A printer driver operating in an information processing device transmitting print job data to printing devices causes the information processing device to function as: a configuration processing unit configured to hold configuration information about the printer driver, and generate configuration data; a user interface unit configured to generate a print setting screen, and cause a display unit to display the print setting screen; and a drawing unit configured to perform a drawing process on print job data generated in the information processing device, wherein the drawing unit includes specific drawing units prepared for respective model groups classifying the printing devices in accordance with attributes of models of the printing devices, the specific drawing units being configured to perform a model-group-specific drawing process, and selects an appropriate specific drawing unit from among the plurality of specific drawing units, to perform a drawing process with the selected specific drawing unit.

Field of the Invention
The present invention relates to a printer driver and an information processing device.
Description of the Related Art
Version 3 printer drivers (V3 printer drivers) developed for Windows 2000 to Windows 7 have been provided as printer drivers that operate on operating systems (OS) of Windows (a registered trade name). A structure that uses the architecture of the V3 printer drivers is also known as a universal printer driver (UPD) that supports printing devices of various models with a single printer driver.
Since Windows 8 was released, manufacturers have developed version 4 printer drivers (V4 printer drivers) using new architecture. As the architecture of the V4 printer drivers is expected to be dominant in Windows to be released in the future, there is a demand for supplies of universal printer drivers based on the current architecture.
JP 2012-43161 A discloses a technology relating to a universal printer driver based on the architecture of the V3 printer drivers. According to JP 2012-43161 A, child drivers are prepared for respective models, and the child drivers are switched in accordance with the printing device designated as the output destination. In this structure, printing devices of two or more models can be supported by a single printer driver.
According to the technique disclosed in JP 2012-43161 A, one driver is compatible with two or more models. However, the respective child drivers in this driver are V3 printer drivers compatible with specific models, and these child drivers are simply switched to cope with the two or more models. Since a V4 printer driver has completely different architecture than a V3 printer driver, it is difficult to form a universal printer driver based on a V4 printer driver in the same manner as in forming a universal printer driver based on a V3 printer driver.

Printer driver and information processing device


The present invention relates to a Fab fragment based switchable antibody system for generating site-specific antibody conjugates. Methods are described for the attachment of molecules to specific sites the Fab fragment and for the attachment of the Fab fragment to a target molecule (e.g., an antibody) directed against any desired target antigen (tumor, bacterial, fungal, viral, parasitic etc.) The attachment is via binding of the Fab fragment to an epitope linked to the target molecule.

Over the past decades, antibody conjugates with small molecules (Hernandez et al., Theranostics 2016, 6 (11), 1918-1933; Lewis Phillips et al., Cancer Res. 2008, 68 (22), 9280-9290; Wang et al., J. Am. Chem. Soc. 2015, 137 (9), 3229-3232), oligomers (Sano et al., Science 1992, 258 (5079), 120-122), and proteins (Gill et al., J. Immunoassay Immunochem. 2006, 27 (4), 303-318) have been extensively pursued for immuno-assay, imaging-based detection and diagnosis, as well as therapeutic development. In particular, antibody-drug conjugates (ADCs) emerge as a promising class of immunotherapeutic, with trastuzumab-DM1, brentuximab vedotin, and inotuzumab-ozogamicin being recently FDA-approved for treatment of breast cancer, Hodgkin's lymphoma, and acute lymphoblastic leukemia, respectively (Lewis Phillips et al., Cancer Res. 2008, 68 (22), 9280-9290; Wang et al., J. Am. Chem. Soc. 2015, 137 (9), 3229-3232). The most common antibody conjugation method relies on a random reaction with surface-exposed cysteines or lysines which results in a heterogeneous mixture of conjugates with distinct stabilities, efficacies, and pharmacokinetics/pharmacodynamics (Adumeau et al., Mol. Imaging Biol. 2016, 18 (1), 1-17; Schumacher et al., J. Clin. Immunol. 2016, 36 Suppl 1, 100-107). With the use of site-specific conjugation, a precise control of sites and stoichiometry, homogeneous antibody conjugates can be generated to possess improved signal-to-noise ratios, efficacy, pharmacokinetics, and therapeutic indexes relative to conventionally-made random conjugates (Adumeau et al., Mol. Imaging Biol. 2016, 18 (1), 1-17; Junutula et al., Nat. Biotechnol. 2008, 26 (8), 925-932; Shen et al., Nat. Biotechnol. 2012, 30 (2), 184-189). One method for synthesizing site-specific antibody conjugates involves the amber-suppression mediated genetic incorporation of unnatural amino acids (UAAs) (Wu and Schultz, J. Am. Chem. Soc. 2009, 131 (35), 12497-12515), in which a pair of orthogonal tRNA/aminoacyltRNA synthetase specific for the UAA were evolved in order to incorporate the UAA based on the amber codon TAG to the selected sites of a protein (Wu and Schultz, J. Am. Chem. Soc. 2009, 131 (35), 12497-12515; Adumeau et al., Mol. Imaging Biol. 2016, 18 (2), 153-165; Lu et al., J. Am. Chem. Soc. 2013, 135 (37), 13885-13891). To date, approximately 200 structurally distinct UAAs have been systematically added to proteins (Xiao et al., Cold Spring Harb. Perspect. Biol. 2016, 8 (9)).
A typical UAA with the desired chemical reactivity is p-acetylphenylalanine (pAcF), which has been successfully coupled to small molecules, oligonucleotides, polymers, or proteins of interest via a stable oxime linkage (Lu et al., J. Am. Chem. Soc. 2013, 135 (37), 13885-13891; Axup et al., Proc. Natl. Acad. Sci. U.S.A. 2012, 109 (40), 16101-16106; Hutchins et al., Chem. Biol. 2011, 18 (3), 299-303; Kazane et al., Proc. Natl. Acad. Sci. U.S.A 2012, 109 (10), 3731-3736; Kularatne et al., Angew. Chem. Int. Ed. Engl. 2014, 53 (44), 11863-11867). Yet the strategy based on UAA is deemed intrinsically complicated, costly and consuming in terms of time and labor (Schumacher et al., J. Clin. Immunol. 2016, 36 Suppl 1, 100-107; Adumeau et al., Mol. Imaging Biol. 2016, 18 (2), 153-165). More importantly, the yields of UAA mutants, conjugation efficiency, and conjugate stability vary and largely depend on each individual antibody (Adumeau et al., Mol. Imaging Biol. 2016, 18 (1), 1-17; Schumacher et al., J. Clin. Immunol. 2016, 36 Suppl 1, 100-107; Adumeau et al., Mol. Imaging Biol. 2016, 18 (2), 153-165; Axup et al., Proc. Natl. Acad. Sci. U.S.A 2012, 109 (40), 16101-16106; Kularatne et al., Angew. Chem. Int. Ed. Engl. 2014, 53 (44), 11863-11867).
Thus, there is a need in the art for an orthogonal switch as a general and effective strategy to endow versatility to a single antibody conjugate, which facilitates the application of UAA-based site-specific antibody conjugates for a host of therapeutic uses. The present invention satisfies this unmet need.

Temple University—Of The Commonwealth System of Higher Education


A method and a device for compressing a gas-phase medium, particularly hydrogen or natural gas, in a single-stage or multistage process using at least one piston compressor, wherein the medium may have a water content up to total saturation with water. The medium to be compressed is heated before the compression at least to such point that the water is unable to condense out during the compression process, and the compressed medium undergoes a water separation process.

The invention relates to a method and a device for the single- or multistage compression of a gas-phase medium, particularly hydrogen or natural gas, by means of at least one piston compressor, wherein the medium may have a water content up to total saturation with water.
Species-related compression methods and devices are known sufficiently well from the prior art. Such methods and devices are used for example for compressing gas-phase hydrogen or natural gas. In this context, until now the problem that has presented itself has been that the hydrogen to be compressed inevitably contains water by virtue of the method of its production—by electrolysis for example. Previously, this had to be removed completely before proceeding with the actual compression, because in the compressors of the related art, particularly piston compressors, the compressor valves would be damaged by water droplets or corrosion. For this reason, until now it has been necessary to provide fairly complicated devices or systems for separating the water.
In the case of hydrogen production by electrolysis, for example, molecular sieves are used. However, these need energy because they have to be heated cyclically, and they also consume a portion of the valuable hydrogen, which is used as the purge gas for regenerating the molecular sieve. The necessary separation of the water thus makes hydrogen generation more expensive. Furthermore, devices of such kind require a certain degree of maintenance, which further raises the cost of generating hydrogen.
The same problems are also encountered when compressing other media, such as natural gas for example, which must be compressed for use in refueling vehicles.
The object of the present invention is to suggest a species-related method and a species-related device for compressing a gas-phase medium that avoid the disadvantages outlined in the preceding.


A transfer and introduction tooling for transporting coils from a winding machine and for drawing the coils into a variety of stators of electric motors includes a set of carrier arrangements of differing diameters and a number of interchangeable parts forming a transfer tool, an introduction tool and a cover-strip magazine. Each carrier arrangement has a central opening and a plurality of identical receiving locations disposed about its periphery. The transfer tool is formed by combining a carrier arrangement with a plurality of transfer forks where each transfer fork has two spaced fork prongs and an extension which can be releasably fastened to the receiving locations of the carrier arrangements to form a transfer tool. The extensions of the transfer forks, introduction blades and guide channels of the magazine which can be releasably inserted into receiving locations are identical, and the differing diameters and number of receiving locations of each carrier arrangement correspond to diameters of a variety of stators so that only a corresponding number of blades and forks are necessary for all possible windings of the variety of stators.

