gebhart/patrepeval huggingface dataset:
Variational Lossy Autoencoder (2016)

Representation learning seeks to expose certain aspects of observed data in a learned representation that's amenable to downstream tasks like classification. For instance, a good representation for 2D images might be one that describes only global structure and discards information about detailed texture. In this paper, we present a simple but principled method to learn such global representations by combining Variational Autoencoder (VAE) with neural autoregressive models such as RNN, MADE and PixelRNN/CNN. Our proposed VAE model allows us to have control over what the global latent code can learn and , by designing the architecture accordingly, we can force the global latent code to discard irrelevant information such as texture in 2D images, and hence the VAE only "autoencodes" data in a lossy fashion. In addition, by leveraging autoregressive models as both prior distribution $p(z)$ and decoding distribution $p(x|z)$, we can greatly improve generative modeling performance of VAEs, achieving new state-of-the-art results on MNIST, OMNIGLOT and Caltech-101 Silhouettes density estimation tasks.
Entity resolution for big data (2013)

Entity resolution (ER), the problem of extracting, matching and resolving entity mentions in structured and unstructured data, is a long-standing challenge in database management, information retrieval, machine learning, natural language processing and statistics. Accurate and fast entity resolution has huge practical implications in a wide variety of commercial, scientific and security domains. Despite the long history of work on entity resolution, there is still a surprising diversity of approaches, and lack of guiding theory. Meanwhile, in the age of big data, the need for high quality entity resolution is growing, as we are inundated with more and more data, all of which needs to be integrated, aligned and matched, before further utility can be extracted. In this tutorial, we bring together perspectives on entity resolution from a variety of fields, including databases, information retrieval, natural language processing and machine learning, to provide, in one setting, a survey of a large body of work. We discuss both the practical aspects and theoretical underpinnings of ER. We describe existing solutions, current challenges and open research problems. In addition to giving attendees a thorough understanding of existing ER models, algorithms and evaluation methods, the tutorial will cover important research topics such as scalable ER, active and lightly supervised ER, and query-driven ER.
Structure‐based subsite specificity mapping of human cathepsin D using statine‐based inhibitors (1997)

Human cathepsin D is a lysosomal aspartic protease that has been implicated in breast cancer metastasis and Alzheimer's disease. Based on a crystal structure of a human cathepsin D-pepstatin A complex, a series of statine-containing inhibitors was designed, synthesized, and tested for inhibitory activity toward the enzyme in vitro. The compounds were modified systematically at individual positions (P4, P3, P2, P1, and P2t) with the aim of mapping the cathepsin D subsite preferences. The experimentally obtained SAR data were correlated on the basis of molecular modeling. Side-chain preferences for the peptidomimetic inhibitors differed from those found previously using peptide substrates (Scarborough PE et al., 1993, Protein Sci 2:264-276). In addition, the effects of single side-chain modifications were often nonadditive. Structure-activity relationships, modeling, and thermodynamic analysis indicated that entropy plays a major stabilizing role in inhibitor binding to cathepsin D.
Vitamin D analogs and bone. (2001)

Vitamin D analogs increase intestinal calcium absorption, and have been shown to possess antiresorptive and also bone anabolic properties in vivo. Therefore, the pharmacological profile of vitamin D analogs would be well suited for the treatment of osteoporosis. However, the calcemic side effects of this compound class, especially at higher doses, have hampered their wide use in osteoporotic patients. Nevertheless, the clear potential for bone anabolic properties together with oral availability have stimulated the interest in this substance class, and there is an active search for bone selective vitamin D compounds. After an overview of the physiological functions of vitamin D in bone, this article focuses on the effects of acute and chronic administration of pharmacological doses of vitamin D analogs on bone in animal models and humans. Furthermore, the endocrinological, cellular, and microanatomical mechanisms involved in the skeletal actions of vitamin D analogs are discussed. The final section briefly reviews the available data on possible bone selective vitamin D analogs.
Invasive Shigella flexneri Activates NF-κB Through a Lipopolysaccharide-Dependent Innate Intracellular Response and Leads to IL-8 Expression in Epithelial Cells (2000)

