attached as shown in FIG. 8 , and FIG. 9 ( b ) is a partial enlarged view of FIG. 8 for comparison with FIG. 9 ( a ); FIG. 10 is an explanatory view of a fourth embodiment of the method of machining the work by the NC lathe of the present invention; and FIG. 11 is a plan view showing a schematic constitution of the NC lathe according to a conventional example of the present invention. detailed-description description="Detailed Description" end="lead"? |
Regeneration of air dryer |
A method of initiating a regeneration event of an air braking system of a vehicle includes the steps of calculating the forward air volume in successive time intervals, tallying the total forward air volume and initiating a regeneration event at a saturation threshold of the dessicant material which may be varied in real time. The method also comprises calculating a reverse air volume, and ceasing a regeneration event at a dryness threshold of the dessicant material. |
1. A method of initiating a regeneration event for the air dryer of a vehicle air braking system, the method comprising the steps of: estimating in real time the instantaneous flow rate of air from an air compressor; modifying the instantaneous flow rate according to conditions of the air braking system; calculating the volume of air from the compressor for a predetermined time interval; repeating said estimating, modifying and calculating steps for successive time intervals to provide a current tally of forward air volume; periodically comparing the current tally with a saturation threshold; and initiating a regeneration event when said tally reaches or exceeds said saturation threshold. 2. The method of claim 1 wherein said calculating step is determined from a compressor performance characteristic and instantaneous compressor speed. 3. The method of claim 1 or claim 2 wherein said modifying step makes reference to one or more of ambient air temperature, compressor temperature, air density, reduction in compressor performance over time, and the ratio of compressor on-load to off-load running time. 4. The method claim 1 wherein said time interval is approximately 100 milliseconds. 5. The method of claim 1, and further including the initial step of setting said saturation threshold. 6. The method of claim 1, and further including the step of varying said saturation threshold in real time. 7. The method of claim 1 and further including a method of estimating the volume of backflow of dry air comprising the steps of: estimating in real time the instantaneous reverse flow rate of dry air to the air dryer; modifying the instantaneous reverse flow rate according to conditions to the aft braking system; calculating the volume of reverse air for a predetermined time interval; repeating said estimating, modifying and calculating steps for successive time intervals to provide a current tally of reverse air volume; periodically comparing said tally with a dryness threshold; and ceasing a regeneration event when said tally reaches or exceeds said dryness threshold. 8. The method of claim 7 wherein said reverse air volume is calculated from system pressure, air dryer pressure, and flow characteristic of the air orifice through which high pressure air is expanded. 9. The method of claim 7 or claim 8 wherein said modifying step comprises adjusting the reverse air flow rate according to ambient air temperature. 10. The method of claims 7 or 8 and including the initial step of setting the dryness threshold. 11. The method of claim 10 including the step of varying said dryness threshold in real time. 12. A method according to claim 1 and including the step of reducing said tally of forward air volume by an amount equal to the volume of the delivery line from the compressor to the air dryer. 13. A method according to claim 1, wherein the instantaneous tally of forward air volume is less than the actual volume of forward air by the volume of the delivery line from the compressor to the air dryer. |
Metering pump |
The invention relates to a metering pump comprising a pump barrel (1) housing a dose chamber (32) and control means that can be moved between a discharge position and a rest position. The inventive metering pump is characterised in that the control means comprise: a push rod (2); a piston (3) that can slide in relation to the push rod (2) and in relation to the pump barrel (1) all the while remaining in permanent contact with said two elements; and an elastically-deformable annular valve (4) that rests permanently against the push rod (2). The control means are moved between the rest position and the discharge position in two steps; the push rod (2) slides in relation to the piston (3) in the pump barrel; and subsequently the push rod (2) and the piston (3) slide jointly in the pump barrel (1) and discharge opening (42) is released. |
1. Metering pump designed to be mounted on various receptacles, in particular receptacles containing liquid to creamy cosmetic or pharmaceutical products, and comprising a pump body (1) made from a rigid or semi-rigid material which can be adapted to fit the receptacle R, bounded in its internal part by an annular side wall (100) and by a front-end face (101) incorporating a filling orifice (25) which communicates with the interior of the receptacle, and enclosing a metering chamber (32) as well as elastically deformable control means which can be operated from the outside so as to be displaced in succession between a dispensing position and a non-operating position to enable a dose of product to be ejected from the metering chamber (32) towards the exterior through an ejection orifice (11) and then transfer a new dose of product from the receptacle towards the metering chamber (32) and so on, the control means being automatically returned from the dispensing position to the non-operating position when not subjected to any external constraint with a view to creating a vacuum pressure to enable a dose of product to be sucked towards the metering chamber (32), said metering pump being characterised in that the control means are provided in the form of a push button (2) of a rigid or semi-rigid material, a plunger (3) made from a flexible thermoplastic material designed to slide relative to the push button (2) and relative to the pump body (1) whilst remaining in permanent contact with these two elements, as well as an annular valve (4) made from an elastically deformable material in the form of a cylindrical ring (18), one of the front-end faces of which is closed by an essentially circular, stretchable closing membrane (20) which is permanently supported against the push button (2), this membrane (20) projecting onto the periphery of the cylindrical ring (18) to define a flange (21) which moves into abutment with the side wall (100) of the pump body (1) so as to close off the filling orifice (25), the control means being displaced between the non-operating position and the dispensing position in two stages, namely a first stage on the one hand, during which the push button (2) slides inside the pump body relative to the plunger (3) and the metering chamber (32) is isolated from the ejection orifice (11), and a second stage on the other hand, during which the push button (2) and the plunger (3) slide as a unit inside the pump body (1) and a dispensing orifice (42) permitting communication with the metering chamber (32), thereby uncovering the ejection orifice (11). 2. Metering pump as claimed in claim 1, characterised in that the push button (2) has a support face (5) and a median rod (6) which is constantly supported against the annular valve (4) and is surrounded by an annular ejection passage (9), which is bounded by a tubular wall (10) and communicates with the ejection orifice (11). 3. Metering pump as claimed in claim 2, characterised in that the plunger (3) has a tubular end-piece (12) mounted around the median rod (6) of the push button (2) on a level with the free end (8) thereof, and its external periphery is extended by a peripheral fin (13) so as to define a surface which acts as a stop (14) for the free end (80) of the tubular wall (10) of the push button (2), this plunger (3) being in permanent contact with the push button (2) by means of a first sealing lip (15) constantly supported against the external face of the annular ejection passage (9) on the one hand, and with the pump body (1) by means of a second sealing lip (16) constantly supported against the annular side wall (100) thereof, on the other. 4. Metering pump as claimed in claim 3, characterised in that the annular valve (4) is disposed between the front-end face (101) of the pump body (1) and the free end (8) of the median rod (6) of the push button (2), against which it is constantly supported by the median part of the closing membrane (20) and co-operates with the side wall (100) of the pump body (1) and with a closing wall (33) of the plunger (3), which is contiguous with the second sealing lip (16) to define the metering chamber (32), the tubular end-piece (12) of the plunger (3) moving into abutment with the closing membrane (20) of the annular valve (4) in the non-operating position and during the first stage of the displacement between the non-operating position and the dispensing position so that it closes off the metering chamber (32), and moving back during the second stage of this displacement so as to uncover the dispensing orifice (42) and allow the product contained in the metering chamber (32) to pass between this end-piece (12) and the median rod (6) of the push button (2) so that it can be evacuated via the ejection passage (9) and through the ejection orifice (11) 5. Metering pump as claimed in claim 1 characterised in that the median rod (6) of the push button (2) is provided with at least one longitudinal groove (7) on a level with its free end (8) and is preferably provided with a series of longitudinal grooves (7) uniformly distributed around its periphery. 6. Metering pump as claimed in claim 1, characterised in that the front-end face (101) of the pump body (1) has receiving elements (23) for the annular valve (4). 7. Metering pump as claimed in claim 6, characterised in that the receiving elements (23) of the annular valve (4) are provided in the form of a tubular sleeve (24) surrounding the filling orifice (25) and having an outer face (26) of cylindrical shape on the one hand and a conical inner face (27) inclined towards the filling orifice (25) which is also provided with radial slots (28) in the form quoins, the inner conical face (27) acting as a seat for the closing membrane (20), whilst the outer cylindrical face (26) co-operates with the pump body (1) to define a mounting seat (29) for the cylindrical ring (28) of the annular valve (4). 8. Metering pump as claimed in claim 7, characterised in that the side wall (100) of the pump body (1) is provided with an obliquely inclined shoulder (30), which forms a seat for the flange (21) of the annular valve (4) and extends alongside the mounting seat (29) incorporating a series of slots (31, 34) defining passages to the metering chamber (32) for the product contained in the receptacle. |
Immune-related proteins and the regulation of the same |
Disclosed are novel nucleic acid and amino acid sequences of immune-related proteins. Reagents that bind to immune-related gene products can be used to treat conditions involving inflammatory processes, such as allergy, asthma, autoimmune diseases, and other chronic inflammatory diseases where an over-activation or prolongation of the activation of the immune system causes damage to tissues. |
1. An isolated polynucleotide selected from the group consisting of a) a polynucleotide encoding an Immune-related protein or a protein exhibiting biological properties of a human Immune-related protein and comprising the amino acid sequence of SEQ ID NOS: 5, 19, 21, 23, 26, 28, 30, 33, 38, 44, 51, 55, 71, 77, 79, 81, 83, 86, 90, 93, 95, 97, 99, 102, 104, or 107; b) a polynucleotide comprising the sequence of SEQ ID NOS:1-4, 6-18, 20, 22, 24, 25, 27, 29, 31, 32, 34, 35, 36, 37, 39-43, 45-50, 52, 53, 54, 56-70, 72-76, 78, 80, 82, 84, 85, 87, 88, 89, 91, 92, 94, 96, 98, 100, 101, 103, 105, 106, 108, 109, 110, or 111; c) a polynucleotide which hybridizes under stringent conditions to a polynucleotide specified in (a) and (b) and encodes an Immune-related protein or a protein exhibiting biological properties of a human Immune-related protein; d) a polynucleotide the nucleic acid sequence of which deviates from the nucleic acid sequences specified in (a) to (c) due to the degeneration of the genetic code and encodes an Immune-related protein or a protein exhibiting biological properties of a human Immune-related protein; and e) a polynucleotide, which represents a fragment, derivative or allelic variation of a nucleic acid sequence specified in (a) to (d) and encodes an Immune-related protein or a protein exhibiting biological properties of a human Immune-related protein. 2. An expression vector containing any polynucleotide sequence of claim 1. 3. A host cell containing the expression vector of claim 2. 4. A substantially purified protein exhibiting biological properties of human Immune-related protein, which is encoded by a polynucleotide of claim 1. 5. A method for producing an isolated protein exhibiting biological properties of human Immune-related protein, the method comprising the steps of: a) culturing the host cell of claim 4 under conditions suitable for the expression of the polypeptide; and b) recovering the polypeptide from the host cell culture. 6. A method for the detection of polynucleotides encoding a Immune-related protein or a protein exhibiting biological properties of a human Immune-related protein in a biological sample comprising the steps of: a) hybridizing any polynucleotide of claim 1 to nucleic acid material of a biological sample, thereby forming a hybridization complex; and b) detecting said hybridization complex. 7. The method of claim 6, wherein before hybridization, the nucleic acid material of the biological sample is amplified. 8. A method for the detection of a polynucleotide of claim 1 or a protein of claim 4 comprising the steps of: a) contacting a biological sample with a reagent which specifically interacts with the polynucleotide of claim 1 or the protein of claim 4 and b) detecting the interaction. 9. A diagnostic kit for conducting the method of one of the claims 6, 7 or 8. 10. A method of screening for agents which regulate the activity of human Immune-related protein, comprising the steps of: a) contacting a test compound with a polypeptide encoded by any of the polynucleotides of claim 1; b) detecting binding of the test compound to the polypeptide, wherein a test compound which binds to the polypeptide is identified as a potential therapeutic agent for regulating the activity of human Immune-related protein. 11. A method of screening for agents which regulate the activity of human Immune-related protein, comprising the steps of: a) contacting a test compound with a polypeptide encoded by any of the polynucleotides of claim 1; and b) detecting a Immune-related protein activity of the polypeptide, wherein a test compound which increases the Immune-related protein activity is identified as a potential therapeutic agent for increasing the activity of the human Immune-related protein, and wherein a test compound which decreases the Immune-related protein activity of the polypeptide is identified as a potential therapeutic agent for decreasing the activity of the human Immune-related protein. 12. A method of screening for agents which regulate the activity of human Immune-related protein, comprising the steps of: a) contacting a test compound with any polynucleotide of claim 1 and b) detecting binding of the test compound to any polynucleotide of claim 1, wherein a test compound which binds to the polynucleotide is identified as a potential therapeutic agent for regulating the activity of human Immune-related protein. 13. A method of modulating the activity of human Immune-related protein, comprising the step of: contacting a cell with a reagent which specifically binds to any polynucleotide of claim 1 or a protein of claim 4, whereby the activity of human Immune-related protein is reduced. 14. A purified reagent that modulates the activity of a human Immune-related protein polypeptide or polynucleotide, wherein said reagent is identified by the method of any of the claims 10, 11 or 12. 15. A pharmaceutical composition, comprising: a reagent which modulates the activity of a human Immune-related protein polypeptide or polynucleotide, wherein said reagent is identified by the method of claim 10, 11 or 12; and a pharmaceutically acceptable carrier. 16. A pharmaceutical composition, comprising: an expression vector of claim 3, and a pharmaceutically acceptable carrier. 17. Use of the expression vector of claim 2, or the reagent of claim 14 in the preparation of medicament for modulating the activity of immune-related proteins in a disease. 18. Use of claim 16, wherein the disease an allergic disease, an autoimmune disease, an inflammatory disease, or an infectious disease. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Signal Transducer and Activator of Transcription (Stat) is one of the families of transcription factors, which play a major role in cellular function by inducing the transcription of specific mRNAs. Transcription factors, in turn, are controlled distinct signaling molecules. There are seven known mammalian Stat family members. The recent discovery of Drosophila and Dictyostelium discoideum Stat proteins suggest that Stat proteins have played an important role in signal transduction since the early stages of our evolution [Yan R. et al., Cell 84:421-430 (1996); Kawata et al., Cell 89:909 (1997)]. Stat proteins mediate the action of a large group of signaling molecules including the cytokines and growth factors (Darnell et al. WO 95/08629, 1995). Stat6 is a component of the interleukin-4 (IL-4) signaling pathway that is activated by tyrosine phosphorylation upon the binding of IL-4 to the IL-4 receptor. Activation of Stat6 induces a variety of cellular functions including mitogenesis, T-helper cell differentiation, and immunoglobulin isotype switching. Mice in which the Stat6 gene has been disrupted show no proliferation of B cells in response to stimulation with IL-4 and anti-IgM antibody, no increase in expression of CD23 (FcεRII) and MHC class II molecules in B cells in response to IL-4, a reduction in T cell proliferative responses, and reduced production of Th2 cytokines and IgE and IgG1 after nematode infection. Although the IL-4 receptor is also known to employ at least one other signaling molecule in addition to Stat6, named 4PS, Stat6 appears to be essential for most of the known signaling functions downstream of the IL-4 receptor. Since IL-4 plays a major role in many immune disorders, such as allergy, atopy, and asthma, there is a need in the art to identify novel proteins which is activated by IL-4 and/or turned off upon stimulation by IL-4 to provide therapeutic effects, particularly for diseases and conditions involving immunologically-mediated responses. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides polynucleotides which have been identified as novel immune-related proteins. The polynucleotide of the present invention is selected from the group consisting of; a) a polynucleotide encoding a protein that comprises the amino acid sequence of any one of SEQ ID NOs: 5, 19, 21, 23, 26, 28, 30, 33, 38, 44, 51, 55, 71, 77, 79, 81, 83, 86, 90, 93, 95, 97, 99, 102, 104, and 107; b) a polynucleotide comprising the sequence of any one of SEQ ID NOs:1-4, 6-18, 20, 22, 24, 25, 27, 29, 31, 32, 34, 35, 36, 37, 39-43, 45-50, 52, 53, 54, 56-70, 72-76, 78, 80, 82, 84, 85, 87, 88, 89, 91, 92, 94, 96, 98, 100, 101, 103, 105, 106, 108, 109, 110, and 111; c) a polynucleotide which hybridizes under stringent conditions to a polynucleotide specified in (a) and (b); d) a polynucleotide the nucleic acid sequence of which deviates from the nucleic acid sequences specified in (a) to (c) due to the degeneration of the genetic code; and e) a polynucleotide, which represents a fragment, derivative or allelic variation of a nucleic acid sequence specified in (a) to (d). The present invention also provides an expression vector including the above-mentioned polynucleotide, host cell containing the expression vector, and protein encoded by the above-mentioned polynucleotide. Further, the present invention provides a method for producing a polypeptide. The method of the present invention includes: a) culturing the host cell under conditions suitable for the expression of the polypeptide; and b) recovering the polypeptide from the host cell culture. The present invention also provides a method for the detection of immune-related polynucleotides in a biological sample. The method comprises the steps of: a) hybridizing any polynucleotide of above-identified to nucleic acid material of a biological sample, thereby forming a hybridization complex; and b) detecting said hybridization complex. Another embodiment of the present invention provides a method for the detection of the above-mentioned polynucleotide or the above-mentioned protein. The method comprises a) contacting a biological sample with a reagent that specifically interacts with the above-mentioned polynucleotide or the above-mentioned protein, and detecting the interaction. Yet another embodiment of the present invention provides a diagnostic kit for conducting the above-mentioned method. Further embodiment of the present invention provides a method of screening for agents which regulate (decrease or increase) the activity of immune-related polypeptides of the present invention. The method comprises the steps of: contacting a test compound with a polypeptide encoded by any of the above-mentioned polynucleotides and detecting binding of the test compound to the polypeptide, wherein a test compound which binds to the polypeptide is identified as a potential therapeutic agent for regulating the activity of immune-related polypeptides. Yet another method of screening for agents which regulate the activity of immune-related polypeptides comprises the steps of: contacting a test compound with any of the above-mentioned polynucleotide and detecting binding of the test compound to any of the above-mentioned polynucleotide, wherein a test compound which binds to the polynucleotide is identified as a potential therapeutic agent for regulating the activity of immune-related polypeptides. Further, the present invention provides a method of modulating (reducing or increasing) the activity of immune-related polypeptides of the present invention. The method comprises the step of: contacting a cell with a reagent that specifically binds to any of the above-mentioned polynucleotide or the above-mentioned protein, whereby the activity of the immune-related polypeptide is modulated (reduced or increased). Another embodiment of the present invention provides a purified reagent that modulates the activity of the immune-related polypeptide or polynucleotide, wherein said reagent is identified by any of the above-mentioned method. Yet another embodiment of the present invention provides a pharmaceutical composition. The composition includes a reagent which modulates the activity of the immune-related polypeptide or polynucleotide; or the above mentioned expression vector; and a pharmaceutically acceptable carrier. Further embodiment of the present invention provides a use of the above-mentioned expression vector or the above-mentioned reagent in the preparation of medicament for modulating the activity of the immune-related protein in a diseases. Further embodiment of the present invention provides a method for treating immunologically mediated condition. The method comprises administering to a subject in need of such treatment an effective amount of the reagent or the pharmaceutical composition. |
