The present invention provides methods for identification of antibiotic agents which cause the accumulation of ppGpp in bacterial organisms involving a relA-independent pathway. The methods comprise screening assays in which test compounds are brought into contact with relA.sup.- test cells and observing the effect such compounds have on ppGpp levels in the test cells. The invention also provides genetically manipulated relA.sup.- test cells which contain a reporter gene the expression of which is sensitive to the level of ppGpp. The invention also encompasses agents identified by the screening assays, and uses of these agents in the treatment of infectious diseases.

Resistance to currently available antibiotics has created a need for new antibiotic agents. In the United States alone, 19,000 hospital patients die each year due to nosocomial (hospital-acquired) bacterial infections (Service, R., 1995, Science 270:724-727). These infections, caused by organisms such as Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium and Enterococcus faecalis, have become increasingly resistant to currently approved antibiotics. For example, significant clinical problems include methicillin-resistant strains of S. aureus, which are resistant to all current antibiotics except vancomycin (a drug of last resort because of severe side effects), and a vancomycin-resistant strain of E. faecium enterococci which is now found world-wide. The occurrence of vancomycin-resistant enterococci isolated from nosocomial infections rose from 0.4% to 13.6% in the relatively short time span from 1989 to 1993 (Tenover, F. C. and Hughes, J. M., 1996, JAMA 275(4):300-304) (reporting statistics from the Centers for Disease Control and Prevention). Even community-acquired organisms such as Streptococcus pneumoniae are increasingly resistant to antimicrobial agents, with a significant number of isolates being resistant to penicillin and extended-spectrum cephalosporins. Id.
The emergence and spread of resistant bacterial organisms are primarily caused by acquisition of drug resistance genes, resulting in a broad spectrum of antibiotic resistance (e.g., extended-spectrum cephalosporin-resistant mutant .beta.-lactamases found in several bacterial organisms). Genetic exchange of multiple-resistance genes, by transformation, transduction and conjugation; combined with selective pressures in settings such as hospitals where there is heavy use of antibiotic therapies, enhance the survival and proliferation of antimicrobial agent-resistant bacterial strains occurring by, e.g., spontaneous mutants. Id. Although the extent to which bacteria develop resistance to antimicrobial drugs and the speed with which they do so vary with different types of drugs, resistance has inevitably developed to all antimicrobial agents (Gold and Moellering, Jr., 1996, New Eng. J. Med., 335(19):1445-1453).
To prevent or delay the buildup of a resistant pathogen population, different chemicals that are effective against a particular disease-causing bacterium must be available. Thus, there is a need to develop methods for identifying compounds which can penetrate and specifically kill the pathogenic bacterial cell, or arrest its growth without also adversely affecting its human, animal, or plant host.


A fabric of nanofibers that includes an adhesive is described. The nanofibers can be twisted or both twisted and coiled prior to formation into a fabric. The adhesive can be selectively applied to or infiltrated within portions of the nanofibers comprising the nanofiber fabric. The adhesive enables connection of the nanofiber fabric to an underlying substrate, even in cases in which the underlying substrate has a three-dimensional topography, while the selective location of the adhesive on the fabric limits the contact area between the adhesive and the nanofibers of the nanofiber fabric. This limited contact area can help preserve the beneficial properties of the nanofibers (e.g., thermal conductivity, electrical conductivity, infra-red (IR) radiation transparency) that otherwise might be degraded by the presence of adhesive.

Nanofiber forests, composed of both single wall and multiwalled nanotubes, can be drawn into nanofiber ribbons or sheets. In its pre-drawn state, the nanofiber forest comprises a layer (or several stacked layers) of nanofibers that are parallel to one another and perpendicular to a surface of a growth substrate. When drawn into a nanofiber sheet, the orientation of the nanofibers changes from perpendicular to parallel relative to the surface of the growth substrate. The nanotubes in the drawn nanofiber sheet connect to one another in an end-to-end configuration to form a continuous sheet in which a longitudinal axis of the nanofibers is parallel to a plane of the sheet (i.e., parallel to both of the first and second major surfaces of the nanofiber sheet). Individual nanofiber sheets can be from a few microns thick to tens of nanometers thick. Nanofiber sheets can then be spun into nanofiber yarns.

This patent is subject to a terminal disclaimer.


A method for location estimation employs filtering in both the radio signal domain and the space domain separately. The method filters raw values of the run-time radio signal measurements to reject distorted inputs. A region of confidence (RoC) is formed according to certain algorithms. Only location estimates falling within the RoC are considered for further processing. The location estimate candidates filtered by the RoC are put in a number of time-indexed bins. Each of the bins contains location estimate candidates obtained at similar times. A shortest route connecting a candidate from each bin is calculated to further improve the accuracy of the location estimation.

1. Field of the Invention
The present invention relates to location estimation, and more specifically to estimating the location of both stationary and moving objects in a wireless environment.
2. Description of the Related Art
With the development of pervasive computing and location-aware systems and services, there has been an increased interest in location estimation techniques for both outdoor and indoor object positioning. Because of the poor indoor coverage of the Global Positioning System (GPS), there is a greater interest in indoor location estimation.
One conventional approach to indoor location estimation deploys a dedicated sensor network using, for example, infrared or ultrasound technologies. But this approach has cost and maintenance problems.
Another conventional approach is radio frequency (RF) based static scene analysis. With the existing wireless LAN infrastructure, the RF-based static scene analysis system collects radio signal information from wireless LAN beacons, creates a static location information database that stores the collected radio signal information, and obtains location estimates based on radio wave characteristics.
Static scene analysis collectively refers to location estimation techniques involving measurement, calibration and analysis of a specific metric that can be obtained from sensor reading. Static scene analysis typically consists of an off-line stage, where calibration of the indoor wireless environment is carried out, and an on-line (or runtime) stage, where the calibration is used for location estimation.
Specifically, during the off-line stage, a site survey obtaining RF-characteristics at numerous known locations of a wireless environment takes place first. This typically involves receiving signal strength measurements from multiple access points, such as a received signal strength indicator (RSSI) metric, or a link quality metric. The information collected during the site survey is processed and stored in a location information database. The calibration of the wireless environment is then finished, and the information stored will be compared with inputs acquired during the runtime.
During the on-line (or runtime) stage, a user provides a run-time input that is measured instantly at the location of interest. The user uses the same metric that has been used in the off-line stage. Then a location estimation algorithm, which will be introduced below, is applied to compare the run-time and the off-line measurements and compute the location of the object. In RF-signal measurement, numerous sources of interference and noise, such as fading, blocking, and shadowing, occur both transiently and over significant period of time. These phenomena cause corrupted run-time inputs and introduce location estimate errors.
Three conventional algorithms that are widely used in RF-based static scene analysis, i.e., triangulation, K-nearest neighbor averaging, and smallest M-polygon are described in detail below.
FIG. 1 illustrates the triangulation algorithm for location estimation. The triangulation computes the location estimate by solving systems of quadratic equations. The triangulation forms circles whose centers are the locations of the transmitters, e.g., access points or base stations. In FIG. 1, the locations and RF characteristics of access points 1, 2, and 3 have been obtained at numerous known locations, which are used for off-line calibration, during the off-line stage described above. Distances d1 between the object and the access point 1, d2 between the object and the access point 2, and d3 between the object and the access point 3 are calculated based on radio wave characteristics, e.g., TOA or TDOA. Triangulation forms sets of circles. Each of the reference points, access points 1, 2 or 3, becomes the center of a circle, and the distances between the object and the center, d1, d2 or d3, becomes the radius of that circle.
Triangulation estimates locations based on various intersection areas formed by these circles. If three formed circles meet at a single spot, that spot becomes the location estimate as a result of the triangulation. However, as a practical matter, the three circles rarely will meet at a single spot. More often, if the circles intersect, they will intersect in multiple spots. In FIG. 1, the three circles have six intersection points, P1, P2, P3, P4, P5 and P6. The triangulation algorithm examines areas formed by the intersection points to obtain a location estimate for the object. Specifically, the triangle formed by P2, P4 and P5 has the smallest area among all possible triangles formed by these intersection points, and the centroid X of the triangle (P2, P4, P5) is the best location estimate of the object.
FIG. 2 illustrates the K-nearest neighbor averaging algorithm for location estimate, wherein K=5. Typically, K is larger than 2. Experimental analysis shows that K=3 gives the best performance. Let a triplet (Sa, Sb, Sc) represent a set of run-time signal strength measurements at a location of interest from three base stations a, b, and c. Five triplets which have the least root mean square (RMS) error in signal strength between the run-time and the off-line measurements are found. The root mean square error in signal strength is calculated as follows:rms=√{square root over ((a−ai)2+(b−bi)2+(c−ci)2)}{square root over ((a−ai)2+(b−bi)2+(c−ci)2)}{square root over ((a−ai)2+(b−bi)2+(c−ci)2)}  (1)
wherein (Sa, Sb, Sc) represents off-line signal strength measurements at the location of interest.
In particular, these five triplets are: signal strength triplet (a1, b1, c1) at position L1 (x1, y1) from base stations a, b and c; signal strength triplet (a2, b2, c2) at position L2 (x2, y2) from base stations a, b and c; . . . and signal strength triplet (a5, b5, c5) at position L5 (x5, y5) from base stations a, b and c. L1, . . . , L5 are determined by using the location information database. The location information database for RF-based static scene analysis typically contains entries used to map RF signal metrics to positions (i.e., transfer from signal domain to space domain). The positions of these five locations are averaged to yield the location estimate of the object as follows:L=(L1+L2+L3+L4+L5)/5  (2)
FIG. 3 illustrates the smallest M-polygon algorithm for location estimate, wherein M=3. M is the number of access points, or base stations, used for the system. M=3 gives reasonably good performance for the algorithm. Three base stations A, B, and C provides separate candidate locations A1, A2, B1, B2, C1 and C2 that match best with the off-line measurements. The algorithm then searches for the polygon that has the smallest perimeter formed by candidate locations contributed by each reference base station, wherein one and only one candidate from each base station must constitute a vertex of the polygon. In FIG. 3, candidate locations A1, B2 and C2 form the smallest perimeter polygon, in this case, a triangle. The final location estimate of the object is the centroid X of the polygon:x=(A1+B2+C2)/3  (3)
The conventional static scene analysis maps from the radio signal domain to the space domain. The final estimate is typically within a coordinate system. A main drawback of the static scene analysis is that it cannot effectively cope with the impact of errors in the radio signal domain. Due to interference and noise, objects at different locations might be represented similarly in the radio signal domain, a phenomenon called aliasing. The conventional methods can not detect aliasing, and may provide these different locations with similar location estimates.
A selective fusion location estimation (SELFLOC) algorithm selectively combines or fuses multiple location information sources to yield a combined estimate in a theoretically optimal manner. The SELFLOC algorithm is disclosed in U.S. patent application Ser. No. 10/330,523, filed Dec. 27, 2002, which is incorporated herein by reference.
FIG. 4 illustrates an overview of the SELFLOC algorithm to fuse three information sources 1, 2 and 3. Each input branch is individually weighted by one of the weights 1, 2, and 3. The sum of the weighted input branches provides the SELFLOC estimate.
The branch weights 1, 2 and 3 are calibrated during the off-line stage using error feedback. A minimum mean square error (MMSE) algorithm can be used for SELFLOC weight training and calibration. As shown in FIG. 4, three location estimates available independently are to be fused, and x-coordinates of these estimates are X1, X2 and X3. The weights for these input branches are w1, w2, and W3 respectively. Thus, the SELFLOC estimate X could be written as:X=w1·X1+w2·X2+w3·X3  (4)
It would be advantageous to provide a method for more accurate processing of collected signals to estimate locations of stationary and mobile objects with improved accuracy.

