gebhart/patrepeval huggingface dataset:
Bacterial lipolytic enzymes: classification and properties (1999)

Knowledge of bacterial lipolytic enzymes is increasing at a rapid and exciting rate. To obtain an overview of this industrially very important class of enzymes and their characteristics, we have collected and classified the information available from protein and nucleotide databases. Here we propose an updated and extensive classification of bacterial esterases and lipases based mainly on a comparison of their amino acid sequences and some fundamental biological properties. These new insights result in the identification of eight different families with the largest being further divided into six subfamilies. Moreover, the classification enables us to predict (1) important structural features such as residues forming the catalytic site or the presence of disulphide bonds, (2) types of secretion mechanism and requirement for lipase-specific foldases, and (3) the potential relationship to other enzyme families. This work will therefore contribute to a faster identification and to an easier characterization of novel bacterial lipolytic enzymes.
Lysosomal Enzyme Replacement Using α2-Macroglobulin as a Transport Vehicle1 (1994)

Improvement of the delivery of exogenous enzymes is essential to achieve effective enzyme replacement therapy in lysosomal storage diseases. To test whether alpha 2-macroglobulin, an endogenous plasma protein, could serve as a transport vehicle of therapeutic agents to cells, alpha 2-macroglobulin and acid alpha-glucosidase or alpha-galactosidase A were coupled using two heterobifunctional cross-linking reagents. The alpha-glucosidase-alpha 2-macroglobulin conjugate was internalized and transported into lysosomes of acid alpha-glucosidase-deficient fibroblasts. The enzyme activity was stable after being taken up by the cells. Uptake of the conjugate resulted in the degradation of glycogen accumulated in lysosomes. The alpha-galactosidase A-alpha 2-macroglobulin conjugate was also internalized into the lysosomes of alpha-galactosidase A-deficient fibroblasts. Internalized alpha-galactosidase A-conjugate degraded globotriaosylceramide accumulated in lysosomes. The endocytosis of both conjugate was inhibited by alpha 2-macroglobulin-trypsin complex, indicating that the conjugates were endocytosed by an alpha 2-macroglobulin receptor system. These results showed the usefulness of alpha 2-macroglobulin as a transport vehicle of lysosomal enzymes for effective enzyme replacement.
Toll-Like Receptor 4 Ligation on Intrinsic Renal Cells Contributes to the Induction of Antibody-Mediated Glomerulonephritis via CXCL1 and CXCL2 (2007)

Autoimmune diseases such as glomerulonephritis are exacerbated by infection. This study examined the effect of the Toll-like receptor 4 (TLR4) ligand lipid A on the development of heterologous nephrotoxic nephritis. Administration of nephrotoxic antibody resulted in significant glomerular neutrophil infiltration and albuminuria only when a TLR4 ligand was administered simultaneously. The contribution of TLR4 on renal cells and circulating leukocytes was assessed. Bone marrow chimeras were constructed with TLR4 only on renal cells or bone marrow-derived cells. The administration of nephrotoxic serum and lipid A caused a neutrophil influx in both chimeric groups greater than in sham chimeras that were totally TLR4 deficient but significantly less than in sham chimeras that were totally TLR4 sufficient. Both chimeric groups had greater albuminuria than totally TLR4-deficient sham chimeras; however, the chimeras with TLR4 only on intrinsic renal cells had significantly less than the sham positive group. In situ hybridization showed expression of TLR4 mRNA in mesangial cells and glomerular epithelial cells. For investigation of the potential mechanism by which renal cells could contribute to disease exacerbation, mesangial cells were cultured and found to express mRNA for TLR4, and stimulation of wild-type and TLR4-deficient mesangial cells with LPS caused production of CXC chemokines by wild-type cells only. Treatment of chimeras with TLR4 present only on intrinsic renal cells with anti-CXCL1 and anti-CXCL2 antibody before disease induction significantly reduced renal neutrophil infiltration. These results show that TLR4 on both circulating leukocytes and intrinsic renal cells contributes to the inflammatory effects of antibody deposition within the glomerulus, which depends at least in part on the production of CXC chemokines by intrinsic renal cells.
Single base polymorphism at −511 in the human interleukin-1β gene (IL1β) (1992)

