gebhart/patrepeval huggingface dataset:
Evolutionary Divergence of Substrate Specificity within the Chymotrypsin-like Serine Protease Fold (1997)

We have described a structural scaffold extant in over 500 homologous enzymes, where the catalytic mechanism is identical and the substrate specificity varied. The many known structures of chymotrypsin-fold serine proteases delineate a clear framework showing that this variability is a function of evolved diversity in the structures of surface loops, which surround the extended substrate binding site. Because the loops are conserved in their relative positions with respect to the N to C direction of the scissile peptide, general themes for their individual functions can be described. Thus, loop C is invariably positioned to directly contact the extended substrate on the N-terminal side of the scissile bond, whereas loops A, B, D, and E interact on the leaving group side (Fig. 3). Loops 2 and 3 can modulate either or both of the S1 sites or the subsite preferences on the N-terminal side of the scissile bond. Loop 1 is thus far known to determine only the S1 site specificity.
Performance Characteristics of a Rapid New Immunochromatographic Test for Detection of Antibodies to Human Immunodeficiency Virus (2003)

A new immunochromatographic rapid test (Rapid Check HIV 1 and 2; Núcleo de Doenças Infecciosas) for the detection of antibodies to human immunodeficiency virus type 1 and type 2 in human samples (whole blood, serum, and plasma) was evaluated and compared to the commercially available Determine (Abbott Laboratories). When whole-blood samples were evaluated, the specificity and sensitivity of both tests were 100%. However, when plasma samples were used, sensitivity for the Rapid Check HIV 1&2 and the Determine tests were 100 and 98.58%, respectively. The observed specificity for plasma samples was 98.94% for the Rapid Check HIV 1&2 and 96.97% for the Determine test. The results presented here are encouraging and support the adoption of both tests as an alternative to enzyme-lined immunosorbent assay and/or Western blots in regions where laboratorial infrastructure is not available or for use in the management of occupational accidents for healthcare workers.
The Influence of Cigarette Smoking on Cytokine Levels in Patients with Inflammatory Bowel Disease (1999)

Anecdotal reports suggest that smoking may be beneficial for patients with inflammatory bowel disease (IBD) as nicotine may act through inflammatory mediators within the colonic mucosa. Furthermore, there is increasing evidence that cytokines play a pathologic role in IBD. Our aim was to determine the effects of cigarette smoking on cytokine levels in the colonic mucosa of patients with and without IBD. Mucosal biopsies were obtained from 10 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 10 healthy controls. Five of 10 patients in each of the three groups were smokers and five were nonsmokers. Concentrations of interleukin (IL)-1beta, IL-2, IL-6, and IL-8 were determined using enzyme-linked immunosorbent assay (ELISA). Cytokine levels of smokers were compared with nonsmokers in each group and with controls. Results were analyzed using the Mann-Whitney test; significance was set at p<0.05. The concentration of IL-8 was significantly higher in healthy controls who smoke compared with nonsmokers and significantly reduced in smokers with CD compared with nonsmokers with CD. Moreover, concentrations of IL-1beta and IL-8 were significantly reduced in smokers with UC compared with nonsmokers with UC. Smokers had significantly elevated levels of IL-8 in the colonic mucosa. Smokers with IBD had a significant reduction in cytokine levels; specifically, IL-1beta and IL-8 for patients with UC and IL-8 for patients with CD. Further studies are warranted to determine if this reduction in cytokine levels is histologically and clinically significant.
Early effects of imatinib mesylate on the expression of insulin‐like growth factor binding protein‐3 and positron emission tomography in patients with gastrointestinal stromal tumor (2006)

