gebhart/patrepeval huggingface dataset:
Cell membranes… and how long drugs may exert beneficial pharmacological activityin vivo (2016)

The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future.
Numerical studies of catalytic combustion in a catalytically stabilized combustor (2000)

This work aims to investigate numerically the catalytic combustion of a catalytically stabilized combustor. The numerical model treated a catalytic channel deposited with Pt and used a plug model of laminar, one-dimensional, and steady-state flow. The predicted conversions of mixture and ignition temperatures of surface reaction agreed well with the measured data when a multi-step mechanism was used for the CH4 surface reaction over Pt. The flame speed of a mixture supported by catalytic surface reaction was found to increase compared with a mixture without a catalytic combustion. CO mole fractions were analysed for three cases—gas reaction, surface reaction, and gas reaction coupled with surface reaction. The case of solely gas reaction produced the most CO emission and the case of solely surface reaction generated the least CO emission. The position where flame ignites was also evaluated numerically. There was only a small difference between the measured and predicted results on the starting points of flame in the catalytic channel. As a result, the plug model was shown to model surface ignition very well, however, it did not predict well the position of flame ignition. Copyright © 2000 John Wiley & Sons, Ltd.
Role of interferon-gamma in cutaneous trafficking of lymphocytes with emphasis on molecular and cellular adhesion events. (1988)

(IFNs) are receiving increasing attention by dermatologists for both therapeutic applications,1as well as for investigations of their role as potential mediators of inflammation and cellular proliferation (an International Dermatology Symposium on Interferons and Related Lymphokines is planned for October 1989 in Berlin). As Shiohara et al in this issue of theArchivesindicate, IFNs may be important in psoriasis.2In a previous editorial I reviewed this topic and concluded that due to the multiplicity of biologic effects of IFNs, more basic scientific knowledge was required to determine the role(s) of IFNs in skin diseases.3One of the major new developments that was previously alluded to involves the ability of IFN-γ to modulate T lymphocyte trafficking in the skin.3This editorial focuses primarily on the role of INF-γ in modulating the accumulation of peripheral blood monocytes and lymphocytes (PBML) in the skin, and is divided
NMDA Receptor Activation Contributes to a Portion of the Decreased Mitochondrial Membrane Potential and Elevated Intracellular Free Calcium in Strain-Injured Neurons (2002)

In our previous studies, we have shown that in vitro biaxial strain (stretch) injury of neurons in neuronal plus glial cultures increases intracellular free calcium ([Ca(2+)](i)) and decreases mitochondrial membrane potential (deltapsi(m)). The goal of this study was to determine whether strain injury, without the addition of exogenous agents, causes glutamate release, and whether NMDA receptor antagonists affect the post-strain injury rise in [Ca(2+)](i) and decrease in deltapsi(m). [Ca(2+)](i) and deltapsi(m) were measured using the fluorescent indicators fura-2 AM and rhodamine-1,2,3 (rh123). Strain injury of neuronal plus glial cultures caused an immediate 100-200 nM elevation in neuronal [Ca(2+)]i and a decline in neuronal deltapsi(m) by 15 min post-injury. Pretreatment with the NMDA receptor antagonist MK-801 (10 microM) attenuated the [Ca(2+)](i) elevation after mild, but not moderate and severe injury. MK-801 pretreatment reduced the decline in deltapsi(m) after mild and moderate, but not after severe injury. The NMDA receptor antagonist D-2-amino-5-phosphonopentanoic acid (APV; 100 microM) had effects similar to MK-801. Simultaneous measurement of [Ca(2+)](i) and deltapsi(m) demonstrated a significant correlation and a temporal relationship between [Ca(2+)](i) elevation and depression of deltapsi(m). We conclude that NMDA receptor stimulation contributes to some of the changes in [Ca(2+)](i) and deltapsi(m) after less severe strain injury. However, after more pronounced injury other mechanisms appear to be more involved.
The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas (2006)

The NF-kappaB pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-kappaB pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-kappaB were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-kappaB target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-kappaB pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-kappaB (IkappaB) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-kappaB pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.
Assemblage of Signaling DNA Enzymes with Intriguing Metal-Ion Specificities and pH Dependences (2003)

