bluuebunny/crossref_metadata_2025 huggingface dataset:
Value of Cystatin C–Based e-GFR Measurements to Predict Long-Term Tenofovir Nephrotoxicity in Patients With Hepatitis B
Authors: Koksal Ali Riza , Alkim Huseyin , Boga Salih , Iyisoy Mehmet Sinan , Sen Ilker , Tekin Neijmann Sebnem , Alkim Canan
Published: October 2016

Background:

Cystatin C is a genuine marker for detecting minor reductions in estimated glomerular filtration rate (e-GFR).

Study Question:

We aimed to investigate the efficiency of cystatin C levels in predicting nephrotoxicity due to antiviral therapy in patients with chronic hepatitis B virus infection.

Study Design:

Seventy-six naive hepatitis B virus patients and 44 controls were enrolled in this prospective cohort study.

Measures and Outcomes:

Serum cystatin C, phosphate and creatinine levels, and urinary albumin/creatinine ratios of all patients were measured at baseline, 3rd, 12th, and 24th months. Nephrotoxicity was determined according to the amount of change in creatinine level at the fourth year of treatment compared with baseline (∆Cr0-4).

Results:

Mean age was 36.1 ± 9.2 years and 40 (52.2%) of patients were women. There was no significant difference between baseline values of tenofovir disoproxil fumarate and entecavir groups. Although the creatinine level at the fourth year of treatment was statistically nonsignificant compared with baseline in the entecavir group, it was significantly higher in the fourth year of tenofovir treatment compared with baseline (0.95 ± 0.27 mg/dL vs. 0.76 ± 0.16 mg/dL, P = 0.002). While the increase in ∆Cr0-4 was ≥0.2 mg/dL in 43.2% of patients in the tenofovir group, this rate was 18.8% in the entecavir group. Diagnostic accuracy in identifying decreased renal function as area under the curve (AUC) was high for baseline serum cystatin C level; furthermore, the highest AUC was calculated for cystatin C plus creatinine–based e-GFR equation (AUC: 0.81, P < 0.001).

Conclusions:

Long-term tenofovir disoproxil fumarate nephrotoxicity can be predicted by serum cystatin C plus creatinine–based e-GFR measured before treatment.
One-Year Outcomes of Diabetes Self-Management Training Among Medicare Beneficiaries Newly Diagnosed With Diabetes
Authors: Strawbridge Larisa M. , Lloyd Jennifer T. , Meadow Ann , Riley Gerald F. , Howell Benjamin L.
Published: October 2016

Background:

Diabetes is highly prevalent among Medicare beneficiaries, resulting in costly health care utilization. Strategies to improve health outcomes, such as disease self-management, could help reduce the increasing burden of diabetes.

Objectives:

Short-term benefits of diabetes self-management training (DSMT) are established; however, longer-term impacts among Medicare beneficiaries are unknown.

Research Design:

Claims-based observational study with 1-year follow-up beginning 6 months after diabetes diagnosis.

Subjects:

Twenty percent random sample of Medicare beneficiaries newly diagnosed with diabetes during 2009–2011 who used DSMT (N=14,680), matched to a nonuser comparison group.

Measures:

We compared health service utilization and costs between DSMT users and nonusers. Health service utilization included any utilization of the hospital or emergency department (ED) and any hospitalizations due to diabetes-related ambulatory care sensitive conditions as well as the number of hospitalizations and ED visits within the follow-up year. Costs included all Medicare Parts A and B expenditures.

Results:

Multivariate regression results found that DSMT users had 14% reduced odds of any hospitalization, lower numbers of hospitalizations and ED visits (approximately 3 fewer per 100 for each), and approximately $830 lower Medicare expenditures (95% CI, −$1198, −$470) compared with nonusers. Odds of any hospitalization due to diabetes-related ambulatory care sensitive conditions and any ED visit were lower for DSMT users compared with nonusers, but the reductions were not statistically significant.

Conclusions:

Findings demonstrate benefits from DSMT use, including lower health service utilization and costs. The low cost of DSMT relative to the reduction in Medicare expenditures highlights an opportunity to reduce the burden of diabetes on both individuals and the health care system.
Identifying Specific Combinations of Multimorbidity that Contribute to Health Care Resource Utilization
Authors: Schiltz Nicholas K. , Warner David F. , Sun Jiayang , Bakaki Paul M. , Dor Avi , Given Charles W. , Stange Kurt C. , Koroukian Siran M.
Published: October 2016

Background:

Multimorbidity affects the majority of elderly adults and is associated with higher health costs and utilization, but how specific patterns of morbidity influence resource use is less understood.

