The disclosures herein relate to novel compounds of formula

Glutamate is the major excitatory neurotransmitter in the brain. Glutamate exerts its actions through both ionotropic and metabotropic glutamate receptors. There are eight metabotropic glutamate (mGlu) receptors belonging to the class C G protein-coupled receptor (GPCR) family. The eight mGlu receptors can be further divided into three groups based on their sequence similarity, pharmacological profiles and transduction mechanisms. The mGlu1 and mGlu5 receptors belong to group I; these receptors are primarily located post-synaptically and couple through the Gq/11 pathway. Group II is comprised of mGlu2 and mGlu3 receptors and group III of mGlu4, mGlu6, mGlu7 and mGlu8 receptors; both group II and group III receptors are located pre-synaptically and primarily couple through Gi/o. The mGlu receptors are composed of three distinct regions; the extracellular (Venus fly-trap domain), transmembrane and intracellular regions. Glutamate binds to the extracellular site. Modulators bind to the transmembrane domains where they can act to enhance (positive allosteric modulators or PAMs) or decrease (negative allosteric modulators or NAMs) the activity of glutamate. The mGlu receptors are involved in the fine tuning of neuronal responses and changes in glutamatergic signalling have been implicated in a wide range of disease processes in humans and other species (e.g. see Yasuhara and Chaki, The Open Medicinal Chemistry Journal, 2010, 4, 20-36). Thus modulating the activity of glutamatergic signalling may be efficacious in the treatment of a variety of neurological and psychiatric disorders.
The present invention relates to modulators of metabotropic glutamate receptors, in particular the mGlu5 receptor. The mGlu5 receptor is abundant throughout the cortex, hippocampus, striatum, caudate nucleus and nucleus accumbens, areas involved in emotion, motivational processes and cognitive function. Compounds that act at the mGlu5 receptor have utility in treating, preventing, ameliorating, controlling or reducing the risk of multiple conditions; those of particular importance include one or more of the following: dementia (including senile dementia and dementia caused by AIDS), pain (including headaches (such as migraine and cluster headaches), inflammatory pain (such as inflammatory tongue pain), visceral pain syndromes (such as painful bladder syndrome), gastro-intestinal pain (including irritable bowel syndrome), itch, fibromyalgia, disorders of the urinary tract (including incontinence, prostatitis, urinary frequency, nocturia, overactive bladder, cystitis, benign prostatic hyperplasia, detrusor hyperreflexia, outlet obstruction, urinary urgency, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, idiopathic bladder hypersensitivity), substance-related disorders (including addiction, alcohol abuse, alcohol dependence, alcohol withdrawal, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, opioid dependence, opioid withdrawal), anxiety disorders (including agoraphobia, generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), panic disorder, post-traumatic stress disorders, social and specific phobias, substance-induced anxiety disorder), eating disorders (including obesity, anorexia and bulimia), attention-deficit/hyperactivity disorder (ADHD; ADD), deficits and abnormalties in attention and vigilance, executive functions and memory, movement disorders (including Parkinson's disease, levodopa-induced dyskinesias, Tourette's syndrome, Huntington's disease, dystonias, restless leg syndrome, simple tics, complex tics and symptomatic tics, periodic limb movement syndromes), amyotrophic lateral sclerosis (ALS), multiple sclerosis, schizophrenia, cancer (including melanoma, squamous cell carcinoma and astrocytoma), mood disorders (including major depressive disorder, dysthymia, treatment-resistant depression and bipolar disorders I and II), rare neurological diseases including inherited diseases and developmental disorders (including autistic spectrum disorders [Asperger's syndrome, Rett's syndrome, Pervasive Development Disorder Not Otherwise Specified, Childhood Disintegrative Disorder] and Down's syndrome), fragile X syndrome and other areas of mental retardation, disorders of the gastro-intestinal tract (including gastroesophageal reflux disease, functional dyspepsia, functional heartburn, irritable bowel syndrome, functional bloating, functional diarrhoea, chronic constipation, post-operative ileus), epilepsy, retinopathy, neuroprotection (including Alzheimer's disease, stroke, status epilepticus and head injury), ischemias (including cerebral ischameia especially acute ischemia, ischemic diseases of the eye), muscle spasms (such as local or general spasticity), autoimmune disorders of the nervous system including paraneoplastic syndromes, spinal muscular atrophy, vomiting, skin disorders and any other disorders associated with irregularities of glutamatergic signal transmission.
It has been suggested that the glutamatergic system is a mediator of psychiatric pathology and that, potentially, it is a common pathway for therapeutic action of antidepressant medications (Sanacora et al., Neuropharmacology, 2012, 62, 63-77). The mGlu5 receptor is located on GABAergic interneurones in the hippocampus and prefrontal cortex; inhibition of mGlu5 on these neurones may lead to the disinhibition of intermediate interneurones, ultimately resulting in a decrease in glutamatergic transmission (Chaki et al., Neuropharmacology, 2012, 66, 40-52). It has been shown that acute administration of an mGlu5 NAM (GRN-529) is efficacious in reducing depression (decreasing mobility time in tail suspension test and forced swim test), anxiety (by attenuation of stress-induced hyperthermia) and pain (reversal of hyperalgesia due to sciatic nerve ligation) (Hughes et al., Neuropharmacology, 2012, 66, 202-214). mGlu5 modulators may therefore be useful in the treatment of depression, anxiety and other mood disorders and pain.
Activity of mGlu5 antagonists/NAMs as analgesics has been demonstrated in models of inflammatory pain. In the Complete Freund's adjuvant-injected tongue (a model of inflammatory tongue pain) a selective mGlu5 antagonist significantly depressed mechanical allodynia and heat hyperalgesia whilst continuous intrathecal administration of a selective mGlu5 agonist induced allodynia in naive rats (Liu et al., Journal of Neuroinflammation, 2012, 9:258). NAMs and antagonists of the mGlu5 receptor may have efficacy in reducing visceral pain syndromes. For example, in painful bladder syndrome (a type of visceral pain syndrome) the pharmacological activation of mGlu5 receptors in the central nucleus of the amygdala (a critical site for neuromodulation for processing of bladder nociception) has been shown to lead to increase the response to bladder distension that drives bladder pain sensitization (Crock et al., Journal of Neuroscience, 2012, 32, 14217-14226). Glutamate receptors are distributed in pain relay structures with glutamate having a key role in trigeminovascular activation, central sensitization and cortical spreading depression (CSD); areas that are important for migraine and cluster headache pathophysiology (Monteith & Goadsby, Current Treatment Options in Neurology, 2011, 13, 1-14). A specific role of mGlu5 in central sensitisation was demonstrated by the induction of long-term potentiation in the superficial layer of the trigeminal nucleus caudalis by electrical stimulation of the mandibular nerve by the mGlu5 agonist CHPG which was selectively blocked by the mGlu5 NAM MPEP (Liang et al, Pain, 2005, 114, 417-428).
The mGlu5 receptor plays a critical role in behavioural responses to multiple substances of abuse and may therefore have a role in the treatment of substance abuse related disorders. The mGlu5 receptor is located in brain regions thought to participate in reward-related behaviours such as the bed nucleus of the stria terminalis. Acute pharmacological antagonism of the mGlu5 receptor has been shown to disrupt the reinforcing properties of, for example, pyschostimulants (e.g. cocaine; Grueter et al., The Journal of Neuroscience, 2008; 28, 9261-9270), alcohol (Blednov and Harris, The International Journal of Neuropsychopharmacology 2008, 11, 775-793) and nicotine (Palmatier et al., Neuropsychopharmacology 2008, 33, 2139-2147).
Benzodiazepines are generally regarded as effective anxiolytics but suffer from dose-limiting side effects including sedation, memory impairment and abuse whilst selective-serotonin re-uptake inhibitors suffer from long onset of action. The mGlu5 receptor is expressed in several brain regions associated with anxiety and may play a role in treatment of anxiety disorders. The mGlu5 NAM fenobam was demonstrated to have anxiolytic effects in multiple animal models (stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, conditioned emotional response test) (Porter et al., The Journal of Pharmacology and Experimental Therapeutics, 2005, 315, 711-721). The mGlu5 NAM fenobam also showed efficacy in phase II trials of generalized anxiety disorder (GAD).
Proton spectroscopy has shown an increase in glutamatergic resonance in the right prefrontal cortex and left striatum in attention deficit hyperactivity disorder (ADHD) children compared to healthy controls, with the resonance in the prefrontal cortex correlating with age of onset of ADHD symptoms (MacMaster et al, Biological Psychiatry, 2003, 53, 184-187). Copy number variant association analysis in patients with ADHD have shown variations in the gene encoding the mGlu5 receptor (GRM5) and other glutamatergic signalling pathway genes (Elia et al., Molecular Psychiatry, 2010, 15, 637-646). This suggests that alteration in glutamatergic signalling via mGlu5 antagonism or negative allosteric modulation may be a treatment strategy for ADHD/ADD.
The substantia nigra is a key nucleus in the basal ganglia motor circuit playing a key role in motor function. The mGlu5 receptor is involved in direct excitation of substantia nigra neurones which increase firing frequency and burst-firing activity (Awad et al., Journal of Neuroscience, 2001, 20, 7891-7879). The substantia nigra is the primary site of pathology in a number of movement disorders including Parkinson's disease (PD), Tourette's and Huntington's disease. PD is characterised by the loss of dopamine producing neurones in the substantia nigra. Current treatments for PD include levodopa therapy to counteract the loss of dopamine, although this treatment leads to the development of levodopa-induced dyskinesias (LID). There are two types of dyskinesia, chorea (rapid uncontrolled movements) and dystonia (slow writhing movements). The loss of dopaminergic neurones in the striatum causes an increase in the glutamatergic output from the substantia nigra. Antagonism of the mGlu5 receptor is clinically validated in reducing PD-LID, showing a clinically relevant and significant anti-dyskinetic effect without changing anti-parkisonian effects of dopaminergic therapy and may be useful in the treatment of other movement disorders. Antagonists or negative allosteric modulators of mGlu5 also have the potential to treat anxiety and depression which are high co-morbidities in PD. Studies with the mGlu5 NAM dipraglurant shows efficacy in reversing both chorea and dystonias and dipraglurant is reported to be entering clinical trials as a treatment for other rare dystonias.
In Huntington's disease and Tourette's syndrome there is a decrease in activity in the substantia nigra hence agonists and PAMs of mGlu5 are of interest as therapeutic treatments in these disease settings. In a mouse model of Huntington's disease mGlu5 PAMs were shown to be neuroprotective, protecting striatal neurones from excitotoxic cell death (Doria et al., British Journal of Pharmacology, 2013, 169, 909-921).
Positive allosteric modulators of the mGlu5 receptor may be useful in treatment of positive and negative symptoms of schizophrenia, and have been shown to have anti-psychotic effects in rat behavioural models (Kinney et al., The Journal of Pharmacology and Experimental Therapeutics, 2005, 313, 199-206). The mGlu5 receptor synergistically facilitates NMDA receptor function and mGlu5 PAMs are in pre-clinical trials for the treatment of schizophrenia.
The mGlu5 receptor has been implicated in the growth and migration of many types of non-neuronal cancers including squamous cell carcinoma (Park et al., Oncology reports, 2007, 17, 81-87) and melanoma (Choi et al., PNAS, 2011, 108, 15219-15224) and therefore modulators of mGlu5 may play a role in the treatment of cancer.
Fragile X syndrome (FXS) is a monogenic disease that causes reduction in the levels of fragile X mental retardation peptide 1 (Fmrp1). Fmrp1 works in functional opposition to mGlu5; reduction in Fmrp1 leads to increased mGlu5 signalling. There is good pre-clinical evidence that FXS can be modified by pharmacological intervention; in mouse models (Fmr1 knock-out) symptoms and neuropathology of FXS can be rescued by mGlu5 antagonism (Michalon et al., Neuron, 2012, 74, 49-56) and the mGlu5 negative allosteric modulator (NAM) mavoglurant has been evaluated in phase III clinical trials for the treatment of FXS. FXS is the highest known risk factor for developing autistic spectrum disorders. Under the DSM-IV classification autistic spectrum disorders (ASDs) include autism, Asperger's syndrome, Pervasive Developmental Disorder—Not Otherwise Specified, Rett's syndrome and childhood Disintegrative Disorder. ASDs are characterised by impairments in social interaction, communication and language development and the presence of restricted interests or repetitive behaviours. Hyperactivity in glutamatergic signalling has been implicated in ASDs suggesting mGlu5 antagonism may be therapeutically beneficial for treatment of ASDs.
The most common neurological abnormality in FXS is epilepsy. There is long lasting functional enhancement of group I mGlu receptors in models of epilepsy such as the amygdala-kindled rat (Tang et al., Current Neuropharmacology, 2005, 3, 299-307). mGlu5 receptor negative allosteric modulators have been shown to block seizures in mouse models of epilepsy (Chapman et al., Neuropharmacology, 2000, 39, 1567-1574).
Gastroesophogeal reflux disease (GERD) is frequently caused by transient lower esophageal sphincter relaxation (TLESR), a mechanism thought to be partly regulated by the mGlu5 receptor. A proof-of-concept trial showed a negative allosteric modulator of mGlu5 (ADX10059) had efficacy in the treatment of GERD by significantly decreasing the time with pH4 throughout a 24 h period and reducing the number and duration of symptomatic reflux episodes (Keywood et al., Gut, 2009, 58, 1192-1199).
Selective blockade of the mGlu5 receptor potently protects cultured cortical neurones against NMDA or β-amyloid toxicity and also against neurodegeneration in in vivo models (Bruno et al., Neuropharmacology 2000, 39, 2223-2230). It is widely accepted that amyloid R contributes to the pathogenesis of Alzheimer's disease. The mGlu5 receptor has been shown to be a co-receptor for amyloid R oligomers bound to cellular prion protein to activate the intracellular Fyn kinase (Um et al., Neuron, 2013, 79, 887-902). Activation of the mGlu5 receptor removes the repressive effect of fragile X mental retardation peptide 1 on amyloid precursor protein mRNA translation (a precursor to amyloid 3) (Sokol et al., Neurology, 2011, 76, 1344-1352). The amyloid β-mediated impairment of long term potentiation can be attenuated by co-treatment with mGlu5 NAM MPEP (Wang et al., The Journal of Neuroscience, 2004, 24, 3370-3378), suggesting that mGlu5 negative allosteric modulators may play a role in neuroprotection.
Amyotrophic lateral sclerosis (ALS; also known as motor neurone disease) is a neurological disorder characterised by motor neurone degeneration. Mutations in the superoxide dismutase 1 (SOD1) enzyme have been linked to familial amyotrophic lateral sclerosis. The mGlu5 NAM MPEP has shown efficacy in a mouse model of ALS (hSOD1G93A) with MPEP delaying disease onset, increasing survival and slowing astrocytic degeneration (Rossi et al., Cell Death Differ. 2008, 15, 1691-1800). An up-regulation of mGlu5 expression is seen in ALS spinal cord compared to control (Aronica et al., Neuroscience, 2001, 105, 509-520).