Method and apparatus for location estimation using region of confidence filtering


An apparatus and method for compensating for the frequency offset of a received signal in a receiving apparatus of a mobile communication system. In the present invention, a sine component is calculated by adding I and Q channel signals resulting from downconverting a training sequence inserted between data symbols, and a cosine component is calculated by subtracting the Q channel signal from the I channel signal. Using the cosine and sine components at two time points, tangent components for the two time points are computed and thus first and second phase values are obtained. The frequency offset is estimated by determining the slope of a second-order line derived from the first and second phase values. The frequency offset of the received signal is compensated for based on the estimated frequency offset.

1. Field of the Invention
The present invention relates generally to a mobile communication system, and in particular, to an apparatus and method for performing fine frequency offset compensation to achieve frequency synchronization.
2. Description of the Related Art
In general, phase jitter and Doppler shift as a natural occurance of radio channels. Also, asynchronization between a transmit frequency and a receive frequency arises from instability of a receiver tuner in a mobile communication system. Each of these cause a frequency offset. The transmit frequency is the frequency of a carrier that delivers signals in a transmitter, whereas the receive frequency is the frequency of a carrier by which a receiver receives signals. The tuner instability relates to a phenomenon where tuning is not realized between a transmitter local oscillator and a receiver local oscillator, that is, between the carriers.
FIG. 1 conceptually illustrates transmitting and receiving apparatuses in a typical QPSK (Quadrature Phase Shift Keying) mobile communication system. As illustrated in FIG. 1, the transmitting apparatus transmits information in an in-phase (I channel) signal and a quadrature-phase (Q channel) signal, which have a 90-degree phase difference. The receiving apparatus receives the I and Q channel signals and demodulates desired information from the received signals.
Referring to FIG. 1, a transmitter 110 upconverts input baseband I and Q channel signals to RF (Radio Frequency) signals by a predetermined carrier frequency. A power amplifier (PA) 120 amplifies the RF signals to a predetermined transmit power level and transmits them through an antenna. The RF signals are received at the receiving apparatus through an antenna. A low noise amplifier (LNA) 130 amplifies the received RF signals such that noise is reduced and the strength of an original signal is increased. A receiver 140 downconverts the RF signals received from the LNA 130 to baseband signals. For the downconversion, the receiver 140 must use the same carrier frequency as used in the transmitter 110. However, it is impossible to upconvert or downconvert the signals using the same carrier frequency in the transmitter 110 and the receiver 140 because of the afore-mentioned frequency offset. Therefore, compensation for the frequency offset is essential to the increase of downconversion reliability in the receiver 140.
FIGS. 2, 3 and 4 illustrate implementation examples of the receiver illustrated in FIG. 1.
FIG. 2 illustrates a receiver in which I and Q channel signals are downconverted by means of a single mixer. In FIG. 2, an input signal (i.e. "RF") "A cos ωRFt+B sin ωRFt" is downconverted by "cos (ωLO−Δω)t" and "sin (ωLO−Δω)t", respectively and I and Q channel signals are thus produced.
FIG. 3 illustrates a receiver in which I and Q channel signals are downconverted twice by means of two mixers.
Referring to FIG. 3, the input signal (i.e. "RF") "A cos ωRFt+B sin ωRFt" is primarily downconverted by first multiplying it by a first carrier "cos (ωLO1−Δω1)t". The primary downconversion signal (i.e. "IF") is downconverted by second carriers "cos (ωLO2−Δω2)t" and "sin (ωLO2−Δω2)t. The carrier ωRFt used in a transmitter is defined as "ωLO1+ωLO2" and the frequency offset Δω is defined as "ω1+Δω2". The signal downconverted by the second carrier cos (ωLO2−Δω2)t is output as a I channel signal, whereas the signal downconverted by the second carrier sin (ωLO2−Δω2)t is output as a Q channel signal.
FIG. 4 illustrates another receiver in which I and Q channel signals are downconverted twice by means of two mixers.
Referring to FIG. 4, the input signal. (i.e. "RF") "cos ωRFt+B sin ωRFt" is primarily downconverted by multiplying it by first carriers "cos (ωLO1−Δω1)t" and "sin (ωLO1−Δω1)t". Each of the primary downconversion signals is downconverted by second carriers "cos (ωLO2−Δω2)t" and "sin (ωLO2−Δω2)t". A signal downconverted by the first carrier "sin (ωLO1−Δω1)t" is downconverted by the second carriers "cos (ωLO2−Δω2)t" and "sin (ωLO2−Δω2)t". The carrier ωRFt used in the transmitter is defined as "ωLO1+ωLO2" and the frequency offset Δω is defined as "ω1+Δω2". The signal is downconverted by the first carrier "sin (ωLO1−Δω1)t" and then downconverted by the second carrier "sin (ωLO2−Δω2)t". This signal is subtracted from the signal downconverted by the first carrier "cos (ωLO1−Δω1)t" and then downconverted by the second carrier "cos (ωLO2−Δω2)t". The difference signal is converted to a digital signal and output as an I channel signal. Meanwhile, the signal downconverted by the first carrier "cos (ωLO1−Δω1)t" and then downconverted by the second carrier "sin (ωLO2−Δω2)t" is added to the signal downconverted by the first carrier "sin (ωLO1−Δω1)t" and then downconverted by the second carrier "cos (ωLO2−Δω2)t". The sum signal is converted to a digital signal and output as a Q channel signal.
The I and Q channel signals output from the receivers illustrated in FIGS. 2, 3 and 4 are not ideal signals including only an amplitude component A or B. They also include frequency components due to the frequency offset Δω. In other words, all of the carrier frequency components are not eliminated during the primary and secondary downconversions because of the frequency offset Δω.
This frequency offset changes the phase of the input signal. The resulting loss of orthogonality between the carrier frequencies degrades decoding performance in the system. However minimal the frequency offset is, the frequency offset is a critical factor that degrades the performance of a receiver system. FIG. 5 illustrates simulated received symbol distributions under varying frequency offsets. The frequency offsets illustrated are 0.2, 1, and 10 ppm(pulse position modulation). As noted from FIG. 5, the error rate of received symbols increases with the frequency offset. Therefore, frequency synchronization techniques are essential to prevent the loss of orthogonality between carriers caused by a frequency offset.
One method for correct for the frequency offset is based on the interval between carrier frequencies in the receiver. Being divided by the carrier frequency interval, the frequency offset can be expressed as an integer part and a fraction part. The process of eliminating an initial frequency offset corresponding to the integer part is referred to as coarse frequency synchronization and the process of eliminating a frequency offset corresponding to the fraction part, that is, the residual frequency offset after the coarse frequency synchronization, is referred to as fine frequency synchronization. Frequency synchronization techniques in an OFDM (Orthogonal Frequency Division Multiplexing) mobile communication system are categorized into algorithms using time-domain signals before FFT (Fast Fourier Transform) and algorithms using frequency-domain signals after the FFT. In the former algorithms, a long preamble additionally transmitted together with data is used to compensate for the frequency offset, as proposed in the IEEE 802.11a WLAN (Local Area Network) standards.
As described above, the conventional mobile communication system transmits a long preamble by which the frequency offset is estimated and compensated for. In other words, a transmission frame includes a long preamble and a complex algorithm is used to compensate for the frequency offset by the long preamble in the conventional frequency offset compensation.

