gebhart/patrepeval huggingface dataset:
Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding (2017)

Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A₁, A<sub>2A</sub>, A<sub>2B</sub> and A₃, which belong to the G protein-coupled receptor (GPCR) superfamily. The human A₃AR (hA₃AR) subtype is implicated in several cytoprotective functions. Therefore, hA₃AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anticancer, and cardioprotective agents. Structure-based molecular modeling techniques have been applied over the years to rationalize the structure-activity relationships (SARs) of newly emerged A₃AR ligands, guide the subsequent lead optimization, and interpret site-directed mutagenesis (SDM) data from a molecular perspective. In this review, we showcase selected modeling-based and guided strategies that were applied to elucidate the binding of agonists to the A₃AR and discuss the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates.
A Stewart Platform- Based Manipulator: General Theory and Practical Construction (1986)

The Stewart Platform is one example of a parallel connection robot manipulator. This paper summarizes work that has been done at Oregon State University over the past several years on this topic. The work has fallen into two general areas: theoretical consideration of the generalized Stewart Platform and practical considerations for building a working machine. Both of these areas are covered in this paper. The theoretical part of the paper discusses the following four problems: 1. Given the position and orientation of the end effector, what are the actuator coordinates? 2. Given the velocity, position, and orientation of the end effector, what are the actuator velocities? 3. Given the forces exerted on the end effector by the external world and the accelerations of the end effèc tor, what are the forces at the actuators? 4. What are the singular configurations of the manipu lator? For the Stewart Platform, the singular configu rations are positions where the end effector gains one or more degrees of freedom. After the theoretical problems have been solved, there are still a group of practical problems to be tackled when a real machine is built. How can the general configuration be sim plified to make the solution of the equations practical? Once a configuration is decided upon, what are the construction considerations for building a real machine? What is the range of motion of the end effector? What are the necessary ranges of motion of the joints? What are the implications of the singularities of the Stewart Platform and what are some practical ways of solving the problems they cause? In the process of doing this research, three machines were built and a computer simulation was written and used. The most recent machine and the computer simulation will be described in this paper.
How to Build Scalable On-Chip ILP Networks for a Decentralized Architecture (2000)

The era of billion transistors-on-a-chip is creating a completely different set of design constraints, forcing radically new microprocessor archiecture designs. This paper examines a few of the possible microarchitectures that are capable of obtaining scalable ILP performance. First, we observe that the network that interconnects the processing elements is the critical design point in the microarchitecture. Next, we characterize four fundamental properties that have to be satisfied by the interconnection network. Next, we provide case studies of two different networks that satisfy these properties. Finally, a detailed evaluation of these networks is presented to highlight the scalability and performance of these microarchitectures. We show that by using compile time information, we can build simpler networks and use them efficiently.
Novel orally active inhibitors of passive cutaneous anaphylaxis in rats: N-[2-(4-Pyridinyl)-4-pyrimidinyl] ureas and dialkyl [[[2-(4-pyridinyl)-4-pyrimidinyl]amino]methylene]malonates (1982)

4-Chloro-2-(4-pyridinyl)pyrimidines were treated with alkylamines to afford the corresponding N-substituted amino derivatives. 4-Amino-2-(4-pyridinyl)pyrimidines and their N-substituted analogues were converted to amides, carbamates, aminomethylenemalonates, and ureas. Many of these compounds were found to have potential antiallergic activity as indicated by the rat passive cutaneous anaphylaxis screen. The most compounds were found in the last two series.
Kinetic Analysis by Fluorescence of the Interaction between Ras and the Catalytic Domain of the Guanine Nucleotide Exchange Factor Cdc25Mm (1998)

Guanine nucleotide exchange factors (GEFs) activate Ras proteins by stimulating the exchange of GTP for GDP in a multistep mechanism which involves binary and ternary complexes between Ras, guanine nucleotide, and GEF. We present fluorescence measurements to define the kinetic constants that characterize the interactions between Ras, GEF, and nucleotides, similar to the characterization of the action of RCC1 on Ran [Klebe et al. (1995) Biochemistry 34, 12543-12552]. The dissociation constant for the binary complex between nucleotide-free Ras and the catalytic domain of mouse Cdc25, Cdc25(Mm285), was 4.6 nM, i.e., a 500-fold lower affinity than the Ras.GDP interaction. The affinities defining the ternary complex Ras. nucleotide.Cdc25(Mm285) are several orders of magnitude lower. The maximum acceleration by Cdc25(Mm285) of the GDP dissociation from Ras was more than 10(5)-fold. Kinetic measurements of the association of nucleotide to nucleotide-free Ras and to the binary complex Ras. Cdc25(Mm285) show that these reactions are practically identical: a fast binding step is followed by a reaction of the first order which becomes rate limiting at high nucleotide concentrations. The second reaction is thought to be a conformational change from a low- to a high-affinity nucleotide binding conformation in Ras. Taking into consideration all experimental data, the reverse isomerization reaction from a high- to a low-affinity binding conformation in the ternary complex Ras. GDP.Cdc25(Mm285) is postulated to be the rate-limiting step of the GEF-catalyzed exchange. Furthermore, we demonstrate that the disruption of the Mg2+-binding site is not the only factor in the mechanism of GEF-catalyzed nucleotide exchange on Ras.
Isolation of Swine Influenza Virus from Autopsy Lung Tissue of Man (1976)