Methods of treatment using 4-(3-cyanophenyl)-6-pyridinylpyrimidine mGlu5 modulators

Abstract: wherein R1, R2, R3 and R4 and n are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of inflammation, neurological or psychiatric disorders associated with modulating mGlu5 receptor function.


Proposed is a coating solution for the formation of an interlayer insulating film of silicon dioxide in the manufacture of various kinds of electronic devices having excellent storage stability and coating workability. The principal ingredient of the coating solution, of which the solvent is preferably a dialkyl ether, is a polysilazane compound modified with a trimethylsilylating agent such as hexamethyl disilazane to such an extent that, in the .sup.1 H-NMR spectrometric diagram, the ratio of the area of the peak assignable to SiH.sub.3 to the total area of the peaks assignable to SiH.sub.1 and SiH.sub.2 is in the range from 0.15 to 0.45. An interlayer insulating film can be formed by coating a substrate with the coating solution, drying the coating layer and baking the dried coating layer at 300.degree. to 800.degree. C. in a moisturized atmosphere. The coating solution optionally contains a trialkyl amine compound as an agent to reduce sublimation of the low molecular weight fractions of the polysilazane compound. The reaction of the trialkyl amine and the polysilazane molecules is completed by keeping the coating layer before drying at a temperature of 25.degree. to 100.degree. C. for at least 1 minute.

The present invention relates to a polysilazane-based coating solution for the formation of an interlayer insulating layer as well as to a method for the formation of an interlayer insulating layer by using the coating solution. More particularly, the present invention relates to a polysilazane-based coating solution for the formation of an interlayer insulating film which is excellent in respect of the storage stability and coating workability and capable of giving an insulating film having denseness and good surface profile and has little problem in safety due to the use of an organic solvent of low toxicity against human body so as to be useful for the formation of an insulating interlayer film in the manufacture of semiconductor devices, liquid crystal display panels and the like as well as to a method for the formation of an interlayer insulating film by the use of the coating solution.
It is sometimes required in the manufacture of various kinds of electronic devices such as semiconductor devices, liquid crystal display panels and the like to form an interlayer insulating film on the surface of a solid substrate. Various coating solutions have been proposed as suitable for the purpose of forming an interlayer insulating film including those coating solutions containing a polysilazane-based resin having high inorganic nature (see Denshi Zairyo (Electronic Materials), 1994, December issue, pages 50-55 and Japanese Patent Kokai 4-341705, 6-73340, 6-128529 and 6-142600).
As compared with conventional coating solutions for interlayer insulation containing an alkoxysilane as the film-forming ingredient, the above mentioned polysilazane-based coating solutions are advantageous and highlighted in recent years by virtue of the outstandingly low content of organic matters in the film-forming ingredient because, in the formation of an insulating film by the process involving coating of the substrate surface with the solution, drying and baking treatment, the amount of the organic constituents lost from the coating layer by thermal decomposition in the baking treatment is very small so that the denseness of the insulating interlayer film is high so much.
The above mentioned polysilazane-based coating solutions, however, are practically not quite satisfactory due to the defects in respects of their low storage stability and irreproducibility of the quality to give interlayer insulating films having reproducibly high denseness and good surface configuration only with difficulties. In addition, sublimation of the polysilazane may take place in the course of the drying and baking treatment usually undertaken at 100.degree. to 300.degree. C. and the sublimates from the coating layer deposit on the inner walls of the baking oven to cause heavy contamination of the oven. Moreover, sublimation of the polysilazane constituents from the coating layer necessarily leads to shrinkage of and crack formation in the coating film. It is presumable that the above mentioned sublimation of the polysilazane constituents is caused by the low molecular weight fractions of polysilazane contained in the polysilazane-based coating solution.
Further, while the organic solvent used for the preparation of the polysilazane-based coating solutions is mostly xylene in view of the relatively high storage stability of the coating solution prepared therewith, xylene is not without safety problems against human health so that it is eagerly desired to replace xylene with another organic solvent of low toxicity but still capable of giving a polysilazane-based coating solution exhibiting good storage stability and coating workability of the coating solution.

