gebhart/patrepeval huggingface dataset:
Abstract 6378: An in vitro human CD8 T cell exhaustion model for the functional screening of immune checkpoint inhibitors (2023)

Abstract T cell exhaustion is a state of dysfunction that frequently occurs during chronic infections and cancer due to persistent antigen stimulation and inflammation. It is defined by poor effector function, sustained expression of inhibitory receptors, and a transcriptional state distinct from that of functional effector or memory T cells. In this state, cells remain in the local environment but lack effector functions necessary to combat the tumor or infection. In the current study, we developed an in vitro human antigen-specific CD8 T cell exhaustion model to evaluate the ability of immune checkpoint inhibitors to restore functionality to exhausted T cells. Using the fully human, autologous MIMIC (Modular IMmune In vitro Construct) effector CD8 T cell assay as a framework, we assessed the effect of antigen dose, timing, and frequency of repeated antigen stimulation with antiviral HLA Class I-restricted peptides to drive the development of Ag-specific CD8 T cells toward an exhausted state. Epitope-specific CD8 T cell responses were monitored by HLA class I-restricted pentamers and establishment of an exhausted profile was evaluated by increased expression of inhibitory co-stimulatory receptors and decreased intracellular expression of antiviral effector cytokine via flow cytometry relative to functional Ag-specific CD8 T cells from the same donor. Repeated antigen exposure led to decreased production of IFN-γ and TNF-α and increased expression of inhibitory co-stimulation markers on antigen-specific CD8 T cells. After establishment of an exhausted phenotype, treatment with various immune checkpoint inhibitor molecules restored functionality to Ag-specific CD8 T cells upon an additional antigen re-stimulation. Moreover, here using this model we characterized distinct transcriptomic signatures of functional and exhausted MIMIC CD8 T cells. Development of an in vitro human viral antigen-specific CD8 T cell exhaustion model with characteristic features of dysfunctional CD8 T cells as observed in vivo and the ability to restore effector function by treatment with immune checkpoint inhibitors, provides a platform to assess the effectiveness of therapeutic mono-specific or bi-specific “checkpoint blockade” antibody candidates and, in general, the potential to evaluate a myriad of immunotherapeutic approaches for cancer treatment. Citation Format: Roberto Carrio, Margot Cucchetti, Mikielia Devonish, Louis Poisson, Mihaela Babiceanu, Andrew Kettring, Yingchun Liu, Donald Jackson, Evan Gomes, Jeremy Baudhuin, Donald R. Drake, Valeria Fantin, Anthony Byers, Ingrid Sassoon. An in vitro human CD8 T cell exhaustion model for the functional screening of immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6378.
Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279 (2023)

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate <b>30</b>, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.
Transcriptional Control of the MycobacterialembCABOperon by PknH through a Regulatory Protein, EmbR, In Vivo (2006)

EmbR, a putative transcriptional regulator from Mycobacterium tuberculosis, is homologous to the OmpR class of transcriptional regulators that possess winged helix-turn-helix DNA binding motifs. In contrast to other OmpR-like response regulators that are usually phosphorylated and controlled by histidine kinases, EmbR was recently shown to be phosphorylated by the cognate mycobacterial serine/threonine kinase PknH. Despite the in vitro evidence of phosphorylation and interaction between the kinase and regulator, the physiological function of the PknH-EmbR pair is still unknown. We identify the embCAB operon encoding arabinosyltransferases in M. tuberculosis as the cellular target of EmbR. Phosphorylation of EmbR enhances its DNA binding activity towards promoter regions of embCAB genes. In vivo studies involving expression of PknH in Mycobacterium smegmatis established its positive regulatory effect on transcription of the embCAB operon via phosphorylation of EmbR. Interestingly, increased transcription of embC, catalyzing arabinosylation of lipomannan (LM) to lipoarabinomannan (LAM), results in a high LAM/LM ratio, which in turn is a crucial factor in mycobacterial virulence. The PknH-mediated increase in the transcription of embAB genes significantly alters resistance to ethambutol, a frontline antituberculosis drug known to target embAB genes. These findings and in vivo upregulation of PknH inside the host macrophages suggest a functionally relevant signaling mechanism involving the PknH-EmbR-embCAB system.
High-sensitivity O-glycomic analysis of mice deficient in core 2 β1,6-N-acetylglucosaminyltransferases (2010)

