Cyanines which selectively bind to G-quadruplex DNA complexes, particularly quadruplexes expressed in cancer cells, and methods of making and using thereof are described herein. The cyanine can be a symmetrical or unsymmetrical streptocyanine, hemicyanine, closed chain cyanine, or combinations thereof. The cyanine is preferably substituted with one or more groups that minimize or prevent aggregation of the cyanine and/or inhibit binding of the cyanine to duplex DNA. One or more of the cyanines can be formulated with one or more pharmaceutical excipients and/or carrier to prepare pharmaceutical compositions suitable for administration to a patient, particular a human patient. The compounds and compositions described herein can be used to treat diseases or disorders characterized by the expression of G-quadruplex DNA, such as cancer.

In addition to the typical right-handed double helix, DNA can adopt other biologically relevant conformations that are important in regulating function. Four-stranded G-quadruplexes, for example, are non-canonical DNA structures that are found at the ends of human chromosomes as well as in promoter regions of a number of oncogenes. The quadruplexes are formed by a series of stacked guanine tetrads held together in a coplanar cyclic array that require a coordinated monovalent cation, typically potassium ion (K+). Quadruplex DNA can assume multiple conformations depending on many factors, including sequence length and the nature of the monovalent cation.
In the early 1990's, a correlation between G-quadruplex formation and cancer cells was established. The telomere and several oncogene promoter regions were identified as sequences that could form the quadruplex motif in vitro. Confirmation of these structures in vivo is described in Brooks et al., FEBS J., September 277(17), 3459-69 (2010).
Current DNA targeting drugs on the market include Pentamidine, Berenil, and Trabectadin. These drugs, however, target double stranded DNA by blocking in the minor groove in T. Brucei parasites, intercalating between base pairs of T. Brucei kinetoplast DNA, and alkylating in the minor groove of cancer DNA, respectively. Many other DNA targeting drugs have been investigated. However, most of these drugs are designed to bind in the minor groove, by intercalating or bis-intercalating, or interact with the phosphate backbone. Unfortunately, most of these drugs have been rejected due to poor solubility or selectivity, unacceptable toxicity, and/or the development of resistance.
There exists a need for compounds which preferentially bind to quadruplex DNA complexes and have little or no binding affinity for duplex DNA complexes and methods of making and using thereof. The compounds preferably have sufficient solubility or can be formulated to achieve sufficient solubility for administration in vivo and exhibit minimal toxicity and/or resistance.
Therefore, it is an object of the invention to provide compounds which preferentially bind to quadruplex DNA complexes and have little or no binding affinity for duplex DNA and methods of making and using thereof.

Carbocyanines for G-quadruplex DNA stabilization and telomerase inhibition

GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.


A communication terminal apparatus and its control method which allow the parallel execution of a plurality of communications with use of a plurality of data channels. The terminal apparatus comprises an image main controller and a voice main controller which can be operated independently of each other, two network controllers operated as associated with the operations of these image and voice main controllers respectively, two image transmission control circuits which are operated independently of each other, and an image file capable of storing image and voice data, thereby realizing the simultaneous execution of image and image communications and the simultaneous execution of voice and voice communications on a duplex communication basis.

1. Field of the Invention
The present invention relates to communication terminal apparatuses and control methods thereof which can be connected to an integrated service digital network (hereinafter, which will be referred to as the ISDN) and, more particularly, to a communication terminal apparatus and its control method which allow the realization of parallel operation of a plurality of communications with use of a plurality of data channels allocated to each line of the ISDN.
2. Description of the Related Art
A general communication terminal apparatus such as a facsimile equipment connected to a public telephone line or a DDX line, can execute only one of voice and image data communications or alternately execute the voice and image data, that is, can perform only so-called half duplex operation.
This is because the above public telephone line or DDX line can basically have a band corresponding only to one-channel information, which results in that, the simultaneous transmission of both the voice and image data leads to data deterioration and transmission ate reduction.
As the ISDN is put to practical use these days, the communication apparatus itself connected to the ISDN has been uniquely developed in the practical use of communication services.
As already known, the ISDN is an integrated digital network which integrally handles such service apparatuses different in contents to be handled as telephone sets, telex equipment and facsimile equipment and which has a plurality of channels for each ISDN line.
An attempt has ben made to realize the simultaneous transmission of voice and image data with use of the plural data channels of the ISDN line.
With the communication terminal apparatus connected to the ISDN, however, if a call demanding the reception of image data comes into the apparatus through second one of the plural data channels of the ISDN line, for example, during the reception of image data of the apparatus through first one of the data channels (during operation of an image printer in the apparatus), then the apparatus, in answer to the demand of reception of the new image data, can only send a busy tone back to the party terminal because the image printer is in operation, and thus the call from the party terminal becomes useless.
Further, for example, when the communication terminal apparatus, which is talking with the party through the first data channel of the ISDN line, receives an incoming call demanding a speech, i.e., a voice demanding call through the second data channel; the apparatus, in response to this new speech demand, can only send a busy tone indicative of the busy destination party back to the party terminal a busy tone, thus resulting in that the call from the party terminal becomes useless.
In this way, the prior art communication terminal apparatus has had problems that, when the apparatus receives the new image data demand through the second data channel during execution of the image data trough the first data channel and when the apparatus receives the new speech demand through the second data channel during talk through the first data channel, the apparatus cannot execute the new image and speech demands respectively, inevitably involving the reduction of its communication efficiency.
The present invention also provides a communication terminal apparatus and its control method which allows the simultaneous realization of a plurality of communications.
It is, accordingly, an object of the present invention to provide a communication terminal apparatus and its control method which, when receiving a new image data demand through a second data channel during execution of image data through a first data channel, can accept the new image demand and can perform different-direction full duplex communication over the image data, thus increasing its communication efficiency.
It is another object of the present invention to provide a communication terminal apparatus and its control method which, when receiving a new incoming voice signal through a second data channel during talk through a first data channel, can execute the new voice signal without sending a busy tone back to the party terminal, with a good communication efficiency.

Communication terminal apparatus and its control method


Determination about presence/absence of alcohol in the body is made accurately.

As means for preventing drunken driving, it has been tried to mount an alcohol interlocking device on an automobile in recent years. In an alcohol-drinking detecting device utilizing a breath, however, there is such a concern that the device can be deceived by the breath of a fellow passenger.
On the other hand, the present applicant has disclosed a method for arranging a pressure sensor in a seat cushion section and obtaining and analyzing a pulse wave of a breech of a person to estimate the state of the person as a system which monitors a biological body state of a driver during driving in a non-invasive manner, for example, in Patent Literatures 1 to 3. Specifically, a maximum value and a minimum value of a time-series signal of a pulse wave are obtained by a smoothing differentiation method of Savitzky and Golay, respectively. The maximum value and the minimum value are obtained for each 5 seconds so that their mean values are obtained. Using a square of a difference between the respective mean values of the maximum values and the minimum values obtained as a power value, the power value is plotted for each 5 seconds so that a time-series waveform of the power value is produced. In order to read a global change of the power value from this time-series waveform, a slope of the power value regarding a certain time window Tw (180 seconds) is obtained by least-square method. Next, the slope regarding the next time window Tw is similarly calculated in an overlapped time TI (162 seconds) and the calculation results are plotted. A time-series waveform of the slope of the power value is obtained by repeating this calculation (moving calculation) sequentially. On the other hand, the maximum Lyapunov exponent is obtained by applying Chaos analysis to the time-series signal of the pulse wave, a maximum value is obtained by a smoothing differentiation method like the above, and a time-series waveform of a slope of the maximum Lyapunov exponent is obtained by conducting moving calculation. Then, the time-series waveform of the slope of the power value and the time-series waveform of the slope of the maximum Lyapunov exponent take phases opposite to each other, and a waveform having a large amplitude at a low frequency in the time-series waveform of the slope of the power value is determined as a characteristic signal indicating a sleep prediction and a point at which the amplitude has become small thereafter is determined as a sleep point.
Further, as Patent Literature 4, a system provided with an airbag (air pack) including a three-dimensional solid fabric inserted therein, where the air pack is disposed at a site corresponding to a waist portion of a person, an air pressure fluctuation in the air pack is measured, a biological signal of the person is detected from the time-series waveform of the air pressure fluctuation obtained, and the biological body state of the person is analyzed is disclosed. Further, in Non-Patent Literatures 1 and 2, trials for detecting a biological signal of a person by disposing an air pack sensor along a lumber iliocostal muscle are reported. A pulse wave near a lumber area shows a circulation fluctuation of blood flowing in a descending aorta according to a heartbeat, where a state change of a person corresponding to a heartbeat fluctuation can be captured more accurately in utilization of this aortic pulse wave than in utilizing the breech pulse wave disclosed in Patent Literatures 1 and 2.
The present applicant has reported that it is possible to determine presence/absence of alcohol in the body by further developing the techniques described in Patent Literatures 1 to 4 and Non-Patent Literatures 1 and 2 and performing frequency analysis of a pulse wave obtained from an air-pack sensor as Non-Patent Literature 3.

Alcohol-drinking detecting system and computer program

Abstract: A frequency dynamic information processing means 610 which obtains a tendency of time-series fluctuation regarding a frequency of a pulse wave of a back portion of a person detected by an air pack and an alcohol-drinking determining means 650 which determines an alcohol-drinking state when a tendency of a time-series fluctuation regarding the frequency obtained by the frequency dynamic information processing means 610 is separated from a tendency of time-series fluctuation regarding the frequency at a non-drinking state are provided. Since determination about whether or not a person is in an alcohol-drinking state is made according to comparison with time-series fluctuation regarding the frequency at a non-drinking time, where the determination is made using not only frequency analysis of the frequency of a pulse wave changing according to the physical condition of the person but also the time-series fluctuation thereof, determination about presence/absence of alcohol drinking can be made more accurately as compared with the conventional method.


An anchoring device for use within a body cavity during a surgical procedure is disclosed. The anchoring device includes an external assembly, an internal assembly, a controller, and a module. The external assembly has a first magnetic component. The internal assembly has a second magnetic component. The internal assembly is sized to be placed inside of the body cavity. The electrical current is connected with one of the first and the second magnetic component to produce a magnetic field about the connected magnetic component to approximate the internal and external assemblies. The module determines a parameter and is in communication with a controller. The controller controls the electrical current in response to the parameter.

1. Technical Field
The present disclosure relates to a device for use in a minimally invasive surgery and more particularly, to an anchoring device which is retained and movably arrangeable inside of a body cavity.
2. Related Art
Laparoscopy is minimally invasive surgery (MIS) performed in the abdominal cavity. It has become the treatment of choice for several routinely performed interventions.
However, known laparoscopy technologies are limited in scope and complexity due in part to 1) mobility restrictions resulting from using tools inserted through access ports, and 2) limited visual feedback. That is, long laparoscopic tools inserted through small incisions in the abdomen wall limit the surgeon's range of motion and therefore the complexity of the surgical procedures being performed. Similarly, using a 2-D image from a typical laparoscope inserted through a small incision limits the overall understanding of the surgical environment. Further, current technology requires a third port to accommodate a laparoscope (camera), and each new port requires an additional incision.
There is a need in the art for improved surgical methods, systems, and devices for minimally invasive surgery.

Magnetically secured surgical station with force modulation


Embodiments of the invention provide a system and circuit interconnecting peripheral devices to neurosynaptic core circuits. The neurosynaptic system includes an interconnect that includes different types of communication channels. A device connects to the neurosynaptic system via the interconnect.

The present invention relates to data mapping for neuromorphic and synaptronic computational systems, and in particular, interconnecting peripheral devices for neuromorphic and synaptronic computational systems.
Neuromorphic and synaptronic computation, also referred to as artificial neural networks, are computational systems that permit electronic systems to essentially function in a manner analogous to that of biological brains. Neuromorphic and synaptronic computation do not generally utilize the traditional digital model of manipulating 0s and 1s. Instead, neuromorphic and synaptronic computation create connections between processing elements that are roughly functionally equivalent to neurons of a biological brain. Neuromorphic and synaptronic computation may comprise various electronic circuits that are modeled on biological neurons.
In biological systems, the point of contact between an axon of a neural module and a dendrite on another neuron is called a synapse, and with respect to the synapse, the two neurons are respectively called pre-synaptic and post-synaptic. The essence of our individual experiences is stored in conductance of the synapses. The synaptic conductance changes with time as a function of the relative spike times of pre-synaptic and post-synaptic neurons, as per spike-timing dependent plasticity (STDP). The STDP rule increases the conductance of a synapse if its post-synaptic neuron fires after its pre-synaptic neuron fires, and decreases the conductance of a synapse if the order of the two firings is reversed.
Neuromorphic devices communicate to personal computers (PCs) and peripheral devices via standard interfaces (e.g., universal serial bus (USB), peripheral component interconnect (PCI) using custom protocol converters, etc.). These converters translate the native protocol of neuromorphic chips (spikes) into the desired standard protocols (e.g., USB 2.0) and vice versa. Standard interfaces typically requires a host computer, such as a laptop computer in the loop. Therefore, the minimal neuromorphic system requires a laptop computer, a sensor and a neuromorphic board, which makes it difficult to create real-time systems; and power consumption (>5 W) prohibits embedded systems.

This patent is subject to a terminal disclaimer.

Peripheral device interconnections for neurosynaptic systems

International Business Machines Corporation


The invention provides devices, apparatuses, systems and methods for treating and ameliorating inflammation of the gut. In particular, the invention provides devices, apparatuses and methods in which a neuromodulatory signal is delivered a splenic nerve and/or superior mesenteric plexus (SMP). The signal is able to treat inflammatory disorders, e.g., colitis, for example in Inflammatory Bowel Disease.

Neural mechanisms regulate all key functions of the gastrointestinal tract such as motility, secretion and vasoregulation. The autonomic nervous system (ANS), acting largely autonomously in that its activities are not under direct conscious control, represents the extrinsic control of the intestine, and is divided in sympathetic and parasympathetic branches. The ANS sympathetic and parasympathetic components originate in the central nervous system (CNS) (with cell bodies in the brainstem and spinal cord); while the enteric nervous system (ENS), resides within the wall of the gastrointestinal tract. The ANS forms the major efferent component of the peripheral nervous system containing integrative neuronal connections and even complete reflex arcs.
Studies in neuroscience and immunology have identified a number of indications for bidirectional interactions between the nervous and immune systems. As with other organs, intestinal immune responses and the development of immunity seem to be influenced by neural reflexes. In the last decade the parasympathetic efferent vagus nerve has been added to this immune-regulation network. This system, designated "the inflammatory reflex", is thought to comprise an afferent (i.e., sensory) arm that senses inflammation, and an efferent arm that inhibits systemic and local immune responses.
Vagal parasympathetic preganglionic fibers originate from motor neurons of the dorsal nucleus of the vagus and synapse with postganglionic parasympathetic neurons within the intestine (e.g., the myenteric plexus). The density of the vagal innervation displays a proximodistal gradient along the intestine with the highest density observed in the duodenum and the lowest density observed in the distal part of the ileum. The large intestine differs from the rest of the gastrointestinal tract in that the vagus nerve provides parasympathetic innervation of the proximal colon but provides little if any neural input to the distal colon.
Vagus (or Vagal) nerve innervation has been shown to have importance in controlling systemic inflammation. In a LPS model of sepsis, vagus nerve stimulation has been shown to exert an anti-inflammatory effect (Borovikova et al. 2000, Nature; 405, 458-462). Relatedly, the spleen and the splenic nerve have also been shown to play an important role in the vagally-mediated inhibition of systemic inflammation (Huston et al. 2006, J. Exp. Med, 203. 1623-1628, incorporated herein by reference). It has further been demonstrated that the systemic anti-inflammatory effect can be induced without vagus nerve signalling if the splenic nerve is stimulated (Vida et al, 2011, J. Immunol. 186: 4340-4346, incorporated herein by reference). However, there has been no demonstration that splenic nerve stimulation can result in any local therapeutic mucosal anti-inflammatory effect.
In more extensive mucosal inflammation (for example Inflammatory Bowel Disease or "IBD"), a potential anti-inflammatory reflex arc of the vagus nerve is observed, but the underlying mechanism is less well established than for systemic inflammation. In general terms, pharmacologic nicotinic agonist activation ameliorates gut inflammation. Similarly, the administration of acetylcholinesterase inhibitors ameliorates experimental colitis via central inhibition. The effect of acetylcholinesterase inhibitors is lost in animals that have undergone a vagotomy, indicating that parasympathetic acetylcholine signalling is involved in vagally mediated anti-inflammatory effects (Pavlov, et al Brain Beh Immun 2009, and Ji et al, Muc Immunol 2014, each of which are incorporated herein by reference).
Intervention in this vagal inflammatory reflex as a form of therapy is currently being investigated in trials of vagus nerve stimulation (VNS). VNS uses implantable devices to stimulate the right carotid vagus in the neck in order to influence levels of inflammation in the gut. However, although VNS is considered to have some positive effects, the mode of action remains to be fully established. Importantly, the vagus nerve is a multifunctional mixed nerve that interacts with many bodily systems, and therefore interventions in vagal signalling are known to have a number of undesirable systemic side-effects, such as cardiac arrhythmia and abnormal respiratory patterns. Accordingly, more specific and targeted methods of neuromodulation for regulating the local mucosal inflammatory response in the spleen and gut (e.g., intestines and colon) are desirable.


A counter base for checkout includes a basket placing table on one side thereof to be freely raised and lowered. A driving unit can drive to raise and lower the basket placing table. A first detecting unit detects that a shopping cart enters an access area closer to the basket placing table than a predetermined range. A second detecting unit detects presence or absence of the shopping cart stopped along one side of the counter base. A control unit controls to drive, when the first detecting unit detects entrance of the shopping cart into the access area, the driving unit to move the basket placing table to a lowered position and, thereafter, controls to drive, when the second detecting unit does not detect the shopping cart stopped along the counter base, the driving unit to return the basket placing table to a raised position.

