Mechanisms of recognition and binding of α-TTP to the plasma membrane by multi-scale molecular dynamics simulations

We used multiple sets of simulations both at the atomistic and coarse-grained level of resolution to investigate interaction and binding of α-tochoperol transfer protein (α-TTP) to phosphatidylinositol phosphate lipids (PIPs). Our calculations indicate that enrichment of membranes with such lipids facilitate membrane anchoring. Atomistic models suggest that PIP can be incorporated into the binding cavity of α-TTP and therefore confirm that such protein can work as lipid exchanger between the endosome and the plasma membrane. Comparison of the atomistic models of the α-TTP-PIPs complex with membrane-bound α-TTP revealed different roles for the various basic residues composing the basic patch that is key for the protein/ligand interaction. Such residues are of critical importance as several point mutations at their position lead to severe forms of ataxia with vitamin E deficiency (AVED) phenotypes. Specifically, R221 is main residue responsible for the stabilization of the complex. R68 and R192 exchange strong interactions in the protein or in the membrane complex only, suggesting that the two residues alternate contact formation, thus facilitating lipid flipping from the membrane into the protein cavity during the lipid exchange process. Finally, R59 shows weaker interactions with PIPs anyway with a clear preference for specific phosphorylation positions, hinting a role in early membrane selectivity for the protein. Altogether, our simulations reveal significant aspects at the atomistic scale of interactions of α-TTP with the plasma membrane and with PIP, providing clarifications on the mechanism of intracellular vitamin E trafficking and helping establishing the role of key residue for the functionality of α-TTP.

The Osr1 and Osr2 genes act in the pronephric anlage downstream of retinoic acid signaling and upstream of Wnt2b to maintain pectoral fin development.

Vertebrate odd-skipped related genes (Osr) have an essential function during the formation of the intermediate mesoderm (IM) and the kidney structures derived from it. Here, we show that these genes are also crucial for limb bud formation in the adjacent lateral plate mesoderm (LPM). Reduction of zebrafish Osr function impairs fin development by the failure of tbx5a maintenance in the developing pectoral fin bud. Osr morphant embryos show reduced wnt2b expression, and increasing Wnt signaling in Osr morphant embryos partially rescues tbx5a expression. Thus, Osr genes control limb bud development in a non-cell-autonomous manner, probably through the activation of Wnt2b. Finally, we demonstrate that Osr genes are downstream targets of retinoic acid (RA) signaling. Therefore, Osr genes act as a relay within the genetic cascade of fin bud formation: by controlling the expression of the signaling molecule Wnt2ba in the IM they play an essential function transmitting the RA signaling originated in the somites to the LPM.

Toward optimal early management after whiplash injury to lessen the rate of transition to chronicity: discussion paper 5

Expert debate and synthesis of research to inform future management approaches for acute whiplash disorders.

Potential and limitations of organic and fair trade cotton for improving livelihoods of smallholders: evidence from Central Asia

Cotton is a leading agricultural non-food commodity associated with soil degradation, water pollution and pesticide poisoning due to high levels of agrochemical inputs. Organic farming is often promoted as a means of addressing the economic, environmental and health risks of conventional cotton production, and it is slowly gaining ground in the global cotton market. Organic and fair trade cotton are widely seen as opportunities for smallholder farmers to improve their livelihoods thanks to higher returns, lower input costs and fewer risks. Despite an increasing number of studies comparing the profitability of organic and non-organic farming systems in developing and industrialized countries, little has been published on organic farming in Central Asia. The aim of this article is to describe the economic performance and perceived social and environmental impacts of organic cotton in southern Kyrgyzstan, drawing on a comparative field study conducted by the author in 2009. In addition to economic and environmental aspects, the study investigated farmers’ motivations toward and assessment of conversion to organic farming. Cotton yields on organic farms were found to be 10% lower, while input costs per unit were 42% lower; as a result, organic farmers’ cotton revenues were 20% higher. Due to lower input costs as well as organic and fair trade price premiums, the average gross margin from organic cotton was 27% higher. In addition to direct economic benefits, organic farmers enjoy other benefits, such as easy access to credit on favorable terms, provision of uncontaminated cottonseed cooking oil and cottonseed cake as animal feed, and marketing support as well as extension and training services provided by newly established organic service providers. The majority of organic farmers perceive improved soil quality, improved health conditions, and positively assess their initial decision to convert to organic farming. The major disadvantage of organic farming is the high manual labor input required. In the study area, where manual farm work is mainly women's work and male labor migration is widespread, women are most affected by this negative aspect of organic farming. Altogether, the results suggest that, despite the inconvenience of a higher workload, the advantages of organic farming outweigh its disadvantages and that conversion to organic farming improves the livelihoods of small-scale farmers.

