tbuckley/cabot-search huggingface dataset:
A High-Definition View of Functional Genetic Variation from Natural Yeast Genomes
Authors: Anders Bergström, Jared T. Simpson, Francisco Salinas, Benjamin Barré, Leopold Parts, Amin Zia, Alex N. Nguyen Ba, Alan M. Moses, Edward J. Louis, Ville Mustonen, Jonas Warringer, Richard Durbin, Gianni Liti
Journal: Molecular Biology and Evolution (2014)

The question of how genetic variation in a population influences phenotypic variation and evolution is of major importance in modern biology.Yet much is still unknown about the relative functional importance of different forms of genome variation and how they are shaped by evolutionary processes.Here we address these questions by population level sequencing of 42 strains from the budding yeast Saccharomyces cerevisiae and its closest relative S. paradoxus.We find that genome content variation, in the form of presence or absence as well as copy number of genetic material, is higher within S. cerevisiae than within S. paradoxus, despite genetic distances as measured in single-nucleotide polymorphisms being vastly smaller within the former species.This genome content variation, as well as loss-of-function variation in the form of premature stop codons and frameshifting indels, is heavily enriched in the subtelomeres, strongly reinforcing the relevance of these regions to functional evolution.Genes affected by these likely functional forms of variation are enriched for functions mediating interaction with the external environment (sugar transport and metabolism, flocculation, metal transport, and metabolism).Our results and analyses provide a comprehensive view of genomic diversity in budding yeast and expose surprising and pronounced differences between the variation within S. cerevisiae and that within S. paradoxus.We also believe that the sequence data and de novo assemblies will constitute a useful resource for further evolutionary and population genomics studies.
Type of stress ulcer prophylaxis and risk of nosocomial pneumonia in cardiac surgical patients: cohort study
Authors: B. T. Bateman, K. Bykov, N. K. Choudhry, S. Schneeweiss, J. J. Gagne, J. M. Polinski, J. M. Franklin, M. Doherty, M. A. Fischer, J. A. Rassen
Journal: BMJ (2013)

<b>Objective</b> To examine mortality in a representative nationwide sample of homeless and marginally housed people living in shelters, rooming houses, and hotels. <b>Design</b> Follow-up study. <b>Setting</b> Canada 1991-2001. <b>Participants</b> 15 100 homeless and marginally housed people enumerated in 1991 census. <b>Main outcome measures</b> Age specific and age standardised mortality rates, remaining life expectancies at age 25, and probabilities of survival from age 25 to 75. Data were compared with data from the poorest and richest income fifths as well as with data for the entire cohort <b>Results</b> Of the homeless and marginally housed people, 3280 died. Mortality rates among these people were substantially higher than rates in the poorest income fifth, with the highest rate ratios seen at younger ages. Among those who were homeless or marginally housed, the probability of survival to age 75 was 32% (95% confidence interval 30% to 34%) in men and 60% (56% to 63%) in women. Remaining life expectancy at age 25 was 42 years (42 to 43) and 52 years (50 to 53), respectively. Compared with the entire cohort, mortality rate ratios for men and women, respectively, were 11.5 (8.8 to 15.0) and 9.2 (5.5 to 15.2) for drug related deaths, 6.4 (5.3 to 7.7) and 8.2 (5.0 to 13.4) for alcohol related deaths, 4.8 (3.9 to 5.9) and 3.8 (2.7 to 5.4) for mental disorders, and 2.3 (1.8 to 3.1) and 5.6 (3.2 to 9.6) for suicide. For both sexes, the largest differences in mortality rates were for smoking related diseases, ischaemic heart disease, and respiratory diseases. <b>Conclusions</b> Living in shelters, rooming houses, and hotels is associated with much higher mortality than expected on the basis of low income alone. Reducing the excessively high rates of premature mortality in this population would require interventions to address deaths related to smoking, alcohol, and drugs, and mental disorders and suicide, among other causes.
Mouse Models Address Key Concerns Regarding Autophagy Inhibition in Cancer Therapy
Authors: Ravi Amaravadi, Jayanta Debnath
Journal: Cancer Discovery (2014)

