A note on the use of the generalized odds ratio in meta-analysis of association studies involving bi- and tri-allelic polymorphisms

<p>Abstract</p> <p>Background</p> <p>The generalized odds ratio (GOR) was recently suggested as a genetic model-free measure for association studies. However, its properties were not extensively investigated. We used Monte Carlo simulations to investigate type-I error rates, power and bias in both effect size and between-study variance estimates of meta-analyses using the GOR as a summary effect, and compared these results to those obtained by usual approaches of model specification. We further applied the GOR in a real meta-analysis of three genome-wide association studies in Alzheimer's disease.</p> <p>Findings</p> <p>For bi-allelic polymorphisms, the GOR performs virtually identical to a standard multiplicative model of analysis (e.g. per-allele odds ratio) for variants acting multiplicatively, but augments slightly the power to detect variants with a dominant mode of action, while reducing the probability to detect recessive variants. Although there were differences among the GOR and usual approaches in terms of bias and type-I error rates, both simulation- and real data-based results provided little indication that these differences will be substantial in practice for meta-analyses involving bi-allelic polymorphisms. However, the use of the GOR may be slightly more powerful for the synthesis of data from tri-allelic variants, particularly when susceptibility alleles are less common in the populations (≤10%). This gain in power may depend on knowledge of the direction of the effects.</p> <p>Conclusions</p> <p>For the synthesis of data from bi-allelic variants, the GOR may be regarded as a multiplicative-like model of analysis. The use of the GOR may be slightly more powerful in the tri-allelic case, particularly when susceptibility alleles are less common in the populations.</p

PI3K-C2 alpha Knockdown Results in Rerouting of Insulin Signaling and Pancreatic Beta Cell Proliferation

Insulin resistance is a syndrome that affects multiple insulin target tissues, each having different biological functions regulated by insulin. A remaining question is to mechanistically explain how an insulin target cell/tissue can be insulin resistant in one biological function and insulin sensitive in another at the same time. Here, we provide evidence that in pancreatic beta cells, knockdown of PI3K-C2 alpha expression results in rerouting of the insulin signal from insulin receptor (IR)-B/PI3K-C2 alpha/PKB-mediated metabolic signaling to IR-B/Shc/ERK-mediated mitogenic signaling, which allows the beta cell to switch from a highly glucose-responsive, differentiated state to a proliferative state. Our data suggest the existence of IR-cascade-selective insulin resistance, which allows rerouting of the insulin signal within the same target cell. Hence, factors involved in the rerouting of the insulin signal represent tentative therapeutic targets in the treatment of insulin resistance.11108Ysciescopu

Gate-Controlled Ionization and Screening of Cobalt Adatoms on a Graphene Surface

We describe scanning tunneling spectroscopy (STS) measurements performed on individual cobalt (Co) atoms deposited onto backgated graphene devices. We find that Co adatoms on graphene can be ionized by either the application of a global backgate voltage or by the application of a local electric field from a scanning tunneling microscope (STM) tip. Large screening clouds are observed to form around Co adatoms ionized in this way, and we observe that some intrinsic graphene defects display a similar behavior. Our results provide new insight into charged impurity scattering in graphene, as well as the possibility of using graphene devices as chemical sensors.Comment: 19 pages, 4 figure

The Burkholderia Cenocepacia OmpA-Like Protein BCAL2958: Identification, Characterization, and Detection of Anti-BCAL2958 Antibodies in Serum from B. Cepacia Complex-Infected Cystic Fibrosis Patients

Respiratory infections by bacteria of the Burkholderia cepacia complex (Bcc) remain an important cause of morbidity and mortality among cystic fibrosis patients, highlighting the need for novel therapeutic strategies. In the present work we have studied the B. cenocepacia protein BCAL2958, a member of the OmpA-like family of proteins, demonstrated as highly immunogenic in other pathogens and capable of eliciting strong host immune responses. The encoding gene was cloned and the protein, produced as a 6× His-tagged derivative, was used to produce polyclonal antibodies. Bioinformatics analyses led to the identification of sequences encoding proteins with a similarity higher than 96 % to BCAL2958 in all the publicly available Bcc genomes. Furthermore, using the antibody it was experimentally demonstrated that this protein is produced by all the 12 analyzed strains from 7 Bcc species. In addition, results are also presented showing the presence of anti-BCAL2958 antibodies in sera from cystic fibrosis patients with a clinical record of respiratory infection by Bcc, and the ability of the purified protein to in vitro stimulate neutrophils. The widespread production of the protein by Bcc members, together with its ability to stimulate the immune system and the detection of circulating antibodies in patients with a documented record of Bcc infection strongly suggest that the protein is a potential candidate for usage in preventive therapies of infections by Bcc

New trends in peptide-based anti-biofilm strategies : a review of recent achievements and bioinformatics approaches