Single base polymorphism at −511 in the human interleukin-1β gene (IL1β) Get access F.S. di Giovine, F.S. di Giovine * Section of Molecular Medicine, Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JFUK * To whom correspondence should be addressed at present address: Dip. Fisiopatologia Clinica, Sezione di Genetica Medica, Viale Pieraccini 6, Firenze, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar E. Takhsh, E. Takhsh Section of Molecular Medicine, Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JFUK Search for other works by this author on: Oxford Academic PubMed Google Scholar A.I.F. Blakemore, A.I.F. Blakemore Section of Molecular Medicine, Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JFUK Search for other works by this author on: Oxford Academic PubMed Google Scholar G.W. Duff G.W. Duff Section of Molecular Medicine, Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JFUK Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 1, Issue 6, September 1992, Page 450, https://doi.org/10.1093/hmg/1.6.450 Published: 01 September 1992
Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans (2002)

Pentoxifylline increases erythrocyte flexibility, reduces blood viscosity, and inhibits platelet aggregation and is thus used in the treatment of peripheral vascular disease. It is transformed into at least seven phase I metabolites, of which two, M1 and M5, are active. The reduction of the keto group of pentoxifylline to a secondary alcohol in M1 takes place chiefly in erythrocytes, is rapidly reversible, and creates a chiral center. The aims of this study were: to develop HPLC methods to separate the enantiomers of M1, to investigate the kinetics of the reversible biotransformation of pentoxifylline to (R)- and (S)-M1 in hemolysed erythrocyte suspension, and to quantify the formation of the enantiomers of M1 (as well as M4 and M5) after intravenous and oral administration of pentoxifylline to human volunteers. (R)- and (S)-M1 could be separated preparatively on a cellobiohydrolase column, while determination in blood or plasma was by HPLC after chiral derivatization with diacetyl-L-tartaric acid anhydride. The metabolism of pentoxifylline to (R)-M1 in suspensions of hemolysed erythrocytes followed simple Michaelis-Menten kinetics (K(m) = 11 mM), while that to (S)-M1 was best described by a two-enzyme model (K(m) = 1.1 and 132 mM). Studies with inhibitors indicated that the enzymes were of the carbonyl reductase type. At a therapeutic blood concentration of pentoxifylline, the calculated rate of formation of (S)-M1 is 15 times higher than that of the (R)-enantiomer. Back-conversion of M1 to pentoxifylline was 3-4 times faster for the (S)- than for the (R)-enantiomer. In vivo, the R:S plasma concentration ratio of M1 ranged from 0.010-0.025 after intravenous infusion of 300 or 600 mg of pentoxifylline, and from 0.019-0.037 after oral administration of 600 mg. The biotransformation of pentoxifylline to M1 was thus highly stereoselective in favor of the (S)-enantiomer both in vitro and in vivo.
Speckle-visibility spectroscopy: A tool to study time-varying dynamics (2005)

We describe a multispeckle dynamic light scattering technique capable of resolving the motion of scattering sites in cases that this motion changes systematically with time. The method is based on the visibility of the speckle pattern formed by the scattered light as detected by a single exposure of a digital camera. Whereas previous multispeckle methods rely on correlations between images, here the connection with scattering site dynamics is made more simply in terms of the variance of intensity among the pixels of the camera for the specified exposure duration. The essence is that the speckle pattern is more visible, i.e., the variance of detected intensity levels is greater, when the dynamics of the scattering site motion is slow compared to the exposure time of the camera. The theory for analyzing the moments of the spatial intensity distribution in terms of the electric-field autocorrelation is presented. It is tested for two well-understood samples, a colloidal suspension of Brownian particles and a coarsening foam, where the dynamics can be treated as stationary and hence can be benchmarked by traditional methods. However, our speckle-visibility method is particularly appropriate for samples in which the dynamics vary with time, either slowly or rapidly, limited only by the exposure time fidelity of the camera. Potential applications range from soft-glassy materials, to granular avalanches, to flowmetry of living tissue.
Basic fibroblast growth factor: expression in cultured bovine vascular smooth muscle cells. (1988)