Abstract Summary: With multiple clinical trials under way targeting autophagy against cancer, Yang and colleagues and Karsli-Uzunbas and colleagues address important concerns regarding autophagy inhibition in patients with cancer, using genetically engineered mouse models that more accurately represent the tumor biology found in human patients with pancreatic and lung cancers. Cancer Discov; 4(8); 873–5. ©2014 AACR. See related article by Yang et al., p. 905 See related article by Karsli-Uzunbas et al., p. 914
Outcome of paediatric domiciliary mask ventilation in neuromuscular and skeletal disease
Authors: A.K. Simonds, S. Ward, S. Heather, A Bush, F Muntoni
Journal: European Respiratory Journal (2000)

Noninvasive positive pressure ventilation delivered by nasal mask or facemask has been used widely in the last decade to manage chronic ventilatory failure in adults with neuromuscular and chest wall disease. However, it has been thought that paediatric patients would not be able to tolerate masks, and previous anecdotal reports on the paediatric application of mask ventilation have not assessed the effects on nocturnal and arterial blood gas control. Domiciliary mask ventilation has been used in 40 children with ventilatory insufficiency due to congenital neuromuscular and skeletal disease aged 9 months-16 yrs. Eighteen patients had symptomatic nocturnal hypoventilation, 17 had diurnal ventilatory failure, three were referred for weaning and two had frequent chest infections associated with sleep-disordered breathing. Thirty eight of the 40 patients tolerated mask ventilatory support long-term. Diurnal mean+/-SD oxygen tension in arterial blood (Pa,O2) increased from 8.5+/-1.8-10.9+/-1.7 kPa (p<0.001) and mean carbon dioxide tension in arterial blood (Pa,CO2) fell from 7.0+/-1.6-5.9+/-0.8 kPa (p=0.01) following initiation of ventilatory support. Mean and minimum nocturnal Pa,O2 and peak transcutaneous carbon dioxide tension (Ptc,CO2) (n=21) improved significantly. Mask ventilation can be used successfully in young children and reverses ventilatory insufficiency due to congenital neuromuscular and skeletal disease.
Ultrastructural and Functional Remodeling of the Coupling Between Ca <sup>2+</sup> Influx and Sarcoplasmic Reticulum Ca <sup>2+</sup> Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation
Authors: Ilse Lenaerts, Virginie Bito, Frank R. Heinzel, Ronald B. Driesen, Patricia Holemans, Jan D'hooge, Hein Heidbüchel, Karin R. Sipido, Rik Willems
Journal: Circulation Research (2009)

Rationale : Persistent atrial fibrillation (AF) has been associated with structural and electric remodeling and reduced contractile function. Objective : To unravel mechanisms underlying reduced sarcoplasmic reticulum (SR) Ca 2+ release in persistent AF. Methods : We studied cell shortening, membrane currents, and [Ca 2+ ] i in right atrial myocytes isolated from sheep with persistent AF (duration 129±39 days, N=16), compared to matched control animals (N=21). T-tubule density, ryanodine receptor (RyR) distribution, and local [Ca 2+ ] i transients were examined in confocal imaging. Results : Myocyte shortening and underlying [Ca 2+ ] i transients were profoundly reduced in AF (by 54.8% and 62%, P &lt;0.01). This reduced cell shortening could be corrected by increasing [Ca 2+ ] i . SR Ca 2+ content was not different. Calculated fractional SR Ca 2+ release was reduced in AF (by 20.6%, P &lt;0.05). Peak Ca 2+ current density was modestly decreased (by 23.9%, P &lt;0.01). T-tubules were present in the control atrial myocytes at low density and strongly reduced in AF (by 45%, P &lt;0.01), whereas the regular distribution of RyR was unchanged. Synchrony of SR Ca 2+ release in AF was significantly reduced with increased areas of delayed Ca 2+ release. Propagation between RyR was unaffected but Ca 2+ release at subsarcolemmal sites was reduced. Rate of Ca 2+ extrusion by Na + /Ca 2+ exchanger was increased. Conclusions : In persistent AF, reduced SR Ca 2+ release despite preserved SR Ca 2+ content is a major factor in contractile dysfunction. Fewer Ca 2+ channel–RyR couplings and reduced efficiency of the coupling at subsarcolemmal sites, possibly related to increased Na + /Ca 2+ exchanger, underlie the reduction in Ca 2+ release.
Myocardial Failure in Experimental Hypothermia
Authors: THOMAS A. LOMBARDO, LEO R. RADIGAN, ANDREW G. MORROW
Journal: Circulation Research (1957)