Operation control device for leg-type mobile robot and operation control method, and robot device |
A legged mobile robot gives up a normal walking motion and starts a tumbling motion when an excessively high external force or external moment is applied thereto and a behavior plan of a foot part thereof is disabled. At this time, the variation amount ΔS/Δt of the area S of a support polygon of the body per time t is minimized and the support polygon when the body drops onto a floor is maximized to distribute an impact which acts upon the body from the floor when the body drops onto the floor to the whole body to suppress the damage to the body to the minimum. Further, the legged mobile robot autonomously restores a standing up posture from an on-floor posture thereof such as a supine posture or a prone posture. |
1. A motion controlling apparatus for a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, characterized in that said legged mobile robot has a plurality of postures or states, and that said motion controlling apparatus comprises: first means for calculating an area S of a support polygon formed from landed points of a body of said legged mobile robot and a floor; second means for calculating the variation ΔS/Δt of the area S of the support polygon per time Δt; and third means for determining a motion of said body when the posture or state is to be changed based on the area S of the support polygon or the variation rate ΔS/Δt of the area S. 2. A motion controlling apparatus for a legged mobile robot according to claim 1, characterized in that said third means includes: landed location searching means for searching for a landed location upon tumbling of said legged mobile robot based on the variation per time Δt of the area S of the support polygon formed from the landed points of said body and the floor; target landing point setting means for setting a target landing point at which the location selected by said landed location searching means should be landed so that the variation ΔS/Δt per time Δt of the area S of the support polygon formed from the landed points of said body and the floor may be minimized; and location landing means for landing the location selected by said landed portion searching means at the target landing point set by said target landing point setting means. 3. A motion controlling apparatus for a legged mobile robot according to claim 2, further comprising: support polygon expansion means for moving the landed portion so that the support polygon newly formed by landing of the location selected by said location landing means may be further expanded. 4. A motion controlling apparatus for a legged mobile robot according to claim 2, characterized in that the landing operation of the portion by said landed portion searching means and said target landing point setting means and/or the expansion operation of the support polygon by said support polygon expansion means are performed repetitively. 5. A motion controlling apparatus for a legged mobile robot according to claim 2, characterized in that said legged mobile robot is formed from a link structure wherein a plurality of substantially parallel joint axes having a joint degree-of-freedom are connected to each other in a lengthwise direction, and said target landing point setting means sets a location at which a link with which the number of non-landed links is maximized exists as a target. 6. A motion controlling apparatus for a legged mobile robot according to claim 1, characterized in that said legged mobile robot is formed from a link structure wherein a plurality of substantially parallel joint axes having a joint degree-of-freedom are connected to each other in a lengthwise direction, and said third means includes: means for searching, when said legged mobile robot returns from its tumbling state, for the narrowest support polygon formed from the least number of links from among landed polygons formed, in an on-floor posture of said legged mobile robot in which two or more links including a gravity center link positioned at the center of gravity of said body are landed on the floor, from the landed links; means for taking off the landed links in the landed polygons except those of the searched out support polygon; means for bending two or more continuous ones of non-landed links until end portions of the end links land onto the floor to form a narrower landed polygon; and means for taking off a number of links greater than a first predetermined number from one end side of said link structure to stand said body uprightly in response to that the support polygon is sufficiently narrow. 7. A motion controlling apparatus for a legged mobile robot according to claim 6, characterized in that said means for searching for the support polygon extracts a landed link which can be taken off from the floor while a zero moment point remains plannable. 8. A motion controlling apparatus for a legged mobile robot according to claim 6, characterized in that said means for searching for the support polygon searches for a narrower support polygon while keeping the gravity center link in the landed state. 9. A motion controlling apparatus for a legged mobile robot according to claim 6, characterized in that said means for standing said body uprightly determines whether or not the gravity center link can be taken off in a state wherein the end portions of the opposite end links of the landed polygon are landed thereby to determine whether or not the support polygon is sufficiently narrow. 10. A motion controlling apparatus for a legged mobile robot according to claim 6, characterized in that said means for standing said body uprightly includes: means for taking off the gravity center link from the floor in a state wherein the end portions of the opposite end links of the support polygon are landed; means for reducing the distance between the end portions of the opposite end links of the support polygon in a state wherein the gravity center link is taken off to move a zero moment point to the other end side of said link structure; and means for taking off, in response to that the zero moment point enters a landed polygon formed only from a number of landed links smaller than a second predetermined number from the other end of said link structure, a number of links greater than a first predetermined number from the one end side of said link structure while the zero moment point is kept accommodated in the landed polygon to expand the non-landed links in the lengthwise direction. 11. A motion controlling apparatus for a legged mobile robot according to claim 10, characterized in that said means for expanding the non-landed links in the lengthwise direction operates positively using a joint degree-of-freedom having a comparatively great mass operation amount. 12. A motion controlling apparatus for a legged mobile robot according to claim 6, characterized in that said link structure includes at least shoulder joint pitch axes, a trunk pitch axis, hip joint pitch axes and knee pitch axes connected to each other in the heightwise direction of said body. 13. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for searching for the support polygon extracts two or more continuous links extending from one end side of said link structure which includes at least the shoulder joint pitch axes as links which can be taken off from the floor while the zero moment point remains plannable. 14. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for searching for the support polygon searches for a narrower support polygon while a link which interconnects said trunk pitch axis and said hip joint pitch axes is kept as the gravity center link in the landed state. 15. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for forming a narrower landed polygon bends the non-landed links around said shoulder joint pitch axes to land the hands which are an end portion of one of the end links onto the floor. 16. A motion controlling apparatus for a legged mobile robot according to claim 15, characterized in that, where the length of the upper arms is represented by l1, the length of the forehands by l2, the shoulder roll angle by α, the elbow pitch angle by β, the length from the shoulders to the hands by l12, the angle defined by a line interconnecting each of the shoulders and a corresponding one of the hands by γ, and the height of the shoulders by h, each of the arm parts operates so as to satisfy the following expressions: l12=l1 cos α+l2 sin (α+β−90) l12 sin γ<h 17. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for searching for the support polygon extracts two or more continuous links extending from the other end side of said link structure and including at least said knee joint pitch axes as the links which can be taken off from the floor while the zero moment point remains plannable. 18. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for forming a narrower landed polygon bends the non-landed links around said knee joint pitch axes to land the soles which are end portions of the end links of said link structure. 19. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for standing said body uprightly determines whether or not the gravity center link which interconnects said trunk pitch axis and said hip joint pitch axes can be taken off from the floor in a state wherein the hands and the soles as the end portions of the opposite end links of the landed polygon to determine whether or not the support polygon is sufficiently narrow. 20. A motion controlling apparatus for a legged mobile robot according to claim 12, characterized in that said means for standing said body uprightly includes: means for taking off the gravity center link which interconnects said trunk pitch and said hip joint pitch axes from the floor in a state wherein the hands and the soles as the end portions of the opposite end links of the landed polygon are landed; means for contracting the distance between the hands and the soles as the end portions of the opposite end links of the landed polygon in a state wherein the gravity center link is taken off from the floor to move the zero moment point to the soles; and means for taking off, in response to that the zero moment point enters the landed polygon formed from the soles, the links from said shoulder pitch axes to said knee pitch axes while the zero moment point is kept accommodated in the landed polygon to expand the non-landed links in the lengthwise direction to stand said body uprightly. 21. A motion controlling apparatus for a legged mobile robot according to claim 20, characterized in that said means for expanding the non-landed links in the lengthwise direction operates positively using said knee joint pitch axes having a comparatively great mass operation amount. 22. A motion controlling apparatus for a legged mobile robot according to claim 6, characterized in that said means for producing a narrower landed polygon selectively utilizes one of a step changing motion and a dragging motion on the floor of the hand parts or the foot parts in response to whether it is possible to take off two or more of the links which do not relate to the smallest support polygon from the floor to form a narrower landed polygon. 23. A motion controlling method for a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, characterized in that said legged mobile robot has a plurality of postures or states, and that said motion controlling method comprises: a first step of calculating an area S of a support polygon formed from landed points of a body of said legged mobile robot and a floor; a second step of calculating the variation ΔS/Δt of the area S of the support polygon per time Δt; and a third step of determining a motion of said body when the posture or state is to be changed based on the area S of the support polygon or the variation rate ΔS/Δt of the area S. 24. A motion controlling method for a legged mobile robot according to claim 23, characterized in that said third step includes: a landed location searching step for searching for a landed location upon tumbling of said legged mobile robot based on the variation per time Δt of the area S of the support polygon formed from the landed points of said body and the floor; a target landing point setting step of setting a target landing point at which the location selected at the landed location searching step should be landed so that the variation ΔS/Δt per time Δt of the area S of the support polygon formed from the landed points of said body and the floor may be minimized; and a location landing step of landing the location selected at the landed portion searching step at the target landing point set at the target landing point setting step. 25. A motion controlling method for a legged mobile robot according to claim 24, further comprising: a support polygon expansion step for moving the landed portion so that the support polygon newly formed by landing of the location selected at the location landing step may be further expanded. 26. A motion controlling method for a legged mobile robot according to claim 24, characterized in that the landing operation of the portion at the landed portion searching step and the target landing point setting step and/or the expansion operation of the support polygon at the support polygon expansion step are performed repetitively. 27. A motion controlling method for a legged mobile robot according to claim 24, characterized in that said legged mobile robot is formed from a link structure wherein a plurality of substantially parallel joint axes having a joint degree-of-freedom are connected to each other in a lengthwise direction, and the target landing point setting step sets a location at which a link with which the number of non-landed links is maximized exists as a target. 28. A motion controlling method for a legged mobile robot according to claim 23, characterized in that said legged mobile robot is formed from a link structure wherein a plurality of substantially parallel joint axes having a joint degree-of-freedom are connected to each other in a lengthwise direction, and the third step includes the steps of: searching, when said legged mobile robot returns from its tumbling state, for the narrowest support polygon formed from the least number of links from among landed polygons formed, in an on-floor posture of said legged mobile robot in which two or more links including a gravity center link positioned at the center of gravity of said body are landed on the floor, from the landed links; taking off the landed links in the landed polygons except those of the searched out support polygon; bending two or more continuous ones of non-landed links until end portions of the end links land onto the floor to form a narrower landed polygon; and taking off a number of links greater than a first predetermined number from one end side of said link structure to stand said body uprightly in response to that the support polygon is sufficiently narrow. 29. A motion controlling method for a legged mobile robot according to claim 28, characterized in that, at the step of searching for the support polygon, a landed link which can be taken off from the floor while a zero moment point remains plannable is extracted. 30. A motion controlling method for a legged mobile robot according to claim 28, characterized in that, at the step of searching for the support polygon, a narrower support polygon is searched for while keeping the gravity center link in the landed state. 31. A motion controlling method for a legged mobile robot according to claim 28, characterized in that it is determined at the step of standing said body uprightly whether or not the gravity center link can be taken off from the floor in a state wherein the end portions of the opposite end links of the landed polygon are landed thereby to determine whether or not the support polygon is sufficiently narrow. 32. A motion controlling method for a legged mobile robot according to claim 28, characterized in that, at the step of standing said body uprightly, the gravity center link is taken off from the floor in a state wherein the end portions of the opposite end links of the support polygon are landed, and the distance between the end portions of the opposite end links of the support polygon is reduced to move a zero moment point to the other end side of said link structure, and, in response to that the zero moment point enters a landed polygon formed only from a number of landed links smaller than a second predetermined number from the other end of said link structure, a number of links greater than a first predetermined number from the one end side of said link structure are taken off from the floor while the zero moment point is kept accommodated in the landed polygon to expand the non-landed links in the lengthwise direction. 33. A motion controlling method for a legged mobile robot according to claim 32, characterized in that, at the step of expanding the non-landed links in the lengthwise direction, a joint degree-of-freedom having a comparatively great mass operation amount is positively used for the operation. 34. A motion controlling method for a legged mobile robot according to claim 28, characterized in that said link structure includes at least shoulder joint pitch axes, a trunk pitch axis, hip joint pitch axes and knee pitch axes connected to each other in the heightwise direction of said body. 35. A motion controlling method for a legged mobile robot according to claim 34, characterized in that, at the step of searching for the support polygon, two or more continuous links extending from one end side of said link structure which includes at least the shoulder joint pitch axes are extracted as links which can be taken off from the floor while the zero moment point remains plannable. 36. A motion controlling method for a legged mobile robot according to claim 34, characterized in that, at the step of searching for the support polygon, a narrower support polygon is searched for while a link which interconnects said trunk pitch axis and said hip joint pitch axes is kept as the gravity center link in the landed state. 37. A motion controlling method for a legged mobile robot according to claim 34, characterized in that, at the step of forming a narrower landed polygon, the non-landed links are bent around said shoulder joint pitch axes to land the hands which are an end portion of one of the end links onto the floor. 38. A motion controlling method for a legged mobile robot according to claim 37, characterized in that, where the length of the upper arms is represented by l1, the length of the forehands by l2, the shoulder roll angle by α, the elbow pitch angle by β, the length from the shoulders to the hands by l12, the angle defined by a line interconnecting each of the shoulders and a corresponding one of the hands by γ, and the height of the shoulders by h, each of the arm parts operates so as to satisfy the following expressions: l12=l1 Cos α+l2 sin (α+β−90) l12 sin γ<h 39. A motion controlling method for a legged mobile robot according to claim 34, characterized in that, at the step of searching for the support polygon, two or more continuous links extending from the other end side of said link structure and including at least said knee joint pitch axes are extracted as the links which can be taken off from the floor while the zero moment point remains plannable. 