Active diffusion and microtubule-based transport oppose myosin forces to position organelles in cells.

Even distribution of peroxisomes (POs) and lipid droplets (LDs) is critical to their role in lipid and reactive oxygen species homeostasis. How even distribution is achieved remains elusive, but diffusive motion and directed motility may play a role. Here we show that in the fungus Ustilago maydis ∼95% of POs and LDs undergo diffusive motions. These movements require ATP and involve bidirectional early endosome motility, indicating that microtubule-associated membrane trafficking enhances diffusion of organelles. When early endosome transport is abolished, POs and LDs drift slowly towards the growing cell end. This pole-ward drift is facilitated by anterograde delivery of secretory cargo to the cell tip by myosin-5. Modelling reveals that microtubule-based directed transport and active diffusion support distribution, mobility and mixing of POs. In mammalian COS-7 cells, microtubules and F-actin also counteract each other to distribute POs. This highlights the importance of opposing cytoskeletal forces in organelle positioning in eukaryotes.We thank Dr G. Dagdas, Dr S. Kilaru, Mr M. Schlick and Mrs T. Schrader for technical support. We thank Professor N.J. Talbot for helpful comments on the manuscript. This work was supported by the Biotechnology & Biological Sciences Research Council (BB/J009903/1 to G.S.). S.C.G. was supported by a fellowship from the Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/73532/2010). J.M. is supported by a Wellcome Trust Institutional Strategic Support Award (WT097835MF)

Finding smORFs: getting closer

Millions of small open reading frames exist in eukaryotes. We do not know how many, or which are translated, but bioinformatics is getting us closer to the answer. See related Research article: http://www.genomebiology.com/2015/16/1/179

Hip fracture risk assessment: Artificial neural network outperforms conditional logistic regression in an age- and sex-matched case control study

Copyright @ 2013 Tseng et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background - Osteoporotic hip fractures with a significant morbidity and excess mortality among the elderly have imposed huge health and economic burdens on societies worldwide. In this age- and sex-matched case control study, we examined the risk factors of hip fractures and assessed the fracture risk by conditional logistic regression (CLR) and ensemble artificial neural network (ANN). The performances of these two classifiers were compared. Methods - The study population consisted of 217 pairs (149 women and 68 men) of fractures and controls with an age older than 60 years. All the participants were interviewed with the same standardized questionnaire including questions on 66 risk factors in 12 categories. Univariate CLR analysis was initially conducted to examine the unadjusted odds ratio of all potential risk factors. The significant risk factors were then tested by multivariate analyses. For fracture risk assessment, the participants were randomly divided into modeling and testing datasets for 10-fold cross validation analyses. The predicting models built by CLR and ANN in modeling datasets were applied to testing datasets for generalization study. The performances, including discrimination and calibration, were compared with non-parametric Wilcoxon tests. Results - In univariate CLR analyses, 16 variables achieved significant level, and six of them remained significant in multivariate analyses, including low T score, low BMI, low MMSE score, milk intake, walking difficulty, and significant fall at home. For discrimination, ANN outperformed CLR in both 16- and 6-variable analyses in modeling and testing datasets (p?<?0.005). For calibration, ANN outperformed CLR only in 16-variable analyses in modeling and testing datasets (p?=?0.013 and 0.047, respectively). Conclusions - The risk factors of hip fracture are more personal than environmental. With adequate model construction, ANN may outperform CLR in both discrimination and calibration. ANN seems to have not been developed to its full potential and efforts should be made to improve its performance.National Health Research Institutes in Taiwa

Longitudinal bioimpedance vector plots add little value to fluid management of peritoneal dialysis patients

Bioimpedance (BI) has the potential to enable better management of fluid balance, which can worsen over time on peritoneal dialysis (PD) due to loss of residual kidney function and progressive muscle wasting. We undertook a prospective, randomized, open-label, blinded end-point controlled trial to determine whether availability of longitudinal BI measures as vector plots helped clinicians maintain stable fluid status over 12 months in 308 peritoneal dialysis patients from the United Kingdom and Shanghai, China. Patients were recruited into 4 groups nested within a single trial design according to country and residual kidney function. Nonanuric subjects from both countries demonstrated stable fluid volumes irrespective of randomization. Hydration worsened in control anuric patients in Shanghai with increased extracellular/total body water (ECW/TBW) ratio (0.04; 95% CI: 0.01, 0.06) and reduced TBW (-1.76 L 95% CI: -2.70, -0.82), but was stable in the BI intervention group whose dialysate glucose prescription was increased. However, multilevel analysis incorporating data from both countries showed worsening ECW/TBW in active and control anuric patients. Clinicians in the United Kingdom reduced target weight in the nonanuric BI intervention group causing a reduction in TBW without beneficial effects on ECW or blood pressure. Thus, routine use of longitudinal BI vector plots to improve clinical management of fluid status is not supported.Kidney International advance online publication, 14 October 2015; doi:10.1038/ki.2015.294