A process of this type is known from German Patent Specification 3,409,684. This is to be taken as a starting-point, with the proviso that the introduction blades used are made of plastic with metallic guide lamellae, as described in German Patent 3,501,879.
According to this known process, the introduction tool, together with its empty introduction blades, is first inserted a little way into a vertically arranged stator. The coils to be drawn in are then threaded in between the spread tongue tips of the introduction blades fixed in this way. The pushing tool used has radial driving arms which come up against the coil ends with their front side having a radially directed surface or bevelled slightly relative to the radial plane.
It has been shown that, during the drawing-in operation, the coils hanging freely in the introduction blades are subjected to a pressure stress which is always too high. Whilst, on the one hand, the coil sides can be drawn through the narrow gap between the guide lamellae of the tongues of the introduction blades only coil wires are arranged in a generally very flat cross-section, the driving arms of the pushing tool cause a widening or thickening of the copper cross-section of the coil sides, so that a build-up occurs. Because of the thickness of the guide lamellae, even if it is only very small, the actual clear slot width between the guide lamellae is less than the actual groove-slot width. Very high drawing-in forces have therefore been necessary hitherto, especially when a plurality of coils is drawn in simultaneously. Above all, however, damage to the enamel insulation has repeatedly occurred as a result of the high pulling and frictional forces to which the coil wires are exposed.

Transfer tool and cover-strip magazine for drawing coils into stators of electric motors


A system for heating solvents in processing semiconductor wafers has a coiled solvent tube, a coiled cooling water tube, and electric heater elements, cast in place within an aluminum casting. The solvent flows through the solvent tube and is heated by conduction of heat through the casting. The solvent is safely isolated from the heating elements. Water is pumped through the cooling water tube, to cool the casting if solvent flow is interrupted, or if the measured casting temperature exceeds a predetermined set point temperature. Solvent temperature is maintained by controlling power to the heating elements based on the measured solvent temperature at the processing chamber.

The field of this invention is automated processing systems used for processing semiconductor wafers, hard disk media, substrates, and similar flat media requiring low levels of contamination. The invention also relates to heaters for solvents and other flammable fluids.
Computers, televisions, telephones and other electronic products contain large numbers of electronic semiconductor devices. To produce electronic products, hundreds or thousands of semiconductor devices are manufactured in a very small space, using lithography techniques on semiconductor substrates, such as on silicon wafers. A large number of individual processing steps may be required to manufacture the semiconductor devices. Various machines and methods have been developed for these applications. For example, U.S. Pat. No. 6,279,724, incorporated herein by reference, describes a system having processing chambers for processing and cleaning flat media (referred to below as xe2x80x9cwafersxe2x80x9d).
In certain processing steps, it is advantageous, or necessary, to apply solvents to the wafers. To speed up and to better control the wafer processing, it is desirable to heat the solvent, and to closely control the temperature of the solvent which is applied to, e.g., sprayed onto, the wafers.
Heating solvents in a safe and reliable way presents unique challenges, because many solvents are combustible. Conventional heating techniques used for other types of fluids are generally unacceptable for heating solvents, due to the risk of igniting the solvent by a malfunctioning electrical heater or heater controller; or because they are unsuitable for the semiconductor manufacturing environment, which must be extremely clean and free of particles; or because they cannot meet the duty cycle requirements needed in semiconductor manufacturing. Quartz heater elements, which have been used to heat various liquids used in semiconductor manufacturing, are unacceptable for heating solvents, because of the risk that the brittle quartz will crack or break, exposing the combustible solvent to extreme temperatures and electrical contacts. On the other hand, tougher materials, such as stainless steel or Teflon, which can reduce or eliminate the risk of breakage of a heating element, and which are also compatible for use with solvents, are unfortunately poor conductors of heat. Accordingly, efficiently heating solvents has remained as a significant engineering challenge.
In the past, blanket heaters have been provided to heat a solvent in a storage tank to a specific set point temperature prior to delivery of the solvent to a wafer processing chamber. The tank blanket heaters are controlled to maintain that set point during processing. While this technique overcomes the difficulties presented by the volatile characteristics of solvents, it has certain disadvantages. Initially, as the entire tank contents must be heated, the desired temperature changes occur slowly. In addition, the tank heaters are controlled based on the solvent temperature in the tank, resulting in significant delays in correcting the solvent temperature back, to the set point, during processing. The heat up time is also long, due to the conduction heating through the stainless steel tank walls, and due to the large mass of stationary solvent. As a result, the temperature of the solvent at the chamber cannot be closely controlled, resulting in poor processing uniformity, low strip/removal rates, and longer process times. Typical temperature drops are 4-8xc2x0 C. from a set point of 75xc2x0 C. In addition, the through put of the system, e.g., in the number of wafers processed per hour, is limited due to the time required for heating the solvent.
Accordingly, there is a need for an improved solvent heater, especially for use in processing semiconductor wafers.
In a first aspect of the invention, in a semiconductor processing machine, a heater for heating solvents includes a solvent tube, and a cooling tube, extending through a casting or other solid form. One or more heating elements extend into the casting. Heat from the heating element is conducted through the casting or solid form, to heat solvent flowing through the solvent tube. As the solvent is isolated from the heating element via the solvent tube and solid material of the casting or solid form, the potential for igniting the solvent during heating is reduced or eliminated.
In a second aspect of the invention, the solvent tube and cooling tube are shaped into coils, with the cooling coil surrounded by the solvent coil. The cooling coil can rapidly cool the casting, if necessary, and can also help to control temperature.
In a third aspect of the invention, the heating element has spaced apart legs which straddle the cooling coil.
In a fourth aspect of the invention, the solvent tube, cooling tube, and heating element are cast in place.
In a fifth aspect of the invention, the casting is enclosed within a container. The walls of the container are insulated from the casting. A purge gas is provided in the space between the insulation and the container walls, to provide an inert atmosphere around the casting.
In a sixth aspect of the invention, cool water is circulated through the cooling tube to rapidly cool the solvent to a temperature low enough to allow the used solvent to be drained from the semiconductor processing machine into the waste lines of a semiconductor manufacturing facility.
Other features and advantages will appear hereinafter.

Fluid heating system for processing semiconductor materials


A clearance control arrangement includes first and second components defining a clearance therebetween. The first component includes a surface portion having at least a layer of material that changes thickness when actuated. The clearance control arrangement also includes an actuator to actuate the layer of material.

The present invention relates to a clearance control arrangement, in particular, although not exclusively, a tip clearance control arrangement for controlling the clearance of rotor blades in casings in gas turbine engines.
A gas turbine engine 10 is shown in FIG. 1 and comprises an air intake 12 and a propulsive fan 14 that generates two airflows A and B. The gas turbine engine 10 comprises, in axial flow A, an intermediate pressure compressor 16, a high pressure compressor 18, a combustor 20, a high pressure turbine 22, an intermediate pressure turbine 24, a low pressure turbine 26 and an exhaust nozzle 28. A nacelle 30 surrounds the gas turbine engine 10 and defines, in axial flow B, a bypass duct 32.
Each of the compressors and turbines comprise alternating stages of rotating blades and stationary stators surrounded by a casing. Engine efficiency is improved as the clearance between the rotating blade tips and the casing is minimised so that the working fluid passes over the blade surfaces and does not leak over the tips. However, differential heating of the components occurs during operation of the gas turbine engine. For an aero gas turbine engine used to power an aircraft, the radial growth of the blades is quicker than the radial growth of the casing when the engine accelerates, for example during take off and climb manoeuvres. Thus the minimum clearance between the blade tips and the casing must be set for the worst case scenarios, e.g. take off and step climb. At other flight phases the blades radially shrink more than the casing so that the clearance is larger than optimal.
Selective case cooling has been used to decrease the clearance during aircraft cruise. However, the clearance cannot be wholly minimised because the casing must be able to radially grow quickly enough that the blade tips do not rub against the casing during step climb manoeuvres.
Another method of decreasing the clearance during cruise has been to provide radially moveable segments of casing. These are generally mechanically complex and heavy, requiring significant actuation components. Additionally a casing segment is a relatively large component to move which cannot respond rapidly enough to transient aircraft manoeuvres such as step climb. Thus the minimum clearance must be specified at all flight phases as that required for take off, climb and step climb meaning that the engine is more inefficient in cruise. This is particularly expensive as cruise generally comprises the greatest proportion of the flight, at least for passenger and freight aircraft.


A method and system for supply chain data analysis. The method includes storing supply chain data including test data, genealogy data, repair data, some factors and some items, in one or more databases and selecting a portion of the factors from the stored data, and a time range for analysis. The method then selects one or more criterion for analysis; extracts a portion of the stored data; analyzes the extracted portion of the stored data to detect a combination of factors that result in a test failure, according to the selected factors, the time range, and the selected one or more criterion. The method then detects a root cause for the detected combination of factors; performs correlation analysis between the selected factors; and performs trend analysis on the selected factors.

Data collected in three phases of product design (genealogy data), manufacturing (test and repair data), and customer feedback (product return and maintenance data) need to be jointly analyzed to detect problems and causing factors, find solutions based on historical data, and predict the performance of the system upon any changes in the involving factors. Such analysis leads towards improving time, cost, and quality of the tasks performed in each of the above phases.
Currently, test engineers, production planners, and maintenance engineers perform different levels of analysis on the available data ranging from simple reporting to advanced statistical analysis. The level of analysis depends on the business needs and familiarity of the user with analytics procedures and tools. The following are typical shortcomings of current approaches taken by users:
Since users are limited to reporting tools, they tend to ignore the value of data insights.
The analysis of manufacturing test, return, and product genealogy data is typically performed manually or semi-automatically using, for example, Excel™, Minitab™, or any other similar rudimentary software. Users who value data insights may use various data export tools to download data to their desktop machines and use customized templates available on their desktops to analyze the data by applying filters, sorting, and creating charts. This process is a time consuming process with many deficiencies that does not guarantee to find the problem or suggest a proper solution in a reasonable time.
Sometimes, off-the-shelf Business Intelligence (BI) tools are used to analyze the data. General-purpose BI tools use the various databases that store the desired data and provide features to create data dictionaries, data cubes, various charts, and brows multiple levels of data through well-designed user interfaces. However, directed questions that are specific to a data domain would be impossible or require sophisticated steps that makes the process cumbersome and therefore the users are reluctant to use them.
Therefore, current practices are characterized as time consuming and deficient processes in obtaining deep analytics for test, return and repair, and supply chain analysis.
The vast volume of data collected during test and field study processes requires deep data analysis to find the relations between involving factors, investigate the source of time and cost consuming processes, and study the alternative methods to increase the profit. The invention addresses this issue by demonstrating high speed, accuracy, and usability characteristics.

