Evolutionary Dynamics and Emergence of Panzootic H5N1 Influenza Viruses

The highly pathogenic avian influenza (HPAI) H5N1 virus lineage has undergone extensive genetic reassortment with viruses from different sources to produce numerous H5N1 genotypes, and also developed into multiple genetically distinct sublineages in China. From there, the virus has spread to over 60 countries. The ecological success of this virus in diverse species of both poultry and wild birds with frequent introduction to humans suggests that it is a likely source of the next human pandemic. Therefore, the evolutionary and ecological characteristics of its emergence from wild birds into poultry are of considerable interest. Here, we apply the latest analytical techniques to infer the early evolutionary dynamics of H5N1 virus in the population from which it emerged (wild birds and domestic poultry). By estimating the time of most recent common ancestors of each gene segment, we show that the H5N1 prototype virus was likely introduced from wild birds into poultry as a non-reassortant low pathogenic avian influenza H5N1 virus and was not generated by reassortment in poultry. In contrast, more recent H5N1 genotypes were generated locally in aquatic poultry after the prototype virus (A/goose/Guangdong/1/96) introduction occurred, i.e., they were not a result of additional emergence from wild birds. We show that the H5N1 virus was introduced into Indonesia and Vietnam 3–6 months prior to detection of the first outbreaks in those countries. Population dynamics analyses revealed a rapid increase in the genetic diversity of A/goose/Guangdong/1/96 lineage viruses from mid-1999 to early 2000. Our results suggest that the transmission of reassortant viruses through the mixed poultry population in farms and markets in China has selected HPAI H5N1 viruses that are well adapted to multiple hosts and reduced the interspecies transmission barrier of those viruses

Mechanisms Involved in Nicotinic Acetylcholine Receptor-Induced Neurotransmitter Release from Sympathetic Nerve Terminals in the Mouse Vas Deferens

Prejunctional nicotinic acetylcholine receptors (nAChRs) amplify postganglionic sympathetic neurotransmission, and there are indications that intraterminal Ca2+ stores might be involved. However, the mechanisms by which nAChR activation stimulates neurotransmitter release at such junctions is unknown. Rapid local delivery (picospritzing) of the nAChR agonist epibatidine was combined with intracellular sharp microelectrode recording to monitor spontaneous and field-stimulation-evoked neurotransmitter release from sympathetic nerve terminals in the mouse isolated vas deferens. Locally applied epibatidine (1 µM) produced ‘epibatidine-induced depolarisations’ (EIDs) that were similar in shape to spontaneous excitatory junction potentials (SEJPs) and were abolished by nonselective nAChR antagonists and the purinergic desensitizing agonist α,β-methylene ATP. The amplitude distribution of EIDs was only slightly shifted towards lower amplitudes by the selective α7 nAChR antagonists α-bungarotoxin and methyllcaconitine, the voltage-gated Na+ channel blocker tetrodotoxin or by blocking voltage-gated Ca2+ channels with Cd2+. Lowering the extracellular Ca2+ concentration reduced the frequency of EIDs by 69%, but more surprisingly, the Ca2+-induced Ca2+ release blocker ryanodine greatly decreased the amplitude (by 41%) and the frequency of EIDs by 36%. Ryanodine had no effect on electrically-evoked neurotransmitter release, paired-pulse facilitation, SEJP frequency, SEJP amplitude or SEJP amplitude distribution. These results show that activation of non-α7 nAChRs on sympathetic postganglionic nerve terminals induces high-amplitude junctional potentials that are argued to represent multipacketed neurotransmitter release synchronized by intraterminal Ca2+-induced Ca2+ release, triggered by Ca2+ influx directly through the nAChR. This nAChR-induced neurotransmitter release can be targeted pharmacologically without affecting spontaneous or electrically-evoked neurotransmitter release

Functional Analysis of an Acid Adaptive DNA Adenine Methyltransferase from Helicobacter pylori 26695

HP0593 DNA-(N6-adenine)-methyltransferase (HP0593 MTase) is a member of a Type III restriction-modification system in Helicobacter pylori strain 26695. HP0593 MTase has been cloned, overexpressed and purified heterologously in Escherichia coli. The recognition sequence of the purified MTase was determined as 5′-GCAG-3′and the site of methylation was found to be adenine. The activity of HP0593 MTase was found to be optimal at pH 5.5. This is a unique property in context of natural adaptation of H. pylori in its acidic niche. Dot-blot assay using antibodies that react specifically with DNA containing m6A modification confirmed that HP0593 MTase is an adenine-specific MTase. HP0593 MTase occurred as both monomer and dimer in solution as determined by gel-filtration chromatography and chemical-crosslinking studies. The nonlinear dependence of methylation activity on enzyme concentration indicated that more than one molecule of enzyme was required for its activity. Analysis of initial velocity with AdoMet as a substrate showed that two molecules of AdoMet bind to HP0593 MTase, which is the first example in case of Type III MTases. Interestingly, metal ion cofactors such as Co2+, Mn2+, and also Mg2+ stimulated the HP0593 MTase activity. Preincubation and isotope partitioning analyses clearly indicated that HP0593 MTase-DNA complex is catalytically competent, and suggested that DNA binds to the MTase first followed by AdoMet. HP0593 MTase shows a distributive mechanism of methylation on DNA having more than one recognition site. Considering the occurrence of GCAG sequence in the potential promoter regions of physiologically important genes in H. pylori, our results provide impetus for exploring the role of this DNA MTase in the cellular processes of H. pylori