Core 2 β1,6-N-acetylglucosaminyltransferase (C2GnT), which exists in three isoforms, C2GnT1, C2GnT2 and C2GnT3, is one of the key enzymes in the O-glycan biosynthetic pathway. These isoenzymes produce core 2 O-glycans and have been correlated with the biosynthesis of core 4 O-glycans and I-branches. Previously, we have reported mice with single and multiple deficiencies of C2GnT isoenzyme(s) and have evaluated the biological and structural consequences of the loss of core 2 function. We now present more comprehensive O-glycomic analyses of neutral and sialylated glycans expressed in the colon, small intestine, stomach, kidney, thyroid/trachea and thymus of wild-type, C2GnT2 and C2GnT3 single knockouts and the C2GnT1-3 triple knockout mice. Very high-quality data have emerged from our mass spectrometry techniques with the capability of detecting O-glycans up to at least 3500 Da. We were able to unambiguously elucidate the types of O-glycan core, branching location and residue linkages, which allowed us to exhaustively characterize structural changes in the knockout tissues. The C2GnT2 knockout mice suffered a major loss of core 2 O-glycans as well as glycans with I-branches on core 1 antennae especially in the stomach and the colon. In contrast, core 2 O-glycans still dominated the O-glycomic profile of most tissues in the C2GnT3 knockout mice. Analysis of the C2GnT triple knockout mice revealed a complete loss of both core 2 O-glycans and branched core 1 antennae, confirming that the three known isoenzymes are entirely responsible for producing these structures. Unexpectedly, O-linked mannosyl glycans are upregulated in the triple deficient stomach. In addition, our studies have revealed an interesting terminal structure detected on O-glycans of the colon tissues that is similar to the RM2 antigen from glycolipids.
One-Pot Synthesis of Alkyl 4-Alkoxypentanoates by Esterification and Reductive Etherification of Levulinic Acid in Alcoholic Solutions (2016)

Levulinic acid reacts with alcohols under hydrogen at 200–220 °C and 1000 psig in the presence of a Pd/C catalyst to give alkyl 4-alkoxypentanoates (4-alkoxyvalerates) in 54–77% yield. The reaction has been demonstrated with four different alcohols. The biorenewable nature of these compounds along with boiling points exceeding 280 °C for heptyl and higher alkyls makes them interesting candidates for a new class of sustainable, non-VOC solvents.
Well-Defined N/S Co-Doped Nanocarbons from Sulfurized PAN-b-PBA Block Copolymers: Structure and Supercapacitor Performance (2019)

While nanocarbons doped with more than one heteroatom continue attracting growing interest owing to a wide range of applications, precise control of their nanostructure and porosity remains a major challenge. Herein, we report a new route to synthesize N/S co-doped nanocarbons with precise porosity control through introduction of sulfur into the synthesis copolymer-templated nitrogen-enriched carbons (CTNC). Sulfur served as both a heteroatom source and morphology stabilizing agent. The produced N/S co-doped nanocarbons showed interconnected pores with relatively high specific surface area (∼480 m2/g) and high heteroatom content (N, 8.2 atom %; S, 8.8 atom %). To demonstrate the dual benefits of sulfur stabilization (incorporation of heteroatoms and improved morphology control), such prepared nanocarbons were fabricated into supercapacitors with geometric capacitance (50 μF/cm2), well above the value observed for single N-doped carbon (33 μF/cm2). Importantly, linear relationship of mesopore size with block length of copolymer precursor was observed for N/S co-doped nanocarbons, allowing optimization of the mesopore size for supercapacitor applications. This new technique not only expands CTNC method from N-doping to N/S co-doping systems with excellent porosity control but also opens up new possibilities widely applicable to other PAN-based soft-templating systems.
Cell-based and biomaterial approaches to connective tissue repair (2008)