Objective:

The objective was to identify specific combinations of chronic conditions, functional limitations, and geriatric syndromes associated with direct medical costs and inpatient utilization.

Design:

Retrospective cohort study using the Health and Retirement Study (2008–2010) linked to Medicare claims. Analysis used machine-learning techniques: classification and regression trees and random forest.

Subjects:

A population-based sample of 5771 Medicare-enrolled adults aged 65 and older in the United States.

Measures:

Main covariates: self-reported chronic conditions (measured as none, mild, or severe), geriatric syndromes, and functional limitations. Secondary covariates: demographic, social, economic, behavioral, and health status measures. Outcomes: Medicare expenditures in the top quartile and inpatient utilization.

Results:

Median annual expenditures were $4354, and 41% were hospitalized within 2 years. The tree model shows some notable combinations: 64% of those with self-rated poor health plus activities of daily living and instrumental activities of daily living disabilities had expenditures in the top quartile. Inpatient utilization was highest (70%) in those aged 77–83 with mild to severe heart disease plus mild to severe diabetes. Functional limitations were more important than many chronic diseases in explaining resource use.

Conclusions:

The multimorbid population is heterogeneous and there is considerable variation in how specific combinations of morbidity influence resource use. Modeling the conjoint effects of chronic conditions, functional limitations, and geriatric syndromes can advance understanding of groups at greatest risk and inform targeted tailored interventions aimed at cost containment.
Lack of Evidence for Racial Disparity in 30-Day All-Cause Readmission Rate for Older US Veterans Hospitalized with Heart Failure
Authors: Kheirbek Raya Elfadel , Wojtusiak Janusz , Vlaicu Sorina O. , Alemi Farrokh
Published: October 2016

Background:

Heart failure is the leading cause for 30-day all-cause readmission. Although racial disparities in health care are well documented, their impact on 30-day all-cause readmission rate is inconclusive.

Objective:

We examined the impact of racial disparity on 30-day readmission for hospitalized patients with heart failure.

Methods:

This is a retrospective secondary data analysis for a large veteran cohort in 130 Veterans Affairs Medical Centers. Propensity scores were used to reduce differences in age, gender, survival days, and comorbidities in index hospitalization among 46 524 whites and 14 124 African Americans (AA).

Results:

At index hospitalization, AA patients were younger (73.04 vs 67.10 years, t = −54.58, P < .000) and less likely to have myocardial infarcts (8.02% vs 9.80%, t = −6.36, P = .000), peripheral vascular disease (15.25% vs 22.51%, t = −18.68, P = .000), chronic obstructive pulmonary disease (39.59% vs 50.05%, t = −21.89, P < .000), and complicated diabetes (23.42% vs 26.24%, t = −6.73, P = .000). AA patients had lower mortality 30 days post–index hospitalization (3.51% vs 5.69%, t = −10.23, P = .000). In contrast, AA patients were more likely to have renal disease (44.03% vs 38.71%, t = 11.32, P < .000) and HIV/AIDS (1.56% vs 0.20%, t = 19.71, P < .000). The 30-day all-cause readmission rate before adjustments was 17.82% for AA patients versus 18.72% for white patients. There was no difference in the 2 rates after adjustments (18% vs 18%; odds of readmission = 1.002, z = 0.08, P = .937).

Conclusions:

In a large Department of Veterans Affairs (VA) cohort, white and AA veterans hospitalized for heart failure had similar 30-day all-cause readmission rates after adjustments were made for age, gender, survival days, and comorbidities. However, the 30-day all-cause mortality rate was higher for white patients than for AA patients. Future prospective studies are needed to validate results and test generalizability outside the VA system of care.
Patient-Centered Handovers: Ethnographic Observations of Attending and Resident Physicians
Authors: Mount-Campbell Austin F. , Rayo Michael F. , O'Brien James J. , Allen Theodore T. , Patterson Emily S.
Published: October 2016

