In a method for using a dumpster bag, the bag comprises: a flexible bag member including a bottom and a sidewall structure extending upward from the bottom to a rim; and a plurality of loops. The method comprises: engaging a hoist to a group of the loops; using the hoist to lift the bag containing contents; releasing the hoist from one or more of the loops; and using the hoist to again lift the bag to discharge the contents from the bag.

The disclosure relates to large waste bags or dumpster bags.
Several forms of dumpster bags have been sold commercially. One example is in International Application No. WO2007/108833A2, entitled "Bulk Material Handling System and Apparatus, published Sep. 27, 2007, the disclosure of which is incorporated by reference herein in its entirety as if set forth at length. An example of such a bag is seen in FIG. 3. As is discussed below, to hold its open form, this bag includes PVC pipe rim stays and sewn-in corner stay panels. Another bag has a generally rectangular planform wherein right angle corners are replaced by flat panels forming a near-rectangular octagon. Another bag is shown in U.S. Patent Application Ser. No. 61/745,938, filed Dec. 26, 2012, and entitled "Waste Bag and Assembly Methods" and U.S. patent application Ser. No. 14/141,267, filed Dec. 26, 2013, and entitled "Waste Bag and Assembly Methods", the disclosures of which are incorporated by reference herein in their entireties as if set forth at length.
Each of these exemplary bags has eight lifting/carry/securing/dumping loops: four top; and four bottom at or near the respective corners of the rectangular footprint. Typically, the upper four loops may be simultaneously used to lift whereas the lower four are dedicated to tie-down securing and dumping. For example, the upper four loops may be hooked to a hoist to lift a full bag into a metal dumpster or to another dump location. The hoist may be disconnected from those four and connected to an adjacent pair of the lower loops. The hoist may then use those two lower loops to invert and dump the bag contents.


An apparatus for performing mode scrambling in a multimode optical fibre 1 comprises an electromechanical transducer 3 and a signal generator 9. A portion of the fibre 1, which is in the form of a loop 5, is arranged with its ends 6 fixed to the transducer 3, but with the remainder of the portion being left free to vibrate. The signal generator 9 drives the transducer 3 so as to form a succession of bends of differing bend radii in the portion of the fibre as a beam of electromagnetic radiation travels through the fibre, thereby “scrambling” the beam as it travels through the fibre.

The present invention relates to methods and apparatus for use with optical fibres, and in particular to methods and apparatus that may be used for optical fibre mode scrambling.
As is known in the art, optical fibres for carrying electromagnetic radiation (such as laser light) can principally have two forms, so-called "single mode" and "multimode" fibres. A "mode" can be thought of as a small range of angles within an optical fibre core that a beam of electromagnetic radiation can propagate within and as, in effect, defining a transmission path of the beam through the optical fibre.
A "single mode" fibre is an optical fibre that only supports one mode (path) through the fibre, for example because its core and numerical aperture are so small that, in effect, radiation can only propagate along the axis of the fibre.
A "multimode" fibre on the other hand will support multiple modes or transmission paths through the fibre, such as a mode that travels along the axis of the fibre and other modes where the beam path travels at an angle to the axis of the fibre and undergoes total internal reflection at the boundary between the core and cladding of the fibre as it propagates down the fibre. Multimode fibres typically have a larger core diameter and/or numerical aperture than single mode fibres, so that they will support multiple transmission modes.
Single mode fibres can be useful because as there is only a single transmission mode (path) through the fibre, the geometry of their output beams (e.g. in terms of the beam diameter and numerical aperture) tends to be stable over time.
However, there can be situations in which a multimode fibre may be preferred. For example, in certain applications, such as fluorescence imaging of samples and flow cytometry, it can be important to achieve a uniform intensity distribution across the sample being analysed (i.e. to have the same intensity across the entire cross-section of the sample-illuminating laser beam). The output beam from a single mode fibre has a Gaussian power distribution, and therefore, to achieve a uniform intensity distribution across the output beam cross-section, additional optics are required.
On the other hand, a multimode fibre more naturally produces a uniform intensity cross-section output beam, and, indeed, would produce an output beam having this form if all the available modes in the fibre were "excited" (i.e. had electromagnetic radiation propagating along them).
A multimode fibre that has all its modes "excited" is typically referred to as being "filled", since the electromagnetic radiation is propagating in all available modes in the fibre.
However, a difficulty with using multimode fibres is that it can be difficult in practice to "fill" the fibre efficiently with electromagnetic radiation, i.e. to excite efficiently all the transmission modes that the fibre supports. This is because a typical laser beam that is launched into an optical fibre may be a single mode laser (i.e. where the output beam from the laser source propagates in a single, very small range of angles) and/or may have a restricted angular and/or spatial distribution, such that the input beam will not fill the entire acceptance angle cone and/or radiation-accepting cross-section of the multimode fibre. In this case, the input beam may only travel along a few of, rather than all of, the modes that are supported by the fibre (i.e. such that only a subset of the available transmission modes in the fibre will be excited by the laser beam).
Similar issues arise in the context of other electromagnetic radiation sources, such as other more spatially coherent sources, such as super-luminescent LEDs. Again, a super-luminescent LED may be unable in itself to "fill" all the modes of a multimode optical fibre.
A problem that arises when electromagnetic radiation propagates via only some but not all of the modes available in a multimode fibre is that this can make the output beam less consistent and not uniform over time. For example, any disturbance of the fibre in use, or variation in the launch conditions of the beam into the fibre (such as the launch alignment), can cause the "subset" of modes that the radiation is propagating via in the fibre to change. This in turn can lead to a variation in the output of the fibre, for example in terms of the output beam's direction, size, shape, and/or intensity. For example if the input beam is "swept" across the end of the fibre, the beam in the fibre will "sweep" through the available transmission modes in the fibre, and the output beam will correspondingly sweep across a range of output angles.
These effects, together with effects such as relative dispersion and interference between different modes in a multimodal fibre, result in what is commonly referred to as "modal noise".
One important effect and drawback of modal noise is that the intensity distribution of a beam output by a multimode optical fibre typically is not uniform across the beam's cross-section. This is shown in FIG. 1, which shows an exemplary output beam profile (cross-section) from a typical multimode optical fibre (i.e. in its natural, "raw" state without any adjustment or modification of the fibre or the optical system).
It is accordingly known to try to remove or reduce these effects of modal noise in the output beam from a multimode fibre. Typically this is done by trying to ensure that more, and ideally all, of the modes supported by the fibre are excited (i.e. traveled along) by the beam of electromagnetic radiation, since if all the modes in the fibre are excited (i.e. the beam "fills" the fibre), any variation in, e.g., launch conditions, will not cause a change in the modes propagating in the fibre (as all modes are excited in any event) (and thus should not cause a change in the output beam).
One way to try to achieve this is to try to "launch" the beam from the source into the fibre in such a way that the beam, in effect, "overfills" the core diameter and numerical aperture of the fibre as it enters the fibre. This is intended to ensure that the beam "fills" all the modes in the fibre. Such arrangements typically seek to expand or diffuse the beam before it enters the fibre, i.e. to, in effect, provide an "extended" source that can then completely "fill" the fibre. Another known similar approach is to attempt to raster scan the beam across the input face of the fibre core, again so as to try to ensure that the beam "fills" the fibre.
However, a drawback with these arrangements is that the necessary optical, etc., arrangements tend to result in loss of power from the beam. The arrangements can also be complex to use and maintain.
Another known technique for trying to excite all modes in a multimode optical fibre is known as "mode scrambling" (and the devices used to achieve this are typically referred to as "mode scramblers"). FIG. 2 shows schematically a perfectly "scrambled" output beam profile from a multimode fibre. It can be seen that the intensity of the beam is substantially uniform across the cross-section of the beam. The aim of mode-scrambling is to, in effect, make the overall geometry of the output beam (and in particular at least the beam diameter and numerical aperture) more stable over time, and, e.g., more robust to variable launch conditions (such as launch alignment). Mode-scrambling typically involves introducing perturbations into the optical fibre along its length, which perturbations will act to "excite" different and/or more modes in the fibre.
One known mode scrambling technique involves placing a series of bends of differing bend radii along the length of the optical fibre, for example by placing the fibre between two irregularly corrugated surfaces. This serves to "excite" extra propagation modes in the fibre, because at each bend, the beam will strike the core/cladding interface at a different angle or angles, thereby changing the angular distribution of modes in the fibre. The intention is that by forcing the beam around the bends of different radii as it travels along the fibre, these internal reflections will act to sweep the beam through and into all the modes that the fibre supports (i.e. to cause the beam to "fill" the fibre).
However, a disadvantage of this arrangement is that transmission losses may occur at each bend in the fibre, because, for example, one or more of the propagation modes may strike the cladding at an angle that does not cause total internal reflection (such that radiation is lost into the cladding).
It is also known to try to achieve mode scrambling by using a "daisy chain" of multimode fibres of different core diameters and/or numerical apertures. In this case, the intention is that as the beam passes from one fibre to the next in the "daisy chain", different or more propagation modes will be excited.
However, this arrangement can again cause transmission losses as the beam propagates through the fibres, as there may, for example, be losses at each interface between different fibre sections.
A third known mode scrambling technique is to include "scattering centres", such as non-optically clear regions, in a multimode optical fibre. Again, the intention is that the electromagnetic radiation (e.g. laser) beam will be "scattered" into different or more modes of propagation by the scattering centres. However, there is again a risk of transmission losses at each scattering centre that the beam encounters.
It is also known to use combinations of two or more of these techniques, but again this does not avoid the problem of transmission losses being caused by the "mode scrambling", etc.
Therefore, there remains scope for improvement to current mode scrambling techniques for use with optical fibres.