The pathogenesis of Shigella flexneri infection centers on the ability of this organism to invade epithelial cells and initiate an intense inflammatory reaction. Because NF-kappa B is an important transcriptional regulator of genes involved in inflammation, we investigated the role of this transcription factor during S. flexneri infection of epithelial cells. Infection of HeLa cells with invasive S. flexneri induced NF-kappa B DNA-binding activity; noninvasive S. flexneri strains did not lead to this activation. The pathway leading to NF-kappa B activation by invasive S. flexneri involved the kinases, NF-kappa B-inducing kinase, I kappa B kinase-1, and I kappa B kinase-2. NF-kappa B activation was linked to inflammation, because invasive S. flexneri activated an IL-8 promoter-driven reporter gene, and the kappa B site within this promoter was indispensable for its induction. Microinjection of bacterial culture supernatants into HeLa cells suggested that LPS is responsible for NF-kappa B activation by S. flexneri infection. In conclusion, the eukaryotic transcription factor NF-kappa B was activated during S. flexneri infection of epithelial cells, which suggests a role for this transcriptional regulator in modulating the immune response during infection in vivo.
Tumor necrosis factor-alpha inhibition of 17 alpha-hydroxylase/C17-20 lyase gene (Cyp17) expression. (1995)

Testosterone biosynthesis in Leydig cells is dependent on the action of 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 (P450c17), which is encoded by the Cyp17 gene. Tumor necrosis factor-alpha (TNF alpha), a proinflammatory cytokine, inhibits cAMP-stimulated testosterone production in mouse Leydig cells. The inhibition of testosterone production is parallel to the inhibition of P450c17 messenger RNA and protein levels. To examine the mechanism of TNF alpha-mediated inhibition of steroidogenesis, the effect of TNF alpha on cAMP-stimulated induction of Cyp17 expression was investigated. To determine whether the protein kinase C (PKC) signaling pathway is involved in TNF alpha inhibition of steroidogenesis, the effects of the PKC activator, phorbol 12-myristate 13-acetate (PMA), and the PKC inhibitor, calphostin C, were examined. Treatment of normal mouse Leydig cells in primary culture with 50 microM 8-bromo-cAMP (cAMP) plus 1 ng/ml TNF alpha or 10 nM PMA caused a similar (approximately 90%) decrease in testosterone accumulation and cAMP-stimulated P450c17 messenger RNA levels compared to those after treatment with cAMP alone. To determine whether TNF alpha inhibits the cAMP-induced expression of the Cyp17 gene, plasmids containing two different size fragments of the 5'-flanking region of the Cyp17 gene upstream of the chloramphenicol acetyltransferase (CAT) reporter gene were transiently transfected into MA-10 tumor Leydig cells, and the effect of TNF alpha on cAMP-induced CAT activity was determined. Treatment of cells, transfected with either plasmid, with 500 microM cAMP plus increasing concentrations (0.1, 1.0, and 10 ng/ml) of TNF alpha resulted in a dose-dependent repression of cAMP-stimulated CAT activity. Higher concentrations of TNF alpha (up to 100 ng/ml) did not result in greater inhibition. Treatment of transfected cells with 10 nM PMA resulted in a 51 +/- 6.6% inhibition of cAMP-stimulated CAT activity. Calphostin C (1 microM) completely reversed the inhibitory effect of TNF alpha or PMA. Calphostin C alone had no effect on promoter activity. TNF alpha-stimulated PKC alpha translocation was quantitated by Western blot. After treatment for 3 h, the distribution of immunoreactive PKC alpha in cytosol vs. nucleus was 55%/45%, 60%/40%, and 29%/71% in control, cAMP-treated, and TNF alpha-treated cells, respectively. TNF alpha-stimulated PKC alpha translocation was further demonstrated by indirect immunofluorescence assay. PMA, a known activator of PKC, and TNF alpha had a similar inhibitory effect on P450c17 expression, testosterone production, and Cyp17-CAT activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Presence of an SH2 Domain in the Actin-Binding Protein Tensin (1991)