Conventionally, in various stores such as a supermarket and a drug store, checkout counters are set in checkout processing areas. Each of the checkout counters includes a barcode reader for reading commodity codes attached to commodities, which are stored in a shopping basket and carried to the checkout processing area, in a form of a barcode. The barcode reader transmits the read commodity codes to a POS terminal set near the checkout counter. The POS terminal performs checkout processing on the basis of the received commodity codes. In such commodity sales, in general, a customer places a shopping basket, which stores commodities, on one side of the barcode reader on the checkout counter. A store clerk takes out the commodities from the shopping basket, reads commodity codes of the commodities with the barcode reader, and stores the commodities after the reading of the commodity codes in an empty shopping basket placed on the other side of the barcode reader. The checkout counter is formed large to some extent in order to carry out work in such a work procedure.
The large checkout counter is not suitable for setting in a small store such as a drug store. In the first place, the small store may not have a space for setting the large checkout counter. Even if the large checkout counter can be set, the large checkout counter may improperly occupy a store space or cause customers to feel a strong sense of oppression. Therefore, mainly taking into account the use in such a small store, a checkout counter in which a basket placing table for setting a shopping basket, which stores commodities, is provided on a side of a counter base formed in a small size is developed and put to practical use. For example, JP-A-2005-209089 discloses a checkout counter in which a basket placing table is arranged on a side of a counter base on which a barcode reader is set. The checkout counter can slide and draw the basket placing table to below a top plate of the counter base and open a setting space for the basket placing table.
A store often includes shopping carts in addition to shopping baskets. A shopping cart is extremely convenient for a customer to carry, when the customer purchases many commodities that the shopping basket cannot store, the commodities from a selling floor to the checkout counter. However, when the customer uses the shopping cart, the customer has to move a shopping basket from the shopping cart to the counter. This work is unexpectedly heavy because the customer has to vertically lift the shopping basket filled with commodities from the shopping cart. Therefore, the work for moving the shopping basket from the shopping cart to the counter imposes an excessive burden on, in particular, a customer with little power like an aged person.
On the other hand, in the checkout counter disclosed in JP-A-2005-209089, if the basket placing table is drawn to below the top plate of the counter base, the customer can stop the shopping cart along the side of the counter base. This allows the customer to omit the work for moving the shopping basket from the shopping cart to the counter. However, when commodities are carried to the checkout counter, the shopping basket is directly carried to the checkout counter in some case and is carried to the checkout counter by the shopping cart in other cases. Therefore, the store clerk has to expose the basket placing table when the shopping basket is directly carried to the checkout counter and draw the basket placing table to below the top plate when the shopping basket is carried by the shopping cart. The work is extremely troublesome and the store clerk cannot withstand the troublesomeness.

Checkout counter and self checkout terminal


A resin composition comprises a base resin containing a urethane (meth)acrylate oligomer, a monomer and a photopolymerization initiator, and a hydrophobized spherical inorganic oxide, wherein the inorganic oxide is dispersed in the resin composition and a content of the inorganic oxide is 1 to 60% by mass based on a total amount of the resin composition.

Generally, an optical fiber has a coating resin layer for protecting a glass fiber which is an optical transmission medium. The optical fiber has been required to have excellent lateral pressure characteristics in order to reduce an increase in transmission loss induced by micro-bend generated when lateral pressure is applied to the optical fiber.
For example, Patent Literature 1 has investigated the improvement of the lateral pressure characteristics of the optical fiber by forming a resin layer using an ultraviolet-curable resin composition containing a filler made of synthetic silica.


A process for magnetorelaxometric quantitative detection of analytes in the liquid and solid phases, compounds for magnetorelaxometric detection, and their use in analysis and immunomagnetography is described.