Methods and apparatus for use with optical fibres


A separable electrical connector with a housing formed of electrically insulating material includes an external grounding terminal anchor positioned in a grounding strip groove on the surface of the housing. The groove, in the form of an open-sided recess, receives and positions a suitably dimensioned grounding strip of electrically conductive material. The strip is coupled to the anchor by a screw fastener which engages mating screw threads formed in the anchor. One or more display surfaces surrounded by upstanding protective wall surfaces are formed on the exterior surface of the housing for the display of identifying indicia, and the base surf ace of the external grounding strip groove may be used as a display surface, if desired, in the absence of a grounding strip. The grounding terminal anchor may be made of electrically conductive material so that an anchored conductive grounding strip will be coupled to the housing both electrically and mechanically. When formed of conductive material, the grounding terminal anchor may serve as an electrical coupling between a conductive member mounted on the housing and one or more external conductors, or it may serve as a coupling between two or more conductors external to the housing, while serving at the same time as a mechanical coupling between the housing and the external conductors.

This invention relates generally to separable electrical connectors, and more specifically to an improved connector having provision for a separable and removable grounding strip to achieve electrical grounding and mechanical coupling with or between one or more mating devices independently of the current-carrying electrical contacts associated with the connector, and also having provision for conveniently labeling the connector with desired identifying indicia.
Electrical connectors with grounding contact members are well known in this art. It is common in such connectors, to provide one or more grounding contact elements which engage and disengage from mating connectors in a manner identical to the current-carrying contact elements. Such grounding contacts do not perform any significant additional mechanical coupling functions; and, by their nature, they must be engaged and disengaged simultaneously with the current-carrying contacts.
In various electrical connector applications, there is a need to separate the grounding function connections from the current carrying connections, for such purposes as: completing these connections independently of each other; or dispensing with the grounding connection entirely; or providing grounding for circuit elements which are not readily connectable through the interior of the connector. In addition, it may be desirable in some applications to combine the grounding connection with a mechanical coupling of the connector to a mating connector or utilization device, independently of the current-carrying function. In connectors such as these, which are capable of diverse coupling arrangements, it may be necessary or desirable to provide a means for informing users and operators about specific coupling arrangements or other unique aspects of particular applications.
Accordingly, it is an object of this invention to provide an electrical connector having the capability of being electrically grounded and mechanically coupled to a mating device independently of the current-carrying function of the connector.
It is another object of this invention to provide a connector having means for combining the grounding connection and a mechanical coupling function in a simple and economical manner.
It is another object of this invention to provide a connector in which grounding between circuit elements external to the connector can be accommodated readily.
It is still another object of this invention to provide a connector of the type described having readily locatable and clearly visible means for displaying identifying indicia.
It is still another object of this invention to provide a connector of the type described which is convenient to use and which is adaptable for grounding with various different mating connectors and devices in a wide variety of installations and configurations.
A feature of this invention is a connector housing having an open-sided guide recess formed in an outer wall of the housing, for receiving and positioning a separate and independent grounding strip of conductive material, and a grounding element, accessible within the recess and engageable with the grounding strip for electrically coupling the connector to a mating device.
Another feature of this invention is a connector housing having an open-sided guide recess for a grounding element of the type described, together with a display recess formed in a visible location on an outer wall of the housing and having a planar base surface for supporting and displaying indicia thereon.
These and other and further objects, features and advantages of this invention will be made apparent to those having skill in this art, by reference to the following description and to the accompanying drawings, in which:

Electrical connector with adaptable external ground and indicia display


A new and distinct variety of clingstone peach tree which is characterized principally as to novelty by a date of harvesting and shipment approximately July 1 through July 5 under the ecological conditions prevailing in the Sacramento Valley of California.

The present invention relates to a new and distinct variety of peach tree which has been denominated varietally as "Thiara", and more particularly to such a peach tree which produces clingstone fruit which are mature for commercial harvesting and shipment from approximately July 1 to July 5, under the ecological conditions prevailing in the Sacramento Valley of California and which is further distinguished as to novelty by producing a clingstone fruit, the flesh of which is firm, fine-textured, and which has a golden yellow color, and which further has a nearly globose form; the fruit of the subject variety being sweet, mild, and well-balanced in flavor and having a pleasant aroma.
It has long been known that the marketability of peaches can be influenced, to some degree, by numerous factors including its date of harvesting and shipment, as well as its external appearance.
The new and novel variety of peach tree described, herein, is noteworthy for producing an attractively colored, early season clingstone peach which is ripe for commercial harvesting and shipment from approximately July 1 to July 5 under the environmental conditions existing in the Sacramento Valley of Calirornia.


The invention provides improved methods of introducing site-directed mutations into circular DNA molecules of interest by means of mutagenic primer pairs. The mutagenic primer pairs are also selected so as to be either completely complementary or partially complementary to each other, wherein the mutation site (or sites) is located within the region of complementarity. A mutagenic primer pair is annealed to opposite strands of a circular DNA molecule containing the DNA sequence to be mutagenized. After annealing, first and second mutagenized DNA strands, each incorporating a member of the mutagenic oligonucleotide primer pair is synthesized by a linear cyclic amplification reaction. After the linear cyclic amplification mediated synthesis step is completed, the reaction mixture is treated with a selection enzyme that digests the parental template strands. After the digesting step, a double-stranded circular DNA intermediate is formed. The double-stranded circular DNA intermediates is transformed in suitable competent host cells and closed circular double-stranded DNA corresponding to the parental template molecules, but containing the desired mutation or mutations of interest, may be conveniently recovered from the transformed cells. The invention also provide kits for site-directed mutagenesis in accordance with methods of the present invention.

Site-directed mutagenesis has proved to a remarkably useful tool in molecular biology. Polynucleotides having pre-determined sequences may now be designed at will. Polymerase chain reaction (PCR) and various other cyclic amplification reactions have been adapted for use in site-directed mutagenesis. Although site-directed mutagenesis through PCR (the polymerase chain reaction) is widely used, PCR based site-directed mutagenesis techniques, have several shortcomings.
Several problems exist when trying to perform site-directed mutagenesis on double-stranded DNA molecules. These problems include strand separation and selection against the parental (non-mutated) DNA. Efficient strand separation is important because in a typical site-directed procedure, a single polynucleotide primer containing the desired sequence alteration must compete with the much longer complementary strand for a hybridization site. Both physical and chemical methods for strand separation have been used. Physical methods include the attachment of the DNA strands to a solid phase, such as a plastic bead (Hall, et al. Protein Eng. 4:601 (1991); Hultman, et al. Nucleic Acids Research 18:5107–5112 (1990); Weiner, et al. Gene 126:35–41 (1993), or the use of heat as a denaturant (Landt, et al. Gene 96:125–128 (1990); Sugimoto Analytical Biochemistry 179.:309–311 (1989). Chemical methods for strand separation usually rely on increasing the pH of the solution containing the DNA duplex (Weiner, et al. Gene 126:35–41 (1993).
Following strand separation, the primer is annealed to the parental strand and used to initiate DNA replication. After replication a means must be used to reduce the parental plasmid DNA contribution of the heteroduplex before or after cell transformation. Both in vivo and in vitro methods have been developed for this reduction. In non-amplification based in vivo site-directed methods, the incorporation of dUTP into parental DNA during growth of the vector can be selected against in dut*, ung* E coli cells (Kunkel Proc. Natl. Acad. Sci. (U.S.A.) 82:488–492 (1985). In vitro methods for selection of the mutated strand include; i) unique restriction site elimination (Deng, et al. Analytical Biochemistry 200:81–88 (1992), ii), solid phase techniques (where the parental DNA remains attached to the solid phase; Hultman, et al. Nucleic Acids Research 18:5107–5112 (1990); Weiner, et al. Gene 126:35–41 (1993), and iii) incorporation of modified bases in the newly replicated DNA (Taylor et al. Nucleic Acids Research 13:8765–8785 (1985); Vandeyar, et al. Gene 65:129–133 (1988).
When PCR has been used for site-specific mutagenesis, a strand separation is accomplished during the high temperature denaturation step in the cycling reaction. Selection against the parental DNA is usually accomplished by decreasing the amount of starting template and increasing the number of rounds of cycling. This increase in the number of cycles has the adverse effect of increasing the rate of spontaneous second-site mutations, especially if an error-prone polymerase such as Taq DNA polymerase is used. In a typical experiment, the mutated fragment is often subcloned from one vector to another. Often, different antibiotic resistance markers are alternated or the mutated fragment is gel isolated. Descriptions of the use of the polymerase chain reaction (PCR) in site specific mutagenesis can be found in Hall, et al. Protein Eng. 4:601 (1991); Hemsley, et al. Nucleic Acids Research 17:6545–6551 (1989); Ho, et al. Gene 77:51–59 (1989); Hultman, et al. Nucleic Acids Research 18:5107–5112 (1990); Jones, et al. Nature 344:793–794 (1990); Jones, et al. Biotechniques 12:528–533 (1992); Landt, et al. Gene 96:125–128 (1990); Nassal, et al. Nucleic Acids Research 18:3077–3078 (1990); Nelson, et al. Analytical Biochemistry 180:147–151 (1989); Vallette, et al. Nucleic Acids Research 17:723–733 (1989); Watkins, et al. Biotechniques 15:700–704 (1993); Weiner, et al. Gene 126:35–41 (1993). Yao, et al. PCR Methods and Applications 1:205–207 (1992). The use of site-directed mutagenesis is also described in Weiner et al, Gene 151:1/9–123(1994).
Given the many different methods of site-directed mutagenesis that are in use, it is clear that no single technique currently available solves all of the problems associated with the site-directed mutagenesis. Given the state of the art, it is clearly of interest to provide researchers (both industrial and academic) with useful new methods of site-directed mutagenesis. To this end, the inventors have developed new techniques for site-direct mutagenesis that have an advantageous combination of features as compared to other techniques for site-directed mutagenesis. These useful features include: (1) low secondary mutation frequency, (2) high mutation efficiency, and (3) a minimal number of steps, thereby permitting the generation of host cells containing the mutant sequences in less than 24 hours.


A controller of a field winding type synchronous motor is provided that can stably output torque even if the d-axis current pulsates by reducing torque pulsation without causing fluctuation in the magnetic flux acting on the torque. A motor control unit 100 performs control so that a desired torque can be generated from a field winding type motor 20 having a field winding 22f on the rotor. Based on a current Id flowing in the d-axis direction out of the current flowing in a stator winding 22a of the field winding type motor 20, the motor control unit 100 calculates an induced voltage Vf2 being induced in the field winding 22f and compensates a field voltage Vf of the field winding based on the induced voltage Vf2, thus suppressing pulsation of the field current flowing in the field winding of the field winding type motor 20.

Recent years have seen an increase in the number of motor-driven vehicles including electric vehicles, hybrid automobiles, and other environmentally friendly vehicles. Further, in addition to environmentally friendly vehicles, electric four wheel driving vehicles having an engine for directly driving front wheels and a motor for driving rear wheels are also becoming widely used. As a drive motor for these electric automobiles, a synchronous motor is mainly used because of its compact size and high efficiency. There are several types of synchronous motors: an embedded type permanent magnet motor having an embedded permanent magnet in the rotor, a surface type permanent magnet motor having a permanent magnet attached at the periphery of the rotor, a field winding type synchronous motor having a field winding on the rotor side to draw a current therein to generate a magnetic flux, etc.
All of these synchronous motors have a magnetic flux on the rotor side. There are various methods of having a magnetic flux. For example, a permanent magnet motor includes a permanent magnet on the rotor, and a field winding type motor generates a magnetic flux by sending a current to the field winding. A motor generates torque by drawing a current in a stator winding on the stator side in such a way that the current perpendicularly intersects with the magnetic flux on the rotor side.
As mentioned above, the motor has a magnetic flux; therefore, at high rotational speeds of the motor, an induced voltage occurs according to the rotational speed. The greater the rotational speed of the motor becomes, the higher the induced voltage becomes. If the induced voltage exceeds a system voltage, an adequate current to output a required torque cannot be sent at that rotational speed.
Measures generally taken to restrain the rise of the induced voltage are referred to as "field weakening control." With a permanent magnet motor, field weakening control is achieved by sending a current in the negative direction of the d axis so as to cancel the magnetic flux generated by the rotor in the magnetic flux direction of the rotor (generally in the d-axis direction) out of the stator winding currents. With a field winding type synchronous motor, on the other hand, the magnetic flux can be reduced by directly reducing the field current.
Further, when a field winding type motor is used, the above-mentioned two field weakening control methods are used together in some applications. In this case, as disclosed in Japanese Patent No. 3331734, there are two different methods. In one method, the field current is sent in inverse proportion to the rotational speed. In the other method, the stator winding current is split into a component having the same phase as the induced voltage and a component perpendicularly intersecting therewith (so-called d-axis current and q-axis current, respectively), and each current is controlled. Under the methods disclosed in Japanese Patent No. 3331734, it is possible to generate a desired torque while suppressing a voltage induced by the motor because each of the field current and the d-axis current can be controlled.    Patent reference 1: Japanese Patent No. 3331734

Controller of field winding type synchronous motor, electric drive system, electric four wheel driving vehicle, and hybrid automobile


A method for operating a user equipment (UE) comprises receiving configuration information including P>1 beam switching time (BST) values and a set of TCI states; receiving, based on the configuration information, a transmission configuration indicator (TCI) state update; determining a beam based on the TCI state update; and applying the beam for a downlink (DL) reception or an uplink (UL) transmission, at least after a duration of time from receiving the TCI state update, wherein the duration of time is determined based on the P BST values.

Understanding and correctly estimating the channel between a user equipment (UE) and a base station (BS) (e.g., gNode B (gNB)) is important for efficient and effective wireless communication. In order to correctly estimate the DL channel conditions, the gNB may transmit a reference signal, e.g., CSI-RS, to the UE for DL channel measurement, and the UE may report (e.g., feedback) information about channel measurement, e.g., CSI, to the gNB. With this DL channel measurement, the gNB is able to select appropriate communication parameters to efficiently and effectively perform wireless data communication with the UE. For a millimeter wave communication systems, the reference signal can correspond to a spatial beam, and the CSI can correspond to a beam report which indicates a preferred spatial beam for communication. In such beamformed systems, a beam indication mechanism is needed in order to align the spatial beams at both gNB and UE.

Method and apparatus for dynamic multi-beam operations


An electro-optic modulator includes a doped semiconductor crystal having a crystallographic surface having an amplitude modulation orientation, a first metal electrode located on a first surface of the doped semiconductor crystal, a second metal electrode located on a second surface of the doped semiconductor crystal, and accumulation space charge regions located within surface regions of the doped semiconductor crystal that are proximal to the first metal electrode and the second metal electrode and including excess charge carriers of a same type as majority charge carriers of the doped semiconductor crystal.