We report a group of new DNA enzymes that possess a synchronized RNA-cleavage/fluorescence-signaling ability and exhibit wide-ranging metal-ion and pH dependences. These DNA catalysts were derived from a random-sequence DNA pool in a two-stage process: (1) establishment of a catalytic DNA population through repetitive rounds of in vitro selection at pH 4.0, and (2) sequence-diversification and catalytic-activity optimization through five parallel paths of in vitro evolution conducted at pH 3.0, 4.0, 5.0, 6.0, and 7.0, respectively. The deoxyribozymes were evolved to cleave the phosphodiester bond of a single ribonucleotide embedded in DNA and flanked immediately by two deoxyribonucleotides modified with a fluorophore and a quencher, respectively--a setting that synchronizes catalysis with fluorescence signaling. The most dominant catalyst from each pool was examined for metal-ion specificity, catalytic efficiency, pH dependence, and fluorescence-signaling capability. Individual catalysts have different metal-ion requirements and can generate as much as a 12-fold fluorescence enhancement upon RNA cleavage. Most of the DNA enzymes have a pH optimum coinciding with the selection pH and exhibit a rate constant approximating 1 min(-)(1) under optimal reaction conditions. The demonstration of DNA enzymes that are functional under extremely high acidity (such as pH 3 and 4) indicates that DNA has the ability to perform efficient catalysis even under harsh reaction conditions. The isolation of many new signaling DNA enzymes with broad pH optima and metal-ion specificities should facilitate the development of diverse deoxyribozyme-based biosensors.
Regulation of the Bacillus subtilis pyrimidine biosynthetic (pyr) gene cluster by an autogenous transcriptional attenuation mechanism (1994)

A complete transcript of the Bacillus subtilis pyr operon contains the following elements in 5' to 3' order: a 151-nucleotide (nt) untranslated leader; pyrR, encoding a 20-kDa protein; a 173-nt intercistronic region; pyrP, encoding a 46-kDa protein; a 145-nt intercistronic region; and eight overlapping cistrons encoding all of the six enzymes for de novo pyrimidine biosynthesis. Transcription is controlled by the availability of pyrimidines via an attenuation mechanism. There are three transcription terminators within the operon, each of which is preceded by another stem-loop structure, the antiterminator, whose formation would prevent formation of the terminator stem-loop. These are located in the leader, the pyrR-pyrP intercistronic region, and the pyrP-pyrB intercistronic region. Northern (RNA) blot analysis has identified transcripts of lengths which coincide with termination at these proposed attenuation sites and whose relative abundances vary in the expected pyrimidine-dependent manner. Each antiterminator contains a 50-base conserved sequence in its promoter-proximal half. Various transcriptional fusions of the pyr promoter and surrounding sequences to promoterless reporter genes support an attenuation mechanism whereby when pyrimidines are abundant, the PyrR protein binds to the conserved sequence in the pyr mRNA and disrupts the antiterminator, permitting terminator hairpin formation and promoting transcription termination. Deletion of pyrR from the chromosome resulted in the constitutive, elevated expression of aspartate transcarbamylase, which is encoded by pyrB, the third gene in the operon. Complementation of an E. coli upp mutant, as well as direct enzymatic assay, has demonstrated that pyrR also confers uracil phosphoribosyltransferase activity. Analysis of pyrR and upp deletion mutants demonstrated that upp, not pyrR, encodes the quantitatively important uracil phosphoribosyltransferase activity. The pyrP gene probably encodes an integral membrane uracil permease.
Scanning and transmission electron microscopic study of the small intestine of colostrum-fed calves infected with selected strains of Escherichia coli. (1982)