Apparatus and method for compensating for frequency offset in a mobile communication system

Korea Advanced Institute of Science and Technology (KAIST)


Described is a triazole derivative represented by the formula (1): ##STR1## wherein R.sup.1 represents a lower alkyl group or an aralkyl group, R.sup.2 represents a hydrogen atom, a lower alkyl group, an aralkyl group or an acyl group, X.sup.1 and X.sup.2 are the same or different and each independently represents a hydrogen atom, a halogen atom or a trifluoromethyl group, n stands for an integer of 0 to 2 and m stands for an integer of 1 to 5, or salt thereof; and also a pharmaceutical comprising the derivative or salt thereof as an effective ingredient. The compound as described above has a high antimycotic activity and is useful for the prevention and treatment of mammalian mycotic infections.

Mycosis can be classified into two types, that is, superficial mycosis represented by various trichophytosis, marginated eczema, psoriasis, cutaneous candidiasis or the like and deep seated mycosis represented by mycotic meningitis, mycotic infectious disease of respiratory organ, fungemia, mycosis of urinary tract or the like. Of these, deep seated mycosis such as candidiasis or aspergillosis tends to show a marked increase in recent days owing to the frequent use of an anticancer chemotherapeutic agent or immunosuppressive agent or lowering in the bioimmunology due to HIV infection or the like. There is accordingly a demand for a pharmaceutical efficacious against fungi causing such diseases. At present, pharmaceuticals effective against Aspergillus spp. and Candida spp. are not so many. As a remedy for such deep seated mycosis, Amphotericin B and azole-based compounds such as Fluconazole and Itraconazole are conventionally known, but they involve problems in safety and antimycotic activity. There is accordingly a demand for an antimycotic effective against Aspergillus spp. and Candida spp. Now, more effective azole-based compounds are under development. For example, as a compound having a hydroxyethyl group, compounds described in Japanese Patent Application Laid-Open No. 247944/1994 or the like and as a compound having a difluoromethylene group, those described in Japanese Patent Application Laid-Open No. 163374/1984, Japanese Patent Application Laid-Open No. 163269/1993 or the like are known. As an azole-based compound having a substituted tertiary hydroxyl group, cyclic compounds as described in Japanese Patent Application Laid-Open Nos. 217778/1996 and 333367/1996, acyl compounds as described in Japanese Patent Application Laid-Open Nos. 104676/1996 and 183769/1997, and the like are known but they are not fully satisfactory.
Accordingly, an object of the present invention is to provide a compound which has high safety and has antimycotic activity effective against Aspergillus spp. and Candida spp.


A fuel injection control apparatus for a diesel engine (1) is provided that eliminates a torque step occurring when shifting from a pilot fuel injection mode to a normal injection mode. After finding a total fuel injection quantity QFIN per cycle (block 101), a pilot fuel injection quantity QPILOTB is subtracted therefrom to determine a pilot fuel injection quantity QPILOT and a main fuel injection quantity QMAIN (block 103). Corrected pilot fuel injection quantity QPILOTF and corrected main fuel injection quantity QMAINF are determined using a fuel temperature correction coefficient KQTHF and a pilot fuel injection thermal efficiency CEHPILOT (block 104) and a main fuel injection thermal efficiency CEHMAIN (block 105). The thermal efficiencies are established based on the respective injection timings. A change in torque does not occur because the change in the thermal efficiency caused by the injection timing is offset.

1. Technical Field
The present invention generally relates to a fuel injection control apparatus, especially for a diesel engine. More specifically, the present invention relates to an improvement to a fuel injection control apparatus that can execute the fuel injection of one cycle in response to the operating conditions by dividing the fuel injection into a main fuel injection and a preceding pilot fuel injection of small quantity.
2. Description of Related Art
In recent years, the fuel injection modes of diesel engines are equipped with a pilot fuel injection mode that executes the fuel injection of one cycle by dividing the fuel injection into a main fuel injection and preceding pilot fuel injection of small quantity. Japanese Laid-Open Patent Publication No. 9-264159 discloses a fuel injection control apparatus for a diesel engine equipped with a pilot fuel injection mode. Under low load conditions, low temperature conditions, and other conditions where the ignitability of the fuel is low, this pilot fuel injection mode improves ignitability and contributes to reducing combustion noise by executing the main fuel injection from a state in which the small quantity of fuel of the pilot fuel injection has been combusted. Meanwhile, in regions where the load and engine speed are somewhat high, the pilot fuel injection is generally not executed and the normal injection mode is used. In short, this type of diesel engine switches between normal injection mode and pilot fuel injection mode in response to the operating conditions.
In view of the above, there exists a need for an improved fuel injection control apparatus. This invention addresses this need in the prior art as well as other needs, which will become apparent to those skilled in the art from this disclosure.
It has been discovered that during pilot fuel injection mode the total fuel injection quantity Q to be fed to the engine is first found in response to the operating conditions. FIG. 15 shows the change in fuel injection quantity and torque when the engine shifts from the pilot fuel injection mode to the normal injection mode. Next, the optimum pilot fuel injection quantity Q1 is determined and the main fuel injection quantity Q2 is found by subtracting the pilot fuel injection quantity Q1 from the total fuel injection quantity Q. Meanwhile, during the normal injection mode, the total fuel injection quantity Q is injected once at a prescribed injection timing.
In short, even during the pilot fuel injection mode, the quantity of fuel fed into the cylinder during one cycle is the same as during the normal injection mode. However, the fuel fed by the pilot fuel injection is injected relatively early and, therefore, generally has an inferior thermal efficiency to that of the fuel supplied during the main fuel injection. That is, even if the quantity of fuel is the same, the pilot fuel injection contributes little to torque generation. During the normal injection mode, in which the fuel is injected with a single injection, the thermal efficiency is relatively high because the fuel is injected at the optimum time. Likewise, the thermal efficiency is relatively high in the main fuel injection because the fuel is injected at the optimum time. Therefore, there is a drawback in that, as shown in FIG. 15, the generated engine torque increases and a torque step occurs when the engine shifts from the pilot fuel injection mode to the normal injection mode, even if the total fuel injection quantity Q is the same.
It is feasible that this kind of torque step could be avoided by taking the value of pilot fuel injection quantity Q1 that is provided in advance by the shape of the map in response to the operating conditions and correcting it further in response to the load. However, it would be difficult to reliably avoid a torque step because the load would change depending on the air-fuel ratio, supercharge pressure, etc., when the engine switched from the pilot fuel injection mode to the normal injection mode.
These and other objects, features, aspects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description, which, taken in conjunction with the annexed drawings, discloses a preferred embodiment of the present invention.

Fuel injection control apparatus for a diesel engine


A device for collecting multiple samples for use by a single user while avoiding cross-contamination under adverse conditions is disclosed. A multiple sampling device comprising a single handle actuator with a trigger, connected to a shaft assembly further connected to a claw assembly for actuating a self-sealing sampling sphere in the process of collecting a desired sample, is disclosed. The sampling sphere comprises two halves that separate when the trigger and claw assembly are actuated, and close together when the trigger is released using springs on the claw assembly and sampling sphere. Additional sampling spheres are stored on the shaft assembly. In operation, once a sample is collected by one sampling sphere, the sampling sphere is exchanged with an empty sampling sphere stored on the shaft assembly.

