gebhart/patrepeval huggingface dataset:
Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase: Nevirapine as a Prototype Drug (1992)

Nevirapine, a dipyridodiazepinone, is a highly specific inhibitor of HIV-1 reverse transcriptase (RT) which exhibits an IC50 = 84nM in enzyme assays and IC50 = 40nM against HIV-1 replication in cell culture. This nonnucleoside inhibitor acts noncompetitively with respect to nucleoside triphosphates, template and primer suggesting that nevirapine does not bind to the active site of RT. Studies employing an azido analogue of nevirapine as a photoaffinity probe indicated that one molecule of inhibitor is sufficient to inactivate one molecule of heterodimeric enzyme and demonstrated that only the p66 subunit of p66/p51 heterodimeric RT is covalently labeled by this probe. When subjected to trypic mapping, Tyr 181 and Tyr 188 were labeled with probe and consequently these aromatic residues are apparently near or actually within the RT binding site for nevirapine. The extent to which Tyr 181 and Tyr 188 participate/contribute to nevirapine binding was determined by making amino acid substitutions at these positions using the corresponding residues from HIV-2 RT which is not sensitive to nevirapine. A change at either position dramatically decreased the enzymes' sensitivity to nevirapine, as well as to TIBO derivative and Merck L-693,593, indicating that both Tyr 181 and 188 are crucial for inhibitor-enzyme interaction. Cell culture selection in the continued presence of nevirapine results in the appearance of resistant HIV-1, Tyr 181 to Cys, raising the concern that combination drug therapy will be required in the clinic.
Immunolocalization of keratin polypeptides in human epidermis using monoclonal antibodies (1982)

Three monoclonal antibodies (AE1, AE2, and AE3) were prepared against human epidermal keratins and used to study keratin expression during normal epidermal differentiation. Immunofluorescence staining data suggested that the antibodies were specific for keratin-type intermediate filaments. The reactivity of these antibodies to individual human epidermal keratin polypeptides (65-67, 58, 56, and 50 kdaltons) was determined by the immunoblot technique. AE1 reacted with 56 and 50 kdalton keratins, AE2 with 65-67 and 56-kdalton keratins, and AE3 with 65-67 and 58 kdalton keratins. Thus all major epidermal keratins were recognized by at least one of the monoclonal antibodies. Moreover, common antigenic determinants were present in subsets of epidermal keratins. To correlate the expression of specific keratins with different stages of in vivo epidermal differentiation, the antibodies were used for immunohistochemical staining of frozen skin sections. AE1 reacted with epidermal basal cells, AE2 with cells above the basal layer, and AE3 with the entire epidermis. The observation that AE1 and AE2 antibodies (which recognized a common 56 kdalton keratin) stained mutually exclusive parts of the epidermis suggested that certain keratin antigens must be masked in situ. This was shown to be the case by direct analysis of keratins extracted from serial, horizontal skin sections using the immunoblot technique. The results from these immunohistochemical and biochemical approaches suggested that: (a) the 65- to 67-kdalton keratins were present only in cells above the basal layer, (b) the 58-kdalton keratin was detected throughout the entire epidermis including the basal layer, (c) the 56-kdalton keratin was absent in the basal layer and first appeared probably in the upper spinous layer, and (d) the 50-kdalton keratin was the only other major keratin detected in the basal layer and was normally eliminated during s. corneum formation. The 56 and 65-67-kdalton keratins, which are characteristic of epidermal cells undergoing terminal differentiation, may be regarded as molecular markers for keratinization.
Expression and Differential Glycosylation of Human Sex Hormone-Binding Globulin by Mammalian Cell Lines (1991)