The molecular cloning of the complementary DNA coding for a 90-kilodalton fragment of tensin, an actin-binding component of focal contacts and other submembraneous cytoskeletal structures, is reported. The derived amino acid sequence revealed the presence of a Src homology 2 (SH2) domain. This domain is shared by a number of signal transduction proteins including nonreceptor tyrosine kinases such as Abl, Fps, Src, and Src family members, the transforming protein Crk, phospholipase C-gamma 1, PI-3 (phosphatidylinositol) kinase, and guanosine triphosphatase-activating protein (GAP). Like the SH2 domain found in Src, Crk, and Abl, the SH2 domain of tensin bound specifically to a number of phosphotyrosine-containing proteins from v-src-transformed cells. Tensin was also found to be phosphorylated on tyrosine residues. These findings suggest that by possessing both actin-binding and phosphotyrosine-binding activities and being itself a target for tyrosine kinases, tensin may link signal transduction pathways with the cytoskeleton.
The Interplay Between Chemistry and Biology in the Design of Enzymatic Catalysts (1988)

Chemists and biologists are focusing considerable effort on the development of efficient, highly selective catalysts for the synthesis or modification of complex molecules. Two approaches are described here, the generation of catalytic antibodies and hybrid enzymes, which exploit the binding and catalytic machinery of nature in catalyst design. Characterization of these systems is providing additional insight into the mechanisms of molecular recognition and catalysis which may, in turn, lead to the design of tailor-made catalysts for applications in chemistry, biology, and medicine.
Polyangitis overlap syndrome: A fatal case combined with adult Henoch‐Schönlein purpura and polyarteritis nodosa (2003)

Henoch-Schönlein purpura (HSP) is a rather common disease characterized by systemic hypersensitivity vasculitis in the skin and other visceral organs. It has a favorable prognosis unless it is complicated by severe glomerular disease. We report a distinctive fatal case of systemic vasculitis combined with HSP and polyarteritis nodosa (PN) in a 56-year-old man who died of progressive renal failure one month after the onset of the disease. He complained of arthralgia, purpura of both lower extremities, nasal bleeding and tarry stool, and acute renal failure was noted at the time of admission to hospital. A skin biopsy from the purpura lesion exhibited leucocytoclastic vasculitis with IgA deposition, and HSP was considered. However, renal failure progressed rapidly and subsequently was complicated by acute myocardial infarction. Postmortem examination revealed PN type necrotizing vasculitis in the kidneys, heart and mesentery resulting in acute multiple infarctions of these organs. We think the current case was a polyangitis overlap syndrome. It is important to suspect the polyangitis overlap syndrome positively when progressive acute renal failure is seen in a patient with HSP and to begin appropriate therapy immediately.
Targeting Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1): Structure-Based Design of MKP-1 Inhibitors and Upregulators (2012)

Mitogen-activated protein kinase phosphatases (MKPs) are dual specificity protein phosphatases (DUSPs) that dephosphorylate both phospho-tyrosine and phospho-threonine residues on mitogen-activated protein kinases (MAPKs). Because the MAPK family of signalling molecules (phospho-p38 MAPK, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)) play essential roles in cell signalling pathways that regulate cell growth and inflammation, controlling MAPK-mediated pathways is a therapeutically attractive strategy. While small molecule MAPK inhibitors have utility, in this review we will focus on exploring the potential of targeting the endogenous MAPK deactivator--MKP-1. Importantly, there is a strong justification for developing both inhibitors and upregulators of MKP-1 because of the diverse roles played by MAPKs in disease: for example, in cancer, MKP-1 inhibitors may prove beneficial, as MKP-1 is overexpressed and is considered responsible for the failure of JNK-driven apoptotic pathways induced by chemotherapeutics; conversely, in inflammatory diseases such as asthma and arthritis, MKP-1 reduces MAPK-mediated signalling and developing novel ligands to upregulate MKP-1 levels would be a therapeutically attractive anti-inflammatory strategy. Thus, in this review we utilise MKP-1 homology modeling to highlight the structural features of MKP-1 inhibitors that permit potent and selective inhibition, and to provide insights into the structural requirements for selective MKP-1 upregulators.
Emerging drugs for schizophrenia: an update (2014)

