gebhart/patrepeval huggingface dataset:
DIABETES MELLITUS TYPE II: REVIEW OF ORAL TREATMENT OPTIONS (2010)

Introduction: Type 2 diabetes is a chronic disease that has very serious complications if not appropriately treated. Many oral hypoglycemic agents have been effective recommendations in treating type 2 diabetes. Sitagliptin (Januvia), Exenatide (Byetta), and Exubera are 2 newer agents that have proven efficacious in disease management. The purpose of this paper is to review the efficacy, use, and tolerability of oral hypoglycemic agents that are older compared to Sitagliptin (Januvia), Exubera, and Exenatide (Byetta). Treatment Options: Oral hypoglycemic agents for treatment of type 2 diabetes comprise of seven different classes. Each one of those classes has its advantages and disadvantages. Sulfonylureas, Short‐acting insulin Secretagogues, Biguanides, alpha‐Glucosidase inhibitors, and Thiazolidinediones are the older classes. Sitagliptin (Januvia) is a dipeptidyl‐peptidase‐4 inhibitor (DPP‐4), and Exenatide is an incretin mimetic which inhibits the enzymatic activity of DPP‐4 . E xubera is an inhaled newly approved interesting technique in treatment of type 2 diabetes. Oral combinations have improved patients’ compliance and had supportive data in mastering disease management. Discussion: Selection of an appropriate pharmacological agent is based on considerations of it’s clinical efficacy as far as the risk versus benefit, cost, characteristics of the patient, and levels of glucose control. Sulfonylureas are best for patients with diagnosis of type 2 diabetes when they are less than 40 years of age. Short ‐acting insulin secretagogues have a rapid onset of action. Metformin is an appropriate agent to reduce weight and decrease insulin resistance. Thiazolidinediones are very important in maintaining glycemic control and improve beta cell function. They have enormous evidence of reducing HbA1C and Blood glucose levels. Sitagliptin and Exenatide are new innovations proven to improve glycemic control as well as inhaled Exubera therapy. Conclusion: Sitagliptin, Exenatide, and Exubera do offer a new approach in assisting patients with type 2 diabetes. Benefits of pharmacological agents are not complete unless accompanied by non‐pharmacological treatments.
Molecular characterization of phycobilisome regulatory mutants of Fremyella diplosiphon (1989)

Three classes of pigment mutants were generated in Fremyella diplosiphon in the course of electroporation experiments. The red mutant class had high levels of phycoerythrin in both red and green light and no inducible phycocyanin in red light. Thus, this mutant behaved as if it were always in green light, regardless of light conditions. Blue mutants exhibited normal phycoerythrin photoregulation, whereas the inducible phycocyanin was present at high levels in both red- and green-light-grown cells. Furthermore, the absolute amount of allophycocyanin was increased threefold in comparison with our wild-type strain. Green mutants lost the capacity to accumulate phycoerythrin in green light but showed normal photoregulation of phycocyanin. Analyses of transcript abundance in these mutants demonstrated that changes in the levels of the different phycobilisome components correlated with changes in the levels of mRNAs encoding those components. The characterization of these mutants supports hypotheses previously discussed concerning molecular mechanisms involved in the regulation of the phycobiliprotein gene sets during chromatic adaptation.
Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy (2015)

The term 'inhibitory checkpoint' refers to the broad spectrum of co-receptors expressed by T cells that negatively regulate T cell activation thus playing a crucial role in maintaining peripheral self-tolerance. Co-inhibitory receptor ligands are highly expressed by a variety of malignancies allowing evasion of anti-tumour immunity. Recent studies demonstrate that manipulation of these co-inhibitory pathways can remove the immunological brakes that impede endogenous immune responses against tumours. Antibodies that block the interactions between co-inhibitory receptors and their ligands have delivered very promising clinical responses, as has been shown by recent successful trials targeting the CTLA-4 and PD-1 pathways. In this review, we discuss the mechanisms of action and expression pattern of co-inhibitory receptors on different T cells subsets, emphasising differences between CD4(+) and CD8(+) T cells. We also summarise recent clinical findings utilising immune checkpoint blockade.
Elastic strain of freely suspended single-wall carbon nanotube ropes (1999)

We have induced large elastic strains in ropes of single-wall carbon nanotubes, using an atomic force microscope in lateral force mode. Freely suspended ropes were observed to deform as elastic strings with tension proportional to elongation. Ropes were elastically deformed over &amp;gt;10 cycles without showing signs of plastic deformation. The maximum strain observed, 5.8±0.9%, gives a lower bound of 45±7 GPa for the tensile strength (specifically, yield stress) of single-wall nanotube ropes.
The chemical biology of modular biosynthetic enzymes (2009)

Fatty acid synthase (FAS), polyketide synthase (PKS), and nonribosomal peptide synthetase (NRPS) modular biosynthetic enzymes are responsible for the production of a multitude of structurally diverse and biologically important small molecule natural products. Traditional biochemical and genetic studies of these enzymes have contributed substantially to the understanding of their underlying biosynthetic mechanisms. More recently these investigations have been aided by the skillful application of a combination of chemical and biological techniques to aid in overcoming the unique challenges associated with the enzymology of these large multifunctional enzymes. This critical review provides a historical context and details studies (through July 2008) which aim to identify and characterize these enzymes using synthetically and/or chemoenzymatically generated small molecule probes (233 references).
Proteome study of colorectal carcinogenesis (2001)

Development of cancer is a complex process involving multiple changes in gene expression. To unravel these alterations, a proteome approach aimed at the identification of qualitative and quantitative changes in protein composition, including their post-translational modifications, attracts great attention. Our study was focused on the identification of proteins whose amount is altered in the course of malignant transformation of colon mucosa. Proteins extracted from tissue specimens or cell lysates were separated by two-dimensional gel electrophoresis (2-DE). Comparative analyses of 2-DE protein patterns were done using computerized image analysis. Selected proteins exhibiting statistically significant abundance alterations comparing healthy and diseased tissues were identified by mass spectrometry. Globally, we have found 57 proteins that exhibited either a significant decrease or increase in amount in pathological tissues, and 18 of these were annotated by mass spectrometry. The alterations in the expression of nine proteins were common for both precancerous and neoplastic tissues suggesting their role in colon tumorigenesis. The epithelial origin of all identified spots was checked in two cell lines Caco-2 and DLD-1 originating from well-differentiated and poorly differentiated colon carcinoma, respectively.
Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. (1996)

Voltage-gated Na+ channels are the molecular targets of local anesthetics, class I antiarrhythmic drugs, and some anticonvulsants. These chemically diverse drugs inhibit Na+ channels with complex voltage- and frequency-dependent properties that reflect preferential drug binding to open and inactivated channel states. The site-directed mutations F1764A and Y1771A in transmembrane segment IVS6 of type IIA Na+ channel alpha subunits dramatically reduce the affinity of inactivated channels for the local anesthetic etidocaine. In this study, we show that these mutations also greatly reduce the sensitivity of Na+ channels to state-dependent block by the class Ib antiarrhythmic drug lidocaine and the anticonvulsant phenytoin and, to a lesser extent, reduce the sensitivity to block by the class Ia and Ic antiarrhythmic drugs quinidine and flecainide. For lidocaine and phenytoin, which bind preferentially to inactivated Na+ channels, the mutation F1764A reduced the affinity for binding to the inactivated state 24.5-fold and 8.3-fold, respectively, while Y1771A had smaller effects. For quinidine and flecainide, which bind preferentially to the open Na+ channels, the mutations F1764A and Y1771A reduced the affinity for binding to the open state 2- to 3-fold. Thus, F1764 and Y1771 are common molecular determinants of state-dependent binding of diverse drugs including lidocaine, phenytoin, flecainide, and quinidine, suggesting that these drugs interact with a common receptor site. However, the different magnitude of the effects of these mutations on binding of the individual drugs indicates that they interact in an overlapping, but nonidentical, manner with a common receptor site. These results further define the contributions of F1764 and Y1771 to a complex drug receptor site in the pore of Na+ channels.
Silhouette scores for assessment of SNP genotype clusters (2005)

"Silhouette scores" for assessing the quality of SNP genotyping clusters is convenient for evaluating the quality of SNP genotype assignment, and provides an objective, numeric measure for comparing the performance of SNP assays. The program we created for calculating Silhouette scores is freely available, and can be used for quality assessment of the results from all genotyping systems, where the genotypes are assigned by cluster analysis using scatter plots.
Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12 (2008)

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.
Neural Event Extraction from Movies Description (2018)

We present a novel approach for event extraction and abstraction from movie descriptions. Our event frame consists of 'who", "did what" "to whom", "where", and "when". We formulate our problem using a recurrent neural network, enhanced with structural features extracted from syntactic parser, and trained using curriculum learning by progressively increasing the difficulty of the sentences. Our model serves as an intermediate step towards question answering systems, visual storytelling, and story completion tasks. We evaluate our approach on MovieQA dataset.
FADD is required for multiple signaling events downstream of the receptor Fas. (1999)

To identify essential components of the Fas-induced apoptotic signaling pathway, Jurkat T lymphocytes were chemically mutagenized and selected for clones that were resistant to Fas-induced apoptosis. We obtained five cell lines that contain mutations in the adaptor FADD. All five cell lines did not express FADD by immunoblot analysis and were completely resistant to Fas-induced death. Complementation of the FADD mutant cell lines with wild-type FADD restored Fas-mediated apoptosis. Fas activation of caspase-2, caspase-3, caspase-7, and caspase-8 and the proteolytic cleavage of substrates such as BID, protein kinase Cdelta, and poly(ADP-ribose) polymerase were completely defective in the FADD mutant cell lines. In addition, Fas activation of the stress kinases p38 and c-Jun NH2 kinase and the generation of ceramide in response to Fas ligation were blocked in the FADD mutant cell lines. These data indicate that FADD is essential for multiple signaling events downstream of Fas.
Microbiotas from UC patients display altered metabolism and reduced ability of LAB to colonize mucus (2013)

We compared fecal microbial communities derived either from Ulcerative Colitis (UC) patients in remission (n = 4) or in relapse (n = 4), or from healthy subjects (n = 4). These communities were used for inoculation of a dynamic in vitro gut model, which contained integrated mucin-covered microcosms. We found that the microbiota of the 'mucus' largely differed from that of the 'lumen'. This was partly due to decreased mucus-associated populations of lactic acid producing bacterial populations (LAB), as LAB originating from UC patients had a significantly decreased capacity to colonize the mucin-covered microcosms as compared to those originating from healthy subjects. We found significant differences between the metabolomes of UC patients in relapse and remission, respectively, while the metabolome of patients in remission resembled that of healthy subjects. These novel findings constitute an important contribution to the understanding of the complex etiology of UC.
Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma (2008)

Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found. We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decrease in the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC. In an association study of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a common polymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a role in the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through target genes whose expression is affected by the SNP status.
Fabrication of Three-Dimensional ZnO−Carbon Nanotube (CNT) Hybrids Using Self-Assembled CNT Micropatterns as Framework (2007)

Large-scale pyramid-like micropatterns were prepared via capillarity-driven self-assembly during the evaporation of water from aligned carbon nanotubes (ACNTs) wrapped by a polyelectrolyte, poly (sodium 4-styrenesulfonate) (PSS). PSS wrapping results in providing negative charges on every tube, which makes it possible to balance the capillary force and to form uniformed pyramid-like architecture. By using such regular three-dimensional CNT patterns as an idea candidate for the framework/template, two complex architectures consisting of ZnO nanorods and CNT patterns were successfully fabricated, which show revisable surface wettability properties.
Tumor Therapy with Bispecific Antibody: The Targeting and Triggering Steps Can Be Separated Employing a CD2-Based Strategy (1999)

