tbuckley/cabot-search huggingface dataset:
Structural Basis of Cytochrome c Presentation by IEk
Authors: Daved H. Fremont, Shaodong Dai, Herbert Chiang, Frances Crawford, Philippa Marrack, John Kappler
Journal: The Journal of Experimental Medicine (2002)

The COOH-terminal peptides of pigeon and moth cytochrome c, bound to mouse IEk, are two of the most thoroughly studied T cell antigens. We have solved the crystal structures of the moth peptide and a weak agonist–antagonist variant of the pigeon peptide bound to IEk. The moth peptide and all other peptides whose structures have been solved bound to IEk, have a lysine filling the p9 pocket of IEk. However, the pigeon peptide has an alanine at p9 shifting the lysine to p10. Rather than kinking to place the lysine in the anchor pocket, the pigeon peptide takes the extended course through the binding groove, which is characteristic of all other peptides bound to major histocompatibility complex (MHC) class II. Thus, unlike MHC class I, in which peptides often kink to place optimally anchoring side chains, MHC class II imposes an extended peptide conformation even at the cost of a highly conserved anchor residue. The substitution of Ser for Thr at p8 in the variant pigeon peptide induces no detectable surface change other than the loss of the side chain methyl group, despite the dramatic change in recognition by T cells. Finally, these structures can be used to interpret the many published mutational studies of these ligands and the T cell receptors that recognize them.
Racial Disparity in the Use of Atypical Antipsychotic Medications Among Veterans
Authors: Laurel A Copeland, John E Zeber, Marcia Valenstein, Frederic C Blow
Journal: American Journal of Psychiatry (2003)

This study assessed the current state of antipsychotic prescription practices regarding race among veterans receiving care through the Department of Veterans Affairs.The authors examined pharmacy records over a 12-month period for all veterans with schizophrenia and antipsychotic prescriptions in fiscal year 1999. They used logistic regression analysis to assess the effect of race on the use of various atypical antipsychotic agents. Analytic models controlled for age, sex, comorbid substance use, bipolar disorder, and other psychosis.The sample of 69,787 veterans with schizophrenia was 61.3% white, 30.1% African American, and 8.5% Hispanic. Among them, 39% had prescriptions for conventional antipsychotics, 37% for atypical antipsychotics, and 23% for both atypical and conventional antipsychotics. Use of any atypical agent during the year was less likely for Hispanic veterans (55%) than for two other groups (both 61%). When examining specific medications in a multivariate model, the authors found that African American and Hispanic veterans were much less likely to receive clozapine than were white veterans.Overall use of atypical antipsychotics was slightly less common for African American and Hispanic veterans with schizophrenia than for white patients. However, use of clozapine, the first choice for refractory illness and possibly uniquely effective for patients with comorbid substance abuse, did vary greatly by race. This may reflect concern over serious side effects, such as loss of white blood cells and fluctuations of serum glucose levels, or patient preference.
Moral evaluation shapes linguistic reports of others' psychological states, not theory-of-mind judgments
Authors: Florian Cova, Emmanuel Dupoux, Pierre Jacob
Journal: Behavioral and Brain Sciences (2010)

Abstract We use psychological concepts (e.g., intention and desire ) when we ascribe psychological states to others for purposes of describing, explaining, and predicting their actions. Does the evidence reported by Knobe show, as he thinks, that moral evaluation shapes our mastery of psychological concepts ? We argue that the evidence so far shows instead that moral evaluation shapes the way we report , not the way we think about, others' psychological states.
CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury
Authors: Xiuda Shen, Yue Wang, Feng Gao, Feng Ren, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Yuan Zhai
Journal: Hepatology (2009)

