tbuckley/cabot-search huggingface dataset:
Genomic Evidence for Adaptive Inversion Clines in<i>Drosophila melanogaster</i>
Authors: Martin Kapun, Daniel K. Fabian, Jérôme Goudet, Thomas Flatt
Journal: Molecular Biology and Evolution (2016)

Clines in chromosomal inversion polymorphisms-presumably driven by climatic gradients-are common but there is surprisingly little evidence for selection acting on them. Here we address this long-standing issue in Drosophila melanogaster by using diagnostic single nucleotide polymorphism (SNP) markers to estimate inversion frequencies from 28 whole-genome Pool-seq samples collected from 10 populations along the North American east coast. Inversions In(3L)P, In(3R)Mo, and In(3R)Payne showed clear latitudinal clines, and for In(2L)t, In(2R)NS, and In(3R)Payne the steepness of the clinal slopes changed between summer and fall. Consistent with an effect of seasonality on inversion frequencies, we detected small but stable seasonal fluctuations of In(2R)NS and In(3R)Payne in a temperate Pennsylvanian population over 4 years. In support of spatially varying selection, we observed that the cline in In(3R)Payne has remained stable for >40 years and that the frequencies of In(2L)t and In(3R)Payne are strongly correlated with climatic factors that vary latitudinally, independent of population structure. To test whether these patterns are adaptive, we compared the amount of genetic differentiation of inversions versus neutral SNPs and found that the clines in In(2L)t and In(3R)Payne are maintained nonneutrally and independent of admixture. We also identified numerous clinal inversion-associated SNPs, many of which exhibit parallel differentiation along the Australian cline and reside in genes known to affect fitness-related traits. Together, our results provide strong evidence that inversion clines are maintained by spatially-and perhaps also temporally-varying selection. We interpret our data in light of current hypotheses about how inversions are established and maintained.
Characteristics and Outcome Of Acute Myeloid Leukemia Following Breast Cancer: Analysis Of 408 Cases and Controls
Authors: Marine Gilabert, Jean-Baptiste Micol, Austin G Kulasekararaj, Stephane de Botton, Claude Chahine, Benjamin Esterni, Ghulam J. Mufti, Norbert Vey, Thomas Prebet
Journal: Blood (2013)
Giant air-inflated hydatid cyst of the lung mimicking massive pneumothorax
Authors: Dania Nachira, Marco Chiappetta, Maria Teresa Congedo, Maria Letizia Vita, Stefano Margaritora
Journal: Thorax (2016)

A 68-year-old Caucasian man was admitted to our emergency department with a 6-month history of progressive dyspnoea, tachycardia, chronic cough and purulent sputum production. The patient's medical history was notable for hepatic echinococcosis diagnosed in 2002.

Physical examination revealed no chest wall movement, a hyper-resonant sound on percussion, absent tactile fremitus and no audible breath sound in the right hemithorax. A slight tracheal deviation towards the left could also be felt on palpation …
A phase III, randomized, controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with ofatumumab for previously treated chronic lymphocytic leukemia (CLL).
Authors: Ian Flinn, Eva Kimby, Finbarr E. Cotter, Francis J. Giles, Ann Janssens, Elisa Jacobsen Pulczynski, Loic Ysebeart, Andrzej Pluta, Jose Antonio Garcia Marco, Kerry Taylor, Carolyn Owen, David Michael Johnson, Maria Aiello, Roger D. Dansey, Ronald L. Dubowy, Jeffrey Alan Jones
Journal: Journal of Clinical Oncology (2013)

TPS7131 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Ofatumumab (O) is an anti-CD20 monoclonal antibody approved for the treatment of pts with CLL refractory to fludarabine and alemtuzumab. Phase 1 studies demonstrated that idelalisib, as monotherapy or combined with O, is highly active in pts with heavily pretreated CLL: pts experienced profound and rapid regression of lymphadenopathy, reductions in disease-associated chemokines, and durable clinical benefit with an acceptable safety profile (Furman et al, 2012). Methods: This study will enroll 210 pts with CLL previously treated with a purine analog and/or bendamustine, with measurable lymphadenopathy who require treatment for CLL and have disease that is not refractory to ofatumumab, and are expected to benefit from a change in therapy because of CLL progression &lt;24 months since completion of their last prior treatment. Pts are randomized in a 2:1 ratio (Arm A:Arm B). In Arm A, pts receive idelalisib at 150 mg BID continuously in combination with 12 infusions of O at 1000 mg over ~24 weeks (weekly x 8 then monthly x 4). In Arm B, pts receive 12 infusions of O at 2,000 mg over ~24 weeks. Stratification factors address IGHV mutational status, del(17p)/p53 mutation status, and refractory vs relapsed disease. The primary study endpoint is PFS. Secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012. Clinical trial information: NCT01659021.
Let us be careful with the evidence on mentalizing, cognitive biases, and religious beliefs
Authors: Marjaana Lindeman, Annika M. Svedholm-Häkkinen
Journal: Behavioral and Brain Sciences (2016)