Connective tissue injuries of skin, tendon and ligament, heal by a reparative process in adults, filling the wound site with fibrotic, disorganized scar tissue that poorly reflects normal tissue architecture or function. Conversely, fetal skin and tendon have been shown to heal scarlessly. Complete regeneration is not intrinsically ubiquitous to all fetal tissues; fetal diaphragmatic and gastrointestinal injuries form scars. In vivo studies suggest that the presence of fetal fibroblasts is essential for scarless healing. In the orthopaedic setting, adult anterior cruciate ligament (ACL) heals poorly; however, little is known about the regenerative capacity of fetal ACL or fetal ACL fibroblasts. We characterized in vitro wound healing properties of fetal and adult ACL fibroblasts demonstrating that fetal ACL fibroblasts migrate faster and elaborate greater quantities of type I collagen, suggesting the healing potential of the fetal ACL may not be intrinsically poor. Similar to fetal ACL fibroblasts, fetal dermal fibroblasts also exhibit robust cellular properties. We investigated the age-dependent effects of dermal fibroblasts on tendon-to-bone healing in rat supraspinatus tendon injuries, a reparative injury model. We hypothesized delivery of fetal dermal fibroblasts would increase tissue organization and mechanical properties in comparison to adult dermal fibroblasts. However, at 1 and 8 weeks, the presence of dermal fibroblasts, either adult or fetal, had no significant effect on tissue histology or mechanical properties. There was a decreasing trend in cross-sectional area of repaired tendons treated with fetal dermal fibroblasts in comparison to adult, but this finding was not significant in comparison to controls. Finally, we synthesized a novel polysaccharide, methacrylated methylcellulose (MA-MC), and fabricated hydrogels using a well-established photopolymerization technique. We characterized the physical and mechanical properties of MA-MC hydrogels in vitro as well as in a subcutaneous mouse model. Stable MA-MC hydrogels, of varying weight percentages, demonstrated tunable swelling and mechanical properties in the absence of cytotoxic degradation products. In vivo, 6wt% MA-MC hydrogels maintained their shape and mechanical integrity while eliciting a minimal inflammatory response; highly desirable properties for soft tissue reconstruction. These cellulose-based photopolymerizable hydrogels can be further optimized for drug delivery and tissue engineering applications to enhance wound repair.
Ferrapyrrolinone and ferraazetine complexes formed from the reaction of Fe2(.mu.-CH2)(CO)8 with phosphinimines (1989)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFerrapyrrolinone and ferraazetine complexes formed from the reaction of Fe2(.mu.-CH2)(CO)8 with phosphiniminesChad A. Mirkin, Kuang Lieh Lu, Gregory L. Geoffroy, Arnold L. Rheingold, and Donna L. StaleyCite this: J. Am. Chem. Soc. 1989, 111, 18, 7279–7281Publication Date (Print):August 1, 1989Publication History Published online1 May 2002Published inissue 1 August 1989https://pubs.acs.org/doi/10.1021/ja00200a068https://doi.org/10.1021/ja00200a068research-articleACS PublicationsRequest reuse permissionsArticle Views232Altmetric-Citations27LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Structures of the anticancer compounds N-(2-hydroxyethyl)-2-(3-nitro-1,2,4-triazol-1-yl)acetamide (RB-6110) and 5-(1-aziridinyl)-3-nitro-1-(3-oxo-1-butyl)-1,2,4-triazole (RB-6162) (1988)

RB-6110: C6H9N5O4, Mr = 215.17, monoclinic, C2/c, a = 20.595 (3), b = 4.713 (1), c = 19.914 (4) A, beta = 110.69 (1) degree, V = 1808.3 A3, Z = 8, Dx = 1.588 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.838 mm-1, F(000) = 675, T = 298 K, final R = 0.042 for 1219 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6162: C8H11N5O3, Mr = 225.21, monoclinic, P2(1)/c, a = 7.515 (1), b = 14.758 (2), c = 9.813 (1) A, beta = 108.49 (1) degree, V = 1032.1 A3, Z = 4, Dx = 1.450 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.927 mm-1, F(000) = 472, T = 298 K, final R = 0.042 for 1113 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6110 and RB-6162 are 3-nitro-1,2,4-triazoles with potential application as anticancer agents. The nitro groups are in the plane of the aromatic triazole ring with dihedral angles of 1.2 (4) and 4.6 (4) degrees, respectively. The arizidine substituent of RB-6162 is almost perpendicular [dihedral angle 80.1 (4) degrees] to the triazole plane. Molecular-orbital calculations on RB-6162 have confirmed that this geometry is energetically favoured. The energy barrier to rotation about the triazole-aziridine bond has been determined as 51.5 (5) kJ mol-1 by the dynamic NMR method.
RE: STRATEGIES FOR TRANSPLANTATION OF CADAVERIC KIDNEYS WITH CONGENITAL FUSION ANOMALIES (2002)

No AccessJournal of UrologyCLINICAL UROLOGY: Letters to the Editor1 Mar 2002RE: STRATEGIES FOR TRANSPLANTATION OF CADAVERIC KIDNEYS WITH CONGENITAL FUSION ANOMALIES Otto B. Stroosma, Gauke Kootstra, Geert Willem H. Schurink, R.G. Uzzo, T.H.S. Hsu, D.A. Goldfarb, R.J. Taylor, A.C. Novick, and I.S. Gill Otto B. StroosmaOtto B. Stroosma More articles by this author , Gauke KootstraGauke Kootstra More articles by this author , Geert Willem H. SchurinkGeert Willem H. Schurink More articles by this author , R.G. UzzoR.G. Uzzo More articles by this author , T.H.S. HsuT.H.S. Hsu More articles by this author , D.A. GoldfarbD.A. Goldfarb More articles by this author , R.J. TaylorR.J. Taylor More articles by this author , A.C. NovickA.C. Novick More articles by this author , and I.S. GillI.S. Gill More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)65320-7AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "RE: STRATEGIES FOR TRANSPLANTATION OF CADAVERIC KIDNEYS WITH CONGENITAL FUSION ANOMALIES." The Journal of Urology, 167(3), p. 1405 References 1 : Horseshoe kidney transplantation: an overview. Clin Transplant2000; 14: 515. Google Scholar 2 : Strategies for the successful transplantation of the horseshoe kidney.. J Urol1993; 150: 958. Abstract, Google Scholar Department of SurgeryUniversity Hospital Maastricht6202 AZ MaastrichtThe Netherlands© 2002 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 167Issue 3March 2002Page: 1405 Advertisement Copyright & Permissions© 2002 by American Urological Association, Inc.MetricsAuthor Information Otto B. Stroosma More articles by this author Gauke Kootstra More articles by this author Geert Willem H. Schurink More articles by this author R.G. Uzzo More articles by this author T.H.S. Hsu More articles by this author D.A. Goldfarb More articles by this author R.J. Taylor More articles by this author A.C. Novick More articles by this author I.S. Gill More articles by this author Expand All Advertisement PDF DownloadLoading ...
Sequential XylS-CTD Binding to the Pm Promoter Induces DNA Bending Prior to Activation (2010)

