gebhart/patrepeval huggingface dataset:
TRPM3 in temperature sensing and beyond (2015)

TRPM3, also known as melastatin 2 (MLSN2), LTRPC3 (long TRPC3) and KIAA1616, is a member of the TRPM subfamily of transient receptor potential (TRP) ion channels. The channel was originally identified as a volume-regulated ion channel that can be activated upon reduction of the extracellular osmolality. Later, the channel was proposed to be involved in the modulation of insulin release in pancreatic islets. However, new evidence has uncovered a role of TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat. The channel is functionally expressed in a subset of neurons of the somatosensory system and can be activated by heat. The purpose of the present review is to summarize existing knowledge of the expression, biophysics and pharmacology of TRPM3 and to serve as a guide for future studies aimed at improving the understanding of the mechanism of thermosensation and proposed physiological functions of TRPM3.
Drug Form Selection in Albuterol-Containing Metered-Dose Inhaler Formulations and Its Impact on Chemical and Physical Stability (1997)

New albuterol-containing metered-dose inhaler (MDI) formulations were under development to replace chlorofluorocarbon (CFC) propellants with more environmentally friendly hydrofluoroalkane (HFA) propellants. To achieve good chemical and physical stability of MDI formulations with HFA propellants, different drug forms were evaluated in model formulations (drug, oleic acid, and one of the following: P12/P11, P12/ethanol, P12, P134a/ethanol, P134a). The effects of drug form (base versus sulfate), propellant type (P12 versus P134a), and cosolvent type (P11 or ethanol versus none) on the chemical and physical stability were examined. The chemical stability of the formulations was determined by monitoring the percent drug remaining in the formulations using HPLC. The physical stability of the formulations was followed by visually assessing the suspension appearance, and by determining the mass median diameter (MMD) of the suspended particles using laser diffraction analysis. The drug form has a great impact on the chemical and physical stability of the formulations. The sulfate formulations were chemically stable up to 12 months when stored at 30 degrees C and 40 degrees C/85% relative humidity (RH). Poor chemical stability was observed for the base formulations, except for ethanol-free formulations (P12/P11, P12, and P134a) at 30 degrees C and a P134a formulation at 40 degrees C/85% RH. The chemical instability of albuterol base formulations at 30 degrees C correlates with its solubility. The presence of a cosolvent greatly improved the dispersion characteristics of both sulfate and base formulations. The sulfate formulations in the presence of a cosolvent (P12/P11, P12/ethanol, and P134a/ethanol) showed good physical stability when stored for up to 12 months at 30 degrees C and 40 degrees C/85% RH. The physical stability of the base formulations was not acceptable due to crystal growth/agglomeration in all formulations, except for the P12/P11 formulation. The physical instability of both sulfate and base formulations not only correlates with the drug solubility, but also with particle agglomeration. In conclusion, good chemical and physical stability of albuterol-containing suspension formulations can be achieved with the appropriate choice of drug form and formulation constituents.
Virtual ring routing (2006)

This paper presents Virtual Ring Routing (VRR), a new network routing protocol that occupies a unique point in the design space. VRR is inspired by overlay routing algorithms in Distributed Hash Tables (DHTs) but it does not rely on an underlying network routing protocol. It is implemented directly on top of the link layer. VRR provides both raditional point-to-point network routing and DHT routing to the node responsible for a hash table key.VRR can be used with any link layer technology but this paper describes a design and several implementations of VRR that are tuned for wireless networks. We evaluate the performance of VRR using simulations and measurements from a sensor network and an 802.11a testbed. The experimental results show that VRR provides robust performance across a wide range of environments and workloads. It performs comparably to, or better than, the best wireless routing protocol in each experiment. VRR performs well because of its unique features: it does not require network flooding or trans-lation between fixed identifiers and location-dependent addresses.
Extracellular purines, purinergic receptors and tumor growth (2016)

Virtually, all tumor cells as well as all immune cells express plasma membrane receptors for extracellular nucleosides (adenosine) and nucleotides (ATP, ADP, UTP, UDP and sugar UDP). The tumor microenvironment is characterized by an unusually high concentration of ATP and adenosine. Adenosine is a major determinant of the immunosuppressive tumor milieu. Sequential hydrolysis of extracellular ATP catalyzed by CD39 and CD73 is the main pathway for the generation of adenosine in the tumor interstitium. Extracellular ATP and adenosine mold both host and tumor responses. Depending on the specific receptor activated, extracellular purines mediate immunosuppression or immunostimulation on the host side, and growth stimulation or cytotoxicity on the tumor side. Recent progress in this field is providing the key to decode this complex scenario and to lay the basis to harness the potential benefits for therapy. Preclinical data show that targeting the adenosine-generating pathway (that is, CD73) or adenosinergic receptors (that is, A2A) relieves immunosuppresion and potently inhibits tumor growth. On the other hand, growth of experimental tumors is strongly inhibited by targeting the P2X7 ATP-selective receptor of cancer and immune cells. This review summarizes the recent data on the role played by extracellular purines (purinergic signaling) in host-tumor interaction and highlights novel therapeutic options stemming from recent advances in this field.
Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes (2005)

Reactive microglia in the CNS have been implicated in the pathogenesis of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, the mechanism by which activated microglia kill oligodendrocytes (OLs) remains elusive. Here we show that lipopolysaccharide (LPS)-induced death of developing OLs is caused by microglia-derived peroxynitrite, the reaction product of nitric oxide (NO) and superoxide anion. Blocking peroxynitrite formation with nitric oxide synthase inhibitors, superoxide dismutase mimics, or a decomposition catalyst abrogated the cytotoxicity. Only microglia, but not OLs, expressed inducible NO synthase (iNOS) after LPS challenge; microglia from iNOS knockout mice were not cytotoxic upon activation. The molecular source for superoxide was identified as the superoxide-generating enzyme NADPH oxidase. The oxidase was activated upon LPS exposure, and its inhibition prevented microglial toxicity toward OLs. Furthermore, microglia isolated from mice deficient in the catalytic component of the oxidase, gp91(phox), failed to induce cell death. Our results reveal a role for NADPH oxidase in LPS-induced OL death and suggest that peroxynitrite produced by iNOS and NADPH oxidase in activated microglia may play an important role in the pathogenesis of white matter disorders.
Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. (2003)

Previous studies of oncogene and tumor suppressor gene alterations have suggested that differences exist in the molecular pathogenesis of the various histological types of endometrial cancer. To elucidate further the molecular events involved in endometrial carcinogenesis, we examined global expression patterns of 16 nonendometrioid cancers (13 serous papillary and 3 clear cell), 19 endometrioid cancers, and 7 age-matched normal endometria using cDNA microarrays. Unsupervised analysis of gene expression identified 191 genes that exhibited >2-fold differences (P < 0.001) between the histological groups. Many genes were similarly dysregulated in both nonendometrioid and endometrioid cancers relative to normal endometria. Gene expression differences in only 24 transcripts could distinguish serous from endometrioid cancers, the two most common subgroups. These data provide the basis for investigation of previously unrecognized novel pathways involved in the development of endometrial cancers.
LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B<sub>2</sub> receptor (1998)

1. In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-p henyl]sulphonyl] -2(S) - [[4 -[4-(aminoiminomethyl)phenylcarbonyl]piperazin-1-yl]ca rbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B2 receptor. 2. LF 16.0335 displaced [3H]-BK binding to membrane preparations from CHO cells expressing the cloned human B2 receptor, INT 407 cells and human umbilical vein with Ki values of 0.84+/-0.39 nM, 1.26+/-0.68 nM and 2.34+/-0.36 nM, respectively. 3. In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, max values of [3H]-BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist. 4. LF 16.0335 had no affinity for the cloned human kinin B1 receptor stably expressed in 293 cells. In addition, this compound at 1 microM did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M2 and M1 receptors for which an IC50 value of 0.9 and 1 microM was obtained. 5. BK stimulates in a concentration-dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration-response-curves to BK were shifted to the right in the presence of LF 16.0335 (0.1 microM) without reduction of the maximum. LF 16.0335 inhibited the concentration-contraction curve to BK in the human umbilical vein giving a pA2 value of 8.30+/-0.30 with a Schild plot slope that was not different from unity. 6. These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B2 receptor.
Positive and Negative Symptom Response to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome (1998)

For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome.
Protocatechuate is not metabolized via catechol in Enterobacter aerogenes (1987)

Protocatechuate is generally metabolized in bacteria by direct oxygenative cleavage to produce beta-carboxymuconate. An exception to this pattern has been suggested by reports that protocatechuate might be metabolized by nonoxidative decarboxylation to catechol in Enterobacter aerogenes. In the present investigation, analysis of mutant strains indicated that this proposed pathway did not make a significant contribution to protocatechuate metabolism in E. aerogenes because mutations blocking catechol metabolism did not impair protocatechuate utilization. In addition, all the enzymes required for the oxygenative cleavage of protocatechuate and its further metabolism were induced in E. aerogenes during protocatechuate metabolism, and mutations inactivating this oxygenative pathway prevented protocatechuate degradation. The strains of E. aerogenes examined exhibited broad specificities of inductive control over genes associated with protocatechuate and catechol metabolism; it appears that a number of metabolites may trigger the expression of these genes.
Phase <scp>I</scp>/<scp>II</scp> trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma (2012)