As space technologies and exploration rapidly expand, the capability will soon exist to send astronauts to asteroids, Mars, and beyond. These nearby extraterrestrial bodies are full of unexplored areas and harbor undiscovered materials with the potential to yield extraordinary benefits for science and the public. In particular, asteroids have the potential to be mined, providing scientific data on our solar system and possibility of lucrative material resources. The invention described herein is a sampling device that is designed to contribute to the goal of exploring and mining asteroids, although many other terrestrial uses are also contemplated. The sampling device is designed to enable a single user, under adverse conditions, such as an astronaut, to collect soil, rock, liquid and floating samples with relative ease.
For example, the design of the within sampling device will allow astronauts to collect multiple samples in a zero gravity environment through its use of contained sample spheres which will seal in free-floating material. The purpose of this sampling device, among other things, is to allow astronauts to collect float samples on an asteroid, or any other environment with reduced gravity. The device is designed to be very easy to operate. Astronauts have previously spacewalked when they are operating aboard the International Space Station. In this environment, it is difficult to control one's motion and any slight motion or disturbance can cause unwanted instability. A sampling device is needed that will not create any unbalancing forces or torques. The within invention satisfies this need through its design in that all motion is in a direct line from the user, and all mechanical action takes place within a vertical two-dimensional plane defined by the orientation of the components of the device. Additionally, actuating handle is oriented such the actuating motion is directly aligned with the shaft of the device, preventing the need for any large motions that might create unwanted disturbance torques. If the astronaut has to strain, he may lose equilibrium, and as a result lose control of his movements making the collection process more difficult. Accordingly, ease of operation is paramount in the design of the within sampling device.
Further, when studying completely foreign samples any cross-contamination can lead to confusion and ruined data. When testing material properties, characteristics of a certain material may be mixed with others, and the result is that the analysis of these materials will take longer or be ruled impossible. The within sampling device prevents this harmful contamination through the use of sealed, self-contained sampling spheres. These self-contained spheres are previously unknown on a handheld sampling device like the one described above.
While the goal of this invention is to provide a device for collecting samples in a zero gravity environment, with little or no atmosphere, it can also function well in other extreme environments. To confirm this performance, the invention was tested in a Neutral Buoyancy Laboratory (NBL) at NASA's Johnson Space Center, in a giant pool which "simulated" a zero gravity environment. In this test, gravity a ad a surrounding fluid were present. The sampling device of this invention performed beyond our expectations in the ease of sampling under these conditions as well as maintaining the integrity of the samples taken. This demonstration confirmed many of the device's design properties, such as the sampling spheres, the sphere tether hook, and its disturbance torque mitigation are also well suited to the underwater environment.

Device for taking multiple samples while avoiding cross-contamination


Some embodiments include an assembly having active material structures arranged in an array having rows and columns. Each of the active material structures has a first side which includes a bit contact region, and has a second side which includes a cell contact region. Each of the bit contact regions is coupled with a first redistribution pad. Each of the cell contact regions is coupled with a second redistribution pad. The first redistribution pads are coupled with bitlines, and the second redistribution pads are coupled with programmable devices. Some embodiments include methods of forming memory arrays.

Dynamic random access memory (DRAM) may be utilized for storing information in programmable systems. DRAM may be fabricated in an array comprising individual memory cells containing a transistor in combination with a programmable device. In some applications, the programmable device may be a charge-storage device (such as, for example, a capacitor). Bitlines (i.e., digit lines) and wordlines (i.e., access lines) may extend across the array, and may be utilized for accessing individual memory cells.
A continuing goal is to increase integration, and accordingly to increase packing density of DRAM and other circuitry. An example memory array architecture 10 is described with reference to FIG. 1, and in some applications such memory array architecture may be utilized to achieve high-density packing.
The architecture 10 includes wordlines WL1, WL2 and WL3 extending along a first direction of an axis 5; and includes bitlines BL1, BL2 and BL3 extending along a second direction of an axis 7; with the second direction crossing the first direction. The wordlines may be considered to extend along rows of the memory array architecture, and the bitlines may be considered to extend along columns of the memory architecture.
Active material structures 12 are within the architecture 10, and are provided at intersections of the wordlines and bitlines. The active material structures 12 may comprise pillars of monocrystalline silicon, and may be generally shaped as parallelograms (as shown). The active material structures are provided in dashed-line view to indicate that they may be beneath other materials relative to the top view of FIG. 1.
Each of the active material structures 12 has a bit contact region BC and a cell contact region CC, with the bit contact regions being on opposing sides of the active material structures relative to the cell contact regions.
The bit contact regions BC are coupled with the bitlines BL1, BL2 and BL3; and the cell contact regions CC are coupled with programmable devices 14 (e.g., charge-storage structures, such as, for example, capacitors).
The memory array architecture 10 of FIG. 1 may be analogous to architecture described in U.S. Pat. No. 9,472,542, which is assigned to Micron Technology, Inc., and which lists Wolfgang Mueller and Sanh D. Tang as inventors.
A problem with the architecture 10 of FIG. 1 is that it may be difficult to couple the bitlines BL1, BL2 and BL3 with the bit contact regions BC and/or to couple the programmable devices 14 with the cell contact regions CC due to the tight packing of such architecture. Specifically, there are very small regions of the active material structures 12 available for making connection to the bitlines and the programmable devices. Such problem may become more severe as corners of the active material structures 12 are rounded in accordance with particular embodiments described in U.S. Pat. No. 9,472,542. Accordingly, it is desired to develop improved architectures which enable better connection between bit contact regions and bitlines, and/or which enable better connection between cell contact regions and programmable devices.

Memory arrays, and methods of forming memory arrays


The present invention refers to a cell culture system especially for investigating the sensitizing, allergenic and/or irritating effect of substances, comprising a first and a second compartment that can communicate with each other via a permeable interlayer, whereby the first compartment has an epidermis model and the second a cell culture based on immune cells.

Allergy is a disorder of the immune system that is inclusive of atopy. Allergic reactions occur in response to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Allergy is characterized by excessive activation of certain white blood cells, called mast cells, and basophils by a type of antibody, known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees.
Different types of allergens are known. Inhaled allergens include dust or aerosols, e.g., pollen or house dust. Food allergens are substances contained in food to which the body reacts by hypersensitization (allergic reactions). Medicinal product allergens comprise certain active substances in medicinal products, for example antibiotics or analgesics. A particularly important group of allergenic substances are the contact allergens. These can cause an allergic reaction in those affected through skin contact. Certain metals and odoriferous substances belong among the contact allergens.
In recent decades, especially in the Western industrial countries a sudden rise in the number of allergens has been observed. Many allergenic substances are ingredients of cosmetics or other topically applied substances (compositions for local external application). Cosmetics or topical agents are tested for their allergenic properties by means of experiments on animals. The findings thus gained, however, are only of limited value because experimental animals do not always react to the same allergens as human beings and vice versa. This situation frequently gives rise to false positive and false negative results. Meanwhile there are also practical and ethical concerns associated with animal testing.
In light of the state of testing for allergenic activity, there is a need for effective new tools and methods for determining allergenic activity.

Cell culture system for determining the sensitizing, allergenic and/or irritating effect of a substance


The present invention relates to vancomycin analogs in which the vancosamine residue is substituted with a lipid-like substituent that includes a first aryl moiety and a second aryl moiety joined together by a flexible linker moiety, that is not a single bond directly joining the first aryl moiety and the second aryl moiety, and a glucose C-6 substituent modified to be other than the naturally occurring hydroxyl group, or pharmaceutically acceptable salts thereof.

