gebhart/patrepeval huggingface dataset:
The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia (2008)

Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair beta-cell function and survival. A recent clinical trial shows that blocking IL-1beta signaling by IL-1 receptor antagonist (IL-1Ra) improves beta-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the beta-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the beta-cell. IL-1Ra protected islets from HFD treated animals from beta-cell apoptosis, induced beta-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves beta-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes.
Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance (2019)

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of-function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.
Proteases in Mycobacterium Tuberculosis Pathogenesis: Potential as Drug Targets (2013)

TB is still a major global health problem causing over 1 million deaths per year. An increasing problem of drug resistance in the causative agent, Mycobacterium tuberculosis, as well as problems with the current lengthy and complex treatment regimens, lends urgency to the need to develop new antitubercular agents. Proteases have been targeted for therapy in other infections, most notably these have been successful as antiviral agents in the treatment of HIV infection. M. tuberculosis has a number of proteases with good potential as novel drug targets and developing drugs against these should result in agents that are effective against drug-resistant and drug-sensitive strains. In this review, the authors summarize the current status of proteases with potential as drug targets in this pathogen, particularly focusing on proteases involved in protein secretion (signal peptidases LepB and LspA), protein degradation and turnover (ClpP and the proteasome) and virulence (mycosins and HtrA).
Preparation of noncondensed 2-substituted 1-methylimidazoles via ipso substitution reaction on 2-sulfinyl or 2-sulfonyl derivatives of 4,5-disubstituted 1-methylimidazoles (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPreparation of noncondensed 2-substituted 1-methylimidazoles via ipso substitution reaction on 2-sulfinyl or 2-sulfonyl derivatives of 4,5-disubstituted 1-methylimidazolesMark A. Jarosinski and Wayne K. AndersonCite this: J. Org. Chem. 1991, 56, 12, 4058–4062Publication Date (Print):June 1, 1991Publication History Published online1 May 2002Published inissue 1 June 1991https://pubs.acs.org/doi/10.1021/jo00012a050https://doi.org/10.1021/jo00012a050research-articleACS PublicationsRequest reuse permissionsArticle Views279Altmetric-Citations15LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Comparative Immunohistochemical Analysis of Pediatric Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma (2004)

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) account for nearly all pediatric nonlymphoblastic B-cell lymphomas. Because clinical behavior, prognosis, and response to therapy might differ, diagnostic accuracy is important. Morphologic examination often is sufficient, but occasionally, diagnostic ancillary studies are required. In adults, immunophenotyping is useful; however, pediatric data are limited. We characterized the immunohistochemical expression of 6 proteins (c-myc, CD10, bcl-6, bcl-2, CD138, and MIB-1) in pediatric BL (33 cases) and DLBCL (20 cases) with classic morphologic features. Significant differences in c-myc (BL, 30/33 [91%] vs DLBCL, 5/20 [25%]; P < .0001), bcl-2 (BL, 1/25 [4%] vs DLBCL, 7/19 [37%]; P < .02), and mean MIB-1 (BL, 99% vs DLBCL, 56%; P < .0001) expression were observed. There were no significant differences for CD10 (100% expression in BL and DLBCL), bcl-6 (BL, 23/33 [70%] vs DLBCL, 15/20 [75%]), or CD138 (no expression). Thus, pediatric BL and DLBCL have distinctive immunohistochemical profiles, and staining for c-myc, MIB-1, and bcl-2 might be useful in morphologically difficult cases.
Lithium Insertion in Carbon‐Silicon Composite Materials Produced by Mechanical Milling (1998)

Carbons containing nanosize silicon particles were prepared by mechanical milling of graphite and silicon mixtures with different atomic ratios. The microstructure, morphology, and electrochemical performance of ballmilled (x = 0, 0.1, 0.2, 0.25) were analyzed by X‐ray diffraction, Raman, high‐resolution and transmission electron microscopy, and electrochemical methods. After ballmilling, the crystal size of graphite increased but the size of silicon decreased with increasing content of silicon. Ballmilled materials reacted reversibly with lithium, and the reversible specific capacity increased from 437 mAh/g in the ballmilled pure graphite to 1039 mAh/g in ballmilled materials. The excess capacity due to the Li extraction from silicon appeared at a potential about 0.4 V vs. Li metal. After 20 charge/discharge cycles the reversible capacity of was 794 mAh/g. This behavior is a result of nanosize silicon particles decreasing the crumbling rate during Li insertion and extraction. These materials appear to be promising candidates for negative electrodes in lithium‐ion rechargeable batteries.
Bioavailability and anticataract effects of a topical ocular drug delivery system containing disulfiram and hydroxypropyl-beta-cyclodextrin on selenite-treated rats (2004)