The human sex hormone-binding globulin (SHBG) gene is responsible for the production of plasma SHBG by the liver and androgen-binding protein in the testis. Cell-specific glycosylation events during synthesis may account for minor differences in the biochemical properties of SHBG and androgen-binding protein, and we have, therefore, expressed a human SHBG cDNA in chinese hamster ovary (CHO) cells and a mouse hepatoma cell line (BW-1), and compared the products to SHBG in serum. The SHBG produced in this way is a homodimer of subunits that exhibit size microheterogeneity similar to SHBG in human serum, and its affinity for 5 alpha-dihydrotestosterone (Kd = 0.6 nM) and other steroids is essentially identical to that of natural SHBG. When medium from transfected CHO and BW-1 cells was subjected to Concanavalin-A (Con-A) chromatography, the relative amounts of SHBG retained by Con-A were 74% and 86%, respectively. In addition, when SHBG produced by CHO cells was separated into two fractions by Con-A chromatography and analyzed by polyacrylamide gel electrophoresis, SHBG that did not interact with Con-A migrated with a slightly larger apparent mol wt than that of SHBG that binds Con-A; this can be explained by the presence of triantennary, rather than biantennary, N-linked oligosaccharide chains. These data also demonstrate that the subunit microheterogeneity associated with plasma SHBG reflects differences in glycosylation during synthesis, which appear to be cell type specific.
Gaucher's disease in the Cape coloured population of the RSA, including a family with 5 affected siblings. (1987)

Nine Cape Coloured children from 4 families with severe non-neuropathic Gaucher's disease are documented. The diagnosis was confirmed histologically in the bone marrow, spleen and liver, and by serum acid phosphatase and leucocyte beta-glucosidase assays. This represents a minimum prevalence for Gaucher's disease of 1 in 247,350 in this population and an approximate genetic carrier rate of 1 in 230 for the abnormal gene. A family with 5 affected siblings is recorded. The severe early clinical expression documented in these coloured patients is similar to that described in the Afrikaner population and differs from the less severe expression of Gaucher's disease in the South African Ashkenazi Jewish population. Gaucher's disease in the Cape Coloured population presents with a precocious onset, causes severe complications and progresses rapidly.
Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. (1995)

Myotonic dystrophy is caused by an expansion of a CTG triplet repeat sequence in the 3' noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. This report demonstrates that a DNase I hypersensitive site is positioned 3' of the triplet repeat in the wild-type allele in both fibroblasts and skeletal muscle cells. In three unrelated individuals with myotonic dystrophy that have large expansions of the triplet repeat, the allele with the triplet repeat expansion exhibited both overall DNase I resistance and inaccessibility of nucleases to the adjacent hypersensitive site. These results indicate that the triplet repeat expansion alters the adjacent chromatin structure, establishing a region of condensed chromatin, and suggests a molecular mechanism for myotonic dystrophy.
Targeting Dendrimer-Chelates to Tumors and Tumor Cells Expressing the High-Affinity Folate Receptor (1997)

These data demonstrate that folate-conjugated magnetic resonance imaging contrast agents represent a promising new approach to tumor targeting.
LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality (2016)

Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, crossover studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants' desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.
Diabetes, Obesity, and the Brain (2005)

Recent evidence suggests a key role for the brain in the control of both body fat content and glucose metabolism. Neuronal systems that regulate energy intake, energy expenditure, and endogenous glucose production sense and respond to input from hormonal and nutrient-related signals that convey information regarding both body energy stores and current energy availability. In response to this input, adaptive changes occur that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in this control system are implicated in the link between obesity and type 2 diabetes.
RNA-mediated therapies in myotonic dystrophy (2018)

Myotonic dystrophy 1 (DM1) is a multisystemic neuromuscular disease caused by a dominantly inherited 'CTG' repeat expansion in the gene encoding DM Protein Kinase (DMPK). The repeats are transcribed into mRNA, which forms hairpins and binds with high affinity to the Muscleblind-like (MBNL) family of proteins, sequestering them from their normal function. The loss of function of MBNL proteins causes numerous downstream effects, primarily the appearance of nuclear foci, mis-splicing, and ultimately myotonia and other clinical symptoms. Antisense and other RNA-mediated technologies have been applied to target toxic-repeat mRNA transcripts to restore MBNL protein function in DM1 models, such as cells and mice, and in humans. This technique has had promising results in DM1 therapeutics by alleviating pathogenic phenotypes.
Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer (2013)