System and method for supply chain data mining and analysis


Implementations disclosed herein provide systems and methods for improved processing of touch sensor data with improved scalability and reduced standby power. Touch-related algorithms may be partitioned between the touch screen controller and the application processor or host such that the system can function with low standby power and low interface bandwidth while providing a scalable solution for enhanced user experience. In some aspects, a small digital processing engine and memory remains in the analog front end (AFE) of the touch screen controller to perform imagine forming algorithms that are mostly related to noise reduction and filtering schemes.

Advances in technology have resulted in smaller and more powerful computing devices. For example, there currently exist a variety of portable computing devices, including wireless computing devices such as wireless telephones, personal digital assistants (PDAs), and tablet computers that are small, lightweight, and easily carried by users. In order to simplify user interfaces and to avoid pushbuttons and complex menu systems, such portable computing devices may use touch screen displays that detect user gestures on the touch screen and translate the detected gestures into commands to be performed by the device. Such gestures may be performed using one or more fingers or a stylus type pointing implement. Multi-touch screens (touch screens having multi-touch capability) are designed to recognize and track several simultaneous touches. For example, when a user moves two fingers on a screen, information indicating touch/movement for both fingers is provided by a multi-touch screen.
One drawback of implementing multi-touch technology on portable computing devices is the processing overhead typically required for recognizing multi-touch gestures by a user. Processing overhead measures the total amount of work the central processing unit (CPU) of the device can perform and the percentage of that total capacity which is used by individual computing tasks, such as touch detection. In total, these tasks should require less than the CPU's overall capacity, or the processor becomes overloaded. Simple touch coordinates detection may typically be handled by a touch screen controller (TSC), which is a separate processor associated with the touch screen, but more complex touch gestures interpretation usually requires the use of a secondary processor running the operating system, often the mobile device's CPU. As the number of fingers or touch contacts increases, the processing overhead required for multi-touch detection and recognition may require a large percentage of the overall CPU capacity, impairing device performance.
The current generation of mobile computing devices is not well adapted to deal with increasing touch complexity and corresponding CPU overheads, especially in conjunction with the many other common high performance use cases. At the heart of most mobile devices is a baseband (BB) or an applications processor (AP) responsible for running an operating system and a variety of applications, as well as lower level software drivers. Increasing the size of the mobile processor core or cache delivers performance increases only up to a certain level beyond which heat dissipation issues make any further increase in core and cache size impractical. Overall processing capacity is further limited by the smaller size of many mobile devices, which limits the number of processors that can be included in the device. Additionally, because mobile computing devices are generally battery-powered, high performance use also shortens battery life.
Despite mobile processing limitations, many common mobile applications such as maps, games, email clients, web browsers, etc., are making increasingly complex use of touch recognition. Further, touch processing complexity increases proportional to touch-node capacity, which in turn increases proportional to display size. Capacitive touch screen displays are trending towards higher display sizes (10.1 to 17 inches). Additionally, multi-touch use cases involving up to 10 fingers and/or a pen or stylus also require higher responsiveness and improved performance from the touch screen device. Therefore, because there is a trend in many portable computing devices toward increasing display size and touch complexity, touch processing is increasingly reducing device performance and threatening battery life. Further, user interaction with a device through touch events is highly sensitive to latency, and user experience can suffer from low throughput interfaces between the touch screen panel and the host processor resulting in processing delay and response lag.
Current stand-alone touch screen controllers lack scalability in terms of digital processing and memory for supporting multi-touch use cases and algorithms. However, sending touch sensor raw data to the application processor or host for digital processing results in high standby power consumption and high interface bandwidth.
Conventional touch screen controllers incorporate an analog front end and a digital core. The analog front end performs sensing and acquisition of touch sensor data and sends this raw data to a digital core that performs noise reduction, image forming, touch validation and contact identification and tracking functions. This increases the memory and processing demand on the touch screen controllers. Existing solutions have moved many of the functions to the application processor or host while leaving the analog front end to perform relatively "dumb" functions such as sensing and acquisition of touch sensor data. This solution, however, requires a continuous flow of raw data to the host which increases standby power consumption. This solution also requires high interface bandwidth or pin counts due to the large amount of raw data continuously flowing from the analog front end to the application processor over the interface.

System and method for improved processing of touch sensor data


A power driver of an unmanned aerial vehicle is disclosed and includes a main body, a fluid actuation system and a controller, wherein the fluid actuation system includes a driving zone, a converging chamber, a plurality of valves and a fluid discharging zone. The driving zone includes a plurality of flow guiding units which arranged in series, parallel or series-parallel, each of the flow guiding unit generates an inside pressure gradient after being actuated, so as to inhale fluid and diverge fluid by guiding channels, and flow into the convergence chamber for storage, wherein the amount of the fluid transported is controlled by the plurality of valves disposed in the connection channels through the controller, and fluid is finally converged to the fluid discharging zone for discharging the specific transportation amount of fluid.

Nowadays, in various fields such as pharmaceutical industries, computer techniques, printing industries or energy industries, the products are developed toward elaboration and miniaturization. The fluid transportation devices are important components that are used in, for example micro pumps, micro atomizers, print heads or industrial printers. Therefore, how to utilize an innovative structure to break through the bottleneck of the prior art has become an important part of development.
For example, in the pharmaceutical industry, there are many instruments or equipment that require pneumatic power to drive them. Usually, traditional motors and pneumatic valves are used to achieve the purpose of gas transportation. However, due to the volume limitation of these traditional motors and pneumatic valves, it is difficult to reduce the entire size of such instruments and equipment. Namely, it is difficult to achieve the purpose of thinning, and it is impossible to make them portable.
In addition to the aforementioned pharmaceutical industry, driving devices, such as conventional motors, compressors, engines and so on are usually utilized in other electronics, printing, energy, or even traditional industries. However, in order to achieve the required kinetic energy, these conventional driving devices usually need to have a huge volume to accommodate all kinds of complicated driving cores. Moreover, when the conventional driving devices are operated, huge noise or flying dust and other pollution are generated. Consequently, a lot of inconvenience and discomfort are caused in use.
Therefore, it is necessary to provide a power driver of an unmanned aerial vehicle to solve the problems of huge volume and huge noise caused by the traditional driving devices, such as traditional motors, compressors, engines and so on.


Provided are an array substrate, display panels and display devices. The array substrate includes: a base substrate; an insulating layer located on one side of the substrate and including at least one plateau-shaped protrusion, where the plateau-shaped protrusion includes a first surface and a second surface, wherein the first surface and the second surface are arranged opposite to each other along a direction perpendicular to the base substrate, the first surface is located at a side of the second surface opposite to the base substrate, and an area of the first surface is less than an area of the second surface in a direction perpendicular to the base substrate; and an electrostatic conductive layer located on a side of the insulating layer away from the substrate, where the electrostatic conductive layer includes a first wire and at least one first discharge tip electrically connected to the first wire, the first discharge tip is located on a side slope of the plateau-shaped protrusion and is located in a non-display area. The electrostatic conductive layer further includes an auxiliary discharge structure disposed opposite to the first discharge tip.

With the development of display technology, more and more display devices are applied to people's daily life and work, bringing great convenience to people's daily life and work. Static electricity exists everywhere in daily life and work. During the use of display devices, electrostatic discharge (ESD) is a necessary means to avoid display device failure.
Usually, the ESD can be implemented via point discharge. However, the discharge voltage of the existing point discharge structure is relatively high, so that the static electricity can be released through other ways before the point discharge, thereby causing display abnormality of the display panel and display device.

Array substrate, display panels and display devices

Shanghai Tianma Micro-Electronics Co., Ltd.


Disclosed herein are a more efficient method for manufacturing paints and a universal extender pigment grind that can be used for the paints in the same paint line as well as in different paint lines, while producing paints with similar properties as paints manufactured under traditional manufacturing techniques. The universal extender pigment grind comprises a minimum amount of diatomaceous earth.