The cyclodextrin-based drug delivery system enhances both the solubility of DSF in aqueous eye drops and permeability of the drug into the rabbit eye. DSF ocular bioavailability in rabbit aqueous humor exceeded those reported for the DSF ophthalmic preparation. DSF eye drops effectively prevent the development of selenite-induced cataracts.
Characterization of the Shank Family of Synaptic Proteins (1999)

Shank1, Shank2, and Shank3 constitute a family of proteins that may function as molecular scaffolds in the postsynaptic density (PSD). Shank directly interacts with GKAP and Homer, thus potentially bridging the N-methyl-D-aspartate receptor-PSD-95-GKAP complex and the mGluR-Homer complex in synapses (Naisbitt, S., Kim, E., Tu, J. C. , Xiao, B., Sala, S., Valtschanoff, J., Weinberg, R. J., Worley, P. F., and Sheng, M. (1999) Neuron 23, 569-582; Tu, J. C., Xiao, B., Naisbitt, S., Yuan, J. P., Petralia, R. S., Brakeman, P., Doan, A., Aakalu, V. K., Lanahan, A. A., Sheng, M., and Worley, P. F. (1999) Neuron 23, 583-592). Shank contains multiple domains for protein-protein interaction including ankyrin repeats, an SH3 domain, a PSD-95/Dlg/ZO-1 domain, a sterile alpha motif domain, and a proline-rich region. By characterizing Shank cDNA clones and RT-PCR products, we found that there are four sites for alternative splicing in Shank1 and another four sites in Shank2, some of which result in deletion of specific domains of the Shank protein. In addition, the expression of the splice variants is differentially regulated in different regions of rat brain during development. Immunoblot analysis of Shank proteins in rat brain using five different Shank antibodies reveals marked heterogeneity in size (120-240 kDa) and differential spatiotemporal expression. Shank1 immunoreactivity is concentrated at excitatory synaptic sites in adult brain, and the punctate staining of Shank1 is seen in developing rat brains as early as postnatal day 7. These results suggest that alternative splicing in the Shank family may be a mechanism that regulates the molecular structure of Shank and the spectrum of Shank-interacting proteins in the PSDs of adult and developing brain.
Optical characterization of contrast agents for optical coherence tomography (2003)

The use of contrast agents in almost every imaging modality has been known to enhance the sensitivity of detection and improve diagnostic capabilities by site-specifically labeling tissues or cells of interest. The imaging capabilities of Optical Coherence Tomography (OCT) need to be improved in order to detect early neoplastic changes in medicine and tumor biology. We introduce and characterize the optical properties of several types of optical contrast agents in OCT, namely encapsulating microspheres that incorporate materials including melanin, gold, and carbon. Micron-sized microspheres have been fabricated by state-of-the-art sonicating and ultrasound technology. The optical properties of optical contrast agents have been characterized according to their scattering and absorption coefficients and lifetimes using OCT and the oblique incidence reflectometry method. Finally, we demonstrate the use of these optical contrast agents in in vitro mice liver and analyze the contrast improvement from the OCT images. These optical contrast agents have the potential to improve the detection of <i>in vivo</i> pathologies in the future.
Angst und Faszination in der Balint-Arbeit (2004)

Das Referat soll Teilnehmer in die konkrete Arbeit in Balint-Gruppen einführen. Es wird versucht zu zeigen, wie faszinierend es sein kann, die eigenen emotionalen Reaktionen auf sein Patienten-Gegenüber wahr- und ernst zu nehmen und damit zu arbeiten. Das sich Einlassen auf z. B. die eigene Angst kann zum Schlüssel werden, der das Verhalten des „schwierigen” Patienten verstehen lässt. Ohne das sich Einlassen auf die vorerst Unbekannte der eigenen Angst (z. B. vor schwierigen Gefühlen) gibt es keine Faszination des plötzlichen Verstehens. Dazu braucht es auch Vertrauen in den Prozess in sich und in der Gruppe (und im Patienten), dem man sich auf der Reise ins Unbekannte ein Stück weit überlassen kann.
Site-Directed Antibodies against the Stem Region Reveal Low pH-Induced Conformational Changes of the Semliki Forest Virus Fusion Protein (2006)

The E1 envelope protein of the alphavirus Semliki Forest virus (SFV) is a class II fusion protein that mediates low pH-triggered membrane fusion during virus infection. Like other class I and class II fusion proteins, during fusion E1 inserts into the target membrane and rearranges to form a trimeric hairpin structure. The postfusion structures of the alphavirus and flavivirus fusion proteins suggest that the "stem" region connecting the fusion protein domain III to the transmembrane domain interacts along the trimer core during the low pH-induced conformational change. However, the location of the E1 stem in the SFV particle and its rearrangement and functional importance during fusion are not known. We developed site-directed polyclonal antibodies to the N- or C-terminal regions of the SFV E1 stem and used them to study the stem during fusion. The E1 stem was hidden on neutral pH virus but became accessible after low pH-triggered dissociation of the E2/E1 heterodimer. The stem packed onto the trimer core in the postfusion conformation and became inaccessible to antibody binding. Generation of the E1 homotrimer on fusion-incompetent membranes identified an intermediate conformation in which domain III had folded back but stem packing was incomplete. Our data suggest that E1 hairpin formation occurs by the sequential packing of domain III and the stem onto the trimer core and indicate a tight correlation between stem packing and membrane merger.
Conquering HIV’s capsid (2017)

For most of his career at Gilead Sciences, medicinal chemist Winston Tse has lived and breathed one thing. While his peers at other companies hopped from project to project, Tse has spent the past decade obsessing over a single target: the HIV capsid. HIV’s capsid is a complex, protein-rich shell that protects the genetic payload the virus is trying to sneak into the cells of its host. Tse’s goal? To prove that a small molecule can disrupt that shield and keep the virus from replicating. Getting to his goal has taken tenacity. For perspective, Tse’s daughter was born the year he started working on capsid inhibitors; this fall, she’ll be in the fourth grade. Finally, Tse and a sizable team of medicinal chemists, biologists, virologists, and academic partners have done it. By 2018, Gilead expects to begin human studies of a capsid inhibitor with the potential to be dosed once
Expression of Fcγ receptors type II (FcγRII) in chronic lymphocytic leukemia B cells (2003)

We have read with interest the paper from Damle et al analyzing the surface membrane phenotype of B lymphocytes in chronic lymphocytic leukemia (B-CLL). The authors stated that the leukemic cells from all B-CLL patients evaluated (irrespective of immunoglobulin heavy chain (IgVH) gene mutational status) bear the phenotype of antigen-experienced B cells based, among other features, on the very low expression of Fcγ receptors type IIb (FcγRIIb, CD32), which is the main isoform of FcγRII in B lymphocytes.
Stereoselective Syntheses of Epothilones A and B via Nitrile Oxide Cycloadditions and Related Studies (2001)

The expedient and fully stereocontrolled synthesis of epothilones A and B are described. The routes described make extensive study of nitrile oxide cycloadditions as surrogates for aldol addition reactions and have led to the realization of a highly convergent synthesis based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition. As well, our synthetic efforts have led to the development of new reaction methodologies and served as the proving ground for several modern methods for asymmetric carbon-carbon bond formation.
Evaluation of live attenuated plague vaccines in Praomys (Mastomys) natalensis (1977)

A live attenuated Yersinia pestis vaccine designated EV76-51f, which had previously been shown to be pathogenic in vervet monkeys but not in guinea pigs, was tested in the multimammate mouse Praomys (Mastomys) natalensis. Doses of 10(6) viable organisms inoculated subcutaneously as either a lyophilized suspension or an agar-grown culture resulted in vaccination fatalities in Praomys but not in white mice. Hemagglutinating antibodies to the fraction 1 antigen were not stimulated by doses lower than 10(4) viable organisms. Agar-grown cultures of the vaccine gave better protection against a virulent Y. pestis challenge than did a lyophilized suspension. All Praomys vaccinated with a dose of 10(6) agar-grown EV76-51f protected against a virulent challenge, whereas even doses up to 10(8) lyophilized bacilli failed to give complete protection. The pathogenicity of a live attenuated plague vaccine derived from the Y. pestis EV76 vaccine strain can be detected in Praomys (Mastomys) natalensis, a rodent species highly susceptible to plague. This animal species may therefore be valuable for the testing of live attenuated plague vaccines before they are tested in costly nonhuman primates.
Printability of submicron 5x reticle defects at i-line and DUV exposure wavelengths (1993)