This invention relates to processes for magnetorelaxometric qualitative and/or quantitative detection of analytes in the liquid and solid phases, compounds for magnetorelaxometric detection, and their use in analysis and immunomagnetography.
It is already known that immunoscintigraphy makes it possible to detect pathological structures in vivo with the aid of radiolabeled structure-specific substances, which are also referred to below as markers. To this end, antibodies that are labeled with xcex3-rays or antibody fragments are usually used. In addition, other structure-specific substances, such as, e.g., peptides or oligonucleic or polynucleic acids are also used or are being researched. The portion of specifically bound radioactivity is, however, generally small in all these processes. Consequently, in the case of these studies, the levels of markers that are not specifically bound and thus circulate in the blood or accumulate in organs such as the liver, kidney, efferent urinary passages, or bladder are very high. In many cases, this high background radiation impedes adequate detection of pathological structures. In EP 0251494, in Panchapakesan et al., 1992 Immunol. Cell Biol. 70:295 and in Ziegler et al., 1991, New England Journal of Medicine 324:430, reference is therefore made to ways of improving immunoscintigraphy. The goal of most of the processes is to accelerate the elimination of radioactivity that is not specifically bound.
In addition, the use of antibodies that are conjugated with paramagnetic or superparamagnetic substances or antibody fragments for locating pathological structures in vivo has been proposed on various occasions. To date, nuclear spin tomography or the magnetometry that is based on changes in susceptibility (WO93/05818 and WO91/15243) have been considered as detection processes for such labeled antibodies. In the case of these detection processes, the problem of the variable portion of the signal owing to unbound portions of the marker as well as owing to natural variations in the susceptibility and relaxivity of the tissue also remains present. In addition, the methods often are not sensitive enough to be able to detect just small amounts of specifically bound markers.
A process that makes it possible to detect only the portion of bound markers and thus is not influenced by the extent of the unbound markers is not known, however.
One of the objects of this invention is therefore to develop new processes and substances that are superior to the above-mentioned prior art and that make it possible to detect the retention site without using radioactive substances and the extent of the bound markers without the influence of markers that circulate in the blood.
In addition, it is also already known that quantitative immunoassays as well as other binding assays (e.g., receptor binding assays) make it possible to determine a very large number of substances that can also be of biological relevance in samples of varying composition. Generally, however, only one parameter per sample in an assay is determined in this way. An existing survey of the various processes is: T. Chard; An Introduction to Radioimmunoassay and Related Techniques: Laboratory Techniques in Biochemistry and Molecular Biology, 4th ed., Elsevier Science Publishers, Amsterdam (1990). The basis of all binding assays is the high detection sensitivity of compounds that are labeled with isotopes or by some other means with the high specificity of ligand-receptor reactions.
The known assay processes have the following drawbacks, however:
1. The processes for simultaneous determination of various analytes within the same sample are based on the binding of various radio-, fluorescence- or enzymologically-labeled probes to the analytes. In this case, the unbound or bound activity of the probes for quantitative determination of the analyte is generally measured after subsequent separation and washing. In this case, the amount of usable different probe labels is very limited. Thus, for example, in the case of different radioisotopes as probe labels, so-called overlapping phenomena occur which lead to a rapid loss of the quantitative accuracy of individual signals. The combination of various enzymes as probe labels causes comparable problems, whereby the feasibility here is further hampered by the necessary search for reaction conditions that allow the simultaneous determination of enzyme reactions in a system.
2. The sensitivity of the process is limited by, for example, non-specific interactions between matrix and probe, or else by limited labeling capability on the part of the probe (low specific activity).
3. The successful implementation of the process often requires that the sample material obtained be worked up (e.g., production of serum or plasma from whole blood, extraction of samples with organic solvents, concentration of the analyte using chromatographic processes, etc.).
4. For successful implementation of the processes, separation and washing steps, which are used in the separation of bound and unbound receptors or ligand, are essential in most cases.
5. To carry out radioimmunoassays, the use of radiating nuclides, which are costly and complicated to handle, is necessary.
6. In practice, the storage of previously used markers often causes problems since they are either unstable (radioimmunoassays) and must therefore constantly be made up fresh or else react in a sensitive manner to environmental influences.
Another object of this invention is therefore to develop novel, economical processes and substances that overcome the drawbacks of the above-mentioned prior art.
First processes are now described that overcome the drawbacks of the known processes for implementing immunoassays or other binding assays.
The processes according to the invention are based on the use of colloidal ferromagnetic or ferrimagnetic substances, also referred to below as magnetic labeling, which are combined with substances to be identifiedxe2x80x94also referred to below as analytesxe2x80x94or structure-specific substances. Such combinations, according to the invention, of magnetic labelings with analytes or structure-specific substances, which are described in more detail in this patent, are also referred to below as magnetic markers. Through the use of the term colloidal substances or colloidal particles, both the range of sizes of the particles or substances in the size range of colloids, i.e., the range of 1 nm up to about 1000 nm, and their use as a dispersed phase in a suitable dispersion medium, which is aqueous in most cases, is described. To ensure improved storability and transportability, the colloidal substances or particles can also be present in dried form or frozen; while measurements are being made, however, they are present in the liquid phase in the dispersed state.
In addition, the processes are based on special measuring techniques, which make it possible to determine the relaxation of magnetization after the magnetic labeling or the magnetic markers are magnetized. Such measuring processes according to the invention, which are described in more detail in this patent, are also referred to below as magnet-relaxometry or magnetorelaxometry or magnet-relaxometric detection.
An important principle of the invention is that after an external magnetizing field is turned off, the magnetization of freely movable ferromagnetic or ferrimagnetic colloidal particles relaxes by two different mechanisms:
i) Turning of the whole colloidal particle inside the surrounding liquid, whereby the time constant depends on the hydrodynamic diameter of the particles including the shell, the viscosity of the carrier liquid, and temperature, which mainly reflects parameters of the environs of the particles; this mechanism is also referred to below as Brownian relaxation or extrinsic superparamagnetism,
and
ii) Turning of the internal magnetizing vector inside the colloidal particles, whereby the time constant depends in a very sensitive manner on material and shape (the anisotropy constants of the particle material used), volume and the temperature of the particles used. These are basically intrinsic parameters of the particles; this mechanism is also referred to below as Nxc3xa9elian relaxation or intrinsic superparamagnetism.
The object according to the invention is achieved by virtue of the fact that in immunoassays or other binding assays, ferromagnetic or ferrimagnetic colloidal particles, whose Brownian relaxation proceeds faster than the Nxc3xa9elian relaxation under measurement conditions in the unbound state, are used as magnetic labeling to be identified. Owing to the change in the predominant relaxation mechanism or to the scaling-up of the particle volume, which is caused by the binding, the use of such ferromagnetic or ferrimagnetic colloidal particles then makes it possible to determine specifically the portion of bound magnetic markers in addition to the unbound magnetic labels that are simultaneously present in the measuring sample.
By the use of sensitive measuring processes, in the case of the procedure according to the invention, ultrahighly sensitive binding-specific immunoassays or other binding assays which can be performed both in the liquid phase and in the solid phase can be set up using ferromagnetic or ferrimagnetic colloidal particles. As an especially sensitive measuring process, after the sample is magnetized in a magnetizing field and after the field is turned off, the relaxation of the magnetization can be determined with the aid of highly sensitive magnetic field detectors (such as, e.g., superconducting quantum interference devices (SQUIDs), induction coils, flux gate magnetometers, giant magnetoresistance sensors, or magnetoresistive converters), or the complex susceptibility of the sample can be determined as a function of frequency.
The process for magnet-relaxometric quantitative detection of analytes in the liquid and solid phases is also characterized according to the invention in that the structure-specific substances that bind the analytes first
i) are labeled with ferrimagnetic or ferromagnetic colloidal particles
and then
ii) these magnetically labeled structure-specific substances are used in a liquid or immobilized sample to be measured, the sample to be measured is magnetized with the aid of a magnetic field that is applied from the outside and, after the outside field is turned off, the relaxation of the magnetization of the magnetic markers is measured with the aid of magnetic field sensors.
The process for magnet-relaxometric quantitative detection of analytes in the liquid and solid phases according to the invention can also be carried out in such a way that analytes first
i) are labeled with ferrimagnetic or ferromagnetic colloidal particles
and then
ii) these magnetically labeled analytes are used in a liquid or immobilized sample to be measured, the substances that specifically bind the analytes are added, and the sample to be measured is magnetized with the aid of a magnetic field that is applied from the outside and, after the outside field is turned off, the relaxation of the magnetization of the magnetic markers is measured with the aid of magnetic field sensors.
In both above-named cases, the measurement of the complex susceptibility of the magnetic labeling or the magnetic marker that is altered by the binding can also be used as a function of frequency for analysis.
The discrimination between bound and unbound markers, which previously could be done only in exceptional cases, is made possible by the use of their different relaxation mechanisms or the influence of the relaxation time of the magnetic marker that is caused by the binding.
Solid-phase-bound analytes can be identified according to the invention especially by the structure-specific substances that bind the analytes first
i) being labeled with the ferrimagnetic or ferromagnetic colloidal particles that relax in the time range of the measurement, whereby the ferrimagnetic or ferromagnetic colloidal particles are selected in such a way that under the measurement conditions, the Brownian relaxation has a shorter relaxation time than the Nxc3xa9elian relaxation
and then
ii) these magnetically labeled substances being used in an immobilized sample to be measured, and the sample to be measured is magnetized with the aid of a magnetic field of suitable intensity that is applied from the outside and, after the outside field is turned off, the relaxation of the magnetization of the magnetic markers is measured with the aid of magnetic field sensors, whereby the different relaxation behaviors of solid-phase-bound and unbound magnetic markers are used for analysis. As a measurement variable, the complex susceptibility of the samples can also be determined as a function of frequency.
Also in this case, it is possible to combine the analytes to be identified, instead of structure-specific substances, with the magnetic labelings.
In the liquid phase, analytes according to the invention can be detected especially by the structure-specific substances that bind the analytes first
i) being labeled with ferrimagnetic or ferromagnetic colloidal particles, whereby the ferrimagnetic or ferromagnetic colloidal particles are selected in such a way that under the measurement conditions the Brownian relaxation has a shorter relaxation time than the Nxc3xa9elian relaxation
and then
ii) these magnetically labeled substances being used in a sample to be measured, and the sample to be measured is magnetized with the aid of a magnetic field of suitable intensity that is applied from outside and, after the outside field is turned off, the relaxation of the magnetization of the magnetic markers is measured with the aid of magnetic field sensors, whereby the different relaxation behaviors of the magnetic markers bound with the analyte relative to the unbound magnetic markers are used for analysis.
As a measurement variable, the complex susceptibility of the samples can also be determined as a function of frequency.
Also in this case, it is possible to combine the analytes to be identified, instead of structure-specific substances, with the magnetic labelings.
Structure-specific substances are defined as all substances that bind specifically to certain structures. Structure-specific substances are defined as especially antibodies, antibody fragments, biotin, or substances that bind biotin such as avidin and streptavidin, agonists that bind specifically to receptors, such as cytokines, lymphokines, endothelins or their antagonists, specific peptides and proteins, receptors, enzymes, enzyme substrates, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates, lipoproteins, etc. As structure-specific substances, substances are preferred whose binding constant is in the range of 105-1015 (mol/1)xe2x88x921. Especially preferred are substances whose binding constant is in the range of 107-1015 (mol/1)xe2x88x921.
The structure-specific substances or analytes to be identified can be labeled with the ferrimagnetic or ferromagnetic particles with the aid of processes that are familiar in immunochemistry, peptide chemistry, and protein chemistry. Especially advantageous are covalent bonds between the structure-specific substances or the analytes to be identified with the substances that form the stabilizing shell of ferrimagnetic or ferromagnetic particles. Examples of especially suitable methods are activation and coupling with the aid of carbodiimides (Jakoby and Wilchek, eds., 1974 Methods Enzymol. 34), the formation of Schiff bases after periodates are exposed to compounds that contain carbohydrates (Wicheck and Bayer, eds., Methods Enzym. 184:177), which are then optionally reduced for further stabilization, coupling with the aid of glutaric dialdehyde (Heitzmann and Richards, 1974 Proc. Natl. Acad. Sci. USA 71:3537), cross-linking of bromoacetylated particles with thiolylated substances (Angerer et al., 1976 Cell 9:81), as well as reductive alkylation (Bayer et al., 1976 J. Histochem. Cytochem. 24:933).
Ferromagnetic or ferrimagnetic colloidal particles can also be produced with a stabilizing shell made of the structure-specific substance or the analyte to be identified, by the particles being put after production directly into a solution of the structure-specific substance, optionally in the presence of other adjuvants, such as, e.g., proteins, carbohydrates, as well as natural, synthetic, or partially synthetic surface-active substances, etc., or by being produced directly in the presence of structure-specific substances.
The process according to the invention can be used in, e.g., fertility, histocompatibility, allergology, infectiology, hygiene, genetics, virology, bacteriology, toxicology, pathology, environmental analysis, and medical diagnosis.
Also objects of this invention are compounds for magnet-relaxometric detection, which consist of colloidal suspensions of freely movable ferrimagnetic or ferromagnetic particles and structure-specific substances or analytes to be identified, whereby structure-specific substances are defined as especially antibodies, antibody fragments, biotin, or substances that bind biotin such as avidin and streptavidin, agonists that bind specifically to receptors, such as cytokines, lymphokines, endothelins or their antagonists, other specific peptides and proteins, receptors, enzymes, enzyme substrates, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates, lipoproteins, etc.
The compounds for magnet-relaxometric detection can also consist of combinations of several ferromagnetic or ferrimagnetic particles with relaxation times that can be discriminated, since measurement results that can be discriminated individually can be achieved through the use of different magnetic labelings with respectively a very narrow distribution of relaxation times and/or magnetic moments for various structure-specific substances or analytes inside a sample. As a result, direct simultaneous quantitative determination of several analytes is made possible.
As suspension media, all liquids in which the colloidal particles can move freely are suitable. Especially suitable are water, aqueous solutions of surface-active adjuvants, such as, e.g., surfactants or oligomeric or polymeric carbohydrates and proteins, as well as mixtures of water and alcohols such as, e.g., glycerol and polyethylene glycol. The suspension media can additionally contain adjuvants that change the osmotic pressure, such as, e.g., common salt. In addition, buffer substances that determine pH, such as, e.g., phosphates, can be contained.
The compounds made of ferromagnetic or ferrimagnetic colloidal particles with structure-specific substances or analytes to be identified can also be present in dried form, optionally in combination with other adjuvants which, e.g., facilitate drying or increase the stability of the dried product (e.g., as lyophilizates).
Finding of the analyte can be done with or without separation and washing steps. In carrying out measurements with separation steps between bound and unbound magnetic markers, all ferromagnetic or ferrimagnetic colloidal substances according to the invention can be used as magnetic labelings for magnetrelaxometric detection. In these cases, special requirements with regard to the Brownian relaxation times and the Nxc3xa9elian relaxation times no longer need be imposed.
Due to the binding identification based on physical mechanisms, non-specific measurement signals (matrix phenomena) can be largely ruled out. The specificity of the process thus depends only on the xe2x80x9ctruexe2x80x9d specificity of the structure-specific substance (cross reactivity of antibodies, non-specific binding of ligands).
Due to the high sensitivity of the process according to the invention, it is easy to remain under the detection limits of binding assays that are otherwise commonly encountered.
As substances for magnetic labeling, all ferromagnetic or ferrimagnetic materials that can be dispersed colloidally in a medium that is suitable for magnetorelaxometric detection can be used. When using substances for magnetorelaxometric detection, which is carried out without separation steps between bound and unbound magnetic markers, the Nxc3xa9elian relaxation time of the magnetic labelings under the measurement conditions must be longer than the Brownian relaxation time of the magnetic markers. Especially suitable are all ferromagnetic or ferrimagnetic colloidal particles with Brownian relaxation times in aqueous media in the range of 10xe2x88x928-10xe2x88x921 s and Nxc3xa9elian relaxation times of more than 10xe2x88x928 s. To carry out measurements without separation steps, the viscosity of the dispersing medium used must be matched to the relaxation times of the ferromagnetic and ferrimagnetic particles and the measurement time since the suspension medium basically determines the time constant of Brownian relaxation.
Preferred are especially ferromagnetic or ferrimagnetic colloidal particles made of iron, iron oxides, barium ferrites, strontium ferrites, cobalt, nickel, nickel ferrites, cobalt ferrites, and chromium dioxide, whose Nxc3xa9elian relaxation time is longer than the Brownian relaxation time.
The use of magnetic labelings with narrowly distributed particle sizes and/or magnetic moments is generally advantageous. Separation of magnetic labelings into fractions with a narrow distribution of particle sizes can be achieved by, e.g., chromatographic processes or by using special filtration processes (e.g., glass capillary systems or tangential filtration), by using molecular sieves, or by means of centrifuging. Magnetic labelings with moments that are as uniform as possible can be produced, e.g., by classification in a magnetic gradient field.
The ferromagnetic and ferrimagnetic substances can be stabilized with a shell made of oligomeric or polymeric carbohydrates, proteins, peptides, nucleotides, surfactants, other monomers, oligomers, or polymers and/or lipids.
The particle sizes of the ferromagnetic and ferrimagnetic substances are advantageously between 1 nm and 400 nm. Especially preferred are particle sizes between 1 nm and 100 nm.
According to the process, the magnet-relaxometric detection is carried out with measurement arrangements that first make it possible to magnetize the sample to be studied with the aid of a suitable magnetic field and then to measure the magnetic relaxation of the magnetic markers. The measurement arrangement used for the examples is depicted in FIG. 2. In contrast to all other already known processes (JP-235774 and WO 91/15243), in the measurement of the relaxation of magnetization in the process according to the invention, it is not static magnetization in the presence of the magnetizing field that is measured but rather its time change in the absence of the magnetizing field. Only thus are data on the binding state of the markers available. In addition, influencing of the measurement signal by diamagnetic or paramagnetic components or contaminants is thus avoided. Further, measurement sensitivity is increased decisively.
It is further possible to carry out the measurement of the frequency-dependent magnetization of the marker because of a suitable alternating magnetic field (determination of complex susceptibility as a function of frequency) with the aid of highly sensitive sensors, such as, for example, SQUIDs, in the presence of the field. In this case, use is made of the specific frequency dependence of the susceptibility of the magnetic marker, in contrast to the frequency dependence of the paramagnetic or diamagnetic components that can be determined separately. Also, this procedure differs from the process for determining the susceptibility of superparamagnetic substances that is proposed in WO91/15243. In WO91/15243, neither the frequency dependency of the susceptibility of the magnetic markers is described, nor is a process for using this property indicated.
Below, processes are described that make it possible to detect in vivo the retention site and the extent of the specifically bound markers without being influenced by markers that circulate in the blood. In addition, in these processes, the use of radioactive substances, as has been required thus far in carrying out scintigraphy processes, is avoided.
The processes according to the invention are based on the fact that the relaxation time differences between bound and unbound magnetic markers in liquids, as well as the change of the predominant relaxation mechanism by binding the magnetic markers to solid phases, can also be used for magnet-relaxometric detection of substances or structures in vivo. Such processes are also referred to below as immune magnetography or immunomagnetography.
The in vivo measurement of the spatial distribution of a relaxing magnetic markers that are used in humans in the time range of the measurement can be carried out by two different measuring methods:
1. Production of as homogeneous a magnetic field as possible in advantageous volume, turning off the field and measuring the spatial distribution of the relaxing magnetic field with the aid of a multichannel sensor. Said sensor should enclose the measurement object as completely as possible. For the production of sufficient measurement information, repeated measurement with sequential rastering of the measurement object is also possible.
2. Sequential production of a local field that is limited in space, turning off the field and measuring the spatial distribution of the relaxing magnetic field with the aid of a single-channel sensor. The use of a multichannel sensor is also possible.
In the case of both methods, to obtain as many data as possible both the magnetization of the measurement object and the measuring of the resulting magnetic field in all three spatial directions are to be preferred.
The measurement is described by a suitable model. Preferably, the model of the magnetic dipole, multipole or multi-dipole is used as a basis. The special parameters of the model, especially the sites of the dipoles or multipoles, are found by a suitable approximation process, which minimizes the deviations between measurement data and model parameters. These parameters provide information on the spatial distribution of the magnetized particles.
An analogous approach is known and proven for the analysis of magnetic fields of bioelectric currents.
As processes and compounds that are suitable for immune magnetography, all processes and substances that are cited for magnet-relaxometric detection can be used.
Especially suitable for carrying out immune magnetography are magnetic labelings, which are biodegradable and compatible. This is especially true of magnetic labelings, which consist of iron oxides.
To carry out binding-specific magnet-relaxometric detection in vivo, it is necessary that the Brownian relaxation times of the combinations, introduced in the human body, of ferrimagnetic or ferromagnetic substances with structure-specific substances at body temperature in bodily fluids be shorter than the Nxc3xa9elian relaxation times.
In immune magnetography, structure-specific substances are defined especially as all substances that bind specifically to structures of the human body to be identified. Especially suitable are antibodies, antibody fragments, agonists that bind specifically to receptors or their antagonists, specific peptides and proteins, receptors, enzymes, enzyme substrates, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates, or lipoproteins. Among the agonists that bind to receptors, especially cytokines, lymphokines, or endothelins are suitable.
Well suited are all structure-specific substances that have a binding constant in the range of 105-1015 (mol/1)-xe2x88x921. Especially suitable are all structure-specific substances that have a binding constant in the range of 107-1015 (mol/1)xe2x88x921.