XylS protein, a member of the AraC family of transcriptional regulators, comprises a C-terminal domain (CTD) involved in DNA binding and an N-terminal domain required for effector binding and protein dimerization. In the absence of benzoate effectors, the N-terminal domain behaves as an intramolecular repressor of the DNA binding domain. To date, the poor solubility properties of the full-length protein have restricted XylS analysis to genetic approaches in vivo. To characterize the molecular consequences of XylS binding to its operator, we used a recombinant XylS-CTD variant devoid of the N-terminal domain. The resulting protein was soluble and monomeric in solution and activated transcription from its cognate promoter in an effector-independent manner. XylS binding sites in the Pm promoter present an intrinsic curvature of 35 degrees centered at position -42 within the proximal site. Gel retardation and DNase footprint analysis showed XylS-CTD binding to Pm occurred sequentially: first a XylS-CTD monomer binds to the proximal site overlapping the RNA polymerase binding sequence to form complex I. This first event increased Pm bending to 50 degrees and was followed by the binding of the second monomer, which further increased the observed global curvature to 98 degrees. This generated a concomitant shift in the bending center to a region centered at position -51 when the two sites were occupied (complex II). We propose a model in which DNA structure and binding sequences strongly influence XylS binding events previous to transcription activation.
Direct Observation of Preceramic and Organic Binder Decomposition in 2‐D Model Microstructures (1994)

Preceramic and organic binder decomposition processes were studied during thermolysis to determine how the physico‐chemical properties of the binder affected the microstructural development of the ceramic component. Specifically, the behavior of two organic polymers, poly(methyl methacrylate) (PMMA) and a cross‐linked poly(methyl methacrylate) (x‐PMMA), and two preceramic polymers, polycarbosilane (PCS) and vinylic polysilane (VPS) was observed as a function of temperature. Binder‐filled two‐dimensional (2‐D) model microstructures were fabricated to simulate ceramic green bodies whose pores were completely filled with binder. Examination of these 2‐D samples by hot‐stage optical microscopy enabled direct observations of pore development and changes in polymer morphology during binder thermolysis. These observations revealed that the mass transport processes involved during thermolysis as well as the developing microstructural features, depend on the properties of the binder system during thermal decomposition. The organic polymers were investigated because of their chemical similarity and markedly different physical behavior upon heating. It was shown that thermoplastic polymers (e.g., PMMA) are influenced by capillary forces during thermolysis, while thermosetting polymers (e.g., x‐PMMA) do not flow within these porous microstructures. Both of the preceramic polymers displayed a range of physical behavior over the temperatures Studied. The decomposition chemistry and weight loss at a given temperature combined with the associated physical behavior had a dramatic effect on the final distribution of the pyrolyzed product (amorphous silicon carbide and glassy carbon) formed during thermolysis. The pyrolysis product formed from PCS was observed to segregate to the smaller pore channels in the 2‐D microstructures, while the pyrolysis product formed from VPS was observed to be homogeneously distributed in these model microstructures. This work offers guidelines to improve the microstructural homogeneity of ceramic–ceramic composites derived from particulate–preceramic polymer green bodies.
Hybrid Oxidation Catalysts from Immobilized Complexes on Inorganic Microporous Supports (2006)

This chapter contains sections titled: Introduction and scope Oxygenation potential of heme-type complexes in zeolite Oxygenation potential of zeolite encapsulated nonheme complexes Conclusions Acknowledgements References
Deep Learning Framework for Epithelium Density Estimation in Prostate Multi-Parametric Magnetic Resonance Imaging (2020)

Multi-parametric magnetic resonance imaging (mpMRI) permits non-invasive visualization and localization of clinically important cancers in the prostate. However, it cannot fully describe tumor heterogeneity and microstructures that are crucial for cancer management and treatment. Herein, we develop a deep learning framework that could predict epithelium density of the prostate in mpMRI. A deep convolutional neural network is built to estimate epithelium density per voxel-basis. Equipped with an advanced design of the neural network and loss function, the proposed method obtained a SSIM of 0.744 and a MAE of 6.448% in a cross-validation. It also outperformed the competing network. The results are promising as a potential tool to analyze tissue characteristics of the prostate in mpMRI.