At the paint manufacturing facility or factory, each finish (e.g., flat, matte, eggshell, satin, semi-gloss) and each tint base (e.g., white, pastel/light, medium/mid-tone or deep) of each paint line (e.g., Regal™, Ben™, Aura™, Natura™, etc.) has its own paint formulation, which includes a pigment grind with an opacifying pigment such as TiO2 and a specific extender pigment or combination of extender pigments and let down with one or more polymer latex film-forming resins. Opacifying pigments have high refractive index and function to hide the colors or markings on the substrate that the paint composition covers. Lower refractive index pigments such as extender pigments increase the pigment volume of a paint and modify various properties of paints and paint films. See "Calcium Carbonate Extender Pigments," by Herbert Siesholtz and Leonard Cohan, Ind. Eng. Chem., 41(2), 390-395 (1949). Extender pigments can be used to reduce the amount of TiO2 in the formulation to reduce costs, and can be specifically selected to impart certain properties, such as sheen/finish, and to modify the critical pigment volume (CPV), hardness/scrub-ability, etc. to the dried paint film. The effects of extender pigments in paints are discussed in "Extenders", PCI Paint & Coatings Industry Magazine, Feb. 26, 2001, available at www.pcimagcom/articles/84133-extenders, which is incorporated herein by reference in its entirety.
One paint line, e.g., Regal™, may have 20 different formulations to be used at the factory, i.e., five finishes×four tint bases. Two paint lines, e.g., Regal™ and Ben™, may have 40 different formulations. Three paint lines, e.g., Regal™, Ben™ and Aura™, may have 60 different formulations. A paint factory may manufacture up to 20 or more paint lines, which may have up to 400 unique paint formulations or more. Paint lines include both interior and exterior paints.
Moreover, the combinations of extender pigments can be complex and unpredictable from one paint formulation to another paint formulation. In one example, one eggshell, white tint base paint may have an extender combination of nepheline syenite, potassium carbonate, multifunctional silica, silica and alumina. An eggshell, clear tint base paint may have silica and alumina. A matte, white tint base paint may have potassium carbonate, nepheline, diatomaceous earth and multifunctional silica. Similar extenders produced by different manufacturers may contain small amounts of impurities or other unknown components that can affect the extenders' properties or how they react within paint compositions, which add another layer of complexity. As used herein, extenders and extender pigments have the same meaning.
A paint factory must follow hundreds of different formulations and must store the various extender pigments indicated in the many formulations. This technique had led to a decrease in operational efficiency and an increase in costs and complexity of storage of multiple extender pigments on site.
The patent literature describes earlier attempts to simplify the manufacturing of paints, not at the factories but at the small-scale, retail level. These references teach various pre-paints or modules that are mixed at the point of sale on-demand to make paints for individual purchasers. These references are summarized in commonly owned U.S. Pat. No. 9,994,722, which is also published as international patent application publication No. WO2017/053190A1 and which is incorporated by reference herein in its entirety. The '722 patent teaches a system and method for adjusting factory-manufactured paints at the points of sale or points of use by adjusting the paints' sheen or finishes by using a gloss enhancer and/or flattening agent.
One of these pre-paint references is U.S. Pat. No. 6,531,537 to Friel et al. Friel teaches a point of sale paint manufacturing technique, which has three principal pre-paints: (i) opacifying pre-paint, (ii) extender pre-paint, and (iii) binder pre-paint. Properties of the paint, such as sheens/finishes, tint bases, etc., can be varied at the point of sale when these three pre-paints are mixed with one or more of the same pre-paints. Friel acknowledges that point of sale manufacturing has its drawbacks, including inconsistent key properties of paints, such as viscosity, gloss or color. Friel proposes to test for the key properties through feedback loops in the paint making machine to ensure that these properties are controlled.
U.S. Pat. No. 6,221,145 to McClain and its progenies, i.e., subsequent cases that claims priority thereto, disclose manufacturing paints at the point of sale by mixing four pre-paints, including (a) pigment module, (b) dispersant thickener/diluent module, (c) low resin module and (d) high resin module. The low resin module contains a number of extender pigments as well as resin and the pigment module may contain small amount of resin. Progeny U.S. Pat. No. 7,339,000 to McClain et al further explains that the four modules can be varied to produce various color bases so that they are suitable for use to make different paint colors. Progeny U.S. Pat. No. 7,919,546 to Trevino et al adds an extender pre-paint and teaches that the pre-paints can be varied to produce paints with various tint bases so that they are suitable to form different types of color paints. Trevino also discloses that every formula or recipe for every base paints can be entered into a database for the retail paint production apparatus to produce all the paints that can be produced at the factories.
U.S. Pat. No. 5,672,649 to Brock et al discloses five or more modules for making special effect paints, including (a) special effect module, (b) binder module, (c) dye module, (d) rheology module and (e) cross-linking module. Four modules contain various binders and the fifth module may also contain binder. The special effect module and the dye module contain pigments.
However, the methodologies described in these pre-paint references have not simplified paint manufacturing process at the point of sale, retail level or at the factory level. The majority of retail paint stores do not manufacture paint on site and none is known to the present inventors. Paint factories still rely on hundreds of different paint formulations and store scores of extender pigments on site for their production needs.
Moreover, paint factories still grind or mix dry opacifying pigments and dry extender pigments with water, surfactants, dispersants and other additives into slurries or wet grinds to make paints while consuming additional energy, wasting production time and emitting excess green-house gases. A conventional paint formulation is as follows. All weights are in grams.
Pigment Grind:
Propylene Glycol10.8Water104.5Biocide 11.5Antimicrobial 11.9Dispersant/Surfactant 17.7Potassium carbonate1.7Titanium dioxide pigment232.1Extender Pigment 137.1Extender Pigment 225.5Extender Pigment 334.8Extender Pigment 48.5Extender Pigment 58.5Defoamer 10.7Thereafter, the pigment grind is letdown or admixed with the aqueous film-forming resin composition.
Letdown:
Phosphate Ester Surfactant 2, Ammonium Salt (25%)1.5Nonionic Surfactant 33.5Nonionic surfactant 40.8Anionic Surfactant 1 (60%)1.5Coalescent13.2Acrylic Latex with/without Crosslinking Functionality321.1(~50% solids)Polyurethane resin19.3Hydrophobically modified polyether rheology modifier18.6Hydrophobically modified polyethylene oxide urethane7.0Defoamer 22.3Defoamer 32.3Water33.1
As shown above, dry opacifying pigment such as titanium dioxide is mixed under agitation with a plurality of dry extender pigments along with dispersant/surfactant, biocides and other additives for each individual paint formulation. This opacifying and extender pigment grind is then admixed with the aqueous film-forming resin composition along with an optional second film-forming resin and various other additives such as surfactants, rheological modifiers, optional coalescent aids and defoamers. Each of the hundreds of paint formulations is similar to the above exemplary formulation. Having to make hundreds of such paint formulations would challenge any effort to improve efficiency and to reduce costs at the paint factories.
Hence, there remains a need to improve the efficiency and reduce the complexity and costs of manufacturing at the paint factories.

Manufacturing method for multi paint finishes and a multi-finish extender grind


A method for providing a semiconductor structure includes forming a sacrificial structure by etching a plurality of trenches from a first main surface of a substrate. The method further includes covering the plurality of trenches at the first main surface with a cover material to define cavities within the substrate, removing a part of the substrate from a second main surface opposite to the first main surface to a depth at which the plurality of trenches are present, and etching away the sacrificial structure from the second main surface of the substrate.

A number of applications in the field of micro-electronics require structuring semiconductor substrates down to deep regions of the substrate. Examples of these applications can be found in the field of power electronics (high voltage components), the field of sensory devices, micro-electromechanical systems (MEMS), etc. The deep structuring of the semiconductor substrate is sometimes referred to as "3D Integration". Creating cavities and/or recesses in the semiconductor substrate typically requires etching the substrate from one of its main surfaces, or depositing new matter on the main surface of the semiconductor substrate while masking the site or location of the future cavity or recess. Particularly when the cavities are obtained by means of an etching process, the dimensions of the cavities are subject to constraints imposed by the etching process. For example, the so-called "Deep Trench" etching process obeys a relatively fixed relation between a width of a trench to be etched and a depth of this trench. In cases where the closed cavity or a partly closed cavity is to be obtained within the substrate, the creation of a cover layer to close the cavity typically requires extensive manufacturing methods, due to the large dimensions of the cavities which cannot be closed with conventional semiconductor manufacturing technologies in a satisfactory manner.
The manufacturing of a pressure sensor shall illustrate the encountered problems in a representative manner for all types of applications requiring a similar 3D structuring of a semiconductor substrate. Pressure sensors are typically used to measure the pressure of a liquid or a gas, such as air. Pressure sensors typically provide an output signal that varies, based on the pressure sensed by the pressure sensor. One type of pressure sensor includes a standalone pressure sensor that is coupled to, or bonded to, a sensor surface, such as an application specific integrated circuit (ASIC). This type of pressure sensor is expensive to fabricate. Connecting this type of pressure sensor to a sensor circuit is also expensive. Another type of pressure sensor is a pressure capsule (e.g. a poly-silicon plate) that is integrated with a sensor circuit, such as an ASIC, during a back-end-of-line (BEOL) process. This type of pressure sensor is also expensive to produce, since several additional mask levels are required to fabricate the pressure sensor.
Semiconductor structures manufactured by 3D integration often require an electrical insulation between different parts of the semiconductor structure. This requires creating or providing an insulating region possibly deep within the semiconductor substrate so that conventional surface-oriented methods such as doping are unsuitable.

Method of providing a semiconductor structure with forming a sacrificial structure


A license management server manages a license to perform a service of remote maintenance related to one or more image forming apparatuses installed in a customer's site. The maintenance server includes a maintenance unit and a history management unit. If the license management server notified of expiration of an expiration date of the license defined by a contract, the maintenance unit stores history information acquired from the one or more image forming apparatuses corresponding to the expired license into a storage unit, and stops the service. If the license management server notified of grant of the license by a re-contract, the history management unit obtains the history information about the one or more image forming apparatuses corresponding to the granted license from the storage unit, and passes the obtained history information to the maintenance unit. By using the passed history information, the maintenance unit resumes the service.

1. Field of the Present Disclosure
The present disclosure relates to a maintenance server, a maintenance method, a non-transitory computer-readable storage medium in which the maintenance program is stored, and a management server.
2. Description of the Related Art
Manufacturers of copying machines, multifunction peripherals (MFPs), printers, and the like (hereinafter, referred to collectively as image forming apparatuses) have made various contrivances to centralizedly manage image forming apparatuses installed in customers' sites and do remote maintenance.
For example, in a typical system, the customers' image forming apparatuses are not managed by respective service shops. Instead, a center is provided to manage the image forming apparatuses in an integrated manner. The center provides information for managing maintenance and inspection schedules, including the usages of the image forming apparatuses and peripheral equipment, to the service shops. This can reduce man-hours of the service shops for managing the customers' equipment.
In another typical system, a server obtains customer information about customers with which sales shops have traded in products, as well as product information. The server extracts other customers having the same attributes as those of the traded customers, and provides the product information about the traded products for sales shops in charge of the extracted customers.
The remote maintenance system is mostly used by sales companies and sales shops which sell image forming apparatuses. Since fees are charged for use, a trial contract is sometimes concluded for a trial operation before an actual contract to use the system. After the effectiveness of the system is confirmed, the actual contract is concluded to start official operations.
If a sales company or the like performs a trial operation before official operations, the sales company or the like becomes unable to use the system at the end of the trial operation. History information about image forming apparatuses acquired during the trial period is discarded. This means a problem that the sales company or the like that conducts official operations after the trial operation cannot use the history information of the trial operation for the official operations.