Cadmium telluride (CdTe) single crystals and Cadmium Zinc Telluride (CZT) single crystals exhibit high electro-optic coefficients and a wide infrared (IR) transmission wavelength range. For this reason, CdTe single crystals and (CZT) single crystals are the materials of choice for electro-optic modulators and switches in the near IR to long IR wavelengths. In these crystals, the electro-optic effect is realized either by amplitude modulation or by frequency modulation. The crystal is cut in specific directions which provide the maximum amplitude modulation and/or frequency shifting effects. For amplitude modulation (AM), single crystal bars are cut such that the light propagates in the <110> direction and metal electrodes are applied on the (1Ī0) surfaces as illustrated in FIG. 1. FIG. 2 shows an alternative configuration disclosed in R. O. Bell, "Review of optical applications of CdTe"; Revue de Physique Appliquee, 12 (2), pp. 391-399 (1977). In the configuration of FIG. 2, the optic axis is in <211> direction and the metal electrodes are applied on the (111) surfaces albeit at lower modulation efficiencies. A key benefit of electro-optic modulators is that very high modulation frequency can be achieved which are not otherwise possible. For example, acousto-optic modulation frequencies are lower than the modulation frequencies provided by electro-optic modulators as discussed in T. A. Maldonado, "Handbook of optics Vol. 2—Electro-Optic Modulators," McGraw-Hill Inc., (1995).
Semiconductors or semi-insulators such as CdTe, CZT and Gallium Arsenide (GaAs) absorb photon energies in the near infrared (NIR) frequency ranges close to the band edge region, and generate photon-induced charge carriers in the crystal bulk. With the application of an electric field, the electrons and holes move towards the positive and negative terminals respectively and constitute the photo current. Presence of impurities and lattice defects in the crystal disturb the periodicity of the lattice and create energy levels in the forbidden energy gap. These defect levels appear as either positively charged or negatively charged in ionized state and act as traps or recombination centres for electrons or holes respectively. They thus reduce the mobility and life time of the charge carriers under bias and detrimental to applications which require fast charge carrier transport. The probability of trapping and/or recombination depends on the density of these traps and the capture cross-section of each trap. Furthermore, the de-trapping time depends on the position of the energy level occupied by the trap in the forbidden gap.
In general, charge carriers trapped in shallow levels which are located closer to the conduction band minimum and the valance band maximum de-trap fast. But traps located deep into the forbidden gap near the mid-gap can have long de-trapping time of the order of several milliseconds. The resulting volume spatial charge distribution due the charge carriers trapped or recombined at deep levels creates an opposite electric field to the applied electric field. This is called space charge induced polarization effect, whose magnitude will increase with increase in the absorbed photon flux and will reduce with the magnitude of the applied voltage. At large enough optical fluxes (such as at 108-109 photons per mm2 per second) and photogenerated carrier densities, the space charge field can counter balance, or even overwhelm, the applied electric field. At such conditions, the electric field in the volume of the semiconductor can collapse and the crystal will no longer be birefringent.
European Patent No. EP 1285309 A1 to Boffi et al. describes a CZT based electro-optic modulator, and discloses that CdxZn1-xTe with x in the range of 0.8 to 0.95 unexpectedly experience only slight or no polarisation or auto-inhibition effect near the band edge, i.e., in a wavelength band of about 1,000 nm to 1,650 nm.
U.S. Pat. No. 7,099,069 B2 to Zappetini et al. describes a method of eliminating the space charge polarization effects in a Cd1-xZnxTe (where x ranges from 0.07 to 0.1) based electrooptic modulator that operates in the band edge region, i.e., in a wavelength band of about 1,000 nm to 1,650 nm. Zappetini et al. disclose that by holding the semiconducting crystal at a temperature higher than the room temperature (i.e., in the range of 50° C.-150° C.), the deleterious effects of the space charge polarization can be eliminated. The underlying mechanism is that the raise in temperature creates enough thermally generated charge carriers which fill, or neutralize, the deep level charge centres. Once filled and neutralized, these deep level trap centers can no longer pose impediment to free movement of charge carriers and hence will not create space charge polarization issues.
Several studies have also explored the possibility of eliminating the space charge effects by illuminating with sub-band gap or above band gap wavelength lights. A. L. Washington et al., "Response of the Internal Electric Field in CdZnTe to Illumination at Multiple Optical Powers"; Journal of Electronic Materials, Volume 41, Issue 10, pp. 2874-2879 (2012) reported manipulation of the internal electric field of CZT using multiple wavelengths of light at various optical power settings. The use of multiple optical power levels allows the internal electric field or polarization to be gradually controlled and observed. The internal electric field was shown through the polarization in the infrared (IR) transmission image under illumination as observed by the Pockels set up. J. Franc et al, "Control of electric field in CdZnTe radiation detectors by above-bandgap light", Journal of Applied Physics 117, 165702; doi: 10.1063/1.4919073 (2015) investigated the effects of illumination with sub-bandgap and above band gap wavelength lights on the polarisation and depolarisation effects of CZT detectors.
Crystals having cubic symmetry such as CdTe and CZT are piezoelectric. The piezoelectric constant d14 for CdTe has been reported to be 1.54 C/N by D. Berlincourt et al. "Electroelastic Properties of the Sulfides, Selenides, and Tellurides of Zinc and Cadmium", Phys. Rev. 129, 1009 (1963). Due to the converse piezoelectric effect, a voltage applied to the modulator will induce strain in the crystal lattice. When operated below the first resonance frequency, the lattice is free to move with the applied field and this frequency range is termed 'unclamped.' The electro optic coefficient will then have contributions from the linear electro optic effect and the elasto-optic effect and can be expressed as: r41′=r41+p44d14, where r41 is the linear electro-optic coefficient measured at 'clamped' condition above the first resonant frequency, p44 is the elasto-optic coefficient and d14 is the piezoelectric coefficient. The values of r41′ and r41 are reported to be in the range of 5.4-5.8 pm/V and 3.8-4.2 pm/V, respectively by G. L. Herrit and Herman E. Reedy, "Measurement of the electro-optic coefficient for Gallium Arsenide and Cadmium Telluride modulator rods"; Materials Research Society Symposium Proceedings, Vol. 152, pp. 152-169 (1989).
Other publications which discuss general operational properties of electro-optic modulators and metal-semiconductor contacts include: R. O. Bell, "Review of optical applications of CdTe"; Revue de Physique Appliquee, 12 (2), pp. 391-399, (1977); L. J. Brillson in "Surfaces and Interfaces of Electronic Materials" WILEY-VCH, ISBN: 978-3-527-40915-0, pp. 19-63 (2010); S. Li et al., "Optimizing CdTe-metal interfaces for high performance solar cells"; Journal of Materials Chemistry A, 5, pp. 7118-7124 (2017); D. Odkhuu et al., "Atomic and electronic structure of CdTe/metal (Cu, Al, Pt) interfaces and their influence to the Schottky barrier"; Journal of Applied Physics 120, pp. 185703-1-185703-8 (2016); and J. P. Ponpon, "A Review of ohmic and rectifying contacts on Cadmium Telluride"; Solid State Electronics, Vol. 28, No. 7, pp. 689-706 (1985). All of the various cited publications are incorporated herein by reference in their entirety.

Fast-switching electro-optic modulators and method of making the same


A process of forming milled solid particles of a compound comprising milling solid particles of the compound in a liquid organic medium continuous phase in the presence of polymeric milling media to reduce the average size of the compound particles, wherein the liquid continuous phase comprises a solvent for the milling media polymer in the uncrosslinked form and the milling media is crosslinked sufficiently to prevent 50 vol. % swelling of the polymeric milling media in the liquid continuous phase within four hours at 25.degree. C. In various preferred embodiments of the invention, polymeric milling media having a mean particle size of less than about 100 .mu.m in the unswelled state (i.e., prior to addition to the liquid organic continuous phase) is used; the compound particles are milled to an average particle size of less than 100 nm; the compound comprises electrophotographic toner pigment; the liquid continuous phase comprises an ethylenically unsaturated polymerizable monomer; and the milling media polymer comprises polymerized styrene and divinylbenzene monomers. In an additional preferred embodiment of the invention wherein the compound comprises electrophotographic toner pigment and the liquid organic medium continuous phase comprises an ethylenically unsaturated polymerizable monomer, electrophotographic toner particles are formed by polymerizing the ethylenically unsaturated polymerizable monomer after the toner pigment compound is milled. It is a particularly advantageous feature of this invention that there is provided a method of preparing extremely fine solid particles of a compound free of unacceptable contamination and/or discoloration using polymeric milling media in a liquid continuous phase which is an effective solvent for the milling media polymer in uncrosslinked form. It is a further advantage of the invention to allow for preparing electrophotographic toner particles directly from a milled toner pigment particle dispersion without first needing to separate the milled particles from the liquid milling medium continuous phase. The ability to form extremely fine, e.g., less than 100 nm, size pigment particles in accordance with the invention is especially advantageous where toner particles are subsequently formed by suspension polymerization of ethylenically unsaturated monomers after milling of the pigment particles.

