tbuckley/cabot-search huggingface dataset:
Abstract 5138: Structural insights into the dynamic functionality of Bax through molecular dynamics simulations.
Authors: Annette Khaled, Rebecca Boohaker, Craig Finch, Sergio Tafur
Journal: Cancer Research (2013)

Abstract The Bcl-2 protein family modulates the balance between cellular life and death. Bax, a pro-apoptotic member of this family, participates in mitochondria-mediated apoptosis but also supports mitochondrial bioenergetics. In previous work, we showed that a peptide derived from the alpha 9-helix of Bax is cytotoxic, specifically when used to treat breast cancer cells. Such structural and biochemical studies are useful for identifying functional domains within Bax that can be developed into therapeutic peptides, but are limiting when ascribing function to domains at a molecular level. Computational modeling and molecular dynamics simulations of Bax provides a high-power analysis of the subtle changes that modulate the regulatory and effector activities of the protein. This study seeks to elucidate the consequence of alterations in micro-domains that confer activity, apoptotic or otherwise, to the protein. Molecular dynamics simulation was used to determine how the trans-membrane region of Bax conferred stability to the protein, identifying regions of high flexibility and differential exposure. Computationally rotating the Ψ angle at Pro168 altered the position of the α9-helix of Bax, mimicking the “active” and “inactive” forms of Bax. We found that “active” Bax, but not “inactive” Bax, presented a more relaxed structure which altered the conformation and exposure of the BH3 domain, potentially enhancing interactions among the family of Bcl-2 proteins. Since dysregulation of Bcl-2 proteins is implicated in a number of cancers, examining the basic structural dynamics at a molecular level yielded information that can aid in the design novel Bcl-2 family-targeting chemotherapeutics. Citation Format: Annette Khaled, Rebecca Boohaker, Craig Finch, Sergio Tafur. Structural insights into the dynamic functionality of Bax through molecular dynamics simulations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5138. doi:10.1158/1538-7445.AM2013-5138
Methadone Treatment of Heroin Addicts
Authors: Robert G. Newman
Journal: JAMA (1972)

ABSTRACT To the Editor.— The EDITORIAL referring to Dobbs' recent article in the Dec 6, 1971, issue of The Journal (218:1536, 1971) seems to discourage the rapid expansion of methadone maintenance programs. This position is supported by the experience which Dobbs describes. In fact, the article has absolutely no relevance, since his clinic bears little or no resemblance to what is commonly thought of as a methadone facility, and the data presented are without value.Dr. Dobbs explains that the clinic was implemented in response to inadequate detoxification capacity. Clearly, this is not the goal of a maintenance program. Additionally, the dosages shown for many patients are far below the blocking levels used in most programs. Thus, any extrapolation of results from Dobbs' clinic is unjustified.The data itself, as the editors admit, lack the manifestations of statistical sophistication—but to such a degree that the figures presented do not permit
Cardiac Function in Fetuses With Congenital Diaphragmatic Hernia
Authors: Hratch L. Karamanoukian
Journal: JAMA (1994)

<h3>To the Editor.</h3> — We commend Dr Harrison and colleagues<sup>1</sup>for undertaking a thorough study that details the natural history of fetuses with congenital diaphragmatic hernia (CDH). However, it is still impossible to prospectively determine which fetuses or neonates will or will not survive, as only the latter group of patients may be considered for fetal surgical correction of CDH. The major challenge to investigators in this field has been to identify prenatal risk factors in the fetus with CDH that will more accurately predict outcome (and better select candidates for fetal surgery). Although the study by Harrison and colleagues begins to address this challenge, we have several questions. First, subjects enrolled in the study had "isolated CDH" based on "ultrasound studies and karyotypic analysis." Recent studies have suggested that there may be a significant but subtle cardiac disease in CDH, manifested as maldevelopment of the left ventricle.<sup>2</sup>
The Act of Love
Authors: Jack Coulehan
Journal: JAMA (1994)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A reference genome for common bean and genome-wide analysis of dual domestications
Authors: Jeremy Schmutz, Phillip E McClean, Sujan Mamidi, G Albert Wu, Steven B Cannon, Jane Grimwood, Jerry Jenkins, Shengqiang Shu, Qijian Song, Carolina Chavarro, Mirayda Torres-Torres, Valerie Geffroy, Samira Mafi Moghaddam, Dongying Gao, Brian Abernathy, Kerrie Barry, Matthew Blair, Mark A Brick, Mansi Chovatia, Paul Gepts, David M Goodstein, Michael Gonzales, Uffe Hellsten, David L Hyten, Gaofeng Jia, James D Kelly, Dave Kudrna, Rian Lee, Manon M S Richard, Phillip N Miklas, Juan M Osorno, Josiane Rodrigues, Vincent Thareau, Carlos A Urrea, Mei Wang, Yeisoo Yu, Ming Zhang, Rod A Wing, Perry B Cregan, Daniel S Rokhsar, Scott A Jackson
Journal: Nature Genetics (2014)