Maintenance server, maintenance method, non-transitory computer-readable storage medium in which maintenance program is stored, and management server


Apparatus for color printing on a re-inkable belt, the re-inkable belt being moveable along an endless path and trained about a transport roller and including an ink transfer layer where an ink can be transferred to a moveable receiver and the moveable receiver moves into ink transfer relationship with the re-inkable belt at a nip position for transferring ink imagewise from the re-inkable belt to the receiver. The depleted ink is replenished and the re-inkable belt is arranged so that ink will be diffused into the ink transfer surface, and tension is adjustedly applied at two spaced locations to the transport roller and including two spaced steering actuators which, when actuated, apply tension to opposite positions on the transport roller, a sensor for determining the position of the re-inkable belt, and a computer coupled to the sensor for selectively actuating the steering actuators so as to apply tension to the transport roller which compensates for lateral distortion of the re-inkable belt.

Color transfer thermal printers use a color donor member that may be a sheet, but usually is in the form of a web advanced from a supply roll to a take-up roll. The color donor member passes between a print head and a dye receiver member. The thermal print head comprises a linear array of resistive heat elements. In operation, the resistive heat elements of the print head are selectively energized in accordance with data from a print head control circuit. As a result, the image defined by the data from the print head control circuit is placed on the receiver member.
A significant problem in this technology is that the color donor members used to make the thermal prints are generally intended for single (one time) use. Thus, although the member has at least three times the area of the final print and contains enough colorant to make a solid black image, only a small fraction of the color is ever used.
After printing an image, the color donor cannot be easily reused, although this has been the subject of several patents. The primary reason that inhibits reuse of the color donor is that the color transfer process is very sensitive to the concentration of the colorant in the donor layer. During the first printing operation, color is selectively removed from the layer thus altering its concentration. In subsequent printings, regions of the donor that had been previously imaged have lower transfer efficiency than regions that were not imaged. This results in a ghost image appearing in subsequent prints.
The cost associated with having a single use donor ribbon is large because of the large area of ribbon required, as well as the large excess of colorant coated on the donor member. While this technology is able to produce high quality continuous tone prints, it is desired to provide an approach which has all of the good attributes of thermal color transfer imaging but without the limitations associated with single use donor members.
Some work has been done by others to accomplish similar goals. For example, U.S. Pat. No. 5,286,521 discusses a reusable wax transfer ink donor ribbon. This process is intended to provide a dye donor ribbon that may be used to print more than one page before the ribbon is completely consumed. U.S. Pat. No. 4,661,393 describes a reusable ink ribbon, again for wax transfer printing. U.S. Pat. No. 5,137,382 discloses a printer device capable of re-inking a thermal transfer ribbon. However, again the technology is wax transfer rather than dye transfer. In the device, solid wax is melted and transferred using a roller onto the reusable transfer ribbon. U.S. Pat. No. 5,334,574 describes a reusable dye donor ribbon for thermal dye transfer printing. This reusable ribbon has multiple layers containing dye which limit the diffusion of dye out of the donor sheet. This enables the ribbon to be used to make multiple prints. In addition, the ribbon may be run at a slower speed than the dye receiver sheet, enabling additional utilization. U.S. Pat. No. 5,118,657 describes a multiple use thermal dye transfer ink ribbon. This ribbon has a high concentration dye layer on the bottom and low concentration dye layer on the top. The low concentration dye layer meters or controls dye transfer out of the ribbon. This enables the ribbon to be used multiple times. U.S. Pat. No. 5,043,318 is another example of a thermal dye transfer ribbon that can be used multiple times.


A neutral returning control system and method for electronic pneumatic shift device adapted to return a striker by way of manipulating an emergency neutral return switch when the striker deviates from a normal shifting position during activation of a shifting operation, the electronic pneumatic shift device including a change lever position sensor for detecting a manipulation of a change lever, a magnetic valve assembly for controllably supplying air according to a signal from the change lever position sensor, a gear shift device actuated by the air supplied via an air pipe connected to the magnetic valve assembly, a shift stage position sensor disposed at one side for detecting an operation of the gear shift device, and an electronic control device for discriminating electrical signals from the shift state position sensor and change lever position sensor and for controlling the magnetic valve assembly, wherein the system comprises an emergency neutral return switch electrically mounted from allowing the electronic control device to discriminate the turn-on manipulation by a driver when there occurs an erroneous shifting.

1. Field of the Invention
The present invention relates to a neutral returning control system and method for electronic pneumatic shift device, and more particularly to a neutral returning control system and method for electronic pneumatic shift device adapted to return a striker by way of manipulating an emergency neutral return switch when the striker deviates from a normal shift position during activation of a gear shift device.
2. Description of the Prior Art
Generally, a transmission gear box is situated in a far place from a driver in rear engine driving vehicles and other large vehicles such as truck, bus, such that a shift device is needed for accurately transmitting manipulation of a clutch and a change lever and for smooth shifting. The latest trend is to replace the current hydraulic or mechanical shift device with a pneumatic one. The pneumatic shift device serves to control air pressure electronically to change meshing of gear.
FIG. 1 is a schematic diagram for illustrating an electronic pneumatic shift device applied to the present invention, where the electronic pneumatic shift device 2 receives an electric signal from a change lever position sensor 6 by sensing manipulation of a change lever (4L) to cause an electronic control device 8 to open and close a magnetic valve assembly 10, such that air is supplied to or discharged from a gear shift device 12 to allow a transmission 14 to perform a shifting. The magnetic valve assembly 10 is connected to an air tank 15 to receive the supply of air. The supply and discharge from the air tank 15 via a repulsive valve 18 which is a 3-way magnetic valve connected to a repulsive cylinder (not shown) makes a driver feel a shifting feel when a shifting is accomplished by manipulation of the change lever (4L).
The electronic control device 8 connects a shift display 20 for detecting and displaying a manipulation signal from the change lever (4L), to a warning lamp 24 for advising and detecting a failure of shifting realized by air supply from the magnetic valve assembly 10 via a shift stage position sensor 22 or for detecting an erroneous operation of the change lever (4L). The gear shaft device 12 is so connected as to supply air to a cylinder MVA 26 and another cylinder MVB 28 by way of the magnetic valve assembly 10 operated by a signal from the electronic control device 8 or discharge the air to the atmosphere.
When the air is controllably supplied to the cylinder MVA 26 or another cylinder MVB 28 by way of actuation of the magnetic valve assembly 10, a shift rod 30 is moved to one direction. By this operation, a striker 32 at the shift rod 30 is so moved leftward that a shifting is realized from a neutral stage of neutral position to a first, third or fifth stage, or so moved rightward that the shifting is initiated to a second, fourth or reverse stage.
That is, when a driver manipulates the change lever (4L), the electronic control device 8 controls the magnetic valve assembly 10 to thereby control the supply and discharge of air to the cylinders MVA 26 and MVB 28 at the gear shift device 12, such that the striker 32 is moved to perform the shifting.
However, there is a problem in the prior art in that a striker at a gear shift device stops at a, b positions which are not the normal shifting positions when air pressure supplied to the cylinders MVA and MVB at the gear shift device is insufficient due to sudden breakage, supply and discharge of air to and from the cylinders MVA and MVB are not smooth due to sudden manipulation of a clutch pedal and when synchronizing force lacks during shifting operation due to abrasion of a transmission synchronizer.
There is another problem in that a driver should stop driving a vehicle and detach an upper cover of the gear shift for maintenance when the striker is not operated at a normal position while the vehicle is running, thereby making it impossible for the striker to return to a neutral position, such that passengers experience inconvenience and technical credibility of the product is decreased.

Neutral returning control system and method for electronic pneumatic shift device


A pin heterojunction photovoltaic element which generates photoelectromotive force by the junction of a p-type semiconductor layer, an i-type semiconductor layer and an n-type semiconductor layer, characterized in that at least one of said p-type and n-type semiconductor layers comprises a polycrystal semiconductor film comprised of boron atoms (B), arsenic atoms (As), hydrogen atoms (H), optionally fluorine atoms (F), and atoms (M) of a p-type or n-type dopant element, said polycrystal semiconductor film contains crystal grains of an average size in the rage of 50 to 800 .ANG., and said polycrystal semiconductor film contains the hydrogen atoms (H) in an amount of 0.5 to 6 atomic %; said i-type comprises either (a) a non-single crystal semiconductor film containing silicon atoms (Si) as a matrix and at least one kind of atoms selected from the group consisting of hydrogen atoms (H) and fluorine atoms (F) or (b) a non-single crystal semiconductor film containing silicon atoms (Si) as a matrix, at least one kind of atoms selected from the group consisting of carbon atoms (C) and germanium atoms (Ge), and at least one kind of atoms selected from the group consisting of hydrogen atoms (H) and fluorine atoms (F).