Acquired radiation resistance is one of the major causes of radio therapy failure and subsequent tumor relapse. Multiple approaches have been utilized to limit the radiation resistance while simultaneously enhancing the efficacy and safety of radiation therapy. The three major approaches for the improvement of radiation therapy have involved (I) ehancing radiosensitization of tumor tissue; (II) rversing of radiation resistance in tumor tissue; and (III) ehancing radioresistance of the healthy tissue. Nanoparticles have played a key role in the enhancement of the radiation therapy by acting both as a therapeutic as well as a carrier for other therapeutics. In this review we summarize the research being carried out using different species of nanoparticles for enhanced radiosensitization in cancer.
Finding high-quality content in social media (2008)

The quality of user-generated content varies drastically from excellent to abuse and spam. As the availability of such content increases, the task of identifying high-quality content sites based on user contributions --social media sites -- becomes increasingly important. Social media in general exhibit a rich variety of information sources: in addition to the content itself, there is a wide array of non-content information available, such as links between items and explicit quality ratings from members of the community. In this paper we investigate methods for exploiting such community feedback to automatically identify high quality content. As a test case, we focus on Yahoo! Answers, a large community question/answering portal that is particularly rich in the amount and types of content and social interactions available in it. We introduce a general classification framework for combining the evidence from different sources of information, that can be tuned automatically for a given social media type and quality definition. In particular, for the community question/answering domain, we show that our system is able to separate high-quality items from the rest with an accuracy close to that of humans
Cloning and characterization of novel rat and mouse low molecular weight Ca(2+)-dependent phospholipase A2s containing 16 cysteines. (1994)

A novel rat 4.4-kilobase (kb) cDNA encoding a low molecular weight Ca(2+)-dependent phospholipase A2 (PLA2) and its murine homologue were cloned. The rat and mouse cDNA predict a mature protein of 130 amino acids (M(r) = 14, 763) preceded by a 28-amino acid prepro-peptide. The deduced amino acid sequences encode a protein containing 16 cysteines which distinguishes them from both mammalian group I and II PLA2s and the recently described group of mammalian PLA2s containing 12 cysteines. A rat RNA blot hybridized with the rat cDNA exhibited an abundant 2.3-kb and a less abundant 5-kb transcript in testis. When the rat cDNA was expressed using an Epstein-Barr virus-based vector in human 293s cells, PLA2 activity accumulated in the culture medium. Conditioned medium optimally hydrolyzed the phospholipids of [1-14C]oleate-labeled Escherichia coli at neutral to alkaline pH with 1-7 mM Ca2+. In assays with individual substrates, L-alpha-1-stearoyl-2-arachidonyl phosphatidylinositol was hydrolyzed more efficiently than L-alpha-1-palmitoyl-2-oleoyl phosphatidylcholine, L-alpha-1-palmitoyl-2-arachidonyl phosphatidylcholine, or L-alpha-1-palmitoyl-2-arachidonyl phosphatidylethanolamine.
Infliximab (Remicade) in the treatment of psoriatic arthritis (2006)

Elucidation of the cellular immunopathology and cytokine profile of psoriatic arthritis (PsA), a chronic inflammatory disease associated with psoriasis, has resulted in the development of a number of novel biologic therapies. Among these biologics, tumor necrosis factor-alpha (TNF-alpha) inhibitors have been used successfully to treat patients suffering from rheumatoid arthritis or psoriasis. The pivotal role of TNF-alpha in the pathogenesis and progression of PsA suggested that anti-TNF-alpha agents could be effective in controlling PsA. The results from two large, randomized, double-blind, placebo-controlled trials in patients with moderate to severe PsA indicated that the anti-TNF-inhibitor, infliximab, can control both the joint and skin manifestations of the disease. This review focuses on the clinical development of infliximab as a treatment for PsA. The development of other anti-TNF-alpha biologics is also discussed.
Down-regulation of microRNAs controlling tumourigenic factors in follicular thyroid carcinoma (2011)