Polysilazane-based coating solution for interlayer insulation


A deflecting subassembly 10 for the guided deflection of a band 12 consisting, in particular, of plastic may be provided, in particular, for a strapping machine 16 comprising a strapping subassembly 14, for the purpose of deflecting the band 12 in a region located between a band store 18 and the strapping subassembly 14. The deflecting subassembly comprises a deflecting roller 20, a band-inlet channel 22, which is arranged upstream of the deflecting roller 20, a band-outlet channel 24, which is arranged downstream of the deflecting roller 20, it being possible for the band-inlet channel 22 and the band-outlet channel 24 to be adjusted relative to one another, and an outer, flexible directing member 26 which bridges the interspace between the band-inlet and band-outlet channels 22 and 24, respectively, and is located opposite the outer circumference of the inner deflecting roller 20.

1. Field of Invention
The invention relates to a deflecting subassembly for the guided deflection of a band consisting, in particular, of plastic, in particular for a strapping machine comprising a strapping subassembly, for the purpose of deflecting the band in a region located between a band store and the strapping subassembly.
2. Description of Related Art
If such a deflecting subassembly is inserted, for example, between the strapping subassembly of a strapping machine, which serves for strapping the relevant item which is to be strapped, and a band store provided, for example, in roll form, then, depending on the design, position and/or relative position of the strapping machine and of the band store, it is also possible, in particular, for different band-deflecting angles to be necessary. If the plastic band is guided, for example, over a deflecting roller, this results in correspondingly different angles of wrap. However, the hitherto conventional deflecting subassemblies are usually only suitable for one specific application or a small number of specific applications. Changeover is quite possible, but usually involves relatively high outlay.
The object of the invention is to provide a deflecting subassembly of the type mentioned in the introduction which, with the construction kept as simple as possible, can easily also be adapted, in particular, to different circumstances.
In order to achieve this object, according to the invention, the deflecting subassembly has a deflecting roller, a band-inlet channel, which is arranged upstream of the deflecting roller, a band-outlet channel, which is arranged downstream of the deflecting roller, it being possible for the band-inlet channel and the band-outlet channel to be adjusted relative to one another, and an outer, flexible directing member which bridges the interspace between the band-inlet and band-outlet channels and is located opposite the outer circumference of the inner deflecting roller.
This design allows the deflecting subassembly to be adapted quickly and easily to different circumstances, reliable band guidance always being ensured irrespective of the relative position of the two band channels in each case and irrespective of the angle of wrap via which the band has to be guided over the deflecting roller in each case. Since the directing member is flexible, it is automatically adapted to the relative position of the two band channels in each case, this ensuring optimum bridging of the interspace and correspondingly reliable band guidance in each case.
In a preferred practical embodiment, the flexible directing member is supported on the band-inlet channel by way of one end and on the band-outlet channel by way of its other end. It is advantageous here if said flexible directing member is fixed on the outside of the band-inlet channel by way of one end and is introduced into the band-outlet channel by way of its other end. Depending on the relative position of the two band channels, the relevant band end thus projects to a more or less pronounced extent into the band-outlet channel. The length of the flexible directing member is to be dimensioned such that, even with a maximum distance between the two mutually facing channel ends, the free end of said directing member is still located in the band-outlet channel. This means that, with all the angles of deflection or wrap, the situation where the band strikes against an edge as it is pushed in is ruled out.
In an expedient practical embodiment of the deflecting subassembly according to the invention, the band-inlet channel can be adjusted into various positions relative to the deflecting roller and can preferably be fixed in these positions in each case. It is thus possible, for example, for the band-inlet channel to be adjusted correspondingly for use in different circumstances, but to maintain the respectively predetermined position during use in each case.
It is possible in this case for the band-inlet channel to be mounted pivotably, for example, on a spindle which preferably coincides with the spindle of the deflecting roller and preferably to be fixed in its respective pivot position.
Alternatively, or in addition, it is also possible for the band-outlet channel to be adjusted into various positions relative to the deflecting roller. In this case, said band-outlet channel can preferably be moved out of the various positions counter to a spring force in each case. This makes it possible for the band-outlet channel to follow changes in the band-running direction as caused, for example, by a respective strapping operation.
It is possible in this case for the band-outlet channel to be mounted pivotably, for example, on a spindle which coincides preferably with the spindle of the deflecting roller and to be retained preferably resiliently in its respective pivot position.
The flexible directing member is preferably formed by a directing plate.
According to a preferred practical embodiment of the deflecting subassembly according to the invention, the band-inlet channel is fastened releasably on a carrier. Alternatively, or in addition, it is also possible for the band-outlet channel to be fastened releasably on such a carrier. The respective band channel can thus be exchanged. This makes it possible, for example, to use elements of different lengths as required.
The invention is explained in more detail hereinbelow, using an exemplary embodiment, with reference to the drawing, in which:


Disclosed are compositions, products, methods and systems for monitoring ecosystems, such as bodies of water, for a parameter of the ecosystems, such as the presence or absence of mercury. In one embodiment, the product may include a plurality of oligonucleotides immobilized at known locations on a substrate as an array, such that each location on the array is an oligonucleotide having a sequence derived from a single, predetermined operational taxonomic unit (OTU) and wherein at least one sequence on the array is associated with the presence or absence of mercury. The sequences immobilized on the array may be from known, or unknown organisms. Also disclosed are methods for identifying and isolating bioindicators diagnostic of ecosystem parameters, such as whether mercury is present. The compositions, products, methods and systems of the invention may be used for rapid, and continual monitoring of ecosystems for parameters of interest, such as the presence or absence of mercury.

Human development can result in chemicals, waste, and/or agricultural runoff being introduced into the ecosystem. Increases in population may lead to over-harvesting of marine resources, landscape alterations that alter the ecosystem, and the introduction of living and non-living contaminants into the ecosystem (Mallin, M. A, et al. 2000, Marine Pollution Bulletin, 41:56-75). Additionally, as the threat of bioterrorist activities has become evident in recent years, concern about the vulnerability of ecosystems such as municipal water supplies to deliberate contamination has grown.
For example, water and/or other ecosystems may be contaminated with heavy metals, such as mercury. Such contamination may enter water supplies through natural deposit erosion, factory and refinery discharges, landfill/cropland runoffs, and coal power plant emissions. Most of the mercury in lakes and sediments exists in the more reactive inorganic mercuric form Hg(II), which can be effectively transported across microbial membranes and subsequently converted to organic mercury compounds, or methyl mercury (MeHg) (Morel et al., 1998, Ann. Rev. Ecol. Syst. 29:543-66.). Although the conversion of inorganic mercury to organic mercury may occur under aerobic conditions, it is predominantly due to dissimilatory sulfate or iron reducing bacteria under anoxic conditions (Kerin et al., 2006, Appl. Environ. Microbiol. 72:7912-7921). MeHg is a highly toxic compound and may constitute up to 20% or more of the total mercury concentration in sediments (Osborne, et al., 1997, FEMS Microbiol. Rev. 19:239-262; Nascimento and Chartone-Souza, 2003, Genet. Mol. Res., 2:92-101). Since mercury can accumulate in living tissues, its concentration tends to be greater at higher trophic levels of the natural food chain. Consequently, ongoing, low-level consumption of mercury-laden food poses a chronic health risk to humans. Other contaminants may be equally as problematic.
Reservoirs, recreational lakes, and coastal areas can be difficult to secure against accidental or intentional contamination. Further, the contamination of a water source has the propensity to impact a relatively large population, and water filtration systems may not sufficiently alleviate the threat. Also troubling is the lack of a real-time test to detect the agents that are most likely to contaminate water supplies. The turnaround times for culturing microbes and/or obtaining chemical test results is slow enough that consumption of contaminated water may occur before the test results are known. Also, the expense involved in frequent monitoring of the water supply with currently available laboratory tests can be prohibitive.
As yet, there has not been a large-scale, deliberate contamination of a municipal water source. However, sporadic and relatively confined natural contaminations have demonstrated the importance in being able to monitor the water supply. The number of outbreaks attributable to contaminated drinking water supplies more than doubled in 1999-2000 over the previous two-year period, with contamination of well water also on the rise. In addition, recreational water sources have also reported significant increases in contamination (Bowman, 2002, Outbreaks of waterborne illnesses on the rise in US, Scripps-Howard News Service, Nov. 23, 2002). These incidents of water contamination were exacerbated by the difficulty in pinpointing the cause of the outbreak and subsequent misdiagnosis of the symptoms, illustrating the importance of "early warning" diagnostics of water supplies.
A number of microbial genome sequencing projects have been initiated to characterize pathogenic organisms. Although identification and characterization of genomic sequence data for individual pathogens may provide for the identification of specific microbes, such targeted testing fails to provide a comprehensive, economically feasible system for monitoring ecosystems of interest, such as municipal water supplies. The accuracy of a molecular diagnostic test for a microbe may be compromised where the pathogenic agent is endemic, or possesses substantial genetic similarity to non-pathogenic organisms (Leff et al., 1995, Appl. Environ. Microbiol., 61:1634-1636; Xiao et al, 1999, Appl Environ. Microbiol., 65:3386-3391). Also, although some putative contaminants of water have been identified, anticipating all possible contaminants is not feasible, and thus, specific tests are inherently limited.
Thus, there is a need for devices and methods that enable real-time monitoring of water supplies and other ecosystems of interest. The monitoring system should allow for detection of known, as well as unknown, contaminants. The monitoring system should be available in a format that is accessible for routine monitoring, as well as for rapid testing in response to a specific event.

Compositions, products, methods and systems to monitor water and other ecosystems

The University of North Carolina at Greensboro


A vehicle internal combustion engine exhaust system featuring two different exhaust routes to which the exhaust gas is directed selectively by an on-off device; the system also comprising a device for comparing parameters, consisting in engine speed, the opening angle of the throttle, and the vacuum inside the intake manifold and/or engine load, with respective predetermined values, for opening the on-off device upon the above parameters reaching the aforementioned predetermined values, and so selectively enabling the exhaust gas to flow along both the exhaust routes.

