gebhart/patrepeval huggingface dataset:
PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS Chemical and Technical Assessment (2008)

1. Summary Phytosterols and phytostanols, also referred to as plant sterols and stanols, are common plant and vegetable constituents and are therefore normal constituents of the human diet. They are structurally related to cholesterol, but differ from cholesterol in the structure of the side chain. Commercially, phytosterols are isolated from vegetable oils, such as soybean rapeseed (canola) sunflower oil or corn or from so-called tall oil, a by-product of the manufacture of wood pulp. These sterols can be hydrogenated to obtain phytostanols. Both phytosterols- and stanols, which are high melting powders, can be esterified with fatty acids of vegetable (oil) origin. The resulting esters are liquid or semi-liquid materials, having comparable chemical and physical properties to edible fats and oils, enabling supplementation of various processed foods with phytosterol- and phytostanol esters. The most common phytosterols and phytostanols are sitosterol (3β-stigmast-5-en-3ol; CAS Number 8346-5), sitostanol (3β,5α-stigmastan-3-ol; CAS Number 83-45-4), campesterol (3β-ergost-5-en-3-ol; CAS Number 474-62-4), campestanol (3β,5α-ergostan-3-ol; CAS Number 474-60-2), stigmasterol (3βstigmasta-5,22-dien-3-ol; CAS Number 83-48-7) and brassicasterol (3β-ergosta-5,22-dien-3-ol; CAS Number 474-67-9). Each commercial source has its own typical composition. Dietary intake of phytosterols ranges from 150-400 mg /day in a typical western diet. Phytosterols and phytostanols, in free or esterified form, are added to foods for their properties to reduce absorption of cholesterol in the gut and thereby lower blood cholesterol levels. It is now generally accepted that sterols and stanols have the same cholesterol lowering efficacy. The daily doses, considered optimal for the purpose of lowering blood cholesterol levels, are 2-3 g of phytostanols and/or phytosterols, which translates to 3.4-5.2 g in esterified form. This recommended daily dose is typically divided in 1-3 portions of food providing 1.7-5.2 g ester, which equals 1-3 g phytostanol and/or phytosterol equivalents. Phytosterols, phytostanols and their esters have not been evaluated previously by the Committee. However, these substances have been evaluated and approved for use in foods in a number of countries world-wide (the European Union, Australia, Switzerland, Norway, Iceland, Brazil, South Africa, Japan, Turkey and Israel). Furthermore, in the USA a ‘self-GRAS’ (GRAS = Generally Recognized As Safe) procedure has been followed for both phytosterols- and phytostanols, to which the US FDA raised no objections.
Structure-Guided Design and Optimization of Small Molecules Targeting the Protein–Protein Interaction between the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities (2014)

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.
Strictures in Crohn’s disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin (1999)

The large accumulation of mast cells in the muscle layer of strictured bowel suggests a functional role for these cells in the hypertrophic and fibrotic response of the smooth muscle cells. The colocalisation with laminin indicates a mechanism of interaction between smooth muscle cells and mast cells that may be important in the role of mast cells in the process of fibrosis.
Bacterial Skin and Soft Tissue Infections in Adults: A Review of Their Epidemiology, Pathogenesis, Diagnosis, Treatment and Site Of Care (2007)

Skin and soft tissue infections (SSTIs) involve microbial invasion of the skin and underlying soft tissues. They have variable presentations, etiologies and severities. The challenge of SSTIs is to efficiently differentiate those cases that require immediate attention and intervention, whether medical or surgical, from those that are less severe. Approximately 7% to 10% of hospitalized patients are affected by SSTIs, and they are very common in the emergency care setting. The skin has an extremely diverse ecology of organisms that may produce infection. The clinical manifestations of SSTIs are the culmination of a two-step process involving invasion and the interaction of bacteria with host defences. The cardinal signs of SSTIs involve the features of inflammatory response, with other manifestations such as fever, rapid progression of lesions and bullae. The diagnosis of SSTIs is difficult because they may commonly masquerade as other clinical syndromes. To improve the management of SSTIs, the development of a severity stratification approach to determine site of care and appropriate empirical treatment is advantageous. The selection of antimicrobial therapy is predicated on knowledge of the potential pathogens, the instrument of entry, disease severity and clinical complications. For uncomplicated mild to moderate infections, the oral route suffices, whereas for complicated severe infections, intravenous administration of antibiotics is warranted. Recognition of the potential for resistant pathogens causing SSTIs can assist in guiding appropriate selection of antibiotic therapy.
Acetylcholine receptor binding site contains a disulfide cross-link between adjacent half-cystinyl residues. (1986)

A conserved feature of all nicotinic receptors is the presence of a readily reducible disulfide bond adjacent to the acetylcholine binding site. Previously we showed that in intact receptor from Torpedo californica electric tissue reduction of this disulfide followed by affinity alkylation with 4-(N-maleimido)benzyltri[3H] methylammonium iodide specifically and uniquely labels the alpha subunit residues Cys-192 and Cys-193. To identify all of the half-cystinyl residues contributing to the binding site disulfide(s), we have now reduced receptor under mild conditions and alkylated with a mixture of 4-(N-maleimido)benzyltri[3H]methylammonium iodide and N-[1-14C]ethylmaleimide and find that Cys-192 and Cys-193 are labeled exclusively. Furthermore, from unreduced receptor we have isolated two cyanogen bromide peptides of alpha, one containing Cys-192 and Cys-193, and the other containing Cys-128 and Cys-142 (which are the other potential contributors to the binding site disulfide(s]. These isolated peptides incorporate iodo[1-14C]acetamide only following reduction by dithiothreitol. Our results demonstrate that: 1) the binding site disulfide is between Cys-192 and Cys-193; 2) Cys-128 is disulfide-cross-linked to Cys-142; and 3) under conditions that reduce Cys-192 and Cys-193 completely, Cys-128 and Cys-142 remain cross-linked. At the acetylcholine binding site, agonists induce a local conformational change that stabilizes the binding site disulfide against reduction. We suggest that a transition between two stable conformations of the vicinal disulfide, both involving a nonplanar cis peptide bond between Cys-192 and Cys-193, is associated with receptor activation by agonists.
Chimeric Anti-CD14 IGG2/4 Hybrid Antibodies for Therapeutic Intervention in Pig and Human Models of Inflammation (2013)

CD14 is a key recognition molecule of innate immune responses, interacting with several TLRs. TLR signaling cross-talks extensively with the complement system, and combined CD14 and complement inhibition has been proved effective in attenuating inflammatory responses. Pig models of human diseases have emerged as valuable tools to study therapeutic intervention, but suitable neutralizing Abs are rare. Undesired Fc-mediated functions, such as platelet activation and IL-8 release induced by the porcine CD14-specific clone Mil2, limit further studies. Therefore, an inert human IgG2/IgG4 hybrid C region was chosen for an rMil2. As revealed in ex vivo and in vivo pig experiments, rMil2 inhibited the CD14-mediated proinflammatory cytokine response similar to the original clone, but lacked the undesired Fc-effects, and inflammation was attenuated further by simultaneous complement inhibition. Moreover, rMil2 bound porcine FcRn, a regulator of t1/2 and biodistribution. Thus, rMil2, particularly combined with complement inhibitors, should be well suited for in vivo studies using porcine models of diseases, such as sepsis and ischemia-reperfusion injury. Similarly, the recombinant anti-human CD14 IgG2/4 Ab, r18D11, was generated with greatly reduced Fc-mediated effects and preserved inhibitory function ex vivo. Such Abs might be drug candidates for the treatment of innate immunity-mediated human diseases.
Cyclical expression of L-selectin (CD62L) by recirculating T cells (2009)

L-Selectin (CD62L) mediates T-cell entry into lymph nodes. Whether the microenvironment modulates L-selectin expression of T cells during diapedesis and transit is unknown. Therefore, L-selectin expression was determined quantitatively on circulating T cells in blood, lymph nodes and thoracic duct by confocal laser scanning microscopy. We show that in contrast to leukocyte function-associated antigen-1 (CD11a/CD18) and ICAM-1 (CD54), L-selectin expression is cyclically expressed on recirculating T cells. It is reduced to approximately 30% of the blood value during entry across high endothelial venules. Within lymph nodes, CD4(+) T-cell subsets maintain reduced L-selectin expression at a similar level in all compartments (T-cell zone, B-cell zone and medulla). After exit, L-selectin is re-expressed to levels comparable to those of T cells in blood. Apparently, L-selectin levels are not only down-regulated during T-cell activation but also routinely reduced while transmigrating within lymph nodes. L-Selectin down-regulation seems to be ligand independent since it also occurs in the white pulp compartments of the spleen which lack classic L-selectin ligands such as GlyCAM-1 and CD34. In addition, T cells in non-lymphoid organs do not reveal reduced L-selectin levels. Thus, the ability of secondary lymphoid organs to reduce L-selectin expression of T cells prior to activation might be a prerequisite for their characteristic property to induce primary immune responses.
Ca(2+)-dependent processes as mediators of neurotoxicity. (1992)

The Ca2+ ion exerts a profound influence on cellular processes and an understanding of control mechanisms of intracellular Ca2 homeostasis while complex is mandatory in this discussion. The identification and recognition of prolonged sustained increase in [Ca2+]i as a manifestation of neurotoxin-induced destabilization of [Ca2+]i homeostasis will be related to a variety of neurotoxicant-induced cell injuries. The sites of toxicant interaction with ATP-regulated Ca2+ pumps located in the neuronal/glial membrane and/or calciosomes; availability of Ca2+ proteins; disruption in mitochondrial mechanisms for Ca2+ storage; triggers of voltage-dependent Ca2+ channels and modulation of the Na+/Ca2+ exchanger will be identified and related to presumptive toxin action. Failure of one or more of these systems will result in continuous elevation of ionized [Ca2+]i--a reflection of Ca2+ destabilization. The targets resulting from Ca2+ destabilization will be identified, to include phospholipase C activation, PLA2 activation, protein kinase C (PKC) translocation, and activation of Ca(2+)-dependent calpain 1. The use of specific inhibitors of neurotoxicity, e.g., natural sphingolipids, sphingosine, down regulation of PKC, inhibitors and activators of adenylate cyclase, and antiprotease agents will allow for investigation of the role of these final common pathways in the evolution of neurotoxicity.
Epidural Clonidine Analgesia following Surgery (1989)

Epidurally administered clonidine has been reported to produce postoperative analgesia. To assess the efficacy, safety, and appropriate dose of epidural clonidine for postoperative analgesia, clonidine (range, 100-900 micrograms in 100-micrograms increments) was injected in 22 patients following abdominal surgery or total knee arthroplasty (TKA). Clonidine produced analgesia, as measured by change in verbal pain scores and supplemental iv morphine usage. The largest doses examined (700-900 micrograms) produced complete pain relief for 5.0 +/- 0.8 h (mean +/- SEM; range 2-11 h), without other sensory or motor blockade. Clonidine also produced dose dependent decreases in blood pressure, being less following small (100-300 micrograms) and large (700-900 micrograms) doses than following intermediate (400-600 micrograms) doses. Six patients required iv ephedrine for treatment of blood pressure decrease of greater than 30%. Clonidine decreased heart rate 10-30% and produced transient sedation. Oxyhemoglobin saturation, serum glucose, and arterial blood gas tensions were not altered by clonidine, whereas there was a small (28%) dose-independent decrease in serum cortisol following clonidine injection. Clonidine was absorbed in a dose-dependent manner into the systemic circulation, with plasma concentrations 0.1-3.3 ng/ml 1 h following injection. These results suggest that hemodynamic depression and short-lasting analgesia may limit the usefulness of bolus epidural clonidine analgesia in the postoperative setting.
The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging‐Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease (2011)

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.
The leader peptide of colicin V shares consensus sequences with leader peptides that are common among peptide bacteriocins produced by Gram-positive bacteria (1994)

Colicin V is a ribosomally synthesized antimicrobial peptide produced by Escherichia coli. Four recently characterized genes, arranged in two convergent operons on the plasmid pCoIV-K30, are required for colicin V synthesis, export and immunity. We report the purification and N-terminal amino acid sequencing of the colicin V protein. Our results demonstrate that the colicin V primary translation product, which consists of 103 amino acids, is proteolytically processed. A leader peptide, consisting of 15 amino acid residues, is removed from the N-terminus during maturation of colicin V. This leader peptide is not related to the N-terminal signal sequences which direct proteins across the cytoplasmic membrane via the Sec pathway. The molecular mass of colicin V, obtained by mass spectrometry analysis, showed that the peptide consists of only unmodified amino acids. The deduced amino acid sequence of the leader peptide was highly homologous to the N-terminal extensions found in non-lantibiotic, peptide bacteriocins produced by Gram-positive bacteria. These findings strongly indicate that colicin V belongs to a family of small peptide bacteriocins that have been found previously only among the Gram-positive lactic acid bacteria.
Virtual bench testing of new generation coronary stents (2011)

For the investigated case, considerable differences were observed between the studied stent platforms in terms of stent strut apposition and stent induced vessel wall stresses. These differences in mechanical behaviour may help to explain clinical observations.
Elevated osteopontin and thrombospondin expression identifies malignant human breast carcinoma but is not indicative of metastatic status (2003)

