gebhart/patrepeval huggingface dataset:
Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances (2000)

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B(4) possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.
Deep inspiration increases the absorption of inhaled sodium cromoglycate. (1989)

The plasma concentrations of sodium cromoglycate were measured for 4 h following a single dose of 20 mg given by inhalation to six normal volunteers. A series of forced expiratory manoeuvres was performed 2 h after the dose, which resulted in a rapid and marked increase in the plasma concentrations of the drug. A similar increase was found in three volunteers who undertook a single deep inspiration at 4 h. These data indicate that the absorption of cromoglycate from the airways can be affected by manoeuvres used to assess lung function.
Real‐time RT‐PCR assays for type and subtype detection of influenza A and B viruses (2007)

Influenza viruses type A (H3N2 and H1N1 subtypes) and B are the most prevalently circulating human influenza viruses. However, an increase in several confirmed cases of high pathogenic H5N1 in humans has raised concerns of a potential pandemic underscoring the need for rapid, point of contact detection. In this report, we describe development and evaluation of 'type,' i.e., influenza virus A and B, and 'subtype,' i.e., H1, H3, and H5, specific, single-step/reaction vessel format, real-time RT-PCR assays using total RNA from archived reference strains, shell-vial cultured and uncultured primary (throat swab/nasal wash) clinical samples. The type A and B specific assays detected all 16 influenza type A viruses and both currently circulating influenza B lineages (Yamagata and Victoria), respectively. 'Type' and 'subtype' specific assays utilize one common set of thermocycling conditions, are specific and highly sensitive (detection threshold of approximately 100 target template molecules). All clinical specimens and samples were evaluated using both the unconventional portable Ruggedized Advanced Pathogen Identification Device (RAPID) and standard laboratory bench LightCycler instruments. These potentially field-deployable assays could offer significant utility for rapid, point of care screening needs arising from a pandemic influenza outbreak.
The Cytomegalovirus m155 Gene Product Subverts Natural Killer Cell Antiviral Protection by Disruption of H60–NKG2D Interactions (2004)

Natural killer (NK) cells are an important early mediator of host immunity to murine cytomegalovirus (MCMV) infection. However, MCMV has evolved mechanisms to elude recognition and clearance by NK cells. We have identified an MCMV immune evasion protein that impairs NKG2D-mediated NK cell antiviral activity. Infection of BALB/c 3T3 cells with the Smith strain of MCMV resulted in strong down-regulation of H60, a high affinity ligand for NKG2D, from the surface of virus-infected cells. The MCMV m155 protein specifically down-regulated H60 without affecting expression of the other known NKG2D ligands, RAE-1 and MULT-1. Treatment with the proteasome inhibitors lactacystin or epoxomicin reversed m155 down-regulation of H60. An MCMV mutant virus lacking m155 was severely attenuated in BALB/c mice; however, treatment with neutralizing anti-NKG2D monoclonal antibody or with NK-depleting anti-asialo GM1 antisera restored virulence of the mutant virus. Thus, down-regulation of H60 by m155 is a powerful mechanism of inhibiting NKG2D-mediated antiviral function.
Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α (2001)

Hypoxia-inducible factor-1alpha (HIF-1alpha) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1alpha is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1alpha overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1alpha in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1alpha did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1alpha overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1alpha could improve therapy of tissue ischemia.
A Tricyclic Template Derived from (2S,4R)‐4‐Hydroxyproline for the Synthesis of Protein Loop Mimetics (1996)

Abstract A tricyclic diketopiperazine, formally derived by coupling (2 S ,4 S )‐4‐aminoproline (Pro(NH 2 )) and (2 S ,4 R )‐4‐(carboxymethyl)proline (Pro(CH 2 COOH)), is synthesized starting from readily available (2 S ,4 R )‐4‐hydroxyproline. The resulting tricyclic template has carboxy and amino groups to which a peptide chain may be attached. The Fmoc‐protected template 5 is incorporated into the cyclic molecule cyclo(‐Ala 1 ‐Asn 2 ‐Pro 3 ‐Asn 4 ‐Ala 5 ‐ ) ( 6 ) where Pro(NH 2 ) 7 = Pro(CH 2 COOH) 8 represents the template, using solid‐phase peptide synthesis with cyclization in solution. The molecule is shown by NMR and dynamic simulated annealing methods to adopt a preferred conformation in aqueous solution, which includes an extended backbone at the residues Asn 2 ‐Pro 3 ‐Asn 4 , and a type‐Iβ‐turn at . These studies show that this novel template may be used in the synthesis of cyclic peptide and protein mimetics having defined secondary structure in aqueous environments.
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix (2004)

