Spatial regulation of MCAK promotes cell polarization and focal adhesion turnover to drive robust cell migration

The asymmetric distribution of microtubule (MT) dynamics in migrating cells is important for cell polarization, yet the underlying regulatory mechanisms remain underexplored. Here, we addressed this question by studying the role of the MT depolymerase, MCAK (mitotic centromere-associated kinesin), in the highly persistent migration of RPE-1 cells. MCAK knockdown leads to slowed migration and poor directional movement. Fixed and live cell imaging revealed that MCAK knockdown results in excessive membrane ruffling as well as defects in cell polarization and the maintenance of a major protrusive front. Additionally, loss of MCAK increases the lifetime of focal adhesions by decreasing their disassembly rate. These functions correlate with a spatial distribution of MCAK activity, wherein activity is higher in the trailing edge of cells compared with the leading edge. Overexpression of Rac1 has a dominant effect over MCAK activity, placing it downstream of or in a parallel pathway to MCAK function in migration. Together, our data support a model in which the polarized distribution of MCAK activity and subsequent differential regulation of MT dynamics contribute to cell polarity, centrosome positioning, and focal adhesion dynamics, which all help facilitate robust directional migration

Neutrinoless Double Beta Decay within QRPA with Proton-Neutron Pairing

We have investigated the role of proton-neutron pairing in the context of the Quasiparticle Random Phase approximation formalism. This way the neutrinoless double beta decay matrix elements of the experimentally interesting A= 48, 76, 82, 96, 100, 116, 128, 130 and 136 systems have been calculated. We have found that the inclusion of proton-neutron pairing influences the neutrinoless double beta decay rates significantly, in all cases allowing for larger values of the expectation value of light neutrino masses. Using the best presently available experimental limits on the half life-time of neutrinoless double beta decay we have extracted the limits on lepton number violating parameters.Comment: 16 RevTex page

Does rearing laying hens in aviaries adversely affect long-term welfare following transfer to furnished cages?

This study tests the hypothesis that hens that are reared in aviaries but produce in furnished cages experience poorer welfare in production than hens reared in caged systems. This hypothesis is based on the suggestion that the spatial restriction associated with the transfer from aviaries to cages results in frustration or stress for the aviary reared birds. To assess the difference in welfare between aviary and cage reared hens in production, non-beak trimmed white leghorn birds from both rearing backgrounds were filmed at a commercial farm that used furnished cage housing. The videos were taken at 19 and 21 weeks of age, following the birds' transition to the production environment at 16 weeks. Videos were analysed in terms of the performance of aversion-related behaviour in undisturbed birds, comfort behaviour in undisturbed birds, and alert behaviour directed to a novel object in the home cage. A decrease in the performance of the former behaviour and increase in the performance of the latter two behaviours indicates improved welfare. The results showed that aviary reared birds performed more alert behaviour near to the object than did cage reared birds at 19 but not at 21 weeks of age (P = 0.03). Blood glucose concentrations did not differ between the treatments (P>0.10). There was a significant difference in mortality between treatments (P = 0.000), with more death in aviary reared birds (5.52%) compared to cage birds (2.48%). The higher mortality of aviary-reared birds indicates a negative effect of aviary rearing on bird welfare, whereas the higher duration of alert behavior suggests a positive effect of aviary rearing

A Large Scale Double Beta and Dark Matter Experiment: GENIUS

The recent results from the HEIDELBERG-MOSCOW experiment have demonstrated the large potential of double beta decay to search for new physics beyond the Standard Model. To increase by a major step the present sensitivity for double beta decay and dark matter search much bigger source strengths and much lower backgrounds are needed than used in experiments under operation at present or under construction. We present here a study of a project proposed recently, which would operate one ton of 'naked' enriched GErmanium-detectors in liquid NItrogen as shielding in an Underground Setup (GENIUS). It improves the sensitivity to neutrino masses to 0.01 eV. A ten ton version would probe neutrino masses even down to 10^-3 eV. The first version would allow to test the atmospheric neutrino problem, the second at least part of the solar neutrino problem. Both versions would allow in addition significant contributions to testing several classes of GUT models. These are especially tests of R-parity breaking supersymmetry models, leptoquark masses and mechanism and right-handed W-boson masses comparable to LHC. The second issue of the experiment is the search for dark matter in the universe. The entire MSSM parameter space for prediction of neutralinos as dark matter particles could be covered already in a first step of the full experiment - with the same purity requirements but using only 100 kg of 76Ge or even of natural Ge - making the experiment competitive to LHC in the search for supersymmetry. The layout of the proposed experiment is discussed and the shielding and purity requirements are studied using GEANT Monte Carlo simulations. As a demonstration of the feasibility of the experiment first results of operating a 'naked' Ge detector in liquid nitrogen are presented.Comment: 22 pages, 12 figures, see also http://pluto.mpi-hd.mpg.de/~betalit/genius.htm

An Allograft Glioma Model Reveals the Dependence of Aquaporin-4 Expression on the Brain Microenvironment

Aquaporin-4 (AQP4), the main water channel of the brain, is highly expressed in animal glioma and human glioblastoma in situ. In contrast, most cultivated glioma cell lines don’t express AQP4, and primary cell cultures of human glioblastoma lose it during the first passages. Accordingly, in C6 cells and RG2 cells, two glioma cell lines of the rat, and in SMA mouse glioma cell lines, we found no AQP4 expression. We confirmed an AQP4 loss in primary human glioblastoma cell cultures after a few passages. RG-2 glioma cells if grafted into the brain developed AQP4 expression. This led us consider the possibility of AQP4 expression depends on brain microenvironment. In previous studies, we observed that the typical morphological conformation of AQP4 as orthogonal arrays of particles (OAP) depended on the extracellular matrix component agrin. In this study, we showed for the first time implanted AQP4 negative glioma cells in animal brain or flank to express AQP4 specifically in the intracerebral gliomas but neither in the extracranial nor in the flank gliomas. AQP4 expression in intracerebral gliomas went along with an OAP loss, compared to normal brain tissue. AQP4 staining in vivo normally is polarized in the astrocytic endfoot membranes at the glia limitans superficialis and perivascularis, but in C6 and RG2 tumors the AQP4 staining is redistributed over the whole glioma cell as in human glioblastoma. In contrast, primary rat or mouse astrocytes in culture did not lose their ability to express AQP4, and they were able to form few OAPs

The IGNITE (investigation to guide new insight into translational effectiveness) trial: Protocol for a translational study of an evidenced-based wellness program in fire departments

<p>Abstract</p> <p>Background</p> <p>Worksites are important locations for interventions to promote health. However, occupational programs with documented efficacy often are not used, and those being implemented have not been studied. The research in this report was funded through the American Reinvestment and Recovery Act Challenge Topic 'Pathways for Translational Research,' to define and prioritize determinants that enable and hinder translation of evidenced-based health interventions in well-defined settings.</p> <p>Methods</p> <p>The IGNITE (investigation to guide new insights for translational effectiveness) trial is a prospective cohort study of a worksite wellness and injury reduction program from adoption to final outcomes among 12 fire departments. It will employ a mixed methods strategy to define a translational model. We will assess decision to adopt, installation, use, and outcomes (reach, individual outcomes, and economic effects) using onsite measurements, surveys, focus groups, and key informant interviews. Quantitative data will be used to define the model and conduct mediation analysis of each translational phase. Qualitative data will expand on, challenge, and confirm survey findings and allow a more thorough understanding and convergent validity by overcoming biases in qualitative and quantitative methods used alone.</p> <p>Discussion</p> <p>Findings will inform worksite wellness in fire departments. The resultant prioritized influences and model of effective translation can be validated and manipulated in these and other settings to more efficiently move science to service.</p

Physical exercise, fitness and dietary pattern and their relationship with circadian blood pressure pattern, augmentation index and endothelial dysfunction biological markers: EVIDENT study protocol

Background: Healthy lifestyles may help to delay arterial aging. The purpose of this study is to analyze the relationship of physical activity and dietary pattern to the circadian pattern of blood pressure, central and peripheral blood pressure, pulse wave velocity, carotid intima-media thickness and biological markers of endothelial dysfunction in active and sedentary individuals without arteriosclerotic disease. Methods/Design Design: A cross-sectional multicenter study with six research groups. Subjects: From subjects of the PEPAF project cohort, in which 1,163 who were sedentary became active, 1,942 were sedentary and 2,346 were active. By stratified random sampling, 1,500 subjects will be included, 250 in each group. Primary measurements: We will evaluate height, weight, abdominal circumference, clinical and ambulatory blood pressure with the Radial Pulse Wave Acquisition Device (BPro), central blood pressure and augmentation index with Pulse Wave Application Software (A-Pulse) and SphymgoCor System Px (Pulse Wave Analysis), pulse wave velocity (PWV) with SphymgoCor System Px (Pulse Wave Velocity), nutritional pattern with a food intake frequency questionnaire, physical activity with the 7-day PAR questionnaire and accelerometer (Actigraph GT3X), physical fitness with the cycle ergometer (PWC-170), carotid intima-media thickness by ultrasound (Micromax), and endothelial dysfunction biological markers (endoglin and osteoprotegerin). Discussion: Determining that sustained physical activity and the change from sedentary to active as well as a healthy diet improve circadian pattern, arterial elasticity and carotid intima-media thickness may help to propose lifestyle intervention programs. These interventions could improve the cardiovascular risk profile in some parameters not routinely assessed with traditional risk scales. From the results of this study, interventional approaches could be obtained to delay vascular aging that combine physical exercise and diet

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Cost of hospital management of Clostridium difficile infection in United States - a meta-analysis and modelling study

Background: Clostridium difficile infection (CDI) is the leading cause of infectious nosocomial diarrhoea but the economic costs of CDI on healthcare systems in the US remain uncertain. Methods: We conducted a systematic search for published studies investigating the direct medical cost associated with CDI hospital management in the past 10 years (2005-2015) and included 42 studies to the final data analysis to estimate the financial impact of CDI in the US. We also conducted a meta-analysis of all costs using Monte Carlo simulation. Results: The average cost for CDI case management and average CDI-attributable costs per case were $42,316 (90$ 39,886, $44,765) and$ 21,448 (90 % CI: $21,152,$ 21,744) in 2015 US dollars. Hospital-onset CDIattributable cost per case was $34,157 (90$ 33,134, $35,180), which was 1.5 times the cost of communityonset CDI ($ 20,095 [ 90 % CI: $4991,$ 35,204]). The average and incremental length of stay (LOS) for CDI inpatient treatment were 11.1 (90 % CI: 8.7-13.6) and 9.7 (90 % CI: 9.6-9.8) days respectively. Total annual CDI-attributable cost in the US is estimated US$6.3 (Range:$ 1.9-$ 7.0) billion. Total annual CDI hospital management required nearly 2.4 million days of inpatient stay. Conclusions: This review indicates that CDI places a significant financial burden on the US healthcare system. This review adds strong evidence to aid policy-making on adequate resource allocation to CDI prevention and treatment in the US. Future studies should focus on recurrent CDI, CDI in long-term care facilities and persons with comorbidities and indirect cost from a societal perspective. Health-economic studies for CDI preventive intervention are needed.Sanofi PasteurSCI(E)[email protected]