Fluorescent probes of the orientation of myosin regulatory light chains in relaxed, rigor, and contracting muscle.

The orientation of the light-chain region of myosin heads in relaxed, rigor, and isometrically contracting fibers from rabbit psoas muscle was studied by fluorescence polarization. Cysteine 108 of chicken gizzard myosin regulatory light chain (cgRLC) was covalently modified with iodoacetamidotetramethylrhodamine (iodo-ATR). Native RLC of single glycerinated muscle fibers was exchanged for labeled cgRLC in a low [Mg2+] rigor solution at 30 degrees C. Troponin and troponin C removed in this procedure were replaced. RLC exchange had little effect on active force production. X-ray diffraction showed normal structure in rigor after RLC exchange, but loss of axial and helical order in relaxation. In isolated myofibrils labeled cgRLC was confined to the regions of the sarcomere containing myosin heads. The ATR dipoles showed a preference for orientations perpendicular to the fiber axis, combined with limited nanosecond rotational motion, in all conditions studied. The perpendicular orientation preference was more marked in rigor than in either relaxation or active contraction. Stretching relaxed fibers to sarcomere length 4 microns to eliminate overlap between actin- and myosin-containing filaments had little effect on the orientation preference. There was no change in orientation preference when fibers were put into rigor at sarcomere length 4.0 microns. Qualitatively similar results were obtained with ATR-labeled rabbit skeletal RLC

Inflammatory Activity on Natalizumab Predicts Short-term but not Long-term Disability in Multiple Sclerosis

BACKGROUND: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis. OBJECTIVE: To study this association in those receiving natalizumab. METHODS: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline. RESULTS: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3. CONCLUSIONS: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability

Within-guild dietary discrimination from 3-D textural analysis of tooth microwear in insectivorous mammals

Resource exploitation and competition for food are important selective pressures in animal evolution. A number of recent investigations have focused on linkages between diversification, trophic morphology and diet in bats, partly because their roosting habits mean that for many bat species diet can be quantified relatively easily through faecal analysis. Dietary analysis in mammals is otherwise invasive, complicated, time consuming and expensive. Here we present evidence from insectivorous bats that analysis of three-dimensional (3-D) textures of tooth microwear using International Organization for Standardization (ISO) roughness parameters derived from sub-micron surface data provides an additional, powerful tool for investigation of trophic resource exploitation in mammals. Our approach, like scale-sensitive fractal analysis, offers considerable advantages over twodimensional (2-D) methods of microwear analysis, including improvements in robustness, repeatability and comparability of studies. Our results constitute the first analysis of microwear textures in carnivorous mammals based on ISO roughness parameters. They demonstrate that the method is capable of dietary discrimination, even between cryptic species with subtly different diets within trophic guilds, and even when sample sizes are small. We find significant differences in microwear textures between insectivore species whose diet contains different proportions of ‘hard’ prey (such as beetles) and ‘soft’ prey (such as moths), and multivariate analyses are able to distinguish between species with different diets based solely on their tooth microwear textures. Our results show that, compared with previous 2-D analyses of microwear in bats, ISO roughness parameters provide a much more sophisticated characterization of the nature of microwear surfaces and can yield more robust and subtle dietary discrimination. ISO-based textural analysis of tooth microwear thus has a useful role to play, complementing existing approaches, in trophic analysis of mammals, both extant and extinct

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Acknowledgments We would like to gratefully acknowledge all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). Alz-50, CP13, MC-1 and PHF-1 antibodies were gifted from Dr. Peter Davies and brain lystates from BACE1−/−mice were obtained from Prof Mike Ashford. The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUKPPG2014A-21 and ARUK-NSG2015-1 to BP and DK and NIH/NIA grants NIH/NINDS R01 NS082730 and R01 AG044372 to NK)Peer reviewedPublisher PD

Mode-switching: a new technique for electronically varying the agglomeration position in an acoustic particle manipulator