BCL-2 family proteins constitute a critical control point for the regulation of apoptosis. Protein interaction between BCL-2 members is a prominent mechanism of control and is mediated through the amphipathic alpha-helical BH3 segment, an essential death domain. We used a chemical strategy, termed hydrocarbon stapling, to generate BH3 peptides with improved pharmacologic properties. The stapled peptides, called "stabilized alpha-helix of BCL-2 domains" (SAHBs), proved to be helical, protease-resistant, and cell-permeable molecules that bound with increased affinity to multidomain BCL-2 member pockets. A SAHB of the BH3 domain from the BID protein specifically activated the apoptotic pathway to kill leukemia cells. In addition, SAHB effectively inhibited the growth of human leukemia xenografts in vivo. Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.
Measuring Ecology in Social Work Supervision: The Relationship Between Work and Treatment Environments and the Quality of Supervision in Israeli Public Welfare Agencies (1984)

This study measures the interaction between work and treatment environments in public welfare agencies and social work supervision. One hundred and twenty-four social work students enrolled in B.S.W. studies at two Israeli universities, who were doing field work in these agencies, were randomly sampled. The work and treatment environments were measured utilizing an adapted version of a scale developed by Rudolf H. Moos. The student's evaluation of supervision was measured using a revised version of Carlton Munson's questionnaire. Supervisory variables such as administrative capability, effective use of time, and relationships were positively correlated with work environment variables such as order and organization, clarity, cohesiveness and support, and with treatment environment variables such as innovation, spontaneity, anger -and aggression. Conflicts in the supervisory relationship were correlated with a controlling and unsupportive work environment. The use of technology was perceived as limiting the clients' autonomy. While some logical influences were drawn concerning the direction of these correlations and the possible paths these create, further research is needed in order to address the direction of these correlations. Some practice implications of the findings were discussed briefly.
Using green fluorescent protein to study intracellular signalling (2001)

Subcellular compartmentalisation of signalling molecules is an important phenomenon not only in defining how a signalling pathway is activated but also in influencing the desired physiological output of that pathway (e.g. cell growth or differentiation, regulation of metabolism, cytoskeletal changes etc.). Biochemical analyses of protein and lipid compartmentalisation by, for example, subcellular fractionation presents many technical difficulties. However, this aspect of cell signalling research has seen a major revolution thanks to the cloning and availability of a variety of mutant green fluorescent protein derivatives with distinct molecular properties. Mutants with increased brightness, altered excitation and emission maxima, altered stability and differential sensitivity to pH, are now in widespread use for following the trafficking and function of proteins in living cells and for monitoring the intracellular environment. In this review we focus on some of the recent developments in the use of green fluorescent proteins for studying intracellular signalling pathways often with special reference to the actions of insulin. We also discuss the future utility of these proteins to analyse protein--protein interactions in signalling pathways using fluorescence resonance energy transfer.
Does cannabidiol protect against the negative effects of THC? (2010)

A recent study by Morgan and colleagues found that cannabidiol attenuates the acute cognitive effects of delta-9-tetrahydrocannabinol (THC). This is of interest as THC has been associated with the detrimental effects of cannabis on mental health in at-risk users, and the potency of cannabis is increasing across Europe.
Characterizing sudden death and dead‐in‐bed syndrome in Type 1 diabetes: analysis from two childhood‐onset Type 1 diabetes registries (2010)

Sudden unexplained death in Type 1 diabetes seems to be increased 10-fold and associated with male sex, while dead-in-bed individuals have a high HbA(1c) and insulin dose and low BMI. Although sample size is too small for definitive conclusions, these results suggest specific sex and metabolic factors predispose to sudden unexplained death and dead-in-bed death.
Error and failure analysis of a UNIX server (2002)