The possible expression of fibroblast growth factor in cultured bovine vascular smooth muscle (VSM) cells derived from bovine adult aortic arch has been examined. VSM cells were found to express the basic fibroblast growth factor (bFGF) gene but not that of acidic fibroblast growth factor (aFGF), a related mitogen. Expression of bFGF was further examined. VSM cells contain 3.7 and 7.0 kilobase bFGF gene transcripts, which are translated into material closely related, if not identical, with bFGF when analyzed by its chromatographic behavior on heparin Sepharose, by immunoblot and by radioimmuno- and radioreceptor assays. Essentially all of the bFGF-like material is bioactive, i.e., it can stimulate the proliferation of capillary endothelial or VSM cells and the stimulation is blocked by anti-bFGF antibodies. Our results indicate that bFGF derived from VSM cells may act as a paracrine and autocrine growth factor for that cell type. Thus, bFGF could play an important role in vivo, in controlling the proliferation of VSM cells during embryonic growth of blood vessels or during atherosclerosis.
Phylogenetic analysis of the genus Borrelia: a comparison of North American and European isolates of Borrelia burgdorferi (1992)

We have sequenced the 16S rRNA molecules from four species of Borrelia and from six isolates of Borrelia burgdorferi via the reverse transcriptase primer extension method. The sequences were aligned and evolutionary relationships were determined, including the calculation of evolutionary distances and the construction of a phylogenetic tree. These analyses demonstrate significant divergence among B. burgdorferi isolates, with the European isolates G1 and G2 residing most distant from the main cluster. Signature nucleotides which distinguish B. burgdorferi from all other members of this genus and which distinguish the European isolates G1 and G2 from the North American isolates B31, Sh-2-82, and 1352 were identified. Finally, Southern blot analyses were performed to compare the restriction patterns of the genes coding for rRNA and to relate our data to the grouping scheme of Postic et al. (D. Postic, C. Edlinger, C. Richaud, F. Grimont, J. Dufresne, P. Perolat, G. Baranton, and P. A. D. Grimont, Res. Microbiol. 141:465-475, 1990).
Selective Peroxisome Proliferator-Activated Receptor-γ Modulation to Reduce Cardiovascular Risk in Patients with Insulin Resistance (2012)

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone improve glucose homeostasis through activation of peroxisome proliferator-activated receptor (PPAR)-γ. Their use, however, has been limited due to adverse effects that include body weight gain and edema leading to congestive heart failure. Selective PPAR-γ modulators (SPPARMs) are second generation PPAR-γ ligands designed to improve insulin sensitivity with minimal undesirable effects associated with first generation PPAR-γ agonists. INT131 is one of the first SPPARMs to reach human trials. Early phase human studies with INT131 look promising with changes in plasma lipids and glucose being equal or better than what is seen with rosiglitazone and pioglitazone treatment but without evidence of edema. This profile of improved glucose homeostasis, improved plasma lipids, and reduced inflammation in the absence of edema would be expected to reduce cardiovascular risk in patients with Type 2 diabetes mellitus. Recent patents of novel approaches for the use of PPAR-γ related compounds with the potential for this improved risk-benefit ratio are discussed.
Proliferation and differentiation of rat calvarial osteoblasts on type I collagen‐coated titanium alloy (2001)

Several attempts have been made to improve osseointegration of titanium alloy as an implant material by modification of its surface. In the present study, proliferation, differentiation, and mineralization of osteoblasts on type I collagen-coated Ti6Al4V were investigated. The activity of alkaline phosphatase and the accumulation of calcium by osteoblasts grown on titanium alloy were significantly higher compared to cells grown on polystyrene. Precoating of the implant surface with type I collagen did not extensively affect proliferation, the activity of alkaline phosphatase, collagen synthesis, calcium accumulation, or the mRNA levels for collagen I alpha1, osteopontin, osteocalcin, MMP-2, and TIMP-2. Maximum collagen synthesis by osteoblasts was observed at day 4 of culture independent of the type of implant material. The specific activity of alkaline phosphatase reached its maximum at day 18 of culture. Accumulation of calcium and elevated mRNA levels for osteocalcin were found at day 22. These results indicate that collagen-coating alone is not sufficient to accelerate differentiation of rat calvarial osteoblasts on Ti6Al4V.
협심증환자에서 관동맥조영술상 관동맥병변의 진행 (1996)