40. A motion controlling method for a legged mobile robot according to claim 34, characterized in that, at the step of forming a narrower landed polygon, the non-landed links are bent around said knee joint pitch axes to land the soles which are end portions of the end links of said link structure. 41. A motion controlling method for a legged mobile robot according to claim 34, characterized in that it is determined at the step of standing said body uprightly whether or not the gravity center link which interconnects said trunk pitch axis and said hip joint pitch axes can be taken off from the floor in a state wherein the hands and the soles as the end portions of the opposite end links of the landed polygon to determine whether or not the support polygon is sufficiently narrow. 42. A motion controlling method for a legged mobile robot according to claim 34, characterized in that, at the step of standing said body uprightly, the gravity center link which interconnects said trunk pitch and said hip joint pitch axes is taken off from the floor in a state wherein the hands and the soles as the end portions of the opposite end links of the landed polygon are landed and the distance between the hands and the soles as the end portions of the opposite end links of the landed polygon is reduced in a state wherein the gravity center link is taken off from the floor to move the zero moment point to the soles, and, in response to that the zero moment point enters the landed polygon formed from the soles, the links are taken off from said shoulder pitch axes to said knee pitch axes while the zero moment point is kept accommodated in the landed polygon to expand the non-landed links in the lengthwise direction to stand said body uprightly. 43. A motion controlling method for a legged mobile robot according to claim 42, characterized in that, at the step of expanding the non-landed links in the lengthwise direction, said knee joint pitch axes having a comparatively great mass operation amount are used positively for the operation. 44. A motion controlling method for a legged mobile robot according to claim 28, characterized in that, at the step of producing a narrower landed polygon, one of a step changing motion and a dragging motion on the floor of the hand parts or the foot parts is selectively utilized in response to whether it is possible to take off two or more of the links which do not relate to the smallest support polygon from the floor to form a narrower landed polygon. 45. A legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, comprising: external force detection means for detecting application of an external force to a body of said legged mobile robot; zero moment point trajectory planning means for disposing a zero moment point at which moments applied to said body balance each other on or on the inner side of a side of a support polygon formed from a sole landed point and a floor based on a result of the detection by said external force detection means; and tumbling motion execution means for executing a tumbling motion of said body in response to that the disposition of the zero moment point in the support polygon by said zero moment point trajectory planning means is rendered difficult or impossible by the external force applied to said body. 46. A legged mobile robot according to claim 45, characterized in that said external force detection means detects the external force applied to said body using a floor reactive force sensor or an acceleration sensor disposed on each of the soles or an acceleration sensor disposed at a position of the waist of the body. 47. A motion controlling method for a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, comprising: an external force detection step of detecting application of an external force to a body of said legged mobile robot; a zero moment point trajectory planning step of disposing a zero moment point at which moments applied to said body balance each other on or on the inner side of a side of a support polygon formed from a sole landed point and a floor based on a result of the detection at the external force detection step; and a tumbling motion execution step of executing a tumbling motion of said body in response to that the disposition of the zero moment point in the support polygon by said zero moment point trajectory planning means is rendered difficult or impossible by the external force applied to said body. 48. A motion controlling method for a legged mobile robot according to claim 47, characterized in that, at the external force detection step, the external force applied to said body is detected using a floor reactive force sensor or an acceleration sensor disposed on each of the soles or an acceleration sensor disposed at a position of the waist of the body. 49. A motion controlling apparatus for a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, comprising: means for calculating an impact moment applied to a body of said legged mobile robot at each stage upon tumbling of said body; means for calculating an impact force applied to said body from the floor at each stage upon tumbling; means for calculating an area S of a support polygon formed from a landed point of said body and the floor; first landed location searching means for selecting a next landed location so that the area S of the support polygon may be minimized or fixed; and second landed location searching means for selecting a next landed location so that the area S of the support polygon may be increased. 50. A motion controlling apparatus for a legged mobile robot according to claim 49, characterized in that a tumbling motion of said body is performed by said second landed location searching means if the impact force applied to said body from the floor is within a predetermined tolerance, but a tumbling motion of said body is performed by said first landed location searching means if the impact force is outside the predetermined tolerance. 51. A motion controlling method for a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, comprising: a step of calculating an impact moment applied to a body of said legged mobile robot at each stage upon tumbling of said body; a step of calculating an impact force applied to said body from the floor at each stage upon tumbling; a step of calculating an area S of a support polygon formed from a landed point of said body and the floor; a first landed location searching step of selecting a next landed location so that the area S of the support polygon may be minimized or fixed; and a second landed location searching step of selecting a next landed location so that the area S of the support polygon may be increased. 52. A motion controlling method for a legged mobile robot according to claim 51, characterized in that a tumbling motion of said body is performed by the second landed location searching step if the impact force applied to said body from the floor is within a predetermined tolerance, but a tumbling motion of said body is performed by the first landed location searching step if the impact force is outside the predetermined tolerance. 53. A motion controlling apparatus for controlling a series of motions relating to tumbling and standing up of a body of a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, characterized in that said legged mobile robot is formed from a link structure wherein a plurality of substantially parallel joint axes having a joint degree-of-freedom are connected to each other in a lengthwise direction, and said motion controlling apparatus comprises: means for searching for the narrowest support polygon formed from a minimum number of links from among landed polygons formed from landed links in an on-floor posture wherein two or more links including a gravity center link at which the center of gravity of said body is positioned are landed on a floor upon tumbling of said legged mobile robot; means for setting a zero moment point at a location at which the number of links which do not relate to the smallest support polygon is maximized to perform a tumbling motion; means for searching for a link or links which can be taken off from the floor in the tumbling posture of said body; and means for taking off all of the links which can be taken off from the floor to perform a standing up motion. 54. A motion controlling method for controlling a series of motions relating to tumbling and standing up of a body of a legged mobile robot which includes movable legs and performs a legged operation in a standing posture thereof, characterized in that said legged mobile robot is formed from a link structure wherein a plurality of substantially parallel joint axes having a joint degree-of-freedom are connected to each other in a lengthwise direction, and said motion controlling method comprises the steps of: searching for the narrowest support polygon formed from a minimum number of links from among landed polygons formed from landed links in an on-floor posture wherein two or more links including a gravity center link at which the center of gravity of said body is positioned are landed on a floor upon tumbling of said legged mobile robot; setting a zero moment point at a location at which the number of links which do not relate to the smallest support polygon is maximized to perform a tumbling motion; searching for a link or links which can be taken off from the floor in the tumbling posture of said body; and taking off all of the links which can be taken off from the floor to perform a standing up motion. 55. A robot apparatus having a trunk part, leg parts connected to said trunk part and arm parts connected to said trunk part, comprising: support polygon detection means for detecting a first support polygon formed from a plurality of end portions of said leg parts, trunk part and/or arm parts at which said leg parts, trunk part and/or arm parts are landed on a floor; support polygon changing means for bending said leg parts toward said trunk part to reduce the area of the first support polygon; zero moment point motion controlling means for determining whether or not a zero moment point which is positioned in the changed first support polygon can be moved into a landed polygon formed from the soles of said leg parts; and control means for moving, when said zero moment point motion controlling means determines that the zero moment point can be moved, the zero moment point from within the first support polygon into the landed polygon formed by the soles and changing the posture of said robot apparatus from a tumbling posture to a basic posture while the zero moment point is maintained within the landed polygon. 56. A robot apparatus which includes at least a body, one or more arm links connected to an upper portion of said body each through a first joint (shoulder), a first leg link connected to a lower portion of said body through a second joint (hip joint), and a second leg link connected to an end of said second leg link through a third joint (knee), comprising: means for landing ends of said arm links and a foot part at an end of said second leg link to form a first support polygon; means for moving said second joint upwardly higher than said third joint in a normal direction to the floor while the ends of said arm links and said foot part are kept landed, decreasing the area of the first support polygon and moving a zero moment point into a landed polygon formed from said foot part; and means for standing a body of said robot apparatus uprightly while the zero moment point is kept in the landed polygon formed from said foot part. |
<SOH> BACKGROUND ART <EOH>A mechanical apparatus which performs movements similar to motions of a human being using mechanical or magnetic actions is called “robot”. It is said that the word “robot” originates from a word ‘ROBOTA’ (slave machine) of a Slavic language. Here in Japan, robots began to be popularized at the end of the nineteen sixties. Most of them, however, were industrial robots such as manipulators or transport robots intended for automation and unmanning of manufacturing works in a factory. Recently, research and development regarding legged mobile robots such as pet type robots which copy body mechanisms and motions of animals that perform four-leg walking like a dog or a cat, or robots (humanoid robot) called “human-type” or “humanoid” robots which are designed by modeling body mechanisms and motions of animals which perform bipedal upright walking such as a human being have proceeded, and also expectation that they be placed into practical use is increasing. The significance in research and development of legged mobile robots of bipedal locomotion type called human-like or humanoid robots can be grasped, for example, from the following two points of view. One of them is a human scientific point of view. In particular, a mechanism of a natural motion of a human being beginning with walking can be clarified in an engineering sense through a process that a robot having a structure similar to the lower limbs and/or the upper limbs of a human being is produced and a controlling method for the robot is devised to simulate a walking motion of a human being. It is expected that results of such research can be fed back significantly to the progress in various other research fields which handle a movement mechanism of a human being such as the human engineering, rehabilitation engineering or sports engineering. Another point is development of a robot for practical use which supports the life of a human being as a partner of the human being, that is, which supports human activities in dwelling environments and other various scenes in everyday life. It is necessary for a robot of the type just described to learn a method of adaptation to human beings having individually different identities and to environments while being taught by human beings in various phases of life environments of human beings. It is considered that, in this instance, if the robot is a “human type” robot, that is, if the robot has a same configuration or a same structure as that of the human being, then the robot functions effectively in smooth communication between a human being and the robot. For example, in such a case that it is tried to actually teach to a robot a method of passing through a room while bypassing an obstacle which must be kept off, where the robot which is an object of teaching is a bipedal locomotion robot having a similar configuration to that of a user (operator), it is much easier for the user to teach the robot and also it is easier for the robot to learn than where the robot has a structure quite different from the user such as a crawler type robot or a four-legged robot (refer to, for example, TAKANISHI, “Control of a Bipedal locomotion Robot”, the Kanto Branch of the Society of Automotive Engineers of Japan <Koso>, No. 25, April, 1996). A great number of proposals have been made for a technique for posture control or stable walking relating to a robot of the type which performs legged movement by bipedal locomotion. The stable “walking” here can be defined as “traveling without tumbling through use of the legs”. Posture stabilization control of a robot is very important in order to prevent tumbling of a robot. This is because tumbling of a robot signifies interruption of a work being performed and considerable labor and time are required until the robot stands up uprightly from the tumbling state and resumes the work. Above all, there is the possibility that the tumbling may critically damage the robot body itself or also damage a substance with which the tumbling robot collides. Accordingly, in research and development of legged mobile robots, posture stabilization control upon walking or upon any other legged operation is considered one of the most significant technical subjects. Upon walking of a robot, the gravity and the force of inertia and moments of them originating from the gravity and an acceleration generated by the walking movement act from the walking system of the robot upon the road surface. According to the “d'Alembert's principle”, they are balanced with a floor reactive force and a floor reactive force moment as a reaction from the road surface to the walking system. As a consequence of mechanical inference, a point at which the pitch axis moment and the roll axis moment are zero, that is, a “ZMP (Zero Moment Point)”, is present on or on the inner side of a side of a support polygon formed by landed points (contact points) of the soles and the road surface. Most of proposals regarding posture stabilization control of legged mobile robots and prevention of tumbling upon walking uses the ZMP as a criterion for determination of the stability of walking. Production of a bipedal locomotion pattern based on the ZMP criterion is advantageous in that a sole landing point can be set in advance and it is easy to take a kinetic restriction condition of the sole according to a shape of the road surface into consideration. Further, to adopt the ZMP as a stability determination criterion does not signify to handle not a force but a trajectory as a target value on motion control, and therefore, it technically raises the feasibility. It is to be noted that a concept of the ZMP and application of the ZMP to a stability determination criterion for a walking robot are disclosed in Miomir Vukobratovi'c, “LEGGED LOCOMOTION ROBOTS” (Ichiro KATO et al., “Walking Robot and Artificial Feet”, the Nikkan Kogyo Shimbun, Ltd.). Normally, a bipedal locomotion robot such as a humanoid robot is higher in the position of the center of gravity and narrower in the ZMP stable region upon walking than a four-legged walking robot. Accordingly, the problem of a posture variation caused by a variation of the road surface condition is significant particularly with a bipedal locomotion robot. Several proposals are already available which use the ZMP as a posture stability determination criterion for a bipedal locomotion robot. For example, a legged mobile robot disclosed in Japanese Patent Laid-Open No. Hei 5-305579 performs stable walking by making a point on a floor at which a ZMP is zero coincide with a target value. Meanwhile, another legged mobile robot disclosed in Japanese Patent Laid-Open No. Hei 5-305581 is configured such that a ZMP is positioned in the inside of a supporting polyhedron (polygon) or, upon landing or upon taking off, the ZMP is positioned at a position having at least a predetermined margin from an end portion of the support polygon. In this instance, even if the legged mobile robot is subject to some disturbance, it has a margin for the ZMP by the predetermined distance, and the stability of the body upon walking is improved. Further, Japanese Patent Laid-Open No. Hei 5-305583 discloses that the walking speed of a legged mobile robot is controlled depending upon a ZMP target position. In particular, walking pattern data set in advance is used, and a leg part joint is driven so that a ZMP may coincide with a target position whereas a slope of the upper part of the body is detected and the discharging rate of the set walking pattern data is changed in response to the detection value. If the robot steps on an unknown concave or convex place and tilts forwardly, then the posture thereof can be restored by raising the discharging rate. Further, since the ZMP is controlled to the target position, there is no trouble even if the discharging rate is changed within a double support phase. Japanese Patent Laid-Open No. Hei 5-305585 discloses that the landing position of a legged mobile robot is controlled in accordance with a ZMP target position. In particular, the legged mobile robot disclosed in the patent document mentioned detects a displacement between a ZMP target position and an actually measured position and drives one or both of the leg parts so that the displacement may be canceled. Or, the legged mobile robot detects a moment around a ZMP target position and drives the leg parts so that the moment may be reduced zero. The legged mobile robot thereby achieves stabilized walking. Japanese Patent Laid-Open No. Hei 5-305586 discloses that a tilting posture of a legged mobile robot is controlled in accordance with a ZMP target position. In particular, a moment around a ZMP target position is detected, and if a moment appears, then the leg parts are driven so that the moment may be reduced to zero thereby to achieve stabilized walking. Posture stabilization control of a robot which adopts a ZMP as a stability determination criterion basically resides in search for a point at which a moment is zero on or on the inner side of a side of a support polygon formed from landed points of the soles and the road surface. As described hereinabove, for a legged mobile robot, possible much effort has been made to prevent the robot from tumbling during walking or during execution of some other motion pattern by taking such a countermeasure as to introduce a ZMP as a posture stabilization criterion. Naturally, the state of tumbling of a robot signifies interruption of a work being performed by the robot and considerable labor and time are required until the robot stands up uprightly from the tumbling state and resumes the work. Further, there is the possibility that, above all, the tumbling may critically damage the robot body itself or also damage a substance with which the tumbling robot collides. Although the possible best posture stabilization control