Colostrum-fed calves were fed milk replacer containing 10(11) enteropathogenic Escherichia coli (EEC) or nonenteropathogenic E coli (NEEC). The NEEC failed to colonize the small intestine or to be associated with the intestinal wall. The EEC colonized the middle and caudal portions of the small intestine, and in these areas, 80% of the organisms were associated with the intestinal wall. Light, immunofluorescence, scanning, and transmission electron microscopic studies demonstrated a layer of EEC adherent to the mucosal surface of the jejunum and ileum of infected calves. Transmission electron microscopy revealed that each EEC was surrounded by an electron-lucent zone and that some organisms had dense fuzzy surface structures which resembled pili. In the staining with ruthenium red, the electron-lucent areas were occupied by thick capsular material which seemed to be in contact with the microvilli. In some areas of contact with EEC, the microvilli were elongated and projected into the intestinal lumen. Light microscopy demonstrated stunted, thickened, and fused villi with the lamina propria expanded by inflammatory infiltrate. Changes in the villous surface topography, such as denudation of the tips of the villi and exposure of the lamina propria into the lumen, were observed by light and scanning microscopies in samples taken after death of the calves, but not in adjacent samples removed from calves under general anesthesia.
Augmented Post-Induction Therapy for Children with High-Risk Acute Lymphoblastic Leukemia and a Slow Response to Initial Therapy (1998)

Children with high-risk acute lymphoblastic leukemia (ALL) who have a slow response to initial chemotherapy (more than 25 percent blasts in the bone marrow on day 7) have a poor outcome despite intensive therapy. We conducted a randomized trial in which such patients were treated with either an augmented intensive regimen of post-induction chemotherapy or a standard regimen of intensive post-induction chemotherapy.
Presentation of a Viral T Cell Epitope Expressed in the CDR3 Region of a Self Immunoglobulin Molecule (1993)

Synthetic peptides corresponding to microbial epitopes stimulate T cell immunity but their immunogenicity is poor and their half-lives are short. A viral epitope inserted into the complementarity-determining region 3 (CDR3) loop of the heavy chain of a self immunoglobulin (Ig) molecule was generated from the Ig context and was presented by I-Ed class II molecules to virus-specific, CD4+ T cells. Chimeric Ig-peptide was presented 100 to 1000 times more efficiently than free synthetic peptide and was able to prime virus-specific T cells in vivo. These features suggest that antigenized Ig can provide an improved and safe vaccine for the presentation of microbial and other peptides.
Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticusR0052 andBifidobacterium longumR0175) in rats and human subjects (2010)

In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0·05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0·05; somatisation, P < 0·05; depression, P < 0·05; and anger-hostility, P < 0·05), the HADS (HADS global score, P < 0·05; and HADS-anxiety, P < 0·06), and by the CCL (problem solving, P < 0·05) and the UFC level (P < 0·05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.
Anti-Inflammatory Drugs and Risk of Alzheimer's Disease: An Updated Systematic Review and Meta-Analysis (2015)

Observational studies support the use of NSAIDs for prevention of AD, but RCT do not. Well-designed studies and innovative approaches are required to illuminate the exact relationship between NSAID use and AD risk. The appropriate dosage and duration of use to benefit and the safety are also needed to determine.
Purification and Properties of NADP‐Dependent l(+)‐3‐Hydroxybutyryl‐CoA Dehydrogenase from Clostridium kluyveri (1973)

l (+)‐3‐Hydroxybutyryl‐CoA dehydrogenase was purified 18 fold with a 29% yield from extracts of Clostridium kluyveri. The enzyme was found to be homogeneous by gel electrophoresis and ultracentrifugation. The analysis of the sedimentation equilibrium and gel filtration experiments gave a molecular weight of 220000 and 215000, respectively. Gel electrophoresis in the presence of sodium dodecylsulfate revealed the presence of 8 subunits per enzyme molecule. The subunits contain approx. 5 sulfhydryl groups per mole of protein (26000× g ). l (+)‐3‐Hydroxybutyryl‐CoA dehydrogenase from C. kluyveri is NADP‐dependent. The enzyme does not oxidize 3‐hydroxyvaleryl‐CoA or 3‐hydroxycaproyl‐CoA. The specific activity of the pure enzyme as measured by acetoacetyl‐CoA reduction at the optimum pH of 6.5 is approx. 450 U/mg protein at 25°C. The oxidation of 3‐hydroxybutyryl‐CoA at pH 9.5 proceeds with 7% of the rate of acetoacetyl‐CoA reduction. N ‐Acetyl‐ S ‐acetoacetyl‐cysteamine is reduced with 15% of the rate of acetoacetyl‐CoA. Measurements of the Michaelis constants for the substrates of l (+)‐3‐hydroxybutyryl‐CoA dehydrogenase gave values of 50 μM for acetoacetyl‐CoA and 70 μM. for NADPH 2 .
Electrospray mass spectrum of a per(onio)-substituted benzene: Retention of coulombic charge upon collisionally activated decomposition (1998)