Antimicrobial peptides (AMPs) have a broad spectrum of activity and unspecific mechanisms of action. Therefore, they are seen as valid alternatives to overcome clinically relevant biofilms and reduce the chance of acquired resistance. This paper reviews AMPs and anti-biofilm AMP-based strategies and discusses ongoing and future work. Recent studies report successful AMP-based prophylactic and therapeutic strategies, several databases catalogue AMP information and analysis tools, and novel bioinformatics tools are supporting AMP discovery and design. However, most AMP studies are performed with planktonic cultures, and most studies on sessile cells test AMPs on growing rather than mature biofilms. Promising preliminary synergistic studies have to be consubstantiated and the study of functionalized coatings with AMPs must be further explored. Standardized operating protocols, to enforce the repeatability and reproducibility of AMP anti-biofilm tests, and automated means of screening and processing the ever-expanding literature are still missing.Financial support from IBB-CEB and Fundacao para a Ciencia e Tecnologia (FCT) and European Community fund FEDER, through Program COMPETE, in the ambit of the FCT project 'PTDC/SAU-SAP/113196/2009/ FCOMP-01-0124-FEDER-016012' is gratefully acknowledged

The role of the tyrosine kinase Wzc (Sll0923) and the phosphatase Wzb (Slr0328) in the production of extracellular polymeric substances (EPS) by Synechocystis PCC 6803

Many cyanobacteria produce extracellular polymeric substances (EPS) mainly composed of heteropolysaccharides with unique characteristics that make them suitable for biotechnological applications. However, manipulation/optimization of EPS biosynthesis/characteristics is hindered by a poor understanding of the production pathways and the differences between bacterial species. In this work, genes putatively related to different pathways of cyanobacterial EPS polymerization, assembly, and export were targeted for deletion or truncation in the unicellular Synechocystis sp. PCC 6803. No evident phenotypic changes were observed for some mutants in genes occurring in multiple copies in Synechocystis genome, namely ¿wzy (¿sll0737), ¿wzx (¿sll5049), ¿kpsM (¿slr2107), and ¿kpsM¿wzy (¿slr2107¿sll0737), strongly suggesting functional redundancy. In contrast, ¿wzc (¿sll0923) and ¿wzb (¿slr0328) influenced both the amount and composition of the EPS, establishing that Wzc participates in the production of capsular (CPS) and released (RPS) polysaccharides, and Wzb affects RPS production. The structure of Wzb was solved (2.28 Å), revealing structural differences relative to other phosphatases involved in EPS production and suggesting a different substrate recognition mechanism. In addition, Wzc showed the ATPase and autokinase activities typical of bacterial tyrosine kinases. Most importantly, Wzb was able to dephosphorylate Wzc in vitro, suggesting that tyrosine phosphorylation/dephosphorylation plays a role in cyanobacterial EPS production.Norte Portugal Regional Operational Programme (NORTE 2020), Grant/Award Number: NORTE‐01‐0145‐FE?ER‐000008 and NORTE‐01‐0145‐FE?ER‐000012; FCT ‐ Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Ensino Superior, Grant/Award Number: PTDC/BIA‐ MIC/28779/2017, SFRH/BD /119920/2016, SFRH/B?/84914/2012 and SFRH/BD/99715/ 2014; FEDER ‐ Fundo Europeu de Desen‐ volvimento Regional funds through the COMPETE 2020 ‐ Operational Programme for Competitiveness and Internationalisation (POCI), Grant/Award Number: POCI‐01‐0145‐ FE?ER‐007274 ACKNOWLEDGMENTS: This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020— Operational Programme for Competitiveness and Internationalisation (POCI); projects NORTE‐01‐0145‐FEDER‐000012—Structured Programme on Bioengineering Therapies for Infectious ?iseases and Tissue Regeneration and NORTE‐01‐0145‐FEDER‐000008— Porto Neurosciences and Neurologic Disease Research Initiative at i3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement; and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI‐01‐0145‐FEDER‐007274 and PTDC/BIA‐ MIC/28779/2017) and grants SFRH/BD /119920/2016 (MS), SFRH/ BD /99715/2014 (CF), and SFRH/BD /129921/2017 (JPL). The au‐ thors thank F. Chauvat and the Commissariat à l’Energie Atomique (CEA), Direction des Sciences du Vivant, for providing the cas‐ sette for the deletion of the Synechocystis sll0923, the staff of the European Synchrotron Radiation Facility (Grenoble, France) and SOLEIL (Essonne, France) synchrotrons, Filipe Pinto, Frederico Silva, Hugo Osório, and Joana Furtado for their technical assistance

Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations

The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation

Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders

A whole cell pathway screen reveals seven novel chemosensitizers to combat chloroquine resistant malaria

Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/ chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine