gebhart/patrepeval huggingface dataset:
Recent Developments in Tau-Based Therapeutics for Neurodegenerative Diseases (2010)

Neurodegenerative diseases constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of Alzheimer's disease (AD), the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists has demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. Drug development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some targets with significant potential in the field and which might be on the verge of providing new treatment paradigms within the coming years. Among those strategies, immunotherapy approaches will be mostly discussed. An update on 2010 patents regarding different aspects of tau-based therapeutic strategies is also provided.
Fine Mapping and Functional Characterization of Two Immuno-Dominant Regions from the preS2 Sequence of Hepatitis B Virus (1994)

A set of monoclonal antibodies (mAbs) directed against the preS2 region of hepatitis B virus (HBV) surface antigen (HBsAg) was generated by immunization of mice with native HBsAg isolated from the blood of HBV carriers. According to (1) mutual competition binding of mAb to natural HBsAg, (2) recognition of full-length preS2 displayed on hepatitis B core particles, (3) recognition of synthetic partial preS2 peptides, and (4) Western blotting using a fusion protein library of truncated preS2 fragments of different legths, mAbs were assigned to two groups which coincided with groups I and III described by Mimms et al. [Virology 1990; 176:604-619]. All mAbs recognized linear epitopes and were glycosylation independent. Six out of eight fine-mapped mAbs recognized common epitopes located in the amino-terminal part of the preS sequence between amino acids 131 and 144 (group I), and inhibited binding of HBsAg to polymerized human serum albumin. Only two mAbs recognized a carboxy-terminal HBV-genotype-specific epitope covering amino acid residues 162 to 168 (group III). These mAbs bound to the highly variable proteolysis-sensitive hinge of preS2. Although four out of six mAbs targeted to immunodominant region I require the full-length sequence 131-L[Q/L]DPRVRGLY[F/L]PAG-144, two mAbs recognize the shorter and slightly carboxy-terminal-shifted sequences 133-DPRVRGLY[F/L]-141 or 135-PVRGLY[F/L]PAG-144. Together with previously identified preS2 epitopes 133-DPRVRGL-139, 137-RGLYFPA-143, and 132-QDPR-135, these data indicate diversity of the immune response against epitopes within the same immunodominant region. This diversity may be generated by a labile secondary structure. Sequence analysis suggests the transition from an alpha-helix to a loop structure at this site.
Electrochemically Nanostructured Polyvinylferrocene/Polypyrrole Hybrids with Synergy for Energy Storage (2015)

Unconjugated redox polymers, such as polyvinylferrocene (PVF), have rarely been used for energy storage due to their low intrinsic conductivity. Conducting polymers with conjugated backbones, though conductive, may suffer from insufficient exposure to the electrolyte due to the often formed nonporous structures. The present work overcomes this limitation via simultaneous electropolymerization of pyrrole and electroprecipitation of PVF on electrode surfaces. This synthesis method relies on the π–π stacking interactions between the aromatic pyrrole monomers and the metallocene moieties of PVF. This fabrication process results in a highly porous polymer film, which enhances the ion accessibility to polypyrrole (PPy). PPy serves as a “molecular wire,” improving the electronic conductivity of the hybrid and the utilization efficiency of ferrocene. The PVF/PPy hybrid exhibited a specific capacitance of 514.1 F g −1 , which significantly exceeds those of PPy (27.3 F g −1 ) and PVF (79.0 F g −1 ), respectively. This approach offers an alternative to nanocarbon materials for improving the electronic conductivity of polymer hybrids, and suggests a new strategy for fabricating nanostructured polymer hybrids. This strategy can potentially be applied to various polymers with π‐conjugated backbones and redox polymers with metallocene moieties for applications such as energy storage, sensing, and catalysis.
PPARγ2 Regulates Adipose Expression of the Phosphoenolpyruvate Carboxykinase Gene (1995)

Phosphoenolpyruvate carboxykinase (PEPCK) is expressed at high levels in liver, kidney, and adipose tissue. This enzyme catalyzes the rate-limiting step in hepatic and renal gluconeogenesis and adipose glyceroneogenesis. The regulatory factors important for adipose expression of the PEPCK gene are not well defined. Previous studies with transgenic mice established that the region between bp -2086 and -888 is required for expression in adipose tissue but not for expression in liver or kidney tissue. We show here that a DNA fragment containing this region can function as an enhancer and direct differentiation-dependent expression of a chloramphenicol acetyltransferase gene from a heterologous promoter in cultured 3T3-F442A preadipocytes and adipocytes. We further demonstrate that the adipocyte-specific transcription factor PPAR gamma 2, previously identified as a regulator of the adipocyte P2 enhancer, binds in a heterodimeric complex with RXR alpha to the PEPCK 5'-flanking region at two sites, termed PCK1 (bp -451 to -439) and PCK2 (bp -999 to -987). Forced expression of PPAR gamma 2 and RXR alpha activates the PEPCK enhancer in non-adipose cells. This activation is potentiated by peroxisome proliferators and fatty acids but not by 9-cis retinoic acid. Mutation of the PPAR gamma 2 binding site (PCK2) abolishes both the activity of the enhancer in adipocytes and its ability to be activated by PPAR gamma 2 and RXR alpha. These results establish a role for PPAR gamma 2 in the adipose expression of the PEPCK gene and suggest that this factor functions as a coordinate regulator of multiple adipocyte-specific genes.
Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia (2005)

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.
Designing a multiuser HDTV storage server (1993)

The authors present a quantitative study of designing a multiuser HDTV server, and they present efficient techniques for storing multiple HDTV videos on disk and servicing multiple subscriber requests simultaneously, both under the constraint of guaranteeing HDTV playback rates. They develop a model that relates disk and device characteristics to the HDTV playback rate and derive a storage pattern for HDTV video streams that guarantees their real-time retrieval. Given multiple HDTV streams, mechanisms for merging their individual storage patterns are developed. Merging algorithms that yield a large improvement in space utilization over storing each of the streams independently are proposed. Policies such as round robin and quality proportional for servicing multiple subscribers simultaneously are studied. These studies provide a quantitative demonstration of the technological feasibility and economic viability of HDTV-on-demand servers on metropolitan area networks (MANs).< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Transgenic-Mouse Model of Amyotrophic Lateral Sclerosis (1994)

To the Editor: The article by Dr. Brown (Oct. 20 issue)1 highlights the studies that my colleagues and I have performed with a transgenic model of human motor neuron disease.2 Our experiments built...
Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (2004)

The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
Multiresolution statistical object recognition (1994)

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1994.
The anti‐inflammatory activity of metal complexes and salts of amine carboxyboranes (1994)

Abstract The metal complexes and salts of amine carboxyboranes were shown to be potent anti‐inflammatory agents in rodents at 8 mg kg −1 . They were effective in blocking induced edema, pleurisy and endotoxic shock while blocking both local and central pain processes. The ability of the agents to function as anti‐inflammatory agents is multi‐fold. First, lysosomal enzymes of specific cells, e.g. macrophages, were inhibited with IC 50 values in the range of 10 −6 M . Collagenase I and II activities were inhibited with IC 50 values approximately equal to 10 −4 M . The anti‐inflammatory activity of these agents at the molecular levels appears to be due to inhibition of the release of TNFα and Il‐1 from macrophages which indirectly control chemotaxic migration of white blood cells as indicated by the suppression of PMN and macrophage invasion into sponges implanted subcutaneously (SC) in mice. Furthermore, in these invading cells, the agents' blockage of TNFα and Il‐1 or Il‐2 release down‐regulates prostaglandin and leukotriene enzymatic synthetic rates and, consequently, their release, resulting in a reduction of the inflammation process.
A color segmentation scheme for object-based video coding (2002)