Swine influenza virus, or an antigenically closely related virus, has been considered to be the etiologic agent of the 1918 influenza pandemic.1 2 3 4 Influenza in swine has continued to occur in the United States5 and other countries, but despite frequent and close contact between human beings and swine, human infection with the swine influenza virus has been difficult to ascertain even by serologic methods.6 We report the isolation of swine influenza virus from lung specimens obtained at autopsy from a 16-year-old boy.Case ReportThe patient, who lived on a farm where swine were raised, was seen in November, 1971, at . . .
Minimum energy mobile wireless networks (2002)

We describe a distributed position-based network protocol optimized for minimum energy consumption in mobile wireless networks that support peer-to-peer communications. Given any number of randomly deployed nodes over an area, we show that a simple local optimization scheme executed at each node guarantees strong connectivity of the entire network and attains the global minimum energy solution for the stationary case. Due to its localized nature, this protocol proves to be self-reconfiguring and stays close to the minimum energy solution when applied to the case of mobile nodes. Our simulations verify its performance.
Primary myocardial disease in the diabetic mouse. An ultrastructural study. (1979)

The hearts from C57BL/KsJ db+/db+ mice and controls were examined by light and electron microscopy at intervals during 5 to 28 weeks of age. C57BL/6J ob/ob mice and their lean littermates served as other controls. The percentage of increase in body and heart weights of the diabetic animals was 150% and 64% greater, respectively, than that of the controls. Over the period of observation there was progressive damage to the ventricular myocytes and intramural small arteries and arterioles of the diabetic animals. Initially, the cardiac muscle cells of both ventricles contained large numbers of lipid droplets. Subsequently, there was shrinkage and increased electron density of mitochondria that were enveloped by single limiting membranes that in turn gave rise to large residual bodies. This was followed by loss of myofilaments and atrophy of myocytes. Similar changes occurred in the smooth muscle cells of intramural arteries and arterioles but not in those of epicardial arteries. Reduplicated layers of basal laminae were seen around interstitial capillaries. Degenerative changes also occurred in perivascular nerve endings. These changes are discussed in relation to the altered metabolism of the diabetic state. It is concluded that the pathologic lesions in the cardiac muscle cells and intramural arterial vessels and capillaries constitute a primary myocardial disease in the genetically diabetic mouse.
Effect of Protein Ingestion on the Glucose and Insulin Response to a Standardized Oral Glucose Load (1984)

Type II diabetic subjects were given 50 g protein, 50 g glucose, or 50 g glucose with 50 g protein as a single meal in random sequence. The plasma glucose and insulin response was determined over the subsequent 5 h. The plasma glucose area above the baseline following a glucose meal was reduced 34% when protein was given with the glucose. When protein was given alone, the glucose concentration remained stable for 2 h and then declined. The insulin area following glucose was only modestly greater than with a protein meal (97 +/- 35, 83 +/- 19 microU X h/ml, respectively). When glucose was given with protein, the mean insulin area was considerably greater than when glucose or protein was given alone (247 +/- 33 microU X h/ml). When various amounts of protein were given with 50 g glucose, the insulin area response was essentially first order. Subsequently, subjects were given 50 g glucose or 50 g glucose with 50 g protein as two meals 4 h apart in random sequence. The insulin areas were not significantly different for each meal but were higher when protein + glucose was given. After the second glucose meal the plasma glucose area was 33% less than after the first meal. Following the second glucose + protein meal the plasma glucose area was markedly reduced, being only 7% as large as after the first meal. These data indicate that protein given with glucose will increase insulin secretion and reduce the plasma glucose rise in at least some type II diabetic persons.
Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes (2010)

Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy number mutations in SNCA which encodes alpha-synuclein, a primary protein constituent of Lewy bodies, the pathognomonic protein aggregates found in neurons in PD. We set out to develop transgenic mice expressing mutant alpha-synuclein (either A53T or A30P) from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines show robust abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also has abnormal motor behavior but neither demonstrates cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions or neurodegeneration. These animals recapitulate the early gastrointestinal abnormalities seen in human PD. The animals also serve as an in vivo system in which to investigate therapies for reversing the neurological dysfunction that target alpha-synuclein toxicity at its earliest stages.
The metagenomics RAST server – a public resource for the automatic phylogenetic and functional analysis of metagenomes (2008)