is performed in order to prevent tumbling of a robot, the robot may still lose its stability in posture because of some defect in control, some unpredictable external factor (such as, for example, accidental collision with another substance, a road surface situation such as a projection or a depression on the floor, appearance of an obstacle or the like) to such a degree that it cannot be supported only with the movable legs thereof, resulting in tumbling. Particularly in the case of a robot which performs bipedal legged traveling such as a human-type robot, since the position of the center of gravity is high and an uprightly standing stationary state itself of the robot is originally instable, the robot is likely to tumble. If the robot tumbles, then there is the possibility that critical damage may be applied to the robot itself or to the other party side with which the robot collides by the tumbling. For example, Japanese Patent Laid-Open No. Hei 11-48170 discloses a control apparatus for a legged mobile robot by which, when the legged mobile robot is in a situation wherein it seems to tumble, the damage which may be given to the robot by the tumbling or the damage to the other party side with which the robot may collide upon the tumbling can be reduced as far as possible. However, the patent document merely proposes control by which the center of gravity of the robot when landing upon tumbling is merely lowered, but does not make such an argument that, in order to minimize the possible damage when the robot actually tumbles, in what manner the entire body including not only the leg parts but also the body and the arm parts should operate. In the case of a legged mobile robot of the uprightly standing walking type, a posture which makes a reference when a movement of a body such as walking is taken into consideration is a standing posture in which the robot stands uprightly with the two feet. For example, a state in which the robot is most stable among various standing postures (that is, a point at which the instability is in the minimum) can be positioned as a basic standing posture. Such a basic standing posture as just described requires generation of torque by joint axis motors for the leg parts and so forth by execution of posture stabilization control and control instruction. In other words, in a no-power supply condition, no standing posture is stable. Therefore, it is considered preferable that the robot starts activation thereof from an on-floor posture in which the robot is physically most stable such as a supine posture or a prone posture. However, even if power supply to the robot in such an on-floor posture as just described is made available, if the robot cannot stand up autonomously, then an operator must give a hand to lift the body, which is cumbersome to the operator. Further, when the robot once assumes a standing posture and performs walking or some other autonomous legged operation, it basically makes an effect to travel using the legs without tumbling. However, the robot may sometimes tumble unfortunately. “Tumbling” is inevitable when a robot operates under dwelling environments of human beings which involve various obstacles and unforeseeable situations. In the first place, a human being also tumbles. Also in this instance, it still is cumbersome if an operator must give a hand to lift the body. If the robot cannot stand up by itself every time it assumes an on-floor posture, then it cannot be operated in unmanned environments after all, and the operation lacks in self-conclusion. Thus, the robot cannot be placed into fully self-contained environments. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a schematic view showing a legged mobile robot to which the present invention is applied when it is in an uprightly standing state as viewed from obliquely forward; FIG. 2 is a perspective view showing the legged mobile robot to which the present invention is applied when it is in an uprightly standing state as viewed from obliquely backward; FIG. 3 is a schematic view showing a joint degree-of-freedom configuration of the legged mobile robot; FIG. 4 is a diagrammatic view schematically showing a basic control system configuration of the legged mobile robot 100 ; FIG. 5 is a diagrammatic view illustrating basic state transitions of a movement system of the legged mobile robot 100 has; FIG. 6 is a view showing a basic supine posture of the legged mobile robot 100 ; FIG. 7 is a view showing a basic prone posture of the legged mobile robot 100 ; FIG. 8 is a view showing a basic standing posture of the legged mobile robot 100 ; FIG. 9 is a view showing a basic walking posture of the legged mobile robot 100 ; FIG. 10 is a schematic diagrammatic view showing a multiple mass point approximation model of the legged mobile robot 100 ; FIG. 11 is an enlarged view showing a portion around a waist portion of the multiple mass point approximation model; FIG. 12 is a flow chart illustrating a processing procedure for producing a body movement with which the legged mobile robot 100 can walk stably; FIG. 13 is a flow chart illustrating a general processing procedure for motion control of the body when the legged mobile robot 100 performs a legged operation; FIG. 14 is a schematic view illustrating a principle of maintaining a supporting area when the body tumbles; FIG. 15 is a diagrammatic view illustrating a principle that a support polygon becomes maximum when the body drops onto the floor; FIG. 16 is a view illustrating a motion of maintaining the supporting area upon tumbling when the legged mobile robot 100 tumbles rearwardly to be a supine posture; FIG. 17 is a view illustrating the motion of maintaining the supporting area upon tumbling when the legged mobile robot 100 tumbles rearwardly to be a supine posture; FIG. 18 is a view illustrating a motion of maintaining the supporting area upon tumbling when the legged mobile robot 100 tumbles forwardly to be a prone posture; FIG. 19 is a view illustrating the motion of maintaining the supporting area upon tumbling when the legged mobile robot 100 tumbles forwardly to be a prone posture; FIG. 20 is a flow chart illustrating a processing procedure of the legged mobile robot 100 according to the present embodiment for performing a tumbling motion because the foot parts are unplannable; FIG. 21 is a view illustrating motions of the legged mobile robot 100 when, where it is modeled as a link structure including a plurality of substantially parallel axes connected in a vertical direction such as a shoulder joint pitch axis 4 , a trunk pitch axis 9 , a hip joint pitch axis 12 and a knee joint pitch axis 14 , it tumbles to be a supine posture with the joint pitch axes driven synchronously and cooperatively; FIGS. 22 to 38 are side elevational views illustrating a manner wherein the legged mobile robot 100 tumbles from its standing posture into a supine posture; FIGS. 39 to 55 are perspective views illustrating the manner wherein the legged mobile robot 100 tumbles from its standing posture into a supine posture; FIG. 56 is a view illustrating motions of the legged mobile robot 100 when, where it is modeled as a link structure including a plurality of substantially parallel axes connected in a vertical direction such as the shoulder joint pitch axis 4 , trunk pitch axis 9 , hip joint pitch axis 12 and knee joint pitch axis 14 , it tumbles to be a prone posture with the joint pitch axes driven synchronously and cooperatively; FIGS. 57 to 73 are side elevational views illustrating a manner wherein the legged mobile robot 100 tumbles from its standing posture into a prone posture; FIGS. 74 to 90 are perspective views illustrating the manner wherein the legged mobile robot 100 tumbles from its standing posture into a prone posture; FIG. 91 is a flow chart illustrating a processing procedure when the legged mobile robot 100 according to the embodiment of the present invention performs a standing up motion through synchronous and cooperative driving of the shoulder joint pitch axis 4 , trunk pitch axis 9 , hip joint pitch axis 12 and knee joint pitch axis 14 ; FIG. 92 is a view illustrating a manner wherein the legged mobile robot 100 according to the embodiment of the present invention performs a standing up motion from its supine posture through synchronous and cooperative driving of the shoulder joint pitch axis 4 , trunk pitch axis 9 , hip joint pitch axis 12 and knee joint pitch axis 14 in the form of a joint link model; FIG. 93 is a view illustrating a manner wherein a legged mobile robot of the type which does not include a trunk pitch axis performs a standing up motion from its supine posture through synchronous driving of a plurality of joint pitch axes; FIGS. 94 to 111 are side elevational views illustrating a manner wherein the legged mobile robot 100 stands up from its basic supine posture; FIGS. 112 to 129 are perspective views illustrating the manner wherein the legged mobile robot 100 stands up from its basic supine posture; FIG. 130 is a view illustrating a modification to a series of motions when the left and right hands are contacted with the floor rearward of the body; FIG. 131 is a view illustrating the modification to the series of motions when the left and right hands are contacted with the floor rearward of the body; FIG. 132 is a diagrammatic view illustrating the motions of an arm illustrated in FIGS. 130 and 131 ; FIG. 133 is a diagrammatic view showing the legged mobile robot shown in FIG. 92 but in a generalized form wherein it is replaced with a link structure; FIG. 134 is a view illustrating a manner wherein the legged mobile robot 100 according to the embodiment of the present invention performs a standing up motion from its prone posture through synchronous and cooperative driving of the shoulder joint pitch axis 4 , trunk pitch axis 9 , hip joint pitch axis 12 and knee joint pitch axis 14 in the form of a joint link model; FIG. 135 is a side elevational view illustrating a manner wherein the legged mobile robot 100 stands up from its basic spine posture; FIGS. 136 to 153 are side elevational views illustrating a manner wherein the legged mobile robot 100 stands up from its basic spine posture; FIGS. 154 to 172 are perspective views illustrating the manner wherein the legged mobile robot 100 stands up from its basic prone posture; FIG. 173 is a flow chart illustrating a processing procedure for determining whether or not a sufficiently narrowed support polygon is obtained; FIG. 174 is a flow chart illustrating a standing up operation which makes use of a dragging motion and a step changing motion of hand parts and foot parts; FIGS. 175 to 191 are side elevational views illustrating a manner wherein the legged mobile robot 100 stands up from its basic prone posture while making use of a dragging motion and a step changing motion of the hand parts and the foot parts; FIGS. 192 to 198 are views illustrating a series of motions of the body when a standing up motion is performed continuously to a tumbling motion; and FIG. 199 is a flow chart illustrating a processing procedure for searching for a link and a location of the link at which the number of links which do not relate to the smallest support polygon is maximum. detailed-description description="Detailed Description" end="lead"? |
Expression of membrane proteins using an adenylyl cyclase of mycobacterium tube rculosis |
A method for expression of membrane proteins is provided, wherein at least a portion of a nucleotide sequence coding to the membrane protein is fused to at least a portion of a nucleotide sequence coding for an adenylyl cyclase of Mycobacterium tuberculosis or a sequence at least about 70% identical to said sequence of Mycobacterium tuberculosis. In a second step the fused nucleotide sequence is introduced into an organism and/or a living cell. Another aspect of the invention is a method for searching active agents, which interact directly with adenylyl cyclases. |
1. Method for expression of membrane proteins, characterized by the following steps: at least a portion of a nucleotide sequence coding for the membrane protein is fused to at least a portion of the nucleotide sequence Rv1625c (SEQ ID NO 1) and/or Rv2435c (SEQ ID NO 2) of Mycobacterium tuberculosis coding for an adenylyl cyclase and/or at least a portion of a nucleotide sequence at least about 70% identical to Rv1625c and/or Rv2435c and the fused nucleotide sequence is introduced into an organism and/or a living cell. 2. Method according to claim 1, characterized in that said portion of the nucleotide sequence Rv1625c and/or Rv2435c codes for at least a part of the N-terminal domain of the adenylyl cyclase. 3. Method according to claim 1 or claim 2, characterized in that said portion of the nucleotide sequence Rv1625 and/or Rv2435c codes at least partly for one or more transmembrane spans of the adenylyl cyclase. 4. Method according to one of the preceding claims, characterized in that said membrane proteins are enzymes. 5. Method according to one of the preceding claims, characterized in that said membrane proteins are adenylyl cyclases, especially mammalian adenylyl cyclases. 6. Method according to one of the preceding claims, characterized in that said introduction of the nucleotide sequence is performed by use of an appropriate vector. 7. Method according to one of the preceding claims, characterized in that said organism and/or living cell is a bacterium, especially Escherichia coli. 8. Method according to one of claims 1 to 6, characterized in that said organism and/or living cell is at least one eukaryotic cell, especially a mammalian cell. 9. Method according to one of the preceding claims, characterized in that said expression is a heterologous expression. 10. Fused nucleotide sequence, comprising at least a portion of the nucleotide sequence Rv1625c (SEQ ID NO 1) and/or Rv2435c (SEQ ID NO 2) of Mycobacterium tuberculosis coding for an adenylyl cyclase and/or at least a portion of a nucleotide sequence at least about 70% identical to Rv1625c and/or Rv2435c and at least a portion of a nucleotide sequence coding for a membrane protein. 11. Fused nucleotide sequence according to claim 10, characterized in that said membrane protein is an enzyme. 12. Fused protein, comprising at least a portion of an adenylyl cyclase of Mycobacterium tuberculosis and/or at least a portion of an amino acid sequence at least about 70% identical to an adenylyl cyclase of Mycobacterium tuberculosis and at least a portion of a membrane protein. 13. Fused protein according to claim 12, characterized in that said membrane protein is an enzyme. 14. Kit for expression of membrane proteins, comprising at least a portion of the nucleotide sequence Rv1625c (SEQ ID NO 1) and/or Rv2435c (SEQ ID NO 2) of Mycobacterium tuberculosis. 15. Method for searching active agents which interact directly or indirectly with adenylyl cyclases, characterized by the following steps: an adenylyl cyclase of Mycobacterium tuberculosis is expressed in an organism and/or a living cell, a potential active agent is brought in contact with the adenylyl cyclase, an influence of the active agent on the adenylyl cyclase is analysed. 16. Method according to claim 15, characterized in that the expression of the adenylyl cylase is performed by an introduction of a nucleotide sequence coding for the adenylyl cyclase, especially the sequence Rv1625c (SEQ ID NO 1) and/or the sequence Rv2435c (SEQ ID NO 2), or portions thereof, into an organism. 17. Method according to claim 16, characterized in that said introduction of the nucleotide sequence is performed by use of an appropriate vector. 18. Method according to one of claims 15 to 17, characterized in that said organism is a bacterium, especially Escherichia coli. 19. Method according to one of claims 15 to 17, characterized in that said organism and/or living cell is at least one eukaryotic cell, especially a mammalian cell. 20. Method according to one of claims 15 to 19, characterized in that said influence is analysed by a direct interaction of the adenylyl cyclase and the potential active agent. 21. Method according to one of claims 15 to 20, characterized in that said influence is analysed by an altered enzyme activity of the adenylyl cyclase. 22. Active agent which interacts directly or indirectly with adenylyl cyclases, characterized in that it is obtained by a method according to one of claims 15 to 21. 23. Method for expression of membrane proteins, comprising the following steps: at least a portion of a nucleotide sequence coding for the membrane protein is fused to at least a portion of at least one nucleotide sequence selected from the group consisting of the nucleotide sequences Rv1625c (SEQ ID NO 1) and Rv2435c (SEQ ID NO 2) of Mycobacterium tuberculosis coding for an adenylyl cyclase or at least a portion of a nucleotide sequence at least about 70% identical to at least one nucleotide sequence selected from the group consisting of Rv1625c and Rv2435c, the fused nucleotide sequence is introduced into an organism or a living cell, and the introduced sequence is expressed. 24. Method according to claim 23, wherein said portion of the nucleotide sequence Rv1625c or Rv2435c codes for at least a part of the N-terminal domain of the adenylyl cyclase. 25. Method according to claim 23, wherein said portion of the nucleotide sequence Rv1625c or Rv2435c codes at least partly for one or more transmembrane spans of the adenylyl cyclase. 26. Method according to claim 23, wherein said membrane proteins are enzymes. 27. Method according to claim 23, wherein said membrane proteins are adenylyl cyclases. 28. Method according to claim 23, wherein said introduction of the nucleotide sequence is performed by use of an appropriate vector. 29. Method according to claim 23, wherein said organism or living cell is a bacterium. 30. Method according to claim 23, wherein said organism or living cell is at least one eukaryotic cell. 31. Method according to claim 23, wherein said expression is a heterologous expression. 32. Fused nucleotide sequence, comprising at least a portion of at least one nucleotide sequence selected from the group consisting of the nucleotide sequences Rv1625c (SEQ ID NO 1) and Rv2435c (SEQ ID NO 2) of Mycobacterium tuberculosis coding for an adenylyl cyclase or at least a portion of a nucleotide sequence at least about 70% identical to at least one nucleotide sequence selected from the group consisting of Rv1625c and Rv2435c, and at least a portion of a nucleotide sequence coding for a membrane protein. 33. Fused nucleotide sequence according to claim 32, wherein said membrane protein is an enzyme. 34. Fused protein, comprising at least a portion of an adenylyl cyclase of Mycobacterium tuberculosis or at least a portion of an amino acid sequence at least about 70% identical to an adenylyl cyclase of Mycobacterium tuberculosis, and at least a portion of a membrane protein. 35. Fused protein according to claim 34, wherein said membrane protein is an enzyme. 36. Kit for expression of membrane proteins, comprising at least a portion of at least one nucleotide sequence selected from the group consisting of the nucleotide sequences Rv1625c (SEQ ID NO 1) and Rv2435c (SEQ ID NO 2) of Mycobacterium tuberculosis. 37. Method for searching active agents which interact directly or indirectly with adenylyl cyclases, comprising the following steps: an adenylyl cyclase of Mycobacterium tuberculosis is expressed in an organism or a living cell, a potential active agent is brought in contact with the adenylyl cyclase, an influence of the active agent on the adenylyl cyclase is analysed. 38. Method according to claim 37, wherein the expression of the adenylyl cyclase is performed by an introduction of a nucleotide sequence coding for the adenylyl cyclase into an organism. 39. Method according to claim 38, wherein said introduction of the nucleotide sequence is performed by use of an appropriate vector. 40. Method according to claim 37, wherein said organism is a bacterium. 41. Method according to claim 37, wherein said organism or living cell is at least one eukaryotic cell. 42. Method according to claim 37, wherein said influence is analysed by a direct interaction of the adenylyl cyclase and the potential active agent. 43. Method according to claim 37, wherein said influence is analysed by an altered enzyme activity of the adenylyl cyclase. 44. Active agent which interacts directly or indirectly with adenylyl cyclases, wherein the active agent is obtained by a method according to claim 37. 45. Method according to claim 27, wherein said adenylyl cyclases are mammalian adenylyl cyclases. 46. Method according to claim 29, wherein said bacterium is Escherichia coli. 47. Method according to claim 30, wherein said eukaryotic cell is a mammalian cell. 48. Method according to claim 38, wherein said nucleotide sequence coding for the adenylyl cyclase is at least one nucleotide sequence selected from the group consisting of the nucleotide sequences Rv1625c (SEQ ID NO 1) and Rv2435c (SEQ ID NO 2) or portions thereof. 49. Method according to claim 40, wherein said bacterium is Escherichia coli. 50. Method according to claim 41, wherein said eukaryotic cell is a mammalian cell. |
Artificial human chromosome containing human antibody a light chain gene |