A color segmentation scheme is presented for use in an object-based video coding environment. The proposed technique employs the HSV (hue, saturation, value) color space to partition a video-phone type sequence into a facial area and a set of arbitrarily shaped regions. The facial region is identified by utilizing the a priori knowledge of the skin-tone distributions along with a series of fuzzy shape-based membership functions. The remaining regions are segmented using a recursive 1D histogram thresholding procedure. The technique is robust, computationally inexpensive, and allows for a higher coding efficiency. Furthermore, it may be used to support the content-based functionalities addressed in future object-based coders.
생석회 혼합토의 압축특성에 관한 연구 (2003)

본 연구에서는 외부적인 원인에 의한 지반의 산성화가 생석회 혼합토의 압축특성에 미치는 영향을 조사하고, 생석회 처리효과를 증대시키기 위해 산화철, 염화칼슘, 황산칼슘 등의 제 2의 화학적 첨가제를 혼합하였다. 이 생석회혼합토의 압축특성을 알아보기 위해 rapid inflection point method을 이용하여 신속한 압밀시험을 실시하였다. 공장폐수 또는, 산성비 등에 기인한 지반 산성화는 토양 속에 존재하는 황산염과 생석회의 칼슘이온이 반응하여 팽창성 광물인 ettringite 등을 생성시키므로 인공 산성비를 이용하여 pH를 변화시켜 생석회 혼합토에 혼합하였다. 실험결과,pH가 감소함에 따라 압축지수는 증가되고, 선행압밀하중과 압밀계수는 감소하는 경향을 보여 생석회 혼합토의 압축특성에 악영향을 미치는 것으로 나타났다. 화학적 첨가제 중 염화칼슘을 혼합한 생석회 혼합토의 경우, 압축지수를 감소시키고, 압밀계수와 투수계수는 증가하는 경향을 보였다. 산화철을 혼합한 생석회 혼합토의 경우, 생석회 혼합토에 비해 선행압밀하중이 크게 증가하는 것으로 나타나 압축특성을 개선시키는데 효과적인 것으로 나타났다.
Radiation-induced lymphoblastic lymphomas/leukemias and sarcomas of mice express conserved, immunogenic 44-kilodalton oncofetal antigen. (1988)

X-ray-induced, lymphoblastic, T-cell lymphoma/leukemias from irradiated RF mice were observed to uniformly expressed a 44-kd oncofetal antigen (OFA). The OFA polypeptide was detected by flow cytometry, affinity column SDS-PAGE analysis, and immunoblotting with monoclonal antibody (MAb) 115 prepared against syngeneic mouse fetus. X-ray and ultraviolet (UV) induced murine fibrosarcoma cell lines, used as classic models in radiation biology, were also found to express the OFA, which suggested that the 44-kd OFA was a general transformation marker of tumors. Adult mouse thymocytes and other adult tissues expressed no OFA. The 44-kd polypeptide was located at the surface membrane of the tumors examined. In contrast to other reports, lymphoblastic lymphoma cell lines expressed the OFA as a cross-protective, rather than an individually-specific, tumor-associated transplantation antigen. Pronase treatment removed OFA from the surface of living lymphoma cells, whereas collagenase, neuraminidase, and hyaluronidase did not. The OFA was rapidly reexpressed upon culture of the pronase-treated cells. Taken together, these results suggest that the 44-kd OFA polypeptide described here may provide a useful cell surface marker for future radiation carcinogenesis studies. MAb 115 is a promising reagent for detecting tumor-associated 44-kd OFA, for assessing immunoregulatory perturbations to the OFA caused by radiation damage and for investigating the immunopathology of OFA-associated radiation damage.
Introduction of Plasmid DNA into Isolated Mitochondria by Electroporation (1997)

Mitochondrial disorders are a large group of phenotypically heterogeneous diseases. An understanding of their molecular basis would benefit greatly from the ability to manipulate the mitochondrial genome and/or to introduce functional exogenous DNA into mitochondria. As a first step toward this approach, we have used electroporation to introduce a 7.2-kilobase plasmid DNA into isolated functional mitochondria. Transfer of the DNA at field strengths between 8 and 20 kV/cm was investigated by Southern blot analysis. Maximal plasmid internalization was achieved at a field strength of 14 kV/cm. The functional integrity of the mitochondria after electroporation was verified by enzymatic assays of specific mitochondrial marker enzymes and by measuring respiratory control. At field strengths above 12 kV/cm, an increasing mitochondrial destruction was observed. 12 kV/cm was found to be optimal for the most efficient plasmid internalization while still retaining the functional integrity of the mitochondria. At this field strength, about half of the internalized plasmid was found in the inner membrane or mitochondrial matrix, as determined by immunoelectron microscopy and Southern blot analysis of electroporated mitochondria treated with digitonin. We estimate that on average one plasmid molecule/mitochondrion reaches the matrix or inner membrane.
Uncoupling protein‐3: clues in an ongoing mitochondrial mystery (2007)

Uncoupling protein (UCP) 3 (UCP3) is a mitochondrial anion carrier protein with highly selective expression in skeletal muscle. Despite a great deal of interest, to date neither its molecular mechanism nor its biochemical and physiological functions are well understood. Based on its high degree of homology to the original UCP (UCP1), early studies examined a role for UCP3 in thermogenesis. However, evidence for such a function is lacking. Recent studies have focused on two distinct, but not mutually exclusive, hypotheses: 1) UCP3 mitigates reactive oxygen species (ROS) production, and 2) UCP3 is somehow involved in fatty acid (FA) translocation. While supportive evidence exists for both hypotheses, the interpretation of the corresponding evidence has created some controversy. Mechanistic studies examining mitigated ROS production have been largely conducted in vitro, and the physiological significance of the findings is questioned. Conversely, while physiological evidence exists for FA translocation hypotheses, the evidence is largely correlative, leaving causal relationships unexplored. This review critically assesses evidence for the hypotheses and attempts to link the outcomes from mechanistic studies to physiological implications. Important directions for future studies, using current and novel approaches, are discussed.
Antipsychotic augmentation for treatment resistant obsessive???compulsive disorder: what if antipsychotic is discontinued? (2003)

The aim of the present study was to retrospectively review the charts of obsessive–compulsive disorder (OCD) patients who responded to the addition of an antipsychotic to the seroronin reuptake inhibitor (SRI), and who subsequently discontinued the antipsychotic, in order to evaluate whether antipsychotic discontinuation resulted in a relapse of the disorder. Charts of patients with a principal diagnosis of OCD (DSM-IV) treated with pharmacotherapy were reviewed in order to select patients who: (i) did not respond to a trial with a first-line drug (clomipramine or a selective SRI); (ii) received an antipsychotic at low doses (haloperidol, pimozide, risperidone or olanzapine) in order to potentiate the SRI; (iii) responded to this augmentation strategy; and (iv) discontinued the antipsychotic drug for any reason while continuing the SRI at the same dose. Relapse was defined as a worsening of Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) total score ≥ 35% with respect to last evaluation before antipsychotic discontinuation or, for patients with a Y-BOCS < 16 at the end of the combination period, as a Y-BOCS total score ≥ 16 at any time after antipsychotic discontinuation. According to our definition of relapse, 15 patients out of 18 (83.3%) relapsed after antipsychotic discontinuation, with a mean worsening of symptoms of 6.6 ± 1.7 points in the Y-BOCS total score. Thirteen patients out of the 15 who relapsed did so by week 8 after discontinuation. Two subjects relapsed at the end of the 1-year study. Although retrospective, our study provides initial evidence that antipsychotic augmentation has to be maintained for patients who respond to this strategy, because the vast majority of subjects who discontinue the antipsychotic relapse within 2 months.
Characteristics of lipid substances activating the ileal brake in the rat. (1990)

Studies were carried out in 36 adult male rats to determine the characteristics of lipid substances which, after infusion into the ileum, slow the stomach to caecum transit time of the head of a bean meal in the rat. Stomach to caecum transit time was measured by environmental hydrogen analysis. Ileal infusion of a range of free fatty acids including petroselinic, oleic, myristoleic, erucic, linoleic, and linolenic all significantly slowed stomach to caecum transit time, as did the detergents (sodium bis (2-ethyl hexyl) sulphosuccinate and sodium linoleyl sulphate), the triglyceride corn oil, and the phospholipid lecithin. Although the lipid soluble deconjugated bile acid deoxycholic acid slowed stomach to caecum transit time, the water soluble conjugated bile acid taurocholic acid accelerated it. Infusion of the lipid alcohol oleyl alcohol and the calcium chelating agent disodium edetate (EDTA) into the ileum did not delay the passage of the meal through the stomach and small intestine. The diversity of lipid substances activating the ileal brake suggest a nonspecific effect by lipid soluble substances that can penetrate cell membranes. The lack of effect of EDTA suggested that calcium binding was not important.
Adenoid cystic carcinomas of the breast and salivary glands (or ‘The strange case of Dr Jekyll and Mr Hyde’ of exocrine gland carcinomas) (2010)

Adenoid cystic carcinoma (AdCC) is a tumour with myoepithelial differentiation and characterised by the presence of a dual population of basaloid and luminal cells arranged in specific growth patterns. These tumours, regardless of the anatomical site, are characterised by expression of the proto-oncogene and therapeutic target c-KIT, and seem to harbour a specific chromosomal translocation t(6;9) leading to the fusion gene MYB-NFIB and overexpression of the oncogene MYB. However, the clinical behaviour of salivary gland and breast AdCC differs; while salivary gland lesions have a relatively high proclivity to metastasise, patients with breast AdCCs have an excellent outcome. Here the clinical, morphological and molecular features, and potential therapeutic targets of salivary gland and breast AdCCs are reviewed.
Re-expression of SynGAP Protein in Adulthood Improves Translatable Measures of Brain Function and Behavior in a Model of Neurodevelopmental Disorders (2018)

Abstract Background Neurodevelopmental disorder (NDD) risk genes have pleiotropic biological functions, such as control over both developmental and non-developmental processes that influence disease-related phenotypes. Currently, it remains unclear how developmental versus non-developmental processes influence the duration and/or effectiveness of permissive treatment windows for NDDs. SYNGAP1 haploinsufficiency causes an NDD defined by autistic traits, cognitive impairment, and epilepsy. Syngap1 heterozygosity in mice disrupts a developmental critical period, and, consistent with this, certain behavioral abnormalities are resistant to gene therapy initiated in adulthood. However, the Syngap1 endophenotype is extensive and this protein has diverse cell biological functions. Therefore, SynGAP pleiotropy may influence the permissive treatment window for previously untested disease-relevant phenotypes. Methods A whole-body gene restoration technique was used to determine how restoration of SynGAP protein in adult heterozygous mice impacted previously untested phenotypes, such as memory, seizure susceptibility, systems-level cortical hyperexcitability, and hippocampal oscillations linked to mnemonic processes. Results Adult restoration of SynGAP protein in haploinsufficient mice reversed long-term contextual memory deficits and behavioral measures of seizure susceptibility. Moreover, SynGAP re-expression in adult mice eliminated brain state-dependent, patient-linked paroxysmal interictal spiking and increased the amplitude of hippocampal theta oscillations. Conclusions SynGAP protein in the mature brain dynamically regulates neural circuit function and influences disease-relevant phenotypes. The impact of these findings is that treatments targeting certain debilitating aspects of SYNGAP1- related disorders may be effective throughout life. Moreover, the efficacy of experimental treatments for SYNGAP1 patients may be quantifiable through changes in species-conserved, state-dependent pathological electroencephalogram signals.
Behavior in Multi-Unit Demand Auctions: Experiments with Uniform Price and Dynamic Vickrey Auctions (2001)

We experimentally investigate the sensitivity of bidders demanding multiple units of a homogeneous commodity to the demand reduction incentives inherent in uniform price auctions. There is substantial demand reduction in both sealed bid and ascending price clock auctions with feedback regarding rivals' drop-out prices. Although both auctions have the same normal form representation, bidding is much closer to equilibrium in the ascending price auctions. We explore the behavioral process underlying these differences along with dynamic Vickrey auctions designed to eliminate the inefficiencies resulting from demand reduction in the uniform price auctions.