gebhart/patrepeval huggingface dataset:
Bioconductor: software and development strategies for statistical genomics (2005)

Abstract Bioconductor is an open source initiative for the creation and dissemination of methods in statistical genomics and computational biology based on R. This article describes the requirements, language features, and methodology of design and development guiding the evolution of this project. Commitments to software interoperability, computable task‐oriented documentation, and full transparency of algorithm development and use are found to be valuable in reducing barriers to access faced by statistical, computational, or biological researchers attempting interdisciplinary work. These commitments are expected to foster the propagation of standards of transparency and explicit reproducibility from wet‐lab science, where they are well accepted, to in silico biology, where explicit reproduction of important published results is often very difficult.
A challenge for 21st century molecular biology and biochemistry: what are the causes of obligate autotrophy and methanotrophy? (2004)

We assess the use to which bioinformatics in the form of bacterial genome sequences, functional gene probes and the protein sequence databases can be applied to hypotheses about obligate autotrophy in eubacteria. Obligate methanotrophy and obligate autotrophy among the chemo- and photo-lithotrophic bacteria lack satisfactory explanation a century or more after their discovery. Various causes of these phenomena have been suggested, which we review in the light of the information currently available. Among these suggestions is the absence in vivo of a functional alpha-ketoglutarate dehydrogenase. The advent of complete and partial genome sequences of diverse autotrophs, methylotrophs and methanotrophs makes it possible to probe the reasons for the absence of activity of this enzyme. We review the role and evolutionary origins of the Krebs cycle in relation to autotrophic metabolism and describe the use of in silico methods to probe the partial and complete genome sequences of a variety of obligate genera for genes encoding the subunits of the alpha-ketoglutarate dehydrogenase complex. Nitrosomonas europaea and Methylococcus capsulatus, which lack the functional enzyme, were found to contain the coding sequences for the E1 and E2 subunits of alpha-ketoglutarate dehydrogenase. Comparing the predicted physicochemical properties of the polypeptides coded by the genes confirmed the putative gene products were similar to the active alpha-ketoglutarate dehydrogenase subunits of heterotrophs. These obligate species are thus genomically competent with respect to this enzyme but are apparently incapable of producing a functional enzyme. Probing of the full and incomplete genomes of some cyanobacterial and methanogenic genera and Aquifex confirms or suggests the absence of the genes for at least one of the three components of the alpha-ketoglutarate dehydrogenase complex in these obligate organisms. It is recognized that absence of a single functional enzyme may not explain obligate autotrophy in all cases and may indeed be only be one of a number of controls that impose obligate metabolism. Availability of more genome sequences from obligate genera will enable assessment of whether obligate autotrophy is due to the absence of genes for a few or many steps in organic compound metabolism. This problem needs the technologies and mindsets of the present generation of molecular microbiologists to resolve it.
Unusual acute promyelocytic leukemia following de novo renal transplant: case report and literature review (2010)

Acute promyelocytic leukemia (APL) with transcripting three isoforms of mRNA from PML-RAR alpha fusion genes following renal transplantation has never been reported in the literature. A 39-year-old man received a cadaveric renal allograft for IgA chronic kidney disease in 2006 and was consecutively immunosuppressed by tacrolimus, mycophenolate mofetil, and prednisolone. In 2008, he presented with gum bleeding and weight loss. Following bone marrow biopsy, we diagnosed acute promyelocytic leukemia. Molecular analysis demonstrated atypical presence consisting of three isoforms of mRNA from PML-RAR alpha fusion genes. The patient was administered with three courses of consolidation chemotherapy plus atretinoin, resulting in complete remission and did not jeopardize his allograft function. This novel finding suggests that the leukemogenesis of APL may be polyclonal, sharing similar progenitor targeting on complicated karyotypes, responding well to current chemotherapy.
Malignant astrocytoma cell attachment and migration to various matrix proteins is differentially sensitive to phosphoinositide 3‐OH kinase inhibitors (1999)

Phosphoinositide 3-OH kinase (PI3-K) has been shown to play an important role in the signaling pathway necessary for cytoskeletal reorganization in non-astrocytic cells. We investigated the role of PI3-K in U-251MG human malignant astrocytoma cell adhesion and migration. Attachment of U-251MG cells to vitronectin, fibronectin, laminin, and collagen was inhibited in a concentration-dependent manner by two specific inhibitors of PI3-K (Wortmannin and LY294002). Attachment to vitronectin, fibronectin, and laminin was more sensitive to inhibition of PI3-K (45% inhibition at 10 nM Wortmannin) than attachment to collagen (25% inhibition at 100 nM Wortmannin). Similarly, migration toward these substrates showed differential sensitivity to inhibition. Attachment of the cells to these matrix proteins resulted in an increase in PI3-K activity, as compared to that of cells in suspension, with attachment to vitronectin resulting in the greatest increase in PI3-K activity. p125 focal adhesion kinase (p125FAK) was found to co-immunoprecipitate with PI3-K from the NP40-soluble cell fraction of a 1% NP40 detergent lysate of cells in the early stages of adhesion to vitronectin and fibronectin, but not during adhesion to collagen. The expression of p125FAK protein and level of phosphorylation were similar on adherence to all three substrates. These data indicate that the sensitivity of U-251MG cell attachment and migration to PI3-K inhibitors is substrate-dependent, and that complex formation of PI3-K and p125FAK correlates with this sensitivity to PI3-K inhibitors. Our data suggest a role for PI3-K and p125FAK complex formation in PI3-K activation. J. Cell. Biochem. 73:533–544, 1999. © 1999 Wiley-Liss, Inc.
Spatial Encoding and Reconstruction in MRI with Quadratic Phase Profiles (1995)

Application of a slice-selective frequency modulated radiofrequency excitation pulse in a magnetic resonance (MR) imaging experiment creates a quadratic phase profile along the direction of slice selection. This quadratic phase profile inherently localizes the signal contribution to its vertex, which can be shifted with the application of a linear magnetic field gradient. Different methods for reconstruction of the spatial profile are discussed. The point spread functions of these reconstructions are similar to that of conventional Fourier transforms; one important difference is the elimination of aliasing at the expense of MR signal amplitude when performing 'local,' or limited, reconstruction. Limited reconstruction together with spatially limited excitation combines some of the advantages of both three-dimensional phase-encoded and two-dimensional multislice techniques in appropriate situations. Applications discussed are three-dimensional gradient echo experiments applied to time of flight MR angiography and T2(+)-weighted data collection.
Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents (2013)

Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC(50) values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine.
Combined use of unsupervised and supervised learning for dynamic security assessment (1992)

It is desirable to assess the security and stability of electric power systems after exposure to large disturbances. In this connection, the critical clearing time (CCT) is an attribute which provides significant information about the quality of the postfault system behavior. It may be regarded as a complex mapping of the prefault, fault-on, and postfault system conditions into the time domain. High prediction and generalization capabilities of artificial neural networks provide the basis for synthesis of such a complex mapping carrying input pattern attributes into the single valued space of the CCT. The authors consider the possibility of using unsupervised and supervised learning programs to discover what combination of raw measurements is significant in determining CCT. Correlation analysis and a Euclidean metric are used to specify interfeature dependencies. An example of a four-machine power system is used to illustrate the suggested approach.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
High Performance Catalyzed Membranes of Ultra‐low Pt Loadings for Polymer Electrolyte Fuel Cells (1992)

Polymer electrolyte membranes are catalyzed by the direct application of thin film catalyst layers cast from solutions of suspended Pt/C catalyst and solubilized Nafion® ionomer. Both the ionomeric membrane and the solubilized ionomer are in the Na+form during casting to enable higher curing temperatures, which results in more robust catalyst layers. In addition to simplifying the fabrication process, the direct application apparently provides enhanced bonding at the interface between the membrane and the catalyst layer. Consequently, the performances of fuel cells utilizing these catalyzed membranes with ultra‐low platinum loadings are superior to those achieved with other approaches to polymer electrolyte membranes of low Pt loading.
Autocrine regulation of growth stimulation in human epithelial ovarian carcinoma by serine-proteinase-catalysed release of the urinary-type-plasminogen-activator N-terminal fragment (1999)

Ovarian carcinomas secrete single-chain urinary-type plasminogen activator (scuPA) and expression of uPA is up-regulated relative to normal ovarian epithelium, leading to an enhanced proteolytic capacity which may facilitate invasion. Furthermore, the uPA receptor (uPAR) is present on ovarian carcinoma cells and is occupied in tumour tissues. In the present study, incubation of scuPA with serum-free conditioned medium from ovarian carcinoma cells resulted in release of a 14 kDa polypeptide. N-terminal sequence analysis identified this fragment as the uPA N-terminal fragment (NTF), which contains a growth-factor and a kringle domain. NTF generation was abolished by serine-proteinase inhibitors, but not inhibitors of matrix metalloproteinases, and was not enhanced by the addition of plasminogen or plasmin. To determine whether ovarian carcinoma-cell growth is altered by uPA, the effect of exogenous scuPA or NTF on proliferation was analysed. Both NTF and scuPA induced a dose-dependent increase in proliferation, with maximal stimulation obtained at 10-20 nM. Furthermore, blocking the interaction of endogenous uPA with uPAR using anti-NTF antibodies significantly inhibited proliferation. Together these data indicate that, in addition to enhancing the invasive activity of ovarian carcinoma cells via increased pericellular proteolysis, uPA also acts as a mitogen for ovarian carcinoma cells, suggesting a biochemical mechanism whereby uPA may contribute to ovarian carcinoma progression by modulating both cell invasion and proliferation.
Synthesis and Structure–Activity Relationship Studies of Novel Dihydropyridones as Androgen Receptor Modulators (2013)

A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure-activity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeling and molecular mechanics were used to build a structural model of the androgen receptor-ligand binding domain and to investigate the structural basis of the antagonism. The model is qualitatively consistent with the observed SAR. Moreover, the enrichment plot shows that screening with the model performs significantly better than random screening. Therefore, the model probably represents a realistic conformation of the antagonist form and can be utilized for structure-based design of novel antiandrogens.
A Pd(II)-Catalyzed Ring-Expansion Reaction of Cyclic 2-Azidoalcohol Derivatives: Synthesis of Azaheterocycles (2009)

A Pd(II)-catalyzed ring expansion-reaction of cyclic 2-azidoalcohol derivatives was found to proceed via an unprecedented C-C bond cleavage-C-N bond formation sequence, providing substituted azaheterocycles.
InGaAs Capacitor-Less DRAM Cells TCAD Demonstration (2018)

2D numerical TCAD simulations are used to infer the behavior of III-V capacitor-less dynamic RAM (DRAM) cells. In particular, indium gallium arsenide on insulator technology is selected to verify the viability of III-V meta-stable-dip RAM cells. The cell performance dependence on several parameters (such as the back-gate voltage, semiconductor thickness, indium/gallium mole fraction or interface traps) and simulation models (like ballisticity or spatial quantum confinement) is analyzed and commented. Functional cells are presented and compared with analogous silicon 1T-DRAM memories to highlight the advantages and drawbacks.
NFATC2 is a novel therapeutic target for colorectal cancer stem cells (2018)

Background: Colorectal cancer stem cells (CRC-SCs) contribute to the initiation and progression of colorectal cancer (CRC). However, the underlying mechanisms for the propagation of CRC-SCs have remained elusive. Purpose: The objective of this study was to study the role of NFATC2 in maintenance of the stemness in CRC-SCs. Method: The expression levels of mRNA and protein were determined by qRT-PCR and western-blot, respectively. CRC-SCs were isolated by spheroid formation assay and flowcytometry. The sphere-forming and self-renewal abilities of CRC-SCs were determined by spheroid formation assay. The tumorigenicity of CRC-SCs was determined by cell-derived xenograft model. Gene manipulation was performed by lentivirus-mediated delivery system. Results: We first found that NFATC2 is upregulated in primary CRC-SCs. Overexpression of NFATC2 promotes self-renewal and the expression of stem cell markers of CRC-SCs. Conversely, knockdown of NFATC2 attenuates stem cell-like properties of CRC-SCs. Mecha­nistic analysis indicated that NFATC2 upregulates the expression of AJUBA, downregulates the phosphorylation level of YAP, and therefore activates the transcriptional activities of YAP and promotes the stemness of CRC-SCs. Conclusion: Our findings demonstrate NFATC2 as an oncogene that can promote the stemness of CRC-SCs. This work suggests a novel therapeutic strategy against CRC caused by aberrant expression of NFATC2. Keywords: NFATC2, colorectal cancer, stem cells, stemness, YAP
A co‐stimulatory molecule on activated T cells, H4/ICOS, delivers specific signals in Th cells and regulates their responses (2002)

We examined the co-stimulatory activity of H4/ICOS on murine activated CD4(+) T cells and found that the cross-linking of H4/ICOS enhanced their proliferation, in addition to raising IFN-gamma, IL-4 and IL-10 production to levels comparable to those induced by CD28. However, IL-2 production was only marginally co-stimulated by H4/ICOS. This distinct pattern of lymphokine production appears to be induced by a specific intracellular signaling event. Compared with CD28, H4/ICOS dominantly elicited the Akt pathway via phosphatidylinositol 3-kinase. In addition, mitogen-activated protein kinase family kinases were activated in different ways by CD28 and H4/ICOS. The strong phosphorylation of p46 c-Jun N-terminal kinase was observed upon CD28 co-stimulation, but was less potently induced by H4/ICOS. The strain diversity in the induction of H4/ICOS was recognized. The expression of H4/ICOS on BALB/c activated CD4(+) T cells was >6-fold higher compared with C57BL/6 activated CD4(+) T cells. Furthermore, BALB/c activated CD4(+) T cells exhibited more T(h)2-deviated lymphokine production as compared with C57BL/6 activated CD4(+) T cells and signaling through H4/ICOS during the primary stimulation of naive CD4(+) T cells promoted the generation of T(h)2 cells. Thus, the difference in H4/ICOS expression on activated CD4(+) T cells, which is regulated among the mouse strains, may also regulate the polarization of T(h) cells.
Canine model for gene therapy: inefficient gene expression in dogs reconstituted with autologous marrow infected with retroviral vectors (1988)

Abstract Successful retroviral gene transfer into murine hematopoietic stem cells indicates the potential for somatic gene therapy in the treatment of certain human hereditary diseases. We developed a canine model to test the applicability of these techniques to a preclinical model of human marrow transplantation. Previously we reported that canine CFU-GM could be infected with retroviral vectors carrying either the gene for a mutant dihydrofolate reductase (DHFR) or neomycin phosphotransferase (NEO). This study reports six lethally irradiated dogs transplanted with autologous marrow cocultivated with retroviral vector-producing cells. This procedure conferred drug resistance to 3% to 13% of the CFU- GM. Three dogs infected with either the NEO or DHFR virus engrafted, but we detected no drug-resistant CFU-GM. Three dogs were given marrow infected with a DHFR virus and received methotrexate (MTX) as in vivo selection; all three had evidence of engraftment. In the surviving dog, we detected 0.03% to 0.1% MTX-resistant CFU-GM at 3 to 5 weeks posttransplant during in vivo selection. These results indicate that we can reconstitute lethally irradiated dogs with autologous marrow exposed to retroviral vectors and suggest that gene transfer into hematopoietic cells is feasible on a large scale. However, the low- level transient gene expression indicates that considerable obstacles remain before human gene therapy can be considered.
Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society (2015)

Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.
Stimulation of proliferation, differentiation, and function of human cells by primate interleukin 3. (1987)

Cloned gibbon interleukin 3 (gIL-3) was found to stimulate the proliferation and differentiation of human bone marrow cells to produce day-14 granulocyte, macrophage, granulocyte-macrophage, and eosinophil colonies in semisolid agar. In the presence of normal human plasma, gIL-3 stimulated megakaryocytes. In methylcellulose cultures, it stimulated erythroid colonies in the presence, but not in the absence, of erythropoietin. When mature human leukocytes were used, gIL-3 stimulated the function of purified mature eosinophils as measured by the capacity to kill antibody-coated target cells, to produce superoxide anions, and to phagocytize opsonized yeast particles in a manner similar to recombinant human granulocyte-macrophage colony-stimulating factor. In contrast, gIL-3 did not significantly stimulate any of the neutrophil functions tested, whereas human recombinant granulocyte-macrophage colony-stimulating factor was active in these assays. Among cytokines that are active on human hematopoietic cells, gIL-3 thus has a distinct set of functions and may predict the range of actions of the human molecule.
1,25-Dihydroxyvitamin D 3 Attenuates of Expression of Experimental Murine Lupus of MRL/1 Mice (1992)

The murine strain MRL/l spontaneously develops a systemic lupus erythematosus (SLE)-like syndrome. An increased number of T cells and polyclonal T helper cell activity has been described in these mice suggesting a potential role for 1,25-dihydroxyvitamin-D3 [1,25-D3], an antiproliferative hormone selecting the T-helper lymphocyte subset. One month old MRL/l mice were submitted or not to 1,25-D3 0.1 microgram for 4 weeks, then 0.15 microgram given i.p. every other day for 18 weeks while maintained on a low calcium chow. Dermatologic lesions, i.e. alopecia, necrosis of the ear and scab formation, were completely inhibited by 1,25-D3 therapy. By 20 weeks, all mice had developed proteinuria. However, the degree of proteinuria was somewhat reduced in treated mice as assessed by urine protein/creatine ratios (less than 4 vs greater than 4 in treated vs untreated mice respectively). Moreover, a trend for a reduction in serum titers for anti-ssDNA antibodies was observed at 18 weeks. The active vitamin D metabolite had no effect on the development of the generalized lymphoid hyperplasia. Hypercalcemia developed when 1,25-D3 was increased to 0.15 microgram (2.62 +/- 0.12 vs 1.97 +/- 0.07 mmol/l, treated vs untreated mice respectively). These results suggest a beneficial role of 1,25-D3 in the prevention or attenuation of some manifestations of murine SLE, a model sharing many immunologic features with human SLE.