Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Effects of conversion of native cerrado vegetation to pasture on soil hydro-physical properties, evapotranspiration and streamflow on the Amazonian agricultural frontier

Understanding the impacts of land-use change on landscape-hydrological dynamics is one of the main challenges in the Northern Brazilian Cerrado biome, where the Amazon agricultural frontier is located. Motivated by the gap in literature assessing these impacts, we characterized the soil hydro-physical properties and quantified surface water fluxes from catchments under contrasting land-use in this region. We used data from field measurements in two headwater micro-catchments with similar physical characteristics and different land use, i.e. cerrado sensu stricto vegetation and pasture for extensive cattle ranching. We determined hydraulic and physical properties of the soils, applied ground-based remote sensing techniques to estimate evapotranspiration, and monitored streamflow from October 2012 to September 2014. Our results show significant differences in soil hydro-physical properties between the catchments, with greater bulk density and smaller total porosity in the pasture catchment. We found that evapotranspiration is smaller in the pasture (639 ± 31% mm yr-1) than in the cerrado catchment (1,004 ± 24% mm yr-1), and that streamflow from the pasture catchment is greater with runoff coefficients of 0.40 for the pasture and 0.27 for the cerrado catchment. Overall, our results confirm that conversion of cerrado vegetation to pasture causes soil hydro-physical properties deterioration, reduction in evapotranspiration reduction, and increased streamflow

Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection

: The urgency to find complementary therapies to current SARS-CoV-2 vaccines, whose effectiveness is preserved over time and not compromised by the emergence of new and emerging variants, has become a critical health challenge. We investigate the possibility of jamming the opening of the Receptor Binding Domain (RBD) of the spike protein of SARS-CoV-2 with small compounds. Through in silico screening, we identified two potential candidates that would lock the Receptor Binding Domain (RBD) in a closed configuration, preventing the virus from infecting the host cells. We show that two drugs already approved by the FDA, mithramycin and dihydroergotamine, can block infection using concentrations in the μM range in cell-based assays. Further STD-NMR experiments support dihydroergotamine's direct interaction with the spike protein. Overall, our results indicate that repurposing of these compounds might lead to potential clinical drug candidates for the treatment of SARS-CoV-2 infection

Motives and comprehension in a public goods game with induced emotions

This study analyses the sensitivity of public goods contributions through the lens of psychological motives. We report the results of a public goods experiment in which subjects were induced with the motives of care and anger through autobiographical recall. Subjects' preferences, beliefs, and perceptions under each motive are compared with those of subjects experiencing a neutral autobiographical recall control condition. We find, but only for those subjects with the highest comprehension of the game, that care elicits significantly higher contributions than anger, with the control treatment in between. This positive influence of the care motive on unconditional giving is accounted for partly by preferences for giving and partly by the beliefs concerning greater contributions by others. Anger also affects attention to own and other's payoffs (using mouse tracking) and perceptions of the game's incentive structure (cooperative or competitive)

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

Sporadic ALS is not associated with VAPB gene mutations in Southern Italy

Mutations in the Cu/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to investigate the entire coding region of this gene in SALS patients. One hundred twenty-five unrelated patients with adult-onset ALS and 150 healthy sex-age-matched subjects with the same genetic background were analyzed. Genetic analysis for all exons of the VAPB gene by DHPLC revealed 5 variant profiles in 83 out of 125 SALS patients. Direct sequencing of these PCR products revealed 3 nucleotide substitutions. Two of these were found within intron 3 of the gene, harbouring 4 variant DHPLC profiles. The third nucleotide variation (Asp130Glu) was the only substitution present in the coding region of the VAPB gene, and it occurred within exon 4. It was found in three patients out of 125. The frequency of the detected exon variation in the VAPB gene was not significantly different between patients and controls. In conclusion, our study suggests that VAPB mutations are not a common cause of adult-onset SALS

Cardiac Alterations in Human African Trypanosomiasis (T.b. gambiense) with Respect to the Disease Stage and Antiparasitic Treatment