Acoustic radiation forces offer a means of manipulating particles within a fluid. Much interest in recent years has focussed on the use of radiation forces in microfluidic (or “lab on a chip”) devices. Such devices are well matched to the use of ultrasonic standing waves in which the resonant dimensions of the chamber are smaller than the ultrasonic wavelength in use. However, such devices have typically been limited to moving particles to one or two predetermined planes, whose positions are determined by acoustic pressure nodes/anti-nodes set up in the ultrasonic standing wave. In most cases devices have been designed to move particles to either the centre or (more recently) the side of a flow channel using ultrasonic frequencies that produce a half or quarter wavelength over the channel, respectively.It is demonstrated here that by rapidly switching back and forth between half and quarter wavelength frequencies – mode-switching – a new agglomeration position is established that permits beads to be brought to any arbitrary point between the half and quarter-wave nodes. This new agglomeration position is effectively a position of stable equilibrium. This has many potential applications, particularly in cell sorting and manipulation. It should also enable precise control of agglomeration position to be maintained regardless of manufacturing tolerances, temperature variations, fluid medium characteristics and particle concentration

Multi-Scale Entropy Analysis as a Method for Time-Series Analysis of Climate Data

Evidence is mounting that the temporal dynamics of the climate system are changing at the same time as the average global temperature is increasing due to multiple climate forcings. A large number of extreme weather events such as prolonged cold spells, heatwaves, droughts and floods have been recorded around the world in the past 10 years. Such changes in the temporal scaling behaviour of climate time-series data can be difficult to detect. While there are easy and direct ways of analysing climate data by calculating the means and variances for different levels of temporal aggregation, these methods can miss more subtle changes in their dynamics. This paper describes multi-scale entropy (MSE) analysis as a tool to study climate time-series data and to identify temporal scales of variability and their change over time in climate time-series. MSE estimates the sample entropy of the time-series after coarse-graining at different temporal scales. An application of MSE to Central European, variance-adjusted, mean monthly air temperature anomalies (CRUTEM4v) is provided. The results show that the temporal scales of the current climate (1960–2014) are different from the long-term average (1850–1960). For temporal scale factors longer than 12 months, the sample entropy increased markedly compared to the long-term record. Such an increase can be explained by systems theory with greater complexity in the regional temperature data. From 1961 the patterns of monthly air temperatures are less regular at time-scales greater than 12 months than in the earlier time period. This finding suggests that, at these inter-annual time scales, the temperature variability has become less predictable than in the past. It is possible that climate system feedbacks are expressed in altered temporal scales of the European temperature time-series data. A comparison with the variance and Shannon entropy shows that MSE analysis can provide additional information on the statistical properties of climate time-series data that can go undetected using traditional method

Accordance to the Dietary Approaches to Stop Hypertension diet pattern and cardiovascular disease in a British, population-based cohort.

The dietary approaches to stop hypertension (DASH) diet could be an important population-level strategy to reduce cardiovascular disease (CVD) in the UK, but there is little UK-based evidence on this diet pattern in relation to CVD risk. We tested whether dietary accordance with DASH was associated with risk of CVD in a population-based sample of 23,655 UK adults. This prospective analysis of the EPIC-Norfolk cohort study analysed dietary intake (assessed using a validated food frequency questionnaire) to measure accordance with DASH, based on intakes of eight food groups and nutrients, ranking the sample into quintiles. Cox proportional hazards regression models tested for association between DASH accordance and incident stroke, ischemic heart disease (IHD) and total incident CVD (stroke and IHD only), as well as CVD mortality, non-CVD mortality and total mortality. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for age, sex, behavioral and clinical risk factors and socioeconomic status. Over an average of 12.4 years follow-up, we ascertained 4129 incident CVD events, of which stroke accounted for 1011. Compared to participants with the least DASH-accordant diets, those with the most DASH-accordant diets had 20% lower risk of incident stroke (HR, 95% CI 0.80, 0.65-0.99) and 13% lower risk of total incident CVD (0.88, 0.79-0.99) but no lower risk of CHD (0.90, 0.79-1.02). CVD-related mortality also showed strong inverse associations with DASH accordance (0.72, 0.60-0.85). This study provides evidence for the cardioprotective effects of DASH diet in a UK context

