Integral field spectroscopy of massive young stellar objects in the N113 H II region in the Large Magellanic Cloud

The Spitzer Surveying the Agents of Galaxy Evolution (SAGE) survey has allowed the identification and analysis of significant samples of Young Stellar Object (YSO) candidates in the Large Magellanic Cloud (LMC). However, the angular resolution of Spitzer is relatively poor meaning that at the distance of the LMC, it is likely that many of the Spitzer YSO candidates in fact contain multiple components. We present high-resolution K-band integral field spectroscopic observations of the three most prominent massive YSO candidates in the N113 H II region using Very Large Telescope/Spectrograph for INtegral Field Observations in the Near Infrared (VLT/SINFONI). We have identified six K-band continuum sources within the three Spitzer sources and we have mapped the morphology and velocity fields of extended line emission around these sources. Br γ, He I and H2 emission is found at the position of all six K-band sources; we discuss whether the emission is associated with the continuum sources or whether it is ambient emission. H2 emission appears to be mostly ambient emission and no evidence of CO emission arising in the discs of YSOs has been found. We have mapped the centroid velocities of extended Br γ emission and He I emission and found evidence of two expanding compact H II regions. One source shows compact and strong H2 emission suggestive of a molecular outflow. The diversity of spectroscopic properties observed is interpreted in the context of a range of evolutionary stages associated with massive star formation

Variant Creutzfeldt-Jakob disease in the United Kingdom: a countrywide or local risk?

BACKGROUND: The aim of this study was to identify factors that may have augmented local risks for variant Creutzfeldt-Jakob disease (vCJD). METHODS: A descriptive study was conducted of local investigations of UK cases of vCJD, who had lived close together at some point since 1980. The main outcome measures were domestic, educational, occupational, healthcare associated, social and recreational links between cases; common dietary, iatrogenic and other possible routes of exposure to vCJD infection; and locally elevated vCJD risk. RESULTS: A cluster of five cases of vCJD in a rural area in North Leicestershire was investigated in 2000 (p=0.004). A further 12 investigations of geographically associated cases of vCJD have been undertaken in the UK. In nine of the 12 locations, some or all of the local cases had consumed beef purchased from the same local retail outlets or provided by a common supplier of school meals, or had some aspect of their medical-dental care in common. In only three of these locations were circumstances identified where the local risk of transmission might have been elevated. In none of the locations was there strong evidence to exclude chance as a likely explanation for the local occurrence of these vCJD cases. CONCLUSION: Although it is possible that in some parts of the UK local factors may have increased the risk of acquiring vCJD, most cases that were geographically close to each other are most likely due to the same factors that gave rise to the large majority of other vCJD cases in the UK

The hand of Homo naledi

A nearly complete right hand of an adult hominin was recovered from the Rising Star cave system, South Africa. Based on associated hominin material, the bones of this hand are attributed to Homo naledi. This hand reveals a long, robust thumb and derived wrist morphology that is shared with Neandertals and modern humans, and considered adaptive for intensified manual manipulation. However, the finger bones are longer and more curved than in most australopiths, indicating frequent use of the hand during life for strong grasping during locomotor climbing and suspension. These markedly curved digits in combination with an otherwise human-like wrist and palm indicate a significant degree of climbing, despite the derived nature of many aspects of the hand and other regions of the postcranial skeleton in H. naledi

Complexity is costly: A meta-analysis of parametric and non-parametric methods for short-term population forecasting

Short-term forecasts based on time series of counts or survey data are widely used in population biology to provide advice concerning the management, harvest and conservation of natural populations. A common approach to produce these forecasts uses time-series models, of different types, fit to time series of counts. Similar time-series models are used in many other disciplines, however relative to the data available in these other disciplines, population data are often unusually short and noisy and models that perform well for data from other disciplines may not be appropriate for population data. In order to study the performance of time-series forecasting models for natural animal population data, we assembled 2379 time series of vertebrate population indices from actual surveys. Our data were comprised of three vastly different types: highly variable (marine fish productivity), strongly cyclic (adult salmon counts), and small variance but long-memory (bird and mammal counts). We tested the predictive performance of 49 different forecasting models grouped into three broad classes: autoregressive time-series models, non-linear regression-type models and non-parametric time-series models. Low-dimensional parametric autoregressive models gave the most accurate forecasts across a wide range of taxa; the most accurate model was one that simply treated the most recent observation as the forecast. More complex parametric and non-parametric models performed worse, except when applied to highly cyclic species. Across taxa, certain life history characteristics were correlated with lower forecast error; specifically, we found that better forecasts were correlated with attributes of slow growing species: large maximum age and size for fishes and high trophic level for birds. © 2014 Nordic Society Oikos

Electrical and network neuronal properties are preferentially disrupted in dorsal, but not ventral, medial entorhinal cortex in a mouse model of Tauopathy

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT: The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia

Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with drug accumulation in the most severe patients

Background: TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored. Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04–0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL). Findings: Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p<0·025 both siRNAs). Interpretation: TKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations. Funding: This work was supported by the Wellcome Trust of Great Britain (grant number 106491/Z/14/Z and 097997/Z/11/A) and by the EU FP7 project PREPARE (602525). The PHE laboratory was funded by the UK Department for International Development. The funders had no role in trial design, data collection or analysis. The views expressed are those of the authors and not necessarily those of Public Health England, the Department of Health, or the EU. Trial registration: Pan African Clinical Trials Registry PACTR201501000997429

Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor

Albumin is the most abundant protein in blood where it has a pivotal role as a transporter of fatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation by pH-dependent recycling mediated by interaction with the neonatal Fc receptor, FcRn. Although the FcRn interaction with IgG is well characterized at the atomic level, its interaction with albumin is not. Here we present structure-based modelling of the FcRn–albumin complex, supported by binding analysis of site-specific mutants, providing mechanistic evidence for the presence of pH-sensitive ionic networks at the interaction interface. These networks involve conserved histidines in both FcRn and albumin domain III. Histidines also contribute to intramolecular interactions that stabilize the otherwise flexible loops at both the interacting surfaces. Molecular details of the FcRn–albumin complex may guide the development of novel albumin variants with altered serum half-life as carriers of drugs

BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found