The open-source metagenomics RAST service provides a new paradigm for the annotation and analysis of metagenomes. With built-in support for multiple data sources and a back end that houses abstract data types, the metagenomics RAST is stable, extensible, and freely available to all researchers. This service has removed one of the primary bottlenecks in metagenome sequence analysis - the availability of high-performance computing for annotating the data. http://metagenomics.nmpdr.org.
Idiopathic pulmonary fibrosis: from clinical trials to real-life experiences (2015)

Randomised controlled clinical trials are fundamental in medicine to develop new effective drugs and new therapeutic regimens and are the strength of evidence-based medicine. These studies allow us to avoid the repetition of misleading experiences that have been reported in the past, where drugs or associations were utilised without compelling evidence and ultimately proven to be ineffective. In recent years, randomised clinical trials have been conducted and concluded for many rare diseases, including idiopathic pulmonary fibrosis. However, clinical trials do not always reflect the real-life scenario. Patients selected for clinical trials present fewer comorbidities, they fall between certain age limits, and the severity of their disease is defined; therefore, they do not always reflect the whole of the population affected by a specific disease. These are the reasons why we also need data that mirror real-life experience. The limitations that these kind of studies present are always several and the studies should be interpreted with caution, although they can fill the important gap between efficacy and effectiveness. In this article, we will review the existing clinical data on real-life treatment of idiopathic pulmonary fibrosis.
TIM‐3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines (2009)

TIM-3 is a molecule selectively expressed on a subset of murine IFN-gamma-secreting T helper 1 (Th1) cells but not Th2 cells, and regulates Th1 immunity and tolerance in vivo. At this time little is known about the role of TIM-3 on human T cells. To determine if TIM-3 similarly identifies and regulates Th1 cells in humans, we generated a panel of mAb specific for human TIM-3. We report that TIM-3 is expressed by a subset of activated CD4(+) cells, and that anti-CD3/anti-CD28 stimulation increases both the level of expression as well as the number of TIM-3(+) T cells. We also find that TIM-3 is expressed at high levels on in vitro polarized Th1 cells, and is expressed at lower levels on Th17 cells. In addition, human CD4(+) T cells secreted elevated levels of IFN-gamma, IL-17, IL-2, and IL-6, but not IL-10, IL-4, or TNF-alpha, when stimulated with anti-CD3/anti-CD28 in the presence of TIM-3-specific, putative antagonistic antibodies. This was not mediated by differences in proliferation or cell death, but rather by induction of cytokines at the transcriptional level. These results suggest that TIM-3 is a negative regulator of human T cells and regulates Th1 and Th17 cytokine secretion.
Expression of SS-A/Ro and SS-B/La Antigens in Skin Biopsy Specimens of Patients With Photosensitive Forms of Lupus Erythematosus (2000)

These findings indicate that photosensitivity and the presence and titer of circulating anti-SS-A/Ro and anti-SS-B/La antibodies are both directly correlated with the expression of accessible and immunoreactive SS-A/Ro and SS-B/La antigens in the skin specimens of patients with LE. Thus, the expression of these antigens in keratinocytes may be an important determinant of the development of both SS-A/Ro and SS-B/La autoantibodies and of photosensitive forms of LE.
A Network Model of a Cooperative Genetic Landscape in Brain Tumors (2009)

The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis.
Cross-Reacting Antibodies Enhance Dengue Virus Infection in Humans (2010)

Dengue virus co-circulates as four serotypes, and sequential infections with more than one serotype are common. One hypothesis for the increased severity seen in secondary infections is antibody-dependent enhancement (ADE) leading to increased replication in Fc receptor-bearing cells. In this study, we have generated a panel of human monoclonal antibodies to dengue virus. Antibodies to the structural precursor-membrane protein (prM) form a major component of the response. These antibodies are highly cross-reactive among the dengue virus serotypes and, even at high concentrations, do not neutralize infection but potently promote ADE. We propose that the partial cleavage of prM from the viral surface reduces the density of antigen available for viral neutralization, leaving dengue viruses susceptible to ADE by antibody to prM, a finding that has implications for future vaccine design.
Buffer sizing for high speed video information retrieval on ATM networks (2002)

Residential multimedia service provisioning is the challenge of future generation high-speed networks. Despite the large bandwidth availability, direct circuit switched connections from customers to remote servers may be critical in terms of network performance. Substantial advantages can be achieved when buffers, placed at the local switching nodes, are in charge of decoupling the retrieval rate on the long distance network from the delivery speed of video information on the local loop. In previous contributions, performance bounds have been obtained in the assumption of very large buffering capability. This paper evaluates the effect of limited buffer size on the blocking probability of video retrieval requests, and shows that optimal performance is achieved with a relatively limited storage capability.
Observation and Photophysical Characterization of Silicon Phthalocyanine J‐Aggregate Dimers in Aqueous Solutions (2014)