Electrophotographic toner particles typically comprise a mixture of a polymer and very fine pigment particles. The toner particles may be made by dispersing the pigments in an organic solvent, such as ethyl acetate or methylene chloride, along with the dissolved polymer and other addenda followed by droplet formation in an aqueous phase and removal of the solvent to solidify the particles (see, e.g., U.S. Pat. No. 4,833,060). Another technique for making electrophotographic toner particles is to disperse pigments in ethylenically unsaturated monomers along with other addenda followed by droplet formation in an aqueous phase and suspension polymerization of the ethylenically unsaturated monomers to solidify the particles (see, e.g., U.S. Pat. No. 4,965,131).
Reducing the pigment's particle size prior to incorporation into a toner particle is desirable in order to increase the covering power of the pigment and therefore reduce the amount required. In view of the electrophotographic toner particle manufacturing procedures described above, it is desirable to mill the pigment particles directly in the organic solvent used to dissolve the toner particle polymer, or in the monomer solution used to form the toner particle, thereby eliminating the need to separate the milled pigment from the liquid milling medium continuous phase prior to formation of the toner particle. The use of conventional organic solvent insoluble milling media such as steel, ceramic or glass beads in an attrition mill to reduce the pigment particle size, however, suffers from several problems. First, excessive levels of metallic, ceramic or other contamination usually result. Metallic contamination is particularly undesirable in an electrophotographic toner where careful control of the toner particle's charging properties is required. Second, while the use of very fine milling media can result in desirably smaller pigment particles, it is generally difficult to obtain metallic, ceramic or glass milling media of a size smaller than 100 mm.
The use of polymeric milling media to grind materials down to a very small size is known, such as described in U.S. Pat. No. 5,478,705, which discloses milling of compounds useful in imaging elements using polymeric milling media, preferably based upon crosslinked or non-crosslinked polymers made from acrylic and styrenic monomers. U.S. Pat. No. 5,500,331 teaches the advantages associated with the use of milling media smaller than 100 .mu.m when milling compounds useful in imaging, and specifically discloses the use of polymeric milling media of such size. While both dry and wet milling is possible when using polymeric milling media, wet milling is generally preferred.
It would be desirable to be able to effectively mill electrophotographic pigment particles using polymeric milling media directly in the organic solvent used to dissolve the toner particle polymer, or in the monomer solution used to form the toner particle, thereby eliminating the problems associated with the use of steel, ceramic or glass beads as the milling media. Such organic liquid media, however, are generally effective solvents for useful polymeric milling media polymers, such as polymers made from acrylic and styrenic monomers, while liquid dispersion medium which does not dissolve polymeric milling media is generally recommended when using polymeric milling media. U.S. Pat. No. 5,478,705, for instance, states that the preferred liquid dispersion medium is water (col 5, line 15), and while additional useful liquid dispersion mediums are indicated (col 4, line 19), all are not significant solvents even for uncrosslinked polystyrene. The use of polymeric milling media in liquid dispersion media comprising good solvents for the polymers which make up the milling media would not be expected to be effective, even if the polymers were sufficiently crosslinked to make the polymers insoluble in the liquid media, due to the plasticizing, or softening effect of the solvent on the polymer.
Additionally, it would also be desirable to provide dispersions of other solid compounds useful in imaging elements in a liquid continuous phase which comprises a good solvent for polymers which would make effective milling media when preparing solvent based coating compositions containing such compounds. The solvent based coating compositions must have unique combinations of properties such as volatility, viscosity, surface tension, etc., to enable effective coating processes, which properties may be advantageously met by liquids which are frequently good solvents for many polymers.
Accordingly, it is an object of the invention to be able to provide a process for forming a dispersion of small solid particles in a liquid dispersion medium continuous phase which comprises a good solvent for polymers which would make effective milling media.

Method to media mill particles using crosslinked polymer media and organic solvent


According to the present invention, there is provided a gene therapy material which includes a nucleic acid material and a carbohydrate wherein the carbohydrate preferably is a modified pectin. Also in accordance with the present invention, there is provided a gene therapy material including a nucleic acid material, a carbohydrate material associated with the nucleic acid material, and a protective coating disposed about the carbohydrate material.

The present invention generally relates to gene therapy. More particularly, the present invention relates to a gene therapy material which includes a nucleic acid material and a carbohydrate as a delivery vehicle.
Gene therapy involves the use of genetic material as a therapeutic agent. More specifically, in gene therapy a natural or synthetic gene or an analog thereof is introduced into a patient""s tissue, where activation of the gene produces a therapeutic effect. Gene therapy shows great promise for curing various metabolic diseases resulting from a deficiency of, or malformation of, enzymes, proteins, neurotransmitters and other biological molecules. Gene therapy also shows significant promise for treating diseases such as cancer, wherein the introduced gene acts to induce apoptosis, which is programmed cell death, or to otherwise shrink tumors.
The most significant problem heretofore encountered in the practical implementation of gene therapies, has been in delivering therapeutically effective amounts of genetic material into a target tissue. A number of approaches to the delivery problem have been implemented in the prior art. In one approach, a DNA plasmid including the therapeutic gene is injected into the patient. Some limited success has been achieved when this naked DNA is directly injected into a tumor; however, problems arise in obtaining access to the tumor and providing a continued delivery of the therapeutic material to the tumor site. Attempts have been made to inject the naked DNA intravenously; however, such attempts have not been very successful. In other instances, the therapeutic material is incorporated into a virus, typically in the form of a plasmid, and this virus is utilized to infect the target tissue. This approach is occasionally successful; however, the virus is often inactivated by the immune system or fails to infect the target tissue. Furthermore, the delivery of genes using viral vectors raises concerns regarding efficacy, efficiency, viral infection, toxicity, and delivery which limit the broader use of gene therapy delivered through viral vectors. Another approach has been to utilize mutated viruses specifically adapted to avoid immune system inactivation and/or better infect the target tissue. Another approach has been to utilize a mixture of a high molecular weight synthetic polymer with the DNA. Limited success has been achieved with such materials.
Thus, it will be appreciated that there is a need for a delivery system and method for providing gene therapy materials to target tissues. The system and methods should preferably be highly effective, simple to implement, the compounds should be highly stable in vivo, and reduce the need for repeated administration.
According to the present invention, there is provided a gene therapy material which includes a nucleic acid material and a carbohydrate wherein the carbohydrate preferably is a modified pectin.
Also in accordance with the present invention, there is provided a gene therapy material including a nucleic acid material, a carbohydrate material associated with the nucleic acid material, and a protective coating disposed about the carbohydrate material.
Also in accordance with the present invention, there is provided a method for treating a tumor of the type which has carbohydrate binding sites expressed on the surface thereof by providing a therapeutic material, incorporating the therapeutic material into a body of a modified pectin material so as to produce a therapeutic composition, and administering the therapeutic composition to a patient.
In accord with the present invention, it has been found that carbohydrates can provide a very effective delivery vehicle for DNA and other such nucleic acid materials used in gene therapy. That is, a therapeutically effective amount of a therapeutic composition of the carbohydrate and the nucleic acid material can be administered to a patient or subject having a tumor to treat the tumor by causing a reduction and/or an elimination of the tumor from the patient. In the context of this disclosure, nucleic acid materials are meant to comprise genes, plasmids containing genes, other strands of DNA, RNA, and like materials. It has been found that when nucleic acid materials are mixed with, and preferably encapsulated by, carbohydrates, these materials are protected and efficiently delivered to target cells. Multiple genes can be delivered at one time and can be delivered in a single vector or in multiple vectors encapsulated by the carbohydrates of the present invention. The carbohydrate based gene therapy materials of the present invention have been found to be effective even when administered orally, although such materials could also be delivered intravenously or by direct injection to a target tissue (i.e. a tumor).
In the context of this disclosure, carbohydrates shall refer to any hexose or pentose structure and shall specifically include complex carbohydrates as well as simple carbohydrates. One particularly preferred carbohydrate which can be employed in the present invention is a modified citrus pectin material, and such materials are disclosed in U.S. patent application Ser. No. 08/024,487 filed Mar. 1, 1993 and U.S. patent application Ser. No. 08/819,356 filed Mar. 18, 1997 and is referred to herein as GBC-590. The modified citrus pectin material is non-toxic, stable for oral administration, has good uptake characteristics, stable in the circulation for days vs. hours, specifically targeted to tumors, and can be packaged for efficient uptake by tumor cells. The main chains of the modified citrus pectin have the structure
[-4)-xcex1-D-GalpA-(1-4)-xcex1-D-GalpA-(1-]n-4)-xcex1-D-GalpA-(1-2)-xcex2-L-Rhap-(1-[-4)-xcex1-D-GalpA-(1-4))-xcex1-D-Galp-(1-] with minor structural features including
(a) interrupted regions in rhamnogalacturonan chains (configurations and linkage types as above)
xe2x80x94GalA-Rha-GalA-Rha-GalA-GalA-Rha-Rha-GalA-,
(b) short side chains
xcex2-D-xylp-(1-3)-xcex2-D-Galp-(1-2)-D-Xylp-(1-xcex1-L-fucp-(1-2)-D-Xylp-(1-L-araf-(1-3)-D-Apif-(103)-D-Apif-(1-, and
(c) extended side chains
-4-xcex2-D-Galp-(1-4)-xcex2-D-Galp-(1-xcex1-L-Araf-(1-5)-xcex1-L-Araf-(1xe2x80x94
3
↑
1
xcex1-L-Araf.
The terms xe2x80x9cpatientxe2x80x9d or xe2x80x9csubjectxe2x80x9d as used herein mean all animals including humans. Examples of patients or subjects include humans, rodents, and monkeys.
Those skilled in the art are easily able to identify patients with cancer. For example, patients having malignant tumors in their bodies.
A xe2x80x9ctherapeutically effective amountxe2x80x9d is an amount of a compound and/or composition of the present invention, that when administered to a patient or subject, causes the reduction and/or the elimination of a tumor in the patient or subject.
In accord with another embodiment of the invention, viral vectors such as modified or unmodified adenovirus, viral proteins or other portions of virus which carry gene therapy materials, can be encapsulated in carbohydrate materials in accord with the present invention. In this manner, the viral vectors are protected from inactivation and delivered more directly to target cells.
Vectors are known or can be constructed by those skilled in the art and should contain all expression elements necessary to achieve the desired transcription of the sequences. Other beneficial characteristics can also be contained within the vectors such as mechanisms for recovery of the nucleic acids in a different form. Phagemids are a specific example of such beneficial vectors because they can be used either as plasmids or as bacteriophage vectors. Examples of other vectors include viruses such as bacteriophages, baculoviruses and retroviruses, DNA viruses such as adenoviruses or adeno-associated viruses (AAV), cosmids, plasmids, liposomes and other recombination vectors. The vectors can also contain elements for use in either prokaryotic or eukaryotic host systems. One of ordinary skill in the art will know which host systems are compatible with a particular vector.
The vectors in accordance with the present invention can be introduced into cells or tissues by any one of a variety of known methods within the art. Such methods can be found generally described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Springs Harbor Laboratory, New York (1989, 1992); in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989); Chang et al., Somatic Gene Therapy, CRC Press, Ann Arbor, Mich. (1995); Vega et al., Gene Targeting, CRC Press, Ann Arbor, Mich. (1995); Vectors: A Survey of Molecular Cloning Vectors and Their Uses, Butterworths, Boston, Mass. (1988); and Gilboa et al. (1986) and include, for example, stable or transient transfection, lipofection, electroporation and infection with recombinant viral vectors. Introduction of nucleic acids by infection offers several advantages over the other listed methods. Higher efficiency can be obtained due to their infectious nature. Moreover, viruses are very specialized and typically infect and propagate in specific cell types. Thus, their natural specificity can be used to target the vectors to specific cell types in vivo or within a tissue or mixed culture of cells. Viral vectors can also be modified with specific receptors or ligands to alter target specificity through receptor mediated events.
Additional features can be added to the vector to ensure its safety and/or enhance its therapeutic efficacy. Such features include, for example, markers that can be used to negatively select against cells infected with the recombinant virus. An example of such a negative selection marker is the TK gene described above that confers sensitivity to the antibiotic gancyclovir. Negative selection is therefore a means by which infection can be controlled because it provides inducible suicide through the addition of antibiotic. Such protection ensures that if, for example, mutations arise that produce altered forms of the viral vector or recombinant sequence, cellular transformation will not occur. Features that limit expression to particular cell types can also be included. Such features include, for example, promoter and regulatory elements that are specific for the desired cell type.
In addition, recombinant viral vectors are useful for in vivo expression of a desired nucleic acid because they offer advantages such as lateral infection and targeting specificity. Lateral infection is inherent in the life cycle of, for example, retrovirus and is the process by which a single infected cell produces many progeny virions that bud off and infect neighboring cells. The result is that a large area becomes rapidly infected, most of which was not initially infected by the original viral particles. This is in contrast to vertical-type of infection in which the infectious agent spreads only through daughter progeny. Viral vectors can also be produced that are unable to spread laterally. This characteristic can be useful if the desired purpose is to introduce a specified gene into only a localized number of targeted cells.
Retroviral vectors can be constructed to function either as infectious particles or to undergo only a single initial round of infection. In the former case, the genome of the virus is modified so that it maintains all the necessary genes, regulatory sequences and packaging signals to synthesize new viral proteins and RNA. Once these molecules are synthesized, the host cell packages the RNA into new viral particles which are capable of undergoing further rounds of infection. The vector""s genome is also engineered to encode and express the desired recombinant gene. In the case of non-infectious viral vectors, the vector genome is usually mutated to destroy the viral packaging signal that is required to encapsulate the RNA into viral particles. Without such a signal, any particles that are formed will not contain a genome and therefore cannot proceed through subsequent rounds of infection. The specific type of vector will depend upon the intended application. The actual vectors are also known and readily available within the art or can be constructed by one skilled in the art using well-known methodology.
The recombinant vector can be administered in several ways. If viral vectors are used, for example, the procedure can take advantage of their target specificity and consequently, do not have to be administered locally at the diseased site. However, local administration can provide a quicker and more effective treatment, administration can also be performed by, for example, intravenous or subcutaneous injection into the subject. Injection of the viral vectors into a spinal fluid can also be used as a mode of administration, especially in the case of neuro-degenerative diseases. Following injection, the viral vectors will circulate until they recognize host cells with the appropriate target specificity for injection.
An alternate mode of administration of the gene therapy material of the present invention is by direct inoculation locally at the site of the disease or pathological condition or by inoculation into the vascular system supplying the tumor with nutrients. Local administration is advantageous because there is no dilution effect and, therefore, a smaller dose is required to achieve expression in a majority of the targeted cells. Additionally, local inoculation can alleviate the targeting requirement required with other forms of administration since a vector can be used that infects all cells in the inoculated area. If expression is desired in only a specific subset of cells within the inoculated area, then promoter and regulatory elements that are specific for the desired subset can be used to accomplish this goal. Such non-targeting vectors can be, for example, viral vectors, viral genome, plasmids, phagemids and the like. Transfection vehicles such as liposomes can also be used to introduce the non-viral vectors described above into recipient cells within the inoculated area. Such transfection vehicles are known by one skilled within the art.
In accord with the present invention, the nucleic acid material is mixed with the carbohydrate and is mildly sonicated. It is speculated that some degree of binding may take place in this combination, although binding is not believed to be essential to the invention. In particularly preferred embodiments, the nucleic acid material is encapsulated by a covering of the carbohydrate, and the carbohydrate-nucleic acid combination is most preferably configured as a relatively small micelle. In some instances, the micelles are further protected with a coating material, and one particularly preferred coating comprises chitin or chitosan, and the chitin or chitosan may be in the form of relatively short chain oligomeric material.
While the present invention can be employed in connection with a variety of different gene therapies and/or specific genes, one particular embodiment has specific utility in cancer therapies. The tyrosine kinase gene (CHK) has been found to be an effective gene therapy material for various cancers. CHK expression has been observed in many human primary tumors including ovarian carcinoma, breast carcinoma, astrocytoma, glioblastoma, pancreatic carcinoma, lung carcinoma, liver carcinoma, and renal carcinoma The CHK gene is up-regulated in many cancers and can suppress tumor development. In some instances the gene appears to induce apoptosis. In breast cancer, the gene has been found to antagonize growth-promoting signals mediated by Src and ErbB-2 tyrosine kinases. Applicant has further found that many tumor cells have sites thereon which actively bind carbohydrates thereto, and the CHK gene, via its stimulation of the production of tyrosine kinases, causes buildup of carbohydrate to occur on the surface of cancer cells. Based on these findings, Applicant has surmised that the CHK gene and carbohydrate materials of the present invention can interact beneficially to provide a gene therapy material for a variety of cancers. Other genes which can be used in the present invention include tumor suppressor genes including p53, angiostatic genes including angiostatin p60-hangio or endostatin p60-hendo, apoptotic genes including Bcl and Bax, and/or mixtures thereof.
The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intreperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chiorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agarxe2x80x94agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and an preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solution are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 1.9 mg/m2 to about 40 mg/m2 of carbohydrate combined with about 1.9 xcexcg/m2 to about 4 mg/m2 of nucleic acid per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.05-1.06 mg/kg/day carbohydrate combined with about 0.00005-0.106 mg/kg/day is preferable. That is, the general ratio of the amount of carbohydrate to the amount of nucleic acid material is approximately 10:1 in the composition which is administered to the patient or subject. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

Modified pectin and nucleic acid composition


A camera comprising a film winder rotatable in a film winding direction for winding an exposed filmstrip into a film cassette, and a closing mechanism movable to a final position to close a light lock of the film cassette and able to be reset to a starting position to be used again, is characterized in that the film winder is rotatable in a reverse direction which is opposite to the film winding direction, and a resetting device coupled with the film winder resets the closing mechanism from its final position to its starting position when the film winder is rotated in the reverse direction.

Commonly assigned prior art U.S. Pat. No. 5,614,976 issued Mar. 25, 1997 discloses a one-time-use camera for use with a film cassette having a light lock that is to be closed after an exposed filmstrip is wound completely into the cassette. The light lock is closed to prevent ambient light from entering the film cassette when the cassette is removed from the camera. The camera includes a manual film winder rotatable in a film winding direction to wind the exposed filmstrip into the film cassette, and a closing mechanism movable to a final position to close the light lock when the film winder is rotated to complete winding the exposed filmstrip into the cassette. The closing mechanism appears to be resettable to a starting position to be used again. However, one must move the closing mechanism manually from its final position at least towards its starting position in order that the closing mechanism can be moved to its starting position.

