gebhart/patrepeval huggingface dataset:
A fungal endophyte of black spruce (Picea mariana) needles is also an aquatic hyphomycete (2006)

An aquatic hyphomycete, Dwayaangam sp., was isolated from superficially sterilized black spruce (Picea mariana) needles submerged in aerated water in a small glass chamber (microcosm). The internal transcribed spacer (ITS) sequence of this fungus and of a commonly encountered foliar endophyte isolated from P. mariana showed a high degree of similarity. When sporulation was induced in the microcosm, both the aquatic hyphomycete and the endophyte isolate produced similar aquatic conidia after 30 days, which is longer than previously documented in similar studies. Without the use of molecular tools, the link between the aquatic and endophytic phases of the fungus would have gone unnoticed. This is the first time that a fungal endophyte of conifer needles has been shown to have an aquatic phase. Its presence both as a foliar endophyte and a sporulating aquatic fungus suggests an alternating life cycle between the two environments.
Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability (2020)

Abstract The rapid spread of SARS-CoV-2 has a significant impact on global health, travel and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated neutralizing antibodies from convalescent COVID-19 patients using a SARS-CoV-2 stabilized prefusion spike protein. Several of these antibodies were able to potently inhibit live SARS-CoV-2 infection at concentrations as low as 0.007 µg/mL, making them the most potent human SARS-CoV-2 antibodies described to date. Mapping studies revealed that the SARS-CoV-2 spike protein contained multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as previously undefined non-RBD epitopes. In addition to providing guidance for vaccine design, these mAbs are promising candidates for treatment and prevention of COVID-19.
Conversion of acetylcholinesterase to butyrylcholinesterase: modeling and mutagenesis. (1992)

Torpedo acetylcholinesterase (AcChoEase, EC 3.1.1.7) and human butyrylcholinesterase (BtChoEase, EC 3.1.1.8), while clearly differing in substrate specificity and sensitivity to inhibitors, possess 53% sequence homology; this permitted modeling human BtChoEase on the basis of the three-dimensional structure of Torpedo AcChoEase. The modeled BtChoEase structure closely resembled that of AcChoEase in overall features. However, six conserved aromatic residues that line the active-site gorge, which is a prominent feature of the AcChoEase structure, are absent in BtChoEase. Modeling showed that two such residues, Phe-288 and Phe-290, replaced by leucine and valine, respectively, in BtChoEase, may prevent entrance of butyrylcholine into the acyl-binding pocket. Their mutation to leucine and valine in AcChoEase, by site-directed mutagenesis, produced a double mutant that hydrolyzed butyrylthiocholine almost as well as acetylthiocholine. The mutated enzyme was also inhibited well by the bulky, BtChoEase-selective organophosphate inhibitor (tetraisopropylpyrophosphoramide, iso-OMPA). Trp-279, at the entrance of the active-site gorge in AcChoEase, is absent in BtChoEase. Modeling designated it as part of the "peripheral" anionic site, which is lacking in BtChoEase. The mutant W279A displayed strongly reduced inhibition by the peripheral site-specific ligand propidium relative to wild-type Torpedo AcChoEase, whereas inhibition by the catalytic-site inhibitor edrophonium was unaffected.
Phosphorylation of Threonine 558 in the Carboxyl-terminal Actin-binding Domain of Moesin by Thrombin Activation of Human Platelets (1995)

The phosphorylation and localization of the membrane-linking protein moesin was analyzed during early activation of platelets with thrombin. Activated platelets elaborate filopodia and spread to assume flat pancake-like shapes, and moesin is localized in filopodia and cell body. In resting platelets, approximately 25% of moesin molecules are phosphorylated as shown by metabolic labeling with 32P(i) and by isoelectric focusing. Within seconds after exposure to thrombin, phosphorylation increases, reaching a maximum of 35% labeled molecules by 1 min, followed by a decrease to a new basal level within 5 min. This modification affects a single residue, Thr558, which is located within or close to a binding site for F-actin. Rapid shifts (0-100%) in the number of phosphorylated molecules are observed in the presence of inhibitors of serine/threonine kinases and phosphatases. Inhibitors affecting tyrosine phosphorylation also modulate phosphorylation at this site suggesting that the enzymes involved in the modification of Thr558 are regulated by tyrosine phosphorylation. Platelets respond to both extremes of modification by forming extremely long filopodia and the absence of spreading on glass. Completely phosphorylated moesin is concentrated together with F-actin in the center of the cell. The rapid modification of moesin at or near its actin-binding domain suggests a model for regulated membrane-cytoskeleton interaction during cell activation.
GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4 (2009)

Glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) binds both LPL and chylomicrons, suggesting that GPIHBP1 is a platform for LPL-dependent processing of triglyceride (TG)-rich lipoproteins. Here, we investigated whether GPIHBP1 affects LPL activity in the absence and presence of LPL inhibitors angiopoietin-like (ANGPTL)3 and ANGPTL4. Like heparin, GPIHBP1 stabilized but did not activate LPL. ANGPTL4 potently inhibited nonstabilized LPL as well as heparin-stabilized LPL but not GPIHBP1-stabilized LPL. Like ANGPTL4, ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. ANGPTL3 also inhibited heparin-stabilized LPL but with less potency than nonstabilized LPL. Consistent with these in vitro findings, fasting serum TGs of Angptl4(-/-)/Gpihbp1(-/-) mice were lower than those of Gpihbp1(-/-) mice and approached those of wild-type littermates. In contrast, serum TGs of Angptl3(-/-)/Gpihbp1(-/-) mice were only slightly lower than those of Gpihbp1(-/-) mice. Treating Gpihbp1(-/-) mice with ANGPTL4- or ANGPTL3-neutralizing antibodies recapitulated the double knockout phenotypes. These data suggest that GPIHBP1 functions as an LPL stabilizer. Moreover, therapeutic agents that prevent LPL inhibition by ANGPTL4 or, to a lesser extent, ANGPTL3, may benefit individuals with hyperlipidemia caused by gene mutations associated with decreased LPL stability.
Explaining species distribution patterns through hierarchical modeling (2006)

Understanding spatial patterns of species diversity and the distributions of individual species is a consuming problem in biogeography and conservation. The Cape Floristic Region (CFR) of South Africa is a global hotspot of diversity and endemism, and the Protea Atlas Project, with some 60,000 site records across the region, provides an extraordinarily rich data set to analyze biodiversity patterns. Analysis for the region is developed at the spatial scale of one minute grid-cells (~37,000$ cells total for the region). We report on results for 40 species of a flowering plant family Proteaceae (of about 330 in the CFR) for a defined subregion. Using a Bayesian framework, we develop a two stage, spatially explicit, hierarchical logistic regression. Stage one models the suitability or potential presence for each species at each cell, given species attributes along with grid cell (site-level) climate, precipitation, topography and geology data using species-level coefficients, and a spatial random effect. The second level of the hierarchy models, for each species, observed presence$/$absence at a sampling site through a conditional specification of the probability of presence at an arbitrary location in the grid cell given that the location is suitable. Because the atlas data are not evenly distributed across the landscape, grid cells contain variable numbers of sampling localities. Indeed, some grid cells are entirely unsampled; others have been transformed by human intervention (agriculture, urbanization) such that none of the species are there though some may have the potential to be present in the absence of disturbance. Thus the modeling takes the sampling intensity at each site into account by assuming that the total number of times that a particular species was observed within a site follows a binomial distribution. In fact, a range of models can be examined incorporating different first and second stage specifications. This necessitates model comparison in a misaligned multilevel setting. All models are fitted using MCMC methods. A "best" model is selected. Parameter summaries offer considerable insight. In addition, results are mapped as the model-estimated potential presence for each species across the domain. This probability surface provides an alternative to customary empirical "range of occupancy" displays. Summing yields the predicted species richness over the region. Summaries of the posterior for each environmental coefficient show which variables are most important in explaining species presence. Other biodiversity measures emerge as model unknowns. A considerable range of inference is available. We illustrate with only a portion of the analyses we have conducted, noting that these initial results describe biogeographical patterns over the modeled region remarkably well.
The Role of α-Cell Dysregulation in Fasting and Postprandial Hyperglycemia in Type 2 Diabetes and Therapeutic Implications (2007)

The hyperglycemic activity of pancreatic extracts was encountered some 80 yr ago during efforts to optimize methods for the purification of insulin. The hyperglycemic substance was named "glucagon," and it was subsequently determined that glucagon is a 29-amino acid peptide synthesized and released from pancreatic alpha-cells. This article begins with a brief overview of the discovery of glucagon and the contributions that somatostatin and a sensitive and selective assay for pancreatic (vs. gut) glucagon made to understanding the physiological and pathophysiological roles of glucagon. Studies utilizing these tools to establish the function of glucagon in normal nutrient homeostasis and to document a relative glucagon excess in type 2 diabetes mellitus (T2DM) and precursors thereof are then discussed. The evidence that glucagon excess contributes to the development and maintenance of fasting hyperglycemia and that failure to suppress glucagon secretion contributes to postprandial hyperglycemia is then reviewed. Although key human studies are emphasized, salient animal studies highlighting the importance of glucagon in normal and defective glucoregulation are also described. The past eight decades of research in this area have led to development of new therapeutic approaches to treating T2DM that have been shown to, or are expected to, improve glycemic control in patients with T2DM in part by improving alpha-cell function or by blocking glucagon action. Accordingly, this review ends with a discussion of the status and therapeutic potential of glucagon receptor antagonists, alpha-cell selective somatostatin agonists, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-IV inhibitors. Our overall conclusions are that there is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.
Estimating Abdominal Adipose Tissue with DXA and Anthropometry (2007)

This study has identified a DXA ROI that can be reliably measured using prominent anatomical landmarks, in this case, the iliac crest. Using this ROI, combined with an abdominal skinfold measurement, we have derived an equation to predict IAAT in overweight/obese postmenopausal women. This approach offers a simpler, safer, and more cost-effective method than CT for assessing the efficacy of lifestyle interventions aimed at reducing IAAT. However, this warrants further investigation and validation with an independent cohort.
A Novel Puncturing Scheme for Polar Codes (2014)

A novel kind of punctured polar codes is proposed in this paper. The codes are constructed by certain constraints on both puncturing patterns and frozen sets such that the values of the punctured bits are known to the decoder. As a result, the initialized log-likelihood ratios of the punctured bits can be set to infinity (or minus infinity), which guarantees a better decoding performance. Furthermore, explicit puncturing patterns are designed for arbitrary code lengths. The simulation results show that the proposed codes outperform the conventional punctured polar codes.
Critical Involvement of Interferon γ in the Pathogenesis of T–Cell Activation–Associated Hepatitis and Regulatory Mechanisms of Interleukin–6 for the Manifestations of Hepatitis (1996)

A single intravenous injection of concanavalin A (Con A) induces T–cell activation and an acute hepatitis in mice. This study investigated the role of interferon γ (IFN–γ) in the pathogenesis of this hepatitis model. Striking increases in the plasma levels of various cytokines, including tumor necrosis factor (TNF), interleukin–2 (IL–2), and IFN–γ, were detected before the increase in plasma aminotransferase levels induced by Con A injection. TNF levels peaked within 2 hours, whereas IFN–γ levels peaked at 6 hours after Con A injection. In contrast to a sharp peak of TNF levels, high IFN–γ levels were detected for a more prolonged period. Passive immunization with anti–IFN–γ monoclonal antibody (MAb) conferred a dose–dependent protection against liver injury in this model. This protection was observed when anti–IFN–γ MAb was administered at least 30 minutes before Con A injection but not when given 1 hour after Con A injection. The protection from Con A–induced hepatitis was also induced by administration of rIL–6 before Con A injection. rIL–6 treatment induced significant albeit incomplete inhibition of IFN–γ and TNF production, whereas this regimen did not affect IL–2 production. Despite striking protective effects of rIL–6 or anti–IFN–γ MAb, comparable levels of cellular (both T cell and polymorphonuclear cell) infiltration were detected in liver sections from animals untreated, or treated with either rIL–6 or anti–IFN–γ MAb. Moreover, electron microscopic examination showed that infiltrating T cells exhibited a blastoid appearance in all groups. These results indicate that IFN–γ plays a critical role in the development of Con A–induced acute hepatitis and suggest that IL–6 administration can regulate the manifestation of hepatitis through mechanisms including the reduced production of inflammatory cytokines such as IFN–γ.
Novel fucolipids of human adenocarcinoma: disialosyl Lea antigen (III4FucIII6NeuAcIV3NeuAcLc4) of human colonic adenocarcinoma and the monoclonal antibody (FH7) defining this structure. (1986)

A new fucoganglioside, disialosyl Lea, has been found in the disialoganglioside fraction of human colonic adenocarcinoma. The ganglioside has been isolated from four other disialogangliosides by high-performance liquid chromatography followed by preparative high-performance thin-layer chromatography. The structure of the antigen was characterized by its conversion to lactofucopentaosyl(II)ceramide (Lea-active ceramide pentasaccharide), methylation analysis, and high-mass range electron-impact as well as field-desorption mass spectrometry of the permethylated derivative, as shown below: (Formula; see text) Specific removal of alpha 2----3-linked sialosyl residue by influenza virus A2 sialidase, or preferential hydrolysis of the same residue by Clostridium perfringens sialidase in the absence of detergent, resulted in the formation of an intermediate product, monosialosyl LeaII (III4FucIII6NeuAcLc4), which reacted with anti-Lea antibody and with monoclonal antibody FH7 and may have a sialic acid linked at the 6 position of GlcNAc. The IgG3 monoclonal antibody FH7 was established, which reacts specifically with disialosyl Lea and monosialosyl LeaII as above, but does not react with disialosyllactotetraosylceramide (IV3NeuAcIII6Neu-AcLc4), monosialosyl LeaI (IV3NeuAcIII4FucLc4), and other mono- and disialogangliosides isolated from the same cancer tissue. The antibody FH7 may be useful in the detection of human cancer.
The SF-36 Arthritis-Specific Health Index (ASHI) (1999)

An arthritis-specific health index (ASHI) for the SF-36 Health Survey was developed by studying its responsiveness to changes in clinical indicators of arthritis severity. Longitudinal data from 1,076 patients participating in four placebo-controlled trials were analyzed. All had at least a 6-month history of moderate to severe osteoarthritis or rheumatoid arthritis of the knee or hip. All had undergone a washout period of 3 to 14 days before baseline assessment to bring about a flare state in osteoarthritis or rheumatoid arthritis symptoms. Their average age was 60 years and 72% were female. Change scores for the eight-scale SF-36 health profile (acute version) and five arthritis-specific measures of disease severity (knee pain on weight bearing, time to walk 50 feet, physician global evaluation of symptom severity and impact, patient global evaluation of symptom severity and impact, and pain intensity visual analogue scale) were computed by subtracting scores before treatment from scores at two-week follow-up. Canonical correlation methods were used to derive weights for changes in SF-36 scales to score a single index (ASHI) that maximized its correlation with changes in the set of five clinical measures of arthritis severity. The weights used to score the ASHI were cross-validated in a 25% holdout group (N = 144) from the first two osteoarthritis trials and in two additional osteoarthritis and rheumatoid arthritis trials (N = 530). Only one SF-36 canonical variate (ASHI) correlated significantly (F = 4.69, P < 0.0001) with the clinical canonical variate that served as the "criterion" measure of change in the severity of arthritis. Changes in the ASHI and clinical canonical variate were substantially correlated in the developmental sample (r = 0.628, P < 0.0001) and on cross-validation (r = 0.629, P < 0.0001). The clinical canonical variate correlated highly (r = 0.75-0.88) with changes in all but one of the five clinical measures (50-foot walk; r = 0.41). The pattern of correlations between changes in SF-36 scales and the ASHI indicated that ASHI is primarily a measure of bodily pain (r = 0.92) and other aspects of physical and role functioning and well-being (r = 0.69 for Role-Physical, r = 0.68 for Physical Functioning, r = 0.52 for Social Functioning, and r = 0.51 Vitality). The patterns of correlations between SF-36 scales and the ASHI were very similar across developmental and cross-validation samples. This research demonstrates the feasibility and generalizability of a single ASHI scored from changes in responses to the SF-36 Health Survey. The generic SF-36 health profile, which has already been shown to be useful in comparing arthritis with other diseases and treatments, can also be scored specifically to make it more useful in studies of osteoarthritis and rheumatoid arthritis.
Mechanical and thermal allodynia in chronic central pain following spinal cord injury (1996)

Spinal cord injury (SCI) results in variable motor recoveries and chronic central pain syndromes develop in the majority of SCI patients. To provide a basis for further studies, we report a new rodent model of chronic central pain following spinal cord trauma. Male Sprague-Dawley rats (N = 10) were hemisectioned at T13 and were tested both preoperatively and postoperatively and compared to sham-operated controls (N = 10) for locomotor function, and mechanical and thermal thresholds of both paw withdrawal and supraspinal responses. Results support the development and persistence of allodynia which persists for 160 days. Locomotor function was tested using the Basso, Beattie and Bresnahan (BBB) open field test and only the limb ipsilateral to the hemisection was affected, demonstrating acute flaccid paralysis with motor recovery which approached normal values by postoperative day (POD) 15. Prior to the hemisection, the rats showed little to no paw withdrawal response to von Frey stimulation of 4.41 mN or 9.41 mN in both forelimbs and hindlimbs. Postoperatively, responses in both ipsilateral and contralateral forelimbs and hindlimbs increased over time and the increase was statistically significant compared to intra-animal presurgical and sham control values (P < 0.05). There were no significant side-to-side differences in limb responses preoperatively or beyond POD 15. The forelimbs and hindlimbs responded to von Frey hair strengths of 122 mN preoperatively and postoperatively with similar withdrawal frequencies that were not statistically significant. Preoperatively, the paw withdrawal latency to heat stimuli was 22.9 +/- 3.0 (mean +/- SE) and 20.1 +/- 3.1 sec for the hindlimbs and forelimbs, respectively. Postoperatively, the mean hindlimb and forelimb latency of paw withdrawals decreased to 11.9 +/- 1.8 and 9.2 +/- 2.5 sec, respectively. This decrease in thermal thresholds is statistically significant when compared to intra-animal preoperative and sham control values (P < 0.05). These data indicate that somatosensory thresholds for non-noxious mechanical and radiant heat which elicit paw withdrawal (flexor reflex) are significantly lowered following SCI. To further support the development and persistence of chronic pain following hemisection, supraspinal responses such as paw lick, head turns, attacking the stimulus, and vocalizations were elicited in response to mechanical and thermal stimuli and were statistically significant compared to presurgical intra-animal or sham control values (P < 0.05). Hemisected animals vocalized to von Frey hair bending forces of 49.8 with a mean of 6.0 +/- 1.2 times out of 10 stimuli compared to intra-animal presurgical and sham control values of zero. Supraspinal responses of hemisected animals to thermal stimuli occurred at lower temperatures that were statistically significant compared to sham control or preoperative values (P < 0.05). These chronic changes in thresholds to both mechanical and thermal stimuli represent the development and persistence of mechanical and thermal allodynia after SCI.
Improvement in Postmenopausal Sexual Dysfunction With TX-004HR (VagiCap™) as Measured by FSFI [2A] (2016)

INTRODUCTION: TX-004HR is a novel, self-inserted (no applicator needed) vaginal softgel capsule (VagiCap™) containing solubilized 17-β estradiol under investigation for the treatment of moderate to severe postmenopausal dyspareunia. Phase 1 and 2 data suggests that TX-004HR may provide an effective dosage form with early onset of action and low systemic estrogen levels. The effect of TX-004HR on female sexual dysfunction (FSD) was assessed utilizing the Female Sexual Function Index (FSFI). METHODS: A multicenter Phase 3, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of TX-004HR. A total of 764 postmenopausal women with self-assessed moderate to severe dyspareunia received TX-004HR (4 µg, 10 µg, or 25 μg) compared to placebo for 12 weeks. Co-primary endpoints were change from baseline to week 12 in: percent superficial and parabasal cells, vaginal pH, and dyspareunia (the self-identified most bothersome symptom). Secondary endpoints included vaginal dryness and vaginal and/or vulvar itching or irritation and an assessment of sexual function, assessed by the FSFI questionnaire. The six individual FSFI domain scores (arousal, desire, orgasm, lubrication, satisfaction, and pain) and the overall score were analyzed as a secondary efficacy endpoint. RESULTS: Results at Week 12 will be included in January. CONCLUSION: TX-004HR, a vaginal softgel estradiol capsule when used in postmenopausal women with dyspareunia is expected to improve female sexual dysfunction as measured by the FSFI Index.