In Human African Trypanosomiasis (HAT), neurological symptoms dominate and cardiac involvement has been suggested. Because of increasing resistance to the available drugs for HAT, new compounds are desperately needed. Evaluation of cardiotoxicity is one parameter of drug safety, but without knowledge of the baseline heart involvement in HAT, cardiologic findings and drug-induced alterations will be difficult to interpret. The electrocardiogram (ECG) is a tool to evaluate cardiac involvement and the risk of arrythmias. We analysed the ECG of 465 HAT patients and compared them with the ECG of 61 healthy volunteers. In HAT patients the QTc interval was prolonged. This comprises a risk of fatal arrhythmias if new drugs with antiarrhythmic potential will be used. Further, repolarization changes and low voltage were more frequent than in healthy controls. This could be explained by an inflammation of the heart. Treatment of HAT was associated with appearance of repolarization changes but not with a QTc prolongation. These changes appear to be associated with the disease, but not with a specific drug. The main conclusion of this study is that heart involvement is frequent in HAT and mostly well tolerated. However, it can become relevant, if new compounds with antiarrhythmic potential will be used

A simple clinical model for planning transfusion quantities in heart surgery

<p>Abstract</p> <p>Background</p> <p>Patients undergoing heart surgery continue to be the largest demand on blood transfusions. The need for transfusion is based on the risk of complications due to poor cell oxygenation, however large transfusions are associated with increased morbidity and risk of mortality in heart surgery patients. The aim of this study was to identify preoperative and intraoperative risk factors for transfusion and create a reliable model for planning transfusion quantities in heart surgery procedures.</p> <p>Methods</p> <p>We performed an observational study on 3315 consecutive patients who underwent cardiac surgery between January 2000 and December 2007. To estimate the number of packs of red blood cells (PRBC) transfused during heart surgery, we developed a multivariate regression model with discrete coefficients by selecting dummy variables as regressors in a stepwise manner. Model performance was assessed statistically by splitting cases into training and testing sets of the same size, and clinically by investigating the clinical course details of about one quarter of the patients in whom the difference between model estimates and actual number of PRBC transfused was higher than the root mean squared error.</p> <p>Results</p> <p>Ten preoperative and intraoperative dichotomous variables were entered in the model. Approximating the regression coefficients to the nearest half unit, each dummy regressor equal to one gave a number of half PRBC. The model assigned 4 units for kidney failure requiring preoperative dialysis, 2.5 units for cardiogenic shock, 2 units for minimum hematocrit at cardiopulmonary bypass less than or equal to 20%, 1.5 units for emergency operation, 1 unit for preoperative hematocrit less than or equal to 40%, cardiopulmonary bypass time greater than 130 minutes and type of surgery different from isolated artery bypass grafting, and 0.5 units for urgent operation, age over 70 years and systemic arterial hypertension.</p> <p>Conclusions</p> <p>The regression model proved reliable for quantitative planning of number of PRBC in patients undergoing heart surgery. Besides enabling more rational resource allocation of costly blood-conservation strategies and blood bank resources, the results indicated a strong association between some essential postoperative variables and differences between the model estimate and the actual number of packs transfused.</p

Indirect exclusion of four candidate genes for generalized progressive retinal atrophy in several breeds of dogs

BACKGROUND: Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina (ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs. RESULTS: Mutation screening was performed initially by PCR and single strand conformation polymorphism (SSCP) analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4, CX36, MERTK and RDH12 in 71 affected dogs of 29 breeds. Yet 30 new sequence variations were identified, both, in the coding regions and intronic sequences. Many of the sequence variations were in heterozygous state in affected dogs. CONCLUSION: Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK (for all 29 breeds) and RDH12 (for 9 breeds)

Cell Surface Sialylation and Fucosylation Are Regulated by L1 via Phospholipase Cγ and Cooperate to Modulate Neurite Outgrowth, Cell Survival and Migration

BACKGROUND: Cell surface glycosylation patterns are markers of cell type and status. However, the mechanisms regulating surface glycosylation patterns remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using a panel of carbohydrate surface markers, we have shown that cell surface sialylation and fucosylation were downregulated in L1(-/y) neurons versus L1(+/y) neurons. Consistently, mRNA levels of sialyltransferase ST6Gal1, and fucosyltransferase FUT9 were significantly reduced in L1(-/y) neurons. Moreover, treatment of L1(+/y) neurons with L1 antibodies, triggering signal transduction downstream of L1, led to an increase in cell surface sialylation and fucosylation compared to rat IgG-treated cells. ShRNAs for both ST6Gal1 and FUT9 blocked L1 antibody-mediated enhancement of neurite outgrowth, cell survival and migration. A phospholipase Cgamma (PLCgamma) inhibitor and shRNA, as well as an Erk inhibitor, reduced ST6Gal1 and FUT9 mRNA levels and inhibited effects of L1 on neurite outgrowth and cell survival. CONCLUSIONS: Neuronal surface sialylation and fucosylation are regulated via PLCgamma by L1, modulating neurite outgrowth, cell survival and migration