The present invention relates to a human artificial chromosome which is genetically transmissible to the next generation with high efficiency and the method for using the same. More specifically, the present invention relates to: a human artificial chromosome in which an about 3.5 Mb to about 1 Mb region containing an antibody λ light chain gene derived from human chromosome 22 is bound to a chromosome fragment which is transmissible to a progeny through a germ line of a non-human animal, said chromosome fragment is derived from another human chromosome; a non-human animal carrying the human artificial chromosome and an offspring thereof; a method for producing the non-human animal; a method for producing a human antibody using the non-human animal or an offspring thereof; and a human antibody-producing mouse carrying the human artificial chromosome. |
1. A human artificial chromosome, wherein an about 3.5 Mb to about 1 Mb region containing an antibody λ light chain gene derived from human chromosome 22 is bound to a chromosome fragment which is transmissible to a progeny through a germ line of a non-human animal, said chromosome fragment is derived from another human chromosome. 2. The human artificial chromosome according to claim 1, wherein the chromosome fragment derived from another human chromosome is a fragment of human chromosome 14. 3. The human artificial chromosome according to claim 2, wherein the fragment of human chromosome 14 is SC20 chromosome vector. 4. The human artificial chromosome according to any one of claims 1 to 3, wherein the size of the region containing an antibody λ light chain gene derived from human chromosome 22 is about 2.5 Mb to about 1.5 Mb. 5. The human artificial chromosome according to any one of claims 1 to 3, wherein the size of the region containing an antibody λ light chain gene derived from human chromosome 22 is about 2.5 Mb. 6. The human artificial chromosome according to claim 5, which is ΔHAC retained by a cell under the accession number of FERM BP-7582. 7. The human artificial chromosome according to any one of claims 1 to 3, wherein the size of the region containing an antibody λ light chain gene derived from human chromosome 22 is about 1.5 Mb. 8. The human artificial chromosome according to claim 7, which is ΔΔHAC retained by a cell under the accession number of FERM BP-7581. 9. A non-human animal, which carries the human artificial chromosome according to any one of claims 1 to 8. 10. The non-human animal according to claim 9, which carries either ΔHAC or ΔΔHAC. 11. The non-human animal according to claim 9 or 10, which is a mammal. 12. The non-human animal according to claim 11, wherein the mammal is a mouse. 13. A method for producing the non-human animal according to any one of claims 9 to 12, which comprises: introducing the human artificial chromosome according to any one of claims 1 to 8 into an embryonic stem cell (ES cell) of the non-human animal by a microcell method; injecting the obtained ES cell into the embryo of the non-human animal; transplanting the resulting injected embryo to a foster parent; obtaining a chimeric non-human animal from the foster parent by parturition; and screening the chimeric non-human animal for the human artificial chromosome. 14. The method according to claim 13, which further comprises producing the offspring of the screened chimeric non-human animal and screening the offspring for the human artificial chromosome. 15. The method according to claim 13 or 14, wherein the non-human animal is capable of expressing human antibody immunoglobulin heavy chain and λ chain proteins. 16. The method according to any one of claims 13 to 15, wherein the non-human animal is a mammal. 17. The method according to claim 16, wherein the mammal is a mouse. 18. A non-human animal carrying the human artificial chromosome according to any one of claims 1 to 8, which can be obtained by the method according to any one of claims 13 to 17. 19. An offspring animal of the non-human animal according to any one of claims 9 to 12 and 18, which carries the human artificial chromosome according to any one of claims 1 to 8. 20. The offspring animal according to claim 19, wherein human antibody immunoglobulin heavy chain and λ light chain proteins can be expressed. 21. The offspring animal according to claim 19, wherein human antibody immunoglobulin heavy chain, κ light chain, and λ light chain proteins can be expressed. 22. The offspring animal according to any one of claims 19 to 21, which is a mouse. 23. A method for producing an antibody, which comprises: immunizing the non-human animal according to any one of claims 9 to 12 and 18 or the offspring animal according to any one of claims 19 to 22 with a desired antigen; and obtaining a human polyclonal antibody against the antigen from the animal. 24. The method according to claim 23, wherein the human polyclonal antibody is obtained from blood of the animal. 25. A method for producing an antibody, which comprises: immunizing the mouse according to claim 12 or 18 or the offspring mouse according to claim 22 with a desired antigen; producing a hybridoma by fusing a spleen cell of the mouse with a mouse myeloma cell; and producing a human monoclonal antibody consisting of human immunoglobulin heavy chain and light chain against the antigen. 26. A method for producing an antibody, which comprises: immunizing the mouse according to claim 12 or 18 or the offspring mouse according to claim 22 with a desired antigen; producing a hybridoma by fusing a spleen cell of the mouse with a mouse myeloma cell; isolating a human antibody gene from the hybridoma; introducing the human antibody gene into an animal cell, a yeast cell, or an insect cell; culturing the cell under a condition capable of expressing a human antibody gene; and producing a human monoclonal antibody consisting of human immunoglobulin heavy chain and light chain against the antigen. 27. A method for producing an antibody, which comprises: immunizing the mouse according to claim 12 or 18 or the offspring mouse according to claim 22 with a desired antigen; selecting an antibody gene derived from a B-cell of the mouse by a phage display method; introducing the selected human antibody gene into an animal cell, a yeast cell, or an insect cell; culturing the cell under a condition capable of expressing a human antibody gene; and producing a human monoclonal antibody consisting of human immunoglobulin heavy chain and light chain against the antigen. 28. A human antibody-producing mouse, wherein an unrearranged human antibody heavy chain locus, an unrearranged human antibody κ light chain locus, and an unrearranged human antibody λ light chain locus are carried, at least both alleles of endogenous antibody heavy chain and κ light chain are disrupted or inactivated, and a human antibody heavy chain comprising a human antibody Ig γ isotype, a human antibody κ light chain, and a human antibody λ light chain are expressed in serum. 29. The human antibody-producing mouse according to claim 28, which carries at least 40% of the variable region of the human antibody κ light chain. 30. The human antibody-producing mouse according to claim 28, which carries all the variable regions of the human antibody heavy chain, the human antibody κ light chain, and the human antibody λ light chain. 31. The human antibody-producing mouse according to claim 28, wherein a human antibody heavy chain locus, a human antibody κ light chain locus, and a human antibody λ locus are retained on a chromosome fragment derived from a human. 32. The human antibody-producing mouse according to claim 28, wherein the human antibody heavy chain locus and the human antibody λ light chain locus are retained on ΔHAC or ΔΔHAC. 33. The human antibody-producing mouse according to claim 28, wherein the human antibody κ light chain locus is retained on a chromosome fragment derived from a human. 34. (canceled) 35. The human antibody-producing mouse according to claim 28, which is not a chimeric mouse. 36. (canceled) 37. (canceled) 38. (canceled) 39. (canceled) 40. (canceled) 41. (canceled) 42. (canceled) 43. (canceled) 44. (canceled) 45. (canceled) 46. (canceled) 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) |
<SOH> BACKGROUND ART <EOH>A technique has been developed in which a chimeric animal is produced from a hybrid cell obtained by fusion between a microcell containing a chromosome fragment and a pluriopotent cell (WO 97/07671). This enabled the production of a non-human animal carrying a very long foreign gene, which was heretofore impossible. Modification of a chromosome fragment to be introduced into a non-human animal is useful because it realizes (1) removal of unnecessary genes, (2) addition of desired genes, (3) stabilization of a chromosome fragment and the like. WO 98/37757 describes a summary of a method for modifying a chromosome fragment to be introduced into a non-human animal and that a deletion chromosome of interest was obtained with high efficiency by targeting a telomeric sequence to a human chromosome retained in the DT-40 cell derived from a chicken. This publication also describes a fragment of a human chromosome which is stably retained in a mouse ES cell and an individual mouse, and has high genetic transmission efficiency. WO 00/10383 describes a method for producing a more stable human artificial chromosome (hereinafter this may be abbreviated to “HAC”) in which a desired region on the human chromosome is translocated to a stable chromosome fragment (chromosome vector). Recently, Kuroiwa et al. (Nature Biotech. 18: 1086, 2000) succeeded, for the first time in the world, in producing a human artificial chromosome (HAC) retaining a specific human chromosome region of mega base (Mb) size as an insert. This HAC (λHAC) is an artificial chromosome that was obtained by using a SC20 fragment derived from human chromosome 14, which was stable and genetically transmissible, as a chromosome vector, and by translocating and cloning a 10 Mb chromosome region containing a human antibody λ light chain gene on human chromosome 22 to the vector as an insert. They demonstrated that this λHAC had a stability substantially equivalent to that of the SC20 fragment used as a vector and regions derived from various unstable chromosomes could be stabilized by being translocated and cloned to SC20 as well. Further, they introduced this λHAC to a mouse, thereby succeeding in producing a chimeric mouse which stably carried λHAC. In a non-human animal, genetic transmission of an introduced human chromosome to the next generation is important not only with regard to mass-production of transchromosomic animals by crossing (i.e., a non-human animal in which heterogenic chromosome fragments have been genetically transmitted through a germ line) having homogeneity, but also with regard to analysis of structures and functions through a germ line of the introduced human chromosome. Several types of human chromosomes have been heretofore introduced into mice and the genetic transmission capacity thereof is considered to depend on the structure of the introduced human chromosome. For the purpose of genetic transmission, at the outset it is essential to obtain a chimeric mouse in which the ES cell contributes with high efficiency to a germ cell and the chimerism is high. This chimerism is considered to be associated with a structure of the introduced human chromosome, that is, which type of human gene is present on the introduced chromosome. For example, when a fragment of human chromosome 2 or 14 is introduced, a chimeric mouse whose chimerism is close to 100% is obtained and its genetic transmission efficiency is high (Tomizuka et al., Proc. Natl. Acad. Sci. USA, 97: 722-727, 2000). In contrast, when a fragment of human chromosome 22 is introduced, a chimeric mouse whose chimerism is low, i.e., 50% or below, is obtained in most cases. This may be because a harmful human gene that adversely affects the development of a mouse is present on human chromosome 22. In fact, it is reported that gene expression-level-dependent hereditary disease-causing regions such as cat's eye syndrome, DiGeorge syndrome, and der22 syndrome exist in the 22q11 region on human chromosome 22 where the human antibody Ig λ gene is present (for example, A. Puech et al., PNAS 97: 10090, 2000). As described above, these hereditary disease-causing regions are removed, and only 10 Mb from the HCF2 locus to the LIF locus on human chromosome 22 is translocated and cloned to the SC20 chromosome vector to construct λHAC, followed by introduction into a mouse. As a result, the chimerism of the chimeric mouse generated from the ES cell retaining λHAC is reported to be enhanced compared to the case where the full length of human chromosome 22 was introduced. Under the above circumstances, the present inventors have attempted to further improve the human artificial chromosome in order to achieve more efficient genetic transmission than the conventional λHAC, and have studied the genetic transmission efficiency. More specifically, an object of the present invention is to provide a human artificial chromosome which is genetically transmissible to the next generation with high efficiency by modification of human chromosome 22 or a fragment thereof, and a non-human animal carrying the human artificial chromosome and an offspring thereof. Another object of the present invention is to provide a method for producing a human antibody using the non-human animal or an offspring thereof. The present inventors have conducted concentrated studies in order to attain the above objects. As a result, they have modified human chromosome 22, selected two types of regions with a clear construction containing an antibody λ light chain gene (Ig λ) region, and constructed a human artificial chromosome in which each of the selected regions was translocated to a fragment of human chromosome 14, thereby producing a mouse with a high chimerism carrying the same. As a result, the present inventors observed that the human artificial chromosome was genetically transmitted to the offspring at the next generation with high efficiency through meiosis in the chimeric mouse, thereby completing the present invention. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows the production of human artificial chromosomes ΔHAC and ΔΔHAC. FIG. 2 shows a cassette vector pTELhisD. FIG. 3 shows a targeting vector pTELhisDλI. FIG. 4 shows a targeting vector p5531oxPHyg. detailed-description description="Detailed Description" end="lead"? This specification includes part or all of the contents as disclosed in the specification of Japanese Patent Application No. 2001-142371, which is a priority document of the present application. |
System and method for cleaning or de-icing a windshield |
A windshield washing system and method including a windshield wiper and sprayer assembly (110). The windshield wiper and sprayer assembly (110) includes a windshield wiper assembly (114), a windshield wiper driver assembly operative to move the windshield wiper assembly (114) in rotational and linear motion along a vehicle windshield, a windshield sprayer assembly (116) mounted on the windshield wiper assembly (114), the windshield sprayer assembly (116) includes at least one sprayer. The sprayer includes a sprayer housing (136) and a sprayer housing closure (138) arranged for selectable positioning relative to the sprayer housing (136) and to assume a first position permitting spraying and a second position not permitting spraying and a windshield sprayer assembly positioning assembly operative in response to the linear motion of the windshield wiper assembly (114) for selectably positioning the sprayer housing closure (138) relative to the sprayer housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly (114). |
1. A windshield washing system comprising: a windshield wiper and sprayer assembly comprising: a windshield wiper assembly; a windshield wiper driver assembly operative to move said windshield wiper assembly in rotational and linear motion along a vehicle windshield; a windshield sprayer assembly mounted on said windshield wiper assembly, said windshield sprayer assembly comprising at least one sprayer comprising: a sprayer housing; and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and to assume a first-position permitting spraying and a second position not permitting spraying; and a windshield sprayer assembly positioning assembly operative in response to said linear motion of said windshield wiper assembly for selectably positioning said sprayer housing closure relative to said sprayer housing in either of said first and second positions in accordance with the rotational position of the windshield wiper assembly. 2-28. (canceled) 29. A windshield sprayer assembly comprising: at least one sprayer comprising: a sprayer housing; and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying; and a heater heating said sprayer housing. 30-33. (canceled) 34. A windshield washing system comprising: a windshield wiper and sprayer assembly comprising: a windshield wiper assembly; a windshield wiper driver assembly operative to move said windshield wiper assembly in rotational motion along a vehicle windshield; a windshield sprayer assembly mounted on said windshield wiper assembly, said windshield sprayer assembly comprising at least one sprayer comprising: a sprayer housing; and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying; and a windshield sprayer assembly positioning assembly operative in response to said rotational motion of said windshield wiper assembly for selectably positioning said sprayer housing closure relative to said sprayer housing in either of said first and second positions in accordance with the rotational position of the windshield wiper assembly. 35-51. (canceled) 52. A liquid heating assembly useful with a windshield wiper and sprayer assembly, said liquid heating assembly comprising: a housing defining a liquid heating chamber; and a liquid heating volume defining subassembly disposed in said liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with a plurality of liquid inlet apertures at various heights therealong. 53-61. (canceled) 62. A liquid heating assembly useful with a windshield wiper and sprayer assembly, said liquid heating assembly comprising: a housing defining a liquid heating chamber; a liquid heating volume defining subassembly disposed in said liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture; and a labyrinthine heating unit receiving heated liquid from said liquid heating volume and providing further heated liquid to an outlet. 63-65. (canceled) 66. A liquid heating assembly useful with a windshield wiper and sprayer assembly, said liquid heating assembly comprising: a housing defining a liquid heating chamber; a liquid heating volume defining subassembly disposed in said liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture; and a pump, which is not part of the original equipment in a vehicle, which pressurizes liquid received via a conduit from a liquid reservoir, which is part of the original equipment of the vehicle. 67-70. (canceled) 71. A liquid heating assembly useful with a windshield wiper and sprayer assembly, said liquid heating assembly comprising: a housing defining a liquid heating chamber; a liquid heating volume defining subassembly disposed in said liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture; and a temperature sensor located in a wall of said liquid heating chamber. 72-113. (canceled) 114. A heated liquid circulation system comprising: a liquid heating assembly; and a heated liquid circulation assembly for supplying heated liquid from said liquid heating assembly for circulation in thermal heat exchange engagement with at least one of a windshield wiper, a windshield sprayer and a liquid supply conduit for supplying liquid to said windshield sprayer. 115. A heated liquid wiper and sprayer assembly comprising: a liquid heating assembly; at least one sprayer; a heated liquid supply assembly including at least one heated liquid supply conduit for supplying heated liquid from said liquid heating assembly to said at least one sprayer for spraying thereof; and a heated liquid circulation assembly for supplying heated liquid from said liquid heating assembly for circulation in thermal heat exchange engagement with at least one of a windshield wiper, said at least one sprayer and to said at least one heated liquid supply conduit for heating thereof. 116-153. (canceled) 154. A windshield sprayer controlling system comprising: a windshield wiper assembly comprising: a windshield wiper support arm; and a windshield wiper; a windshield wiper driver assembly operative to move said windshield wiper assembly in rotational motion along a vehicle windshield; and at least one windshield sprayer mounted on said windshield wiper assembly, said support arm controlling said at least one windshield sprayer in accordance with the direction of movement of said wiper assembly relative to said windshield. 