Handover communication improvement initiatives typically employ a “one size fits all” approach. A human factors perspective has the potential to guide how to tailor interventions to roles, levels of experience, settings, and types of patients. We conducted ethnographic observations of sign-outs by attending and resident physicians in 2 medical intensive care units at one institution. Digitally audiotaped data were manually analyzed for content using codes and time spent using box plots for emergent categories. A total of 34 attending and 58 resident physician handovers were observed. Resident physicians spent more time for “soon to be discharged” and “higher concern” patients than attending physicians. Resident physicians spent less time discussing patients which they had provided care for within the last 3 days (“handbacks”). The study suggested differences for how handovers were conducted for attending and resident physicians for 3 categories of patients; handovers differ on the basis of role or level of expertise, patient type, and amount of prior knowledge of the patient. The findings have implications for new directions for subsequent research and for how to tailor quality improvement interventions based upon the role, level of experience, level of prior knowledge, and patient categories.
Incremental Prognostic Value of Quantified Vulnerable Plaque by Cardiac Computed Tomography
Authors: Dwivedi Girish , Liu Yingwei , Tewari Shrankhala , Inacio Joao , Pelletier-Galarneau Matthieu , Chow Benjamin J.W.
Published: October 2016

Background:

Coronary computed tomography (CT) angiography (CCTA) has the ability to detect, characterize, and quantify atherosclerotic plaques. The aim of our study was to evaluate the prognostic power of CCTA-quantified plaque subtypes.

Materials and Methods:

A total of 36 patients with adverse events and 36 Morise score–matched patients who remained event free on follow-up were identified. Using CCTA images, plaque subtype volumes in the major epicardial arteries were analyzed using predetermined attenuation ranges in Hounsfield units (HU): 1 to 30 HU (low attenuating), 31 to 70 HU (intermediate attenuating), 71 to 150 HU (high attenuating), and mean coronary lumen+2 SD to 1000 HU (calcified). Each epicardial artery was divided into proximal, mid, and distal segments, and plaque volumes were normalized for arterial segment length.

Results:

The baseline characteristics of the 2 cohorts were similar. Low-attenuation and intermediate-attenuation plaque volumes were greater in the proximal segments as well as in the entire length in the adverse event compared with the event-free group. High-attenuation plaque volume was increased only in the proximal segments in the adverse event group. There was no difference in the volume of calcified plaque between the 2 groups. The log rank test using a cutoff of 3.99 mm3/mm for combined intermediate and low plaque volume showed more adverse events in patients with a plaque volume of ≥3.99 mm3/mm.

Conclusions:

Adverse events appear to be associated with greater volumes of low-attenuation and intermediate-attenuation plaques that reflect lipid and fibrous atherosclerosis. The difference between the 2 groups is most apparent in the proximal epicardial arteries.
Predicting off-target effects for end-to-end CRISPR guide design
Authors: Listgarten Jennifer , Weinstein Michael , Elibol Melih , Hoang Luong , Doench John , Fusi Nicolo
Published: October 2016

The CRISPR-Cas9 system provides unprecedented genome editing capabilities. However, off-target effects lead to sub-optimal usage and additionally are a bottleneck in development of therapeutic uses. Herein, we introduce the first machine learning-based approach to this problem, yielding a state-of-the-art predictive model for CRISPR-Cas9 off-target effects which outperforms all other guide design services. Our approach, Elevation, consists of two inter-related machine learning models—one for scoring individual guide-target pairs and another which aggregates guide-target scores into a single, overall guide summary score. Through systematic investigation, we demonstrate that Elevation performs substantially better than competing approaches on both of these tasks. Additionally, we are the first to systematically evaluate approaches on the guide summary score problem; we show that the most widely-used method (and one re-implemented by several other servers) performs no better than random at times, whereas Elevation consistently outperformed it, sometimes by an order of magnitude. In our analyses, we also introduce a method to balance errors on truly active guides with those which are truly inactive, encapsulating a range of practical use cases, thereby showing that Elevation is consistently superior across the entire range. We thus contribute a new evaluation metric for benchmarking off-target modeling. Finally, because of the large computational demands of our tasks, we have developed a cloud-based service for end-to-end guide design which incorporates our previously reported on-target model, Azimuth, as well as our new off-target model, Elevation.
The non-stationary dynamics of fitness distributions: asexual model with epistasis and standing variation
Authors: Martin Guillaume , Roques Lionel
Published: October 2016