The use of macrocyclic molecules for both imaging and photodynamic therapy (PDT) has proven to be a powerful method for assessing and treating diseases, respectively. However, many potential candidates for these applications rely on rigid organic structures which are hydrophobic and thus lead to possible aggregation in aqueous solutions such as blood. Here, we describe the discovery of noncovalent J-aggregate dimers of the asymmetrically, axially modified silicon phthalocyanine 4 (Pc 4) in aqueous solutions through steady-state and time-resolved spectroscopy. Remarkably, the monomer-dimer equilibrium is dictated by water content and pH, with free monomers resulting in favorable solvation conditions even after formation of the dimer complex. This work sheds light on previous observations of Pc 4 behavior in cells during PDT, and can further elucidate the structure-activity relationship of these important molecules.
Requirements for triggering of lysis by cytolytic T lymphocyte clones. (1987)

Cloned murine cytolytic T lymphocytes (CTL) having defined specificity were triggered by the phorbol ester together with a calcium ionophore (either A23187 or Ionomycin) to lyse syngeneic or third party target cells efficiently. Neither phorbol 12-myristate 13-acetate (PMA) nor calcium ionophore alone induced efficient lysis. The characteristics of the lytic process induced by these signals are similar to those of antigen-specific or lectin-facilitated lysis by CTL. Lysis is calcium and temperature dependent and shows kinetics which are not grossly different from lysis mediated via the antigen receptor. Two helper T lymphocyte clones were not induced to lyse efficiently EL-4 target cells by concanavalin A or PMA + ionophore. Triggering of lysis induced with PMA plus ionophore by the CTL clone L3 differed from antigen-mediated lysis in specificity and in the susceptibility to inhibition by cytochalasin B. Properties of the target cell determine which cell surface associative recognition structures are important in the efficient lysis of these cells. Anti-LFA-1 monoclonal antibodies inhibited efficiently both antigen-mediated and PMA + ionophore-induced lysis of P-815 or EL-4 target cells which are of hematopoietic origin. However, anti-LFA-1 antibodies do not inhibit antigen-mediated, lectin-facilitated, or PMA + Ionomycin-induced CTL cytolysis of target cells derived from the L cell fibroblast line. We conclude that two intracellular signals, which can be provided by the combination of PMA + ionophore, are required for efficient lysis by antigen-specific murine CTL clones. When the T cell receptor for antigen is bypassed using PMA + ionophore to trigger lysis, we show that Lyt-2 and LFA-1 molecules may be required for efficient lysis. These associative recognition structures appear to play an important role in postactivation steps leading to efficient delivery of the lethal hit to the target cell.
HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection (1993)

Inasmuch as the hepatitis B virus (HBV) is not directly cytopathic for the infected hepatocyte, it is generally presumed that viral clearance and liver cell injury during viral hepatitis are due to a CTL response to HBV encoded Ag presented by HLA class I molecules. We have previously examined the peripheral blood CTL response to two HBV nucleocapsid epitopes in patients with acute and chronic viral hepatitis, one of which is restricted by HLA-A2, whereas the other is dually restricted by HLA-A31 and Aw68. In this study, we defined the HLA-A2-restricted CTL response to the hepatitis B surface Ag (HBsAg) by using a panel of HBsAg-derived synthetic peptides containing the ideal HLA-A2.1 binding motif (-L------V). Several novel aspects of HBV immunobiology and pathogenesis are evident from this study. First, the peripheral blood CTL response to HBV-encoded Ag is remarkably polyclonal and multispecific in most patients with acute hepatitis. Indeed, HLA-A2-restricted CTL specific for as many as four envelope epitopes and one nucleocapsid epitope were found to be present simultaneously in individual patients with acute viral hepatitis. Second, HBV-specific CTL are not detectable in the peripheral blood in a minority of patients with acute hepatitis, nor have we detected a CTL response in any of the patients with chronic hepatitis that we have studied thus far. Although the cellular and molecular basis for CTL nonresponse remains to be determined, the data suggest that it may contribute to viral persistence. Third, the diversity and the specificity of the CTL response is determined in part by the coding sequence of the viral genome present in each infected patient. Indeed, the apparent nonresponse of some acutely infected patients to at least one HBsAg-specific CTL epitope actually reflects infection by a viral variant that contains a critical substitution in one of the anchor residues within the epitope. Finally, at a fundamental level, the data suggest that the presence of the HLA-A2.1-binding motif in a peptide may not be sufficient for binding; and the capacity of a peptide to bind the class I molecule does not guarantee that it will be immunogenic.