Camera with film winder that can reset closing mechanism for closing light lock of film cassette


The invention provides a drilling system for use in a borehole through an underground formation, comprising:

This invention relates to a system for drilling underground boreholes. In particular the invention relates to such systems in which a drilling tool is moved through the borehole using a tractor or similar device.
In a conventional drilling setup, a drill bit is mounted on a bottom hole assembly (BHA) that is connected to a drill string made up of tubular members connected in an end-to-end arrangement. The BHA can include measuring instruments, a drilling motor, telemetry systems and generators. Penetration is achieved by rotating the drill bit while applying weight on a bit (WOB). Rotation can be achieved by rotating the drill string at the surface or by use of a drilling motor downhole on which the drill bit is mounted. The drilling motor is typically powered by flow of a drilling fluid through the drill string and into a hydraulic motor in the BHA. The drilling fluid exits through the drill bit and returns to the surface outside the drill string carrying drilled cuttings with it. WOB is applied by the use of heavyweight drill pipe in the drill string above the BHA.
Clearly WOB can only be applied when the heavyweight drill pipe is close to the borehole. When it is desired to drill highly deviated borehole sections (close to horizontal), the heavyweight drill pipe may have to be located some distance from the BHA in order for it to be in a borehole section that is close to vertical.
Another form of drilling uses coiled tubing to connect the BHA to the surface. An example of this is found in Hill D, Nerne E, Ehlig-Economides C and Mollinedo M "Reentry Drilling Gives New Life to Aging Fields" Oilfield Review (Autumn 1996) 4-14 which describes the VIPER Coiled Tubing Drilling System. In this case the coiled tubing is used to push the drilling tool along the well and provide WOB. However, problems can occur as the coiled tubing does not have great strength in compression.
Recently, various proposals have been made for drilling systems conveyed on wireline cable. An example of this is found in PCT/EP04/01167. Clearly a flexible cable cannot be used to provide WOB.
The various problems incurred in obtaining WOB, in conventional, coiled tubing and wireline drilling have led to the development of tractor or thruster devices to provide the necessary WOB. These devices typically lock in the borehole above the drill bit to provide a reaction point and use a drive mechanism to urge the drill bit away from the reaction point and provide WOB.
There have been a number of proposals for tractors and thrusters. Tractors are used to convey borehole tools along the borehole in highly deviated situations. These typically pull the tool(s) on a wireline cable down the well which is then logged back up the well on the wireline cable pulled from the surface. Examples of tractors for such uses can be found in U.S. Pat. No. 5,954,131, U.S. Pat. No. 6,179,055 and U.S. Pat. No. 6,629,568. A tractor for use with coiled tubing or drill pipe is described in U.S. Pat. No. 5,794,703.
Rather than pulling the tool, a thruster pushes a tool forward. Examples of such thrusters can be found in U.S. Pat. No. 6,003,606, U.S. Pat. No. 6,230,813, U.S. Pat. No. 6,629,570 and GB 2 388 132. Thrusters often can be used for pulling as well. The term "tractor" is used in this application to indicate both forms of device. Where a distinction is required, the terms "pulling tractor" and "pushing tractor" are used.
There are various mechanisms used by tractors. In one approach, wheels or chains act on the borehole wall to drive the tractor along. Another approach is a push-pull crawler. In this case, the device locks one end against the borehole wall and extends a free end forward. At the limit of its extent, the free end is then locked and the other end released and retracted to the newly locked end. When fully retracted, the other end is locked and the locked end released and advanced again. This is repeated as required to either push or pull equipment connected to the tractor. This can be used for both pushing and pulling actions.
Drilling using a wireline cable from the bottom-hole drilling assembly (BHA) to the surface offers many benefits in terms of reduction of cost to drill, and reduction of assets and personnel. However, with these comes a reduction in the available power available to drill with. This decrease in power creates the need to optimize the drilling process by applying a lower than conventional force and torque at the bit, and also being able to control the rate of penetration (ROP) or advancement in real time. This control by definition requires drilling assemblies that move slowly. With the limited power available downhole from the wireline cable, the drilling speed is typically limited to a few meters per hour. This drilling tool however also needs to trip in and out of the hole for changing the bit or to modify settings. The wireline cable can be used to trip quickly (up to 3000 m/hr) in the vertical section of the well; but a lot of wells today would have an inclination that can even reach horizontal. Wireline tractors of the type described above are used to quickly run the measurement equipment to bottom and log (even at 3000 m/hr) back up the well. These same tractors though are not optimized for very slow and accurate movement as required for the drilling process.

Abstract: a drilling assembly including a drill bit for drilling through the formation and a drilling drive;

Abstract: conveyance means including a conveyance drive connected to the drilling assembly and operable to move the drilling assembly through the borehole,

Abstract: wherein the conveyance drive is operable to move the drilling assembly along the borehole into a drilling position and the drilling drive is operable to urge the drill bit into contact with the formation when drilling takes place in the drilling position.


Disclosed are systems and methods for monitoring and controlling operating modes in a network transceiver. In one embodiment, a computer system is associable with an Ethernet network, and comprises a processing unit, a memory and a transceiver. The transceiver comprises an encoder, a decoder and a controller. The controller controls operating modes of the transceiver, and, specifically, (i) negotiates a communications channel between the computer system and another computer system over the Ethernet network wherein the computer system enters one of a master state and a slave state, and (ii) repeatedly directs, in response to entering the master state or slave state, the encoder to encode data to be transmitted to the another computer in one of an industry-compliant mode and a custom mode until the encoded data is properly received by the other computer.

The commercial availability of more efficient, reliable and and cost effective computer systems and communication networks has enabled businesses and individuals to rely on the same, and related peripheral devices, to meet their information and processing needs.
The immeasurable gains in technology experienced by the computer and communication industries have enabled these computers and communication devices to be standardly equipped with interchangeable and replaceable parts and devices. Interchangeability is typically facilitated through expansion slots, couplable interfaces or the like.
Conventional network communications employ various communications protocols that enable cooperative communication at each networked computer system. Standards bodies, such as the Institute of Electronic and Electrical Engineers ("IEEE"), establish standardized communication protocols to facilitate communication over such communication networks. Since standardized protocols maintain different communication platforms, equipment manufacturers must provide support for connection using many, and theoretically all, communications protocols.
A problem arises however when an equipment manufacturer develops and distributes large quantities of non-standardized communication products and devices into a substantially standardized components market. There exists in such a scenario a need to facilitate compatibility with this established communications and processing base, and thus to enable the operating modes of communication devices to be extendable to both industry-compliant and custom modes to achieve increased connectivity and compatibility than would otherwise be possible.

Systems for monitoring and controlling operating modes in an ethernet transceiver and methods of operating the same


Apparatus and methods for plasticity in a spiking neuron network. In one implementation, a plasticity mechanism is configured based on a similarity measure between neuron post-synaptic and pre-synaptic activity. The similarity measure may comprise a cross-correlogram between the output spike train and input spike train, determined over a plasticity window. Several correlograms, corresponding to individual input connections delivering pre-synaptic input, may be combined. The combination may comprise for example a weighted average. The averaged correlograms may be used to construct the long term potentiation component of the plasticity. The long term depression component of the plasticity may comprise e.g., a monotonic function based on a statistical parameter associated with the adaptively determined long term potentiation component.