This paper presents a measurement-based dependability study of a UNIX server. The event logs of a UNIX server are collected to form the dependability data basis. Message logs spanning approximately eleven months were collected for this study. The event log data are classified and categorized to calculate parameters such as MTBF and availability. Component analysis is also performed to identify modules that are prone to errors in the system. Next, the system error activity proceeding each system failure is analyzed to identify error patterns that may be precursors of the observed failure events. Lastly, the error/failure results from the measurement are reviewed in the perspective of the fault/error assumptions made in several popular fault injection studies.
Terpenoids: Opportunities for Biosynthesis of Natural Product Drugs Using Engineered Microorganisms (2008)

Terpenoids represent a diverse class of molecules that provide a wealth of opportunities to address many human health and societal issues. The expansive array of structures and functionalities that have been evolved in nature provide an excellent pool of molecules for use in human therapeutics. While this class of molecules has members with therapeutic properties including anticancer, antiparasitic, antimicrobial, antiallergenic, antispasmodic, antihyperglycemic, anti-inflammatory, and immunomodulatory properties, supply limitations prevent the large scale use of some molecules. Many of these molecules are only found in ppm levels in nature thus requiring massive harvesting to obtain sufficient amounts of the drug. Synthetic biology and metabolic engineering provide innovative approaches to increase the production of the desired molecule in the native organism, and most importantly, transfer the biosynthetic pathways to other hosts. Microbial systems are well studied, and genetic manipulations allow the optimization of microbial metabolisms for the production of common terpenoid precursors. Using a host of tools, unprecedented advancements in the large scale production of terpenoids have been achieved in recent years. Identification of limiting steps and pathway regulation, coupled with design strategies to minimize terpenoid byproducts wih a high flux to the desired biosynthetic pathways, have yielded greater than 100-fold improvements in the production of a range of terpenoids. This review focuses on the biodiversity of terpenoids, the biosynthetic pathways involved, and engineering efforts to maximize the production through these pathways.
Peptide mapping and evaluation of glycopeptide microheterogeneity derived from endoproteinase digestion of erythropoietin by affinity high-performance capillary electrophoresis (1993)

High-performance capillary electrophoresis (HPCE) has been employed to characterize the peptide map of recombinant human erythropoietin (rHuEPO) expressed from Chinese hamster ovary (CHO) cells. The methodology employs an ion pairing agent, 100 mM heptanesulfonic acid in 40 mM sodium phosphate buffer, pH 2.5, to increase peptide resolution, to decrease analyte wall interactions, and to evaluate glycopeptide microheterogeneity. The total tryptic map is segregated into two regions, nonglycosylated and glycosylated peptides. Reproducibility of the peptide map is excellent; the map results in baseline separation of 16 tryptic peptides and one doublet peak composed of two peptides (resolution 0.22). The map furthermore allows for the evaluation of the microheterogeneity associated with the three rHuEPO glycopeptides. At least 12 glycopeptide forms were separated in the initial peptide map. Peptides were identified by Edman sequencing, and the glycopeptides were further subjected to Dionex anion-exchange chromatography. To simplify the level of complexity associated with the glycopeptides, much of the characterization employed asialoglycopeptides and employed several endoproteolytic diagnosis. The relative percent distribution for each purified asialoglycopeptide was calculated to define the level of complexity and to tentatively assign a known structure to the HPCE peak. The level of structural complexity of the asialoglycopeptides appears to increase from the simplest O-linked form to the more complex N83, N38, and N24 glycosylation positions, respectively. HPCE evaluation of glycopeptide microheterogeneity appears to be simpler, faster, and just as sensitive as other more frequently employed methods for glycopeptide characterizations.
Use of Bacillus subtilis minicells to demonstrate an antigenic relationship between the poles and lateral cylindrical regions of rod-shaped cells (1975)

Purified minicells produced by Bacillus subtilis div IV-B1 mutants were used to immunize rabbits. Immune serum was obtained that agglutinated minicells and was able to form precipitin lines when reacted with minicell antigens in double-diffusion or immunoelectrophoretic procedures. Antiminicell serum agglutinated rod-shaped B. subtilis cells to long filaments produced by growth of a cell division-defective mutant at restrictive temperature. These findings indicate that minicells are immunogens capable of eliciting the production of antibodies that cross-react with the lateral, cylindrical regions of B. subtilis rods. It appears, therefore, that poles share a common antigen(s) with cylindrical regions of the cell.
Deciphering microbial interactions in synthetic human gut microbiome communities (2018)