The present invention relates to novel derivatives of natural products, methods for their preparation, and the determination of their activity. In particular, the present invention relates to novel derivatives of glycopeptide antibiotics, such as vancomycin, methods for their preparation and their uses for the treatment of bacterial infection.
In the preferred embodiment, the present invention relates to vancomycin-derived glycopeptide antibacterial agents, which are characterized by a heptapeptide structure that is covalently linked to at least one saccharide group. The saccharide group(s) can be substituted with various substituent groups as described herein.
An example of a known glycopeptide antibiotic is vancomycin, which contains a disaccharide substituent linked to a heptapeptide structure. See Malabarba A., et al., Med. Res. Rev., 17(1):69-137 (1997a); Nagarajan R. et al., J. Chem. Soc. Chem. Comm. 1306-1307(1988); Nagaranjan R., Antimicr. Agents Chemother., 35:605-609 (1991); and Nagaranjan R., J. Antibiotics, 46:1181-1195 (1993). Vancomycin is effective against gram positive bacteria. However, vancomycin resistant strains have been recently observed, thus increasing the need for new and effective therapeutic agents.
The glycopeptides of the present invention are useful against many gram positive microorganisms, including vacomycin resistant enterococcus (VRE), methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important new contribution to the development of therapeutic regimens for treating infections caused by these difficult to control pathogens and resistant strains.
There is an increasing need for agents effective against such pathogens, which are at the same time relatively free from undesirable side effects. Moreover, the physicochemical and pharmacological characteristics of candidate drugs, including their solubility, charge, hygroscopic characteristics, lipophilicity, bioavailability, tissue distribution, serum half-life and the like can play important roles in determining the success or failure of a candidate drug in the clinic. For example, it has been reported that a vancomycin analog in the Phase III clinical studies, which bears a chlorophenylbenzyl (also referred elsewhere in this application as chlorobiphenyl; other substituents are described in, e.g., Rodriguez, M. J., J. Antibiotics, 51(6):560-569 (1998)) substituent on the amine nitrogen of vancosamine and a free hydroxyl group on the C-6 position of glucose, exhibits a serum half-life in excess of two weeks. It has also been reported that traces of this vancomycin analog can be detected in patients up to a year after drug administration. Clearly, should a patient experience any adverse reaction to any drug, it would be beneficial if the patient""s body could metabolize and/or clear the drug relatively quickly, e.g., within about 24 or less, preferably within about 12 hours or less, most preferably within about 6-8 hours or less.
It should be noted that antibiotics of the type that include vancomycin are typically administered parenterally, that is intravenously. Hence, a relatively high clearance rate would not typically be a disadvantage, and as stated above, would be of potential great benefit to certain patients. Such intravenous formulations impose certain requirements on a drug, not the least of which is adequate solubility in the formulation medium. Thus, poorly soluble drugs may be unsuitable as a practical matter because the clinician is unable to dissolve the drug in a formulation, much less deliver adequate amounts of the drug via intravenous drip. Generally, the pH of the formulation is buffered to correspond to physiological pH, which is about 7.4. While some leeway is possible in the pH of an intravenous formulation, pain at the site of injection typically limits the useful range of pH to no less than about 5 to no greater than about 8. Preferably, the pH of an intravenous formulation ranges from about 6-8, more preferably from about 7-8 and most preferably at or about physiological pH (e.g., about 7.2-7.6).
Hence, there has been an on-going search for compounds that exhibit not only increased potency against resistant strains but also the physicochemical and pharmacological characteristics that enhance the effectiveness of a candidate compound and which may determine ultimately its acceptance in the clinic and resulting commercial success.
The present invention provides new analogs of vancomycin, which exhibit enhanced biological activity and improved physicochemical and pharmacological characteristics. The overall properties of these analogs exhibit substantial potential as drug candidates for treating infections caused by certain pathogens, including various strains of drug resistant bacteria. Accordingly, a general method is provided for the preparation of such compounds, along with methods of using them for the treatment of vertebrate conditions, including those afflicting mammals and especially those suffered by humans. Such conditions typically, although not exclusively, involve infections and other pathological conditions caused by bacteria and other microorganisms.
In particular, it has been observed that certain substituents positioned at the amine nitrogen of vancosamine and at the C-6 position of the glucose of vancomycin provide enhanced biological activity according to in vitro and in vivo assays and give rise to desirable physicochemical and pharmacological characteristics, all of which improve a candidate drug""s chances of success beyond the lab bench and in the clinic. More particularly, the present invention provides for lipid-like substituents on the amine nitrogen of vancosamine, which include at least two aryl moieties that are joined (i.e., covalently bound) together with a flexible linker moiety. By xe2x80x9clipid-likexe2x80x9d substituent is meant a xe2x80x9clipophilicxe2x80x9d substituent which refers to the tendency of the compound or substituent thereon to lack an affinity for, to repel or to fail to absorb water, or to be immiscible in water. The term xe2x80x9clipophilicxe2x80x9d is not meant to exclude compounds or substituents thereon that are not completely immiscible in water. By xe2x80x9cflexible linkerxe2x80x9d is meant that the linker or linking groups provides at least some degree of flexible movement in the substituent containing the lipid-like substituent. The flexible linker moiety joining the two aryl moieties of the lipid-like substituent on the vancosamine nitrogen is not a single bond directly joining the two aryl moieties. The flexible linker moiety appears to increase the lipophilicity of the molecule, as a whole, while potentially providing a site of attack for the metabolic and/or clearance processes of the body.
While a wide range of flexible linker moieties are potentially useful in the present invention, such as alkylene groups, alkylene ethers, alkylene thioethers, ethers, thioethers, acyls, sulfonyls, sulfoxides, alkylene amines, unsaturated aliphatic groups and the like, the preferred embodiments are those that (together with at least the first or second aryl moiety and possibly other functional groups present in the substituent) give rise to benzyl, benzylamino, benzyloxy, benzylthioether groups, phenyl ketones, or combinations thereof. Doubtless, one of ordinary skill in the art could contemplate other flexible linker moieties, which could give rise to increased lipophilicity and increased likelihood of breakdown/clearance by the body. The same or a different flexible linker moiety is also present to join the amine nitrogen of vancosamine to the first aryl moiety part of the lipid-like substituent. In a preferred embodiment of the invention, the lipid-like substituent comprises the formula Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2, as defined further below but which generally includes first and second aryl moieties, Ar1 and Ar2, and flexible linker moieties K and Z, provided that Z is not a single bond directly joining Ar1 and Ar2
It has been observed that of the wide range of possible substituents that can be positioned at the glucose C-6 position of vancomycin, polar substituents (that is, substituents that bear a charge or possess the capacity to bear a charge, either positive or negative, at some useful range of pH, but preferably at or about physiological pH) enhance biological activity and/or provide advantageous physicochemical and/or pharmacological characteristics. The term xe2x80x9cpolarxe2x80x9d as used herein to describe a compound of the present invention or a substituent thereon, refers to the tendency of the compund or substituent thereon to have an affinity for, to attract or to absorb water, or to be miscible in water. The term xe2x80x9cpolarxe2x80x9d is not meant to exclude compounds or substituents thereon that are not completely miscible in water. Most preferably, the polar substituent is part of an N-substituent (that is, an amine or amine based substituent) at the C-6 position, including but not limited to a free amine, substituted amines, alpha-amino acid amides, carboxylic acid amides (e.g., the carboxylic acid amide obtained from the reaction of a C-6 amine with for example succinic acid, other diacids, anhydrides, or other bifinctional acids), quaternary ammonium salts and the like. In particular, when not a free amine at the glucose C-6 position, the invention contemplates those substituents that can be joined to the amine group at the C-6 position of glucose and which (i) introduces a wide variety of functional groups, as part of or which can be added to the substituent, and (ii) also provides for one or more primary or secondary amine sites at a distal position (that is, a position in the substituent which is removed from the C-6 amine by two or more carbon atoms or in which the amine site is separated from the C-6 amine by three or more chemical bonds). Still in other embodiments of the invention, the polar substituent possesses polar groups, such as C(O), C(S), NH2, NHR2 groups and the like and combinations thereof, which may not ordinarily be charged. An example of such a polar substituent is urea or thiourea. It should be understood that the polar substituent contemplated by the present invention does not include the naturally occurring substituent at glucose C-6 of vancomycin, which is a hydroxyl group.
The preferred vancomycin compounds of the invention, including their pharmaceutically acceptable salts, are represented by the general Formula 1, presented below:
in which R represents a polar substituent and Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2 represents a lipid-like substituent, as described above.
The invention is also directed to pharmaceutical compositions, including enteral and parenteral formulations of the compounds disclosed herein. Also disclosed are methods of determining the biological activities of the various compounds of interest to the invention, as well as those of lesser interest. Methods of preparing the compounds and of utilizing same in a treatment regimen are also described and contemplated.
A more detailed description of the preferred embodiments of the invention follows for the benefit of the reader. Additional objects of the invention will become apparent to the reader after consideration of the entire disclosure.
As stated above, it has been observed that certain vancomycin analogs bearing vancosamine lipid-like substituents of the formula Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2 possess enhanced biological activity relative to those conventional substituents that do not fall within the scope of the formula. These vancomycin analogs consistently exhibit at least a two- to four-fold increase in activity over those vancomycin analogs bearing substituents known in the art, especially in those bacterial strains that exhibit the greatest resistance to vancomycin or teicoplanin. These strains include CL 4931, CL 5053, CL 5242 and CL 4877. See, Example 5.8, Table 3 and Table 4, below. Moreover, it is anticipated that improved physicochemical and pharmacological properties of the vancomycin analogs of the invention, including at least improved solubility characteristics and greater clearance rates, will contribute to a higher likelihood of success for these compounds in the clinic.
Broadly speaking, the constituents of the lipid-like substituent, Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2, can be the following:
K and Z can be the same or different and selected from any linking group which will provide the characteristics of flexibility required for the flexible linker. Especially preferred groups of this type comprise carbonyl, sulfonyl, (C1-6)alkylene, (C1-6)alkyleneoxy, oxy(C1-6)alkylene, (C1-6)alkyleneamino, amino(C1-6)alkylene, (C1-3)alkyleneoxy-(C1-3)alkylene, (C1-6)alkylenethio, thio(C1-6)alkylene, (C1-6)alkylenecarbonyl, aminocarbonyl or carbonylamino, (C1-6)alkyleneaminocarbonyl, aminocarbonyl(C1-6)alkylene, oxy, oxycarbonyl or carbonyloxy, (C1-6)alkyleneoxycarbonyl, oxycarbonyl(C1-6)alkylene, aminosulfonyl, or sulfonylamino,
Ar1 and Ar2 can be the same or different and selected from aromatic or heterocyclic groups, each optionally monosubstituted, disubstituted, or trisubstituted with R1; wherein
R1 can be halo; R2; CN; NO2; CF3; OCHxF(3-x)(x=0xe2x88x923); NHSO2R2; OR2, SR2; N(R2)2; N+(R2)3; C(O)N(R2)2; SO2N(R2)2; heterocyclic; CO2R2; C(O)R2; NR2C(O)R2; or NHC(O)R2; and wherein R2 independently (where more than one R2 is present) represents H, aryl, straight or branched (C1-6) alkyl, arylalkyl, heterocyclic, heterocyclic (C1-C6) alkyl, aroyl, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl; and when two R2 groups are present, they may optionally be linked by one or more covalent bonds to form one or more rings, which may be aromatic, aliphatic, or heterocyclic.
In a preferred embodiment of the invention, the polar substituent, R, has the formula:
in which the groups R3 and R4 may independently be present or absent and, if present, may be the same or different and selected from H, alkyl, aryl, heterocyclic, aralkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, heterocycliccarbonyl, aminocarbonyl, substituted arninocarbonyl, substituted oxycarbonyl, alkylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, aminosulfonyl, substituted aminosulfonyl, amidino, or substituted arnidino, said alkyl, aryl, heterocyclic, arylalkyl, heterocyclicalkyl, alkylcarbonyl, arylcarbonyl, or heterocycliccarbonyl being optionally substituted with 1-3 groups of R1; and wherein R3 and R4 may be linked to one another or to one or both of the others by one or more covalent bonds to form one or more aryl or heterocyclic rings of 3-20 members, optionally comprised of C, N, O, or S. Preferably R is NH2 or substituted NH2