There have been proposed a variety of photovoltaic elements such as solar cells and power sources for commercial and home appliances. They utilize pn junctions formed by ion implantation or thermal diffusion of impurities into a single crystal substrate of silicon (Si) or gallium arsenide (GaAs), or by epitaxial growth of an impurity-doped layer on such single crystal substrate. However, there is a disadvantage for any of these photovoltaic elements that they are still costly because of using an expensive specific single crystal substrate. Hence, they have not yet come into general use as solar cells or power sources in commercial and home appliances used by the general public. In order to solve this problem, there have been proposed a photovoltaic element in which there is utilized a pin junction formed by amorphous silicon (hereinafter referred to as "a-Si") semiconductor films laminated on an inexpensive substrate of a non-single crystal material such as glass, metal, ceramic, synthetic resin, etc. by way of a glow discharge decomposition method. This photovoltaic element does not provide a photoelectric conversion efficiency as high as that provided by the foregoing pn junction photovoltaic element in which a single crystal substrate is used. However, this photovoltaic element can be relatively easily produced and is of low production cost, and because of this, it is used as a power source in some kinds of appliances with very small power consumption such as electronic calculators and wrist watches.
In this pin junction amorphous silicon photovoltaic element, the Fermi level of the a-Si semiconductor having a good photoconductive property lies a little toward the conduction band from the center of the band gap and the electric field strength at the interface of the p-i junction is greater than that at the interface of the n-i junction. In this respect, it is advantageous to impinge light from the side of the p-type semiconductor layer in order to provide a desirable photoelectric conversion efficiency.
For the p-type semiconductor layer, it is desired to be formed of such a semiconductor film that does not absorb light and does not have defects since the light to be absorbed within the p-type semiconductor layer does not contribute to generation of photoelectric current in the case where defects acting as recombination centers are present therein. In view of this, for the semiconductor film to constitute the p-type semiconductor layer in the pin junction a-Si photovoltaic element, studies have been made on amorphous silicon carbide films (hereafter referred to as "a-SiC film") which are of wide band gap and also on microcrystal line silicon films (hereinafter referred to as ".mu.C-Si film") which are known as indirect semiconductor films having small absorption coefficient and which are considered to hardly absorb light when they are of 100 to 200 .ANG. in thickness even in the case where they are of narrow band gap. As for the a-SiC semiconductor film, there is an advantage that its band gap can be widened by increasing the composition ratio of the constituent carbon atoms. However, there is a disadvantage that when its band gap is more than 2.1 eV, its film quality is markedly worsened. Therefore, there is a limit for the a-SiC semiconductor film to be used as the p-type semiconductor layer in a pin heterojunction photovoltaic element.
As for the uC-Si semiconductor film, there is still a disadvantage that its band gap is narrow in any case and the quantity of light absorbed thereby is remarkable. Particularly, when the incident light is such that it contains short-wavelength light in a large proportion, the quantity of light absorbed becomes great.
In view of this, in order to provide a desirable pin heterojunction photovoltaic element of the type wherein light is impinged from the side of the p-type semiconductor layer, it necessitates the use of a p-type semiconductor film having a desirably wide band gap and a minimized defect density as the p-type semiconductor layer.
The same situation is present also in the case of a pin heterojunction photovoltaic element of the type wherein light is impinged from the side of the n-type semiconductor layer. That is, the n-type semiconductor layer is required to be constituted by such an n-type semiconductor film having a desirably wide band gap and a minimized defect density.
Further, in the case of a so-called tandem stacked type photovoltaic element or a triple cell tandem stacked type photovoltaic element comprising a plurality of stacked cells, each cell of which comprises a pin heterojunction photovoltaic element in which the residual components of light which are left not absorbed by the upper cell are absorbed by the lower cell to obtain a sufficient photoelectric conversion, both the p-type semiconductor layer and the n-type semiconductor layer of each of the cells are required to have a desirably wide band gap and a minimized defect density.
Further, for any of the foregoing photovoltaic elements, it is required for the material to constitute the p-type or n-type semiconductor layer to be such that it can be directly deposited on a non-single crystal substrate of glass, metal, ceramic or synthetic resin in a desired state and does not give any negative effect to the i-type semiconductor layer laminated thereon.
As semiconductor films having a wide band gap which are capable of satisfying the foregoing requirements, semiconductor films containing atoms of group III and V elements of the Periodic Table have been proposed by Japanese Laid-open No. 116673/1981 (hereinafter referred to as "literature 1"), Japanese Laid-Open No. 6874/1986 (hereinafter referred to as "literature 2"), Japanese Laid-open No. 189629/1986 (hereinafter referred to as "literature 3") and Japanese Laid-open No. 189630/1986 (hereinafter referred to as "literature 4").
That is, literature 1 discloses pin heterojunction amorphous thin film solar cells having the p-type or n-type semiconductor layer comprising a p-type or n-type semiconductor film containing atoms of group III and V elements formed by the glow discharge decomposition method and the i-type semiconductor layer comprising an i-type amorphous silicon film containing fluorine atoms but it does not teach anything about a crystalline BAs semiconductor film.
Literature 1 does not mention anything about the use of an i-type a-SiGe semiconductor film as the i-type semiconductor layer. Literature 2 discloses the use of a doped compound semiconductor layer to improve the photovoltaic characteristics in the pin junction solar cell comprising a compound semiconductor layer and an amorphous silicon layer in combination, but it does not mention anything about a BAs semiconductor film. Literatures 3 and 4 are concerned with methods of forming semiconductor films containing group III-V elements of the Periodic Table by way of the HR-CVD method (Hydrogen Radical Assisted CVD method). But neither of literatures 3 and 4 mentions anything about BAs semiconductor films.
Further, none of literatures 1 to 4 does mentions anything about a tandem type photovoltaic element or a triple cell tandem stacked type photovoltaic element.
Against this background, there is an increased social demand to provide an inexpensive photovoltaic element which exhibits a high photoelectric conversion efficiency particularly for short wavelength light and which is practically usable as a solar cell and also as a power source in various appliances.

Pin heterojunction photovoltaic elements with polycrystal BAs(H,F) semiconductor film


The present invention provides an integrated microfluidic analysis system. The system contains at least a first (pre-reaction treatment) domain for treating a sample prior to subjecting the sample to a chemical reaction. The following domains are optionally added to the first domain: a second (reaction) domain for reacting the chemical of interest in the sample; and a third (post-reaction separation) domain for separating products and reactants coming out of the reaction domain. The integrated microfluidic analysis system of the present invention is most applicable to PCR analysis.

Many applications in the field of chemical and biological requires separation of chemical components prior to or after reacting the chemicals. Examples of reactions requiring separation of components include organic, inorganic, biochemical, and molecular reactions. Examples of chemical reactions include thermal cycling amplification, such as polymerase chain reaction (PCR), ligase chain reaction (LCR), isothermal nucleic acid amplification, self-sustained sequence replication, enzyme kinetic studies, homogeneous ligand binding assays, affinity binding assays, and more complex biochemical mechanistic studies. Conventional separation techniques include electrophoresis, such as capillary electrophoresis, synchronized cyclic electrophoresis, and free flow electrophoresis. Conventional separation techniques also include isoelectric focusing (IEF), hybridization, liquid and gas chromatography, molecular sieving and filtering.
Of increasing interest in the field of chemical separation is the use of devices that include an integrated reaction chamber and separation regions. Such integrated devices provide a number of advantages over conventional devices in which one transfers a fluid sample between a reaction apparatus and a separation device and/or vice versa. For example, where the chemical reaction and separation steps are performed in a single integrated device, one may avoid contamination and crossover of sample or reaction products. In addition, an integrated device may allow for substantially faster sample processing and analysis.
Recent efforts to integrate processing and analytical functionalities in a single device, especially in the field of MEMS, microfabrication, and microfluidics, have resulted in the development of devices that include multiple substrates bonded together. The substrates are usually bonded with adhesives, or by heat sealing, fusion bonding, or anodic bonding. These multi-substrate devices typically include a reaction chamber that is connected to a separate separation component, such as a capillary tube containing a suitable electrophoresis gel, by an adhesive such as epoxy. Alternatively, these multi-substrate devices have reaction chambers and separation channels etched into a plate and a cover bonded over the top of the plate. For example, U.S. Pat. No. 5,849,208 to Hayes et al. and U.S. Pat. No. 6,979,424 to Northrup et al. disclose such devices. However, these prior art devices do not address sample preparation prior to reacting the chemicals. This is a particular difficult problem because certain chemicals used in pre-reaction sample preparation may detrimentally affect the reaction itself.
One application of particular interest is the polymerase chain reaction (PCR). Since the technique was first described two decades ago, PCR has become an essential tool in the field of genetic analysis, providing an in vitro method to amplify DNA sequences of interest. However, while conventional techniques are improving in speed, they are still time consuming (1-3 h per amplification), and the reagents are expensive at the volumes needed for manual transfer of samples between pre-treatment, amplification, and analysis steps. Furthermore, the conventional method of PCR product analysis, gel electrophoresis, has similar limitations in time and reagent volumes.
An solution to these problems was proposed by Manz et al. (Sens. Actuators B, 1990, 1:244-248) in the form of miniaturized total chemical analysis systems (R-TAS), where microfabricated fluidic networks could be utilized for sampling, pre-treatment, and analysis/detection of samples as well as the transport between the different domains. The development of these integrated microfluidic systems for genetic analysis has been a major research focus since the systems were proposed, with particular motivation from the clinical and forensic sciences. However, after more than a decade and a half after Manz et al.'s proposal, no bona fide microfluidic device has been demonstrated that is capable of nanoliter flow control with comprehensive sample pretreatment integrated with an analytical step for genomic analysis of whole blood.
Therefore, there remains a need for a μ-TAS capable of pre-reaction sample treatment, reaction, and post-reaction chemical separation all on one chip; and methods of efficiently operating such μ-TAS to eliminate poisoning of the reaction by reactants used in the sample treatment.

Integrated microfluidic analysis systems

University of Virginia Patent Foundation


Various embodiments comprise apparatuses and methods to allow access to a memory device by an external device. A method includes receiving, at the memory device, a request from the external device to access a storage area of the memory device and performing an unlock procedure of the storage area. The unlock procedure includes sending a first code from the memory device to the external device, and receiving a second code at the memory device from the external device. The second code is to be generated by a first encryption process performed on the first code to obtain the second code. The storage area is temporarily unlocked to allow the external device to access the storage area based on a determination that the received second code has a predetermined relationship to the first code. Additional apparatuses and methods are described.