Elevated expression of OPN and TSP-1 may play a role in the pathogenesis of breast cancer. The multiplex analysis of these molecules may enhance our ability to diagnose and/or prognosticate human breast malignancy.
Pre-beta high density lipoprotein. Unique disposition of apolipoprotein A-I increases susceptibility to proteolysis. (1990)

Apolipoprotein A-I-containing lipoproteins (high density lipoproteins, HDL) can be separated into two subfractions, which have pre-beta and alpha electrophoretic mobilities, respectively. These fractions differ in both composition and structure. Some preparations of pre-beta-migrating HDL, but not alpha-migrating HDL, were found to contain two polypeptides with Mr of approximately 26 and 14 kDa, which are scission products of apolipoprotein (apo) A-I. They are recognized by monospecific antibodies to apo A-I and have N-terminal sequences identical to those of mature apo A-I. This proteolytic scission of apo A-I occurs primarily after venipuncture. Immediate addition of protease inhibitors minimized the appearance of the fragments in plasma. To study the relative susceptibilities of pre-beta and alpha HDL to proteolysis, the lipoproteins were incubated in vitro with plasmin. The apo A-I in pre-beta HDL was extensively degraded, but that in alpha-migrating HDL was degraded to a much lesser extent, indicating that the appearance of apo A-I fragments in pre-beta HDL was due to enhanced sensitivity to proteolysis. To varying degrees, thrombin, kallikrein, elastase, arginine C endoprotease, and chymotrypsin also appear to cleave pre-beta HDL faster than alpha HDL. Most of the proteases generated a 12 to 14 kDa peptide fragment under conditions of limited cleavage. These results suggest that the conformational state of apo A-I in pre-beta-migrating HDL or its spatial relationship to lipids is significantly different from that of apo A-I in alpha-migrating HDL.(ABSTRACT TRUNCATED AT 250 WORDS)
Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis (2010)

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.
Operating Proton Exchange Membrane Fuel Cells Without External Humidification of the Reactant Gases: Fundamental Aspects (1997)

Operation of proton exchange membrane fuel cells (PEMFC) without external humidification of the reactant gases is advantageous for the PEMFC system, because it eliminates the need of a gas-humidification subsystem. The gas-humidification subsystem is a burden in the fuel cell system with respect to weight, complexity, cost, and parasitic power. A model for the operation of PEMFC with internal humidification of the gases is presented and the range of operating conditions for a PEMFC using dry H<sub>2</sub>/air was investigated. The model predicts that dry air, entering at the cathode, can be fully internally humidified by the water produced by the electrochemical reaction at temperatures up to 70°C. This model was experimentally verified for cell temperatures up to 60°C by long-term operation of a PEMFC with dry gases for up to 1800 h. The current densities, obtained at 0.6 V, were 20 to 40% lower than those measured when both gases were humidified. The water distribution in the cell, while operating with dry gases, was investigated by measuring the amount of product water on the anode and cathode sides. It was found that the back-diffusion of product water to the anode is the dominant process for water management in the cell over a wide range of operating conditions. The dominating water back-diffusion also allows internal humidification of the hydrogen reactant and prevents drying out of the anode.
Over-expression of regulator of G protein signaling 5 promotes tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma cells (2013)

These results indicate that over-expression of RGS5 promotes tumor metastasis by inducing epithelial-mesenchymal transition in HCC.
Growth regulation of skin cells by epidermal cell-derived factors: implications for wound healing. (1988)

Epidermal cell-derived factors (EDF), present in extracts and supernatant fluids of cultured epidermal cells, were found to stimulate the proliferation of keratinocytes but to inhibit fibroblasts. In vitro, the effect of EDF on epidermal cells resulted in an increased number of rapidly proliferating colonies composed mainly of basal keratinocytes. Control cultures grown in the absence of EDF had a high proportion of terminally differentiated cells. In fibroblast cultures EDF inhibited the ability of fibroblasts to cause contraction of collagen sponges by 90%. Epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor beta, nerve growth factor, and extracts of WI-38 cells (human embryonic lung fibroblasts) did not have this inhibitory activity. Application of EDF to surgical wounds stimulated extensive migration and proliferation of keratinocytes from remnants of glands, hair follicles, and wound edges. The restoration of complete epidermal coverage of wounds treated with EDF occurred twice as rapidly as that of control wounds. In addition, regenerating dermis in the EDF-treated wounds contained 1/5th to 1/15th as many cells as wounds treated with epidermal growth factor, urogastrone, transforming growth factor, or phosphate-buffered saline. The use of EDF to enhance re-epithelization and to prevent scar formation is proposed.