For tumor therapy with unprimed effector cells, we developed a novel combination of a CD2 x tumor Ag bispecific targeting Ab and an anti-CD2 triggering Ab. These Ab constructs were derived from two novel CD2 mAbs, termed M1 and M2 that, together, but not individually activate T cells. Unlike many other CD2 Abs, M1 and M2 do not interfere with TCR/CD3 triggering nor do they inhibit binding of CD2 to its ligand CD58, thus preserving the physiological functions of these important effector cell molecules. M2 was chemically conjugated with an Ab recognizing the epidermal growth factor-receptor (EGF-R). Incubation of unprimed peripheral blood mononuclear cells with the bispecific F(ab')2 construct (M2xEGF-R) in the presence of trigger Ab M1 led to efficient selective lysis of EGF-R-positive targets by CTL and NK cells. Importantly, the need for trigger Ab M1 for effector cell stimulation allowed to separate targeting from triggering steps in vitro and should thus enable to focus immune responses to sites of target Ag expression in vivo.
Constraining Cyclic Peptides To Mimic Protein Structure Motifs (2014)

Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three-dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein-like structures in water. However, short peptides can be induced to fold into protein-like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic peptides can have protein-like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.
Tolbutamide-Phenformin in Ketoacidosis-Resistant Patients (1960)

The relative effectiveness of combined oral therapy with tolbutamide and phenformin was studied in a group of 80 clinic patients with ketoacidosis-resistant diabetes mellitus who had been imperfectly or inadequately regulated by a single oral drug. The tolbutamide-phenformin regimen was observed to bring about significant improvement in 70 per cent of patients previously imperfectly controlled by tolbutamide alone and in 60 per cent of patients imperfectly controlled by phenformin alone. Many of the gratifying responses to combination therapy occurred in extremely difficult patients in whom prior therapy with chlorpropamide, metahexamide, and insulin had been unsatisfactory. The results indicate that tolbutamide-phenformin combination therapy is the most potent of the oral antihyperglycemic regimens tested and makes adequate control with oral drugs a practical possibility for most ketoacidosis-resistant diabetics in whom single oral agents have been unsuccessful.
Complete Genome Analysis of 33 Ecologically and Biologically Diverse Rift Valley Fever Virus Strains Reveals Widespread Virus Movement and Low Genetic Diversity due to Recent Common Ancestry (2006)

Rift Valley fever (RVF) virus is a mosquito-borne RNA virus responsible for large explosive outbreaks of acute febrile disease in humans and livestock in Africa with significant mortality and economic impact. The successful high-throughput generation of the complete genome sequence was achieved for 33 diverse RVF virus strains collected from throughout Africa and Saudi Arabia from 1944 to 2000, including strains differing in pathogenicity in disease models. While several distinct virus genetic lineages were determined, which approximately correlate with geographic origin, multiple exceptions indicative of long-distance virus movement have been found. Virus strains isolated within an epidemic (e.g., Mauritania, 1987, or Egypt, 1977 to 1978) exhibit little diversity, while those in enzootic settings (e.g., 1970s Zimbabwe) can be highly diverse. In addition, the large Saudi Arabian RVF outbreak in 2000 appears to have involved virus introduction from East Africa, based on the close ancestral relationship of a 1998 East African virus. Virus genetic diversity was low (approximately 5%) and primarily involved accumulation of mutations at an average of 2.9 x 10(-4) substitutions/site/year, although some evidence of RNA segment reassortment was found. Bayesian analysis of current RVF virus genetic diversity places the most recent common ancestor of these viruses in the late 1800s, the colonial period in Africa, a time of dramatic changes in agricultural practices and introduction of nonindigenous livestock breeds. In addition to insights into the evolution and ecology of RVF virus, these genomic data also provide a foundation for the design of molecular detection assays and prototype vaccines useful in combating this important disease.
A uniformly stable conformal FDTD‐method in Cartesian grids (2003)

Abstract A conformal finite‐difference time‐domain algorithm for the solution of electrodynamic problems in general perfectly conducting 3D geometries is presented. Unlike previous conformal approaches it has the second‐order convergence without the need to reduce the maximal stable time step of conventional staircase approach. A novel proof for the local error rate for general geometries is given, and the method is verified and compared to other approaches by means of several numerical 2D examples. Copyright © 2003 John Wiley &amp; Sons, Ltd.