In the field of semiconductor memories, flash memories have become rather popular, because they combine the capability of storing relatively large amounts of data with the possibility of modifying their content directly in the field.
Flash memories are, for example, used to store the code to be executed by data processing units (e.g., microcontrollers, microprocessors, coprocessors, digital signal processors and the like) in a variety of electronic apparatuses, such as personal computers, mobile phones, digital cameras, set-top boxes for cable or satellite or digital terrestrial television, just to mention a few.
In particular, using flash memories it is possible to modify the stored code without having to remove the memory component from the respective socket. It has thus become possible to, e.g., change the code, fix code bugs, update the code version directly at the premises of the users; the new code can be for example downloaded over the internet, or received directly by the mobile phone from the service provider company.
There are applications in which these possibilities offered by flash memories raise problems of security. Electronic piracy acts may for example cause the code stored in the memory to be read without authorization or to be corrupted.
Referring to a conventional flash memory, the modification of the data stored in the memory is related to the erase and program operations. Stored data can be shielded from undesired read, erase and program operations by means of particular protection arrangements, that allow to selectively protect/unprotect distinct sectors of the memory. For example, U.S. Pat. No. 5,974,500 describes a non-volatile memory device comprising a set of first access control bits to control the access authorization (to perform the operations of erasing, programming and reading) to the memory array, and a set of second control bits to control write access to the first access control bits, in such a way to consent to the changing of the memory access authorization. Every time the external devices request an access operation to the memory, they must provide their access authorizations thereto. In fact, according to this solution, to access a protected memory zone, it is necessary to change the memory access authorization; however, this change is performed without any particular security protocol, simply by issuing, on the part of the external device, a request to modify the access authorization; there is no control on which device is requesting to change the access authorization scheme.
Therefore, in view of the state of the art outlined in the foregoing, a need has arisen for a technique to implement security in a semiconductor memory, and particularly in respect of aspects relating the grant of access authorization to external devices in an efficient way, assuring a high level of security.

This patent is subject to a terminal disclaimer.

Security memory access method and apparatus


A method includes transferring a wafer into a first processing chamber by using a robot arm mechanism, and applying a photoresist on the wafer in a first processing chamber. The wafer is transferred from the first processing chamber into a second processing chamber by using the robot arm mechanism, and the photoresist is exposed to a pattern of light in the second processing chamber. The method includes transferring the wafer from the second processing chamber into a third processing chamber by using the robot arm mechanism, and developing the exposed wafer in the third processing chamber. The method includes cleaning the robot arm mechanism in a dummy chamber.

Manufacturing of an integrated circuit (IC) has been driven by increasing the density of the IC formed in a semiconductor device. This is typically accomplished by implementing more aggressive design rules to allow a larger density of the IC device to be formed. Nonetheless, the increased density of IC devices, such as transistors, has also increased the complexity of processing semiconductor devices with decreased feature sizes. IC devices are formed by complex fabrication processes such as lithography. During lithography a semiconductor workpiece is subjected to different processing steps.

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The present invention is related to the development of therapeutics and prophylactics for the treatment and/or prevention of bacterial infections in humans and other mammals. A new class of small molecules is disclosed that inhibits the bacterial trans-translation/ribosome rescue mechanism and thus blocks infection of host cells by bacteria. Also disclosed are methods of using the small molecule inhibitors in the treatment/prevention of bacterial infections.

The increase in multiple drug-resistant organisms (MDROs) poses a severe threat to human health (Antibiotic Resistance Threats in the United States, Centers for Disease Control, U.S. Dept. of Health and Human Services (2013)). There is an immediate need for new antibiotics to combat the threat of drug-resistant bacteria such as multidrug-resistant (MDR) Neisseria gonorrhoeae (Ng); extensively drug resistant (XDR) and MDR Mycobacterium tuberculosis; methicillin-resistant Staphylococcus aureus (MRSA); Community-Acquired Pneumonia (CAP) pathogens (MRSA, Streptococcus pneumonia, Mycoplasma pneumonia, Moraxella catarrhalis, Legionella pneumophila, and Haemophilus influenzae), and Francisella tularensis. The increased prevalence of multidrug resistance has reduced treatment options, leaving patients vulnerable to dangerous infections and complicating care.
Multidrug-resistant (MDR) gonorrhea is an urgent threat to public health. The CDC lists MDR Neisseria gonorrhoeae (Ng) as one of the three most urgent antibiotic resistance threats in the United States (Antibiotic Resistance Threats in the United States, Centers for Disease Control, U.S. Dept. of Health and Human Services (2013)). A Gram-negative fastidious organism, Ng causes gonorrhea, the second-most prevalent sexually transmitted bacterial infection (STI), with more than 800,000 cases in the United States and 78 million cases estimated worldwide [Cornelissen, C. N. and Hollander, A. Frontiers in microbiology, 2:117 (2011); Ohnishi et al., Antimicrob Agents Chemother, 55:3538 (2011); Newman et al., PLoS One, 10:e0143304 (2015)]. Left untreated, gonorrhea can cause pelvic inflammatory disease in women, leading to fallopian tube scarring and infertility (Soper, D. E., Obstetrics and gynecology, 116:419 (2010)), or may disseminate, causing joint and skin manifestations (Mayor et al., American family physician, 86:931 (2012)). Once easily treatable, Ng has evolved resistance to nearly every antibiotic used to treat it, leaving a combination of azithromycin (AZM) and ceftriaxone (CTX) as the only recommended treatment option (Whiley et al., J Antimicrob Chemother, 67:2059 (2012); Obstetrics and gynecology, 127(5):e95-99 (2016)). Strains resistant to sulfonamides (Unemo, M. and Shafer, W. M., Annals of the New York Academy of Sciences, 1230:E19 (2011)), penicillin, streptomycin, erythromycin, tetracycline, spectinomycin, fluoroquinolones (Goldstein et al., Emerg. Infect. Dis., 18:1290 (2012) and CDC MMWR Weekly Rep., 56: 332 (2007)), cefixime (Unemo et al., Antimicrob. Agents Chemother., 56:1273 (2012)), AZM (Unemo, M. and Shafer, W. M., Annals of the New York Academy of Sciences, 1230:E19 (2011)), and CTX (Unemo et al., Antimicrob. Agents Chemother., 56:1273 (2012); Chen et al., J. Antimicrob. Chemother., 71:92 (2016); Camara et al., J. Antimicrob. Chemother., 67:1858 (2012); CDC MMWR Weekly Rep., 62:103 (2013)), have been reported. (See, also, Ohnishi et al., Antimicrob. Agents Chemother., 55:3538 (2011).) Importantly, a cluster of cases was recently reported in Hawaii that are highly resistant to AZM and show reduced susceptibility to CTX (see, CDC webpage, https://www.cdc.gov/nchhstp/newsroom/2016/2016-std-prevention-conference-press-release.html, (2016)), highlighting the critical need for new therapeutics targeting antibiotic-resistant Ng infections. (See, also, Kirkcaldy et al., JAMA, 309:185 (2013)).
Mycobacterium tuberculosis (Mtb) alone is annually responsible for ˜1.5 million deaths (Global Tuberculosis Report, World Health Organization, 2017). Over 1.8 billion people are infected with Mtb worldwide, 10% of whom are predicted to develop active disease. (Global Tuberculosis Teport, World Health Organization, 2017). These infections produce 1.5 million deaths annually. While antibiotic therapy represents the foundation for global health efforts to curb TB, the rise of multi-drug resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains has produced an urgent need for new antibiotics. (Global Tuberculosis Teport, World Health Organization, 2017).
Methicillin-Resistant Staphylococcus aureus (MRSA) is another example of microbial drug resistance that poses a serious and immediate public health threat in the United States. MRSA is a Gram-positive bacterium responsible for several difficult-to-treat infections, including skin and soft tissue infections (SSTIs), bacteremia, infective endocarditis, pneumonia, bone and joint infections (osteomyelitis and septic arthritis) and meningitis, among others. (Liu et al., Clin. Infect. Dis., 52(3): e18-55 (2011)). A pervasive organism found in both community and hospital settings, MRSA causes an estimated 80,000 invasive cases in the United States annually, resulting in ˜11,000 fatalities. (CDC 2013) (2013). Non-invasive cases of MRSA are poorly tracked, but are thought to be far higher in number. (Stryjewski, M. E. and G. R. Corey, Clin. Infect. Dis., 58 Suppl. 1: S10-19 (2014)). Although more stringent procedures in clinical settings have decreased the number of invasive MRSA cases, this pathogen remains problematic due to high mortality rates, growing antimicrobial resistance and high rates of hospitalization with a heavy burden of associated costs. MRSA is characterized by its resistance to methicillin, and various strains have exhibited resistance or decreased sensitivities towards all currently approved antibiotics. (Stryjewski, M. E. and G. R. Corey (2014) supra; Purrello et al., J. Glob. Antimicrob. Resist., 7: 178-186 (2016)). Moreover, while several recently introduced antibacterial drugs are effective against MRSA (e.g., linezolid, daptomycin, tigecycline, and telavancin), the majority of these must be given intravenously, are limited to hospital use, and are not tolerated well by a significant number of patients. (Clark et al., Pharmacotherapy, 26(2): 269-276 (2006); Lodise et al., Clin. Infect. Dis., 49(4): 507-514 (2009)). In addition, clinical resistance to linezolid and daptomycin have already been reported. (Pillai et al., J. Infect. Dis., 186(11): 1603-1607 (2002); Meka et al., J. Infect. Dis., 190(2): (2004); Mangili et al., Clin. Infect. Dis., 40(7): 1058-1060 (2005); Boucher, H. W. and G. Sakoulas, Clin. Infect. Dis., 45(5): 601-608 (2007); Morales et al., Clin. Infect. Dis., 50(6): 821-825 (2010); Sanchez Garcia et al., JAMA, 303(22): 2260-2264 (2010)). This underscores the need for additional anti-MRSA agents. Finally, MRSA has a tendency to relapse and recurrence, likely through biofilm formation and its tendency to survive and multiply in eukaryotic cells, features that add additional challenges to treatment. (Lowy, T. P., Clin. Infect. Dis., 49(4): 507-514 (2009); Ellington et al., J. Bone Joint Surg. Br., 85(6): 918-921 (2003); Hess et al., J. Surg. Res., 114(1): 42-49 (2003); Clement et al., J. Infect. Dis., 192(6): 1023-1028 (2005); Gunther et al., Antimicrob. Resist. Infect. Control, 6: 32 (2017); Li et al., Infect. Immun., 85(5): e00883-16 (2017)). The development of an intracellularly active antibiotic that targets MRSA through a novel mechanism to sidestep existing resistance mechanisms would provide a critically needed tool for the ongoing fight against this deadly and pervasive infectious agent.
Cases of Community-Acquired Pneumonia (CAP), caused by Staphylococcus aureus, Streptococcus pneumonia, Mycoplasma pneumonia, Moraxella catarrhalis, Legionella pneumophila, and Haemophilus influenzae result in an estimated 80,000 hospitalizations annually in the US. (Jain S et. al. N. Engl. J. Med. 373:415 (2015)) Similarly, Ventilator-Associated Pneumonia (VAP), caused predominantly by S. aureus as well as by various Enterobacteriaceae (including Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii (Ahmad, S. et. al. Pak. J. of Pharm. Sci., 30(6):2091 (2017)) affects 25% of patients mechanically ventilated for >48 h, (Torres, A. et. al. Clin. Infect. Dis. 51 Suppl 1:S48 (2010), Kollef, M. H. et. al. Crit. Care Med. 42(10):2178 (2014)) resulting in an estimated 61,000 cases in the US in 2011. (Magil, S. S. et. al. N. Engl. Med. 370(13):1198 (2014)). The specter of antibiotic resistance in nearly all of these pathogens signals an urgent need for development of new drugs (Antibiotic Resistance Threats in the United States, Centers for Disease Control, U.S. Dept. of Health and Human Services (2013)) that target novel bacterial processes and are capable of treating a wide array of infections.
One approach that has been explored for overcoming bacterial resistance mechanisms is targeting/inhibiting the bacterial trans-translation mechanism for ribosome rescue, which is required for viability or virulence in many species. The lack of nuclei in bacterial cells necessitates that the processes of transcription and translation are carried out in the same compartment. This can be advantageous in that it allows bacteria to rapidly adapt to environmental changes by making new proteins. However, this can have serious consequences as this limits the bacterial cell's ability for protein quality control due to limited mRNA proofreading. The bacterial trans-translation system functions to remove non-stop protein translation complexes where the ribosome has reached the 3′ end of the mRNA without terminating at a stop codon. (Hong et al., Mol. Microbiol., 57(2):565-575 (2005); Clinical and Laboratory Standards Institute, 25(21):1-39 (2005); Ramadoss et al., PLoS ONE, 8(2):e57537 (2013)).
The trans-translation process resolves non-stop translation complexes using a ribonucleoprotein complex containing transfer-messenger RNA (tmRNA) and a small protein, SmpB. All species of bacteria tested to date require at least one ribosome rescue mechanism for viability. (Keiler, K. C., Nat. Rev. Microbiol., 13:285 (2015)).
Genes encoding tmRNA and SmpB have been identified in >99.9% of sequenced bacterial genomes, demonstrating the ubiquity of trans-translation. (Hudson et al., Front. Microbiol., 5:421 (2014)). Bacteria that can survive without trans-translation have either the ArfA or the ArfB alternative rescue pathway. (See, FIG. 1).
The trans-translation mechanism is a key component of multiple quality control pathways in bacteria that ensures proteins are synthesized with high fidelity in spite of challenges such as transcription errors, mRNA damage, and translational frameshifting. tmRNA, encoded by the ssrA gene, is a highly structured RNA with properties of both a tRNA and an mRNA. The 5′ and 3′ ends of tmRNA fold into a tRNA-like structure, which is charged with alanine by alanyl-tRNA synthetase (AlaRS). (Komine et al., Proc. Natl. Acad. Sci. USA, 91(20): 9223-9227 (1994); Ushida et al., Nucleic Acids Res., 22(16): 3392-3396 (1994)). Another portion of tmRNA contains a specialized open reading frame that encodes a peptide with multiple proteolytic determinants. (Keiler et al., Science, 271(5251): 990-993 (1996); Gottesman et al., Genes Dev., 12(9): 1338-1347 (1998); Flynn et al., Proc. Natl. Acad. Sci. USA, 98(19): 10584-10589; Choy et al., J. Bacteriol., 189(18):6564-6571 (2007)). During trans-translation, tmRNA bound to SmpB is charged with alanine by AlaRS and binds EF-Tu (FIG. 1). The alanyl-tmRNA/SmpB/EF-Tu complex enters the A site of substrate ribosomes with the acceptor stem of tmRNA in the peptidyl transfer center and SmpB in the anticodon recognition site. (Neubauer et al., Science, 335(6074): 1366-1369 (2012)). The nascent polypeptide is transferred to alanyl-tmRNA by a normal transpeptidation reaction, and then the translational reading frame switches from the original mRNA to a reading frame within tmRNA. The original mRNA is released and degraded. Continued translation of the tmRNA reading frame results in the addition of a peptide tag to the nascent polypeptide and release of the ribosome. The tmRNA-encoded peptide tag targets the incomplete protein for rapid proteolysis.
In E. coli, 2-4% of protein synthesis reactions are targeted for trans-translation. At this rate, the average ribosome goes through trans-translation five times per cell cycle. (Ito et al., PLoS One, 6:e28413 (2011)). The ubiquity and abundance of this reaction suggests that it confers a significant competitive advantage. In fact, trans-translation is essential for viability in many species, including S. aureus, (Chaudhuri et al., BMC Genomics, 10:291 (2009); Fey et al., MBio, 4(1): e00537-00512 (2013)), N. gonorrhoeae, (Huang et al., EMBO J., 19(5): 1098-1107 (2000)), S. flexneri, (Ramadoss et al., PLoS One, 8(2): e57537 (2013)), and M. tuberculosis (Zhang et al., PLoS Pathog., 8(9): e1002946 (2012)). In other species, such as Salmonella enterica, Yersinia pestis, and Francisella tularensis, trans-translation is required for virulence. (Julio et al., J. Bacteriol., 182(6): 1558-1563 (2000); Okan et al., Infect. Immun., 78(3): 1284-1293 (2010); Svetlanov et al., Mol. Microbiol., 85(1): 122-141 (2012)).
Therapeutics based on small molecule inhibitors of trans-translation represent a promising and safe opportunity for treating a broad range of bacterial infections, notably including N. gonorrhoeae, Methicillin-Resistant Staphylococcus aureus (MRSA), B. anthracis, M.tuberculosis, and S. flexnieri, among others. Target-related toxicity of inhibitors of non-stop ribosome rescue is unlikely as trans-translation genes are not found in metazoans. There are no homologs of any of the ribosome rescue pathways for translation in the eukaryotic cytosol, but mammalian mitochondria do have a homolog of ArfB (ICT1). (Feaga et al., PLOS Genet., 12(3): e1005964 (2016)). As genetic knockdown of ICT1 results in apoptosis in cell culture, it is important to limit potential toxicity of non-stop ribosome rescue inhibitors by avoiding inhibitors of ICT1. (Richter et al., EMBO J. 29(6):1116-1125 (2010)). Therefore, compounds that target the trans-translation complex and inhibit trans-translation represent a promising approach to developing therapeutics for treatment and prevention of a number of bacterial infections.
Recently, to explore the potential for targeting bacterial trans-translation with small inhibitor molecules, a high-throughput luciferase-based reporter assay was developed and used to screen a library of 663,000 small molecules to isolate inhibitors of trans-translation. Briefly, to prepare the luciferase reporter assay, a copy of the trpAt transcriptional terminator was inserted before the stop codon of luc, the gene encoding firefly luciferase, on a multicopy plasmid. Induction of luc expression from this reporter (luc-trpAt) produces luc mRNA with no stop codon, and translation of the non-stop luc mRNA in cells with an active trans-translation system results in tagging and proteolysis of the luciferase protein. Alternatively, if trans-translation is inhibited, active luciferase will be released and accumulate in the cells. Therefore, trans-translation activity can be monitored by assaying luciferase activity in cells expressing luc-trpAt. Using the luciferase assay, 24 potential trans-translation inhibitor compounds were identified from the library. One compound, designated KKL-35, was shown to be a specific inhibitor of trans-translation with advantageously no effect on translation. Additionally, KKL-35 demonstrated a lack of cytotoxicity, even in the context of prolonged exposure, indicating that KKL-35 does not inhibit ICT1 and is unlikely to have target-related toxicity in mammalian systems.
KKL-35, having an oxadiazole core structure, demonstrated an IC50 value of 0.9 μM in a dose response assay. (Ramadoss et al., PNAS, 110(25):10282-87 (2013)). The combination of potent antimicrobial activity and lack of mammalian cytotoxicity suggested that KKL-35 was of potential interest for pharmaceutical development. Unfortunately, KKL-35 demonstrates poor stability in the presence of mouse or human liver microsomes in vitro and preliminary PK studies indicated extremely poor bioavailability in mice as evidenced by no detectable material after 5 min in the presence of microsomes or within 6 h of IV or IP dosing in mice at 10 mg/kg (data not shown), prohibiting further development of this and closely related analogs.
It has therefore been shown that trans-translation is a viable target for controlling bacterial infections, but there remains a need to develop trans-translation inhibitors with improved exposure in living systems that are suitable for safe and effective administration to mammals and in particular administration to humans. Therapeutic compositions based on effective trans-translation inhibitors have the potential for treating and/or preventing a wide range of both Gram-positive and Gram-negative bacterial infections.

Metabolically stable N-acylaminooxadiazoles useful as antibacterial agents