gebhart/patrepeval huggingface dataset:
Structure-Based Approach for Discovery of Small Molecule Inhibitors Targeted at Bcl-2 (2002)

Abstract : Overexpression of Bcl-2 has been observed in 70% of breast carcinomas and the expression levels of Bcl-2 proteins correlate with resistance to a wide spectrum of chemotherapeutic drugs and radiation therapy. In this IDEA grant, we propose an effective structure-based approach to discover small molecule inhibitors of Bcl-2 through structure-based 3D-database search over large chemical databases containing >500,000 structurally diverse, non-peptide, drug-like synthetic compounds or natural products. Using this powerful approach, we have discovered 10 classes of structurally diverse, non-peptidic, drug-like, small-molecule inhibitors of Bcl-2. Our studies also showed that the most promising small-molecule inhibitors of Bcl-2 we have discovered potently bind to Bcl-2 protein, inhibit cell growth and induce apoptosis in breast cancer cells with high levels of Bcl-2 proteins and display good selectivity in cancer cells with low levels of Bcl-2 proteins. Furthermore, our most potent small-molecule inhibitor of Bcl-2 inhibits tumor growth in animal models of human breast cancer. Our results have demonstrated that potent small-molecule inhibitors of Bcl-2 may have a great therapeutic potential for the treatment of human breast cancer by overcoming apoptosis resistance of breast cancer cells.
Impact of a moderately energy-restricted diet on energy metabolism and body composition in non-obese men. (1995)

Under conditions of a controlled moderately energy-restricted diet in daily life a significant weight loss can be induced, similar to that observed after a balanced dietary deficit, providing 5 MJ/day. In addition, moderate energy restriction induces a decrease in fat-free mass and a fall in RMR.
Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection (2013)

Previous studies have shown that some respiratory virus infections leave local populations of tissue TRM cells in the lungs which disappear as heterosubtypic immunity declines. The location of these TRM cells and their contribution to the protective CTL response have not been clearly defined. Here, fluorescence microscopy is used to show that some CD103(+) TRM cells remain embedded in the walls of the large airways long after pulmonary immunization but are absent from systemically primed mice. Viral clearance from the lungs of the locally immunized mice precedes the development of a robust Teff response in the lungs. Whereas large numbers of virus-specific CTLs collect around the bronchial tree during viral clearance, there is little involvement of the remaining lung tissue. Much larger numbers of TEM cells enter the lungs of the systemically immunized animals but do not prevent extensive viral replication or damage to the alveoli. Together, these experiments show that virus-specific antibodies and TRM cells are both required for optimal heterosubtypic immunity, whereas circulating memory CD8 T cells do not substantially alter the course of disease.
Topologies for wavelength-routing all-optical networks (1993)

Three regular meshed topologies are compared in light of their possible use for the implementation of large all-optical wavelength-routing communication networks (or interconnection systems). These systems provide all source-destination pairs with end-to-end transparent channels that are identified through a wavelength and a physical path. The considered topologies are the K-dimensional bidirectional square lattice, the twin shuffle, and the de Bruijn graph. The comparison is based on the maximum and average distance between source and destination (number of traversed nodes), on the degree of connectivity for each node (number of input and output fibers), and on the minimum number of wavelengths in the WDM comb necessary to discriminate all source-destination pairs.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Gleason Score 2–4 Adenocarcinoma of the Prostate on Needle Biopsy (2000)

From the Departments of Pathology, Urology, and Oncology, The Johns Hopkins Hospital, Baltimore, Maryland, U.S.A. Address correspondence and reprint requests to Jonathan I. Epstein, MD, Johns Hopkins Hospital, Department of Pathology, 600 N. Wolfe St., Baltimore, MD 21287, U.S.A.
Microbial lipids from renewable resources: production and characterization (2010)

A number of microorganisms belonging to the genera of algae, yeast, bacteria, and fungi have ability to accumulate neutral lipids under specific cultivation conditions. The microbial lipids contain high fractions of polyunsaturated fatty acids and have the potential to serve as a source of significant quantities of transportation fuels. This paper reviews the current state of the art of this field. It summarizes the various microorganism used, feed stocks available, environmental factors that influence growth of cells and accumulation of lipids, major fatty acid composition of lipids, and the technology.
Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma (2011)

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
Permitting Problems: Environmental Justice and the Miccosukee Indian Tribe (2013)

The Miccosukee Tribe of Indians is a federally recognized tribe that works and resides in the Everglades region of the State of Florida. The Miccosukee have been battling lax water quality standards through lawsuits since the 1990’s. Recent rulings in federal court held that the State of Florida has failed to comply with the Clean Water Act and ordered the Environmental Protection Agency to set nutrient criteria for the water bodies in the state of Florida until the Florida Department of Environmental Protection complies with the Clean Water Act. This article uses the principles of environmental justice to analyze ways in which the Environmental Protection Agency can lift the undue burden that the Miccosukee Indian Tribe is bearing due to the nutrient pollution occurring in the Everglades. Environmental Justice is a jurisprudence that is used when low-income or minority populations bear a disproportionately high burden of adverse human health or environmental effects. The Environmental Protection Agency has created a new, comprehensive environmental justice plan called Plan EJ 2014. This plan acts as a roadmap to better integrate environmental justice into the program’s activities and policies. The author addresses the environmental justice that is burdening the Miccosukee Indian Tribe, and suggests using environmental justice principles to set nutrient criteria in Florida, particularly the water bodies found within the land of the Miccosukee Tribe of Indians.  Juris Doctorate Candidate, 2013, Barry University School of Law. Bachelors of Science, 2006, Florida Southern College. 164 ENVIRONMENTAL AND [Vol. III EARTH LAW JOURNAL
IgG-Enzyme Fusion Protein: Pharmacokinetics and Anti-Drug Antibody Response in Rhesus Monkeys (2012)

The chronic administration of recombinant fusion proteins in preclinical animal models may generate an immune response and the formation of antidrug antibodies (ADA). Such ADAs could alter the plasma pharmacokinetics of the fusion protein, and mask any underlying toxicity of the recombinant fusion protein. In the present study, a model IgG-enzyme fusion protein was evaluated with chronic dosing of rhesus monkeys. The IgG domain of the fusion protein is a genetically engineered monoclonal antibody (mAb) against the human insulin receptor (HIR), which is shown to cross-react with the primate insulin receptor. The enzyme domain of the fusion protein is human iduronidase (IDUA), the lysosomal enzyme mutated in Mucopolysaccharidosis Type I (MPSI). MPSI affects the brain, but enzyme replacement therapy is not effective for the brain, because IDUA does not cross the blood-brain barrier (BBB). The HIRMAb domain of the fusion protein acts as a molecular Trojan horse to deliver the IDUA across the BBB. The HIRMAb-IDUA fusion protein was administered to rhesus monkeys with weekly intravenous infusions of 3-30 mg/kg for 6 months, and the pharmacokinetics, immune response, and tissue toxicology were assessed. The pharmacokinetics of plasma clearance of the fusion protein was determined with measurements of plasma IDUA enzyme activity. ADAs formed during the course of the 6 months of treatment, as determined by a sandwich ELISA. However, the plasma clearance of the fusion protein at the start and end of the 6-month study was comparable at all drug doses. Fusion protein administration for 6 months showed no evidence of chronic tissue toxicity. These studies demonstrate that the immune response produced with chronic treatment of primates with an IgG-enzyme fusion protein has no effect on the pharmacokinetics of plasma clearance of the fusion protein.
Optimal design of digital IIR filters by model-fitting frequency response data (1995)

A new frequency-domain (FD) approach is presented for optimal estimation of rational transfer functions coefficients. The proposed method seeks to match any arbitrarily-shaped FD specifications in the least-squares sense. The desired specifications may be arbitrarily spaced in frequency. The design is performed directly in the digital domain, and no analog to digital transformation is necessary. The proposed method makes use of the inherent mathematical structure in this rational modeling problem to theoretically decouple the numerator and denominator estimation problems into two lower dimensional problems. The denominator criterion is nonlinear but possesses a weighted-quadratic structure, which is convenient for iterative optimization. The optimal numerator is found linearly by solving a set of simultaneous equations. The decoupled criteria retain the global optimality properties. The performance of the algorithm is demonstrated with some simulation examples.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The role of clusterin in tissue injury (1994)

Clusterin is a widely distributed glycoprotein with a wide range of biologic properties. A prominent and defining feature of clusterin is its marked induction in such disease states as glomerulonephritis, cystic renal disease, renal tubular injury, neurodegenerative conditions, atherosclerosis, and myocardial infarction. The expression of clusterin in these states is intriguing given the apparent incongruity of the conditions listed, the variety of stimuli eliciting such expression, and the multiple proposed roles once induced. This review will outline the conditions associated with clusterin induction and speculate on its role in disease.
Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4 (2008)

Set2-mediated H3 K36 methylation is an important histone modification on chromatin during transcription elongation. Although Set2 associates with the phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII), the mechanism of Set2 binding to chromatin and subsequent exertion of its methyltransferase activity is relatively uncharacterized. We identified a critical lysine residue in histone H4 that is needed for interaction with Set2 and proper H3 K36 di- and trimethylation. We also determined that the N terminus of Set2 contains a histone H4 interaction motif that allows Set2 to bind histone H4 and nucleosomes. A Set2 mutant lacking the histone H4 interaction motif is able to bind to the phosphorylated CTD of RNAPII and associate with gene-specific loci but is defective for H3 K36 di- and trimethylation. In addition, this Set2 mutant shows increased H4 acetylation and resistance to 6-Azauracil. Overall, our study defines a new interaction between Set2 and histone H4 that mediates trans-histone regulation of H3 K36 methylation, which is needed for the preventative maintenance and integrity of the genome.
The determination of the cellular volume of avian, porcine and bovine phagocytes and bovine mammary epithelial cells and its relationship to uptake of tilmicosin (1999)

In order to compare the intracellular concentration of antimicrobial agents in phagocytic and nonphagocytic cells, the knowledge of their cell volume is essential. For the first time, the determination of the avian, porcine, and bovine polymorphonuclear neutrophils (PMN), monocyte-derived macrophages, macrophages, and bovine mammary epithelial cell volume was performed using [3H]-water and [14C]-carboxyinulin. The comparison of all the cells showed that the PMN have a size range between 3.58 and 4.04 microL per mg of protein, and are smaller than the monocyte-derived macrophages and mammary epithelial cells (4.32-5.01 microL per mg of protein). The macrophages show the largest size (5.84-6.57 microL per mg of protein). The cellular uptake of tilmicosin in these cells was then determined. The examination of the intracellular/extracellular concentration ratios (Ci/Ce) after 4 h of incubation with 10 mg/mL of [14C]-labelled tilmicosin revealed that tilmicosin was well accumulated and showed a ratio of 137, 169 and 193 in avian PMN, porcine PMN, and bovine alveolar macrophages, respectively. The cellular uptake data also demonstrated that tilmicosin accumulated in nonphagocytic bovine mammary epithelial cells. The importance of the use of the appropriate species and cell type specific cell volume values for calculations was exemplified by calculating the Ci/Ce of tilmicosin using cell volume data found in the literature for human and mouse cells. The subsequent comparison of these data with the Ci/Ce calculated with the actual cell volume appropriate for the species tested revealed an under evaluation of 3-13% in monocyte-macrophages, an over evaluation of 7-18%, 16-31% and 69% in PMN, macrophages, and epithelial cells, respectively. This study highlights the importance of the proper cell volume in order to determine the Ci/Ce. Moreover, the cell volumes determined here for avian, porcine and bovine cells should facilitate further in vitro and in vivo cellular studies by veterinary researchers.
Go!: results from a quasi-experimental obesity prevention trial with hospital employees (2016)

This study was registered with clinicaltrials.gov (NCT01585480) on April 24, 2012.
Recent advances in understanding and managing gout (2017)

Gout is the most common crystal arthropathy and the leading cause of inflammatory arthritis. It is associated with functional impairment and, for many, a diminished health-related quality of life. Numerous studies have demonstrated the impact of gout and its associated conditions on patient morbidity and mortality. Unfortunately, gout remains under-diagnosed and under-treated in the general community. Despite major advances in treatment strategies, as many as 90% of patients with gout are poorly controlled or improperly managed and their hyperuricemia and recurrent flares continue. The introduction of novel urate-lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes. Here, we spotlight recent advances in the diagnosis and management of gout and discuss novel therapeutics in gout treatment.
Hypothermia (1959)

EIGHTEEN years have elapsed since the first progress report on hypothermia appeared in this journal.1 At that time Talbott originally used the term "hypothermia" to define the deliberate cooling of man as a therapeutic measure. Although observations on the physiology of cold had been made sporadically over the years, the occasion for a progress report was the interest aroused by the work of Smith and Fay,2 who had employed cold for the treatment of advanced cancer. Within a short time, however, interest began to wane, and Talbott could provide only a very limited bibliography. The hope was expressed that further . . .
Isolation and 16S rRNA sequence analysis of the beneficial bacteria from the rhizosphere of rice (2001)

The present study deals with the isolation of plant growth promoting rhizobacteria (PGPR) from rice (variety NIAB IRRI-9) and the beneficial effects of these inoculants on two Basmati rice varieties. Nitrogen-fixing activity (acetylene-reduction activity) was detected in the roots and submerged shoots of field-grown rice variety NIAB IRRI-9. Estimation of the population size of diazotrophic bacteria by ARA-based MPN (acetylene reduction assay-based most probable number) in roots and shoots indicated about 10(5)-10(6) counts/g dry weight at panicle initiation and grain filling stages. Four bacterial isolates from rice roots and shoots were obtained in pure culture which produced phytohormone indoleacetic acid (IAA) in the growth medium. Among these, three isolates S1, S4, and R3 reduced acetylene to ethylene in nitrogen-free semi-solid medium. Morphological and physiological characteristics of the isolates indicated that three nitrogen-fixing isolates S1, S4, and R3 belonged to the genus Enterobacter, while the non-fixing isolate R8 belonged to the genus Aeromonas. 16S rRNA sequence of one isolate from root (R8) and one isolate from shoot (S1) was obtained which confirmed identification of the isolates as Aeromonas veronii and Enterobacter cloacae, respectively. The 1517-nucleotide-long sequence of the isolate R8 showed 99% similarity with Aeromonas veronii (accession No. AF099023) while partial 16S rRNA sequence (two stretches of total 1271 nucleotide length) of S1 showed 97% similarity with the sequence of Enterobacter cloacae (accession No. AJ251469). The seedlings of two rice varieties Basmati 385 and Super Basmati were inoculated with the four bacterial isolates from rice and one Azospirillum brasilense strain Wb3, which was isolated from wheat. In the rice variety Basmati 385, maximum increase in root area and plant biomass was obtained in plants inoculated with Enterobacter S1 and Azospirillum Wb3, whereas in the rice variety Super Basmati, inoculation with Enterobacter R3 resulted in maximum increase of root area and plant biomass. Nitrogen fixation was quantified by using 15N isotopic dilution method. Maximum fixation was observed in Basmati 385 with the inoculants Azospirillum Wb3 and Enterobacter S1 where nearly 46% and 41% of the nitrogen was derived from atmosphere (%Ndfa), respectively. In general, higher nitrogen fixation was observed in variety Basmati 385 than in Super Basmati, and different bacterial strains were found more effective as inoculants for the rice varieties Basmati 385 and Super Basmati.
Efficient Integration Testing using Dependency Analysis (2005)

Although testing starts with individual programs, programs are rarely self-contained in real software environments. They depend on external subsystems like language run time and operating system libraries for various functionalities. These subsystems are developed externally to any given program, with their own test processes. Of course, an uncoordinated change in one of the external subsystems may affect the program’s correctness. Test teams therefore add an integration testing step to their process to ensure that programs will continue to operate with different versions of the external subsystems. As full testing may take days or weeks to run, it is useful to understand how to prioritize these tests. We present an integration testing system to understand and quantify the impact of a change, so test teams can focus their testing efforts on the most likely affected parts of the program. Detecting the impact of a change is a hard problem due to the size and complexity of the control and data dependencies involved. Our new approach is based on a binary dependency framework, MaX, that determines control and data dependencies in a system and represents them in a dependency graph. MaX is designed to work on systems consisting of thousands of binaries and millions of procedures. It constructs the graph in multiple steps to allow the analysis of individual binaries to proceed in parallel. MaX provides simple abstractions for defining systems, and provides a simple programming interface to tools for analysis of the graph. The integration testing system also contains two tools that use MaX to advise test teams. MaxCift quantifies the effect of a change to guide how much testing is likely to be needed. MaxScout prioritizes an existing set of tests based on changes made to external subsystems. All of the tools use a binary code based approach that does not require source code for external subsystems, an important requirement for practical use. MaX runs under the Windows environment and is used by Microsoft product teams. Early results show that the system scales to production software and is effective in guiding testing.
Retinoic Acid Induces Pdx1-Positive Endoderm in Differentiating Mouse Embryonic Stem Cells (2005)

We have generated an embryonic stem (ES) cell line in which sequences encoding green fluorescent protein (GFP) were targeted to the locus of the pancreatic-duodenal homeobox gene (Pdx1). Analysis of chimeric embryos derived from blastocyst injection of Pdx1(GFP/w) ES cells demonstrated that the pattern of GFP expression was consistent with that reported for the endogenous Pdx1 gene. By monitoring GFP expression during the course of ES cell differentiation, we have shown that retinoic acid (RA) can regulate the commitment of ES cells to form Pdx1(+) pancreatic endoderm. RA was most effective at inducing Pdx1 expression when added to cultures at day 4 of ES differentiation, a period corresponding to the end of gastrulation in the embryo. RT-PCR analysis showed that Pdx1-positive cells from day 8 cultures expressed the early endoderm markers Ptf1a, Foxa2, Hnf4alpha, Hnf1beta, and Hnf6, consistent with the notion that they corresponded to the early pancreatic endoderm present in the embryonic day 9.5 mouse embryo. These results demonstrate the utility of Pdx1(GFP/w) ES cells as a tool for monitoring the effects of factors that influence pancreatic differentiation from ES cells.
Transitional Justice as Electoral Politics (2015)

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