IMPROVING INTERACTION BETWEEN TECHNICAL AND CONTRACTING PERSONNEL AT NAVAL SURFACE WARFARE CENTER, PHILADELPHIA DIVISION

Organizational policy changes in contracting have created a competency gap in the pre-award phase contracting activities for acquisition professionals working in technical departments seeking procurement of products or services. Considering current contracting policies and perceived knowledge gaps in the technical community with respect to contract development, the goal of this research is to examine the organizational structure and policies of Naval Surface Warfare Center, Philadelphia Division (NSWCPD) to ensure maximum efficacy of the contracting process. The primary objective of this research is to determine what organizational policies, capability gaps, or other challenges hinder communication and collaboration between the technical and contracting departments at NSWCPD. A secondary objective of this research is to determine what initiatives can be taken at NSWCPD to improve interaction between these two working groups and to document a comprehensive strategic plan for implementation. The research team found several areas worth addressing to improve the efficacy of contract artifact development at NSWCPD. Recommendations are provided to address the communication gap, including establishing an integrated product team to improve the quality of contracting artifacts and networking amongst those teams through working groups, and to capitalize on modern technologies to ensure the production of contracting artifacts are up to speed with current technology.Civilian, Department of the NavyCivilian, Department of the NavyCivilian, Department of the NavyApproved for public release. Distribution is unlimited

Spectral Absorption Coefficient of Additive Manufacturing Polymers

As NASA turns to additive manufacturing processes, there is a need to ensure that the parts they produce are reliable. This is especially true when creating parts in space, where resources are limited and failure could result in catastrophe. Active thermography has shown potential as a non-destructive quality assurance technique for additive manufacturing processes. Heat transfer models used in active thermography techniques require accurate material property measurements in order to extract useful information about the system, including defect location. The spectral absorption coefficient, which determines the depth at which radiative power is absorbed into a surface, is a material property necessary for performing active thermography on AM polymers. This paper presents measurements of spectral absorption coefficients of polymers commonly used in additive manufacturing. Spectral absorption coefficients for fully dense PLA, ABS, and Nylon 12 samples are reported. Future work is needed to measure the spectral absorption coefficients of different materials and colored filaments commonly used in additive manufacturing

The differential associations of positive and negative symptoms with suicidality

BACKGROUND: Suicide is one of the leading causes of death in people with schizophrenia. Identifying risk factors for suicide in schizophrenia is therefore an important clinical and research priority. METHOD: A cross-sectional secondary analysis was conducted on the DNA Polymorphisms in Mental Illness Study (DPIM) data. Suicidality data was extracted, and the number of positive and negative symptoms were established for a total of 1494 participants. Logistic and negative binomial regression analyses were conducted to assess for associations between positive or negative symptoms and suicidal ideation, attempt, or number of attempts, whilst adjusting for potential confounders. RESULTS: Negative symptoms were associated with a reduction in the risk of suicidal ideation (odds ratio [OR]: 0.83; 95 % CI: 0.75-0.91) and suicide attempt (OR: 0.79; 95 % CI: 0.71-0.88) after adjusting for age and sex. Positive symptoms were associated with an increased risk of suicidal ideation (OR: 1.06; 95 % CI: 1.03-1.09), suicide attempt (OR: 1.04; 95 % CI: 1.00-1.07) and number of suicide attempts (incidence rate ratio [IRR]: 1.05; 95 % CI: 1.01-1.08). Further adjusting for depressive symptoms slightly increased the magnitude of associations with negative symptoms but attenuated associations between positive symptoms and suicidality to the null. CONCLUSIONS: Negative symptoms are associated with a reduced risk of suicidality, whilst positive symptoms are associated with an increased risk of suicidality. Depressive symptoms may confound or mediate these associations