gebhart/patrepeval huggingface dataset:
Deacylation Transition States of a Bacterial DD-Peptidase (2006)

Beta-lactam antibiotics restrict bacterial growth by inhibiting DD-peptidases. These enzymes catalyze the final transpeptidation step in bacterial cell wall biosynthesis. Although much structural information is now available for these enzymes, the mechanism of the actual transpeptidation reaction has not been studied in detail. The reaction is known to involve a double-displacement mechanism with an acyl-enzyme intermediate, which can be attacked by water, specific amino acids, peptides, and other acyl acceptors. We describe in this paper an investigation of acyl acceptor specificity and assess the need for general base catalysis in the deacylation transition state of the Streptomyces R61 DD-peptidase. We show, by the criterion of solvent deuterium kinetic isotope effect measurements and proton inventories, that the transition states of specific and nonspecific substrates are very similar, at least with respect to proton motion. The transition states for attack (tetrahedral intermediate formation) by d-amino acids and Gly-l-Xaa dipeptides do not include a general base catalyst, while such catalysis is essential for reaction with water and d-alpha-hydroxy acids. D-Alpha-hydroxy acids act as acyl acceptors for glycyl substrates but not for more specific d-alanyl substrates; hydroxy acids actually behave, more generally, as mixed inhibitors of the DD-peptidase. The structural and mechanistic bases of these observations are discussed; they should inform transition state analogue design.
Protein adsorption from human plasma is reduced on phospholipid polymers (1991)

Protein adsorption from human plasma was investigated on phospholipid polymers, poly (2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA) or glass by radioimmunoassay and immunogold labeling techniques. In the present studies the focus was to determine the composition and distribution of proteins at the surface of these materials after contact with human blood plasma. On all materials, protein adsorption was detected and included identification of albumin, IgG, fibrinogen, fibronectin, Hageman factor (factor XII), factor VIII/von Willebrand factor, high-molecular-weight kininogen (HMWK) and the complement protein C5. The amount of protein adsorbed decreased with an increase in the MPC composition and appeared to adsorb to the surfaces in a uniform and evenly distributed manner. Therefore, we suggest that MPC moieties play an important role in suppression of protein adsorption. From these findings, it is concluded that the reduction of protein adsorption at the blood contacting surface of phospholipid polymers may result in the inhibition of thrombus formation.
Persistent West Nile Virus Infection in the Golden Hamster: Studies on Its Mechanism and Possible Implications for Other Flavivirus Infections (2005)

Golden hamsters (Mesocricetus auratus) experimentally infected with West Nile virus (WNV) developed chronic renal infection and persistent shedding of virus in urine for up to 8 months, despite initial rapid clearance of virus from blood and the timely appearance of high levels of specific neutralizing antibodies. Infectious WNV could be recovered by direct culture of their urine and by cocultivation of kidney tissue for up to 247 days after initial infection. Only moderate histopathologic changes were observed in the kidneys or brain of the chronically infected hamsters, although WNV antigen was readily detected by immunohistochemistry within epithelium, interstitial cells, and macrophages in the distal renal tubules. Comparison of WNV isolates from serial urine samples from individual hamsters over several months indicated that the virus underwent both genetic and phenotypic changes during persistent infection. These findings are similar to previous reports of persistent infection with tickborne encephalitis and Modoc viruses.
A role for T cell-derived interleukin 22 in psoriatic skin inflammation (2007)

Interleukin (IL)-22 is a T cell-derived cytokine that has been reported recently to induce cutaneous inflammation in an experimental murine model of psoriasis, and to induce in vitro an inflammatory-like phenotype. In the present study, we assessed the presence of IL-22 and the IL-22 receptor 1 (IL-22R1) in skin lesions, skin-derived T cells, as well as IL-22 levels in sera from patients with psoriasis. IL-22R1 and IL-10R2 transcripts are expressed at a similar level in psoriatic and healthy skin. In contrast, IL-22 mRNA expression was up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL-22 levels were significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produced higher levels of IL-22 in comparison to peripheral T cells isolated from the same patients. IL-10 was expressed at similar levels in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we show here that supernatants of lesional psoriatic skin-infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions. Taken together, the results reported in this study indicate that IL-22 is a cytokine produced by skin-infiltrating lymphocytes that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.
Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors (2004)

Laboratory mice bearing inactivating mutations in the genes encoding the NPAS1 and NPAS3 transcription factors have been shown to exhibit a spectrum of behavioral and neurochemical abnormalities. Behavioral abnormalities included diminished startle response, as measured by prepulse inhibition, and impaired social recognition. NPAS1/NPAS3-deficient mice also exhibited stereotypic darting behavior at weaning and increased locomotor activity. Immunohistochemical staining assays showed that the NPAS1 and NPAS3 proteins are expressed in inhibitory interneurons and that the viability and anatomical distribution of these neurons are unaffected by the absence of either transcription factor. Adult brain tissues from NPAS3- and NPAS1/NPAS3-deficient mice exhibited a distinct reduction in reelin, a large, secreted protein whose expression has been reported to be attenuated in the postmortem brain tissue of patients with schizophrenia. These observations raise the possibility that a regulatory program controlled in inhibitory interneurons by the NPAS1 and NPAS3 transcription factors may be either substantively or tangentially relevant to psychosis.
Evaluation of deoxygenated oligosaccharide acceptor analogs as specific inhibitors of glycosyltransferases. (1991)

The glycosyltransferases controlling the biosynthesis of cell-surface complex carbohydrates transfer glycosyl residues from sugar nucleotides to specific hydroxyl groups of acceptor oligosaccharides. These enzymes represent prime targets for the design of glycosylation inhibitors with the potential to specifically alter the structures of cell-surface glycoconjugates. With the aim of producing such inhibitors, synthetic oligosaccharide substrates were prepared for eight different glycosyltransferases. The enzymes investigated were: A, alpha(1----2, porcine submaxillary gland); B, alpha(1----3/4, Lewis); C, alpha(1----4, mung bean); D, alpha(1----3, Lex)-fucosyltransferases; E, beta(1----4)-galactosyltransferase; F, beta(1----6)-N-acetylglucosaminyltransferase V; G, beta(1----6)-mucin-N-acetylglucosaminyltransferase ("core-2" transferase); and H, alpha(2----3)-sialyltransferase from rat liver. These enzymes all transfer sugar residues from their respective sugar nucleotides (GDP-Fuc, UDP-Gal, UDP-GlcNAc, and CMP-sialic acid) with inversion of configuration at their anomeric centers. The Km values for their synthetic oligosaccharide acceptors were in the range of 0.036-1.3 mM. For each of these eight enzymes, acceptor analogs were next prepared where the hydroxyl group undergoing glycosylation was chemically removed and replaced by hydrogen. The resulting deoxygenated acceptor analogs can no longer be substrates for the corresponding glycosyltransferases and, if still bound by the enzymes, should act as competitive inhibitors. In only four of the eight cases examined (enzymes A, C, F, and G) did the deoxygenated acceptor analogs inhibit their target enzymes, and their Ki values (all competitive) remained in the general range of the corresponding acceptor Km values. No inhibition was observed for the remaining four enzymes even at high concentrations of deoxygenated acceptor analog. For these latter enzymes it is suggested that the reactive acceptor hydroxyl groups are involved in a critical hydrogen bond donor interaction with a basic group on the enzyme which removes the developing proton during the glycosyl transfer reaction. Such groups are proposed to represent logical targets for irreversible covalent inactivation of this class of enzyme.
Vimentin: the conundrum of the intermediate filament gene family (1998)

