Can simple rules control development of a pioneer vertebrate neuronal network generating behavior?

How do the pioneer networks in the axial core of the vertebrate nervous system first develop? Fundamental to understanding any full-scale neuronal network is knowledge of the constituent neurons, their properties, synaptic interconnections, and normal activity. Our novel strategy uses basic developmental rules to generate model networks that retain individual neuron and synapse resolution and are capable of reproducing correct, whole animal responses. We apply our developmental strategy to young Xenopus tadpoles, whose brainstem and spinal cord share a core vertebrate plan, but at a tractable complexity. Following detailed anatomical and physiological measurements to complete a descriptive library of each type of spinal neuron, we build models of their axon growth controlled by simple chemical gradients and physical barriers. By adding dendrites and allowing probabilistic formation of synaptic connections, we reconstruct network connectivity among up to 2000 neurons. When the resulting "network" is populated by model neurons and synapses, with properties based on physiology, it can respond to sensory stimulation by mimicking tadpole swimming behavior. This functioning model represents the most complete reconstruction of a vertebrate neuronal network that can reproduce the complex, rhythmic behavior of a whole animal. The findings validate our novel developmental strategy for generating realistic networks with individual neuron- and synapse-level resolution. We use it to demonstrate how early functional neuronal connectivity and behavior may in life result from simple developmental "rules," which lay out a scaffold for the vertebrate CNS without specific neuron-to-neuron recognition

Superconformal symmetry and maximal supergravity in various dimensions

In this paper we explore the relation between conformal superalgebras with 64 supercharges and maximal supergravity theories in three, four and six dimensions using twistorial oscillator techniques. The massless fields of N=8 supergravity in four dimensions were shown to fit into a CPT-self-conjugate doubleton supermultiplet of the conformal superalgebra SU(2,2|8) a long time ago. We show that the fields of maximal supergravity in three dimensions can similarly be fitted into the super singleton multiplet of the conformal superalgebra OSp(16|4,R), which is related to the doubleton supermultiplet of SU(2,2|8) by dimensional reduction. Moreover, we construct the ultra-short supermultiplet of the six-dimensional conformal superalgebra OSp(8*|8) and show that its component fields can be organized in an on-shell superfield. The ultra-short OSp(8*|8) multiplet reduces to the doubleton supermultiplet of SU(2,2|8) upon dimensional reduction. We discuss the possibility of a chiral maximal (4,0) six-dimensional supergravity theory with USp(8) R-symmetry that reduces to maximal supergravity in four dimensions and is different from six-dimensional (2,2) maximal supergravity, whose fields cannot be fitted into a unitary supermultiplet of a simple conformal superalgebra. Such an interacting theory would be the gravitational analog of the (2,0) theory.Comment: 54 pages, PDFLaTeX, Section 5 and several references added. Version accepted for publication in JHE

Addressing social issues in a universal HIV test and treat intervention trial (ANRS 12249 TasP) in South Africa: methods for appraisal

Background: The Universal HIV Test and Treat (UTT) strategy represents a challenge for science, but is also a challenge for individuals and societies. Are repeated offers of provider-initiated HIV testing and immediate antiretroviral therapy (ART) socially-acceptable and can these become normalized over time? Can UTT be implemented without potentially adding to individual and community stigma, or threatening individual rights? What are the social, cultural and economic implications of UTT for households and communities? And can UTT be implemented within capacity constraints and other threats to the overall provision of HIV services? The answers to these research questions will be critical for routine implementation of UTT strategies. Methods/design: A social science research programme is nested within the ANRS 12249 Treatment-as-Prevention (TasP) cluster-randomised trial in rural South Africa. The programme aims to inform understanding of the (i) social, economic and environmental factors affecting uptake of services at each step of the continuum of HIV prevention, treatment and care and (ii) the causal impacts of the TasP intervention package on social and economic factors at the individual, household, community and health system level. We describe a multidisciplinary, multi-level, mixed-method research protocol that includes individual, household, community and clinic surveys, and combines quantitative and qualitative methods. Discussion: The UTT strategy is changing the overall approach to HIV prevention, treatment and care, and substantial social consequences may be anticipated, such as changes in social representations of HIV transmission, prevention, HIV testing and ART use, as well as changes in individual perceptions and behaviours in terms of uptake and frequency of HIV testing and ART initiation at high CD4. Triangulation of social science studies within the ANRS 12249 TasP trial will provide comprehensive insights into the acceptability and feasibility of the TasP intervention package at individual, community, patient and health system level, to complement the trial's clinical and epidemiological outcomes. It will also increase understanding of the causal impacts of UTT on social and economic outcomes, which will be critical for the long-term sustainability and routine UTT implementation. Trial registration: Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10-5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10-3) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment

Identification of Lipases Involved in PBAN Stimulated Pheromone Production in Bombyx mori Using the DGE and RNAi Approaches

BACKGROUND: Pheromone biosynthesis activating neuropeptide (PBAN) is a neurohormone that regulates sex pheromone synthesis in female moths. Bombyx mori is a model organism that has been used to explore the signal transduction pattern of PBAN, which is mediated by a G-protein coupled receptor (GPCR). Although significant progress has been made in elucidating PBAN-regulated lipolysis that releases the precursor of the sex pheromone, little is known about the molecular components involved in this step. To better elucidate the molecular mechanisms of PBAN-stimulated lipolysis of cytoplasmic lipid droplets (LDs), the associated lipase genes involved in PBAN- regulated sex pheromone biosynthesis were identified using digital gene expression (DGE) and subsequent RNA interference (RNAi). RESULTS: Three DGE libraries were constructed from pheromone glands (PGs) at different developed stages, namely, 72 hours before eclosion (-72 h), new emergence (0 h) and 72 h after eclosion (72 h), to investigate the gene expression profiles during PG development. The DGE evaluated over 5.6 million clean tags in each PG sample and revealed numerous genes that were differentially expressed at these stages. Most importantly, seven lipases were found to be richly expressed during the key stage of sex pheromone synthesis and release (new emergence). RNAi-mediated knockdown confirmed for the first time that four of these seven lipases play important roles in sex pheromone synthesis. CONCLUSION: This study has identified four lipases directly involved in PBAN-stimulated sex pheromone biosynthesis, which improve our understanding of the lipases involved in releasing bombykol precursors from triacylglycerols (TAGs) within the cytoplasmic LDs

Assessement of tensile strength of graphites by the iosipescu coupon test

Polycrystalline graphites are widely used in the metallurgical, nuclear and aerospace industries. Graphites are particulated composites manufactured with a mixture of coke with pitch, and changes in relative proportions of these materials cause modifications in their mechanical properties. Uniaxial tension tests must be avoided for mechanical characterization in this kind of brittle material, due to difficulties in making the relatively long specimens and premature damages caused during testing set-up. On other types of tests, e.g. bending tests, the specimens are submitted to combined stress states (normal and transverse shear stresses). The Iosipescu shear test, is performed in a beam with two 90° opposite notches machined at the mid-length of the specimens, by applying two forces couples, so that a pure and uniform shear stress state is generated at the cross section between the two notches. When a material is isotropic and brittle, a failure at 45° in relation to the beam long axis can take place, i.e., the tensile normal stress acts parallel to the lateral surface of the notches, controls the failure and the result of the shear test is numerically equivalent to the tensile strength. This work has evaluated a graphite of the type used in rocket nozzles by the Iosipescu test and the resulted stress, ~11 MPa, was found to be equal to the tensile strength. Thus, the tensile strength can be evaluated just by a single and simple experiment, thus avoiding complicated machining of specimen and testing set-up

Electronic Cigarette Advertising Impacts Adversely on Smoking Behaviour Within a London Student Cohort: A Cross-Sectional Structured Survey.