Processes and compounds for magnetorelaxometric detection of analytes and their use


A body contact structure which reduce parasitic capacitance and improves body resistance of a device and methods of manufacture. The method includes forming a gate insulator material and gate electrode material on a substrate. The method further includes patterning the gate insulator material and the gate electrode material to form a gate structure having a shape with a first portion isolated from a second portion. The method further includes forming source and drain regions on sides of the first portion and a body contact at a side and under an area of the second portion, and forming an interlevel dielectric within a space that isolates the first portion from the second portion of the gate structure, and over the gate structure, source and drain regions and the body contact.

Silicon-On-Insulator (SOI) technology realizes lower power consumption and higher speed operation, compared to transistors formed in a bulk semiconductor layer. In SOI technology, the source, body, and drain regions of the transistor are insulated from the substrate, which reduces parasitic junction capacitances and eliminates latch-up. However, floating body effects can result when the body of each transistor is left unconnected. The floating body effect causes the transistor's body to "float" to a potential determined by the various leakage currents into the body. This varying body potential can cause adverse floating body effects such as, e.g., drain current "kink"-effect, lower breakdown voltage and lower drain output resistance, which is problematic for analog circuit applications.
In SOI Analog/Mixed/IO circuits, a body contact transistor can be used to eliminate the floating body effect in SOI technology. SOI transistors are formed in a silicon semiconductor layer (SOI) over a buried insulating layer. SOI transistors also include a body formed in the silicon semiconductor substrate and disposed beneath a gate region of the transistor. In a floating-body SOI FET, the body is not externally accessible. Body-contacted SOI transistors also include a body contact for connecting the body of the SOI transistor to a bias potential. For example, SOI transistors generally require connecting a p-type conductivity body, in the case of an n-channel MOSFET, or an n-type conductivity body, in the case of a p-channel MOSFET, to a bias potential.
One method of connecting the body of the SOI transistor to a bias potential is to provide an edge contact to the body using a T-shaped or H-shaped gate poly layout. However, T-shaped and H-shaped gate poly layouts add significant parasitic gate capacitance to the SOI transistor due to the portion of the poly layer not contributing to drive current of the transistor. Additionally, this type of body contact introduces a resistance between the external body contact and the internal body region, which limits the maximum frequency response of the body contact due to RC delay. The body contact also causes additional gate leakage because of the added polysilicon over gate dielectric. Also, as the SOI thickness is scaled down for high performance devices, increased body resistance may reduce the effectiveness of body contact.
Accordingly, there exists a need in the art to overcome the deficiencies and limitations described hereinabove.