Although modifications and variations of antidopaminergic mechanisms are expected to be successful, the added benefits will likely remain small, at least regarding enhanced efficacy for negative symptoms, cognition and functional outcomes. Greater innovation will likely come from further and deeper exploration of extra-dopaminergic mechanisms. Investment is needed to develop clinically meaningful animal paradigms probing the different symptom domains, to discover more efficient in vivo screening methods for novel drug targets, to optimize clinical trial design and trial conduct, and to parse the heterogeneous groups of schizophrenias into biologically more homogeneous subgroups.
Prayer, the Bible, and the Public Schools (1983)

"Prayer, the Bible, and the Public Schools." National Council on Religion and Public Education. Bulletin, 10(3), pp. 16–17
Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells (2008)

Unlike lower vertebrates, mammals are unable to replace damaged mechanosensory hair cells (HCs) in the cochlea. Recently, ablation of the retinoblastoma protein (Rb) in undifferentiated mouse HC precursors was shown to cause cochlear HC proliferation and the generation of new HCs, raising the hope that inactivation of Rb in postmitotic HCs could trigger cell division and regenerate functional HCs postnatally. Here, we acutely inactivated Rb in nearly all cochlear HCs of newborn mice, using a newly developed HC-specific inducible Cre mouse line. Beginning 48 h after Rb deletion, approximately 40% of HCs were in the S and M phases of the cell cycle, demonstrating an overriding role for Rb in maintaining the quiescent state of postnatal HCs. Unlike Rb-null HC precursors, such HCs failed to undergo cell division and died rapidly. HC clusters were restricted to the less differentiated cochlear regions, consistent with differentiation-dependent roles of Rb. Moreover, outer HCs expressed the maturation marker prestin, suggesting an embryonic time window for Rb-dependent HC specification. We conclude that Rb plays essential and age-dependent roles during HC proliferation and differentiation, and, in contrast to previous hypotheses, cell death after forced cell-cycle reentry presents a major challenge for mammalian HC regeneration from residual postnatal HCs.
IMAGE-GUIDED NON-LOCAL DENSE MATCHING WITH THREE-STEPS OPTIMIZATION (2016)

This paper introduces a new image-guided non-local dense matching algorithm that focuses on how to solve the following problems: 1) mitigating the influence of vertical parallax to the cost computation in stereo pairs; 2) guaranteeing the performance of dense matching in homogeneous intensity regions with significant disparity changes; 3) limiting the inaccurate cost propagated from depth discontinuity regions; 4) guaranteeing that the path between two pixels in the same region is connected; and 5) defining the cost propagation function between the reliable pixel and the unreliable pixel during disparity interpolation. This paper combines the Census histogram and an improved histogram of oriented gradient (HOG) feature together as the cost metrics, which are then aggregated based on a new iterative non-local matching method and the semi-global matching method. Finally, new rules of cost propagation between the valid pixels and the invalid pixels are defined to improve the disparity interpolation results. The results of our experiments using the benchmarks and the Toronto aerial images from the International Society for Photogrammetry and Remote Sensing (ISPRS) show that the proposed new method can outperform most of the current state-of-the-art stereo dense matching methods.
Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases (2013)

Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC50 = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4'-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.
Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells. (2013)

Currently, feeder cells are γ-irradiated immediately before use for the ex vivo expansion of natural killer (NK) cells from human peripheral blood. Storing irradiated feeder cells by cryopreserving them in multiple vials would be more convenient than irradiating cells each time they are needed. We compared NK cell expansion using cryopreserved-irradiated feeder cells (cryopreserved group) and freshly-irradiated feeder cells (fresh group). To expand NK cells, peripheral blood mononuclear cells were isolated and co-cultured with-100 Gy-irradiated K562 leukemia cells that had been modified to express 4-1BB ligand and membrane-bound (mb) interleukin (IL)-15 (K562-mb15-41BBL cells) for three weeks in the presence of IL-2 and IL-15. Fresh and cryopreserved K562-mb15-41BBL feeder cells expressed similar levels of 4-1BB ligand, whereas membrane-bound IL-15 expression was lower in the cryopreserved cells than in the fresh cells. The NK cell expansion rate did not differ between the two groups (980-fold vs. 1058-fold, respectively), although the mean NK cell purity was higher in the fresh-group than in the cryopreserved-group at day 14 (94.1% vs. 92.5%, respectively) and day 21 (97.1% vs. 95.4%, respectively). The NK cells from the two feeder cell groups did not differ in cytotoxicity against various malignant cell lines at effector-to-target ratios of 4:1, 2:1, and 1:1, or in the expression pattern of NK cell receptors [cluster of differentiation (CD)-16, natural killer group-2, member D (NKG2D), CD69, NKp30, NKp44, NKp46, and CD158b] and level of interferon-γ secretion. Our results demonstrate that cryopreserved irradiated feeder cells can be used for the ex vivo expansion of human NK cells and provide a convenient improvement on current methods.
Efficacy of Recombinant Circumsporozoite Protein Vaccine Regimens against ExperimentalPlasmodium falciparumMalaria (2001)

After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups. Of the 41 vaccinees and 23 control subjects who underwent sporozoite challenge, malaria developed in 7 of 10 who received 1 dose, in 7 of 14 who received 2 doses, in 3 of 6 who received 3 standard doses, in 3 of 7 who received 3 one-half doses, in 3 of 4 who received 3 one-fifth doses, and in 22 of 23 control subjects. Overall protective efficacy of RTS,S/SBAS2 was 41% (95% confidence interval, 22%-56%; P=.0006). This and previous studies have shown that 2 or 3 doses of RTS,S/SBAS2 protect against challenge with P. falciparum sporozoites.
Energy is Required for Maturation of Exported Proteins in Escherichia coli (1981)

It has been established in numerous cases that proteins which are exported from Escherichia coli are synthesized on membrane-bound polysomes in precursor forms which are proteolytically cleaved to generate the mature species. Here we present evidence that at least one step in the export of proteins requires energy. Energy requirements for processing of the precursors of both the M13 coat protein [Date, T., Zwizinski, C., Ludmerer, S., and Wickner, W. (1980) Proc. Natl Acad. Sci. USA, 77, 827-831; Date, T., Goodman, J. M., and Wickner, W. T. (1980) Proc. Natl Acad. Sci. USA, 77, 4669-4673] and the B subunit of heat-labile enterotoxin [Palva, T., Hirst, T. R., Hardy, S. J. S., Holmgren, J., and Randall, L. L. (1981) J. Bacteriol. in the press] have been demonstrated previously. An energy requirement for the proteolytic processing of an additional five exported proteins is reported here. Studies utilizing an uncA mutant suggest that the form of energy required is proton-motive force. Thus an energized membrane is probably essential for export of most periplasmic and outer membrane proteins.
Site-specific antibodies to human erythropoietin directed toward the NH2-terminal region. (1983)

Site-specific antibodies to human erythropoietin have been raised in rabbits immunized with a synthetic polypeptide composed of the putative 26 NH2-terminal amino acids of the hormone. The immunogenic peptide was coupled to bovine serum albumin. Antibodies specific for peptide were detected by enzyme-linked immunosorbent assay. They immunoprecipitated both highly purified 125I-labeled erythropoietin and biologically active erythropoietin. The immunoprecipitation of 125I-labeled erythropoietin was inhibited by unlabeled erythropoietin and by peptide, demonstrating their crossreactivity. The antibodies did not neutralize erythropoietin's biological activity. These results indicate that a portion of the NH2-terminal region of erythropoietin is exposed on the surface of the protein at some distance from the receptor-binding domain. These antibodies will be important in further studies of the hormone and its mechanism of action.