Genome Wide Analysis of Inbred Mouse Lines Identifies a Locus Containing Ppar-γ as Contributing to Enhanced Malaria Survival

The genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. We have used a mouse model to detect genes involved in the resistance or susceptibility to Plasmodium berghei malaria infection. To this end we first characterized 32 different mouse strains infected with P. berghei and identified survival as the best trait to discriminate between the strains. We found a locus on chromosome 6 by linking the survival phenotypes of the mouse strains to their genetic variations using genome wide analyses such as haplotype associated mapping and the efficient mixed-model for association. This new locus involved in malaria resistance contains only two genes and confirms the importance of Ppar-γ in malaria infection

Importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study

ABSTRACT: Background: Since mobility and social participation are key determinants of health and quality of life, it is important to identify factors associated with them. Although several investigations have been conducted on the neighborhood environment, mobility and social participation, there is no clear integration of the results. This study aimed to provide a comprehensive understanding regarding how the neighborhood environment is associated with mobility and social participation in older adults.Methods: A rigorous methodological scoping study framework was used to search nine databases from different fields with fifty-one keywords. Data were exhaustively analyzed, organized and synthesized according to the International Classification of Functioning, Disability and Health (ICF) by two research assistants following PRISMA guidelines, and results were validated with knowledge users.Results: The majority of the 50 selected articles report results of cross-sectional studies (29; 58 %), mainly conducted in the US (24; 48 %) or Canada (15; 30 %). Studies mostly focused on neighborhood environment associations with mobility (39; 78 %), social participation (19; 38 %), and occasionally both (11; 22 %). Neighborhood attributes considered were mainly 'Pro ducts and technology' (43; 86) and 'Services, systems and policies' (37; 74 %), but also 'Natural and human- made changes' (27; 54 %) and 'Support and relationships' (21; 42 %). Mobility and social participation were both positively associated with Proximity to resources and recreational facilities, Social support, Having a car or driver's license, Public transportation and Neighborhood security, and negatively associated with Poor user-friendliness of the walking environment and Neighborhood insecurity. Attributes of the neighborhood environment not covered by previous research on mobility and social participation mainly concerned 'Attitudes', and 'Services, systems and policies'.Conclusion: Results from this comprehensive synthesis of empirical studies on associations of the neighborhood environment with mobility and social participation will ultimately support best practices, decisions and the development of innovative inclusive public health interventions including clear guidelines for the creation of age-supportive environments. To foster mobility and social participation, these interventions must consider Proximity to resources and to recreational facilities, Social support, Transportation, Neighborhood security and User-friendliness of the walking environment. Future studies should include both mobility and social participation, and investigate how they are associated with 'Attitudes', and 'Services, systems and policies' in older adults, including disadvantaged older adults

Standard perioperative management in gastrointestinal surgery

The outcome of patients who are scheduled for gastrointestinal surgery is influenced by various factors, the most important being the age and comorbidities of the patient, the complexity of the surgical procedure and the management of postoperative recovery. To improve patient outcome, close cooperation between surgeons and anaesthesiologists (joint risk assessment) is critical. This cooperation has become increasingly important because more and more patients are being referred to surgery at an advanced age and with multiple comorbidities and because surgical procedures and multimodal treatment modalities are becoming more and more complex. The aim of this review is to provide clinicians with practical recommendations for day-to-day decision-making from a joint surgical and anaesthesiological point of view. The discussion centres on gastrointestinal surgery specifically

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Pemphigus autoimmunity: Hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients

The future distribution of wetland birds breeding in Europe validated against observed changes in distribution

Wetland bird species have been declining in population size worldwide as climate warming and land-use change affect their suitable habitats. We used species distribution models (SDMs) to predict changes in range dynamics for 64 non-passerine wetland birds breeding in Europe, including range size, position of centroid, and margins. We fitted the SDMs with data collected for the first European Breeding Bird Atlas and climate and land-use data to predict distributional changes over a century (the 1970s-2070s). The predicted annual changes were then compared to observed annual changes in range size and range centroid over a time period of 30 years using data from the second European Breeding Bird Atlas. Our models successfully predicted ca. 75% of the 64 bird species to contract their breeding range in the future, while the remaining species (mostly southerly breeding species) were predicted to expand their breeding ranges northward. The northern margins of southerly species and southern margins of northerly species, both, predicted to shift northward. Predicted changes in range size and shifts in range centroids were broadly positively associated with the observed changes, although some species deviated markedly from the predictions. The predicted average shift in core distributions was ca. 5 km yr(-1) towards the north (5% northeast, 45% north, and 40% northwest), compared to a slower observed average shift of ca. 3.9 km yr(-1). Predicted changes in range centroids were generally larger than observed changes, which suggests that bird distribution changes may lag behind environmental changes leading to 'climate debt'. We suggest that predictions of SDMs should be viewed as qualitative rather than quantitative outcomes, indicating that care should be taken concerning single species. Still, our results highlight the urgent need for management actions such as wetland creation and restoration to improve wetland birds' resilience to the expected environmental changes in the future