Abstract Although the role of CD4 T cells in tissue inflammation and organ injury resulting from ischemia and reperfusion injury (IRI) has been well documented, it remains unclear how CD4 T cells are activated and function in the absence of a specific antigen (Ag). We used a murine liver warm IRI model to determine first whether de novo Ag-specific CD4 T cell activation was required and then what its functional mechanism was. The critical role of CD4 T cells in liver immune activation against ischemia and reperfusion (IR) was confirmed in CD4 knockout mice and CD4 depleted wild-type mice. Interestingly, the inhibition of CD4 T cell activation without target cell depletion failed to protect livers against IRI, and this suggested that T cells function in liver IRI without Ag-specific de novo activation. To dissect the T cell functional mechanism, we found that CD154 blockade, but not interferon γ (IFN-γ) neutralization, inhibited local immune activation and protected livers from IRI. Furthermore, agonist anti-CD40 antibodies restored liver IRI in otherwise protected CD4-deficient hosts. Finally, fluorescence-activated cell sorting analysis of liver CD4 T cells revealed the selective infiltration of effector cells, which constitutively expressed a higher level of CD154 in comparison with their peripheral counterparts. IR triggered a significant liver increase in CD40 expression but not CD154 expression, and macrophages responded to toll-like receptor 4 and type I IFN stimulation to up-regulate CD40 expression. Conclusion: These novel findings provide evidence that CD4 T cells function in liver IRI via CD154 without de novo Ag-specific activation, and innate immunity–induced CD40 up-regulation may trigger the engagement of CD154-CD40 to facilitate tissue inflammation and injury. (Hepatology 2009.)
Clinical and Pathologic Characteristics of Patients With <i>BRCA</i>-Positive and <i>BRCA</i>-Negative Breast Cancer
Authors: Deann P. Atchley, Constance T. Albarracin, Adriana Lopez, Vicente Valero, Christopher I. Amos, Ana Maria Gonzalez-Angulo, Gabriel N. Hortobagyi, Banu K. Arun
Journal: Journal of Clinical Oncology (2008)

Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations.Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006. A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status. Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status.Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01).These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non-triple-negative groups. Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.
Neuroimmunity: Physiology and Pathology
Authors: Sébastien Talbot, Simmie L. Foster, Clifford J. Woolf
Journal: Annual Review of Immunology (2016)

Evolution has yielded multiple complex and complementary mechanisms to detect environmental danger and protect tissues from damage. The nervous system rapidly processes information and coordinates complex defense behaviors, and the immune system eliminates diverse threats by virtue of mobile, specialized cell populations. The two systems are tightly integrated, cooperating in local and systemic reflexes that restore homeostasis in response to tissue injury and infection. They further share a broad common language of cytokines, growth factors, and neuropeptides that enables bidirectional communication. However, this reciprocal cross talk permits amplification of maladaptive feedforward inflammatory loops that contribute to the development of allergy, autoimmunity, itch, and pain. Appreciating the immune and nervous systems as a holistic, coordinated defense system provides both new insights into inflammation and exciting opportunities for managing acute and chronic inflammatory diseases.
Mitral valve replacement in the presence of severe pulmonary hypertension.
Authors: T K Kaul, W H Bain, J V Jones, A R Lorimer, R M Thomson, M A Turner, A Escarous
Journal: Thorax (1976)

Thirty patients with severe preoperative pulmonary hypertension (pulmonary artery pressure range 90-165 mmHg, mean 118 mmHg) were reviewed following single mitral valve replacement, with prosthetic valves, within the last 10 years (1964-74). The early and late mortality for this group was no different from that of the total series of mitral valve replacements performed over the same period. Marked postoperative clinical improvement was accompanied by corresponding radiological and electrocardiographic changes. In addition there was a statistically highly significant haemodynamic improvement in the 21 survivors (mean survival time 5 1/2 years). At recatheterization the mean pulmonary artery pressure was 41-5%, the mean wedge pressure 46-3%, and the transpulmonary gradient (PAm-LAm) 36-1% of the preoperative values. It is concluded that gross pulmonary hypertension is not per se a contraindication to mitral valve replacement surgery.
Identification of the Nephropathy-Susceptibility Locus HIVAN4
Authors: Sindhuri Prakash, Natalia Papeta, Roel Sterken, Zongyu Zheng, Robert L. Thomas, Zhenzhen Wu, John R. Sedor, Vivette D. D′Agati, Leslie A. Bruggeman, Ali G. Gharavi
Journal: Journal of the American Society of Nephrology (2011)

HIVAN1, HIVAN2, and HIVAN3 are nephropathy-susceptibility loci previously identified in the HIV-1 transgenic mouse, a model of collapsing glomerulopathy. The HIVAN1 and HIVAN2 loci modulate expression of Nphs2, which encodes podocin and several other podocyte-expressed genes. To identify additional loci predisposing to nephropathy, we performed a genome-wide scan in 165 backcross mice generated between the nephropathy-sensitive HIV-1-transgenic FVB/NJ (TgFVB) strain and the resistant Balb/cJ (BALB) strain. We identified a major susceptibility locus (HIVAN4) on chromosome 6 G3-F3, with BALB alleles conferring a twofold reduction in severity (peak LOD score = 4.0). Similar to HIVAN1 and HIVAN2, HIVAN4 modulated expression of Nphs2, indicating a common pathway underlying these loci. We independently confirmed the HIVAN4 locus in a sister TgFVB colony that experienced a dramatic loss of nephropathy subsequent to a breeding bottleneck. In this low-penetrance line, 3% of the genome was admixed with BALB alleles, suggesting a remote contamination event. The admixture localized to discrete segments on chromosome 2 and at the HIVAN4 locus. HIVAN4 candidate genes include killer lectin-like receptor genes as well as A2m and Ptpro, whose gene products are enriched in the glomerulus and interact with HIV-1 proteins. In summary, these data identify HIVAN4 as a major quantitative trait locus for nephropathy and a transregulator of Nphs2. Furthermore, similar selective breeding strategies may help identify further susceptibility loci.
Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo
Authors: Patric Glynn, Hassan Musa, Xiangqiong Wu, Sathya D. Unudurthi, Sean Little, Lan Qian, Patrick J. Wright, Przemyslaw B. Radwanski, Sandor Gyorke, Peter J. Mohler, Thomas J. Hund
Journal: Circulation (2015)

Voltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown.To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload.Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.
Mechanism of Norepinephrine Depletion in Experimental Heart Failure Produced by Aortic Constriction in the Guinea Pig
Authors: JAMES F. SPANN, CHARLES A. CHIDSEY, PETER E. POOL, EUGENE BRAUNWALD
Journal: Circulation Research (1965)

The present study was undertaken to evaluate the influence of heart failure on the cardiac stores of norepinephrine, and to elucidate the mechanisms responsible for the changes observed. Congestive heart failure was produced in the guinea pig by supravalvular aortic constriction. Significant reductions in both the concentration and content of norepinephrine in the ventricles were observed, the magnitude of changes being related to the severity of the constriction. The renal concentration of norepinephrine was not usually affected. Infusions of large quantities of norepinephrine produced elevations of ventricular norepinephrine concentrations which were significantly less in guinea pigs with heart failure than in normal animals. Injections of lesser quantities of radioactive norepinephrine also resulted in smaller amounts of this material in the hearts of animals with failure. Measurement of the decay of specific activity indicated that heart failure did not alter the net turnover of norepinephrine in the left ventricle. From these findings it has been concluded that a defect in the uptake and/or retention of norepinephrine exists in these hearts and that this defect may be responsible for the depletion of norepinephrine.
Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events
Authors: E Lozano, M Segarra, M Corbera-Bellalta, A García-Martínez, G Espígol-Frigolé, A Plà-Campo, J Hernández-Rodríguez, M C Cid
Journal: Annals of the Rheumatic Diseases (2009)

Objective: Approximately 15–20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications. Methods: Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ET A R and ET B R) messenger RNA were measured by real-time quantitative reverse transcriptase–PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot. Results: ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ET A R and ET B R/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1β, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032). Conclusions: The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.
Assessment of the patient, health system, and population effects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach
Authors: Ivor Langley, Hsien-Ho Lin, Saidi Egwaga, Basra Doulla, Chu-Chang Ku, Megan Murray, Ted Cohen, S Bertel Squire
Journal: The Lancet Global Health (2014)

BackgroundSeveral promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm.MethodsWe used an integrated model to assess the effects of different algorithms of Xpert MTB/RIF and light-emitting diode (LED) fluorescence microscopy in Tanzania. To understand the effects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the effects and cost-effectiveness of different diagnostic options.FindingsAmong the diagnostic options considered, we identified three strategies as cost effective in Tanzania. Full scale-up of Xpert would have the greatest population-level effect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36·9 million over 10 years. The incremental cost-effectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104–265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fluorescence microscopy is the next most effective strategy with an ICER of $45 (95% CrI 25–74), followed by LED fluorescence microscopy with an ICER of $29 (6–59). Compared with same-day LED fluorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a follow-on test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania.InterpretationFor Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-effective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation.FundingUnited States Agency for International Development.
PhyloFacts: an online structural phylogenomic encyclopedia for protein functional and structural classification.
Authors: Nandini Krishnamurthy, Duncan P Brown, Dan Kirshner, Kimmen Sjölander
Journal: Genome biology (2006)

Abstract The Berkeley Phylogenomics Group presents PhyloFacts, a structural phylogenomic encyclopedia containing almost 10,000 'books' for protein families and domains, with pre-calculated structural, functional and evolutionary analyses. PhyloFacts enables biologists to avoid the systematic errors associated with function prediction by homology through the integration of a variety of experimental data and bioinformatics methods in an evolutionary framework. Users can submit sequences for classification to families and functional subfamilies. PhyloFacts is available as a worldwide web resource from http://phylogenomics.berkeley.edu/phylofacts .
Activation of Murine Double Minute 2 by Akt in Mammary Epithelium Delays Mammary Involution and Accelerates Mammary Tumorigenesis
Authors: Xiaoyun Cheng, Weiya Xia, Jer-Yen Yang, Jennifer L. Hsu, Jing-Yu Lang, Chao-Kai Chou, Yi Du, Hui-Lung Sun, Shannon L. Wyszomierski, Gordon B. Mills, William J. Muller, Dihua Yu, Mien-Chie Hung
Journal: Cancer Research (2010)

Amplification or overexpression of murine double minute 2 (MDM2) promotes a variety of human tumors by degrading tumor suppressor proteins such as p53. Phosphorylation of MDM2 on Ser(166) and Ser(186) by the survival kinase Akt inhibits p53-mediated apoptosis. However, it is unclear whether this pathway contributes to normal or malignant pathophysiology in vivo. To address these questions, we generated transgenic mice expressing the Akt-phosphorylated form of MDM2 (MDM2DDS166D/S186D) in the mammary epithelium. Activation of MDM2 delayed mammary gland involution and accelerated tumor progression in mouse mammary tumor virus/neu transgenic mice by inhibiting apoptosis in a manner associated with decreased p53 expression. Our findings offer in vivo evidence that activation of MDM2 by Akt contributes to mammary development and tumorigenesis.
822-1 Oral sirolimus to inhibit-recurrent in-stent stenosis: The randomized, double-blind, placebo-controlled OSIRIS trial
Authors: Jörg Hausleiter, Adnan Kastrati, Julinda Mehilli, Helmut Schühlen, Franz Dotzer, Christoph Goos, Gisela Pogatsa-Murray, Michael Vogeser, Martin Breuer, Josef Dirschinger, Albert Schömig
Journal: Journal of the American College of Cardiology (2004)