Intermediate filaments are a major component of the "cytoskeleton" of "higher" eukaryotes. These filaments are composed of a number of different, although structurally related, proteins. Different intermediate filament protein genes are expressed in different tissues. Spontaneous and experimentally produced mutations in the intermediate filament genes indicate that these filaments function to enhance the mechanical stability of epidermal and muscle cells. As a result, the use of transgenic mice with "knockout" or dominant negative mutations in IF genes has become an important approach for investigating the significance of IFs in other cell types. However, a knockout mutation of vimentin (-/-), the intermediate filament protein characteristically expressed in cells of mesenchymal origin, results in very subtle phenotypes that are not obviously related to cell fragility. Although experiments with cultured cells have described a variety of discrete changes in cell properties that are associated with vimentin expression or organization, there is no evidence yet that any of these properties are affected in the vimentin-/- mouse.
A fast and rigorous 2.5D inversion algorithm for cross‐well electromagnetic data (2005)

We present a 2.5D inversion algorithm for the interpretation of electromagnetic data collected in a cross‐well configuration. Some inversion results from simulated data as well as from field measurements are presented in order to show the efficiency and the robustness of the algorithm.
Phenotypic stability of a cytotoxic T-cell line directed against an immunodominant epitope of human carcinoembryonic antigen. (1997)

CTL lines have now been generated against defined peptides of a range of human tumor-associated antigens (TAAs). One of the potential uses of these epitope-specific CTLs is in adoptive transfer immunotherapy. This is a modality, however, that will require long-term in vitro culture of CTLs. To date, little has been reported concerning the phenotypic stability of human epitope-specific CTLs as a consequence of long-term in vitro propagation via peptide stimulation. We report here the serial phenotypic characterization of a CTL line directed against an immunodominant epitope (YLSGANLNL, designated CAP-1) of human carcinoembryonic antigen (CEA). This CTL line was derived from peripheral blood mononuclear cells of a patient with metastatic carcinoma who had been treated with a recombinant CEA-vaccinia vaccine in a Phase I trial; the CTLs were analyzed through 20 in vitro cycle passages of stimulation with CAP-1 peptide and interleukin 2 in the presence of autologous antigen-presenting cells. The CTL line was shown to be phenotypically stable in terms of high levels of cytokine (IFN-gamma, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor) production, expression of homing-adhesion molecules, ability to lyse peptide-pulsed targets, and ability to lyse human carcinoma cells endogenously expressing CEA in a MHC-restricted manner. Vbeta T-cell receptor gene usage was also analyzed. These studies thus present a rationale for the use of long-term cultured epitope-specific human CTLs, directed against a human TAA for potential adoptive transfer immunotherapy protocols.
Norcantharidin induces apoptosis in human breast cancer cell line (2000)

Objective: The current study was designed to identify molecular mechanism of antitumor effect produced by NCTD(norcantharidin) in human breast cancer cell line. Methods: MCF-7 cells were grown in standard conditions. At the indicated time points after NCTD treatment, evaluation of apoptotic morphology by light microscopy, analysis of chromatin condensation by electron microscopy, determination of the percentage of apoptotic cells by flow cytometry and Western blot analysis for detecting of bcl-2 gene expression were conducted. Results: Differences in cellular morphology were observed between NCTD-treated and control MCF-7 cells. Cell shrinkage, cell budding and chromatin condensation were observed in the cells treated with 10μ g/ml NCTD for 12 hours. Percentage of apoptotical cells was increased while the expression of bcl-2 products was decreased with the increasing of incubation time. Conclusion: The results indicate that one of the major antitumor mechanisms of NCTD may be through inducing cell apoptosis which related to the regulation of bcl-2 gene expression.
[Soluble tumor-necrosis-factor-alpha receptor type-1 as a marker of activity of psoriasis vulgaris and effects of its treatment]. (2005)

serum concentration of sTNF-R1 can be a sensitive marker of activity of psoriasis vulgaris and decreases following the effective treatment.
Magnetic resonance evaluation of disease activity during pregnancy in multiple sclerosis (1994)