Abstract BACKGROUND. Imatinib has demonstrated marked clinical efficacy against gastrointestinal stromal tumor (GIST). Microarray technology, real‐time polymerase chain reaction (PCR) validation, and fluorodeoxyglucose‐positron emission tomography (FDG‐PET) imaging were used to study the early molecular effects of imatinib antitumor activity in GIST. METHODS. After exposure of sensitive and resistant sarcoma cell lines to imatinib for 24 to 48 hours, the changes in gene expression were evaluated using a 1146 unique pathway array with Western blot validation. Real‐time PCR was used to confirm changes in gene expression in human GIST samples (preimatinib biopsy and postimatinib surgical specimen after 3–7 days of therapy). FDG‐PET was performed to correlate radiographic findings with the effects of imatinib on gene expression in GIST. RESULTS. In all, 55 genes demonstrated a ≥ 2‐fold change after imatinib treatment of the GIST882 cells. Among these genes there was up‐regulation of insulin‐like growth factor binding protein‐3 (IGFBP‐3), a protein that modulates proliferation and apoptosis. Western blot analysis confirmed the increase of IGFBP‐3 only in imatinib‐sensitive GIST882 cells. Up to a 7‐fold induction (49% mean increase; P = .08) of IGFBP‐3 mRNA was found in tumor samples from patients with low residual FDG uptake, whereas there was an up to 12‐fold reduction (−102% mean decrease; P = .03) in IGFBP‐3 in those patients with high residual FDG uptake after imatinib therapy. CONCLUSIONS. In the current study, imatinib appears to regulate numerous genes and specifically induces IGFBP‐3 in GIST cells and tumor samples. IGFBP‐3 levels also were found to be inversely correlated with residual FDG uptake in GIST patients early in imatinib therapy. These initial observations suggest that IGFBP‐3 is an important early marker of antitumor activity of imatinib in GIST. Cancer 2006. © 2006 American Cancer Society.
Spectrum of susceptibility to malignant hyperthermia--diagnostic dilemma. (1983)

Utilizing established in vitro muscle contracture tests, we have identified three diagnostic contracture phenotypes for malignant hyperthermia susceptibility (MHS) among 103 patients. Phenotype H is an unequivocal diagnostic result for MHS, as is the nonsusceptible phenotype N. The third diagnostic group, phenotype K, represents an equivocal diagnostic response. To provide a basis for understanding relationships between contracture phenotypes and MHS, pigs with phenotypes H, K, and N were exposed to a standardized anesthetic protocol for assessing MHS. During the anesthetic challenge, phenotype H pigs developed a more severe form of the MH syndrome than did phenotype K pigs. Comparing phenotype H v K average responses, VO2 increased four- v twofold; lactate increased 13- v 9-fold; and temperature increased 41.7 degrees C v 39.2 degrees C, respectively. These values either had no change or decreased in the phenotype N pigs. Results of this study suggest that a spectrum of MHS exists among the human population.
Osmolyte-Induced Perturbations of Hydrogen Bonding between Hydration Layer Waters: Correlation with Protein Conformational Changes (2009)

Gadolinium vibronic sideband luminescence spectroscopy (GVSBLS) is used to probe osmolyte-induced changes in the hydrogen bond strength between first and second shell waters on the surface of free Gd(3+) and Gd(3+) coordinated to EDTA and to structured calcium binding peptides in solution. In parallel, Raman is used to probe the corresponding impact of the same set of osmolytes on hydrogen bonding among waters in the bulk phase. Increasing concentration of added urea is observed to progressively weaken the hydrogen bonding within the hydration layer but has minimal observed impact on bulk water. In contrast, polyols are observed to enhance hydrogen bonding in both the hydration layer and the bulk with the amplitude being polyol dependent with trehalose being more effective than sucrose, glucose, or glycerol. The observed patterns indicate that the size and properties of the osmolyte as well as the local architecture of the specific surface site of hydration impact preferential exclusion effects and local hydrogen bond strength. Correlation of the vibronic spectra with CD measurements on the peptides as a function of added osmolytes shows an increase in secondary structure with added polyols and that the progressive weakening of the hydrogen bonding upon addition of urea first increases water occupancy within the peptide and only subsequently does the peptide unfold. The results support models in which the initial steps in the unfolding process involve osmolyte-induced enhancement of water occupancy within the interior of the protein.
Estimation of Clay Proportions in Mixtures by X-Ray Diffraction and Computerized Chemical Mass Balance (1984)

Abstract As part of a laboratory study of the hydrothermal alteration of kimberlite, a mass balance procedure has been developed for estimating the relative proportions of synthetic phyllosilicate phases— chlorite, vermiculite, smectite, kaolinite and serpentine—present in reaction products. The procedure is based on a combination of X-ray powder diffraction (XRD) measurements (for phase identification), atomic absorption determinations (for total Si, Al, Fe, and Mg) and published analyses of clay minerals (for stoichiometric deductions). It centers on the computer inversion of a 4 × 4 matrix form of four simultaneous equations representing the mass balance of Si, Al, Fe, and Mg in four chosen minerals and incorporates a systematic routine for selecting from all possible permutations of high and low estimates of the mineral chemical analyses acceptable sets of product stoichiometries and phase proportions consistent with the total metal analyses. To minimize uncertainties and computing time, the program takes account of elemental relationships and water mass balances associated with phyllosilicates. It also accommodates data relevant to poorly crystalline phases for which a range of theoretical type-analyses modeled on aluminum oxyhydroxides and 9–11-Å, 2:1 layered aluminosilicates are employed. The procedure produces reliable trends in phase proportions consistent with the intensities of characteristic XRD peaks of clay minerals present in the analyzed mixture; for example, increases in estimated kaolinite proportions correspond with larger 7-Å (and other) peaks in analyzed samples. A precision of 7–25% has been routinely achievable.
Synthesis of CdS and ZnS Nanowires Using Single-Source Molecular Precursors (2003)

Single-source molecular precursors were used to synthesize II-VI compound semiconductor nanowires for the first time. Cadmium sulfide and zinc sulfide nanowires were prepared using cadmium diethyldithiocarbamate, Cd(S2CNEt2)2, and zinc diethyldithiocarbamate, Zn(S2CNEt2)2, respectively, as precursors in a gold nanocluster-catalyzed vapor-liquid-solid growth process. High-resolution transmission electron microscopy studies show that the CdS and ZnS nanowires are single-crystal wurtzite structures with stoichiometric compositions. In addition, photoluminescence measurements demonstrate that these nanowires exhibit high-quality optical properties. The applicability of our approach to the synthesis of other compound and alloy semiconductors nanowires as well as nanowire heterostructures of these materials is discussed.
The intracellular deletions of DELTA and SERRATE define dominant negative forms of the Drosophila Notch ligands (1996)

We examined the function of the intracellular domains of the two known Drosophila Notch ligands, Delta and Serrate, by expressing wild-type and mutant forms in the developing Drosophila eye under the sevenless promoter. The expression of intracellularly truncated forms of either Delta (sev-DlTM) or Serrate (sev-SerTM) leads to extra photoreceptor phenotypes, similar to the eye phenotypes associated with loss-of-function mutations of either Notch or Delta. Consistent with the notion that the truncated ligands reduce. Notch signalling activity, the eye phenotypes of sev-DlTM and sev-SerTM are enhanced by loss-of-function mutations in the Notch pathway elements, Notch, Delta, mastermind, deltex and groucho, but are suppressed by a duplication of Delta or mutations in Hairless, a negative regulator of the pathway. These observations were extended to the molecular level by demonstrating that the expression of Enhancer of split m delta, a target of Notch signalling, is down-regulated by the truncated ligands highly expressed in neighbouring cells. We conclude that the truncated ligands act as antagonists of Notch signalling.
Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma. (1998)

TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.
Label-free, all-electrical, in situ human epidermal growth receptor 2 detection (2008)

Using 3-mercaptopropyltrimethoxysilane (MPS)-coated (PbMg 1/3 Nb 2/3 O3)0.63-(PbTiO3)0.37 (PMN-PT)/tin and lead zirconate titanate/glass piezoelectric microcantilever sensors (PEMSs) with single-chain variable fragment (scFv) immobilized on the MPS surface, we have demonstrated real-time, label-free detection of human epidermal growth factor receptor 2 (Her2) in a background of 1 mg/ml bovine serum albumin. Coupled with a scFv with a KD of 3.4 x 10(-8)M, the MPS-insulated PMN-PT/tin PEMS 560 microm long and 720 microm wide exhibited a Her2 concentration sensitivity of 5 ng/ml in a background of 1 mg/ml BSA.
Bim is a suppressor of Myc-induced mouse B cell leukemia (2004)

Impaired apoptosis is now recognized to be central to tumor development. Bcl2, activated by chromosomal translocation in human follicular lymphoma, promotes oncogenesis by inhibiting apoptosis. Bim, a distant proapoptotic relative, is emerging as a major physiologic antagonist of Bcl2. Here, we show that loss of Bim is oncogenic. Bim protein levels were elevated in the apoptosis-prone B lymphoid cells of Emicro-Myc-transgenic mice, and Bim-mutant Emicro-Myc mice had increased numbers of IgM-bearing B cells. Emicro-Myc-expressing B lymphoid cells deficient in Bim were refractory to apoptosis induced in vitro by cytokine deprivation or antigen receptor cross-linking. Thus, Bim is induced by Myc in B cells and mediates apoptosis. Remarkably, inactivation of even a single allele of Bim accelerated Myc-induced development of tumors, particularly acute B cell leukemia. None of the primary tumors from Bim(+/-) Emicro-Myc mice displayed loss of the second allele of Bim. These findings indicate that Bim is a tumor suppressor, at least in B lymphocytes, and is haploinsufficient. Whereas the p19Arf/p53 pathway is frequently mutated in tumors arising in Bim(+/+) Emicro-Myc mice, it was unaffected in most Bim-deficient tumors, indicating that Bim reduction is an effective alternative to loss of p53 function.
Proteomic analysis of extracellular vesicles derived from Mycobacterium tuberculosis (2015)

The release of extracellular vesicles, also known as outer membrane vesicles, membrane vesicles, exosomes, and microvesicles, is an evolutionarily conserved phenomenon from bacteria to eukaryotes. It has been reported that Mycobacterium tuberculosis releases extracellular vesicles harboring immunologically active molecules, and these extracellular vesicles have been suggested to be applicable in vaccine development and biomarker discovery. However, the comprehensive proteomic analysis has not been performed for M. tuberculosis extracellular vesicles. In this study, we identified a total of 287 vesicular proteins by four LC-MS/MS analyses with high confidence. In addition, we identified several vesicular proteins associated with the virulence of M. tuberculosis. This comprehensive proteome profile will help elucidate the pathogenic mechanism of M. tuberculosis. The data have been deposited to the ProteomeXchange with identifier PXD001160 (http://proteomecentral.proteomexchange.org/dataset/PXD001160).
Development of Radicicol Analogues (2003)

Radicicol, a macrocyclic antibiotic produced by fungi, was originally isolated many years ago, and was described as tyrosine kinase inhibitor. We also rediscovered radicicol as an inhibitor of signal transduction of oncogene products, such as K-ras and v-Src, using yeast and mammalian cell-based assays. In a study of mechanisms of action, it was revealed that radicicol depletes the Hsp90 client signaling molecules in cells, and thus inhibit the signal transduction pathway. In addition, direct binding of radicicol to the N-terminal ATP/ADP binding site of Hsp90 was shown, and thus radicicol has been recognized as a structurally unique antibiotic that binds and inhibits the molecular chaperone Hsp90. Although radicicol itself has little or no activity in animals because of instability in animals, its oxime derivatives showed potent antitumor activities against human tumor xenograft models. Hsp90 client proteins were depleted and apoptosis was induced in the tumor specimen treated with radicicol oxime derivatives. Taken together, these results suggest that the antitumor activity of radicicol oxime derivatives is mediated by binding to Hsp90 and destabilization of Hsp90 client proteins in the tumor. Among Hsp90 clients, we focused on ErbB2 and Bcr-Abl as examples of important targets of Hsp90 inhibitors. Radicicol oxime showed potent antitumor activity against ER negative/ErbB2 overexpressing breast cancer and Bcr-Abl expressing CML. Putative mechanisms of action and future directions of radicicol oxime against these kinds of tumor are discussed.
Long Term Prevention of Allergic Lung Inflammation in a Mouse Model of Asthma by CpG Oligodeoxynucleotides (1999)

Asthma is an inflammatory disease of the airways that is induced by Th2 cytokines and inhibited by Th1 cytokines. Despite a steady increase in the incidence, morbidity, and mortality from asthma, no current treatment can reduce or prevent asthma for a prolonged period. We examined the ability of unmethylated CpG oligodeoxynucleotides (ODN), which are potent inducers of Th1 cytokines, to prevent the inflammatory and physiological manifestations of asthma in mice sensitized to ragweed allergen. Administration of CpG ODN 48 h before allergen challenge increased the ratio of IFN-gamma to IL-4 secreting cells, diminished allergen-induced eosinophil recruitment, and decreased the number of ragweed allergen-specific IgE-producing cells. These effects of CpG ODN were sustained for at least 6 wk after its administration. Furthermore, there was a vigorous Th1 memory response to the recall Ag, inhibition of peribronchial and perivascular lung inflammation, and inhibition of bronchial hyperresponsiveness 6 wk after administration of CpG ODN. Administration of CpG ODN in IFN-gamma -/- mice failed to inhibit eosinophil recruitment, indicating a critical role of IFN-gamma in mediating these effects. This is the first report of a treatment that inhibits allergic lung inflammation in presensitized animals for a prolonged period and thus has relevance to the development of an effective long term treatment for asthma.
The Extracranial Vascular Theory of Migraine—A Great Story Confirmed by the Facts (2011)

Over the years, there has been a considerable amount of controversy as to whether the vascular component of migraine pain arises from the intracranial or the extracranial vessels or both. Some have even questioned whether vasodilatation even plays a significant role in migraine pain and have described it as an unimportant epiphenomenon. In this review, evidence is presented that confirms (1) vasodilatation is indeed a source of pain in migraine; (2) this dilatation does not involve the intracranial vasculature; (3) the extracranial terminal branches of the external carotid artery are a significant source of pain in migraine.
High copy number of the pUC plasmid results from a Rom/Rop‐suppressible point mutation in RNA II (1992)

The plasmids pUC18 and pUC19 are pBR322 derivatives that replicate at a copy number several fold higher than the parent during growth of Escherichia coli at 37 degrees C. We show here that the high copy number of pUC plasmids results from a single point mutation in the replication primer, RNA II, and that the phenotypic effects of this mutation can be suppressed by the Rom (RNA one modulator)/Rop protein or by lowering the growth temperature to 30 degrees C. The mutation's effects are enhanced by cell growth at 42 degrees C, at which copy number is further increased. During normal cell growth, the pUC mutation does not affect the length or function of RNA I, the antisense repressor of plasmid DNA replication, but may, as computer analysis suggests, alter the secondary structure of pUC RNA II. We suggest that the pUC mutation impedes interactions between the repressor and the primer by producing a temperature-dependent alteration of the RNA II conformation. The Rom/Rop protein may either promote normal folding of the mutated RNA II or, alternatively, may enable the interaction of sub-optimally folded RNA II with the repressor.
Single‐chain variable fragments selected on the 57–76 p21Ras neutralising epitope from phage antibody libraries recognise the parental protein (1999)

Phage antibodies have been widely prospected as an alternative to the use of monoclonal antibodies prepared by traditional means. Many monoclonal antibodies prepared against peptides are able to recognise the native proteins from which they were derived. Here we show that the same is also true for phage antibodies. We have selected a number of single-chain variable fragments (scFv) from a large phage scFv library against a peptide from the switch region II of p21Ras. This peptide is known to reside in a mobile area of the native protein and is the epitope of a well characterised monoclonal antibody. Selected scFvs were able to recognise native p21Ras in both ELISA and Western blots, indicating that peptides are also likely to be very useful in selecting from phage antibody libraries.
Physiology and Pharmacology of the Vanilloid Receptor (2005)

The identification and cloning of the vanilloid receptor 1 (TRPV1) represented a significant step for the understanding of the molecular mechanisms underlying the transduction of noxious chemical and thermal stimuli by peripheral nociceptors. TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 channel activity is remarkably potentiated by pro-inflammatory agents, a phenomenon that is thought to underlie the peripheral sensitisation of nociceptors that leads to thermal hyperalgesia. Cumulative evidence is building a strong case for the involvement of this receptor in the etiology of both peripheral and visceral inflammatory pain, such as inflammatory bowel disease, bladder inflammation and cancer pain. The validation of TRPV1 receptor as a key therapeutic target for pain management has thrust intensive drug discovery programs aimed at developing orally active antagonists of the receptor protein. Nonetheless, the real challenge of these drug discovery platforms is to develop antagonists that preserve the physiological activity of TRPV1 receptors while correcting over-active channels. This is a condition to ensure normal pro-prioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury. Recent and exciting advances in the function, dysfunction and modulation of this receptor will be the focus of this review.