Body contact structures and methods of manufacturing the same


A hybrid entity recognition system and accompanying method identify composite entities based on machine learning. An input sentence is received and is preprocessed to remove extraneous information, perform spelling correction, and perform grammar correction to generate a cleaned input sentence. A POS tagger tags parts of speech of the cleaned input sentence. A rules based entity recognizer module identifies first level entities in the cleaned input sentence. The cleaned input sentence is converted and translated into numeric vectors. Basic and composite entities are extracted from the cleaned input sentence using the numeric vectors.

There are a number of requirements and/or preferences associated with utilizing unstructured data. Dealing with unstructured data is pretty complex, as the unstructured data does not have predefined or pre-structured information. This leads to unpredictable and unsolvable conditions with prior systems.
Typically, unstructured data has a great amount of text (e.g., natural language heavy). It is important to understand the semantics and syntax of that text, in order to determine the various entities and its underlying linguistic cause.
Prior systems may recognize basic level entities (e.g., names of persons, organizations, locations, expressions of times, quantities, etc.) Prior systems are not accurate because they do not determine the context, semantics and syntax at the same time during entity recognition. Prior systems struggle recognizing second level entities (e.g., credit amount and debit amount that are both similar entities that belong to same class "amount").

Method and system for hybrid entity recognition


A doorway with anti-bubbling sill drain includes spaced vertical side jambs, a head jamb, and a substantially hollow contain-and-drain sill, all of which form a frame. The sill has an outside nosing provided with weep holes and weep doors and a threshold portion that directly underlies a closed door mounted in the frame. A drain insert is mounted within an oblong hole in the threshold portion of the sill for allowing water collected on the threshold portion to drain into the sill and for allowing air within the sill to vent. The drain insert has a top cover, from the end portions of which a pair of drains depend. The tops of the drains are spaced from the underside of the top cover to form drain entrances. An open vent space is formed between the two drains and terminates at its upper extent in drain holes formed through the top cover. When installed, the drains extend down into the interior of the sill with the drain entrances being flush with the floor of the threshold portion. Water on the threshold portion drains into the drain entrances and through the two drains into the sill while air escaping from within the sill vents through the separate vent space and vent holes above. Percolation and bubbling at the drain location is thus eliminated.

Entry doors, patio doors, and the like generally include a pair of spaced vertical side jambs, a head jamb or header extending between the upper ends of the side jambs, and a door sill extending between the bottom ends of the side jambs. Hinged or sliding door panels are mounted within the resulting frame and, when closed, directly overly a threshold portion along the inside of the sill. Many hinged entry doors open into a building in which they are mounted and thus are know as in-swing doors. A variety of sill configurations are available for use with entry doors including wooden sills, aluminum sills, plastic sills, composite sills, and the like.
One type of sill used for entry doors is known as a "contain-and-drain" sill. In general, a contain-and-drain sill typically is extruded from plastic or a composite material and is generally hollow inside with, perhaps, some longitudinal support ribs, which form chambers inside the sill. Openings are formed in the support ribs communicating between adjacent chambers. The ends of the sill are sealed with an end cap and one or more weep holes, which may be provided with weep doors or flaps, are formed along the outside nosing of the sill communicating between its hollow interior and the outside.
Under various conditions, water can collect on the threshold portion of the sill beneath a closed door. For example, rainwater can leak past the weather seals or snow from shoes can be deposited on the sill and melt. In order to manage this water, it is known to provide one or more drains in the threshold portion of the sill through which water can drain into the hollow interior of the sill. Once contained within the interior of the sill, the water can drain out of the sill through the weep holes formed along its outside nosing. Such drains also function as vents that help to equalize pressure differentials between the outside of a doorway and the inside of a building and vent air displaced by rising water in the sill.
A major problem with contain-and-drain sills can arise when it rains in high wind conditions, i.e. when the doorway is under high "DP" loads. The high winds can raise the air pressure on the exterior of a doorway relative to the interior of the doorway, thus creating a partial vacuum within the hollow interior of the sill. As used herein, the term "partial vacuum" means that there exists a negative pressure differential between the outside of the doorway and the hollow interior of the door sill. The partial vacuum, in conjunction with rain water that tends to build up around the sill, can cause air and water to be sucked through the weep holes into the interior of the sill, which can begin to fill with water and bubbles. The water generally rises until the head of water within the sill equals the pressure differential between the outside and inside of the doorway.
As the water level rises within the sill, the air that is displaced by the water, as well as air being sucked into the sill by the partial vacuum, must escape the sill and generally does so through the drains in the threshold portion of the sill. Often, and particularly in driving rains, there is collected water in the threshold portion, which is draining into the interior of the sill through the drains. The simultaneously escaping air through these drains causes percolation and bubbling of the water at the locations of the drains. Even when there is no collected water on the threshold portion of the sill, percolation and bubbling can still occur as a result of bubbles that develop within the sill due to the mixture of water and air being sucked in.
Bubbling and percolation at the drains can result in water leakage into a dwelling, which can cause damage and can cause a doorway to fail to meet building standards for water resistance. It has been known to add vents up the side jambs or in some other remote area of the door unit through which air in the sill can escape. However, it is not always possible to vent to a remote location and, when it is not, venting commonly occurs through the drains resulting in bubbling. Even when air is vented remotely, the result may not always be completely satisfactory.
A need therefore exists for a doorway with a contain-and-drain sill that effectively contains and allows water to rise within the sill under high wind load conditions without percolation and bubbling of the water and air at drain locations. A further need exists for such a doorway that drains water effectively into the interior of the sill from the threshold portion of the sill without percolation or bubbling occurring at the drain site. It is to the provision of such a doorway that the present invention is primarily directed.


Engineered CRISPR from Prevotella and Francisella 1 (Cpf1) nucleases with improved targeting range and enhanced on-target activity, and their use in genomic engineering, epigenomic engineering, base editing, genome targeting, genome editing, and in vitro diagnostics.

CRISPR-Cas Cpf1 nucleases (also referred to as Cas12a nucleases) have recently been described as an alternative to Cas9 nucleases for genome editing applications (Zetsche et al. Cell 163, 759-771 (2015); Shmakov et al., Mol Cell. 2015 Nov. 5; 60(3): 385-97; Kleinstiver et al., Nat Biotechnol. 2016 August; 34(8): 869-74; Kim et al., Nat Biotechnol. 2016 August; 34(8):863-8). Cpf1 nucleases possess a number of potentially advantageous properties that include, but are not limited to: recognition of T-rich protospacer-adjacent motif (PAM) sequences, relatively greater genome-wide specificities in human cells than wild-type Streptococcus pyogenes Cas9 (SpCas9), an endoribonuclease activity to process pre-crRNAs that simplifies the simultaneous targeting of multiple sites (multiplexing), DNA endonuclease activity that generates a 5′ DNA overhang (rather than a blunt double-strand break as observed with SpCas9), and cleavage of the protospacer DNA sequence on the end most distal from the PAM (compared with cleavage at the PAM proximal end of the protospacer as is observed with SpCas9 and SaCas9). To date, Cpf1 orthologues from Acidaminococcus sp. BV3L6, Lachnospiraceae bacterium ND2006, and Francisella tularensis subsp. novicida U112 (AsCpf1, LbCpf1, and FnCpf1 respectively), are the only orthologues that have been described to robustly function in human cells. Despite these capabilities, Cpf1 nucleases have been adopted less rapidly for genome editing compared to SpCas9. One potential reason could be the requirement for a longer PAM that constrains targeting to roughly once in every 43 bps of random DNA sequence, compared to once in every 8 bps for SpCas9.
Here we addressed this targeting range limitation by utilizing a structure-guided engineering approach to generate AsCpf1 variants with not only greatly expanded targeting range, but also substantially improved on-target activities. In addition to improved potency and versatility as nucleases for genome editing, we demonstrate that these variants can be leveraged for other applications including multiplex nuclease targeting, epigenome editing, C-to-T base-editing, and Cpf1-mediated DNA detection, all at levels not previously possible with wild-type AsCpf1.

Variants of Cpf1 (Cas12a) with altered PAM specificity


A wireless device according to the present invention minimizes the need for changing a communication route in an ad hoc network including wireless devices used for base stations, fixed stations, and mobile stations that are turned on/off or moved, wherein, when wireless devices cannot directly send or receive radio waves, data can be transmitted between them by relaying data via other wireless devices that can directly send or receive radio waves (multi-hopping). In selecting a communication route, a communication route that includes wireless devices that are turned off or moved least frequently is selected.

The present invention relates to a wireless device, a control method for a wireless communication system, and a wireless communication system.
A recent advance in the information communication technology has resulted in the development of many electrical appliances with the network communication function. Those electrical appliances, used in the home or offices, have computerized houses and buildings, leading to the development of a technology for providing more convenient, comfortable living environments.
On the other hand, connecting those electrical appliances to a network requires network construction work in the home and buildings, and the network construction work requires technical knowledge about the communication cable wiring and connections as well as hard work and high construction costs. Therefore, there is a need for building a network without doing network construction work.
To satisfy this need, a wireless network technology has been developed. This network technology uses the wireless communication method and allows wireless devices, which cannot directly communicate each other, to communicate via intermediary relay devices (wireless devices that relays communication), thus enabling a plurality of wireless devices to communicate each other with no need to do the network construction work. Such a wireless network, generally called an ad hoc network, is a network where data communication among wireless devices, including base stations, fixed stations, and mobile stations, is performed via a plurality of intermediary wireless devices. The following technologies are disclosed as a technology for building a network where data is relayed via wireless devices (For example, see JP-A-11-239176, JP-A-2003-115858).
In an ad hoc network, the selection of a communication route composed of wireless devices, along which data is passed during the communication, largely affects the throughput and the reliability of the whole network system and the ease of system management. Therefore, the technology for selecting and determining the best communication route is important.
The most popular conventional method for selecting and determining the best communication route from a plurality of communication routes is to select a communication route with the minimum number of hops (the number of intermediary relay devices).
However, when an intermediary relay device moves from one place to another or the power is turned off after a communication route is determined, the communication route using the intermediary relay device cannot be used. As a result, the source wireless device using this intermediary relay device as one of intermediary relay devices of the communication route must search for another communication route to the destination wireless device again.
In general, this communication route search is complex and time-consuming. Another problem is that, immediately after an intermediary relay device moves or the power is turned off, a data packet being transferred is stored in the buffer of the intermediary relay device until a new destination is found. When the buffer of the intermediary relay device becomes full, a packet loss may occur.
Searching for a new communication route also requires the transmission of many data packets and, therefore, more packets tend to be lost due to an increase in the traffic. A packet loss also involves the frequent retransmission of a packet at an application level, meaning that more and more wasteful data packets are generated.
Therefore, in such a network, it is important to select a route that does not require a repeated search for a route.

Wireless device, method for wireless communication system, and wireless communication system


A hand-held tool for terminating connectors onto a coaxial cable has an elongated body and an end stop and plunger on the body, the plunger being controlled by a lever arm which will axially advance the plunger toward and away from the end stop to radially compress a portion of the connector into firm crimping engagement with the end of the coaxial cable. To accommodate different lengths of connectors, a receiver is mounted on the plunger for insertion of different length adapter tips to vary the axial spacing between the receiver and the end stop according to the length of connector being terminated; and in still another form the body may include a hinged adapter adjacent to the end stop to vary the effective distance between the end stop and plunger according to the length of fitting being terminated.

This application relates to crimping tools, and more particularly relates to a novel and improved hand-held crimping tool for crimping different types and lengths of connectors onto coaxial cables in a simplified and highly effective manner. In the hereinbefore referred to U.S. Letters Patent for LENGTHWISE COMPLIANT CRIMPING TOOL, a hand-held crimping tool is automatically adjustable to compensate for slight differences in length of coaxial cable fittings, such as, differences resulting from manufacturing tolerances, dirt or wear. In that tool, the coaxial cable fitting is inserted into a seat on a die portion so that the cable end is in facing relation to a plunger. The plunger has a chuck and spring-loaded biasing member at one end in facing relation to the die portion, and a crimpable connector is loosely assembled on the cable end between the biasing member and seat so that when the plunger is advanced toward the seat it will force a preassembled crimping ring on the connector to radially compress the connector into sealed engagement with the cable end. Thus, the spring-loaded biasing member will absorb any continued movement of the chuck after the crimping ring contracts the connector to its maximum limit onto the cable end and automatically compensate for slight differences in effective length of the connector end.
Previously, in U.S. Pat. No. 5,435,167 for CABLE END COMPRESSOR, assigned to the assignee of this invention, a hand-held tool is disclosed for terminating different length and type cable end connectors and specifically adapted for terminating RG59 and RG6 coaxial cables. This tool is characterized by utilizing a hinged spacer which can be pivoted into position in front of an end stop on the tool to alter the effective length or distance between the spacer and plunger. For example, the spacer has a thickness equal to the difference in length between the RG59 connector and the RG6 connector, although a different type of compression member is employed than in the LENGTHWISE COMPLIANT CRIMPING TOOL. Accordingly, in a modified form of invention, it is proposed to incorporate a hinged spacer as hereinbefore described in combination with different extension tips in terminating different length coaxial cable connectors.
There is a continuing need for a crimping tool which is more versatile and capable of handling different sizes and lengths of connectors including but not limited to the RG59, RG6, RCA, BNA and IEC connectors. In addition, it is highly desirable to simplify the crimping operation by applying an axially directed force to a sleeve portion of the connector which receives the cable end in such a way as to impart radial compression to the connector into crimping engagement with the cable end.


A system for improved emissions performance of a power plant generally includes an exhaust gas recirculation system having an exhaust gas compressor disposed downstream from the combustor, a condensation collection system at least partially disposed upstream from the exhaust gas compressor, and a mixing chamber in fluid communication with the exhaust gas compressor and the condensation collection system, where the mixing chamber is in fluid communication with the combustor.

Gas turbines are widely used in industrial and power generation operations. A typical gas turbine may include a compressor section, a combustor downstream from the compressor section, and a turbine section downstream from the combustor. A working fluid such as ambient air flows into the compressor section where it is compressed before flowing into the combustor. The compressed working fluid is mixed with a fuel and burned within the combustor to generate combustion gases having a high temperature, pressure, and velocity. The combustion gases flow from the combustor and expand through the turbine section to rotate a shaft and to produce work. The combustion gases are then exhausted from the turbine section. In particular gas turbine designs, an exhaust gas recovery system may be positioned downstream from the turbine section.
The compressed working fluid typically contains an excess quantity of oxygen relative to the amount of oxygen required to support the combustion process. As a result, flame temperatures within the combustor may be elevated, thereby increasing thermal stresses within the combustor and/or the turbine section of the gas turbine. In addition, elevated flame temperatures may produce various undesirable emissions, including but not limited to, nitrous oxides (hereinafter NOx), and may also produce other inert components such as nitrogen and water vapor within the exhausted combustion gases.
Typical hydrocarbon fuels used to power modern gas turbines generally include natural gas and oil. However, the supply of hydrocarbon based fuels is generally limited as a non-renewable resource. As a result, high-hydrogen content fuels such as synthetic gas (herein referred to as "syngas") have been developed as an alternative to the hydrocarbon based fuels. One issue with burning high-hydrogen content fuels, as with burning hydrocarbon based fuels within modern gas turbines, is that undesirable levels of thermal NOx are produced during the combustion process. In addition, the exhaust gases resulting from burning high-hydrogen based fuels contain large concentrations of water vapor.
Various methods are known in the art for reducing the flame temperature and/or the production of NOx within the combustor. One known method includes decreasing the oxygen content of the compressed working fluid prior to combustion by capturing at least a portion of the combustion exhaust gases flowing from the turbine section which have a lower oxygen level than the compressed ambient air entering the compressor, and recirculating the exhaust gas into the compressor and/or into the combustor. As a result, the high oxygen content of the compressed working fluid may be diluted with the low oxygen content exhaust gases, while still providing sufficient oxygen in the working fluid to the combustor in order to support combustion. Other known methods for decreasing the flame temperature and/or reducing NOx production include injecting various diluents such as water or steam into a combustion zone within the combustor.
Although known methods for reducing flame temperatures within a gas turbine are somewhat effective, the allowable levels of emissions such as, but not limited to, NOx that may be emitted by a gas turbine continue to be heavily regulated. Therefore, an improved system and method for further reducing flame temperatures and/or emissions such as NOx within a gas turbine, in particular in gas turbines that burn high-hydrogen fuels would be useful.


A method for measuring geometric errors of a numerical control turntable based on a four-station laser tracer system includes: establishing a self-calibration coordinate system and calibrating positions of tracking interferometers; respectively placing each of target lenses at three non-coplanar points that are above the numerical control turntable and keep certain distances from the numerical control turntable, controlling the numerical control turntable to rotate at a certain angular interval θj, and based on positions of the tracking interferometers being known after calibration, solving coordinates of each of measurement points in the self-calibration coordinate system using a non-linear least square method; establishing a turntable coordinate system; perform a conversion between the turntable coordinate system and the self-calibration coordinate system; separating six geometric errors of the numerical control turntable using spatial position errors of the three points at a same position and using the linear least squares method.