The molecular determinants of thyroid follicular nodules are incompletely understood and assessment of malignancy is a diagnostic challenge. Since microRNA (miRNA) analyses could provide new leads to malignant progression, we characterised the global miRNA expression in follicular adenoma (FA) and follicular carcinoma (FC). Comparison of carcinoma and adenoma with normal thyroid revealed 150 and 107 differentially expressed miRNAs respectively. Most miRNAs were down-regulated and especially miR-199b-5p and miR-144 which were essentially lost in the carcinomas. Integration of the changed miRNAs with differentially expressed mRNAs demonstrated an enrichment of seed sites among up-regulated transcripts encoding proteins implicated in thyroid tumourigenesis. This was substantiated by the demonstration that pre-miR-199b reduced proliferation when added to cultured follicular thyroid carcinoma cells. The down-regulated miRNAs in FC exhibited a substantial similarity with down-regulated miRNAs in anaplastic carcinoma (AC) and by gene set enrichment analysis, we observed a significant identity between target mRNAs in FC and transcripts up-regulated in AC. To examine the diagnostic potential of miRNA expression pattern in distinguishing malignant from benign nodules we employed a supervised learning algorithm and leave-one-out-cross-validation. By this procedure, FA and FC were identified with a negative predicted value of 83% (data generated by microarray platform) and of 92% (data generated by qRT-PCR platform). We conclude that follicular neoplasia is associated with major changes in miRNA expression that may promote malignant transformation by increasing the expression of transcripts encoding tumourigenic factors. Moreover, miRNA profiling may facilitate the diagnosis of carcinoma vs adenoma.
Stage-specific and differential expression of gap junctions in the mouse ovary: connexin-specific roles in follicular regulation (2001)

Gap junction communication plays an essential role in follicle growth. Immunocytochemistry and confocal microscopy were used to examine the expression of gap junction connexins of the and subfamilies in follicles from primordial to preovulatory stages in the ovaries of prepubertal and adult mice. Connexin-specific antibodies detected 1 , 4 , 6 , 1 , 2 and 4 connexins within follicles. In adult ovaries connexin immunolabelling was stronger in larger (more mature) follicles than it was in smaller follicles, with comparatively reduced labelling detected in prepubertal ovaries. In healthy follicles, labelling for subfamily con-nexins was detected between granulosa cells, whereas labelling for subfamily connexins was found in the theca. Labelling for subfamily connexins and 4 connexin (preantral stage) was detected on the oocyte surface membrane. In atretic follicles, labelling for 4 connexin appeared between the granulosa cells. These results demonstrate that and connexin subfamilies are segregated to separate cellular compartments in the mouse follicle. The results are discussed in the light of possible roles for differential gap junctional communication in the regulation of folliculogenesis, oocyte maturation and atresia.
Precision wearable accelerometer contact microphones for longitudinal monitoring of mechano-acoustic cardiopulmonary signals (2020)

Mechano-acoustic signals emanating from the heart and lungs contain valuable information about the cardiopulmonary system. Unobtrusive wearable sensors capable of monitoring these signals longitudinally can detect early pathological signatures and titrate care accordingly. Here, we present a wearable, hermetically-sealed high-precision vibration sensor that combines the characteristics of an accelerometer and a contact microphone to acquire wideband mechano-acoustic physiological signals, and enable simultaneous monitoring of multiple health factors associated with the cardiopulmonary system including heart and respiratory rate, heart sounds, lung sounds, and body motion and position of an individual. The encapsulated accelerometer contact microphone (ACM) utilizes nano-gap transducers to achieve extraordinary sensitivity in a wide bandwidth (DC-12 kHz) with high dynamic range. The sensors were used to obtain health factors of six control subjects with varying body mass index, and their feasibility in detection of weak mechano-acoustic signals such as pathological heart sounds and shallow breathing patterns is evaluated on patients with preexisting conditions.
Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys (1998)

Although the role of dopamine dysfunction is well established in Parkinson's disease, the effect of nigrostriatal degeneration on motor performance during normal aging is less well understood. In this study, aged rhesus monkeys (25-27 years old) displayed significant impairments relative to young (3-5 years old) cohorts in motor function as assessed on a fine motor task and home cage activity. Additionally, the clinical motor function of aged monkeys was impaired relative to young monkeys as assessed on a clinical rating scale. Unbiased stereologic measurements of the substantia nigra revealed a significant age-related loss of tyrosine hydroxylase-immunoreactive (TH-ir; 50.3%) and dopamine transporter-immunoreactive (DAT-ir; 33.2%) nigral neurons. The monkeys performance on the fine motor task and on the clinical rating scale was correlated with TH-ir neuronal counts. The number of DAT-ir nigral neurons was correlated with activity and clinical rating scale scores. Our results suggest that age-related motor impairments in nonhuman primates are associated with spontaneous decreases in TH-ir and DAT-ir nigral cells. The correlation of motor deficits with the loss of TH-ir and DAT-ir nigral neurons suggests that aged nonhuman primates may provide a useful model for mimicking changes seen in human aging and early Parkinson's disease.
Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections (1997)

In adults with influenza A or B virus infections, direct administration of a selective neuraminidase inhibitor, zanamivir, to the respiratory tract is safe and reduces symptoms if begun early.
Mechanisms of Hypertension Associated With BAY 43-9006 (2006)

Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.
The danger zone: Systematic review of the role of HMGB1 danger signalling in traumatic brain injury (2016)

A comprehensive review of these reports demonstrated that, following TBI, HMGB1 is released from damaged neurons and is elevated in patient's serum and CSF. Furthermore, these studies showed the potential for HMGB1 to serve as a prognostic biomarker and therapeutic target in patients with TBI. Thus, HMGB1 is a prospective candidate for future studies as it shows promise in treating and/or predicting the sequelae of TBI.
Thrombospondin 2 Regulates Cell Proliferation Induced by Rac1 Redox-Dependent Signaling (2003)

Thrombospondin 2 (TSP2) is a matricellular protein controlling the apoptosis-proliferation balance in endothelial cells. Little is known about its transcriptional regulation compared with that of TSP1. We found that overexpression of a constitutively active mutant of Rac (Rac(V12)) specifically increases TSP2 mRNA levels without affecting TSP1 in human aortic endothelial cells (HAEC). Moreover, TSP2 induction by Rac(V12) is dependent upon reactive oxygen species (ROS) production, as gp91ds-tat peptide, an inhibitor of NADPH oxidase, and the flavoprotein inhibitor diphenylene iodinium (DPI) block TSP2 synthesis. Furthermore, we found that increasing Rac(V12) expression results in a biphasic proliferative curve, with proliferation initially increasing as Rac(V12) expression increases and then returning to levels less than that of control cells at higher expression. This growth inhibition is mediated by TSP2, as either DPI treatment, which blocks TSP2 synthesis, or pan-TSP blocking antibodies restore the proliferative ability of HAEC with high expression. Mechanistically, we show that the effect of TSP2 on cell proliferation is independent of the antiangiogenic TSP2 Hep1 sequence, which is capable of altering actin cytoskeletal reorganization but not proliferation in our experimental conditions. Finally, we show in vivo that Rac-induced TSP2 expression is observed in the aorta of transgenic mice selectively expressing Rac(V12) in smooth muscle cells. These results identify Rac-induced ROS as a new pathway involved in the regulation of TSP2 expression.