Development and remodeling of the vertebrate blood-gas barrier

During vertebrate development, the lung inaugurates as an endodermal bud from the primitive foregut. Dichotomous subdivision of the bud results in arborizing airways that form the prospective gas exchanging chambers, where a thin blood-gas barrier (BGB) is established. In the mammalian lung, this proceeds through conversion of type II cells to type I cells, thinning, and elongation of the cells as well as extrusion of the lamellar bodies. Subsequent diminution of interstitial tissue and apposition of capillaries to the alveolar epithelium establish a thin BGB. In the noncompliant avian lung, attenuation proceeds through cell-cutting processes that result in remarkable thinning of the epithelial layer. A host of morphoregulatory molecules, including transcription factors such as Nkx2.1, GATA, HNF-3, and WNT5a; signaling molecules including FGF, BMP-4, Shh, and TFG- β and extracellular proteins and their receptors have been implicated. During normal physiological function, the BGB may be remodeled in response to alterations in transmural pressures in both blood capillaries and airspaces. Such changes are mitigated through rapid expression of the relevant genes for extracellular matrix proteins and growth factors. While an appreciable amount of information regarding molecular control has been documented in the mammalian lung, very little is available on the avian lung.

Health risk appraisal in older people 2: the implications for clinicians and commissioners of social isolation risk in older people

BACKGROUND: Social isolation is associated with poorer health, and is seen by the World Health Organisation (WHO) as one of the major issues facing the industrialised world. AIM: To explore the significance of social isolation in the older population for GPs and for service commissioners. DESIGN OF STUDY: Secondary analysis of baseline data from a randomised controlled trial of health risk appraisal. SETTING: A total of 2641 community-dwelling, non-disabled people aged 65 years and over in suburban London. METHOD: Demographic details, social network and risk for social isolation based on the 6-item Lubben Social Network Scale, measures of depressed mood, memory problems, numbers of chronic conditions, medication use, functional ability, self-reported use of medical services. RESULTS: More than 15% of the older age group were at risk of social isolation, and this risk increased with advancing age. In bivariate analyses risk of social isolation was associated with older age, education up to 16 years only, depressed mood and impaired memory, perceived fair or poor health, perceived difficulty with both basic and instrumental activities of daily living, diminishing functional ability, and fear of falling. Despite poorer health status, those at risk of social isolation did not appear to make greater use of medical services, nor were they at greater risk of hospital admission. Half of those who scored as at risk of social isolation lived with others. Multivariate analysis showed significant independent associations between risk of social isolation and depressed mood and living alone, and weak associations with male sex, impaired memory and perceived poor health. CONCLUSION: The risk of social isolation is elevated in older men, older persons who live alone, persons with mood or cognitive problems, but is not associated with greater use of services. These findings would not support population screening for individuals at risk of social isolation with a view to averting service use by timely intervention. Awareness of social isolation should trigger further assessment, and consideration of interventions to alleviate social isolation, treat depression or ameliorate cognitive impairment.