Examples of preferred polar substituent groups are provided in the Tables and the Chart included in this disclosure, which also provide examples of preferred lipid-like substituents having two or more flexible linkers.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical comprising 1 to about 20 carbon atoms connected by single or multiple bonds, unless otherwise indicated. The alkyl group may be straight, branched, or cyclic. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, secbutyl, t-butyl, pentyl, cyclopentyl, hexyl and cyclohexyl. The term xe2x80x9calkylenexe2x80x9d refers to a hydrocarbon radical comprising 1 to about 20 carbon atoms connected by single or multiple bonds, unless otherwise indicated, and which is bound to other finctional or chemical groups of the molecule at least at two sites. Examples of alkylene groups include, but are not limited to, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 xe2x80x94CH2CH2CH2xe2x80x94 xe2x80x94CH2(CH3)CH2xe2x80x94, and the like, wherein each dash represents a point of attachment to another chemical or finctional group of the molecule. When substituted, alkyl and alkylene groups may be substituted with up to three substituent groups, selected from Ra and Rh, as defined above, at any available point of attachment. When an alkyl group is described as being substituted with an alkyl group, such a phrase is used interchangeably with xe2x80x9cbranched alkyl group.xe2x80x9d
The term xe2x80x9ccycloalkylxe2x80x9d is a species of alkyl and is a group comprising about 3 to about 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may also contain from 1 to 4 fused rings.
The term xe2x80x9carylxe2x80x9d refers to a group derived from a non-heterocyclic aromatic group having from six to about twenty carbon atoms and from one to four rings, which may be fused, connected by single bonds, or both. An aryl group may be substituted by one or more of alkyl, aralkyl, heterocyclic, heterocyclicalkyl, heterocycliccarbonyl, halo, hydroxyl, protected hydroxyl, amino, nitro, cyano, alkoxy, aryloxy, aralkyloxy, aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, alkyloxycarbonyl, aralkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl and the like.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group bearing an aryl group substituent.
The term xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheteroarylxe2x80x9d refers to a cyclic hydrocarbon group in which at least one of the ring positions is occupied by a heteroatom. A heterocyclic compound may have from one to about four rings, which may be fused, connected by single bonds, or both. A heterocyclic group may comprise from three to about twenty ring atoms, which atoms may be chosen from carbon, nitrogen, oxygen, or sulfur as long as at least one heteroatom is present. A heterocyclic group may have up to 1, 2, or 3 double bonds per ring, thus allowing for an aromatic system. A heterocyclic group may be substituted by one or more of alkyl, aryl, aralkyl, halo, hydroxyl, protected hydroxyl, amino, nitro, cyano, alkoxy, aryloxy, aralkyloxy, aroyloxy, alkylamino, dialkylamino, trialkylammonium, alkylthio, alkanoyl, alkanoyloxy, alkanoylamido, alkylsulfonyl, arylsulfonyl, aroyl, aralkanoyl, alkyloxycarbonyl, aralkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a monovalent alkene group comprising up to about carbon atoms which contains at least one double bond between carbon atoms. The alkene group may be straight chained or branch chained. Examples include vinyl, propenyl, butenyl and pentenyl groups.
The term xe2x80x9calkynylxe2x80x9d refers to a monovalent alkyne group comprising up to about 20 carbon atoms which contains at least one triple bond between carbon atoms. The alkyne group may be straight or branch chained. Examples are propynyl, butynyl and pentynyl.
The term xe2x80x9cheteroatomxe2x80x9d means an atom other than carbon or hydrogen, but is generally associated with the atoms N, O, or S, selected on an independent basis.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine, or iodine.
The terms xe2x80x9calkoxy,xe2x80x9d xe2x80x9caryloxyxe2x80x9d and xe2x80x9caralkyloxyxe2x80x9d refer to a chemical group in which an oxygen atom is covalently bound to an alkyl, aryl, or aralkyl group, respectively.
The terms xe2x80x9calkanoyl,xe2x80x9d xe2x80x9caroylxe2x80x9d and xe2x80x9caralkanoylxe2x80x9d refer to chemical groups in which a carbonyl group is covalently bound to an alkyl, aryl, or aralkyl group, respectively.
The term xe2x80x9cheterocyclicalkylxe2x80x9d or xe2x80x9cheterocycliccarbonylxe2x80x9d refers to chemical groups in which a heterocyclic group is covalently bound to an alkyl or carbonyl group, respectively.
When a group is termed xe2x80x9csubstituted,xe2x80x9d unless otherwise indicated, this means that the group contains from 1 to 3 substituents thereon.
When a functional group is termed xe2x80x9cprotected,xe2x80x9d this means that the group is in a temporary, modified form to inhibit the participation of the protected site in a particular reaction sequence intended to effect some change elsewhere in the molecule. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d Wiley, New York (1991). In addition, examples of suitable protecting groups are presented throughout the specification.
In some of the glycopeptide compounds of the present invention a hydroxyl-protect group might be required. Such conventional protecting groups consist of known groups, which are used to protectively block the hydroxyl group during the synthetic procedures described herein. These conventional blocking groups are readily removable; i.e., they can be removed, if desired, by procedures that will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst, a nucleophile and catalytic hydrogenation.
Examples of suitable C-6 hydroxyl protecting groups include, but are not limited to, triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
The glycopeptide compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects. The term xe2x80x9cpharmaceutically acceptable ester, salt, or hydratexe2x80x9d refers to those esters, salts, or hydrated forms of the compounds of the present invention, which would be apparent to the medicinal chemist. Such forms include, but are not limited to, those that are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel glycopeptide compounds of the present invention, particularly the vancomycin-like glycopeptide compounds disclosed herein.
The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate and the like.
A strategy to introduce a suitable set of protecting groups and to differentiate the C-6 hydroxyl group from all other hydroxyl groups of a glycopeptide having a hexose residue at amino acid number four (A4) is illustrated below in Scheme 1, showing functionalization of the glucose C-6 hydroxyl of vancomycin, wherein Alloc-Su is N-(allyloxycarbonyloxy) succinimide.
In general, introduction of the substituent containing the linker group on the vancosamine nitrogen is preferably by reductive amination, either direct or to a peptide-protective species. In general, introduction of the polar group at C6 is preferably by azide displacement/reduction, amine nucleophilic displacement, and/or acylation.
Protection of both amines by a similar group requires using excess acylation reagent while selective protection of the N-methyl leucine residue is known, allowing selective finctionalization of the vancosamine amine group. See, Pavlov et al., J. Antiobiotics, 1993, 46, 1731. Selectively, introducing the mesitylenesulfonyl group at the glucose-6-position differentiates this position from the other hydroxyl groups and allows further reaction to displace the mesitylenesulfonyl group, affording many derivatives. A variety of functional groups are introduced at the glucose-6 position by using common methods for nucleophilic displacement of primary arylsulfonyl groups directly, or by further synthetic modification of initial displacement products, including azido and iodo groups. For example, the iodo group is displaced by a variety of nucleophiles to produce additional C-6 derivatives. A preferred nucleophile is a thiol compound, especially a heterocyclic thiol. Modification of an azido group at the 6-position is performed, e.g., by reducing the azido group to an amino group, which in turn is functionalized by means of reductive alkylation, nucleophilic substitution, or other amino-group reactions well known to those skilled in the art. These approaches are illustrated in many examples. In a preferred embodiment of the invention, an azido group is partially reduced by reaction with a phosphine compound to produce an iminophosphorane.
More specifically, the amino substituents of vancomycin are protected as indicated while introducing a mesitylenesulfonyl finctional group at the C6 position. The allyloxycarbonyl groups are introduced by reaction of vancomycin hydrochloride in aqueous solution with N-(allyloxycarbonyloxy) succinimide contained in an organic solvent such as acetone. A preferred procedure is to treat the aqueous solution of vancomycin with the organic solvent solution of succimide.
This resulting solid product is reacted with an allyl halide reactant such as allyl bromide in the presence of an alkali metal bicarbonate to form an allyl ester of the carboxyl and protect that position. The resulting allyl ester is then reacted with a compound which will introduce a functional group such as mesitylenesulfonyl chloride by reaction in a solvent such as pyridine so as to introduce the mesitylenesulfonyl moiety at the C6 hydroxy. This compound is then reacted with an alkali metal halide such as KI to introduce I at the C6 position. The protective allyl group is then removed conventionally such as with a palladium compound and a phosphinobutane.
In the next step, the intermediate is reacted with allyloxycarbonyl succinimide to protect the secondary nitrogen while leaving the primary nitrogen unprotected. At this stage the intermediate can be reacted with an aldehyde such as the benzyloxybenzaldehyde as in Example 5.4 to introduce a benzyloxybenzyl group at the vancosamine nitrogen. Similarly, other aldehydes can be reacted with the same or similar intermediate to form other derivatives, such as the use of the aldehyde phenylbenzaldehyde to introduce the Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2 moieties of the compounds of the tables. Similarly, aldehydes or other reactive compounds can be used in a known manner to introduce the Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2 derivatives of the compounds of the tables.
After the vancosamine is suitably substituted, the intermediate is reacted with an alkali azide to form an azide which is then reacted with a phosphine for conversion to the amine. Obviously substituted amines such as the substituents shown in this position in the compounds of the tables can be provided using these reations.
After the vancosamine amine polar group is introduced, the protected secondary amine is deprotected to produce the final product.
A similar procedure for preparation of the glycopeptides of the invention is shown in the following reaction scheme 2 where Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2 is as described above, and Fmoc is Fluorenylmethoxycarbonyl, and NR2R21 is the reactant to introduce the amine substituent. In this reaction with XCHO, deblocking is carried out as described, and X is the Kxe2x80x94Ar1xe2x80x94Zxe2x80x94Ar2 substituent on the vancosamine nitrogen.
In a preferred embodiment of the invention, the vancomycin analog and its pharmaceutically acceptable salt is described by the Formula 1, depicted above, in which the group R represents a group
in which R3 and R4 may independently be H, (C1-12)alkyl, aryl(C1-3)alkyl, heterocyclic (C1-3)alkyl, (C1-12)alkylcarbonyl, arylcarbonyl, or heterocyclic-carbonyl, said alkyl, aryl, heterocyclicalkyl, being optionally substituted with 1-3 groups of R1; or in which R3 and R4 may be linked by one or more covalent bonds to form one or more rings of 3-20 members each;
K is a carbonyl, sulfonyl, (C1-3)alkyl, Oxy(C2-3)alkyl, (C1-3)alkylcarbonyl, or (C1-3)-alkyloxycarbonyl;
Z is a carbonyl, sulfonyl, (C1-3)alkyl, (C1-3)alkyloxy, Oxy(C1-3)alky (C1-3)-alkyloxy(C1-3)alkyl, aminocarbonyl, carbonylamino, aminosulfonyl or, sulfonylamino;
Ar1, is aromatic or heterocyclic, each optionally monosubstituted or disubstituted withR1; and
Ar2 is aromatic or heterocyclic, each optionally monosubstituted, disubstituted, or trisubstituted with R1;
R1 is halo including chloro, bromo, iodo or fluoro, R2, CN, CF3, OCHxF(3-x)(x=0-3), NHSO2R2, OR2, SR2, N(R2)2, N+(R2)3, C(O)N(R2)2, SO2N(R2)2, heterocycle, CO2R2, C(O)R2, OC(O)R2, or NHC(O)R2, and wherein R2 independently represents H, aryl, straight- or branched-chain (C1-3)alkyl group, aryl(C1-3)alkyl, heterocyclic, heterocyclic(C1-3)alkyl, alkylsulfonyl, arylsulfonyl and the like. When two R2 groups are present, they may optionally be linked by covalent bonds to form one or more rings. Said rings may be aromatic, aliphatic, or heterocyclic.
In yet another preferred embodiment of the invention, the group K is a carbonyl, sulfonyl, or CH2 group. The R group is more preferably NH2.
A representative example of a preferred embodiment of the vancomycin analog compounds of the present invention is depicted below:
This compound is Entry Number 13 in Table 2.
The synthesis of the target compound is completed by removing any protecting groups that may be present in the penultimate intermediate using standard techniques that are well known to those skilled in the art. The deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, reverse phase HPLC, MPLC on reverse phase polystyrene gel and the like, or by recrystallization.
The final product may be characterized structurally by standard techniques such as NMR, IR, MS and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
The compounds of the present invention are valuable antibacterial agents active against various gram-positive and, to a lesser extent, gram-negative bacteria. Accordingly, these compounds fmd utility in human and veterinary medicine.
Many of compounds of the present invention are biologically active against VRE/MRSA/MRCNS. In vitro antibacterial activity is generally predictive of in vivo activity. It is contemplated that the compounds of the present invention will be administered to a mammal infected with a susceptible bacterial organism.
Using standard susceptibility tests, the compounds of the invention are determined to be active against VRE/MRSA.
The compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below.
The compounds may be employed in powder or crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection (intravenously or intramuscularly).
Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampoules, or in multidose containers. The injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder (lyophilized or non-lyophilized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water. In injectable compositions, the carrier is typically comprised of sterile water, saline, or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
Topical applications may be formulated in carriers such as hydrophobic or hydrophilic base formulations to provide ointments, creams, lotions, in aqueous, oleaginous, or alcoholic liquids to form paints or in dry diluents to form powders.
Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize carriers such as conventional formulating agents and may include sustained release properties as well as rapid delivery forms.
The dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.
The compositions for human delivery per unit dosage, whether liquid or solid, may contain from about 0.01% to as high as about 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from about 15 mg to about 2.5 g of the active ingredient; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and be made isotonic.
The invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of Formula I in an amount effective to treat said infection.
The preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection.

Glycopeptide antibacterial compounds, compositions containing same and methods of using same


An information distribution system reduces the effort required to change an application in conjunction with changes in process content and changes in the receiver type or specifications while also accommodating broadcast processes. A style sheet database stores a plurality of output style sheets, which are information conversion rules including conditional expressions related to information distribution. An integrated device control service acquires output data and receiver information specifying the address of the receiver and the output style sheet corresponding to said receiver. When the output data satisfies the conditional expression contained in the output style sheet, the integrated device control service distributes converted output data, which is the output data converted based on the output style sheet, to the address of the receiver.

1. Technical Field
The present invention relates to an information distribution system for distributing information between transmitters and receivers, to a service-providing method for an information distribution system, and to a program for the same.
2. Related Art
When information is distributed to a plurality of devices (receivers) such as printers, displays, and card readers that are connected to a computer, an application program (a transmitter, referred to below as simply "application") is installed on the computer and commands are output from the application. In order to cause the plural types of devices to execute a single coordinated process, the application must be written to include processes specific to each device, such as a process instructing a first device to execute an operation and return event information, and another process then instructing a second device to execute an operation and return event information, and writing the application is thus time-consuming.
Japanese Unexamined Patent Appl. Pub. JP-A-2000-242594 therefore teaches a system that inserts a management module between the application and the plural devices. The application sends a device name and process content (process identifier) to the management module, and the management module writes the received content to a table and causes the devices to execute a coordinated process. Because this configuration eliminates the need to write the process content for executing the coordinated process in the application, writing the application is easier. Another advantage is that application changes can be kept to a minimum when the number of devices changes.
When it is necessary to change the format, layout, or print content to be printed by the printer with the system taught in JP-A-2000-242594, however, the application must be changed. When a device is replaced with a different model, the control information (commands) that must be sent also changes and the application must therefore also be changed. The system taught in JP-A-2000-242594 is thus not configured so that changes in process content or differences in device models can be absorbed by the management module.
It is also conceivable that this system may broadcast the same data to a first device and to a second device. However, if the first device and second device are different types of devices, both devices cannot be caused to operate normally when the same data is sent to both. The system may also conditionally broadcast the distributed data so that, for example, the data is sent to the first device when some condition is met and is sent to the second device if the condition is not met, but this system is unable to define the conditions.

Information distribution system, service-providing method for an information distribution system, and a program for the same


Incoming call tones and program numbers as numbers used to specify respective incoming call tones are stored in a memory of a cellular phone so as to be set in correspondence to each other. The program numbers are used to specify corresponding incoming call tone melodies, data of which is stored in the memory. A control circuit of the cellular phone, whenever an incoming call is received, increments a value of a counter indicating the corresponding program number by one, and uses an incoming call tone corresponding to the program number corresponding to the value of the counter.

1. Field of the Invention
The present invention relates in general to a cellular phone, and more particularly to a cellular phone having a function of, when an incoming call is received, generating an incoming call tone to inform a user of reception of the incoming call.
2. Description of the Related Art
In recent years, a user possessing a cellular phone sets an incoming call tone for, when an incoming voice call is received, or when an E-mail call is received, informing the user of reception of the incoming call according to user's own preferences. The incoming call tone thus set is an incoming call tone, the data of which is stored in a cellular phone in advance when the cellular phone is purchased.
In addition, the set incoming call tone is an incoming call tone, the data of which is downloaded by a user from a server of an enterprise providing a service for delivering incoming call tones to be stored in a cellular phone. Moreover, such a set incoming call tone is an original incoming call tone data of which is created by a user to be stored in a cellular phone.
A user may set one incoming call tone (e.g., incoming call tone melody) signaling reception of an incoming voice call and another one signaling reception of an incoming E-mail call in some cases.
Even when a large number of kinds of data of incoming call tone melodies are stored in a cellular phone, only one incoming call tone melody can be used at a time by a user. Thus, when a user desires to generate multiple kinds of incoming call tone melodies to take pleasure in them, the user needs to manipulate the cellular phone to change the setting of an incoming call tone melody. When a user does not change the setting of the incoming call melody tone since a user feels that an operation for changing of the setting of the incoming call melody tone is troublesome, the cellular phone generates the same incoming call melody tone at every reception of an incoming call. Consequently, a user can not take pleasure in multiple kinds of incoming call melody tones.
Then, a system is proposed for selecting at random an incoming call tone melody which is to ring when an incoming call is received (refer to JP 2002-204286 A for example).
In addition, there is a cellular phone in which data of a single incoming call melody tone is divided into a plurality of parts data of which is in turn stored in the form of division data. This cellular phone, when ever an incoming call is received, rings different incoming call melody tone obtained from the division data (refer to JP 2000-354087 A for example).
However, in the system described-in JP 2002-204286 A, an incoming call melody tone ringing when an incoming call is received is selected at random in correspondence to an instantaneous value of a program counter of a microcomputer in the system. Hence, a specific incoming call melody tone may not be selected for a long period of time in some cases. Also, there is a possibility that an incoming call tone melody which, though its data is stored in the cellular phone, is not desired to be used as an incoming call tone melody may be selected.
In addition, the method described in JP 2000-354087 A does not cope with use of a plurality of kinds of incoming call tone melodies. For this reason, in a case where a user desires to use another incoming call tone melody, the user needs to divide data of another incoming call tone melody into a plurality of parts and to set an incoming call tone. For this reason, a user must carry out a complicated manipulation.

Cellular phone and incoming call reception informing method


A solid ion conductor including a garnet oxide represented by Formula 1:L5+x+2y(Dy,E3-y)(Mez,M2-z)Od  Formula 1wherein                L is at least one of a monovalent cation or a divalent cation,        D is a monovalent cation,        E is a trivalent cation,        Me and M are each independently a trivalent, tetravalent, pentavalent, or a hexavalent cation,        0<x+2y≦3, 0≦y≦0.5, 0≦z<2, and 0<d≦12,        wherein O is partially or totally substituted with at least one of a pentavalent anion, a hexavalent anion, or a heptavalent anion; andB2O3.

1. Field
The present disclosure relates to a solid ion conductor with high ionic conductivity, a solid electrolyte including the solid ion conductor, a lithium battery including the solid electrolyte, and a method of manufacturing the solid ion conductor.
2. Description of the Related Art
Lithium batteries have high voltage and energy density, and are used in various fields. For example, in electric vehicles, hybrid electric vehicles (HEVs) and plug-in hybrid electric vehicles (PHEVs), battery operation at high temperatures, charging or discharging a large amount of electricity, and a long period of battery use can be desirable.
In a lithium battery including a liquid electrolyte, i.e., an electrolyte prepared by dissolving a lithium salt in an organic solvent, the liquid electrolyte starts to decompose at a voltage of 2.5 V or more. Also, the liquid electrolyte has a high risk of leakage, fire, and explosion. Further, the liquid electrolyte can support the formation of dendrites, which can cause self-discharging and heating of a lithium battery.
An all-solid-state lithium battery including a lithium ion conductor as a solid electrolyte can have a higher stability than that of a lithium battery including a liquid electrolyte. The lithium ion conductor constituting the solid electrolyte is a single ion conductor in which only Li ions are migrated, and thus it has no risk of ignition, as compared to lithium batteries including a liquid electrolyte. Therefore, all-solid-state lithium batteries are suitable for use in electric vehicles, large-scale storage batteries, and the like.
The solid ion conductor desirably has high lithium ion conductivity, is chemically stable, and has a wide potential window, for use as a solid electrolyte for a lithium battery.
A garnet-type oxide, such as Li5La3M2O12 (M=Nb or Ta), is chemically stable and has a wide potential window, while it has a poor lithium ionic conductivity (e.g., approximately ˜10−6 Siemens per centimeter (S/cm)) at 25° C.

Solid ion conductor, solid electrolyte including the same, lithium battery including the solid electrolyte, and method of manufacturing the solid ion conductor

KOREA UNIVERSITY RESEARCH AND BUSINESS FOUNDATION


In a heat exchanger made of stacked tubular elements, the tubular elements are formed from pressed plates bearing on one another. The plates enclose between them a cavity which is connected via corresponding orifices to the cavity of the tubular element adjacent in each case. In order to fix the stacked plates in their position and reliably prevent slipping along the tubular element plane, all the plates of the heat exchanger are provided with a congruent fixing orifice, into which a fixing rod can be inserted. A method for manufacturing the heat exchanger is also disclosed.

The present invention relates to a heat exchanger, in particular a refrigerant evaporator, of the generic type comprising a plurality of tubular elements assembled to form a stack, wherein each tubular element comprises two pressed plates which enclose between them a cavity Each pressed plate has a pressed-out portion with an orifice therein positioned near at least one end of the tubular element, the pressed-out portion being capable of bearing on the adjacent tubular element and being connected to its cavity via the orifice. Corrugated ribs or fins are arranged between each two adjacent tubular elements.
U.S. Pat. No. 5,176,206 describes a heat exchanger which consists of a multiplicity of flat tubular elements, the tubular elements each being formed from two pressed plates. The tubular elements, with corrugated ribs being interposed, are assembled to form a stack. A side part is arranged at each of the two ends of the stack. The sheet metal plates from which the tubular elements are made have, at one end of their longitudinal extension, pressed-out portions with orifices arranged therein, the pressed-out portions being directed in each case to the adjacent tubular element, so that the tubular elements, succeeding one another in each case, bear with their pressed-out portions against one another. The orifices in the pressed-out portions form passages to the cavity of the next tubular elements in each case, so that a flow duct for the fluid flowing through the heat exchanger is formed.
In the known arrangement, the faces on which two plates forming a tubular element bear against one another in each case are of planar design. The tubular elements in each case adjacent to one another likewise bear with purely planar faces against one another, so that extreme care must be taken with the stack assembled from tubular elements and corrugated ribs, until, after soldering, a displacement of the plates relative to one another is no longer possible. However, such a method of treating a stack consisting of tubular elements cannot be implemented in practice, and therefore complicated fixing and clamping devices are necessary in order to secure the individual plates or tubular elements in their relative position in relation to the arrangement as a whole. However, clamping devices of this type are expensive and impede the production cycle, which is ultimately reflected in the production costs of the heat exchanger.
U.S. Pat. No. 5,086,832 discloses a heat exchanger which consists of stacked tubular elements, each consisting of two pressed plates. In this case, the plates have spacing and interlocking deformations at one end, so that the plates in each case adjacent to one another are fixed at this end to the plate adjacent to them. However, this necessitates corresponding shaping which results in an increased use of material, in an impediment to the production process and in a greater weight of the heat exchanger. Such complicated measures are also ultimately reflected in the price of the heat exchanger.

Heat exchanger suitable for a refrigerant evaporator


The present disclosure is directed to systems and methods for the selective introduction of low-level pseudo-random noise into at least a portion of the weights used in a neural network model to increase the robustness of the neural network and provide a stochastic transformation defense against perturbation type attacks. Random number generation circuitry provides a plurality of pseudo-random values. Combiner circuitry combines the pseudo-random values with a defined number of least significant bits/digits in at least some of the weights used to provide a neural network model implemented by neural network circuitry. In some instances, selection circuitry selects pseudo-random values for combination with the network weights based on a defined pseudo-random value probability distribution.

Neural networks are vulnerable to subliminal signals, "adversarial inputs" that degrade the performance of the neural network, and in extreme circumstances, permit an attacker to cause the neural network to generate a desired, incorrect, outcome. Consider a setting where a neural network model M has been trained to accept an input x and infer an output M(x), which typically represents some class to which x belongs. An adversary, given an input x can craft a perturbed input x′=x+δx that can fool the neural network model as coming from a class M(x′) which is different than the original class M(x). In certain application, including machine vision and voice recognition it is possible to create adversarial examples that are imperceptibly close to the original inputs, i.e., δx, is so small that a human observer cannot recognize a difference between the original benign input x and the malicious input x′. The ability to corrupt the output of a neural network may detrimentally impact the ability of the neural network to provide consistent results. Such may cause significant health and safety concerns where such neural networks are used in control systems, such as in autonomous vehicles.
Although the following Detailed Description will proceed with reference being made to illustrative embodiments, many alternatives, modifications and variations thereof will be apparent to those skilled in the art.

Defending neural networks by randomizing model weights


A multi-phase interleaved PFC converter includes at least six switches coupled in a multi-phase interleaved circuit arrangement, and a control circuit. The control circuit is configured to turn on and turn off a first one of the switches according to a PWM signal to operate the first switch as an active switch having an off-time as a function of a duty cycle of the PWM signal, while turning on and turning off a second one of the switches as a synchronous switch. The control circuit is also configured to receive signal(s) indicative of currents in each phase of the interleaved circuit arrangement, set an on-time of the second switch equal to the off-time of the first switch when the signal(s) indicate continuous mode operation, and set the on-time of the second switch to a duration less than the off-time of the first switch when the signal(s) indicate discontinuous mode operation.

This section provides background information related to the present disclosure which is not necessarily prior art.
In a multi-phase interleaved power factor correction (PFC) converter, a choke current may become discontinuous at light loads or low input voltages near a zero crossing of the AC input. If a synchronous switch is on for a full period of the off-time of its corresponding active switch, a negative current may flow back to the AC input from a bulk output capacitor. The negative current may greatly increase a current imbalance between different phases in the converter.

Multi-phase interleaved power converters with improved current balancing