Norenzayan et al.'s theoretical synthesis is highly plausible and commendable. However, the empirical evidence for the arguments on mentalizing, cognitive biases, and religious belief is currently not as strong as the writers suggest. Although certainly abundant and compelling, this evidence is indirect, contradictory, and weak and must be acknowledged as such. More direct studies are needed to support the theory.
Variability of Insulin Requirements Over 12 Weeks of Closed-Loop Insulin Delivery in Adults With Type 1 Diabetes
Authors: Yue Ruan, Hood Thabit, Lalantha Leelarathna, Sara Hartnell, Malgorzata E. Willinska, Sibylle Dellweg, Carsten Benesch, Julia K. Mader, Manuel Holzer, Harald Kojzar, Mark L. Evans, Thomas R. Pieber, Sabine Arnolds, Roman Hovorka
Journal: Diabetes Care (2016)

OBJECTIVE To quantify variability of insulin requirements during closed-loop insulin delivery. RESEARCH DESIGN AND METHODS We retrospectively analyzed overnight, daytime, and total daily insulin amounts delivered during a multicenter closed-loop trial involving 32 adults with type 1 diabetes. Participants applied hybrid day-and-night closed-loop insulin delivery under free-living home conditions over 12 weeks. The coefficient of variation was adopted to measure variability of insulin requirements in individual subjects. RESULTS Data were analyzed from 1,918 nights, 1,883 daytime periods and 1,564 total days characterized by closed-loop use over 85% of time. Variability of overnight insulin requirements (mean [SD] coefficient of variation 31% [4]) was nearly twice as high as variability of total daily requirements (17% [3], P &amp;lt; 0.001) and was also higher than variability of daytime insulin requirements (22% [4], P &amp;lt; 0.001). CONCLUSIONS Overnight insulin requirements were significantly more variable than daytime and total daily amounts. This may explain why some people with type 1 diabetes report frustrating variability in morning glycemia.
Abstract 9262: Physical Activity, Nutritional Status and the Risk of Normal-weight Obesity in the US Population
Authors: Karine Sahakyan, Virend K Somers, Juan P Rodriguez-Escudero, Ray W Squires, Thomas G Allison, Randal J Thomas, Ondrej Sochor, Prachi Singh, Francisco Lopez-Jimenez
Journal: Circulation (2012)

Purpose: Subjects with normal weight obesity (NWO), defined as normal BMI but high body fat (BF)%, are at increased cardiovascular risk. Factors contributing to NWO are not well studied. We hypothesized that NWO is associated with reduced physical activity and unhealthy eating patterns. Methods: We analyzed 5942 people ≥18 years with normal BMI (18.5-24.9 kg/m 2 ) from the NHANES III survey (1988-1994), a representative sample of the US population. Subjects were classified as NWO based on BF% (&gt;35% in women and &gt;25% in men). Leisure-time physical activity was measured with a standard survey. Subjects were stratified as INACTIVE (no physical activity reported), ACTIVE (3-6 METs for ≥ 5 times/week or &gt;6 METs, ≥3 times/week), or insufficiently active (those who were not INACTIVE but did not meet criteria for ACTIVE). Total activity was expressed in METs/hr/month, assuming an exercise duration of 30 minutes for each day reported. A Healthy Eating Index was based on 24-hour dietary recall data. Analyses were weighted for the complex study design. Results: Mean age was 43 years, 54.4% were men; 1170 people (19.7%) with normal BMI had NWO. Table shows demographics, physical activity and nutritional habits by group. After controlling for age, gender, poverty levels, smoking status and Healthy Eating Index, METs/hr/month was an independent predictor of NWO (OR per 100 MET/hours/month is 0.72(95%CI 0.60;0.88). People who were inactive and insufficiently active had higher odds of NWO as compared with active people (OR-1.47; 95%CI 1.10;1.96 and OR-1.60, 95% CI 1.25; 2.05, respectively). Also, strength training was independently associated with a decreased odds of NWO (0.63; 95%CI 0.44;0.89). Dietary pattern was not predictive of NWO. Conclusions: Physical activity, particularly resistance exercise, but not diet, was associated with NWO independently of potential confounders. Promoting physical activity may be an important interventional strategy in these patients.
Heat Shock Protein 27 modulate mesothelial and epithelial to mesenchymal transition (EMT)
Authors: Guillaume Wettstein, Pierre-Simon Bellaye, Martin Gleave, Martin Kolb, Carmen Garrido, Philippe Camus, Philippe Bonniaud
Journal: European Respiratory Journal (2011)

Introduction: Pulmonary fibrosis (PF) has currently no treatment. We have shown that adenoviral gene transfer of TGF-β1 (AdTGF-β1) to the pleura induces a severe pleural fibrosis that invades the parenchyma. In this process, mesothelial cells differentiate into myofibroblastes (α-SMA positive cells) through an EMT-like process suggesting a key role of mesothelial cells in PF. Heat Shock Protein 27 (HSP27), is a chaperon for actin. Its role in fibrogenesis is unknown.

Methods: Sprague Dawley rats received intrapleural injection of AdTGF-β1 or AdDL (empty vector). Mesothelial Met-5A and A549 cells were treated with rTGF-β1.

Results: in vitro: 1) mesothelial cells are susceptible to rTGF-β1 induced EMT 2) HSP27 is strongly linked to α-SMA during EMT (colocalisation and co-immunoprecipitation). 3) HSP27 overexpression induces an EMT and siRNA mediated HSP27 inhibition blocks TGF-β1 induced EMT and mesothelial cell migration 4) HSP27 modulates the TGF-β1/SMAD pathway. Data were reproduced in A549 epithelial cells.

In vivo: 7 days after AdTGF-β1 injection, HSP27 and α-SMA are overexpressed and colocalize in fibrotic sub-pleura areas. AdTGF-β1 rats treated by intrapleural injections of OGX427 (AntiSens Oligonucleotide, ASO, directed against HSP27) have a strong decrease in HPS27, α-SMA expression, mesothelial cells migration into the parenchyma and fibrosis compare to AdTGF-β1 rats treated with control ASO.

Conclusion: HSP27 plays a major role in EMT and could be a key target to inhibit EMT in PF and others diseases involving EMT.

This work is supported by:

– the EU, 7th FP, HEALTH-F2-2007-202224 eurIPFnet

– La “Recherche en sante Respiratoire” et la Societe de Pneumologie de Langue Francaise
Functional screen identifies regulators of murine hematopoietic stem cell repopulation
Authors: Per Holmfeldt, Miguel Ganuza, Himangi Marathe, Bing He, Trent Hall, Guolian Kang, Joseph Moen, Jennifer Pardieck, Angelica C. Saulsberry, Alba Cico, Ludovic Gaut, Daniel McGoldrick, David Finkelstein, Kai Tan, Shannon McKinney-Freeman
Journal: The Journal of Experimental Medicine (2016)

Understanding the molecular regulation of hematopoietic stem and progenitor cell (HSPC) engraftment is paramount to improving transplant outcomes. To discover novel regulators of HSPC repopulation, we transplanted &amp;gt;1,300 mice with shRNA-transduced HSPCs within 24 h of isolation and transduction to focus on detecting genes regulating repopulation. We identified 17 regulators of HSPC repopulation: Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp521. Knockdown of each of these genes yielded a loss of function, except in the cases of Armcx1 and Gprasp2, whose loss enhanced hematopoietic stem cell (HSC) repopulation. The discovery of multiple genes regulating vesicular trafficking, cell surface receptor turnover, and secretion of extracellular matrix components suggests active cross talk between HSCs and the niche and that HSCs may actively condition the niche to promote engraftment. We validated that Foxa3 is required for HSC repopulating activity, as Foxa3−/− HSC fails to repopulate ablated hosts efficiently, implicating for the first time Foxa genes as regulators of HSPCs. We further show that Foxa3 likely regulates the HSC response to hematologic stress. Each gene discovered here offers a window into the novel processes that regulate stable HSPC engraftment into an ablated host.
Reward-Guided Learning with and without Causal Attribution
Authors: Gerhard Jocham, Kay H. Brodersen, Alexandra O. Constantinescu, Martin C. Kahn, Angela M. Ianni, Mark E. Walton, Matthew F.S. Rushworth, Timothy E.J. Behrens
Journal: Neuron (2016)

When an organism receives a reward, it is crucial to know which of many candidate actions caused this reward. However, recent work suggests that learning is possible even when this most fundamental assumption is not met. We used novel reward-guided learning paradigms in two fMRI studies to show that humans deploy separable learning mechanisms that operate in parallel. While behavior was dominated by precise contingent learning, it also revealed hallmarks of noncontingent learning strategies. These learning mechanisms were separable behaviorally and neurally. Lateral orbitofrontal cortex supported contingent learning and reflected contingencies between outcomes and their causal choices. Amygdala responses around reward times related to statistical patterns of learning. Time-based heuristic mechanisms were related to activity in sensorimotor corticostriatal circuitry. Our data point to the existence of several learning mechanisms in the human brain, of which only one relies on applying known rules about the causal structure of the task.
Comparison between different colon cleansing products for screening colonoscopy. A noninferiority trial in population-based screening programs in Italy
Authors: Manuel Zorzi, Flavio Valiante, Bastianello Germanà, Gianluca Baldassarre, Bartolomea Coria, Michela Rinaldi, Helena Heras Salvat, Alessandra Carta, Francesco Bortoluzzi, Erica Cervellin, Maria Polo, Gianmarco Bulighin, Maurizio Azzurro, Daniele Di Piramo, Anna Turrin, Fabio Monica
Journal: Endoscopy (2016)

<b>Background and study aims:</b> The high volume and poor palatability of 4 L of polyethylene glycol (PEG)-based bowel cleansing preparation required before a colonoscopy represent a major obstacle for patients. The aim of this study was to compare two low volume PEG-based preparations with standard 4 L PEG in individuals with a positive fecal immunochemical test (FIT) within organized screening programs in Italy. <b>Patients and methods:</b> A total of 3660 patients with a positive FIT result were randomized to receive, in a split-dose regimen, 4 L PEG or 2 L PEG plus ascorbate (PEG-A) or 2 L PEG with citrate and simethicone plus bisacodyl (PEG-CS). The noninferiority of the low volume preparations vs. 4 L PEG was tested through the difference in proportions of adequate cleansing. <b>Results:</b> A total of 2802 patients were included in the study. Adequate bowel cleansing was achieved in 868 of 926 cases (93.7 %) in the 4 L PEG group, in 872 out of 911 cases in the PEG-A group (95.7 %, difference in proportions + 1.9 %, 95 % confidence interval [CI] – 0.1 to 3.9), and in 862 out of 921 cases in the PEG-CS group (93.6 %, difference in proportions – 0.2 %, 95 %CI – 2.4 to 2.0). Bowel cleansing was adequate in 95.5 % of cases when the preparation-to-colonoscopy interval was between 120 and 239 minutes, whereas it dropped to 83.3 % with longer intervals. Better cleansing was observed in patients with regular bowel movements (95.6 %) compared with those with diarrhea (92.4 %) or constipation (90.8 %). <b>Conclusion:</b> Low volume PEG-based preparations administered in a split-dose regimen guarantee noninferior bowel cleansing compared with 4 L PEG. Constipated patients require a personalized preparation. Trial registration: EudraCT 2012 – 003958 – 82.
Outcomes After Unrelated Cord Blood Transplantation For Adults With Primary Or Secondary Myelofibrosis: A Retrospective Study On Behalf Of Eurocord and Chronic Malignancy Working Party-EBMT
Authors: Marie Robin, Federica Giannotti, Eric Deconinck, Mohamad Mohty, Mauricette Michallet, Guillermo Sanz, Patrice Chevallier, Jean-Yves Cahn, Faezeh Legrand, Montserrat Rovira, Jakob Passweg, Jan J Cornelissen, Jorge Sierra, Stephanie Nguyen, Natacha Maillard, Ibrahim Yakoub-Agha, Werner Linkesch, Paul Cannell, Magda Marcatti, Jacques-Olivier Bay, Vanderson Rocha, Nicolaus Kröger, Eliane Gluckman, Eduardo Olavarria, Annalisa Ruggeri
Journal: Blood (2013)
Interleukin-12 Preserves the Graft-Versus-Leukemia Effect of Allogeneic CD8 T Cells While Inhibiting CD4-Dependent Graft-Versus-Host Disease in Mice
Authors: Yong-Guang Yang, Justin J. Sergio, Denise A. Pearson, Gregory L. Szot, Akira Shimizu, Megan Sykes
Journal: Blood (1997)
Original Article : Prediction of compensated Liver cirrhosis by ultrasonography and routine blood tests in patients with chronic viral hepatitis
Authors: Hong Sub Lee, Jai Keun Kim, Jae Youn Cheong, Eun Jin Han, So Yeon An, Jun Ha Song, Yun Jung Jung, Sung Chan Jeon, Min Wook Jung, Eun Jung Jang, Sung Won Cho
Journal: Clinical and Molecular Hepatology (2010)

Background/Aims: Liver biopsy is a standard method for diagnosis of liver cirrhosis in patients with chronic hepatitis. Because liver biopsy is an invasive method, non-invasive methods have been used for diagnosis of compensated liver cirrhosis in patients with chronic hepatitis. The current study was designed to evaluate the usefulness of ultrasonography and routine blood tests for diagnosis of compensated liver cirrhosis in patients with chronic viral hepatitis. Methods: Two hundred three patients with chronic viral hepatitis who underwent liver biopsy were included in this study and ultrasonography and routine blood tests were analyzed retrospectively. Ultrasonographic findings, including surface nodularity, parenchyma echogenecity, and spleen size, were evaluated. The diagnostic accuracy of ultrasonography and routine blood tests were examined. Results: Discriminant analysis with forward stepwise selection of variables showed that liver surface nodularity, platelet count, and albumin level were independently associated with compensated liver cirrhosis (p 95% specificity: platelet count  1.3; and surface nodularity. If at least one of the four variables exists in a patient with chronic viral hepatitis, we can predict liver cirrhosis with 90% specificity and 61% sensitivity. Conclusions: These results suggest that four variables (platelet count  1.3, and surface nodularity) can be used for identification of liver cirrhosis in patients with chronic viral hepatitis with high specificity. (Korean J Hepatol 2010;16:369-375)
Abstract P297: A Pathway Analysis of 32 Genetic Variants in Leukotriene Genes and Subclinical Atherosclerosis in American Indians: The Strong Heart Family Study
Authors: Jingyun Yang, Shelley Cole, Karin Haack, Ying Zhang, Barbara V Howard, Lyle G Best, Mary J Roman, Richard B Devereux, Elisa T Lee, Jinying Zhao
Journal: Circulation (2012)

Background: Atherosclerosis is an inflammatory disease involving the joint contribution of multiple genetic polymorphisms. Leukotrienes are inflammatory mediators and genetic polymorphisms in key leukotriene genes have been associated with atherosclerotic cardiovascular disease (CVD). While each genetic variant may have only a minor effect on disease risk, their joint contribution to the occurrence of disease may be larger. Objective: To examine the joint impact of 32 SNPs in key leukotriene genes on subclinical CVD assessed by carotid plaque score using a pathway-based approach. Methods: We genotyped 32 tagSNPs in three genes (ALOX5, ALOX5AP and LTA4H) encoding key enzymes for leukotriene production in 3,665 American Indians recruited by the Strong Heart Family Study from Oklahoma (OK), South/North Dakota (DK) and Arizona (AZ). Subclinical atherosclerosis was assessed by carotid plaque score using ultrasound. We conducted a pathway-based analysis to evaluate the joint impact of these 32 SNPs on atherosclerotic plaque score, adjusting for classical cardiovascular risk factors, including age, sex, body mass index (BMI), cigarette smoking status (current, former vs. never), alcohol intake (current, former vs. never), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), blood pressure, diabetes, levels of physical activity, fibrinogen, and renal function (assessed by estimated glomerular filtration rate, eGFR). To avoid population substructure, all statistical analyses were stratified by study center (OK, AZ, and DK). Multiple testing was adjusted using the Bonferroni correction. Results: Multiple SNPs showed individual marginal association with carotid plaque score, but only one (rs2660880 in LTA4H gene in OK, P=0.001) passed adjustment for multiple testing. However, a genetic pathway analysis demonstrated that the leukotriene pathway as a whole in consideration of the joint contribution of all 32 SNPs was significantly associated with carotid plaque score in participants from OK (P=0.002) and DK (P=0.012), but not those from AZ. Conclusion: Genetic variants in the leukotriene pathway jointly contribute to subclinical atherosclerosis in American Indians. Our results could potentially lead to novel molecular strategies for the prevention and treatment of cardiovascular disease.