155-163. (canceled) 164. A heated liquid spray system for vehicles comprising: a windshield washing subsystem comprising: a windshield wiper and sprayer assembly comprising: a windshield wiper assembly; a windshield wiper driver assembly operative to move said windshield wiper assembly in rotational and linear motion along a vehicle windshield; a windshield sprayer assembly mounted on said windshield wiper assembly, said windshield sprayer assembly comprising at least one sprayer comprising: a sprayer housing; and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying; and a windshield sprayer assembly positioning assembly operative in response to said linear motion of said windshield wiper assembly for selectably positioning said housing closure relative to said housing in either of said first and second positions in accordance with the rotational position of the windshield wiper assembly; and a liquid heating assembly subsystem comprising: a housing defining a liquid heating chamber; and a liquid heating volume defining subassembly disposed in said liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture. 165. A heated liquid spray system for vehicles comprising: a windshield washing subsystem comprising: a windshield wiper and sprayer assembly comprising: a windshield wiper assembly; a windshield wiper driver assembly operative to move said windshield wiper assembly in at least rotational motion along a vehicle windshield; a windshield sprayer assembly mounted on said windshield wiper assembly, said windshield sprayer assembly comprising at least one sprayer comprising: a sprayer housing; and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying; and a windshield sprayer assembly positioning assembly operative in response to said motion of said windshield wiper assembly for selectably positioning said housing closure relative to said housing in either of said first and second positions in accordance with the rotational position of the windshield wiper assembly; and a liquid heating assembly subsystem comprising: a housing defining a liquid heating chamber; and a liquid heating volume defining subassembly disposed in said liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture. 166. A heated liquid spray system for vehicles comprising: a windshield washing subsystem comprising: a windshield wiper and sprayer assembly comprising: a windshield wiper assembly; a windshield wiper driver assembly operative to move said windshield wiper assembly in at least rotational motion along a vehicle windshield; a windshield sprayer assembly mounted on said windshield wiper assembly, said windshield sprayer assembly comprising at least one sprayer comprising: a sprayer housing; and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying; and a windshield sprayer assembly positioning assembly operative in response to said motion of said windshield wiper assembly for selectably positioning said housing closure relative to said housing in either of said first and second positions in accordance with the rotational position of the windshield wiper assembly; and a liquid heating assembly subsystem comprising: a housing defining a liquid heating chamber; a liquid heating volume defining subassembly disposed in said liquid heating chamber; and a labyrinthine heating unit receiving heated liquid from said liquid heating volume and providing further heated liquid to an outlet. 167. (canceled) 168. A method for windshield washing comprising: providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer including a sprayer housing and a sprayer housing closure movable relative to said sprayer housing, said sprayer housing closure providing a first position permitting spraying and a second position not permitting spraying; moving said windshield wiper assembly in rotational and linear motion along a vehicle windshield; and selectably positioning said sprayer housing closure relative to said sprayer housing in either of said first and second positions in response to said linear motion of said windshield wiper assembly in accordance with the rotational position of the windshield wiper assembly. 169-195. (canceled) 196. A method for windshield spraying comprising: providing at least one sprayer including a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to said sprayer housing and for assuming a first position permitting spraying and a second position not permitting spraying; and heating said sprayer housing. 197-200. (canceled) 201. A method for windshield washing comprising: providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer including a sprayer housing and a sprayer housing closure relative to said sprayer housing, said sprayer housing closure having a first position permitting spraying and a second position not permitting spraying; moving said windshield wiper assembly in rotational motion along a vehicle windshield; and selectably positioning said sprayer housing closure relative to said sprayer housing in either of said first and second positions in accordance with the rotational position of said windshield wiper assembly. 202-218. (canceled) 219. A method for heating liquid for use with a windshield wiper and sprayer assembly comprising: providing a housing defining a liquid heating chamber; and disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, with a plurality of liquid inlet apertures at various heights along said wall portion, in said liquid heating chamber. 220-227. (canceled) 228. A method for heating liquid for use with a windshield wiper and sprayer assembly comprising: providing a housing defining a liquid heating chamber; disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in said liquid heating chamber; receiving heated liquid from said liquid heating volume into a labyrinthine heating unit; further heating said heated liquid; and providing said further heated liquid from said labyrinthine heating unit to an outlet. 229-231. (canceled) 232. A method for heating liquid useful with a windshield wiper and sprayer assembly: providing a housing defining a liquid heating chamber; disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in said liquid heating chamber; receiving liquid via a conduit from a liquid reservoir, which is part of the original equipment of a vehicle; and pressurizing said liquid with a pump, which is not part of the original equipment in said vehicle. 233-235. (canceled) 236. A method for heating liquid for use with a windshield wiper and sprayer assembly comprising: providing a housing defining a liquid heating chamber; disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in said liquid heating chamber; locating a temperature sensor in a wall of said liquid heating chamber; and sensing temperature of said liquid via said temperature sensor. 237-319. (canceled) |
<SOH> BACKGROUND OF THE INVENTION <EOH>The following Patent documents are believed to be relevant to the subject matter of the present invention: U.S. patents: 653,629; 1,636,190; 3,202,447; 3,332,045; 3,977,436; 3,979,068; 4,090,668; 4,106,508; 4,159,026; 4,253,493; 4,295,111; 4,306,589; 4,403,756; 4,489,863; 4,561,632; 4,534,539; 4,524,797; 4,574,841; 4,690,371; 4,877,186; 5,012,977; 5,118,040; 5,280,806; 5,254,083; 5,318,071; 5,345,968; 5,351,934; 5,354,965; 5,383,247; 5,509,606; 5,727,769; 5,784,751; 5,927,608; 5,947,348; 5,957,384; 5,988,529; 6,133,546; 6,164,564. JP 2-53656; JP 2-234866; JP 63-93652; JP 83-12824; GB 1,451,666. The disclosures of all publications mentioned in the specification and of the publications cited therein are hereby incorporated by reference. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention seeks to provide improved vehicle window washers, cleaners and de-icers generally. For the purpose of this patent application the term “windshield” is given a broader meaning than usual and refers to any window, mirror or headlight surface of a vehicle. There is thus provided in accordance with a preferred embodiment of the present invention a windshield washing system including a windshield wiper and sprayer assembly including a windshield wiper assembly, a windshield wiper driver assembly operative to move the windshield wiper assembly in rotational and linear motion along a vehicle windshield, a windshield sprayer assembly mounted on the windshield wiper assembly. The windshield sprayer assembly includes at least one sprayer, which includes a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying. The windshield washing system also includes a windshield sprayer assembly positioning assembly operative in response to the linear motion of the windshield wiper assembly for selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. There is also provided in accordance with a preferred embodiment of the present invention a method for windshield washing, which includes providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer, including a sprayer housing and a sprayer housing closure movable relative to the sprayer housing, the sprayer housing closure providing a first position permitting spraying and a second position not permitting spraying, moving the windshield wiper assembly in rotational and linear motion along a vehicle windshield and selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in response to the linear motion of the windshield wiper assembly in accordance with the rotational position of the windshield wiper assembly. Further in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly includes a base, which is arranged for rotation about a rotation axis. Typically, the base is driven for reciprocating rotational motion by a conventional wiper drive assembly, forming part of a conventional motor vehicle. Still further in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly includes a base mounted housing, which cooperates with the base and arranged for driven linear motion relative thereto. Typically, the driven linear motion of the base mounted housing relative to the base is provided by a cam drive assembly. Additionally in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly also includes a support arm, fixed to the base mounted housing for linear and rotational motion therewith. Additionally or alternatively, the sprayer includes at least one heated to liquid sprayer, which undergoes linear and rotational motion together with the base mounted housing and which receives pressurized fluid for spraying via fluid conduits. Further in accordance with a preferred embodiment of the present invention the windshield sprayer assembly positioning assembly includes an upstanding pin fixed to the base for rotary motion together therewith, the upstanding pin slidably engaging a base mounted housing slot formed in a bottom surface of the base mounted housing. Preferably, the upstanding pin also slidingly engages an anchor element slot formed in an anchor element, which anchor element is linearly slidable relative to the base mounted housing and to the base along an axis generally parallel to the anchor element slot. Additionally in accordance with a preferred embodiment of the present invention at least one compression wire is coupled to the anchor element and the at least one compression wire extends through at least one sleeve to the windshield sprayer assembly and being operative for controlling the positioning of the sprayer housing closure relative to the sprayer housing. Typically, the windshield sprayer assembly includes a pressurized fluid chamber, which is defined between the sprayer housing and the sprayer housing closure, the pressurized fluid chamber receiving pressurized fluid to be sprayed from a fluid conduit via an inlet pipe. Further in accordance with a preferred embodiment of the present invention the sprayer housing closure includes a cap which may be sealed and may be held tight against a corresponding sealing surface of the sprayer housing. Still further in accordance with a preferred embodiment of the present invention the cap is arranged to be sealed and to be held tight by a spring loaded shaft assembly, which includes a compression spring. Additionally in accordance with a preferred embodiment of the present invention the sprayer housing closure is normally positioned relative to the sprayer housing in the first position permitting spraying by operation of a spring loaded lever assembly, attached to an end of a compression wire. Still further in accordance with a preferred embodiment of the present invention the spring loaded lever assembly includes a compression spring which normally urges a lever arm forward in engagement with a spring loaded shaft assembly, thereby overcoming the spring force of a further spring and urging the sprayer housing closure away from the sprayer housing. Typically, the spring force of the further spring exceeds the spring force of the compression spring. Additionally in accordance with a preferred embodiment of the present invention, when the base mounted housing is at an extreme inward radial orientation, the engagement of the upstanding pin at a radial outward end of the anchor element slot applies a compressive force to a compression wire, which compressive force is sufficient to overcome the spring force of the further spring and to force the lever arm to an orientation wherein it does not engage the spring loaded shaft assembly and does not overcome the spring force of the compression spring, thereby enabling the compression spring to seal the sprayer housing closure against the sprayer housing. Still further in accordance with a preferred embodiment of the present invention, when base mounted housing is at the extreme inward radial orientation, both the anchor element and the base mounted housing are in their extreme retracted positions and a first separation is defined between an outward facing surface of the anchor element and an inner facing surface of the outer facing wall of the base mounted housing. Further in accordance with a preferred embodiment of the present invention the base mounted housing moves radially outward from the extreme inward radial orientation, the anchor element is slidable relative to the base mounted housing and a second separation, greater than the first separation, is defined between an outward facing surface of the anchor element and an inner facing surface of the outer facing wall of the base mounted housing. Preferably, the anchor element is slidable relative to the base mounted housing and moves radially outwardly together with the base mounted housing. Further in accordance with a preferred embodiment of the present invention the pin engages the anchor element slot to provide a lost motion mechanism, whereby tensioning of the compression wires is avoided. Still further in accordance with a preferred embodiment of the present invention the lost motion mechanism produces a liquid spray by allowing the pressurized fluid to escape from the pressurized fluid chamber. Typically, the base mounted housing travels radially relative to the base. Preferably, sufficient liquid pressure applied to the pressurized fluid chamber overcomes the spring force of the compression spring and permits spraying even when the sprayer housing is in the second position. Additionally or alternatively, the sprayer at least one sprayer includes an electrical heating element for heating thereof. Typically, the electrical heating element is coupled to a source of electrical power by an electrical conductor. Still further in accordance with a preferred embodiment of the present invention the step for windshield spraying also includes receiving pressurized fluid into the at least one sprayer and spraying the pressurized fluid onto the vehicle windshield. There is further provided in accordance with another preferred embodiment of the present invention a windshield sprayer assembly including at least one sprayer. The sprayer includes a sprayer housing, a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying and a heater heating the sprayer housing. There is further provided in accordance with yet another preferred embodiment of the present invention a method for windshield spraying. The method includes providing at least one sprayer, including a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and for assuming a first position permitting spraying and a second position not permitting spraying and heating the sprayer housing. Further in accordance with a preferred embodiment of the present invention the heater includes an electric heater. Additionally or alternatively, the heater includes a thermal heat exchange heater. Still further in accordance with a preferred embodiment of the present invention the heater also heats the sprayer housing closure. Additionally in accordance with a preferred embodiment of the present invention the heater is positioned near an end of the sprayer housing that is in contact with the sprayer housing closure when the sprayer housing closure is in the second position. There is also provided in accordance with a preferred embodiment of the present invention a windshield washing system, which includes a windshield wiper and sprayer assembly including a windshield wiper assembly, a windshield wiper driver assembly operative to move the windshield wiper assembly in rotational motion along a vehicle windshield and a windshield sprayer assembly mounted on the windshield wiper assembly, the windshield sprayer assembly including at least one sprayer. The windshield sprayer assembly includes a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying. The windshield washing system also includes a windshield sprayer assembly positioning assembly operative in response to the rotational motion of the windshield wiper assembly for selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. There is further provided in accordance with a preferred embodiment of the present invention a method for windshield washing, which includes providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer including a sprayer housing and a sprayer housing closure relative to the sprayer housing, the sprayer housing closure having a first position permitting spraying and a second position not permitting spraying, moving the windshield wiper assembly in rotational motion along a vehicle windshield and selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. Further in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly includes a base which is arranged for rotation about a rotation axis. Preferably, the base is driven for reciprocating rotational motion by a conventional wiper drive assembly, forming part of a conventional motor vehicle. Still further in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly includes a base mounted housing, cooperating with the base and arranged for rotational motion therewith. Additionally in accordance with a preferred embodiment of the present invention the windshield sprayer assembly positioning assembly is responsive to the rotational position of the base for governing the relative position of the sprayer housing and the sprayer housing closure. Further in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly also includes a support arm, fixed to the base mounted housing for rotational motion therewith. Additionally or alternatively, the sprayer includes at least one heated liquid sprayer, which undergoes rotational motion together with the base mounted housing and which receives pressurized fluid for spraying via fluid conduits. Still further in accordance with a preferred embodiment of the present invention the compression wire is coupled to at least one engagement element, the at least one compression wire extending through at least one sleeve to the windshield sprayer assembly and being operative for controlling the positioning of the sprayer housing closure relative to the sprayer housing. Additionally in accordance with a preferred embodiment of the present invention the windshield sprayer assembly includes a pressurized fluid chamber, which is defined between the sprayer housing and the sprayer housing closure, the pressurized fluid chamber receives pressurized fluid to be sprayed from a fluid conduit via an inlet pipe. Typically, the sprayer housing closure includes a cap which is arranged to be selectably sealed against a corresponding sealing surface of the sprayer housing. Preferably, the cap may be sealed and may be held tight by a spring loaded shaft assembly, which includes a compression spring. Further in accordance with a preferred embodiment of the present invention the sprayer housing closure is normally positioned relative to the sprayer housing in the first position permitting spraying. Preferably, the sprayer housing closure is normally positioned relative to the sprayer housing in the first position permitting spraying by operation of a spring to loaded lever assembly, attached to an end of the compression wire. Typically, the spring loaded lever assembly includes a compression spring which normally urges a lever arm forward in engagement with a spring loaded shaft assembly, thereby overcoming the spring force of a further spring and urging the sprayer housing closure away from the sprayer housing. Further in accordance with a preferred embodiment of the present invention the spring force of the further spring exceeds the spring force of the compression spring. Still further in accordance with a preferred embodiment of the present invention the windshield sprayer assembly positioning assembly includes push buttons which are arranged to be depressed by engagement with an engagement member when the windshield wiper assembly reaches an extreme position. Additionally in accordance with a preferred embodiment of the present invention, when the windshield wiper assembly is at at least one extreme position, the engagement of the engagement member with the push buttons applies a compressive force to a compression wire, which compressive force is sufficient to overcome the spring force of the further spring and to force the lever arm to an orientation wherein it does not engage the spring loaded shaft assembly and does not overcome the spring force of the compression spring, thereby enabling the compression spring to seal the sprayer housing closure against sprayer housing. Typically, sufficient liquid pressure is applied to the pressurized fluid chamber and overcomes the spring force of the compression spring and permits spraying even when the sprayer housing is in the second position. Further in accordance with a preferred embodiment of the present invention the step for receiving pressurized fluid into the at least one sprayer and spraying the pressurized fluid onto the vehicle windshield. There is also provided in accordance with another preferred embodiment of the present invention a liquid heating assembly, useful with a windshield wiper and sprayer assembly. The liquid heating assembly includes a housing defining a liquid heating chamber, a liquid heating volume defining subassembly disposed in the liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with a plurality of liquid inlet apertures at various heights therealong. There is further provided in accordance with a preferred embodiment of the present invention a method for heating liquid for use with a windshield wiper and sprayer assembly, which includes providing a housing defining a liquid heating chamber and disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, with a plurality of liquid inlet apertures at various heights along the wall portion, in the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention the liquid to be heated is received under pressure at an inlet and passes through a conduit into the liquid heating chamber and thence through the apertures into the liquid heating volume. Still further in accordance with a preferred embodiment of the present invention the heated liquid exits at the top of the liquid heating chamber via a conduit and passes through a labyrinthine heating unit to an outlet. Additionally in accordance with a preferred embodiment of the present invention the liquid to be heated is received under pressure at an inlet and passes through a conduit into the liquid heating chamber and thence into the liquid heating volume. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes a pump, which is not part of the original equipment in a vehicle, which pressurizes liquid received via a conduit from a liquid reservoir, which is part of the original equipment of the vehicle. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly further includes a pump, which pressurizes liquid received via a conduit from a liquid reservoir via a one-way valve. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly is arranged for retrofit installation into an existing motor vehicle. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes a first liquid temperature sensor located near the top of the liquid heating chamber and a second temperature sensor, which is located in a wall of the liquid heating chamber. Typically, the second temperature sensor operates a circuit breaker switch, which is responsive to exceedance of a predetermined temperature threshold at the second temperature sensor for automatically interrupting the supply of electrical power from a vehicle battery to the liquid heating assembly. There is further provided in accordance with yet another preferred embodiment of the present invention a liquid heating assembly useful with a windshield wiper and sprayer assembly. The liquid heating assembly includes a housing defining a liquid heating chamber, a liquid heating volume defining subassembly disposed in the liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture and a labyrinthine heating unit receiving heated liquid from the liquid heating volume and providing further heated liquid to an outlet. There is further provided in accordance with yet a further preferred embodiment of the present invention a method for heating liquid for use with a windshield wiper and sprayer assembly. The method includes providing a housing defining a liquid heating chamber, disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in the liquid heating chamber, receiving heated liquid from the liquid heating volume into a labyrinthine heating unit, further heating the heated liquid and providing the further heated liquid from the labyrinthine heating unit to an outlet. Further in accordance with a preferred embodiment of the present invention the liquid to be heated is received under pressure at an inlet and passes through a conduit into the liquid heating chamber and thence into the liquid heating volume. Still farther in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes a pump, which is not part of the original equipment in a vehicle, which pressurizes liquid received via a conduit from a liquid reservoir, which is part of the original equipment of the vehicle. Additionally in accordance with a preferred embodiment of the present invention the liquid heating assembly further includes a pump, which pressurizes liquid received via a conduit from a liquid reservoir via a one-way valve. There is further provided in accordance with yet a further embodiment of the present invention a liquid heating assembly useful with a windshield wiper and sprayer assembly. The liquid heating assembly includes a housing defining a liquid heating chamber, a liquid heating volume defining subassembly disposed in the liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture and a pump, which is not part of the original equipment in a vehicle, which pressurizes liquid received via a conduit from a liquid reservoir, which is part of the original equipment of the vehicle. There is also provided in accordance with another preferred embodiment a method for heating liquid useful with a windshield wiper and sprayer assembly. The method includes providing a housing defining a liquid heating chamber, disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in the liquid heating chamber, receiving liquid via a conduit from a liquid reservoir, which is part of the original equipment of a vehicle and pressurizing the liquid with a pump, which is not part of the original equipment in the vehicle. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly is arranged for retrofit installation into an existing motor vehicle. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes a first liquid temperature sensor located near the top of the liquid heating chamber. Additionally in accordance with a preferred embodiment of the present invention the liquid heating assembly further includes a second temperature sensor, which is located in a wall of the liquid heating chamber. Typically, the second temperature sensor operates a circuit breaker switch, which is responsive to exceedance of a predetermined temperature threshold at the second temperature sensor for automatically interrupting the supply of electrical power from a vehicle battery to the liquid heating assembly. There is still further provided in accordance with yet another preferred embodiment of the present invention a liquid heating assembly useful with a windshield wiper and sprayer assembly. The liquid heating assembly includes a housing defining a liquid heating chamber, a liquid heating volume defining subassembly disposed in the to liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture and a temperature sensor located in a wall of the liquid heating chamber. There is yet further provided in accordance with still another preferred embodiment of the present invention a method for heating liquid for use with a windshield wiper and sprayer assembly including providing a housing defining a liquid heating chamber, disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in the liquid heating chamber, locating a temperature sensor in a wall of the liquid heating chamber and sensing temperature of the liquid via the temperature sensor. Further in accordance with a preferred embodiment of the present invention the temperature sensor operates a circuit breaker switch, which is responsive to exceedance of a predetermined temperature threshold at the temperature sensor for automatically interrupting the supply of electrical power from a vehicle battery to the liquid heating assembly. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes electronic heating control circuitry. Typically, the electronic heating control circuitry provides electrical power to at least one of first and second heating elements and a labyrinthine heating unit. Preferably, the electronic heating control circuitry controls electrical power to at least one of the heating elements, thereby controlling spraying frequency. Additionally in accordance with a preferred embodiment of the present invention the electronic heating control circuitry controls electrical power to at least two of the heating elements, thereby controlling spraying frequency. Typically, the electronic heating control circuitry also provides electrical power to at least one pump which governs the supply of liquid under pressure to the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention the electronic heating control circuitry also provides at least one of electrical power and an electrical control signal to windshield wipers for producing reciprocating rotation thereof. Still further in accordance with a preferred embodiment of the present invention the electronic heating control circuitry receives an input from an outside air temperature sensor. Typically, the electronic heating control circuitry controls the operation of a labyrinthine heating unit in response to the outside air temperature sensor. Additionally in accordance with a preferred embodiment of the present invention the electronic heating control circuitry receives an input from a dirt sensor for automatically initiating operation of the liquid heating assembly when a sprayable surface is dirty. Preferably, the electronic heating control circuitry includes functionality for inhibiting operation of the liquid heating assembly, when the electric power status of the vehicle does not meet predetermined criteria. Further in accordance with a preferred embodiment of the present invention the electronic heating control circuitry receives inputs from at least one of a battery voltage sensor, a battery charging current sensor and a vehicle engine rotation speed sensor. Additionally or alternatively, the electronic heating control circuitry receives inputs from a battery voltage sensor, a battery charging current sensor and a vehicle engine rotation speed sensor. Further in accordance with a preferred embodiment of the present invention the liquid heating also includes a circulation pump operative for circulating heated liquid from the liquid heating volume through circulation conduits to heat at least one of liquid sprayers, windshield wiper blades and heated liquid supply conduits. Typically, the circulation pump is operated by the electronic heating control circuitry automatically in response to ambient outside temperatures. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly further includes at least one operator control for providing at least one operating input to the electronic heating control circuitry. Additionally in accordance with a preferred embodiment of the present invention the operator control communicates with the electronic heating control circuitry at least partially via existing wiring in a vehicle. Typically, the operator control causes application of signal modulation to electrical power lines interconnecting a vehicle battery with the electronic heating control circuitry and wherein the electronic heating control circuitry includes functionality for decoding such signal modulation and employing it for controlling functions of the liquid heating assembly. Preferably, the liquid heating assembly includes standby mode functionality. Further in accordance with a preferred embodiment of the present invention the standby mode functionality is actuated at least one of automatically and by a vehicle operator using a standby mode actuation switch. Still further in accordance with a preferred embodiment of the present invention the plurality of liquid inlet apertures are located at various azimuthal locations along the cylindrical wall portion. Further in accordance with a preferred embodiment of the present invention the cylindrical wall portion also includes a slot. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly operates in accordance with an operating protocol including the functional step of responding to a heated liquid spray demand signal, typically provided by a vehicle operator pushing a push button, associated with electronic heating control circuitry, operating at least a first heating element substantially continuously, thereby avoiding possible electrical interference resulting from high current switching. Typically, the liquid heating assembly operates in accordance with an operating protocol and includes the additional functional steps of measuring the temperature at the outlet of the liquid heating chamber and causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically varying between the peak threshold value and a somewhat lower threshold value. Preferably, the functional step of causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value, corresponds to cycles of spraying heated liquid onto a vehicle windshield, which in turn corresponds to supplying of unheated liquid to the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly operates in accordance with an operating protocol, which includes the following functional step of responding to a heated liquid spray demand signal, typically provided by a vehicle operator pushing a push button, associated with electronic heating control circuitry, operating at least a first and a second heating element substantially continuously, thereby avoiding possible electrical interference resulting from high current switching. Still further in accordance with a preferred embodiment of the present invention the heating assembly operates in accordance with an operating protocol including the following additional functional steps of measuring the temperature at the outlet of the liquid heating chamber and causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value. Preferably, the functional step of causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value, corresponds to cycles of spraying heated liquid onto a vehicle windshield, which in turn corresponds to supplying of unheated liquid to the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly operates in accordance with an operating protocol including the following functional step of responding to a heated liquid spray demand signal, typically provided by a vehicle operator pushing a push button, associated with electronic heating control circuitry, operating at least a first and a second heating element and a labyrinthine heating unit substantially continuously, thereby avoiding possible electrical interference resulting from high current switching. Preferably, the liquid heating assembly operates in accordance with an operating protocol including the following additional functional steps: measuring the temperature at the outlet of the liquid heating chamber, causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value. Typically, the functional step of causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value, corresponds to cycles of spraying heated liquid onto a vehicle windshield, which in turn corresponds to supplying of unheated liquid to the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly operates in accordance with an operating protocol including the following functional steps: responsive to a heated liquid spray demand signal, typically provided by a vehicle operator pushing a push button, associated with electronic heating control circuitry, operating at least a first heating element substantially continuously, thereby avoiding possible electrical interference resulting from high current switching and responsive to an immediate spray demand signal, provided by a vehicle operator actuating electronic heating control circuitry, providing a supply of pressurized liquid from the liquid heating chamber to the outlet, possibly even before commencement of operation of the at least first heating element. Typically, the liquid heating assembly operates in accordance with an operating protocol including the following additional functional steps: measuring the temperature at the outlet of the liquid heating chamber and causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value. Additionally in accordance with a preferred embodiment of the present invention the functional step of causing the temperature at the outlet of the liquid heating chamber to reach a peak threshold value and then periodically to vary between the peak threshold value and a somewhat lower threshold value, corresponds to cycles of spraying heated liquid onto a vehicle windshield, which in turn corresponds to supplying unheated liquid to the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention a labyrinthine heating unit is actuated prior to heated liquid spray demand signal. Still further in accordance with a preferred embodiment of the present invention the labyrinthine heating unit is actuated upon ignition of a vehicle when the ambient outside temperature is below a threshold. Further in accordance with a preferred embodiment of the present invention the peak threshold temperature varies in accordance with the boiling point of the spray liquid, thereby to provide efficient heating of the spray liquid without unnecessarily heating the liquid beyond its boiling point. Additionally in accordance with a preferred embodiment of the present invention the electronic heating control circuitry is operative: to monitor the temperature of the spray liquid within the liquid heating, once a relatively stable temperature is reached during continuous operation of at least one heating element, indicating that the approximate boiling temperature has been reached to note that stable temperature and to set the peak temperature threshold to be below the sensed stable temperature, whereby the peak temperature threshold is a function of the composition of the spray liquid. Further in accordance with a preferred embodiment of the present invention the standby mode functionality includes the following functional steps: upon vehicle ignition, the electronic heating control circuitry checks at least one of the following vehicle characteristics: vehicle battery voltage; vehicle battery charging current and vehicle engine rotation speed and compares them with predetermined minimum vehicle characteristic thresholds and if the minimum vehicle characteristic thresholds are met, a “GO” authorization is provided. Typically, the liquid heating assembly is operated in a standby mode as follows: if an outside temperature sensor is not available, the electronic heating control circuitry operates a labyrinthine heating unit and also operates at least one heating element in order to maintain the spray liquid in the liquid heating chamber at at least a first predetermined standby liquid temperature, if an outside temperature sensor is available, and the outside temperature measured thereby is greater than a first outside temperature threshold only the labyrinthine heating unit is operated, if the outside temperature measured by the outside temperature sensor is less than the first outside temperature threshold, but greater than a second outside temperature threshold, the labyrinthine heating unit is operated and at least one of the heating elements is additionally operated in order to maintain the liquid in the liquid heating chamber at at least a second predetermined standby liquid temperature and if the outside temperature measured by the outside temperature sensor is less than the second temperature threshold, the labyrinthine heating unit is operated and at least one of the heating elements is also operated in order to maintain the spray liquid at a third standby liquid temperature, greater than the first and second predetermined standby liquid temperatures. Typically, the minimum vehicle characteristic thresholds are approximately as follows: vehicle battery voltage: 12.5 Volts, vehicle battery charging current: 15 Ampere and vehicle engine rotation speed: 1000 RPM. There is also provided in accordance with yet another preferred embodiment of the present invention a heated liquid circulation system including a liquid heating assembly and a heated liquid circulation assembly for supplying heated liquid from the liquid heating assembly for circulation in thermal heat exchange engagement with at least one of a windshield wiper, a windshield sprayer and a liquid supply conduit for supplying liquid to the windshield sprayer. There is further provided in accordance with another preferred embodiment of the present invention a heated liquid circulation method including heating a liquid and supplying the heated liquid for circulation in thermal heat exchange engagement with at least one of a windshield wiper, a windshield sprayer and a liquid supply conduit for supplying liquid to the windshield sprayer. There is provided in accordance with yet a further embodiment of the present invention a heated liquid wiper and sprayer assembly, which includes a liquid heating assembly, at least one sprayer, a heated liquid supply assembly including at least one heated liquid supply conduit for supplying heated liquid from the liquid heating assembly to the at least one sprayer for spraying thereof, a heated liquid circulation assembly for supplying heated liquid from the liquid heating assembly for circulation in thermal heat exchange engagement with at least one of a windshield wiper, the at least one sprayer and to the at least one heated liquid supply conduit for heating thereof. There is further provided in accordance with a preferred embodiment of the present invention a heated liquid wiper and sprayer method. The method includes heating a liquid, supplying heated liquid to at least one sprayer for spraying thereof, via at least one