The EVIDENT-trial: protocol and rationale of a multicenter randomized controlled trial testing the effectiveness of an online-based psychological intervention

BACKGROUND: Depressive disorders are among the leading causes of worldwide disability with mild to moderate forms of depression being particularly common. Low-intensity treatments such as online psychological treatments may be an effective way to treat mild to moderate depressive symptoms and prevent the emergence or relapse of major depression. METHODS/DESIGN: This study is a currently recruiting multicentre parallel-groups pragmatic randomized-controlled single-blind trial. A total of 1000 participants with mild to moderate symptoms of depression from various settings including in- and outpatient services will be randomized to an online psychological treatment or care as usual (CAU). We hypothesize that the intervention will be superior to CAU in reducing depressive symptoms assessed with the Personal Health Questionnaire (PHQ-9, primary outcome measure) following the intervention (12 wks) and at follow-up (24 and 48 wks). Further outcome parameters include quality of life, use of health care resources and attitude towards online psychological treatments. DISCUSSION: The study will yield meaningful answers to the question of whether online psychological treatment can contribute to the effective and efficient prevention and treatment of mild to moderate depression on a population level with a low barrier to entry. TRIAL REGISTRATION: Trial Registration Number: NCT01636752.

Aesthetic outcome of cleft lip and palate treatment. Perceptions of patients, families, and health professionals compared to the general public

The aesthetic outcome of cleft treatment is of great importance due to its complex management and the psychosocial consequences of this defect. The aim of the study was to assess the aesthetic evaluations of patients following cleft surgery by various groups and investigate potential associations of the assessments with life quality parameters. Head photos of 12 adult patients with treated unilateral cleft lip and palate were evaluated by laypeople and professionals. A questionnaire was distributed and answered by the patients and their parents. Intra-panel agreement was high (α > 0.8) for laypeople and professionals. Between-groups agreement was high for both laypeople and professionals, but not when patients and/or parents were tested. Professionals, parents, and patients were more satisfied with patients' appearance than laypeople, although in general all groups were not highly satisfied. Low satisfaction with aesthetics correlated with increased self-reported influence of the cleft in the patients' social activity and professional life (0.56 < rho < 0.74, p < 0.05). These findings highlight the observed negative influence of the cleft on the patient's social activity and professional life and underline the need for the highest quality of surgical outcome for this group of patients.

Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE)

Background Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. Methods and Findings LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm3 or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95–0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19–20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55–12.43). Conclusions LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.

Characteristics and comprehensiveness of adult HIV care and treatment programmes in Asia-Pacific, sub-Saharan Africa and the Americas: results of a site assessment conducted by the International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration

INTRODUCTION HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide. METHODS Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services. RESULTS Most sites reported serving urban (61%; region range (rr): 33-100%) and both adult and paediatric populations (77%; rr: 29-96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services - nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother-to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) - were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services. CONCLUSIONS This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care.

Random Sampling with Interspike-Intervals of the Exponential Integrate and Fire Neuron: A Computational Interpretation of UP-States

Oscillations between high and low values of the membrane potential (UP and DOWN states respectively) are an ubiquitous feature of cortical neurons during slow wave sleep and anesthesia. Nevertheless, a surprisingly small number of quantitative studies have been conducted only that deal with this phenomenon’s implications for computation. Here we present a novel theory that explains on a detailed mathematical level the computational benefits of UP states. The theory is based on random sampling by means of interspike intervals (ISIs) of the exponential integrate and fire (EIF) model neuron, such that each spike is considered a sample, whose analog value corresponds to the spike’s preceding ISI. As we show, the EIF’s exponential sodium current, that kicks in when balancing a noisy membrane potential around values close to the firing threshold, leads to a particularly simple, approximative relationship between the neuron’s ISI distribution and input current. Approximation quality depends on the frequency spectrum of the current and is improved upon increasing the voltage baseline towards threshold. Thus, the conceptually simpler leaky integrate and fire neuron that is missing such an additional current boost performs consistently worse than the EIF and does not improve when voltage baseline is increased. For the EIF in contrast, the presented mechanism is particularly effective in the high-conductance regime, which is a hallmark feature of UP-states. Our theoretical results are confirmed by accompanying simulations, which were conducted for input currents of varying spectral composition. Moreover, we provide analytical estimations of the range of ISI distributions the EIF neuron can sample from at a given approximation level. Such samples may be considered by any algorithmic procedure that is based on random sampling, such as Markov Chain Monte Carlo or message-passing methods. Finally, we explain how spike-based random sampling relates to existing computational theories about UP states during slow wave sleep and present possible extensions of the model in the context of spike-frequency adaptation.