Objectives: Identification of the coronary arterial lesion susceptible to accelerated progression of the atherosclerosis may provide important clinical information in the management of the patients with coronary artery diseases(CAD) or when revascularization procedures are planned especially in patients with multiple coroanry arterial lesions, We performed this study in order to evaluate 1) the changing pattems of coronary artery disease and 2) the possible factors for either progression or regression of the coronary arterial lesion in patients with angina pectors. Methods: 56 patients with angina pectoris who undertook repeated coronary arteriography (CAG) over an interval of 1 year or more were enrolled in the study. Patients who got PTCA, CABG, or thrombolytic therapy were excluded as well as vasospastic angina on initial coronary arteriography. Criteria for the progression and regression were the changes of the luminal narrowing of the coronary arterial segment by 20% or more, Results: Upon follow-up CAG, progression of the coronary arterial lesion was found in 55% of the patients, regression in 18% and no significant changes in 27%. Progression of the lesion was more frequently found in patients with multivessel disease and there was a tendency for new or prgressive lesion in the left anterior descending artery teritory than in any other coronary arteries. Among CAD risk factors, diabetes mellitus was more frequently associated with the progression of the coronary arterial lesion. Conclusion: The coronary arterial lesions in patients with angian pectoris are more frequently progressive rather than stationary or regressive, with a tendency for new or progressive lesion in the left anteior descending coroanry artery territory
Significance of Elevated Procollagen-III-Peptide and Transforming Growth Factor-.BETA. Levels of Bronchoalveolar Lavage Fluids from Idiopathic Pulmonary Fibrosis Patients. (1997)

Although both procollagen III aminopeptide (P-III-P) and transforming growth factor-beta (TGF-beta) are reported to be present in lung tissue and/or elevated in bronchoalveolar lavage fluid (BALF) from idiopathic pulmonary fibrosis (IPF) patients, we have little knowledge concerning the clinical significance of elevated P-III-P and TGF-beta levels in BALF. Using a radioimmunoassay, we measured P-III-P and TGF-beta in BALF from 48 IPF patients (16F and 32M, 59 +/- 2 years, mean +/- S.E.) who received BAL in our clinic over the past 13 years before glucocorticosteroid treatment. Among them, we could detect a significant amount of P-III-P (2.2 +/- 1.0 U/ml; range 0.03 to 16.5 U/ml) in BALF in 18 of the patients (5F and 13M, 58 +/- 3 years) (group B). but not (0.03 U/ml or less) in the other 30 patients (11F and 19M, 59 +/- 2 years) (group A). Lymphocyte (%) and basophil (%) in BALF from group B was much larger than that from group A (33% vs. 8%, p < 0.01). Group B showed a longer duration of onset to BAL (36 months vs. 23 months, p < 0.05). TGF-beta levels were obtained using an ELISA system kit from the same BALF samples. TGF-beta was not detected in 10 patients (100 pg/ml or less) (3F and 7M, 59 +/- 4 years) (group I), while the remaining 38 patients showed a significant amount of TGF-beta (329 +/- 44 pg/ml, range 100 to 1,360 pg/ml). The latter patients were further divided into two groups; group II 100 to 300 pg/ml (10F and 14M, 56 +/- 3 years) and group III 350 or more (3F and 11M, 63 +/- 2 years). Group III showed significantly better values in PaO2, Aa-DO2, %VC and %DLco, and smaller percentage of basophils in BALF than did groups I and/or II, whereas survival after BAL in group III was significantly shorter than in group I (31 vs. 19 months, p < 0.05). There was no significant relationship between P-III-P and TGF-beta levels in BALF. These findings suggest that elevated P-III-P level is accompanied by an increase in lymphocyte population in BALF from IPF patients, resulting in a longer duration of the disease, while elevated TGF-beta level reflects alveolar inflammation at an earlier stage of the disease which induces a progression of the disease, resulting in a shorter survival in IPF patients.
Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape (2014)