heated liquid supply conduit and circulating the heated liquid in thermal heat exchange engagement with at least one of a windshield wiper, the at least one sprayer and the at least one heated liquid supply conduit. Further in accordance with a preferred embodiment of the present invention the heated liquid wiper and sprayer assembly also includes a windshield wiper assembly and a windshield wiper driver assembly operative to move the windshield wiper assembly in rotational and linear motion along a vehicle windshield, the at least one sprayer being mounted on the windshield wiper assembly. Still further in accordance with a preferred embodiment of the present invention the windshield wiper assembly includes a base, which is arranged for rotation about a rotation axis. Typically, the base is driven for reciprocating rotational motion by a conventional wiper drive assembly, forming part of a conventional motor vehicle. Further in accordance with a preferred embodiment of the present invention the sprayer includes a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying. Still further in accordance with a preferred embodiment of the present invention the heated liquid wiper and sprayer also includes a windshield sprayer assembly positioning assembly operative in response to the linear motion of the windshield wiper assembly for selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. Additionally in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly includes a base mounted housing, cooperating with the base and arranged for driven linear motion relative thereto. Typically, the driven linear motion of the housing relative to the base is provided by a cam drive assembly. Further in accordance with a preferred embodiment of the present invention the windshield wiper and sprayer assembly also includes a support arm, fixed to the housing for linear and rotational motion therewith. Still further in accordance with a preferred embodiment of the present invention the sprayer includes at least one heated liquid sprayer, which undergoes linear and rotational motion together with the housing and which receives pressurized fluid for spraying via fluid conduits. Additionally in accordance with a preferred embodiment of the present invention the windshield sprayer assembly positioning assembly includes an upstanding pin fixed to the base for rotary motion together therewith, the upstanding pin slidably engaging a base mounted housing slot formed in a bottom surface of the base mounted housing. Typically, the upstanding pin also slidingly engages an anchor element slot formed in an anchor element, which anchor element is linearly slidable relative to the base mounted housing and to the base along an axis generally parallel to the anchor element slot. Preferably, at least one compression wire is coupled to the anchor element. The one compression wire extends through at least one sleeve to the windshield sprayer assembly and controls the positioning of the sprayer housing closure relative to the sprayer housing. Further in accordance with a preferred embodiment of the present invention the sprayer assembly includes a pressurized fluid chamber, which is defined between the sprayer housing and the sprayer housing closure, the pressurized fluid chamber receiving pressurized fluid to be sprayed from a fluid conduit via an inlet pipe. Typically, the sprayer housing closure includes a cap which is selectably sealed against a corresponding sealing surface of the sprayer housing. Preferably, the cap is selectably sealed by a spring loaded shaft assembly, which includes a compression spring. Additionally in accordance with a preferred embodiment of the present invention the sprayer housing closure is normally positioned relative to the sprayer housing in the first position permitting spraying. Typically, the sprayer housing closure is normally positioned by operation of a spring loaded lever assembly, attached to an end of a compression wire. Typically, the spring loaded lever assembly includes a compression spring which normally urges a lever arm forward in engagement with a spring loaded shaft assembly, thereby overcoming the spring force of a further spring and urging the sprayer housing closure away from the sprayer housing. Additionally in accordance with a preferred embodiment of the present invention the spring force of the further spring exceeds the spring force of the compression spring. Further in accordance with a preferred embodiment of the present invention, when the housing is at an extreme inward radial orientation, the compression spring is enabled to seal the sprayer housing closure against sprayer housing. Typically, the engagement of the upstanding pin at a radial outward end of the anchor element slot applies a compressive force to a compression wire, which compressive force is sufficient to overcome the spring force of the further spring and to force the lever arm to an orientation wherein it does not engage the spring loaded shaft assembly and does not overcome the spring force of the compression spring. Preferably, when the base mounted housing is at the extreme inward radial orientation, both the anchor element and the base mounted housing are in their extreme retracted positions and a first separation is defined between an outward facing surface of the anchor element and an inner facing surface of the outer facing wall of the base mounted housing. Further in accordance with a preferred embodiment of the present invention the liquid heating assembly includes a housing defining a liquid heating chamber, a liquid heating volume defining subassembly disposed in the liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture and a labyrinthine heating unit receiving heated liquid from the liquid heating volume and providing further heated liquid to an outlet. Typically, the liquid to be heated is received under pressure at an inlet and passes through a conduit into the liquid heating chamber and thence into the liquid heating volume. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes a pump, which is not part of the original equipment in the vehicle, which pressurizes the liquid received via a conduit from a liquid reservoir, which is part of the original equipment of the vehicle. Further in accordance with a preferred embodiment of the present invention the also includes a pump, which pressurizes liquid received via a conduit from a liquid reservoir via a one-way valve. Typically, the liquid heating assembly is arranged for retrofit installation into an existing motor vehicle. Additionally in accordance with a preferred embodiment of the present invention the heated liquid wiper and sprayer assembly also includes a first liquid temperature sensor located near the top of the liquid heating chamber. Still further in accordance with a preferred embodiment of the present invention the liquid heating assembly also includes a second temperature sensor which is located in a wall of the liquid heating chamber. Further in accordance with a preferred embodiment of the present invention the second temperature sensor operates a circuit breaker switch, which is responsive to exceedance of a predetermined temperature threshold at the second temperature sensor for automatically interrupting the supply of electrical power from a vehicle battery to the liquid heating assembly. Typically, heated liquid from the liquid heating assembly is circulated alongside the heated liquid supply conduit and through the at least one sprayer by a circulating pump cooperating with a pair of circulation conduits, which are joined at the at least one sprayer to define a continuous circulation path. Preferably, the circulation conduits and the liquid supply conduit are defined in a unitary conduit. Typically, the circulation conduits generally surround the heated liquid supply conduit for efficient heat transfer therewith. Further in accordance with a preferred embodiment of the present invention the sprayer is formed with an internal liquid circulation path to which the circulation conduits are coupled. The liquid circulation path surrounds a heated spray liquid pathway which couples the heated liquid supply conduit to a spray head. Typically, upon initiation of a heated spray operation by a vehicle operator, the circulating pump is immediately actuated to begin circulating liquid from the liquid heating assembly, thus monotonically heating both the at least one sprayer and liquid in the heated liquid supply conduit, such that the liquid in the heated liquid supply conduit, when sprayed, is heated to a temperature above the ambient. Further in accordance with a preferred embodiment of the present invention the sprayer includes a sealed volume which receives spray liquid under pressure from the supply conduit at an inlet and is provided with a plurality of spray outlets for spraying the liquid under pressure onto a vehicle windshield and an internal heat exchanging liquid circulation pathway element, disposed within the sealed volume and coupled to the heated liquid circulation assembly. Additionally in accordance with a preferred embodiment of the present invention the windshield wiper assembly includes a wiper blade formed with an internal heat exchanging liquid circulation pathway element coupled to the heated liquid circulation assembly. Further in accordance with a preferred embodiment of the present invention the heated liquid wiper and sprayer method also includes receiving pressurized fluid into the sprayer and spraying the pressurized fluid onto the vehicle windshield. There is also provided in accordance with another preferred embodiment of the present invention a windshield sprayer controlling system, which includes a windshield wiper assembly, including a windshield wiper support arm and a windshield wiper, a windshield wiper driver assembly, which operates to move the windshield wiper assembly in rotational motion along a vehicle windshield and at least one windshield sprayer mounted on the windshield wiper assembly. The support arm controls the windshield sprayer in accordance with the direction of movement of the wiper assembly relative to the windshield. There is further provided in accordance with another preferred embodiment of the present invention a windshield sprayer controlling method. The method includes providing a windshield wiper assembly including a windshield wiper support arm and a windshield wiper with at least one windshield sprayer mounted thereon, moving the windshield wiper assembly in rotational motion along a vehicle windshield and controlling the at least one windshield sprayer in accordance with the direction of movement of the wiper assembly relative to the windshield. Further in accordance with a preferred embodiment of the present invention the windshield sprayer controlling system also includes at least one second windshield sprayer mounted on the windshield wiper assembly, the support arm controlling the second windshield sprayer in accordance with the direction of movement of the wiper assembly relative to the windshield. Still further in accordance with a preferred embodiment of the present invention the windshield sprayer controlling system according also includes at least one liquid supply conduit supplying liquid to the at least one windshield sprayer. Additionally in accordance with a preferred embodiment of the present invention the windshield sprayer controlling system also includes one liquid supply conduit supplying liquid the windshield sprayer. Moreover in accordance with a preferred embodiment of the present invention the windshield sprayer controlling system further includes one liquid supply conduit supplying liquid to at least one windshield sprayer and to at least one second windshield sprayer. Typically, the support arm also includes a control mechanism. Preferably, the control mechanism is located near an end of the support arm. Further in accordance with a preferred embodiment of the present invention the control mechanism is loosely pivotably mounted onto an end portion of the support arm generally along a first axis and includes a wiper blade which may be slidably and removably mounted within a track support element. The track support element is integrally formed with a pair of side attachment walls which are formed with aligned apertures through which extends an axle which extends generally along the first axis. This allows the windshield wiper assembly to pivot about the first axis in a conventional manner, wherein the loose mounting of the windshield wiper assembly onto the end portion also allows pivoting of the track support element relative to the end portion about a pivot axis, which intersects the first axis, wherein the pivoting about the pivot axis is employed to direct liquid to one or more of the sprayers in accordance with the direction of movement of the windshield wiper assembly at any given instant. Typically, the end portion of the support arm, which ties in a plane generally perpendicular to the surface of the windshield. Still further in accordance with a preferred embodiment of the present invention the end portion is formed with at least one engagement surface which can be brought into liquid flow interrupting operative engagement with one of two liquid conduits, which receive pressurized liquid via the supply conduit, thereby interrupting liquid flow therethrough. There is also provided in accordance with another preferred embodiment of the present invention a heated liquid spray system for vehicles, which includes a windshield washing subsystem. The windshield washing subsystem includes a windshield wiper and sprayer assembly including a windshield wiper assembly, a windshield wiper driver assembly operative to move the windshield wiper assembly in rotational and linear motion along a vehicle windshield, a windshield sprayer assembly mounted on the windshield wiper assembly. The windshield sprayer assembly includes at least one sprayer and the sprayer includes a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying. The windshield wiper and sprayer assembly also includes a windshield sprayer assembly positioning assembly which operates in response to the linear motion of the windshield wiper assembly for selectably positioning the housing closure relative to the housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. The heated liquid spray system further includes a liquid heating assembly subsystem, which includes a housing defining a liquid heating chamber and a liquid heating volume defining subassembly disposed in the liquid heating chamber and includes a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture. There is further provided in accordance with another preferred embodiment of the present invention a heated liquid spray method for vehicles. The method includes providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer including a sprayer housing and a sprayer housing closure movable relative to the sprayer housing, the sprayer housing closure providing a first position permitting spraying and a second position not permitting spraying, moving the windshield wiper assembly in rotational and linear motion along a vehicle windshield, selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in response to the linear motion of the windshield wiper assembly in accordance with the rotational position of the windshield wiper assembly, providing a liquid heating chamber, disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in the liquid heating chamber and supplying heated liquid from the liquid heating chamber to the sprayer. There is further provided in accordance with yet another preferred embodiment of the present invention a heated liquid spray system for vehicles, which includes a windshield washing subsystem. The windshield washing subsystem includes a windshield wiper and sprayer assembly including a windshield wiper assembly, a windshield wiper driver assembly operative to move the windshield wiper assembly in at least rotational motion along a vehicle windshield, a windshield sprayer assembly mounted on the windshield wiper assembly. The windshield sprayer assembly includes at least one sprayer, including a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying. The windshield wiper and sprayer assembly also includes a windshield sprayer assembly positioning assembly operative in response to the motion of the windshield wiper assembly for selectably positioning the housing closure relative to the housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. The heated liquid spray system also includes a liquid heating assembly subsystem and the liquid heating assembly subsystem includes a housing defining a liquid heating chamber and a liquid heating volume defining subassembly disposed in the liquid heating chamber and including a base portion and a generally cylindrical wall portion which is provided with at least one liquid inlet aperture. There is also provided in accordance with yet another preferred embodiment of the present invention a heated liquid spray method for vehicles. The method includes providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer including a sprayer housing and a sprayer housing closure movable relative to the sprayer housing, the sprayer housing closure providing a first position permitting spraying and a second position not permitting spraying, moving the windshield wiper assembly in at least rotational motion along a vehicle windshield, selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in response to the linear motion of the windshield wiper assembly in accordance with the rotational position of the windshield wiper assembly, providing a liquid heating chamber, disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in the liquid heating chamber and supplying heated liquid from the liquid heating chamber to the sprayer. There is also provided in accordance with yet another preferred embodiment of the present invention a heated liquid spray system for vehicles, which includes a windshield washing subsystem. The windshield washing subsystem includes a windshield wiper and sprayer assembly, which includes a windshield wiper assembly, a windshield wiper driver assembly operative to move the windshield wiper assembly in at least rotational motion along a vehicle windshield, a windshield sprayer assembly mounted on the windshield wiper assembly, the windshield sprayer assembly including at least one sprayer. The sprayer includes a sprayer housing and a sprayer housing closure arranged for selectable positioning relative to the sprayer housing and to assume a first position permitting spraying and a second position not permitting spraying. The windshield wiper and sprayer assembly also includes a windshield sprayer assembly positioning assembly operative in response to the motion of the windshield wiper assembly for selectably positioning the housing closure relative to the housing in either of the first and second positions in accordance with the rotational position of the windshield wiper assembly. The heated liquid spray system also includes a liquid heating assembly subsystem. The liquid heating subsystem includes a housing defining a liquid heating chamber, a liquid heating volume defining subassembly disposed in the liquid heating chamber and a labyrinthine heating unit receiving heated liquid from the liquid heating volume and providing further heated liquid to an outlet. There is also provided in accordance with yet another preferred embodiment of the present invention a heated liquid spray method for vehicles. The method includes providing a windshield wiper assembly having mounted thereon a windshield sprayer assembly including at least one sprayer including a sprayer housing and a sprayer housing closure movable relative to the sprayer housing, the sprayer housing closure providing a first position permitting spraying and a second position not permitting spraying, moving the windshield wiper assembly in rotational and linear motion along a vehicle windshield, selectably positioning the sprayer housing closure relative to the sprayer housing in either of the first and second positions in response to the linear motion of the windshield wiper assembly in accordance with the rotational position of the windshield wiper assembly, providing a liquid heating chamber, disposing a liquid heating volume defining subassembly, including a base portion and a generally cylindrical wall portion, including at least one liquid inlet aperture, in the liquid heating chamber, receiving heated liquid from the liquid heating volume into a labyrinthine heating unit, further heating the heated liquid and providing the further heated liquid from the labyrinthine heating unit to the sprayer. Further in accordance with a preferred embodiment of the present invention the heated liquid wiper and sprayer assembly also includes a heated liquid circulation assembly subsystem for supplying heated liquid from the liquid heating chamber for circulation in thermal heat exchange engagement with at least one of a windshield wiper, the at least one sprayer and the at least one heated liquid supply conduit, for heating thereof. |
Assays for identifying modulators of rhomboid polypeptides |
The present invention relates to proteins of the conserved Rhomboid family, which are involved in various signalling pathways within cells. Rhomboid proteins are found to possess a novel serine protease activity which cleaves within the transmembrane domain of a polypeptide substrate. Methods and uses of this activity are provided. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.