Hypothermic animals subjected to total venous inflow occlusion and open cardiotomy develop elevations in right atrial mean pressure and postmortem evidences of myocardial failure. Acetyl strophanthidin, given before inflow stasis, prevented myocardial failure and increased survival. Myocardial failure was attributed to anoxia resulting from decreased coronary blood flow and alterations in the oxygen content of the blood supplying the myocardium. Perfusion of the coronary system with small quantities of oxygenated blood obtained from donor animals permitted open cardiotomy with survival.
The evolution of misbelief
Authors: Ryan T. McKay, Daniel C. Dennett
Journal: Behavioral and Brain Sciences (2009)

From an evolutionary standpoint, a default presumption is that true beliefs are adaptive and misbeliefs maladaptive. But if humans are biologically engineered to appraise the world accurately and to form true beliefs, how are we to explain the routine exceptions to this rule? How can we account for mistaken beliefs, bizarre delusions, and instances of self-deception? We explore this question in some detail. We begin by articulating a distinction between two general types of misbelief: those resulting from a breakdown in the normal functioning of the belief formation system (e.g., delusions) and those arising in the normal course of that system's operations (e.g., beliefs based on incomplete or inaccurate information). The former are instances of biological dysfunction or pathology, reflecting "culpable" limitations of evolutionary design. Although the latter category includes undesirable (but tolerable) by-products of "forgivably" limited design, our quarry is a contentious subclass of this category: misbeliefs best conceived as design features. Such misbeliefs, unlike occasional lucky falsehoods, would have been systematically adaptive in the evolutionary past. Such misbeliefs, furthermore, would not be reducible to judicious - but doxastically noncommittal - action policies. Finally, such misbeliefs would have been adaptive in themselves, constituting more than mere by-products of adaptively biased misbelief-producing systems. We explore a range of potential candidates for evolved misbelief, and conclude that, of those surveyed, only positive illusions meet our criteria.
Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview
Authors: Daniela Tardito, Jorge Perez, Ettore Tiraboschi, Laura Musazzi, Giorgio Racagni, Maurizio Popoli
Journal: Pharmacological Reviews (2006)

Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.
Endoscopic Corticosteroid Injections Do Not Reduce Dysphagia After Endoscopic Dilation Therapy in Patients With Benign Esophagogastric Anastomotic Strictures
Authors: Meike M.C. Hirdes, Jeanin E. van Hooft, Jan J. Koornstra, Robin Timmer, Max Leenders, Rinse K. Weersma, Bas L.A.M. Weusten, Richard van Hillegersberg, Mark I. van Berge Henegouwen, John T.M. Plukker, Renee Wiezer, Jaques G.H.M. Bergman, Frank P. Vleggaar, Paul Fockens, Peter D. Siersema
Journal: Clinical Gastroenterology and Hepatology (2013)
Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
Authors: Michael Kloth, Vanessa Ruesseler, Christoph Engel, Katharina Koenig, Martin Peifer, Erika Mariotti, Helen Kuenstlinger, Alexandra Florin, Ursula Rommerscheidt-Fuss, Ulrike Koitzsch, Claudia Wodtke, Frank Ueckeroth, Stefanie Holzapfel, Stefan Aretz, Peter Propping, Markus Loeffler, Sabine Merkelbach-Bruse, Margarete Odenthal, Nicolaus Friedrichs, Lukas Carl Heukamp, Thomas Zander, Reinhard Buettner
Journal: Gut (2015)

Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) MSI CRC.Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2-directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown.Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms (p=0.008). Characterisation of BRAF(wt) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors.We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.
Commentary: Evidence to Guide Gun Violence Prevention in America
Authors: Daniel W. Webster
Journal: Annual Review of Public Health (2015)

Gun violence is a major threat to the public's health and safety in the United States. The articles in this volume's symposium on gun violence reveal the scope of the problem and new trends in mortality rates from gunfire. Leading scholars synthesize research evidence that demonstrates the ability of numerous policies and programs-each consistent with lessons learned from successful efforts to combat public health problems-to prevent gun violence. Each approach presents challenges to successful implementation. Future research should inform efforts to assess which approaches are most effective and how to implement evidence-based interventions most effectively.
Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart
Authors: J. Meyer-Kirchrath, M. Martin, C. Schooss, C. Jacoby, U. Flogel, A. Marzoll, J. W. Fischer, J. Schrader, K. Schror, T. Hohlfeld
Journal: Cardiovascular Research (2008)

AimsProstaglandin E2 (PGE2) has been shown to mediate anti-ischaemic effects and cardiomyocyte hypertrophy and there is evidence for an involvement of the prostaglandin EP3-receptor subtype. This study focuses on the EP3-mediated hypertrophic action and investigates intracellular signalling pathways of the EP3-receptor subtype in the murine heart.
Antineutrophil antibodies associated with ulcerative colitis interact with the antigen(s) during the process of apoptosis
Authors: J Mallolas
Journal: Gut (2000)

Cell death by apoptosis seems to be an important mechanism for translocation to the cell surface of a variety of intracellular components capable of inducing autoantibody production.To identify the cellular location of antigen (Ag)-antineutrophil cytoplasmic antibodies (ANCA) in non-apoptotic human neutrophils, and to assess if ANCA associated with ulcerative colitis reacts with neutrophil antigen(s) during neutrophil apoptosis. The cellular distribution of Ag-ANCA in apoptotic neutrophils was also investigated.Sera from 18 ulcerative colitis patients known to be positive for perinuclear IgG-ANCA (titre > or =1/320), as assessed by indirect immunofluorescence (IIF), were analysed by immunofluorescent confocal laser scanning microscopy. ANCA were identified with fluorescein isothiocyanate (FITC) and tetramethylrhodamine isothiocyanate (TRITC) in non-apoptotic and apoptotic neutrophils, respectively. Apoptotic and non-apoptotic DNA was labelled with FITC and propidium iodide, respectively. Cycloheximide was added to polymorphonuclear leucocyte culture to induce apoptosis.Three patterns of scanning laser immunofluorescence microscopy in non-apoptotic neutrophils were observed with respect to cellular ulcerative colitis associated ANCA distribution: (1) diffuse nuclear localisation (16.7%); (2) nuclear localisation in the nuclear periphery (50%); and (3) mixed nuclear and cytoplasmic localisation (33.4%). In all sera ANCA fluorescence colocalised almost completely with apoptotic DNA, with persistence of a diffuse and intense fluorescence. No significant changes in ANCA titres were found in non-apoptotic neutrophils.The antigen(s) of ANCA associated with ulcerative colitis seems to be localised in most cases in the neutrophil nucleus. The almost identical colocalisation of ANCA and apoptotic cleaved DNA suggests that intracellular DNA redistribution during neutrophil apoptosis may play a role in antigen exposure to the immune system and ANCA production in ulcerative colitis.
Fractional Flow Reserve–Guided Versus Angiography-Guided Coronary Artery Bypass Graft Surgery
Authors: Gabor Toth, Bernard De Bruyne, Filip Casselman, Frederic De Vroey, Stylianos Pyxaras, Luigi Di Serafino, Frank Van Praet, Carlos Van Mieghem, Bernard Stockman, William Wijns, Ivan Degrieck, Emanuele Barbato
Journal: Circulation (2013)