The present invention relates to a vehicle internal combustion engine exhaust system.
The performance of an internal combustion engine in terms of output and the manner in which this is supplied (i.e. the characteristic curve of the engine) is known to depend, not only on the engine itself, but also on the exhaust system, the characteristics of which in turn depend on the type and degree of noise attenuation required.
At the design stage, therefore, a trade-off is invariably involved between the characteristics of the engine and the exhaust system, and which generally results in impaired performance of the engine, particularly at high speed, due to the conflicting exhaust system design features required for achieving given performance characteristics at both high and low engine speeds. On catalyzed engines of high-performance (so-called Grand Touring) vehicles, operation of the catalyst has also been found to be impaired at high engine speed, due to the fuel supply system supplying a "richer" air/fuel mixture, i.e. having a lower dilution coefficient.

Vehicle internal combustion engine exhaust system


By repeatedly obtaining acceleration data, a gravity direction acceleration acting in a gravity direction of a housing and a horizontal direction acceleration acting in a horizontal direction perpendicular to the gravity direction are calculated. By using a first coefficient, a first step count in accordance with a change in the gravity direction acceleration is calculated and by using a second coefficient which is different from the first coefficient, a second step count in accordance with a change in the horizontal direction acceleration is calculated. Based on a predetermined condition, one of the first step count and the second step count is selected as a user's step count.

1. Field
Example embodiments of the present invention relate to a storage medium having a step count calculation program stored therein, a step count calculation apparatus, and a step count calculation system. More particularly, example embodiments of the present invention relate to a storage medium having stored therein a step count calculation program for calculating the number of steps made by a user; a step count calculation apparatus; and a step count calculation system.
2. Description of the Background Art
Conventionally, a pedometer is attached to a body of a user and measures the number of steps in accordance with vibration received from the user. As one example of such a pedometer, Japanese Laid-Open Patent Publication No. 2004-141669 (hereafter, referred to as patent document 1) discloses a body motion detection apparatus which includes acceleration sensors. The body motion detection apparatus disclosed in the above-mentioned patent document 1 includes a plurality of acceleration sensors whose acceleration directions to be detected vary respectively. And the body motion detection apparatus determines a posture of the apparatus by using signals obtained from the respective acceleration sensors and based on the posture, detects body motions (the number of steps) of a user. For example, in the body motion detection apparatus, a waveform of acceleration is analyzed and when the acceleration is reduced from a lower threshold after the acceleration has exceeded an upper threshold, it is determined that the user has made one step.
However, it may occur that the body motion detection apparatus disclosed in the above-mentioned patent document 1 cannot accurately measure the number of steps depending on a manner in which the user carries the body motion detection apparatus. Specifically, when the user walks with the body motion detection apparatus attached to the user's clothing or with the body motion detection apparatus put into a bag, the body motion detection apparatus can detect the number of steps by detecting an acceleration generated by up and down vibration of a body, which is caused when the user walks. On the other hand, when the user walks with the body motion detection apparatus held in his or her hand, because an acceleration generated by back and forth vibration, which is caused when the user swings his or her arms, the body motion detection apparatus cannot accurately measure the number of steps. In other words, because the number of the user's steps, which corresponds to one cycle of a waveform of the acceleration generated by the body's up and down vibration, is different from the number of the user's steps, which corresponds to one cycle of a waveform of the acceleration generated by the up and down vibration which is caused by swinging his or her arms, the body motion detection apparatus cannot accurately measure the number of steps. Since the user does not always carries the body motion detection apparatus so as to generate the acceleration caused by the body's up and down vibration, it is considered that the number of steps could be erroneously detected. In addition, since when the user tries to accurately detect the number of steps, the user is subject to limitations in a manner of carrying the body motion detection apparatus, usability of the body motion detection apparatus is worsened.

Storage medium having step count calculation program stored therein, step count calculation apparatus, and step count calculation system


A phytase having improved enzymatic activity is disclosed. The phytase has a modified amino acid sequence of SEQ ID NO: 2, wherein the modification is a substitution of Valine at position 90 with Threonine. Alternatively, the phytase has a modified amino acid sequence of SEQ ID NO: 6, wherein the modification is a substitution of Asparagine at position 204 with Alanine or a substitution of Serine at position 206 with Alanine.

Phytic acid or phytate (myo-inositol hexakisphosphate) is the primary storage form of phosphorus in most plants and is abundant in seeds and legumes. However, the monogastric animals cannot utilize phosphorous from phytate due to the lack of necessary enzymes in digestive tract. Supplementation of inorganic phosphates was used to compensate the shortage in phosphorus ingestion but the excessive phosphorus in animal excretion has caused environmental pollution. In addition, the insoluble complexes formed by the highly negatively charged phytate with proteins and metal ions are major anti-nutritional factors. Phytase can hydrolyze phytate to lower inositol phosphates to release inorganic phosphate and thus has been widely applied in animal feeds to increase phosphorus availability and reduce phosphorus pollution. To date, phytase is estimated to account for 60% of feed enzyme products. Therefore, searching for phytases with higher specific activity and thermostability to lower the production cost and to survive the transient high-temperature step in pelleting procedure (80-85° C.) is of great interest to industries.
Classified by protein structure and catalytic property, there are four types of phytases including histidine acid phosphatases (HAPs), protein tyrosine phosphatase (PTP)-like phytases, purple acid phosphatases (PAPs) and β-propeller phytases (BPPs), with a majority of the characterized enzymes belonging to HAP. From previous studies, the crystal structures of all families except for PAP have been solved. Among the characterized phytases, Escherichia coli phytase (EcAppA), a member of the HAP family, has drawn much attention. First, EcAppA has high specific activity (up 56 to 2000 U/mg) under the favorable pH profile for feed additive. Second, large scale production of EcAppA in an industrial strain of Pichia pastoris has been successfully achieved by using fermentor for commercial applications. However, the need to enhance the enzymatic activity of EcAppA still remains.
Molecular engineering is a powerful approach to modify enzyme performances. Directed evolution involving random mutagenesis which builds a library provides a large pool of mutants for subsequent screening for useful mutants. But the efficiency is low and the procedure is laborious. A more ideal way is rational design, which is realized by the increasing information of protein structure and the development of powerful bioinformatics tools. Major obstacle in conducting a successful rational design is how to choose the useful residues or structural features.
In the present invention, site-directed mutagenesis of EcAppA is performed based on sequence comparison and structure analysis, so as to improve the industrial value of EcAppA.

Phytase having improved enzymatic activity


A pen-based personal computer includes a main power switch for initial power-up. The pen-based portable personal computer includes a keyboard controller which controls power management of the battery and places the pen-based portable personal computer in a hibernate state after a predetermined period of inactivity. The system can be awakened from the hibernate state by contact of a passive stylus with the digitizer panel. In order to place the power management of the battery under the control of the keyboard controller, a wake-up signal is generated at power-up just long enough to enable the keyboard controller to take control of the power management of the battery.

1. Field of the Invention
The present invention relates to a pen-based portable personal computer system and more particularly to a pen-based portable personal computer system which automatically goes into a low-power state after a predetermined period of inactivity in order to conserve battery power under the control of a keyboard controller. A main power switch is provided for initially powering up the system. On power up, a wake-up signal is generated just long enough to enable the keyboard controller to take control of the power management of the battery.
2. Description of the Prior Art
Portable personal computers are known to automatically go into a low power state after a predetermined period of inactivity. Even in the low power state, such portable personal computers place a significant drain on the battery power. As such, for extended periods of non-use, the main power switch is normally switched off to totally disconnect the battery power from the computer system. In order to awaken the portable personal computer from such a state, a main power switch must be switched on.
Some known portable personal computers are known to have a hibernate state during which there is a relatively insignificant drain on the battery. As such, these systems can be left in the hibernate state for relatively long periods of time without the need to use the main power switch. Such systems are known for notebook-type portable personal computer systems which utilize a mechanical switch that is interlocked with the cover such that anytime the cover is closed, the personal computer system will go into a hibernate state. In such systems, when the cover is placed in an open position, the switch is used to wake the portable computer system up and place it in a full-power state. While such systems obviate the need to switch the main power switch on and off, such systems do require a mechanical switch which not only adds to the cost of the portable personal computer system, but is subject to wear, and thus failure. In addition, some known portable personal computers do not utilize a cover and thus would not be able to utilize a mechanical switch in the same manner discussed above to place the computer system into a suspend state. Thus, the user is forced to utilize the main power switch, which can be cumbersome.

System and method for delaying a wake-up signal


An imaging lens includes a first lens having positive refractive power; a second lens having positive refractive power; and a third lens having negative refractive power, arranged in the order from an object side to an image plane side. The first lens and the third lens respectively have an object-side surface and an image plane-side surface whose curvature radii are both positive. The second lens has an image plane-side surface whose a curvature radius is negative. In addition, when the first lens has refractive power P1, the second lens has refractive power P2, the third lens has refractive power P3, the curvature radius of the image plane-side surface of the second lens is R2r, and the curvature radius of the object-side surface of the third lens is R3f, the imaging lens satisfies specific conditional expressions.

The present invention relates to an imaging lens for forming an image of an object on an imaging element such as a CCD sensor and a CMOS sensor. In particular, the present invention relates to an imaging lens suitable for mounting in a relatively small-sized camera such as a camera for mounting in a portable device, which includes a cellular phone, a smartphone, and a portable information terminal, a digital still camera, a security camera, a vehicle onboard camera, and a network camera.
In these years, in place of cellular phones that are intended mainly for making phone calls, so-called "smartphones" have been more widely used, i.e., cellular phones with functions of portable information terminals (PDA) and/or personal computers. Since the smart phones generally are highly functional and exhibit high performance as opposed to the cellular phones, it is possible to directly edit images taken by a camera thereof without importing the images in personal computers or the like. In case of the smartphones, it is possible to use images taken by the cameras thereof in various applications. For example, the images may be used for creating characters of online games or makeup simulations. Such uses of the images, which were not conventionally common, are becoming increasingly popular every year with an increase in popularity of the smartphones.
Generally speaking, an imaging lens to be mounted in a portable device such as a cellular phone or a smartphone, which is developed for advanced users, is required to have optical performances that are equivalent to those of digital still cameras such as a high resolution and excellent color reproduction, as well as a small size due to limited space in a portable device. However, as the imaging lens to be mounted in a camera used for the above-described applications, it is not essential for the imaging lens for mounting in a camera to have the high resolution, but rather than that, it is more critical to have a wide angle of view, i.e., wide angle, in some applications.
An imaging lens having a three lens configuration can relatively satisfactorily correct aberrations and is also suitable for downsizing, so that such a lens has been widely used in the lens configuration of the imaging lens of the camera for mounting in the above-described portable devices. As the three lens configuration, there has been a well-known lens configuration, which includes a first lens having positive refractive power; a second lens having negative refractive power; and a third lens having positive or negative refractive power, arranged in this order from an object side. In the lens configuration, since the second lens has negative refractive power, it is relatively easy to achieve downsizing of the imaging lens. In addition, chromatic aberration generated in the first lens is suitably corrected through the second lens. Therefore, the lens configuration is one of effective lens configurations in view of downsizing of the imaging lens and satisfactory correction of aberrations.
However, in the lens configuration described above, since the second lens has negative refractive power, when it is attempted to attain both downsizing of the imaging lens and a wider angle, refractive power of each lens tends to be relatively strong. As a result, it is necessary to improve the fabrication accuracy and assembly accuracy of the lenses. For this reason, there has been recently proposed a lens configuration, in which refractive powers of all of the three lenses are positive. As the imaging lens having such three lens configuration, for example, an imaging lens described in Patent Reference 1 has been known.
According to the imaging lens disclosed in Patent Reference 1, the second lens and the third lens have inflexion points, and with aspheric surface shapes having the inflexion points, downsizing of the imaging lens and a wider angle are attained, while correcting aberrations.
In addition, although the lens configuration is slightly unfavorable in view of downsizing of the imaging lens and satisfactory correction of aberrations, as a lens that has a small F number and is bright, for example, there is known an imaging lens described in Patent Reference 2. Similar to the imaging lens disclosed in Patent Reference 1, in the imaging lens disclosed in Patent Reference 2, the first lens and the second lens have positive refractive powers. However, different from that in Patent Reference 1, the third lens has negative refractive power.    Patent Reference 1: Japanese Patent Application Publication No. 2012-014139    Patent Reference 2: Japanese Patent Application Publication No. 2010-145648
According to the imaging lens described in Patent Reference 1, it is possible to attain downsizing of the imaging lens while correcting aberrations to some extent. However, with increasing diversification in uses of images taken by cameras each year, imaging lenses are demanded to have even wider angles as one of added values of the imaging lens. Although the imaging lens described in Patent Reference 1 has the wider angle of view than that of conventional one, there is a limit by itself for attaining even wider angle.
Further, in case of the imaging lens described in Patent Reference 2, the whole lens system has a long focal length, and an axial length of the imaging lens is also long. Accordingly, it is difficult to achieve both wider angle and downsizing of the imaging lens.
Here, difficulty of attaining both downsizing and the wider angle while correcting aberrations satisfactorily is not a problem specific to the imaging lens to be mounted in portable devices such as the cellular phones and the smartphones. Rather, it is a common problem also for an imaging lens to be mounted in a relatively small camera such as digital still cameras, security cameras, vehicle onboard cameras, and network cameras.
In view of the above-described problems in conventional techniques, an object of the present invention is to provide an imaging lens that can attain both downsizing and a wider angle, while satisfactorily correcting aberrations.
Further objects and advantages of the invention will be apparent from the following description of the invention.


A laminated-type multi-joint portion drive mechanism includes a bone member having at least two elastic deformation portions, a laminated-type pneumatic tube member having at least twoline-tubes which are stacked on the bone member and which are connected to a pneumatic drive source, and a planar-type joint-portion deformation member which is stacked on the laminated-type pneumatic tube member and has pneumatic operation chambers which are placed at joint portions confronting the deformation portions, respectively, and which are connected to the tubes, wherein when pneumatic pressure is applied to one of the pneumatic operation chambers, the joint portion corresponding to the pneumatic operation chamber to which the pneumatic pressure is applied is deformable.

Conventionally, a grasping hand with a multi-joint portion drive mechanism has been used for grasping of particular components in a limited working environment of a factory interior primarily as a hand of industrial robots, and has been under discussions and contrivance in view of higher precision, higher speed, and the like for specialized operations. In recent years, in contrast to this, there has been brisk development pertaining to robot introduction in household aid and work aid, care aid for aged or physically challenged, and the like in home, hospitals, and the like, giving rise to a desire for a grasping hand which satisfies such conditions as grasping of various and diverse objects, which could not be implemented by industrial robots, and safety to persons who use the grasping hand and which is capable of fulfilling flexible operations. For grasping of diverse objects, there has been known a robot hand described in Japanese Patent No. 3245095. This robot hand has five fingers consisting of a 4-degree-of-freedom thumb having one 4-joint-portion and four 3-degree-of-freedom fingers each having a 4-joint-portion, where miniature servomotors are contained at joint portions other than a finger-tip first joint portion, respectively, to drive the joint portions.
However, this robot hand, involving large numbers of component parts, requiring assembly and being high-priced, is still limited to research use at the present time.
With regard to a grasping hand capable of fulfilling flexible operations, a pneumatic actuator, which is one constituent element, is known as described in Japanese Patent No. 3226219. This actuator is so designed that a plurality of partition walls are provided in a cylindrical elastic member to define pressure chambers, wherein each of the pressure chambers is to be pressurized to flex the elastic member. This actuator is combined in a plurality to form a grasping hand, thus being enabled to grasp objects.
However, since there is provided no constituent element equivalent to a human bone, there would arise an issue in that it may become hard for the actuator to continue grasping an object depending on its configuration and weight. Also, in order to drive each actuator, there would arise a need for drive tubes of a number corresponding to a number of internal pressure chambers of cylindrical elastic members. In this case, the number of tubes would increase, causing a load more than a flexural operation force of the actuators to be involved depending on rigidity of the tubes, thereby posing a possibility that the actuators might no longer sufficiently flex.
With regard to these already reported grasping hands, there has been disclosed no grasping hand which comprises pneumatic pressure as a drive source and which includes a laminated-type pneumatic tube formation member, a planar-type joint-portion flexural deformation member and a bone member having a joint portion according to the present invention.
For introduction of robots for performing various kinds of aid into human living space, there is a need for a multi-joint portion drive mechanism for fulfilling a grasping hand that serves as a main part for aid operation. Also, the grasping hand provided with the multi-joint portion drive mechanism is required to have a grasping performance for grasping various and diverse objects and to be safe, simple in structure, and implementable with low cost.
An object of the present invention is to provide a laminated-type multi-joint portion drive mechanism, as well as a manufacturing method therefor, and further to provide a grasping hand and a robot arm provided with the laminated-type multi-joint portion drive mechanism as well as a robot provided with the grasping hand and the robot arm each of which solves the foregoing issues and each of which is capable of implementing a grasping hand having a grasping performance for various and diverse objects, and which is safe and simple in terms of structure and implementable with low cost.

Laminated-type multi-joint portion drive mechanism and manufacturing method therefor, grasping hand and robot arm provided with the same

Matsushita Electric Industrial Co., Ltd.


A RF microwave connector for telecommunication comprises a plug; a metal housing of the plug is combined with an insulator; a female terminal is combined with the hollow portion of the insulator; the female terminal has a main body, two opposite contact plates are extended from two sides of one end of the main body for clamping a male terminal; an arc shape of clamping section is disposed at another end of the main body, two edges of the clamping section are symmetrically arched so as to allow the edges of the clamping section to be bended oppositely smoothly to clamp inner wires of a coaxial cable stably when that the clamping section is combined with the inner wires is processed.

1. Field of the Invention
The present invention relates to an electric connector, and more particularly to a RF (Radio Frequency) microwave connector for telecommunication.
2. Description of Related Art
Please refer to FIGS. 1A and 1B. A conventional coaxial microwave connector consists of a plug and a receptacle, in which the plug has a female terminal 10. Two opposite contact plates 11 are disposed at one side of the female terminal 10 and a stop plate 12 is disposed at another side thereof. A slit 121 exists in the stop plate 12. The contact plates 11 are used to clamp a male terminal of the receptacle. The slit 121 is used to allow the inner wires 131 of a coaxial cable 13 to be passed through it and welded on the upper side of the female terminal 10, as FIG. 1B shows.
Please refer to 2A and 2B. Another conventional coaxial microwave connector, a plug thereof has a female terminal 20. Two opposite contact plates 21 are disposed at one side of the female terminal 20 and opposite stop plate 22 and raised plate 23 are disposed at another side thereof, in which a slit 221 exists in the stop plate 22. The contact plates 21 are used to clamp a male terminal of a receptacle. The slit 221 is used to allow the inner wires 241 of a coaxial cable 24 to be passed through it and welded at the upper side of the female terminal 20, as FIG. 2B shows.
The U.S. Pat. No. 6,648,653 entitled "super mini coaxial microwave connector" discloses a plug and a receptacle, in which the plug has a metal housing; the metal housing is connected to an insulator and a female terminal is connected with the hollow portion of the insulator. Please refer to FIG. 3. A female terminal 30 has two opposite contact plates 31 and two opposite stop plates 32 and an upper plate 33. The contact plates 31 are used to clamp a male terminal of the plug and inner wires 361 of a coaxial cable 36 are welded on the upper plate 33 and between the stop plates 32.
The manufacturing way welding the coaxial cable and the female terminal manually mentioned above cannot be replaced with an automatic machine manufacturing way, it is labor and time wasting.
Please refer to FIGS. 4A to 4C. Two opposite contact plates 41 are disposed at one end of another kind of known coaxial microwave connector 40 and a clamping section 42 is disposed at another end thereof. Two contact plates 41 are used to clamp a male terminal of a receptacle. The bottom of the clamping section 42 is formed as an arc shape and a bendable edge 421 is extended upward from one side of the bottom thereof. Inner wires 431 of a coaxial cable 43 are wrapped in between the bottom of the clamping section 42 and the bended bendable edge 421, as FIG. 4B shows.
Although an automatic machine can replace manual labor in the manufacturing way clamping the inner wires 431 of the coaxial cable 43 tightly by bending the bendable edge 421 of the clamping section 42 mentioned above is rather labor and time saving, the bendable edge 421 is very long and a more sophisticated and expensive bending facility is needed to bend the bendable edge 421 into a half circle type smoothly to contact closely with another edge of the arc bottom. If the bended radian of the bendable edge 421 is not smooth so that it cannot contact closely with another edge of the arc bottom of the clamping section 42, this will influence the function clamping the inner wires 431 closely and further influence the transmission quality of the connector and produce a bad product.


The disclosure relates to a method of reducing crosstalk in a crosstalk cancelation system. The method comprises at least the steps of applying to the at least one first signal a crosstalk cancelation according to a set of crosstalk coefficients; monitoring crosstalk received in the at least one first signal at a first end of the first path during the application of the crosstalk cancelation; and updating the crosstalk coefficients during the monitoring. The disclosure also includes a device, which can carry out the method.

For data transmission over a crosstalk limited channel, crosstalk cancelation techniques have been introduced to increase transmission performance. To reduce the computation effort for crosstalk cancelation, partial crosstalk cancelation may be used.
The selection of dominant crosstalk couplings is based on the coupling strength of every coupling path between the transmission lines. Spectrum balancing methods which reduce the transmission power of specific links to mitigate crosstalk also need information of the crosstalk coupling strength.
A crosstalk canceller has access to signals to perform crosstalk compensation or pre-compensation. The links may use multiple carrier frequencies for transmission. The receivers report a receiver error, the difference between a received signal and the corresponding symbol (slicer error). The receivers may be synchronized so that it is possible to define specific symbols which were received at all receivers synchronously.
Current methods for partial cancelation do a static selection that is based on an estimation of the transmission channel. The optimization of transmission powers (spectrum balancing) is also optimized based on a transmission channel estimate.

Adaptive monitoring of crosstalk coupling strength


A system and method for determining a quantitative measure of qualitative usability of related Web pages. Web pages are accepted that each include at least one hyperlink referencing and proximal cues relating to distal content included in another Web page. An information goal identifying a target Web page is specified. An activation network is formed. A directed graph including nodes corresponding to the Web pages and arcs corresponding to the hyperlinks is built. A weight is assigned to each arc to represent a probability of traversal of the corresponding hyperlink based on a relatedness of keywords in the information goal to the proximal cues included in the referenced Web page. A traversal through the activation network to the node corresponding to the target Web page is evaluated as a quantitative measure of usability.

The Worldwide Web, or simply, the "Web," has become a form of global information resource that can be easily accessed with just a Web browser and a connection to a wide area internetnetwork, particularly, the Internet. Generally, individual pages of Web content are freely available for browsing and can contain both static and interactive content of multiple media types, particularly, textual and visual content. Web content can be navigated through a read, point, and click procedure to "surf" through successive Web pages to satisfy an information goal. Typically, collections of related Web pages are structured into a hierarchical Web site through hyperlinks that associate distal information contained in a linked Web page through proximal cues contained in the linking Web page.
By virtue of the wide spread acceptance enjoyed by the Web, individuals, businesses, and other interests are placing increasing reliance on the Web as a major means of communication, particularly in the commercial sector where effective advertising, information dissemination, and collaborative data sharing are necessary aspects of electronic commerce. Ensuring user satisfaction is crucial, particularly where revenue is derived, for instance, through advertising for third parties, and where generating traffic through repeat visits is tied to revenue goals.
However, user satisfaction in browsing a particular Web page is subjective. Indirect measures for gauging user satisfaction include capturing click patterns and counting repeat visits, but such measures only provide generalized indications of potential interest level in the Web content. Observable indicia, such as clicks, are not tied to an objective measure of goodness or satisfaction and could equally reflect a random or wrong choice by the user. Similarly, user satisfaction in browsing an entire Web site is also subjective. Click patterns can be traced to identify the most popular hyperlinks, but such measures fail to reflect whether users were satisfied with the results of their visit. Quantifying user satisfaction therefore requires assigning meaning to user actions.
User satisfaction on per page and entire Web site bases can be quantified by tying user satisfaction to an information need or goal. Generally, users visiting a Web site are looking for particular information and will stop searching when either the information is found through page-by-page navigation, a dead end or wrong result is reached, or they give up in their search. Accordingly, user satisfaction can be quantitatively measured by determining whether user information needs are being satisfied by the Web site.
Conventional Web site quantitative evaluation focuses on performing traffic analyses. Individual visits are traced and repeat visits are tracked to generate statistics on Web site traffic. Although these measures provide a general idea of user behaviors, such information fails to provide an indication of whether user information needs were met or how a Web site might be improved through modified structuring and proximal cues.
Therefore, there is a need for an approach to providing quantitative measures of the goodness of a Web site based on a priori user information needs. Preferably, such an approach would provide an upper bound on the potential goodness of a Web site effected through changes in hyperlink structure and information cues.

System and method for determining a quantitative measure of qualitative usability of related Web pages


The invention relates to a conduit for circulation of fluid comprising a sealed pipe (A) fixed to a rigid supporting body (B) comprising a horizontal base having a lower face bearing on a laying surface (C) and two lateral wings going up vertically along the sites of the lower section of the pipe (A), said supporting body (B) comprising, on either side of the tubular enclosure (A), a single-piece portion (31, 31xe2x80x2) having, as a transversal section, a L-shaped profile comprising a substantially vertical branch (32) forming the wing extending along the corresponding side of the enclosure (A) and a substantially horizontal branch (33) extending beneath the former in order to form at least a portion of the base (3) of the supporting body (B) resting on the ground (C).

This invention relates to a fluid circulation conduit, of very large transversal section, liable to exceed 2 m2, which can be buried under an embankment and more particularly intended for the circulation of fluid under high pressure, in the order of several bars.
A fluid transportation conduit can be made simply in the form of metal or concrete pipe elements, butt jointed and having ends inserted into one another, with interposed joints. In case of sinking, some elements may come loose and therefore, to resist relatively high pressures, it is preferable to use metal pipes whose elements are welded at their adjacent ends, for instance, in the case of forced conduit for hydro-electrical plants.
In such a case, the conduit is composed of prefabricated pipe elements or of curved panels, which are transported to the site and welded there. At that point; however, the pipe is not under pressure and may deform while taking an oval shape, which makes welding more difficult since the sheets would no longer be aligned.
Besides, such pipes must often be buried, for instance in the case of pipelines or gas-lines. When the pipe is under pressure, it can easily sustain the loads applied externally by the embankment. But the pressure may vary and even become negative with respect to the outside. There is then a high risk of deformation of the pipe.
For all these reasons, the pipes made by welding metal elements generally have a relatively limited section, most often smaller than 2 m2.
The present invention is intended to produce conduits for the transportation of fluid under pressure which do not exhibit such shortcomings.
With such a technique, the conduit is composed of a sealed thin-walled pipe, normally a metal pipe, fastened to a rigid supporting body, usually made of reinforced concrete or preloaded concrete. Thus, the metal pipe enables the system to be sealed and to resist the internal pressure, the thin wall being solely subjected to traction stresses, while the concrete body makes the conduit rigid while bearing upon the laying surface on a widened surface which distributes the loads applied and better resists differential sinking.
In the technique described in parent U.S. patent application Ser. No. 08/765,422 filed Jun. 28, 1995, now U.S. Pat. No. 5,904,185, the concrete supporting body consists advantageously of three sections, respectively a horizontal base bearing on the ground and two lateral bearing parts forming vertical legs along each side of the pipe, whereby the assembly exhibits a U-shaped profile completely surrounding the lower section of the pipe. The pipe therefore consists, as a straight section, of four panels, respectively a lower panel applied onto the base, two lateral panels applied respectively onto both lateral legs and an upper panel with two lateral edges which connect tangentially to the corresponding ends of two side panels. The side panels are held by both legs of the supporting body and their opposite edges can thus be perfectly aligned for welding purposes.
Such a conduit can be made easily from prefabricated elements whose length is compatible with the transportation and handling capacities.
The invention further in simplifies the production technique of such a conduit, in particular to make the various prefabricated elements lighter and to facilitate their installation, while retaining the various advantages provided by the prior.
The invention relates generally to a fluid circulation conduit, of large transversal section, in excess of 2 m2, comprising a pipe having a longitudinal axis and fixed on a rigid supporting body bearing on a laying surface. The pipe forms a sealed tubular enclosure constituted of a plurality of juxtaposed than walled panels and comprising a lower part having a U-shaped profile with two sides and an upper part, the supporting body comprising a horizontal base with a lower plane face bearing on the laying surface and two lateral wings extending vertically along the sides of the lower part of the tubular enclosure. The supporting body comprises, on either side of the tubular enclosure, a single-piece portion having, in cross-section, an L-shaped profile comprising a substantially vertical branch forming a lateral wing of the supporting body extending along the corresponding side of the lower part of the pipe and a substantially horizontal branch extending beneath the lower part of the pipe and forming at least a portion of the base of the supporting body resting on the laying surface.
Particularly advantageously, at least over a certain length of the pipe, both lateral wings and the base of the supporting body form a unitary piece.
According to another embodiment, at least over a certain length of the pipe, the supporting body comprises two L-shaped profile pieces whose horizontal branches connect on either side of the median plane of the pipe passing through the longitudinal axis, so as to form a continuous base.
Normally, the supporting body is made of reinforced concrete and the reinforcement can be made conventionally to sustain the loads applied, in particular, loads tending to spread the lateral sections apart. However, according to another particularly advantageous feature, the reinforcement may be made of at least one curved sheet, embedded in the concrete supporting body and having two branches, respectively horizontal and vertical, each into the corresponding branch of each L-shaped portion of the supporting body.
Preferably, to ensure transmission continuity of the loads, each L-shaped lateral part of the supporting body comprises an internal face for application and fixation of the enclosure, whose orientation varies gradually between a substantially horizontal lower section and a substantially vertical upper section.
The invention will be understood better by the following description of certain embodiments given by way of example and shown in the appended drawings.

Conduit for circulation of fluid under pressure


A method for scheduling transmission in a wireless communications system, and a device are disclosed, to resolve a technical problem that uplink transmission in a cell in which the uplink transmission is performed may be interfered with by downlink transmission. The method includes: determining, by a network device, a priority of each transmission time interval used for first-direction transmission in a transmission time interval set, where the first-direction transmission is along a downlink direction from the network device to user equipment or along an uplink direction from the user equipment to the network device; selecting, by the network device, for a first cell, at least one transmission time interval from the transmission time interval set based on the priority; and performing, by the network device, in the first cell, the first-direction transmission with the user equipment by using the selected at least one transmission time interval.

Duplex modes of a Long Term Evolution (LTE)/Long Term Evolution Advanced (LTE-A) communications system may be mainly categorized into a frequency division duplex (FDD) mode and a time division duplex (TDD) mode. For a wireless communications system working in the TDD mode, during a period of time, an entire frequency band may be used only for downlink transmission, or may be used only for uplink transmission, and for an area covered by a same frequency band, all cells in the area are synchronous, to be specific, transmission in all the cells at a same moment needs to be downlink transmission or uplink transmission. For a wireless system working in the FDD mode, spectrums are used in pairs, to be specific, one uplink frequency band is used to transmit an uplink service and uplink signaling, one downlink frequency band is used to transmit a downlink service and downlink signaling, the uplink frequency band can be used only for uplink transmission, and the downlink frequency band can be used only for downlink transmission.
Considering that user equipments in a system are unevenly distributed, communications services for different user equipments are quite different, and at a same moment, a downlink service quantity and an uplink service quantity are quite different for a cell covered by a same frequency band, and service requirements for different cells cannot be satisfied if a same uplink and downlink transmission configuration is used for all the cells. For a same cell, a downlink service quantity and an uplink service quantity vary greatly at different time. Therefore, to increase utilization of a transmission resource in the system, a flexible duplex technology may be used, to separately configure a transmission direction of each cell. For example, an uplink-downlink transmission configuration in a current cell may be determined based on a ratio of an uplink service to a downlink service in the cell.
In this case, within a same transmission time interval (TTI), due to flexible duplex, when uplink transmission is performed in a cell, downlink transmission may be performed in a neighboring cell. In this case, because a signal transmit end of the downlink transmission is a base station and transmit power is relatively large, the downlink transmission causes relatively large interference to the uplink transmission in the cell in which the uplink transmission is performed. However, there is no solution to this currently.

Method for scheduling transmission in wireless communications system, and device


A compact and high-precision rotating shaft holding mechanism is provided which can be utilized for a device that requires a small amount of rotation.

Conventionally, for many a rotating shaft, a structure such as a ball bearing in which rotating bodies are held have been used. This reduces the precision of the rotating shaft and the frictional resistance of the rotating shaft. However, the rotating bodies held in the bearing affect the precision of the rotating shaft and, furthermore, cause the resistance of rotation to fluctuate with the rotation of the shaft. In the case of a use where this poses a problem, especially in a case where high precision and low frictional resistance are required, an air bearing of a structure in which an air film is held is used (see Patent Literature 5). However, the air bearing has the drawbacks of requiring a high-pressure air source and, what is more, of being not so compactible and being therefore high in moment of rotation. Further, the pressure of air that is supplied to the air bearing can be a source of generation of torque in some cases, and is a matter that requires attention when the air bearing is used as a bearing for high-precision torque measurement. Meanwhile, there has conventionally been known a holding mechanism that permits an object in translational motion within a range limited by deformation of a spring (see Patent Literatures 1 to 4).

Rotating shaft holding mechanism and rotational viscometer with same

Abstract: A rotating shaft holding mechanism includes a plurality of parallel spring links, each of the plurality of parallel spring links including: a movable side connected to a rotating shaft by a hinge at a connection point at a distance h radially away from a center of rotation of the rotating shaft; a plurality of deformable sides which are parallel to each other; hinges each of which connects one end of a corresponding one of the deformable sides to the movable side; and hinges each of which connects the other end of a corresponding one of the deformable sides to the stationary section, the effective length of each of the deformable sides being set to h to permit the rotating shaft, which is connected to the movable side by the hinge at the connecting point at the distance h radially away from the center of rotation of the rotating shaft, to rotate within a range of finite angles, the plurality of parallel spring links including at least two parallel spring links oriented in different directions. A rotational viscometer uses the rotating shaft holding mechanism.

National Institute of Advanced Industrial Science and Technology


Various aspects of the present disclosure are directed toward introducer apparatuses, systems, and methods for positioning an implantable medical device within a patient. The introducer may include a housing having a proximal opening and a distal opening and configured to position the implantable medical device adjacent the distal opening prior to ejection and an ejection rod configured to pass through the proximal opening and eject the implantable medical device from the housing through the distal opening of the housing.

Medical devices may be implanted subcutaneously under a patient's skin with minimal intervention and without the deeply positioning the device in the patient's body. Positioning of the medical device may be difficult due to high insertion forces necessary to manipulate the medical device and form a pocket for the device under the patient's skin. Improperly positioning functional aspects of the device may result in poor performance.

Implantable monitor introducer design features


A power transmission device includes an input rotary member, an intermediate rotary member, an output rotary member, a friction engaging part and a load adjusting mechanism. A torque is inputted to the input rotary member. The torque is inputted from the input rotary member to the intermediate rotary member. The torque is outputted from the output rotary member. The friction engaging part is engaged by friction with a friction force depending on a load applied thereto. The friction engaging part is configured to transmit the torque between the intermediate rotary member and the output rotary member. The load adjusting mechanism is configured to adjust the load applied to the friction engaging part in accordance with the torque inputted to the input rotary member.

Power transmission devices transmit a torque from a drive source (an engine, a motor, etc.) to a drive wheel side. The power transmission devices include a torque limiting mechanism for blocking transmission of a torque of a predetermined magnitude or greater. For example, a power transmission device described in Japan Laid-open Patent Application Publication No. 2017-035991 includes a torque limiting mechanism disposed between an input shaft and an output shaft. The power transmission device causes the torque limiting mechanism to limit the magnitude of a torque transmitted between a prime mover and a drive wheel.
In the torque limiting mechanism, one friction plate disposed on an output shaft side and another friction plate disposed on an input shaft side are pressed against each other by an urging force of a disc spring. Accordingly, the friction plates are engaged by friction with each other. When the torque of the predetermined magnitude or greater is inputted thereto, the friction plates slip against each other.
In the torque limiting mechanism configured as described above, the torque causing the slip is instable, whereby transmission of the torque of the predetermined magnitude or greater cannot be stably prevented.


The present intervention generally relates to compositions comprising a PDE11 inhibitor for increasing cortisol levels in a subject, or for increasing the production of cortisol from adenocortical cells in a subject. Aspects of the invention relate to the use of a PDE11 inhibitor in a method of treatment of low cortisol levels and/or adrenal insufficiency in a subject, or a method of treating a disease or disorders associated with adrenal insufficiency. Aspects of the invention relate to PDE11 inhibitors belonging to compounds of formula (I)-(VI), and their use alone or in combination with long-term corticosteroid treatment to elevate cortisol levels in a subject, and/or to treat adrenal insufficiency. Another aspect relates to kits comprising PDE11 inhibitors for administration to a subject, pharmaceutical compositions comprising compounds of formula (I)-(VI) for use in methods to increase cortisol levels and/or treat adrenal insufficiency, and their use as an adjuvant for treatment of cancer or other disorders such as psychiatric diseases where elevating cortisol levels would be beneficial to the subject.