Scott Jackson, Jeremy Schmutz, Phillip McClean and colleagues report the genome sequence of the common bean (Phaseolus vulgaris) and resequenced wild individuals and landraces from Mesoamerican and Andean gene pools, showing that common bean underwent two independent domestications. Common bean (Phaseolus vulgaris L.) is the most important grain legume for human consumption and has a role in sustainable agriculture owing to its ability to fix atmospheric nitrogen. We assembled 473 Mb of the 587-Mb genome and genetically anchored 98% of this sequence in 11 chromosome-scale pseudomolecules. We compared the genome for the common bean against the soybean genome to find changes in soybean resulting from polyploidy. Using resequencing of 60 wild individuals and 100 landraces from the genetically differentiated Mesoamerican and Andean gene pools, we confirmed 2 independent domestications from genetic pools that diverged before human colonization. Less than 10% of the 74 Mb of sequence putatively involved in domestication was shared by the two domestication events. We identified a set of genes linked with increased leaf and seed size and combined these results with quantitative trait locus data from Mesoamerican cultivars. Genes affected by domestication may be useful for genomics-enabled crop improvement.
Cdc42 is an antihypertrophic molecular switch in the mouse heart
Authors: Marjorie Maillet, Jeffrey M. Lynch, Bastiano Sanna, Allen J. York, Yi Zheng, Jeffery D. Molkentin
Journal: Journal of Clinical Investigation (2009)

To improve contractile function, the myocardium undergoes hypertrophic growth without myocyte proliferation in response to both pathologic and physiologic stimulation. Various membrane-bound receptors and intermediate signal transduction pathways regulate the induction of cardiac hypertrophy, but the cardioprotective regulatory pathways or effectors that antagonize cardiac hypertrophy remain poorly understood. Here we identify the small GTPase Cdc42 as a signaling intermediate that restrained the cardiac growth response to physiologic and pathologic stimuli. Cdc42 was specifically activated in the heart after pressure overload and in cultured cardiomyocytes by multiple agonists. Mice with a heart-specific deletion of Cdc42 developed greater cardiac hypertrophy at 2 and 8 weeks of stimulation and transitioned more quickly into heart failure than did wild-type controls. These mice also displayed greater cardiac hypertrophy in response to neuroendocrine agonist infusion for 2 weeks and, more remarkably, enhanced exercise-induced hypertrophy and sudden death. These pathologies were associated with an inability to activate JNK following stimulation through a MEKK1/MKK4/MKK7 pathway, resulting in greater cardiac nuclear factor of activated T cells (NFAT) activity. Restoration of cardiac JNK signaling with an Mkk7 heart-specific transgene reversed the enhanced growth effect. These results identify what we believe to be a novel antihypertrophic and protective cardiac signaling pathway, whereby Cdc42-dependent JNK activation antagonizes calcineurin-NFAT activity to reduce hypertrophy and prevent transition to heart failure.
In the absence of a CD40 signal, B cells are tolerogenic
Authors: Janet E. Suhlmann, Teresa M. Foy, Alejandro Aruffo, Karen M. Crassi, Jeffrey A. Ledbetter, William R. Green, Jianchao C. Xu, Leonard D. Shultz, Derry Roopeslan, Richard A. Flavell, Loren Fast, Randolph J. Noelle, Fiona H. Durie
Journal: Immunity (1995)

When B cells are deprived of signaling through CD40, they exhibit the ability to induce T cell tolerance. The in vivo administration of anti-gp39 and allogeneic B cells diminished the ability of mice to mount an allogeneic response. Tolerance induction was specific for the haplotype expressed on the allogeneic B cells. Selective allospecific unresponsiveness was induced in the CD8 and CD4 compartments by the administration of anti-gp39 and class II-deficient B cells or class I-deficient B cells, respectively. As predicted by studies with anti-gp39 treatment, diminished allospecific responsiveness was induced by the administration of B cells to mice genetically deficient in gp39. Taken together, these data are consistent with the premise that deprivation of CD40 signaling engenders B cells with enhanced tolerogenicity. These studies provide insights into the tolerogenic capacity of resting B cells and outlines a practical approach to exploit this function.
Molecular Testing for Lymph Node Metastases as a Determinant of Colon Cancer Recurrence: Results from a Retrospective Multicenter Study
Authors: Daniel J. Sargent, Qian Shi, Sharlene Gill, Christophe Louvet, Richard B. Everson, Udo Kellner, Thomas E. Clancy, J. Marc Pipas, Murray B. Resnick, Michael O. Meyers, Tsung-Teh Wu, David Huntsman, Pierre Validire, Umar Farooq, Emily S. Pavey, Guillaume Beaudry, Jean-Francois Haince, Yves Fradet
Journal: Clinical Cancer Research (2014)

Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95% CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77, 95% CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24-5.17, P = 0.011). GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique.
Relationship Between Type of Outflow Tract Repair and Postoperative Right Ventricular Diastolic Physiology in Tetralogy of Fallot
Authors: Gunnar Norgård, Michael A. Gatzoulis, Fernando Moraes, Christopher Lincoln, Darryl F. Shore, Elliot A. Shinebourne, Andrew N. Redington
Journal: Circulation (1996)

Background Restrictive right ventricular (RV) physiology can be present early and late after tetralogy of Fallot repair. It is associated with a complicated early postoperative course but is favorable late after repair because it is associated with less pulmonary regurgitation, better exercise tolerance, and less QRS prolongation and symptomatic ventricular arrhythmias. It is not known, however, whether in the current surgical era, this physiology is present in tetralogy of Fallot patients at mid-term follow-up and whether it is related to the type of RV outflow tract repair. Finally, the impact of this physiology on the early evolution of QRS prolongation has not been examined previously. In this study we attempted to address these issues in a cohort of recently operated patients. Methods and Results Ninety-five patients were studied 4.3 years after repair by Doppler echocardiography, serial electrocardiograms, and chest radiographs. Restrictive RV physiology defined by the presence of antegrade pulmonary artery flow in late diastole was present in 38% of the patients. It was more common in patients with transannular patch (TAP) repair compared with non-TAP repair (50% versus 21%, P &lt;.05). QRS duration at follow-up was 121.2±17.6 and 132.6±11.8 ms in restrictive and nonrestrictive patients with TAP repair, respectively ( P &lt;.02). Conclusions Restrictive RV physiology has been identified at mid-term follow-up in a contemporary surgical series. It is associated with less QRS prolongation, regardless of the technique used for outflow tract repair, and may be associated with fewer long-term complications. Nonrestrictive physiology is associated with the most marked QRS prolongation. This subgroup is most at risk from the late deleterious consequences of chronic pulmonary regurgitation.
Empyema and Legionella bozemanii
Authors: MICHAEL J. STRAMPFER
Journal: Annals of Internal Medicine (1986)

Letters and Corrections1 October 1986Empyema and Legionella bozemaniiMICHAEL J. STRAMPFER, M.D., PAUL E. SCHOCH, Ph.D., SALVATORE SCOMA, M.D., BURKE A. CUNHA, M.D.MICHAEL J. STRAMPFER, M.D., PAUL E. SCHOCH, Ph.D., SALVATORE SCOMA, M.D., BURKE A. CUNHA, M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-105-4-626_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: To date, there have been only 12 detailed reports and 10 culture-proven cases of Legionella bozemanii pneumonia (1, 2). These limited data suggest that the clinical manifestations of L. bozemanii infection are similar to those of L. pneumophila and L. micdadei infection. We report the first case of L. bozemanii empyema, which was successfully treated with doxycycline after erythromycin failed.A 54-year-old obese white woman with leukopenia of undetermined cause was hospitalized with intermittent periods of confusion, fever, chills, dyspnea, cough, and pleuritic chest pain. Examination revealed tachypnea and relative bradycardia. Crackles were heard throughout the right...References1. PARRYSTAMPLEMANHUTCHINSONFOLTASTEINBERGKRASNOGOR MLJDML. Waterborne Legionella bozemanii and nosocomial pneumonia in immunosuppressed patients. Ann Intern Med. 1985;103:205-10. LinkGoogle Scholar2. MITCHELLPASVOLNEWNHAM RGR. Pneumonia due to Legionella bozemanii: first report of a case in Europe. J Infect. 1984;8:251-5. CrossrefMedlineGoogle Scholar3. KIRBYSNYDERMEYER BKR. Legionnaires' disease: report of sixty-five nosocomially acquired cases and review of the literature. Medicine (Baltimore). 1980;59:188-205. CrossrefMedlineGoogle Scholar4. MUDERYuZURAVLEFF RVJ. Pneumonia due to the Pittsburgh pneumonia agent: new clinical perspective with a review of the literature. Medicine (Baltimore). 1983;62:120-8. CrossrefMedlineGoogle Scholar5. PACKERMACHERSHELHAMERBALOWGILLPARRILLO MAJJVJ. Unresponsiveness of Legionella bozemanii pneumonia to erythromycin administration despite in vitro sensitivity. Am Rev Respir Dis. 1983;128:955-6. MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Winthrop-University Hospital Mineola, NY 11501 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByBacterial InfectionsPotential importance of Legionella Species as etiologies in community acquired pneumonia (CAP)Bacterial InfectionsLegionella bozemanii Pneumonia in an Immunocompromised PatientLegionella and Mycoplasma Pneumonia—A Community Hospital Experience with Atypical PneumoniasPneumonias acquired from others 1 October 1986Volume 105, Issue 4Page: 626-626KeywordsBradycardiaDoxycyclineDyspneaErythromycinFeversIschemiaLegionellaOverweightPneumoniaTachypnea Issue Published: 1 October 1986 PDF DownloadLoading ...
Purification and characterization of a novel soluble receptor for interleukin 1.
Authors: J A Symons, J A Eastgate, G W Duff
Journal: The Journal of Experimental Medicine (1991)

Affinity chromatography and reverse-phase high-performance liquid chromatography was used to purify a soluble interleukin 1 beta (IL-1 beta) specific binding protein from the supernatant of a human B cell line, Raji. The purified protein specifically bound 125I IL-1 beta forming a 60-kD complex in nonreducing conditions and a 70-kD complex in reducing conditions. Binding was found to be displaceable by mature human and murine IL-1 beta and human 31-kD IL-1 beta propeptide, but not displaceable by human and murine IL-1 alpha or human IL-1 receptor (IL-1R) antagonist. Ligand blotting revealed a 47-kD molecule that specifically bound IL-1 beta. Measurement of binding affinity of the cell surface Raji IL-1R (Kd = 2.2 nm) and the Raji soluble (s)IL-1R (Kd = 2.7 nm) demonstrated a similar affinity for 125I IL-1 beta. Purified sIL-1R inhibited binding of IL-1 beta to cell lines with both type I (80 kD) and type II (65 kD) IL-1Rs, but did not interfere with IL-1 alpha binding. This natural sIL-1R may function as an important regulatory molecule of IL-1 beta in vivo.
Regulation of AMPA Receptor Gating by Ligand Binding Core Dimers
Authors: Michelle S Horning, Mark L Mayer
Journal: Neuron (2004)

Ionotropic glutamate receptors are tetramers, the isolated ligand binding cores of which assemble as dimers. Previous work on nondesensitizing AMPA receptor mutants, which combined crystallography, ultracentrifugation, and patch-clamp recording, showed that dimer formation by the ligand binding cores is required for activation of ion channel gating by agonists. To define the mechanisms responsible for stabilization of dimer assembly in native AMPA receptors, contacts between the adjacent ligand binding cores were individually targeted by amino acid substitutions, using the GluR2 crystal structure as a guide to design mutants. We show that disruption of a salt bridge, hydrogen bond network, and intermolecular van der Waals contacts between helices D and J in adjacent ligand binding cores greatly accelerates desensitization. Conservation of these contacts in AMPA and kainate receptors indicates that they are important determinants of dimer stability and that the dimer interface is a key structural element in the gating mechanism of these glutamate receptor families.
From the Depths
Authors: James Mann
Journal: JAMA (2006)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Isoniazid Prophylaxis-Reply
Authors: David N. Rose
Journal: JAMA (1987)

<h3>In Reply.—</h3> The study Dr Moulding refers to, from which we derived the risks of isoniazid hepatitis, was the Public Health Service cooperative surveillance study.<sup>1</sup>The investigators found 0.578 deaths per 1000 isoniazid recipients. We calculated the 95% confidence interval to range from 0.2 to 1.0 deaths per 1000 isoniazid recipients. Among other well-documented studies that were sufficiently large to uncover this low risk, the rates vary from 0.1 to 0.9 deaths per 1000 isoniazid recipients.<sup>2-4</sup>Consequently, we used 0.578 deaths per 1000 isoniazid recipients as our best estimate, and used 0.1 and 1.0 deaths per 1000 isoniazid recipients as the low and high estimates in our sensitivity analysis. Even at the high estimate, the decision favors taking isoniazid. Dr Moulding suggests that the tuberculosis case fatality rate may be lower in people compliant enough to have taken isoniazid chemoprophylaxis. To our knowledge, this hypothesis has not been
Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study
Authors: O. Ciani, M. Buyse, R. Garside, T. Pavey, K. Stein, J. A. C. Sterne, R. S. Taylor
Journal: BMJ (2013)

To quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes.
Sub-optimal reasons for rejecting optimality
Authors: David R. Shanks, David Lagnado
Journal: Behavioral and Brain Sciences (2000)

Although we welcome Gigerenzer, Todd, and the ABC Research Group's shift of emphasis from “coherence” to “correspondence” criteria, their rejection of optimality in human decision making is premature: In many situations, experts can achieve near-optimal performance. Moreover, this competence does not require implausible computing power. The models Gigerenzer et al. evaluate fail to account for many of the most robust properties of human decision making, including examples of optimality.