Fractional flow reserve (FFR) is well established for patients undergoing percutaneous coronary intervention, yet little is known about candidates for coronary artery bypass graft surgery.From 2006 to 2010, we retrospectively included in this registry 627 consecutive patients treated by coronary artery bypass graft surgery having at least 1 angiographically intermediate stenosis. In 429 patients, coronary artery bypass graft surgery was based solely on angiography (angiography-guided group). In 198 patients, at least 1 intermediate stenosis was grafted with an FFR ≤0.80 or deferred with an FFR >0.80 (FFR-guided group). The end point was major adverse cardiovascular events at 3 years, defined as the composite of overall death, myocardial infarction, and target vessel revascularization. The rate of angiographic multivessel disease was similar in the angiography-guided and FFR-guided groups (404 [94.2%] versus 186 [93.9%]; P=0.722). In the FFR-guided group, this was significantly downgraded after FFR measurements to 86.4% (P<0.001 versus before FFR) and was associated with a smaller number of anastomoses (3 [2-3] versus 3 [2-4]; P<0.001) and rate of on-pump surgery (49% versus 69%; P<0.001). At 3 years, major adverse cardiovascular events were not different between the angiography-guided and FFR-guided groups (12% versus 11%; hazard ratio, 1.030; 95% confidence interval, 0.627-1.692; P=0.908). However, the FFR-guided group compared with the angiography-guided group presented a significantly lower rate of angina (Canadian Cardiovascular Society class II-IV, 31% versus 47%; P<0.001).FFR-guided coronary artery bypass graft surgery was associated with a lower number of graft anastomoses and a lower rate of on-pump surgery compared with angiography-guided coronary artery bypass graft surgery. This did not result in a higher event rate during up to 36 months of follow-up and was associated with a lower rate of angina.
Treatment of Esophageal Atresia With a Short Proximal Esophageal Segment
Authors: Alfred A. de Lorimier
Journal: JAMA (1966)

ESOPHAGEAL atresia occurs once in approximately every 4,000 births. Because this anomaly is uncommon, few medical centers have had sufficient experience to make a reliable analysis of the results of operative treatment. The Surgical Section of the American Academy of Pediatrics recently surveyed the results obtained from observation of 916 patients who had esophageal atresia with tracheoesophageal fistulas to the distal esophageal segments. 1 In the retropleural and transpleural approaches to the esophageal anastomosis there was no difference in the incidence of anastomotic leakage. However, when the anastomosis leaks into the retropleural space, infection is confined, extensive empyema is prevented, and the survival rate (60% vs 37%) is considerably higher than in the transpleural approach (Fig 1). Furthermore, the overall survival rate is better in retropleural anastomosis without leakage (78% vs 72%).  This study as well as others have shown that premature infants have a poorer survival rate than full-term
Ambulatory oxygen in idiopathic pulmonary fibrosis: of what benefit?: Table 1–
Authors: Rebecca C. Frank, Sophie Hicks, Annette M. Duck, Lisa Spencer, Colm T. Leonard, Emma Barnett
Journal: European Respiratory Journal (2012)

To the Editors:

We read with interest the Letter by Visca et al. [1], recently published in the European Respiratory Journal , which described improvement in 6-min walk distance with ambulatory oxygen in patients with interstitial lung disease (ILD). We have looked specifically at the effects of ambulatory oxygen on walk distance in patients with idiopathic pulmonary fibrosis (IPF), and here describe a practical way of ensuring patients are prescribed an optimum flow rate of ambulatory oxygen.

Between 2004 and 2007, we conducted a retrospective review of anonymised data, studying the effect of ambulatory oxygen on the distance walked in patients with IPF …