Rapid CD4⁺ T-cell responses to bacterial flagellin require dendritic cell expression of Syk and CARD9

Toll‐like receptors (TLRs) can recognize microbial patterns and utilize adaptor molecules, such as‐MyD88 or (TRIF TIR‐domain‐containing adapter‐inducing interferon‐β), to initiate downstream signaling that ultimately affects the initiation of adaptive immunity. In addition to this inflammatory role, TLR5 expression on dendritic cells can favor antigen presentation of flagellin peptides and thus increase the sensitivity of flagellin‐specific T‐cell responses in vitro and in vivo. Here, we examined the role of alternative signaling pathways that might regulate flagellin antigen presentation in addition to MyD88. These studies suggest a requirement for spleen tyrosine kinase, a noncanonical TLR‐signaling adaptor molecule, and its downstream molecule CARD9 in regulating the sensitivity of flagellin‐specific CD4⁺ T‐cell responses in vitro and in vivo. Thus, a previously unappreciated signaling pathway plays an important role in regulating the dominance of flagellin‐specific T‐cell responses

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related. © 2013 Rattray et al

H-alpha +[NII] Observations of the HII Regions in M81

In a first of a series of studies of the H-alpha + [NII] emission from nearby spiral galaxies, we present measurements of H-alpha + [NII] emission from HII regions in M81. Our method uses large-field-CCD images and long-slit spectra, and is part of the ongoing Beijing-Arizona-Taipei-Connecticut Sky Survey. The CCD images are taken with the NAOC 0.6/0.9m f/3 Schmidt telescope at the Xinglong Observing Station, using a multicolor filter set. Spectra of 10 of the brightest HII regions are obtained using the NAOC 2.16m telescope with a Tek 1024 X 1024 CCD. The continua of the spectra are calibrated by flux-calibrated images taken from the Schmidt observations. We determine the continuum component of our H-alpha + [NII] image via interpolation from the more accurately-measured backgrounds (M81 starlight) obtained from the two neighboring (in wavelength) BATC filter images. We use the calibrated fluxes of H-alpha + [NII] emission from the spectra to normalize this interpolated, continuum-subtracted H-alpha + [NII] image. We estimate the zero point uncertainty of the measured H-alpha + [NII] emission flux to be $\sim$ 8%. A catalogue of H-alpha + [NII] fluxes for 456 HII regions is provided, with those fluxes are on a more consistent linear scale than previously available. The logarithmically-binned H-alpha + [NII] luminosity function of HII regions is found to have slope $\alpha$ = -0.70, consistent with previous results (which allowed $\alpha=-0.5 \sim -0.8$). From the overall H-alpha + [NII] luminosity of the HII regions, the star formation rate of M81 is found to be $\sim 0.68 M_{\odot} {\rm yr}^{-1}$, modulo uncertainty with extinction corrections.Comment: 18 pages, 7 figures, accepted for publication in the Astronomical Journa

Parallelization of Kinetic Theory Simulations

Numerical studies of shock waves in large scale systems via kinetic simulations with millions of particles are too computationally demanding to be processed in serial. In this work we focus on optimizing the parallel performance of a kinetic Monte Carlo code for astrophysical simulations such as core-collapse supernovae. Our goal is to attain a flexible program that scales well with the architecture of modern supercomputers. This approach requires a hybrid model of programming that combines a message passing interface (MPI) with a multithreading model (OpenMP) in C++. We report on our approach to implement the hybrid design into the kinetic code and show first results which demonstrate a significant gain in performance when many processors are applied.Comment: 10 pages, 3 figures, conference proceeding

Control of magnetic anisotropy by orbital hybridization in (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattice

The asymmetry of chemical nature at the hetero-structural interface offers an unique opportunity to design desirable electronic structure by controlling charge transfer and orbital hybridization across the interface. However, the control of hetero-interface remains a daunting task. Here, we report the modulation of interfacial coupling of (La0.67Sr0.33MnO3)n/(SrTiO3)n superlattices by manipulating the periodic thickness with n unit cells of SrTiO3 and n unit cells La0.67Sr0.33MnO3. The easy axis of magnetic anisotropy rotates from in-plane (n = 10) to out-of-plane (n = 2) orientation at 150 K. Transmission electron microscopy reveals enlarged tetragonal ratio > 1 with breaking of volume conservation around the (La0.67Sr0.33MnO3)n/(SrTiO3)n interface, and electronic charge transfer from Mn to Ti 3d orbitals across the interface. Orbital hybridization accompanying the charge transfer results in preferred occupancy of 3d3z2-r2 orbital at the interface, which induces a stronger electronic hopping integral along the out-of-plane direction and corresponding out-of-plane magnetic easy axis for n = 2. We demonstrate that interfacial orbital hybridization in superlattices of strongly correlated oxides may be a promising approach to tailor electronic and magnetic properties in device applications

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine