Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury.

A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection

Differential pathways to adult metabolic dysfunction following poor nutrition at two critical developmental periods in sheep

Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk

Warm Cores around Regions of Low-Mass Star Formation

Warm cores (or hot corinos) around low-mass protostellar objects show a rich chemistry with strong spatial variations. This chemistry is generally attributed to the sublimation of icy mantles on dust grains initiated by the warming effect of the stellar radiation. We have used a model of the chemistry in warm cores in which the sublimation process is based on extensive laboratory data; these data indicate that sublimation from mixed ices occurs in several well-defined temperature bands. We have determined the position of these bands for the slow warming by a solar-mass star. The resulting chemistry is dominated by the sublimation process and by subsequent gas-phase reactions; strong spatial and temporal variations in certain molecular species are found to occur, and our results are, in general, consistent with observational results for the well-studied source IRAS 16293-2422. The model used is similar to one that describes the chemistry of hot cores. We infer that the chemistry of both hot cores and warm cores may be described by the same model (suitably adjusted for different physical parameters).Comment: 11 pages, 5 figures, 2 tables. Accepted by MNRA

Genosenor Technology Development

Contains table of contents for Part IV, table of contents for Section 1, and reports on two research projects.Genometrix, Inc. Contract GMX-GH00776-04Defense Advanced Research Projects AgencyU.S. Air Force - Office of Scientific Researc

The HTA risk analysis chart: visualising the need for and potential value of managed entry agreements in health technology assessment

Background Recent changes to the regulatory landscape of pharmaceuticals may sometimes require reimbursement authorities to issue guidance on technologies that have a less mature evidence base. Decision makers need to be aware of risks associated with such health technology assessment (HTA) decisions and the potential to manage this risk through managed entry agreements (MEAs). Objective This work develops methods for quantifying risk associated with specific MEAs and for clearly communicating this to decision makers. Methods We develop the ‘HTA risk analysis chart’, in which we present the payer strategy and uncertainty burden (P-SUB) as a measure of overall risk. The P-SUB consists of the payer uncertainty burden (PUB), the risk stemming from decision uncertainty as to which is the truly optimal technology from the relevant set of technologies, and the payer strategy burden (PSB), the additional risk of approving a technology that is not expected to be optimal. We demonstrate the approach using three recent technology appraisals from the UK National Institute for Health and Clinical Excellence (NICE), each of which considered a price-based MEA. Results The HTA risk analysis chart was calculated using results from standard probabilistic sensitivity analyses. In all three HTAs, the new interventions were associated with substantial risk as measured by the P-SUB. For one of these technologies, the P-SUB was reduced to zero with the proposed price reduction, making this intervention cost effective with near complete certainty. For the other two, the risk reduced substantially with a much reduced PSB and a slightly increased PUB. Conclusions The HTA risk analysis chart shows the risk that the healthcare payer incurs under unresolved decision uncertainty and when considering recommending a technology that is not expected to be optimal given current evidence. This allows the simultaneous consideration of financial and data-collection MEA schemes in an easily understood format. The use of HTA risk analysis charts will help to ensure that MEAs are considered within a standard utility-maximising health economic decision-making framework

Predictors of vitamin D status and its association with parathyroid hormone in young New Zealand children.

BACKGROUND: Despite increased awareness of the adverse health effects of low vitamin D status, few studies have evaluated 25-hydroxyvitamin D [25(OH)D] status in young children. OBJECTIVES: We aimed to assess vitamin D status on the basis of 25(OH)D and its relation with parathyroid hormone (PTH) and to identify possible predictors of 25(OH)D status in young children living in a country with minimal vitamin D fortification. DESIGN: Serum 25(OH)D and PTH concentrations were measured in a cross-sectional sample of children aged 12-22 mo [n = 193 for 25(OH)D, n = 144 for PTH] living in Dunedin, New Zealand (latitude: 45 degrees S). Anthropometric, dietary, and sociodemographic data were collected. RESULTS: The majority of children sampled in the summer (94%; 47 of 50) had 25(OH)D >50 nmol/L; however, nearly 80% of children sampled in the winter (43 of 55) had serum concentrations 60-65 nmol/L, a plateau in PTH was evident. CONCLUSIONS: Seasonal variation in 25(OH)D concentration implies that postsummer vitamin D stores were insufficient to maintain status >50 nmol/L year-round. Examination of the predictors of 25(OH)D in our model shows few modifiable risk factors, and thus effective dietary strategies may be required if future research determines that children with 25(OH)D concentrations <50 nmol/L are at significant health risk. This trial was registered at www.actr.org.au as ACTRN12605000487617

Entry, Descent, and Landing Aerothermodynamics: NASA Langley Experimental Capabilities and Contributions

A review is presented of recent research, development, testing and evaluation activities related to entry, descent and landing that have been conducted at the NASA Langley Research Center. An overview of the test facilities, model development and fabrication capabilities, and instrumentation and measurement techniques employed in this work is provided. Contributions to hypersonic/supersonic flight and planetary exploration programs are detailed, as are fundamental research and development activities

Global Observations from PHOBOS

Particle production in Au+Au collisions has been measured in the PHOBOS experiment at RHIC for a range of collision energies. Three empirical observations have emerged from this dataset which require theoretical examination. First, there is clear evidence of limiting fragmentation. Namely, particle production in central Au+Au collisions, when expressed as $dN/d\eta'$ ($\eta' \equiv \eta-y_{beam}$), becomes energy independent at high energy for a broad region of $\eta'$ around $\eta'=0$. This energy-independent region grows with energy, allowing only a limited region (if any) of longitudinal boost-invariance. Second, there is a striking similarity between particle production in e+e- and Au+Au collisions (scaled by the number of participating nucleon pairs). Both the total number of produced particles and the longitudinal distribution of produced particles are approximately the same in e+e- and in scaled Au+Au. This observation was not predicted and has not been explained. Finally, particle production has been found to scale approximately with the number of participating nucleon pairs for $N_{part}>65$. This scaling occurs both for the total multiplicity and for high \pT particles (3 <\pT< 4.5 GeV/c).Comment: QM2002 plenary talk, 10 pages, 11 figure

A synopsis of the Ordovician System in its birthplace - Britain and Ireland

Rock successions in Britain and Ireland, and more especially those in North Wales, were instrumental in the founding and naming of the Ordovician System, and the Anglo-Welsh series established both initially and subsequently were used widely as a standard for Ordovician chronostratigraphy. Although now largely superseded in the global scheme of series and stages, they retain their local and regional importance. The Ordovician System in Britain and Ireland documents the history of a segment of the Earth's crust that incorporated opposing peri-Gondwanan and peri-Laurentian/Laurentian margins of the Iapetus Ocean during its closure, and is accordingly complex. The complexity arises from the volcanic and tectonic processes that accompanied oceanic closure coupled with the effects of eustatic sea-level changes, including the far-field effects of the Late Ordovician glaciation. For the past three decades, Ordovician successions in Britain and Ireland have been discussed in terms of terranes. Here we review Ordovician successions in each terrane, incorporating the results of recent research and correlating those successions via biostratigraphical schemes and radiometric dates to the global Ordovician series and stages

Using human genetics to understand the disease impacts of testosterone in men and women.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.A.R.W. and T.M.F. are supported by the European Research Council grant: SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. R.B. is funded by the Wellcome Trust and Royal Society grant 104150/Z/14/Z. J.T. is supported by the Academy of Medical Sciences Springboard award which is supported by the Wellcome Trust and GCRF [SBF004\1079]. This work was supported by the Medical Research Council [Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2]