We followed two women with MS during pregnancy by means of serial unenhanced MR imaging. On each follow-up image, we assessed the number of new or enlarging lesions. Both women showed a decrease in MR disease activity during the second half of pregnancy and a return of MR disease activity to prepregnancy levels in the first months postpartum. These findings support the view that pregnancy reduces disease activity in MS.
TWO ALLELES OF MAIZE ALCOHOL DEHYDROGENASE 1 HAVE 3' STRUCTURAL AND POLY(A) ADDITION POLYMORPHISMS (1986)

Two standard electrophoretic alleles of the maize alcohol dehydrogenase 1 locus (Adh1-1S and Adh1-1F) have been isolated and characterized. Restriction endonuclease mapping shows that a region of less than 5 kb is conserved in both alleles and is flanked both 5' and 3' by regions highly polymorphic for restriction sites. Nucleotide sequence comparison of these two alleles reveals that polymorphism in the 3' flanking region is due to rearrangements including tandem duplications, a transposable element-like insertion and a deletion. S1 nuclease analysis shows that both the Adh1-1S and the Adh1-1F alleles contain multiple poly(A) addition sites; four sites are observed for the Adh1-1S alleles and seven sites for the Adh1-1F allele. Only two of these poly(A) addition sites appear to be identical in the two alleles. No consensus signal for poly(A) addition is observed near any of these sites.
Urine Derived Cells are a Potential Source for Urological Tissue Reconstruction (2008)

A subpopulation of cells isolated from urine had progenitor cell features and the potential to differentiate into several bladder cell lineages. Urine derived cells could serve as an alternative cell source for urinary tract tissue engineering and reconstruction.
Pharmaceutical product development technologies based on the biopharmaceutical classification system. (2009)

Poor solubility and poor permeability account for many pharmacokinetic failures and about thirty percent of drug molecules are rejected due to pharmacokinetic failures. When poor pharmaceutical properties are discovered in development, the cost of bringing a potent, but poorly absorbable molecule to the product stage by formulation can become very high. Fast and reliable in vitro prediction strategies are needed to filter out problematic molecules at the earliest stage of discovery. This communication will consider recent developments in physiochemical profiles used to identify molecules with physical properties related to good oral absorption. FDA's biopharmaceutical classification system (BCS) is an attempt to rationalize the critical components related to oral absorption and utilization of these principles for selection of a suitable technology to serve the interests of the early stages of drug discovery.
Self assembly in semiconductor microelectronics: self-aligned sub-lithographic patterning using diblock copolymer thin films (2006)

Self-assembling diblock copolymer thin films are an intriguing possible photolithography alternative for high-resolution patterning of advanced integrated circuit device elements. Cylindrical- and lamellar-phase materials spontaneously form patterns suggestive of contact-hole arrays and transistor gates at critical dimensions below 20nm. Besides high resolution, any serious lithographic process requires a means of pattern registration, and we discuss our efforts to develop self-aligned self assembly techniques using diblock copolymer materials. We describe the critical role of polymer surface interactions in affecting self-assembled pattern orientations. Control and design of surface properties allow precise registration of sub-20nm polymer domains to larger-scale lithographic layers.
GASTRORETENTIVE DRUG DELIVERY SYSTEM: AN APPROACH TO ENHANCE GASTRIC RETENTION FOR PROLONGED DRUG RELEASE (2014)

Oral route has been the most convenient and accepted route of drug delivery. Owing to tremendous curative benefits of the oral controlled release dosage forms are being preferred as the interesting topic in pharmaceutical field to achieved improved therapeutics advantages. Gastroretentive drug delivery system is novel drug delivery systems which has an upper hand owing to its ability of prolonged retaining ability in the stomach and thereby increase gastric residence time of drugs and also improves bioavailability of drugs. Attempt has been made to summarize important factors controlling gastroretentive drug delivery systems. This review covers the advantages, disadvantages, marketed preparation and some patents of gastroretentive drug delivery system and represents the floating and non-floating gastroretentive system and also highlights some of the current gastroretentive approaches. Recent approaches to increase the gastric residence time of drug delivery systems include bioadhesive systems, floating systems (low density systems), non-floating systems (high density systems) , magnetic systems, swelling systems, unfoldable and expandable systems, raft forming systems and superporous systems, biodegradable hydrogel systems.
Peroxisome proliferator-activated receptor γ contributes to T lymphocyte apoptosis during sepsis (2005)

In the last two decades, extensive research failed to significantly improve the outcome of patients with sepsis. In part, this drawback is based on a gap in our knowledge about molecular mechanisms understanding the pathogenesis of sepsis. During sepsis, T cells are usually depleted. Recent studies in mice and human cells suggested a role of the peroxisome proliferator-activated receptor gamma (PPARgamma) in provoking apoptosis in activated T lymphocytes. Therefore, we studied whether expression/activation of PPARgamma might contribute to T cell death during sepsis. We observed PPARgamma up-regulation in T cells of septic patients. In contrast to controls, PPARgamma expressing cells from septic patients responded with apoptosis when exposed to PPARgamma agonists. Cell demise was attenuated by SR-202, a synthetic PPARgamma antagonist, and specificity was further verified by excluding a proapoptotic response to a PPARalpha agonist. We propose that up-regulation of PPARgamma sensitizes T cells of septic patients to undergo apoptosis. PPARgamma activation in T cells requires an exogenous PPARgamma agonist, which we identified in sera of septic patients. Septic sera were used to study reporter gene expression containing a PPAR-responsive element. We conclude that PPARgamma plays a significant role in T cell apoptosis, contributing to lymphocyte loss in sepsis. Thus, inhibition of PPARgamma may turn out to be beneficial for patients suffering from lymphopenia during sepsis.
Cell‐based assay for screening 11 β ‐hydroxysteroid dehydrogenase inhibitors using liquid chromatography/tandem mass spectrometry detection (2006)

Cortisol is an important glucocorticoid that regulates many physiological pathways by activating various intracellular receptors. The type 1 isozyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) functions in vivo predominantly as a reductase by converting cortisone into cortisol. A high-throughput liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed to screen for inhibitors of 11beta-HSD1 by monitoring cortisol and cortisone simultaneously. The injection cycle time can be as fast as 1 min/sample, making it amenable to the analysis of large numbers of the cell-assay samples in the screening of 11beta-HSD inhibitors. The reductase and dehydrogenase activities of 11beta-HSD1 are assessed separately.
Cardiometabolic Syndrome and Chronic Kidney Disease: What Is the Link? (2006)

The term metabolic syndrome or cardiometabolic syndrome describes the clustering of several cardiovascular and renal risk factors, including type 2 diabetes mellitus, central obesity, hypertension, and dyslipidemia. Over the past 15 years, several studies have examined the association between the metabolic/cardiometabolic syndrome or its central component, insulin resistance, with the presence of elevated urine albumin excretion. Intrarenal changes associated with the cardiometabolic syndrome result in elevated glomerular filtration rate, impaired pressure natriuresis, endothelial dysfunction related to changes in nitric oxide and, hence, impaired renal autoregulation and enhanced chronic inflammation. The aforementioned changes that occur in the cardiometabolic syndrome all contribute to the development of renal injury. While this review focuses on the epidemiology and mechanisms associated with vascular/renal injury, it must be remembered that prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet and exercise can reverse many of these pathophysiologic adaptations. Pharmacologic intervention should be aimed at achieving guideline goals and include insulin sensitizers to aid in tight glycemic control, lipid control, blockade of the renin-angiotensin-aldosterone system for blood pressure reduction, and anti-inflammatory therapies.