Various models describe asexual evolution by mutation, selection and drift. Some focus directly on fitness, typically modelling drift but ignoring or simplifying both epistasis and the distribution of mutation effects (travelling wave models). Others follow the dynamics of quantitative traits determining fitness (Fisher’s geometrical model), imposing a complex but fixed form of mutation effects and epistasis, and often ignoring drift. In all cases, predictions are typically obtained in high or low mutation rate limits and for long-term stationary regimes, thus loosing information on transient behaviors and the effect of initial conditions. Here, we connect fitness-based and trait-based models into a single framework, and seek explicit solutions even away from stationarity. The expected fitness distribution is followed over time via its cumulant generating function, using a deterministic approximation that neglects drift. In several cases, explicit trajectories for the full fitness distribution are obtained, for arbitrary mutation rates and standing variance. For non-epistatic mutation, especially with beneficial mutations, this approximation fails over the long term but captures the early dynamics, thus complementing stationary stochastic predictions. The approximation also handles several diminishing return epistasis models (e.g. with an optimal genotype): it can then apply at and away from equilibrium. General results arise at equilibrium, where fitness distributions display a ‘phase transition’ with mutation rate. Beyond this phase transition, in Fisher’s geometrical model, the full trajectory of fitness and trait distributions takes simple form, robust to details of the mutant phenotype distribution. Analytical arguments are explored for why and when the deterministic approximation applies.

Significance statement

How fast do asexuals evolve in new environments? Asexual fitness dynamics are well documented empirically. Various corresponding theories exist, to which they may be compared, but most typically describe stationary regimes, thus losing information on the shorter timescale of experiments, and on the impact of the initial conditions set by the experimenter. Here, a general deterministic approximation is proposed that encompasses many previous models as subcases, and shows surprising accuracy when compared to stochastic simulations. It can yield predictions over both short and long timescales, hopefully fostering the quantitative test of alternative models, using data from experimental evolution in asexuals.
A Neural Locus for Perceptually-Relevant Saccadic Suppression in Visual-Motor Neurons of the Primate Superior Colliculus
Authors: Chen Chih-Yang , Hafed Ziad M.
Published: October 2016

Saccadic eye movements cause rapid retinal-image shifts that go perceptually unnoticed several times per second. The mechanisms for perceptual saccadic suppression have been controversial, in part due to sparse understanding of neural substrates. Here we uncovered an unexpectedly specific neural locus for saccadic suppression in the primate superior colliculus (SC). We first developed a sensitive behavioral measure of perceptual suppression in two male macaque monkeys (Macaca mulatta), demonstrating known selectivity to low spatial frequencies. We then investigated visual responses in either purely visual SC neurons or anatomically-deeper visual-motor neurons, which are also involved in saccade generation commands. Surprisingly, visual-motor neurons showed the strongest visual suppression, and the suppression was dependent on spatial frequency like in perception. Most importantly, visual-motor neuron suppression selectivity was highly predictive of behavioral suppression effects in each individual animal, with our recorded population explaining up to ~74% of behavioral variance even on completely different experimental sessions. In contrast, purely visual SC neurons only had mild and unselective suppression (only explaining up to ~48% of behavioral variance). These results run contrary to a hypothesized SC mechanism for saccadic suppression, in which a motor command in the visual-motor and motor neurons is relayed to the more superficial purely visual neurons to suppress them, and to then potentially be fed back to cortex. Instead, our results indicate that an extra-retinal modulatory signal mediating perceptual suppression is already established in visual-motor neurons.

New & Noteworthy

Saccades, which repeatedly re-align the line of sight, introduce spurious signals in retinal images that normally go unnoticed. In part, this happens because of peri-saccadic suppression of visual sensitivity. Here we discovered that a specific sub-type of superior colliculus (SC) neurons may play a critical role in saccadic suppression. Curiously, it is the neurons that help mediate the saccadic command itself that exhibit perceptually-relevant changes invisualsensitivity, not the previously hypothesized purely visual neurons.
Portable and Error-Free DNA-Based Data Storage
Authors: Tabatabaei Yazdi S. M. Hossein , Gabrys Ryan , Milenkovic Olgica
Published: October 2016

DNA-based data storage is an emerging nonvolatile memory technology of potentially unprecedented density, durability, and replication efficiency1,2,3,4,5,6. The basic system implementation steps include synthesizing DNA strings that contain user information and subsequently reading them via high-throughput sequencing technologies. All existing architectures enable reading and writing, while some also allow for editing3and elementary sequencing error correction3,4. However, none of the current architectures offers error-free and random-access readouts from a portable device. Here we show through experimental and theoretical verification that such a platform may be easily implemented in practice using MinION sequencers. The gist of the approach is to design an integrated pipeline that encodes data to avoid synthesis and sequencing errors, enables random access through addressing, and leverages efficient portable nanopore sequencing via new anchored iterative alignment and insertion/deletion error-correcting codes. Our work represents the only known random access DNA-based data storage system that uses error-prone MinION sequencers and produces error-free readouts with the highest reported information rate and density.
Polyphyletic ancestry of expanding Patagonian Chinook salmon populations
Authors: Correa Cristian , Moran Paul
Published: October 2016

Chinook salmon native to North America are spreading through South America’s Patagonia and have become the most widespread anadromous salmon invasion ever documented. To better understand the colonization history and role that genetic diversity might have played in the founding and radiation of these new populations, we characterized ancestry and genetic diversity across latitude (39-48°S). Samples from four distant basins in Chile were genotyped for 13 microsatellite loci, and allocated, through probabilistic mixture models, to 148 potential donor populations in North America representing 46 distinct genetic lineages. Patagonian Chinook salmon clearly had a diverse and heterogeneous ancestry. Lineages from the Lower Columbia River were introduced for salmon open-ocean ranching in the late 1970s and 1980s, and were prevalent south of 43°S. In the north, however, a diverse assembly of lineages was found, associated with net-pen aquaculture during the 1990s. Finally, we showed that possible lineage admixture in the introduced range can confound allocations inferred from mixture models, a caveat previously overlooked in studies of this kind. While we documented high genetic and lineage diversity in expanding Patagonian populations, the degree to which diversity drives adaptive potential remains unclear. Our new understanding of diversity across latitude will guide future research.
A new synthetic route to the electron-deficient ligand tris(3,4,5-tribromopyrazol-1-yl)phosphine oxide
Authors: Nicolas Emmanuel , Cheisson Thibault , Jong G. Bas de , Tazelaar Cornelis G. J. , Slootweg J. Chris
Published: October 2016

The anionic tris(pyrazolyl)borates, or scorpionates, have proven to be extremely useful ligands. Neutral tris(pyrazolyl)methane ligands, however, are difficult to prepare and require numerous purification steps for a number of substitution patterns. We have previously outlined two different routes for accessing neutral tris(pyrazolyl) ligands. We describe here an adaptation of the previously published procedures for the synthesis of the electron-poor ligand tris(3,4,5-tribromopyrazol-1-yl)phosphine oxide, C9Br9N6OP. Similar electron-deficient ligands have been proven to unlock unique chemistry for the anionic scorpionates. The title perbrominated tris(pyrazolyl)phosphine oxide displays a network of halogen bonds in the solid state. All the bonds in the pyrazole ring are rather similar to the reported borate analogues, which makes this molecule promising as a ligand for applications where very electron-poor metal complexes are required.
Population‐level variation in senescence suggests an important role for temperature in an endangered mollusc
Authors: Hassall C. , Amaro R. , Ondina P. , Outeiro A. , Cordero‐Rivera A. , San Miguel E.
Published: October 2016

Age‐related declines in survival and function (senescence) were thought not to exist in wild populations, as organisms, and particularly in invertebrates, do not live long enough. While recent evidence has demonstrated that senescence is both common and measurable even in wild populations under field conditions, there are still organisms that are thought to exhibit ‘negligible senescence’. We explore variation in rates and patterns of senescence in the biogerontological model organism, the freshwater pearl mussel Margaritifera margaritifera, across five populations, which differ in their age profile. In particular, we tested the theory of negligible senescence using time‐at‐death records for 1091 specimens of M. margaritifera. There is clear evidence of senescence in all populations, as indicated by an increase in mortality with age, but the nature of the relationship varies subtly between populations. We find strong evidence of a mortality plateau at later ages in some populations, but this is unequivocally absent from others. We then demonstrate that the temporal scaling of the rates of senescence between five populations of M. margaritifera can be explained by the variation in the thermal environment of the population. Hence, climate change may pose a threat to the demography of this long‐lived, endangered species, and a greater understanding of the relationship between river temperature and population structure will be essential to secure the species against global temperature increases. Our findings demonstrate that useful insights can be drawn from a non‐invasive monitoring method to derive demographic data, and we suggest a wide‐scale application of this method to monitor populations across the whole latitudinal (and, hence, thermal) range of the species.
Online Sequential Learning of Neural Networks in Solar Radiation Modeling Using Hybrid Bayesian Hierarchical Approach
Authors: Hussain Sajid , AlAlili Ali
Published: October 2016

Traditional learning process in solar radiation modeling usually requires historical data to perform regularization using training and cross-validation approaches. However, in applications where no historical data are available, regularization cannot be performed using traditional techniques. This paper presents a hierarchical Bayesian framework with the extended Kalman filter (Bayesian-EKF) to perform regularization in sequential learning of the artificial neural network (ANN) for solar radiation modeling. A highly stochastic time series for daily solar radiation, the global horizontal irradiance (GHI), is modeled based on different meteorological variables including temperature (T), relative humidity (RH), wind speed (WS), and sunshine duration (SSD). A comparison is made with well-known methods including the ANN-based nonlinear autoregressive with exogenous inputs neural network (NARX-NN) and Wiener filter-based multivariate linear regression (MLR). The method is validated on test data using coefficient of determination (R2) and root mean squared error (RMSE). The proposed technique effectively estimates the noise components in the data and achieves superior performance as compared to the traditional learning processes of NARX-NN and MLR. Moreover, it is more robust to statistical outliers in the data and does not require prior history for training and cross-validation. In the presence of the outliers, the performance of the NARX-NN degrades from R2 = 94.73% to R2 = 85.85% but there is virtually no difference in the case of Bayesian-EKF. Over and above, MLR performs better than NARX-NN but worse than Bayesian-EKF.
Extraction of bulk and interface trap densities in amorphous InGaZnO thin-film transistors
Authors: Jeong Chan-Yong , Kim Hee-Joong , Kim Jong In , Lee Jong-Ho , Kwon Hyuck-In
Published: October 2016

The authors determine the density of interface and bulk trap states in the amorphous indium-gallium-zinc oxide (a-IGZO) thin-film transistors (TFTs) by using a simple extraction method. To determine the bulk trap density, the current–voltage curve is measured between the source and drain electrodes of the TFT at room temperature under the flat-band condition. In the high voltage region, the carrier transport is well described by the space charge limited current controlled by the bulk trap states that are exponentially distributed in energy with a trap density at the conduction band edge of 6.27 × 1017 cm−3 eV−1 and an inverse slope for the trap distribution of 0.12 eV. The density of traps at the a-IGZO/gate dielectric interface is calculated by subtracting the bulk trap components from the density of total subgap trap states extracted from the subthreshold slope in the transfer curve and the frequency-independent capacitance-voltage characteristics. The experimental results show that the contribution of the interface trap is more significant compared to that of the bulk trap in the subgap density of states of the fabricated a-IGZO TFTs.
Niche- Versus Mainstream-Sport Spectators: An Analysis of Need for Uniqueness and Sport eFANgelism
Authors: Dwyer Brendan , Greenhalgh Greg , LeCrom Carrie
Published: October 2016

The sport marketplace is overcrowded, and contemporary sport fans have more choices than ever. This makes it difficult for new teams, leagues, and sports to enter the marketplace. In addition, a cultural oligarchy of mainstream sport leagues currently dominates media coverage. As a result, marketers and managers of emerging sports need to understand the attributes for which sport fans connect with entities. Little is known, however, about the differences between fans of niche (emerging or nonmainstream) sports and their mainstream-sport counterparts. Guided by social-identity theory, this study explored the dispositional and behavioral differences between niche- and mainstream-sport fans as a means of psychometric and behavioral segmentation. In particular, an individual’s need for uniqueness and communication behaviors were compared. The results suggest that dispositional differences between the segments were minimal. However, potentially important behavioral differences were uncovered related to how sport fans assimilate with others and advertise their sport affiliations.
Fluid Retention and Utility of Practical Hydration Markers to Detect Three Levels of Recovery Fluid Intake in Male Runners
Authors: Wilcoxson Mary Caitlin Stevenson , Johnson Samantha Louise , Pribyslavska Veronika , Green James Mathew , O’Neal Eric Kyle
Published: October 2016

