Bax Inhibitor-1 down-regulation in the progression of chronic liver diseases

<p>Abstract</p> <p>Background</p> <p>Bax inhibitor-1 (BI-1) is an evolutionary conserved endoplasmic reticulum protein that, when overexpressed in mammalian cells, suppresses the apoptosis induced by Bax, a pro-apoptotic member of the Bcl-2 family. The aims of this study were: (1) to clarify the role of intrinsic anti- and pro-apoptotic mediators, evaluating Bax and BI-1 mRNA and protein expressions in liver tissues from patients with different degrees of liver damage; (2) to determine whether HCV and HBV infections modulate said expression.</p> <p>Methods</p> <p>We examined 62 patients: 39 with chronic hepatitis (CH) (31 HCV-related and 8 HBV-related); 7 with cirrhosis (6 HCV-related and 1 HBV-related); 13 with hepatocellular carcinoma (HCC) [7 in viral cirrhosis (6 HCV- and 1 HBV-related), 6 in non-viral cirrhosis]; and 3 controls. Bax and BI-1 mRNAs were quantified by real-time PCR, and BI-1 protein expression by Western blot.</p> <p>Results</p> <p>CH tissues expressed significantly higher BI-1 mRNA levels than cirrhotic tissues surrounding HCC (P < 0.0001) or HCC (P < 0.0001). Significantly higher Bax transcripts were observed in HCV-genotype-1-related than in HCV-genotype-3-related CH (P = 0.033). A positive correlation emerged between BI-1 and Bax transcripts in CH tissues, even when HCV-related CH and HCV-genotype-1-related CH were considered alone (P = 0.0007, P = 0.0005 and P = 0.0017, respectively).</p> <p>Conclusions</p> <p>BI-1 expression is down-regulated as liver damage progresses. The high BI-1 mRNAs levels observed in early liver disease may protect virus-infected cells against apoptosis, while their progressive downregulation may facilitate hepatocellular carcinogenesis. HCV genotype seems to have a relevant role in Bax transcript expression.</p

Going Coastal: Shared Evolutionary History between Coastal British Columbia and Southeast Alaska Wolves (Canis lupus)

Many coastal species occupying the temperate rainforests of the Pacific Northwest in North America comprise endemic populations genetically and ecologically distinct from interior continental conspecifics. Morphological variation previously identified among wolf populations resulted in recognition of multiple subspecies of wolves in the Pacific Northwest. Recently, separate genetic studies have identified diverged populations of wolves in coastal British Columbia and coastal Southeast Alaska, providing support for hypotheses of distinct coastal subspecies. These two regions are geographically and ecologically contiguous, however, there is no comprehensive analysis across all wolf populations in this coastal rainforest.By combining mitochondrial DNA datasets from throughout the Pacific Northwest, we examined the genetic relationship between coastal British Columbia and Southeast Alaska wolf populations and compared them with adjacent continental populations. Phylogenetic analysis indicates complete overlap in the genetic diversity of coastal British Columbia and Southeast Alaska wolves, but these populations are distinct from interior continental wolves. Analyses of molecular variation support the separation of all coastal wolves in a group divergent from continental populations, as predicted based on hypothesized subspecies designations. Two novel haplotypes also were uncovered in a newly assayed continental population of interior Alaska wolves.We found evidence that coastal wolves endemic to these temperate rainforests are diverged from neighbouring, interior continental wolves; a finding that necessitates new international strategies associated with the management of this species

Computations of uncertainty mediate acute stress responses in humans

The effects of stress are frequently studied, yet its proximal causes remain unclear. Here we demonstrate that subjective estimates of uncertainty predict the dynamics of subjective and physiological stress responses. Subjects learned a probabilistic mapping between visual stimuli and electric shocks. Salivary cortisol confirmed that our stressor elicited changes in endocrine activity. Using a hierarchical Bayesian learning model, we quantified the relationship between the different forms of subjective task uncertainty and acute stress responses. Subjective stress, pupil diameter and skin conductance all tracked the evolution of irreducible uncertainty. We observed a coupling between emotional and somatic state, with subjective and physiological tuning to uncertainty tightly correlated. Furthermore, the uncertainty tuning of subjective and physiological stress predicted individual task performance, consistent with an adaptive role for stress in learning under uncertain threat. Our finding that stress responses are tuned to environmental uncertainty provides new insight into their generation and likely adaptive function. Copyright The Authors

Polyamide-Scorpion Cyclam Lexitropsins Selectively Bind AT-Rich DNA Independently of the Nature of the Coordinated Metal