The hexakis (4-diemthylaminopyridyl) benzene hexacation of 1 is investigated as an extreme example of the ability of electrospray ionization to allow transfer of small multivalent ions to the gas phase. The hexacationized benzene ring ions are stabilized by forming gas phase complexes with two to five trifluoromethanesulfonate counterions. MS/MS analysis reveals that their fragmentation takes place by loss of neutrals such as trifluoromethanesulfonic acid and 4-dimethylaminopyridine; no rupture of the benzene or pyridine rings was observed in spite of accumulation of positive charge in a restricted geometry.
Influence of Structural Principles on the Mechanics of a Biological Fiber‐Based Composite Material with Hierarchical Organization: The Exoskeleton of the Lobster Homarus americanus (2009)

Abstract The cuticle of the lobster Homarus americanus is a nanocomposite, such as most structural biological materials. It consists of a matrix of chitin‐protein fibers associated with various amounts of crystalline and amorphous calcium carbonate in the rigid parts of the body, and is organized hierarchically at all length scales. One prominent design principle found in the hierarchical structure of such biological fibrous composite materials is the twisted plywood structure. In the lobster cuticle, it is formed by superimposing and gradually rotating planes of parallel aligned chitin‐protein fibers. To adjust the mechanical properties to the requirements on the macroscopic level, the spatial arrangement and the grade of mineralization of the fibers can be modified. A second design principle of lobster cuticle is its honeycomb‐like structure, generated by the well‐developed pore canal system, whose twisted ribbon‐shaped canals penetrate the cuticle perpendicular to its surface. Due to the hierarchical structure, the mechanical properties of the lobster cuticle have to be investigated at different length scales, which is essential for the understanding of the structure–mechanical function relations of mineralized tissues (e.g., potentially also bone and teeth). In order to investigate the influence of the structural principles on the mechanical properties on the macroscopic scale miniaturized tensile, compression, and shear tests were carried out to obtain integral mechanical data. Characterization of the microstructure included scanning electron microscopy (SEM) combined with energy dispersive X‐ray (EDX) measurements.
Genomic Expression Analyses Reveal Lysosomal, Innate Immunity Proteins, as Disease Correlates in Murine Models of a Lysosomal Storage Disorder (2012)

Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.
Identification of Platinum-Resistance Associated Proteins through Proteomic Analysis of Human Ovarian Cancer Cells and Their Platinum-Resistant Sublines (2006)

Chemoresistance is a major therapeutic obstacle in cancer patients, and the mechanisms of drug resistance are not fully understood. In the present study, we established platinum-resistant human ovarian cancer cell lines and identified differentially expressed proteins related to platinum resistance. The total proteins of two sensitive (SKOV3 and A2780) and four resistant (SKOV3/CDDP, SKOV3/CBP, A2780/CDDP, and A2780/CBP) human ovarian cancer cell lines were isolated by two-dimensional gel electrophoresis (2-DE). The differentially expressed proteins were identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). In total, 57 differential protein spots were identified, and five proteins, including annexin A3, destrin, cofilin 1, Glutathione-S-transferase omega 1 (GSTO1-1), and cytosolic NADP+-dependent isocitrate dehydrogenase (IDHc), were found to be co-instantaneous significance compared with their parental cells. The expression of the five proteins was validated by quantitative PCR and western blot, and the western blot results showed complete consistency with proteomic techniques. The five proteins are hopeful to become candidates for platinum resistance. These may be useful for further study of resistance mechanisms and screening of resistant biomarkers.