Printability of sub-micron 5X reticle defects at i-line and duv. wavelengths is assessed by use of a specifically designed test reticle incorporating defects whose size, and proximity to adjacent features, varies within sub-micron line/space arrays. Results are presented by plotting minimum resolved defect vs. array linewidth for both adjacent and isolated defect sites. Results on defect printability enable future reticle procurement specifications to be established. Results at i-line have been successfully modelled using SOLID which has a powerful graphics package enabling results to be displayed in 3D.
Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura (2001)

The role of rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) has not been determined. The effectiveness and side effects of this therapeutic modality were investigated in a cohort of 25 individuals with chronic ITP. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already failed splenectomy. Patients were scheduled to receive intravenous rituximab at the dose of 375 mg/m(2) once weekly for 4 weeks. Rituximab infusion-related side effects were observed in 18 patients, but were of modest intensity and did not require discontinuation of treatment. A complete response (platelet count greater than 100 x 10(9)/L) was observed in 5 cases, a partial response (platelet count between 50 and 100 x 10(9)/L) in 5 cases, and a minor response (platelet count below 50 x 10(9)/L, with no need for continued treatment) in 3 cases, with an overall response rate of 52%. In 7 cases, responses were sustained (6 months or longer). In 2 patients with relapsed disease, repeat challenge with rituximab induced a new response. In patients with a complete or partial response, a significant rise in platelet concentrations was observed early during the course of treatment, usually 1 week after the first rituximab infusion. No clinical or laboratory parameter was found to predict treatment outcome, although there was a suggestion that women and younger patients have a better chance of response. In conclusion, rituximab therapy has a limited but valuable effect in patients with chronic ITP. In view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted. (Blood. 2001;98:952-957)
Global Identification of O-GlcNAc-Modified Proteins (2005)

The O-linked N-acetylglucosamine (O-GlcNAc) modification of serine/threonine residues is an abundant posttranslational modification present in cytosolic and nuclear proteins. The functions and subproteome of O-GlcNAc modification remain largely undefined. Here we report the application of the tagging-via-substrate (TAS) approach for global identification of O-GlcNAc-modified proteins. The TAS method utilizes an O-GlcNAc azide analogue for metabolic labeling of O-GlcNAc-modified proteins, which can be chemoselectively conjugated for detection and enrichment of the proteins for proteomics studies. Our study led to the identification of 199 putative O-GlcNAc-modified proteins from HeLa cells, among which 23 were confirmed using reciprocal immunoprecipitation. Functional classification shows that proteins with diverse functions are modified by O-GlcNAc, implying that O-GlcNAc might be involved in the regulation of multiple cellular pathways.
The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis (2015)

Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans.
Substrate effects on the characteristics of haze defect formation on the photomask surface under exposure condition (2007)

We have explored substrate effects upon the characteristics of haze creation on the mask surface by performing surface analysis for each of Cr, MoSiON, and Qz substrates of the mask before and after laser exposure. We found out chemical ions such as sulfur and ammonium ions should have different mobility behavior towards haze defect creation depending on each substrate during laser exposure. This fact can partially clarify the reason why haze occurrence on the mask in real mass production mainly comes up with Qz substrate surface even though it has the lowest level of chemical residue on it. We also realized that sulfur ions are penetrating into a sub layer of Qz substrate and even deeper during laser exposure, which signifies that we may have to remove a thin surface layer from Qz substrate to further improve haze issue from the current standpoint.
The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional (2009)

We have solved the structures of mammalian mesencephalic astrocyte-derived neurotrophic factor (MANF) and conserved dopamine neurotrophic factor (CDNF). CDNF protects and repairs midbrain dopaminergic neurons in vivo; MANF supports their survival in culture and is also cytoprotective against endoplasmic reticulum (ER) stress. Neither protein structure resembles any known growth factor but the N-terminal domain is a saposin-like lipid-binding domain. MANF and CDNF may thus bind lipids or membranes. Consistent with this, there are two patches of conserved lysines and arginines. The natively unfolded MANF C-terminus contains a CKGC disulphide bridge, such as reductases and disulphide isomerases, consistent with a role in ER stress response. The structure thus explains why MANF and CDNF are bifunctional; neurotrophic activity may reside in the N-terminal domain and ER stress response in the C-terminal domain. Finally, we identified three changes, (MANF)I10-->K(CDNF), (MANF)E79-->M(CDNF) and (MANF)K88-->L(CDNF), that may account for the biological differences between the proteins.