Cyclam was attached to 1-, 2- and 3-pyrrole lexitropsins for the first time through a synthetically facile copper-catalyzed “click” reaction. The corresponding copper and zinc complexes were synthesized and characterized. The ligand and its complexes bound AT-rich DNA selectively over GC-rich DNA, and the thermodynamic profile of the binding was evaluated by isothermal titration calorimetry. The metal, encapsulated in a scorpion azamacrocyclic complex, did not affect the binding, which was dominated by the organic tail

Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system

The immune response is essential for keeping an organism healthy and for defending it from different types of pathogens. It is a complex system that consists of a large number of components performing different functions. The adequate and controlled interaction between these components is necessary for a robust and strong immune response. There are, however, many factors that interfere with the way the immune response functions. Stress and ageing now consistently appear in the literature as factors that act upon the immune system in the way that is often damaging. This review focuses on the role of stress and ageing in altering the robustness of the immune response first separately, and then simultaneously, discussing the effects that emerge from their interplay. The special focus is on the psychological stress and the impact that it has at different levels, from the whole system to the individual molecules, resulting in consequences for physical health

Is the Kampala Trauma Score an Effective Predictor of Mortality in Low-Resource Settings? A Comparison of Multiple Trauma Severity Scores

BackgroundIn the developed world, multiple injury severity scores have been used for trauma patient evaluation and study. However, few studies have supported the effectiveness of different trauma scoring methods in the developing world. The Kampala Trauma Score (KTS) was developed for use in resource-limited settings and has been shown to be a robust predictor of death. This study evaluates the ability of KTS to predict the mortality of trauma patients compared to other trauma scoring systems.MethodsData were collected on injured patients presenting to Central Hospital of Yaoundé, Cameroon from April 15 to October 15, 2009. The KTS, Injury Severity Score, Revised Trauma Score, Glasgow Coma Scale, and Trauma Injury Severity Score were calculated for each patient. Scores were evaluated as predictors of mortality using logistic regression models. Areas under receiver operating characteristic (ROC) curves were compared.ResultsAltogether, 2855 patients were evaluated with a mortality rate of 6 per 1000. Each score analyzed was a statistically significant predictor of mortality. The area under the ROC for KTS as a predictor of mortality was 0.7748 (95% CI 0.6285-0.9212). There were no statistically significant pairwise differences between ROC areas of KTS and other scores. Similar results were found when the analysis was limited to severe injuries.ConclusionsThis comparison of KTS to other trauma scores supports the adoption of KTS for injury surveillance and triage in resource-limited settings. We show that the KTS is as effective as other scoring systems for predicting patient mortality

Modern tests of Lorentz invariance

Motivated by ideas about quantum gravity, a tremendous amount of effort over the past decade has gone into testing Lorentz invariance in various regimes. This review summarizes both the theoretical frameworks for tests of Lorentz invariance and experimental advances that have made new high precision tests possible. The current constraints on Lorentz violating effects from both terrestrial experiments and astrophysical observations are presented.Comment: Modified and expanded discussions of various points. Numerous references added. Version matches that accepted by Living Reviews in Relativit

El desafío de la administración adecuada de antimicrobianos en pediatría.

Background: Antibiotics are among the drugs most commonly prescribed to children in hospitals and communities. Unfortunately, a great number of these prescriptions are unnecessary or inappropriate. Antibiotic abuse and misuse have several negative consequences, including drug-related adverse events, the emergence of multidrug resistant bacterial pathogens, the development of Clostridium difficile infection, the negative impact on microbiota, and undertreatment risks. In this paper, the principle of and strategies for paediatric antimicrobial stewardship (AS) programs, the effects of AS interventions and the common barriers to development and implementation of AS programs are discussed. Discussion: Over the last few years, there have been significant shortages in the development and availability of new antibiotics; therefore, the implementation of strategies to preserve the activity of existing antimicrobial agents has become an urgent public health priority. AS is one such approach. The need for formal AS programs in paediatrics was officially recognized only recently, considering the widespread use of antibiotics in children and the different antimicrobial resistance patterns that these subjects exhibit in comparison to adult and elderly patients. However, not all problems related to the implementation of AS programs among paediatric patients are solved. The most important remaining problems involve educating paediatricians, creating a multidisciplinary interprofessional AS team able to prepare guidelines, monitoring antibiotic prescriptions and defining corrective measures, and the availability of administrative consensuses with adequate financial support. Additionally, the problem of optimizing the duration of AS programs remains unsolved. Further studies are needed to solve the above mentioned problems. Conclusions: In paediatric patients, as in adults, the successful implementation of AS strategies has had a significant impact on reducing targeted- and nontargeted-antimicrobial use by improving the quality of care for hospitalized patients and preventing the emergence of resistance. Considering that rationalization of antibiotic misuse and abuse is the basis for reducing emergence of bacterial resistance and several clinical problems, all efforts must be made to develop multidisciplinary paediatric AS programs in hospital and community settings