High cortisol levels can lead to a variety of different health issues and cortisol levels can increase in the aging population or related to stress. In many instances, the key to controlling intracellular levels of these molecules is their hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic nucleotides, such as the second messengers cAMP (cyclic adenosine 3′5′-monophosphate) and cGMP (cyclic guanine 3′5′-monophosphate). Thus, different PDEs play pivotal regulatory roles in a wide variety of signal transduction pathways (Beavo, Physiol. Rev. 75: 725-48, 1995). For example, certain PDEs mediate processes involved in vision (McLaughlin et al., Nat. Genet. 4: 130-34, 1993), olfaction (Yan et al., Proc. Natl. Acad. Sci. USA 92: 9677-81, 1995), platelet aggregation (Dickinson et al. Biochem. J. 323: 371-77, 1997), aldosterone synthesis (MacFarland et al., J. Biol. Chem. 266: 136-42, 1991), insulin secretion (Zhao et al., J. Clin. Invest. 102: 869-73, 1998), T cell activation (Li et al., Science 283: 848-51, 1999), and smooth muscle relaxation (Boolell et al., Int. J. Impot. Res. 8: 47-52, 1996; Ballard et al., J. Urol. 159: 2164-71, 1998).
Mammals express eleven families of PDEs (3 cAMP-specific, 3 cGMP-specific, and 5 dual-specificity), encoded by 21 genes that produce over 100 distinct PDE isoenzymes due to alternative splicing of the transcript (Beavo, Physiol. Rev. 75: 725-48, 1995; Beavo et al., Mol. Pharmacol. 46: 399-05, 1994; Soderling et al., Proc. Natl. Acad. Sci. USA 95: 8991-96, 1998; Fisher et al., Biochem. Biophys. Res. Commun. 246: 570-77, 1998; Hayashi et al., Biochem. Biophys. Res. Commun. 250: 751-56, 1998; Soderling et al., J. Biol. Chem. 273: 15553-58, 1998; Fisher et al., J. Biol. Chem. 273: 15559-64, 1998; Soderling et al., Proc. Natl. Acad. Sci. USA 96: 7071-76, 1999; and Fawcett et al., Proc. Natl. Acad. Sci. USA 97: 3702-07, 2000). These enzymes perform distinct functions in the body due to tissue-specific expression, as well as subcellular localization of PDE isoforms and the effector proteins regulated by cAMP or cGMP levels. Given the complexity of this superfamily for which there are only two substrates; cAMP and cGMP, compounds that specifically and selectively inhibit individual PDEs can be powerful tools to advance our understanding of the function of a given PDE and can allow one to investigate the potential of that PDE as a therapeutic target.
However, given the difficulty of predicting transcriptional start sites and splice variants from primary genomic sequence data, it is still not known with exact certainty for any species how many different PDE mRNAs are transcribed. Furthermore, it also is not yet clear whether all transcript variants are present in all species.
Each PDE family is distinguished functionally by unique enzymatic characteristics and pharmacological profiles. In addition, each family exhibits distinct tissue, cell, and subcellular expression patterns (Beavo et al., Mol. Pharmacol. 46: 399-405, 1994; Soderling et al., Proc. Natl. Acad. Sci. USA 95: 8991-96, 1998; Fisher et al., Biochem. Biophys. Res. Commun. 246: 570-77, 1998; Hayashi et al., Biochem. Biophys. Res. Commun. 250: 751-56, 1998; Soderling et al., J. Biol. Chem. 273: 15553-58, 1998; Fisher et al., J. Biol. Chem. 273: 15559-64, 1998; Soderling et al., Proc. Natl. Acad. Sci. USA 96: 7071-76, 1999; Fawcett et al., Proc. Natl. Acad. Sci. USA 97: 3702-07, 2000; Boolell et al., Int. J. Impot. Res. 8: 47-52, 1996; Ballard et al., J. Urol. 159: 2164-71, 1998; Houslay, Semin. Cell Dev. Biol. 9: 161-67, 1998; and Torphy et al., Pulm. Pharmacol. Ther. 12: 131-35, 1999). Therefore, by administering a compound that selectively regulates the activity of one family or subfamily of PDE enzymes, it is possible to regulate cAMP and/or cGMP signal transduction pathways in a cell- or tissue-specific manner.
PDE11 is one of the most recently described families of PDEs; PDE11A has been identified (Fawcett et al., Proc. Natl. Acad. Sci. USA 97: 3702-07, 2000, hereinafter "Fawcett, 2000," Yuasa et al., J. Biol. Chem. 275: 31469-79, 2000, hereinafter "Yuasa, 2000"). While PDE11A is known to be expressed in, e.g., testis, skeletal muscle, kidney, liver, various glandular tissue (e.g., pituitary, salivary, adrenal, mammary, and thyroid), pancreas, spinal cord, and trachea (Fawcett, 2000), little is known about PDE11A function. The present invention provides biological tools to study PDE11A function and methods to identify agents that regulate PDE11A activity for use in treating diseases and conditions that are linked to these PDE11A functions.
Presently, little is known about the PDE11 enzymes beyond their biochemical characteristics and basic genetics. Four variants of PDE11A have been identified (PDE11A1-4). The longest variant, PDE11A4, has two N-terminal GAF domains, whereas the other variants are truncations of this variant of varying lengths. The drug tadalafil (an approved PDE5 inhibitor) is also a potent inhibitor of PDE11, thus there is significant evidence that pharmacological inhibition of PDE11 is not harmful to humans.
It is clear that the PDE11A variants demonstrate differential tissue expression. In humans, PDE11A1 mRNA is most prominent in skeletal muscle and prostate. PDE11A3 mRNA is found specifically in testis and PDE11A4 mRNA is highly expressed in prostate. PDE11A protein localization studies have been somewhat contradictory in their findings, probably because of differences in the specificity of the antibodies used. PDE11A1 protein was originally detected in prostate and skeletal muscle, although a later study did not detect PDE11A1 protein in any tissues. In fact, only PDE11A4 protein has been verified and is found in prostate, pituitary, heart, and liver. Another study suggested that PDE11A is widely expressed, and immunohistochemistry using an antibody reported to recognize all PDE11A variants localized it to the epithelial, endothelial, and smooth muscle cells of many tissues, but at highest levels in the prostate, testis, kidney, adrenal gland, colon, and skin. However, a separate study did not find any PDE11 protein expression in human testis. As with many PDEs, it is still not clear if the same tissue, cellular, and subcellular localization is found among species. PDE11 is highly expressed in the testis, prostate, and developing spermatozoa.
Relatively little is known about the function of PDE11A, in part due to the lack of selective PDE11 inhibitors. However, recent reports with a PDE11 knockout mouse model have been interpreted to suggest that PDE11 may be important for sperm development and function, as well as psychiatric diseases such as schizophrenia (PNAS, 2010; 107(8); 8457-62), while gene association studies link mutations in PDE11A with adrenocortical tumors and Cushing's Syndrome in which cortisol levels in the blood are elevated. As such, a small molecule inhibitor of PDE11 could, and does, increase cortisol synthesis providing a therapeutic route to for treating adrenal insufficiency and adrenal insufficiency associated diseases. The present invention is directed toward overcoming one or more of the problems discussed above.

Inhibitors of phosphodiesterase 11 (PDE11)


A semiconductor device is disclosed. The semiconductor device includes: a substrate; a first tensile dielectric layer on the substrate; a metal gate in the first tensile dielectric layer; a second tensile dielectric layer on the first tensile dielectric layer; and a contact plug in the first tensile dielectric layer and the second tensile dielectric layer. Preferably, the top surface of the contact plug is even with the top surface of the second tensile dielectric layer, and a carbon content of the second tensile dielectric layer is greater than the carbon content of the first tensile dielectric layer.

1. Field of the Invention
The invention relates to an interlayer dielectric (ILD) layer, and more particularly, to an ILD layer having two tensile dielectric layers.
2. Description of the Prior Art
Semiconductor devices are typically joined together to form useful circuits using interconnect structures comprising conductive materials (e.g., metal lines) such as copper (Cu) or aluminum (Al) and dielectric materials such as silicon dioxide (SiO2). The speed of these interconnects can be roughly assumed to be inversely proportional to the product of the line resistance (R), and the capacitance (C) between lines. To reduce the delay and increase the speed, it is desirable to reduce the capacitance (C). This can be done by reducing the dielectric constant k of the dielectric material in the interlayer dielectric (ILD) layers.
Conventional approach for fabricating ILD layer typically includes forming a single layer of silicon dioxide on a substrate. This design is particularly disadvantageous when planarizing process, such as chemical mechanical polishing (CMP) process is conducted to remove the contact metal along with the ILD layer, a major portion of the ILD is lost due to topography loading effect during process and the height of the ILD layer is affected substantially.

Interlayer dielectric layer with two tensile dielectric layers


Analogs of CRF, which are based upon hCRF, oCRF, sauvagine and alpha-helical CRF, are disclosed that can be administered to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin, other products of the pro-opiomelanocortin gene and corticosterone levels and/or an increase in blood pressure over an extended period of time. One CRF agonist which has been found to be particularly potent is: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-D-Phe-His-Leu-Leu-Arg-Glu-Va l-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-L eu-Leu-Asp-Ile-Ala-NH.sub.2. In these agonist analogs, one or more of the first six N-terminal residues may be deleted and/or the N-terminal alpha-amino group may be acylated by an acylating agent containing up to 7 carbon atoms. A number of other substitutions may also be made throughout the chain. These analogs or pharmaceutically or veterinarily acceptable salts thereof, dispersed in a pharmaceutically or veterinarily acceptable liquid or solid carrier, can be administered to mammals, including humans. These analogs may also be used as stimulants to elevate mood and improve memory and learning, as well as diagnostically.

Experimental and clinical observations have supported the concept that the hypothalamus plays a key role in the regulation of adenohypophysial corticotropic cells secretory functions. Over 25 years ago, Guillemin, Rosenberg and Saffran and Schally independently demonstrated the presence of factors in hypothalamus which would increase the rate of ACTH secretion by the pituitary gland incubated in vitro or maintained in an organ culture. None of the secretagogs characterized met the criteria expected of a physiologic corticotropin releasing factor (CRF) until ovine CRF (oCRF) was characterized in 1981 as disclosed in U.S. Pat. No. 4,415,558, the disclosure of which is incorporated herein by reference. oCRF lowers blood pressure in mammals and stimulates the secretion of ACTH and .beta.-endorphin.
Rat CRF(rCRF) has been isolated, purified and characterized as a homologous hentetracontapeptide as disclosed in U.S. Pat. No. 4,489,163, the disclosure of which is incorporated herein by reference. The formula of human CRF has now been determined to be the same as that of rCRF, and the terms rCRF and hCRF are used interchangeably. Synthetic rCRF and oCRF stimulate ACTH and .beta.-endorphin-like activities (.beta.-END-LI) in vitro and in vivo and substantially lower blood pressure when injected peripherally, e.g. intravenously.

The Salk Institute for Biological Studies