The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer.
In vivo Atoh1 targetome reveals how a proneural transcription factor regulates cerebellar development (2011)

The proneural, basic helix-loop-helix transcription factor Atoh1 governs the development of numerous key neuronal subtypes, such as cerebellar granule and brainstem neurons, inner ear hair cells, and several neurons of the proprioceptive system, as well as diverse nonneuronal cell types, such as Merkel cells and intestinal secretory lineages. However, the mere handful of targets that have been identified barely begin to account for Atoh1's astonishing range of functions, which also encompasses seemingly paradoxical activities, such as promoting cell proliferation and medulloblastoma formation in the cerebellum and inducing cell cycle exit and suppressing tumorigenesis in the intestine. We used a multipronged approach to create a comprehensive, unbiased list of over 600 direct Atoh1 target genes in the postnatal cerebellum. We found that Atoh1 binds to a 10 nucleotide motif (AtEAM) to directly regulate genes involved in migration, cell adhesion, metabolism, and other previously unsuspected functions. This study expands current thinking about the transcriptional activities driving neuronal differentiation and provides a framework for further neurodevelopmental studies.
Airway Surface Liquid Volume Regulates ENaC by Altering the Serine Protease-Protease Inhibitor Balance (2006)

Efficient clearance of mucus and inhaled pathogens from the lung is dependent on an optimal airway surface liquid (ASL) volume, which is maintained by the regulated transport of sodium and chloride across the airway epithelium. Accumulating evidence suggests that impaired mucus clearance in cystic fibrosis (CF) airways is a result of ASL depletion caused by excessive Na(+) absorption through the epithelial sodium channel (ENaC). However, the cellular mechanisms that result in increased ENaC activity in CF airways are not completely understood. Recently, proteases were shown to modulate the activity of ENaC, but the relevance of this mechanism to the physiologic regulation of ASL volume is unknown. Using primary human airway epithelial cells, we demonstrate that: (i) protease inhibitors are present in the ASL and prevent the activation of near-silent ENaC, (ii) when the ASL volume is increased, endogenous protease inhibitors become diluted, allowing for proteolytic activation of near-silent channels, and (iii) in CF, the normally present near-silent pool of ENaC is constitutively active and the alpha subunit undergoes increased proteolytic processing. These findings indicate that the ASL volume modulates the activity of ENaC by modification of the serine protease-protease inhibitor balance and that alterations in this balance contribute to excessive Na(+) absorption in cystic fibrosis.
A Single-Molecule Study of RNA Catalysis and Folding (2000)

Using fluorescence microscopy, we studied the catalysis by and folding of individual Tetrahymena thermophila ribozyme molecules. The dye-labeled and surface-immobilized ribozymes used were shown to be functionally indistinguishable from the unmodified free ribozyme in solution. A reversible local folding step in which a duplex docks and undocks from the ribozyme core was observed directly in single-molecule time trajectories, allowing the determination of the rate constants and characterization of the transition state. A rarely populated docked state, not measurable by ensemble methods, was observed. In the overall folding process, intermediate folding states and multiple folding pathways were observed. In addition to observing previously established folding pathways, a pathway with an observed folding rate constant of 1 per second was discovered. These results establish single-molecule fluorescence as a powerful tool for examining RNA folding.
Herpetic neuralgia. Use of combination therapy for pain relief in acute and chronic herpes zoster. (2001)

Herpes zoster (shingles) is a localized infection that begins in the dorsal root ganglla of the cranial or spinal nerves and spreads as a rash over the corresponding dermatome. It usually is caused by reactivation of latent varicella-zoster virus remaining from childhood chicken pox. Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome that occurs as a complication of shingles, most commonly in older persons. Acute zoster and PHN can be severe conditions associated with impaired sleep, decreased appetite, depression, anxiety disorder, and diminished libido. Management of zoster-related pain should begin as soon as possible after the onset of symptoms. Combination therapy--including antiviral, antidepressant, corticosteroid, opioid, and topical agents--provides the most effective analgesia.