1. Technological Field
The present disclosure relates generally to artificial neural networks, and more particularly in one exemplary aspect to computer apparatus and methods for plasticity implementation in a pulse-code neural network.
2. Description of Related Art
Artificial spiking neural networks are frequently used to gain an understanding of biological neural networks, and for solving artificial intelligence problems. These networks typically employ a pulse-coded mechanism, which encodes information using timing of the pulses. Such pulses (also referred to as "spikes" or 'impulses') are short-lasting (typically on the order of 1-2 ms) discrete temporal events. Several exemplary embodiments of such encoding are described in commonly owned and co-pending U.S. patent application Ser. No. 13/152,084 entitled "APPARATUS AND METHODS FOR PULSE-CODE INVARIANT OBJECT RECOGNITION", filed Jun. 2, 2011, and co-owned U.S. patent application Ser. No. 13/152,119,filed Jun. 2, 2011, entitled "SENSORY INPUT PROCESSING APPARATUS AND METHODS", and patented as U.S. Pat. No. 8,942,466 on Jan. 27, 2015, each incorporated herein by reference in its entirety.
Typically, artificial spiking neural networks, such as the exemplary network described in owned U.S. patent application Ser. No. 13/541,531, entitled "CONDITIONAL PLASTICITY SPIKING NEURON NETWORK APPARATUS AND METHODS", may comprise a plurality of units (or nodes), which correspond to neurons in a biological neural network. Any given unit may be connected to many other units via connections, also referred to as communications channels, and/or synaptic connections. The units providing inputs to any given unit are commonly referred to as the pre-synaptic units, while the unit receiving the inputs is referred to as the post-synaptic unit.
Each of the unit-to-unit connections may be assigned, inter alia, a connection efficacy, which in general may refer to a magnitude and/or probability of input spike influence on unit output response (i.e., output spike generation/firing). The efficacy may comprise, for example a parameter—synaptic weight—by which one or more state variables of post-synaptic unit are changed. During operation of a pulse-code network, synaptic weights may be dynamically adjusted using what is referred to as the spike-timing dependent plasticity (STDP) in order to implement, among other things, network learning. In some implementations, larger weights may be associated with a greater effect a synapse has on the activity of the post-synaptic neuron.
In some existing plasticity implementations, connections that deliver inputs (to a given unit) prior to generation of post-synaptic response may be potentiated, while connections that deliver inputs after the generation of the post-synaptic response may be depressed. The choice of plasticity functional dependence may determine network behavior. Accordingly, various implementations plasticity mechanisms exist including, for example, the use of target connection efficiency (that may be defined as a ratio of a number of input (pre-synaptic) spikes Nfire delivered to a neuron via the connection that are followed by neuron response (e.g., post-synaptic spike) generation, to the total number of input spikes Ntot delivered to the neuron via the connection. However, existing plasticity implementations do not always provide for network behavior, particularly when input characteristics change.
Consequently there is a salient need for improved adaptive plasticity mechanisms to enable a spiking neuron network capable of operating in a wide variety of input and network dynamic regimes.

Adaptive plasticity apparatus and methods for spiking neuron network


A semiconductor device includes: a package including: a lower surface, at least one first metal surface at an outer periphery of the lower surface, and at least one second metal surface at the lower surface at a location different from the at least one first metal surface; a mounting substrate disposed below the package and including: an upper surface, at least one first metal pattern disposed at the upper surface below the at least one first metal surface, and at least one second metal pattern disposed at the upper surface below the at least one second metal surface; a first bonding member containing a metal material and bonding the at least one first metal surface and the at least one first metal pattern; and a second bonding member containing a metal material and bonding the at least one second metal surface and the at least one second metal pattern.

The present disclosure relates to a semiconductor device and a method of manufacturing the semiconductor device.
Japanese Patent Publication No. 2009-130147A describes a method of mounting in which a chip-shaped electronic component is soldered on a mounting substrate. In Japanese Patent Publication No. 2009-130147A, the chip-shaped electronic component is disposed on the mounting substrate via solder pastes, and the solder pastes are melted. Due to surface tension of the melted solders, the chip-shaped electronic component is self-aligned to be soldered with high precision in alignment. In Japanese Patent Publication No. 2009-130147A, fillets formed by the melted solders cause self-alignment in good balance, aligning the chip-shaped electronic component with respect to the mounting substrate.

Semiconductor device and method of manufacturing the semiconductor device


An image processing method includes: obtaining a facial skin tone area in an image to be processed; filtering the image to be processed to obtain a filtered smooth image; obtaining a high-frequency image based on the smooth image and the image to be processed; obtaining a facial skin tone high-frequency image based on the high-frequency image and a facial skin tone mask; and superimposing the high-frequency image and the image to be processed based on the facial skin tone mask and preset first superimposition strength in a luma channel, and superimposing a luma channel signal of the facial skin tone high-frequency image onto a luma channel signal of the image to be processed, to obtain a first image.

In recent years, with the popularization and development of artificial intelligence technologies, the use of computers to beautify images has been applied to more and more scenarios, for example, face beautification, scene beautification, and other applications, among which face beautification has gradually become a main application in image beautification applications since face beautification can bring a better user experience.

Image processing method and apparatus, electronic device, and computer storage medium


An appliance for facilitating the blood drawing process comprising a band to be worn across the wrist of the phlebotomist intending to draw the blood, the wrist band including a holder for retaining a blood collection barrel in place on the phlebotomist's wrist and in clear view while both of the phlebotomist's hands are free to perform the blood drawing process.

This invention relates generally to an appliance for facilitating the blood drawing process. More particularly, this invention relates to an appliance uniquely adapted for use in drawing blood from children or adults. In one especially important embodiment, the appliance is used with a conventional vacuum blood collection container system and a conventional blood draw cannula assembly such as a "butterfly" blood drawing assembly.

Holding appliance for facilitating blood drawing process


The morphology of a polymer alloy displaying miscibility over some region of composition and temperature may be varied by thermodynamically altering the miscibility, such as raising the temperature for an LCST system, to phase separate the components then quenching the alloy below the glass transition temperature of the matrix phase. Such phase separated alloys have improved toughness.

Thermoplastic polymers, that is polymers which have a Tg above room temperature, and more preferably polymers which melt above about 100.degree. C., have been known for a considerable length of time. Unfortunately many thermoplastic polymers tend to fail in a brittle mode; that is the polymer tends to fail due to crack propagation and there is not significant polymer deformation.
There are a number of approachs to reduce the brittleness of thermoplastics by either copolymerizing or grafting the thermoplastic polymer onto a rubbery polymer, such as high impact polystyrene (HIPS) or by blending an impact modifier in the thermoplastic polymer.
Polymer morphology is extremely important if the reduction in brittleness is to be achieved. For example in U.S. Pat. Nos. 4,172,859 and 4,174,358 polyesters or polycarbonates may be toughened by physically blending into the polyester or polycarbonate a modifier polymer which adheres (reacts) with the thermoplastic and which is distributed so that it has a particle size from 0.01 to 1.0 micron.
The manufacture of HIPS requires dissolving a rubbery polymer in a monomer which is then polymerized to form a thermoplastic polymer. Epstein teaches dispersing (not forming a miscible blend of a rubbery polymer in a thermoplastic matrix using an extruder. In both cases it is essential to control the shear exerted on the mixture of thermoplastic and rubbery polymer to obtain the required particle size distribution and morphology. According to the present invention, while shear may be commercially used to provide good mixing of the miscible components the phase separation depends on, and is caused by altering the temperature conditions.
There is another method for creating/controlling the particle size distribution within a matrix. A blend of miscible polymers may undergo thermally induced phase separation as discussed in "Thermally Induced Phase Separation Behaviour of Compatible Polymer Mixtures" T. Nishi, T. T. Wang, and T. K. Kwei Macromolecules Vol. 8 No. 2 March-April 1975 page 227. These studies have focused on the optical properties of the polymer blends. To the best of applicants knowledge this procedure has not been considered for modifying the brittleness of thermoplastic polymers. Surprisingly, applicants have discovered that the thermally induced phase separation of a blend of a thermoplastic and a rubbery polymer results in a polyblend having reduced brittleness. It is not necessary that the rubbery phase be grafted to or chemically combined with the thermoplastic polymer.

Phase separated polystyrene/polyvinyl methyl ether alloys


A method determines a correction amount of an EGR valve opening degree. A basic correction amount map is generated indicating a correlation between rotating speed, load factor, and the correction amount, while the opening degree is maintained at a reference opening degree and the EGR rate is maintained at a target EGR rate, based on correction amounts obtained for mutually different individual combinations of the rotating speed and the load factor. Estimated values of the correction amounts not contained in the basic map are acquired by estimating the distribution of the amounts not in the basic map based on a distribution trend. An extended correction amount map is generated indicating a correlation between the estimated values of the rotating speed, the load factor, and the correction amount while the opening degree is maintained at a reference opening degree and the EGR rate is maintained at a target rate.

In an EGR apparatus, an intake pipe and an exhaust pipe are linked through an EGR pipe so that exhaust gas is supplied through the EGR pipe to the intake pipe. Further, in the inside of the EGR pipe, an EGR valve is provided for controlling the flow rate of the EGR gas (the exhaust gas flowing through the intake pipe).
In a technique investigated presently, a differential pressure between the exhaust pressure and the intake pressure is detected and then the opening degree of the EGR valve is corrected in accordance with the differential pressure so that changing of the EGR rate caused by changing of the differential pressure is suppressed. An example of such a technique is, for example, a technique described in Patent Document 1 by the present applicant.
Here, the EGR rate, the EGR gas amount, the air intake amount, the differential pressure, and the opening degree satisfy the following relations shown in Formulas (1) and (2).EGR rate=EGR gas amount/(air intake amount+EGR gas amount)  (1)EGR Gas Amount=Proportionality Constant*Differential Pressure*Opening Degree Of an EGR Valve  (2)
The EGR rate is specified by detecting the air intake amount, the differential pressure, and the opening degree of the EGR valve. Therefore, when the opening degree is changed in accordance with changing of the differential pressure, the EGR rate can be maintained at a predetermined target rate.

Method of determining correction amount of opening degree of EGR valve, method of controlling opening degree of EGR valve, and engine