With the continuous development of modern manufacturing and national defense industry, precision and ultra-precision machining and manufacturing technology have increasing demands for high-end multi-axis numerical control machine tools with ultra-high-precision rotation axes, especially in the field of large-aperture optical free-form surface components required for national defense such as inertial confinement nuclear fusion, ground observation, lidar, EUV lithography. The geometric precision of the rotation axis directly affects key optical performance of large processed optical lenses, such as axis position, surface-shape accuracy, and surface roughness. In addition, it has more stringent requirements on the geometric precision and performance of the rotation axis of the numerical control machine tool when using off-axis to process large-aperture optical components.
Commonly used measurement methods of geometric errors of the rotation axis mainly include a laser interferometer measurement method and a ballbar measurement method. The laser interferometer measurement method is mostly used to measure positioning errors of a turntable, and it is difficult to adjust an optical path in the measurement process, and the adjustment is extremely dependent on operating skills of an operator. Thus, the laser interferometer measurement method has a relatively low measurement efficiency. The ballbar measurement method requires installation for many times to achieve separation of the geometric errors, and eccentricity needs to be adjusted in a test process, which takes a lot of time to adjust and has a relatively small test range and a relatively low measurement accuracy.

Measurement method for geometric errors of numerical control turntable based on four-station laser tracer system


A high-pressure fluorescence flow cell comprises a cell body made of a light-transmissive material, wherein the cell body is penetrated by a straight-line flow path for a high-pressure fluid, wherein the flow path is formed with a cross section of 0.1 mm2 to 5 mm2, both inclusive, orthogonal to its longitudinal direction, wherein the ratio t/d of the wall thickness t (mm) to the width d (mm) of the flow path satisfies formula (1) below,

1. Field of the Invention
The present invention relates to high-pressure fluorescence flow cells, assemblies thereof, fluorescence detectors using the high-pressure fluorescence flow cells, and supercritical fluid chromatographs.
2. Description of the Related Art
Supercritical Fluid Chromatograph
Supercritical fluid chromatographs (SFCs) and subcritical fluid chromatographs using carbon dioxide (CO2) as the mobile phase have attracted attention as separation-analysis apparatuses and separation-purification apparatuses that can replace liquid chromatographs (LCs), which utilize an organic solvent. Thanks to the low viscosity and high diffusion coefficient of the fluid utilized as the mobile phase, SFCs can perform quick analysis by increasing the flow velocity without decreasing the column efficiency.
SFCs can be divided broadly into two categories depending on the type of column used. The SFCs utilizing a packed column use techniques developed for liquid chromatographs (LCs), and the SFCs utilizing a capillary column use techniques developed for gas chromatographs (GCs). Since packed-column SFCs developed from LCs are easy to handle and their separation technology is extensible, they have been used to analyze a variety of samples and have been finding a broader range of applications. SFCs are used to separate optical isomers and cc separate polymer oligomers in polymer chain units, are environmentally friendly, and have low running costs. SFCs require a few aftertreatment steps for eliminating the solvent and are suitable for easily-oxidizable material and heat-labile material. In recent studies, SFCs have found wide applications, including separation of achiral matter.
Such separation-analysis apparatuses have also attracted attention from the perspective of environmental conservation. There seems to a tendency to shift from liquid chromatographs (LCs) to supercritical fluid chromatographs (SFCs).
Detectors for Supercritical Fluid Chromatographs
Detectors used for supercritical fluid chromatographs (SFCs) include ultraviolet-visible (UV-VIS) absorbance detectors, evaporative light scattering detectors (ELSDs), and mass spectrometers (MSs). Some of the detectors, such as ultraviolet-visible absorbance detectors, require an optical flow cell. The flow cell for SFCs must have high pressure resistance because the inner pressure reaches 10 MPa or higher.
Fluorescence Detectors
Fluorescence detectors (FLDs) for detecting fluorescence (including phosphorescence) of excited sample constituents also require an optical flow cell, FLDs are used with liquid chromatographs (LCs). The conventional fluorescence detectors have a rectangular flow cell made of silica glass, for example. The sample constituents separated in the column of the LC are introduced successively into the flow cell together with a mobile phase For example, the sample constituents are introduced into the rectangular flow cell from the bottom, travel through an internal flow path, and are drawn out from the top of the flow cell. While they are in the flow path, the sample constituents are irradiated with excitation light from one side of the flow cell. When fluorescence is produced in the sample constituents, the fluorescence is detected in a direction perpendicular to the irradiation direction of the excitation light.
In general separation and analysis of a sample by using a chromatograph, it is important to reduce the volume of the cell to prevent the sample constituents separated in the column from diffusing in the flow cell. For example, low-volume flow cells have been formed by fusing four light-transmissive members made of silica glass into a hollow prismatic shape, as disclosed in Patent Literature 1. By minimizing the cell volume, diffusion of the sample constituents in the cell can be suppressed, and consequently peaks in the detected chromatogram can be sharpened.
In order to prevent the minimized cell volume from lowering the sensitivity of the fluorescence detector, a flow cell configured so allow internal sample constituents to be irradiated efficiently with as much excitation light as possible is used. If the sample is irradiated with excitation light in a direction perpendicular to the flow path of the cell, as the cross section of the flow path in the cell decreases, the optical path length of the cell inevitably decreases. For example, the flow cell disclosed in Patent Literature 2 is configured to direct excitation light parallel to the direction of the flow path. A long optical path length is kept to produce a large amount of fluorescence.

High-pressure fluorescence flow cell, flow cell assembly, fluorescence detector, and supercritical fluid chromatograph

Abstract: t          d                ≧                              1            2                    ×                      [                                                                                σ                    +                    P                                                        σ                    -                    P                                                              -              1                        ]                    ×          1.5                                    (        1        )            where σ indicates the tensile stress (MPa) of the material of the cell body, and P indicates the withstand pressure (MPa) of the cell body.


A lamp ignition circuit provides a high voltage electrical pulse to ignite a gas discharge lamp. A non-linear filter element within a charge circuit regulates the voltage of the ignition pulse such that the ignition pulse remains within a prescribed voltage range over a wide variety of conduit lengths between the lamp and the lamp ignition circuit. This allows for the ballast and lamp ignition circuit to be mounted either close to the lamp or far from the lamp without modifying the ignition circuitry.

This invention relates generally to ballasts used to power gas discharge lamps. More particularly, this invention pertains to circuits used in conjunction with a magnetic ballast to ignite a gas discharge lamp.
Gas discharge lamps require a high voltage pulse of electricity for ignition. The design of the lamp determines the voltage requirements for the ignition pulse, and there is typically a minimum and maximum voltage requirement for the ignition pulse. After a gas discharge lamp is ignited, the lamp presents a negative resistance. Therefore, a ballast is used to control and limit the amount of current going to the lamp after ignition. In many commercial lighting environments, the ballast and ignition circuit (sometimes referred to as a "starter" circuit) are connected to the lamp using electrical wires placed in a conduit. This arrangement creates a parasitic capacitance which increases with increased conduit length. The larger the parasitic capacitance, the greater the load affecting the amplitude of an ignition pulse from a lamp starter circuit. The conduit length actually installed in the field is variable, so the amount of parasitic capacitance associated with the conduit is variable. A starter circuit which can simply and reliably provide ignition pulses having a voltage within the prescribed range over a wide variety of conduit lengths is desirable.
Many circuits have been developed to deliver ignition pulses to lamps over varying starter-circuit-to-lamp conduit lengths. For example, U.S. Pat. No. 6,522,088 describes a starter circuit having a voltage clamping device connected between the two leads to the lamp. The ballast circuitry is capable of generating an ignition pulse having a voltage in excess of the prescribed range for the lamp. Due to the higher voltage of the ignition pulse, a longer conduit length between the lamp and the ballast circuitry is possible. If the longer length is used, the parasitic capacitance reduces the voltage of the ignition pulse to within the prescribed range. The voltage clamping device has an impedance which varies with voltage such that if the voltage exceeds the clamping voltage, the impedance drops and thereby lowers the voltage of the ignition pulse delivered to the lamp. The voltage clamping device is typically comprised of two varistors connected in series wherein the combined clamping voltage of the two varistors is near the maximum voltage acceptable for the lamp. Unfortunately, using a clamping device in the starting circuit adds cost which is disadvantageous in the highly competitive lighting industry. Also, the clamping device may be required to dissipate significant energy when clamping high voltage ignition pulses. This decreases reliability of the device.
Publication No. JP2005251722 describes a device having a second starting device positioned close to the lamp when the conduit length between the first starting device and the lamp is long. When the conduit between the first starting device and the lamp is short, a second starting device is not used. This provides for a wider range of acceptable conduit lengths between the first starter device and the lamp.
U.S. Pat. No. 6,396,220 describes circuitry with a first and a second reactive energy source. The first reactive energy source generates ignition pulses for longer conduit lengths, and the second reactive energy source generates ignition pulses for shorter conduit lengths. A switch is provided so that either the first or the second reactive energy source is utilized. There are several embodiments wherein different components of the ignition circuitry are switched on and off, but in all embodiments a switch is used to select between components which generate ignition pulses having different voltages.
In the highly competitive field of lighting electronics cost and reliability are important considerations. Costs can be reduced by using fewer components and/or using components designed for lower voltages. Also, as a general rule, the fewer components used, the more reliable the system. Therefore, a system using fewer components and/or components designed for lower voltage is preferred.

Lamp circuit with controlled ignition pulse voltages over a wide range of ballast-to-lamp distances