INTRODUCTION: In contrast to tobacco smoking, electronic cigarette ("vaping") advertisement had been approved in the United Kingdom (UK) in January 2013. Currently, there are an estimated 3.2 million UK e-cigarette users. The impact of e-cigarette advertisement on tobacco use has not been studied in detail. We hypothesised that e-cigarette advertisement impacts on conventional smoking behaviour. METHODS: A cross-sectional structured survey assessed the impact of e-cigarette advertising on the perceived social acceptability of cigarette and e-cigarette smoking and on using either cigarettes or e-cigarettes (on a scale of 1 to 5/'not at all' to 'a lot'). The survey was administered between January to March 2015 to London university students, before and after viewing 5 UK adverts including a TV commercial. RESULTS: Data were collected from 106 participants (22 ± 2 years, 66% male), comprising cigarette smokers (32%), non-smokers (54%) and ex-smokers (14%). This included vapers (16%), non-vapers (77%) and ex-vapers (7%). After viewing the adverts, smokers (2.6 ± 1.0 vs. 3.8 ± 1.1, p = 0.001) and non-smokers (3.2 ± 0.7 vs. 3.7 ± 0.8, p = 0.007) felt smoking was more socially acceptable, compared to before viewing them. Participants were more likely to try both e-cigarettes (1.90 ± 1.03 to 3.09 ± 1.11, p < 0.001) and conventional cigarettes (1.73 ± 0.83 to 2.27 ± 1.13, p < 0.001) after viewing the adverts compared to before. Vapers were less likely to smoke both an e-cigarette, and a conventional cigarette after viewing the adverts. CONCLUSION: E-cigarette advertising encourages both e-cigarette and conventional cigarette use in young smokers and non-smokers. The adverts increase the social acceptability of smoking without regarding the importance of public health campaigns that champion smoking cessation

The potential benefits of low-molecular-weight heparins in cancer patients

Cancer patients are at increased risk of venous thromboembolism due to a range of factors directly related to their disease and its treatment. Given the high incidence of post-surgical venous thromboembolism in cancer patients and the poor outcomes associated with its development, thromboprophylaxis is warranted. A number of evidence-based guidelines delineate anticoagulation regimens for venous thromboembolism treatment, primary and secondary prophylaxis, and long-term anticoagulation in cancer patients. However, many give equal weight to several different drugs and do not make specific recommendations regarding duration of therapy. In terms of their efficacy and safety profiles, practicality of use, and cost-effectiveness the low-molecular-weight heparins are at least comparable to, and offer several advantages over, other available antithrombotics in cancer patients. In addition, data are emerging that the antithrombotics, and particularly low-molecular-weight heparins, may exert an antitumor effect which could contribute to improved survival in cancer patients when given for long-term prophylaxis. Such findings reinforce the importance of thromboprophylaxis with low-molecular-weight heparin in cancer patients

Predicted risks of radiogenic cardiac toxicity in two pediatric patients undergoing photon or proton radiotherapy

BACKGROUND: Hodgkin disease (HD) and medulloblastoma (MB) are common malignancies found in children and young adults, and radiotherapy is part of the standard treatment. It was reported that these patients who received radiation therapy have an increased risk of cardiovascular late effects. We compared the predicted risk of developing radiogenic cardiac toxicity after photon versus proton radiotherapies for a pediatric patient with HD and a pediatric patient with MB. METHODS: In the treatment plans, each patient’s heart was contoured in fine detail, including substructures of the pericardium and myocardium. Risk calculations took into account both therapeutic and stray radiation doses. We calculated the relative risk (RR) of cardiac toxicity using a linear risk model and the normal tissue complication probability (NTCP) values using relative seriality and Lyman models. Uncertainty analyses were also performed. RESULTS: The RR values of cardiac toxicity for the HD patient were 7.27 (proton) and 8.37 (photon), respectively; the RR values for the MB patient were 1.28 (proton) and 8.39 (photon), respectively. The predicted NTCP values for the HD patient were 2.17% (proton) and 2.67% (photon) for the myocardium, and were 2.11% (proton) and 1.92% (photon) for the whole heart. The predicted ratios of NTCP values (proton/photon) for the MB patient were much less than unity. Uncertainty analyses revealed that the predicted ratio of risk between proton and photon therapies was sensitive to uncertainties in the NTCP model parameters and the mean radiation weighting factor for neutrons, but was not sensitive to heart structure contours. The qualitative findings of the study were not sensitive to uncertainties in these factors. CONCLUSIONS: We conclude that proton and photon radiotherapies confer similar predicted risks of cardiac toxicity for the HD patient in this study, and that proton therapy reduced the predicted risk for the MB patient in this study