The ecological forces that govern the assembly and stability of the human gut microbiota remain unresolved. We developed a generalizable model-guided framework to predict higher-dimensional consortia from time-resolved measurements of lower-order assemblages. This method was employed to decipher microbial interactions in a diverse human gut microbiome synthetic community. We show that pairwise interactions are major drivers of multi-species community dynamics, as opposed to higher-order interactions. The inferred ecological network exhibits a high proportion of negative and frequent positive interactions. Ecological drivers and responsive recipient species were discovered in the network. Our model demonstrated that a prevalent positive and negative interaction topology enables robust coexistence by implementing a negative feedback loop that balances disparities in monospecies fitness levels. We show that negative interactions could generate history-dependent responses of initial species proportions that frequently do not originate from bistability. Measurements of extracellular metabolites illuminated the metabolic capabilities of monospecies and potential molecular basis of microbial interactions. In sum, these methods defined the ecological roles of major human-associated intestinal species and illuminated design principles of microbial communities.
Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides (1991)

Chimeric (murine/human) anti-CD4 monoclonal antibody was infused into seven patients with mycosis fungoides. Successive patients received doses of 10, 20, 40, and 80 mg of antibody twice a week for 3 consecutive weeks. All patients had some clinical improvement, but responses were of relatively short duration. Serum levels of chimeric antibody varied as a function of dose. At the 80-mg dose level, antibody was readily observed in biopsied skin lesions. Although there was coating by antibody of most CD4 positive cells in the blood, there was no significant depletion of CD4 positive cells. Low-level antibody responses against the mouse Ig variable region and human Ig allotypic constant region determinants were observed in several patients, but none were of clinical significance. All but two patients made primary antibody and T-cell proliferative responses to a simultaneously administered foreign protein test antigen. However, there was marked suppression of the mixed lymphocyte reaction. We conclude that at the dose levels studied, a chimeric anti-CD4 monoclonal antibody (1) had some clinical efficacy against mycosis fungoides; (2) was well tolerated; (3) had a low level of immunogenicity; (4) had immediate immunosuppressive effects; and (5) did not induce tolerance to a co-injected antigen.
Classified vector quantisation with variable block-size DCT models (1994)

The paper describes the classified vector quantisation (CVQ) of an image, based on quadtrees and a classification technique in the discrete cosine transform (DCT) domain. In this scheme, a quadtree is used to segment low-detail regions into variable sized blocks and high-detail regions into uniform 4*4 blocks of various edge and mixed classes. High-detail blocks are classified by an edge-oriented classifier which employs a pattern-matching technique with edge models defined in the normalised DCT domain. The proposed classifier is simple to implement, and efficiently classifies edges to good visual accuracy. The low-detail regions are encoded at very low bit rates with little perceptual degradation, while the encoding of the high-detail regions is performed to achieve a good perceptual quality in the decoded image. Decoded images of high visual quality are obtained for encoding rates between 0.3 and 0.7 bpp.
Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine (2002)

ABSTRACT The methionine-to-valine mutation in codon 184 (M184V) in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) confers resistance to (−)-2′-deoxy-3′-thiacytidine (3TC; lamivudine) and increased sensitivity to 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir). We have used the SIV model to evaluate the effect of the M184V mutation on the emergence of resistance to the combination of 3TC plus PMPA. A site-directed mutant of SIVmac239 containing M184V (SIVmac239-184V) was used to select for resistance to both 3TC and PMPA by serial passage in the presence of increasing concentrations of both drugs. Under these selection conditions, the M184V mutation reverted in the majority of the selections. Variants resistant to both drugs were found to have the lysine-to-arginine mutation at codon 65 (K65R), which has previously been associated with resistance to PMPA in both SIV and HIV. Similarly, in rhesus macaques infected with SIVmac239-184V for 46 weeks and treated daily with (−)-2′-deoxy-5-fluoro-3′-thiacytidine [(−)-FTC], there was no reversion of M184V, but this mutation reverted to 184 M in all three animals within 24 weeks of treatment with (−)-FTC and PMPA. Although the addition of PMPA to the (−)-FTC therapy induced a decrease in virus loads in plasma, these loads eventually returned to pre-PMPA levels in each case. All animals receiving this combination developed the K65R mutation. These results demonstrate that the combination of PMPA with 3TC or (−)-FTC selects for the K65R mutation and against the M184V mutation in SIV RT.