Bendamustine, active in multiple myeloma (MM), is a bifunctional mechlorethamine derivative with alkylating properties. Bortezomib, approved to treat MM, is effective in combination with alkylators. The tolerability and efficacy of bendamustine plus bortezomib in relapsed/refractory MM was assessed in an open-label, dose-escalating, phase I/II study. Patients aged ≥18 years received intravenous bendamustine 50, 70, or 90 mg/m(2) (days 1 and 4) plus bortezomib 1·0 mg/m(2) (days 1, 4, 8, and 11) for up to eight 28-day cycles. No dose-limiting toxicity was observed after cycle 1; bendamustine 90 mg/m(2) plus bortezomib 1·0 mg/m(2) was designated the maximum tolerated dose (MTD). The most common grade 3/4 adverse events were leucopenia (58%), neutropenia (50%), lymphopenia (45%), and thrombocytopenia (30%). Primary efficacy measure was overall response rate (ORR), which was the combined complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR). ORR was 48% (one CR, two VGPR, nine PR, and seven MR) for all 40 enrolled patients, 52% (16/31) at the MTD (90 mg/m(2) ), and 42% and 46% for prior use of bortezomib (n = 31) or alkylators (n = 28) respectively. Bendamustine plus bortezomib was well tolerated with promising efficacy in this heavily pretreated population.
Speaking mode dependent pronunciation modeling in large vocabulary conversational speech recognition (1997)

In spontaneous conversational speech there is a large amount o f v ariability due to accents, speaking styles and speaking rates also known as the speaking mode 3 .Because current recognition systems usually use only a relatively small number of pronunciation variants for the words in their dictionaries, the amount o f v ariability that can be modeled is limited.Increasing the number of variants per dictionary entry is the obvious solution.Unfortunately, this also means increasing the confusability between the dictionary entries, and thus often leads to an actual performance decrease.In this paper we present a framework for speaking mode dependent pronunciation modeling.The probability of encountering pronunciation variants is de ned to be a function of the speaking style.The probability function is learned through decision trees from rule based generated pronunciation variants as observed on the Switchboard corpus.The framework is successfully applied to increase the performance of our state-of-the-art Janus Recognition Toolkit Switchboard recognizer signi cantly.
Diode-bar side pumping of double-clad fibers (2007)

We demonstrate direct diode-bar side pumping of a Yb-doped fiber laser using embedded-mirror side pumping (EMSP). In this method, the pump beam is launched by reflection from a micro-mirror embedded in a channel polished into the inner cladding of a double-clad fiber (DCF). The amplifier employed an unformatted, non-lensed, ten-emitter diode bar (20 W) and glass-clad, polarization-maintaining, large-mode-area fiber. Measurements with passive fiber showed that the coupling efficiency of the raw diode-bar output into the DCF (ten launch sites) was ~84%; for comparison, the net coupling efficiency using a conventional, formatted, fiber-coupled diode bar is typically 50-70%, i.e., EMSP results in a factor of 2-3 less wasted pump power. The slope efficiency of the side-pumped fiber laser was ~80% with respect to launched pump power and 24% with respect to electrical power consumption of the diode bar; at a fiber-laser output power of 7.5 W, the EMSP diode bar consumed 41 W of electrical power (18% electrical-to-optical efficiency). When end pumped using a formatted diode bar, the fiber laser consumed 96 W at 7.5 W output power, a factor of 2.3 less efficient, and the electrical-to-optical slope efficiency was lower by a factor of 2.0. Passive-fiber measurements showed that the EMSP alignment sensitivity is nearly identical for a single emitter as for the ten-emitter bar. EMSP is the only method capable of directly launching the unformatted output of a diode bar directly into DCF (including glass-clad DCF), enabling fabrication of low-cost, simple, and compact, diode-bar-pumped fiber lasers and amplifiers.
The World Bank and telecommunications lending (2004)

This paper focuses on the performance of the World Bank Group's activities in the telecommunications sector during the 1990s, using data on telecommunications rollout and reform as well as data on WBG's projects. The data suggests that World Bank projects are associated with progress in telecommunications reform and an increase in the growth rate of telecommunications networks. The data also suggests that International Finance Corporation (IFC) projects are associated with more rapid rollout of telecommunications services at the national level. This note looks at the success of WBG in fostering reform and improving teledensity in client countries on a crosscountry basis. It also evaluates the impact of projects on rollout of telecommunications services as a result of reform. WBG ICT projects are associated with significant improvements in the environment for private, competitive provision of services in developing countries. These results of the study are preliminary, using simple techniques and imperfect data. Nonetheless, it is fair to say that World Bank projects appear to be associated with progress on the telecommunications reform agenda and with faster rollout of services as a result. IFC projects also appear to be associated with faster rollout of services. While the lion's share of credit should be attributed to the governments that implement the reforms and the companies that provide the services, this evidence suggests that the WBG's project work facilitated the rapid rollout of telecommunications services to the citizens of its client countries over the last 10 years.
Hemodynamics and Autonomic Control of Heart Rate Turbulence (2005)

Delayed sympathetically mediated vasomotor response to VPC produces systolic blood pressure overshoot. This subsequently induces vagally mediated late heart rate deceleration. Under physiologic conditions, there is no evidence of other hemodynamic and/or mechanical effect outside the autonomic reflex arch. In patients with LV dysfunction, both depressed vagal and sympathetic modulation and, indirectly, enhanced postextrasystolic potentiation account for attenuated HRT.
Effect of Pimobendan on Echocardiographic Values in Dogs with Asymptomatic Mitral Valve Disease (2009)

Abstract Background Pimobendan (PIMO) is a novel inodilator that has shown promising results in the treatment of advanced mitral valve disease (MVD), but little is known about its hemodynamic effects, especially regarding the mitral regurgitant volume in naturally occurring MVD. Hypothesis The addition of pimobendan to treatment decreases the regurgitant fraction (RF) in dogs with asymptomatic MVD. Animals Twenty-four client-owned dogs affected by International Small Animal Cardiac Health Council class Ib MVD. Methods Prospective, blinded, and controlled clinical trial. Dogs were assigned to a PIMO treatment group (n = 19) (0.2–0.3 mg/kg q12h) or a control group (n = 5). Echocardiographic evaluations were performed over a 6-month period. Results The addition of PIMO to treatment did not decrease the RF of dogs affected by asymptomatic class 1b MVD over the study period (P= .85). There was a significant increase in the ejection fraction of the PIMO treated dogs at 30 days (80.8 ± 1.42 versus 69.0 ± 2.76, corrected P= .0064), and a decrease in systolic left ventricular diameter (corrected P= .011) within the PIMO group compared with baseline. However, this improvement in systolic function was not sustained over the 6-month trial period. Conclusion and Clinical Importance This study did not identify beneficial long-term changes in the severity of mitral regurgitation after addition of PIMO to angiotensin converting enzyme inhibitor treatment of dogs with asymptomatic MVD.
Effects of two direct-fed microbials on the ability of pigs toresist an infection with Salmonella enterica serovarTyphimurium (2008)

Materials and methods: Forty finishing pigs were used in a 12-day disease challenge study. Dietary treatments included no DFM (Control; 20 pigs), DFM provided in drinking water (E faecium), or DFM provided in feed (Bacillus). Ten Control pigs were not challenged with Salmonella Typhimurium; the remaining 30 pigs were inoculated on Day 0. Fecal samples were cultured for Salmonella Typhimurium on Days 0 to 5, 9, and 12. Serum haptoglobin (Hp), α1-acid glycoprotein (AGP), IgG, and IgM concentrations were measured. Pigs were euthanized on Day 12, and tissue and digesta were tested for presence and numbers of salmonellae.
X-ray Structure of Motor and Neck Domains from Rat Brain Kinesin<sup>,</sup> (1997)

We have determined the X-ray structure of rat kinesin head and neck domains. The folding of the core motor domain resembles that of human kinesin reported recently [Kull, F. J., et al. (1996) Nature 380, 550-554]. Novel features of the structure include the N-terminal region, folded as a beta-strand, and the C-terminal transition from the motor to the rod domain, folded as two beta-strands plus an alpha-helix. This helix is the beginning of kinesin's neck responsible for dimerization of the motor complex and for force transduction. Although the folding of the motor domain core is similar to that of a domain of myosin (an actin-dependent motor), the position and angle of kinesin's neck are very different from those of myosin's stalk, suggesting that the two motors have different mechanisms of force transduction. The N- and C-terminal ends of the core motor, thought to be responsible for the directionality of the motors [Case, R. B., et al. (1997) Cell 90, 959-966], take the form of beta-strands attached to the central beta-sheet of the structure.
Tarnished Vision (2004)

Too much iron wrinkles vision, according to new work. Mice that lack two iron-oxidizing enzymes show signs of age-related macular degeneration, the most common cause of vision loss in elderly people. The study suggests that drugs that reduce iron amounts might prevent or slow the disease.
Transmission parameter selection in an adaptive packet-radio network (2002)

Packet-radio networks (PRNs) can experience variations in radio-channel quality due to nodal mobility, network congestion, and adversarial behavior. For this reason, PRNs must be designed with adaptivity in mind. A link-layer protocol termed the transmission parameter selection algorithm (TPSA)-that provides real-time, distributed control of radio transmission parameters including power level, data rate, and forward error correction (FEC) rate is discussed. TPSA design methodology is presented, including the implementation details of a specific TPSA designed with the single goal of maximizing throughput in a direct-sequence spread-spectrum network. The related topic of link quality assessment is discussed, with attention given to a technique which infers link quality from the presence or absence of acknowledgments. Finally, suggestions for TPSA interaction with routing algorithms are offered. >