Runners are unlikely to consume fluid during training bouts increasing the importance of recovery rehydration efforts. This study assessed urine specific gravity (USG) responses following runs in the heat with different recovery fluid intake volumes. Thirteen male runners completed 3 evening running sessions resulting in approximately 2,200 ± 300 ml of sweat loss (3.1 ± 0.4% body mass) followed by a standardized dinner and breakfast. Beverage fluid intake (pre/postbreakfast) equaled 1,565/2,093 ml (low; L), 2,065/2,593 ml (moderate; M) and 2,565/3,356 mL (high; H). Voids were collected in separate containers. Increased urine output resulted in no differences (p > .05) in absolute mean fluid retention for waking or first postbreakfast voids. Night void averages excluding the first void postrun (1.025 ± 0.008; 1.013 ± 0.008; 1.006 ± 0.003), first morning (1.024 ± 0.004; 1.015 ± 0.005; 1.014 ± 0.005), and postbreakfast (1.022 ± 0.007; 1.014 ± 0.007; 1.008 ± 0.003) USG were higher (p < .05) for L versus M and H respectively and more clearly differentiated fluid intake volume between L and M than color or thirst sensation. Waking (r = -0.66) and postbreakfast (r = -0.71) USG were both significantly correlated (p < .001) with fluid replacement percentage, but not absolute fluid retention. Fluid intake M was reported as most similar to normal consumption (5.6 ± 1.0 on 0–10 scale) after breakfast and equaled 122 ± 16% of sweat losses. Retention data suggests consumption above this level is not warranted or actually practiced by most runners drinking ad libitum, but that periodic prerun USG assessment may be useful for coaches to detect runners that habitually consume low levels of fluids between training bouts in warm seasons.
Extreme Rapid Weight Loss and Rapid Weight Gain Observed in UK Mixed Martial Arts Athletes Preparing for Competition
Authors: Matthews Joseph John , Nicholas Ceri
Published: October 2016

There is a lack of research documenting the weight-making practices of mixed-martial-arts (MMA) competitors. The purpose of the investigation was to quantify the magnitude and identify the methods of rapid weight loss (RWL) and rapid weight gain (RWG) in MMA athletes preparing for competition. Seven athletes (mean ± SD, age 24.6 ± 3.5 yrs, body mass 69.9 ± 5.7 kg, competitive experience 3.1 ± 2.2 yrs) participated in a repeated-measures design. Measures of dietary intake, urinary hydration status, and body mass were recorded in the week preceding competition. Body mass decreased significantly (p < .0005) from baseline by 5.6 ± 1.4 kg (8 ± 1.8%). During the RWG period (32 ± 1 hr) body mass increased significantly (p < .001) by 7.4 ± 2.8 kg (11.7 ± 4.7%), exceeding RWL. Mean energy and carbohydrate intake were 3176 ± 482 kcal・day-1 and 471 ± 124 g・day-1, respectively. At the official weigh-in 57% of athletes were dehydrated (1033 ± 19 mOsmol・kg-1) and the remaining 43% were severely dehydrated (1267 ± 47 mOsmol・kg-1). Athletes reported using harmful dehydration-based RWL strategies, including sauna (43%) and training in plastic suits (43%). Results demonstrated RWG greater than RWL, this is a novel finding and may be attributable to the 32 hr duration from weigh-in till competition. The observed magnitude of RWL and strategies used are comparable to those which have previously resulted in fatalities. Rule changes which make RWL impractical should be implemented with immediate effect to ensure the health, safety and wellbeing of competitors.
Relative impacts of mitigation, temperature, and precipitation on 21st-century megadrought risk in the American Southwest
Authors: Ault Toby R. , Mankin Justin S. , Cook Benjamin I. , Smerdon Jason E.
Published: October 2016

Higher temperatures will make megadroughts more likely in the American Southwest, but cutting emissions reduces risk.
Chromatin untangled: New methods map genomic structure
Authors: Perkel Jeffrey M.
Published: October 2016

With some 2 meters of DNA squished into the micron-sized nucleus of every mammalian cell, to call that space "cozy" is an understatement. Yet for cells, the genome poses issues not only of compaction but of functionality: The DNA must be packaged such that it remains accessible to gene regulatory factors. Indeed, chromatin architecture plays a key role in gene regulation, but until recently, researchers had few tools with which to study that relationship.

Read the Feature (Full-Text HTML)

Read the Feature (PDF)

Read New Products (PDF)
Transgenerational inheritance: Models and mechanisms of non–DNA sequence–based inheritance
Authors: Miska Eric A. , Ferguson-Smith Anne C.
Published: October 2016

Heritability has traditionally been thought to be a characteristic feature of the genetic material of an organism—notably, its DNA. However, it is now clear that inheritance not based on DNA sequence exists in multiple organisms, with examples found in microbes, plants, and invertebrate and vertebrate animals. In mammals, the molecular mechanisms have been challenging to elucidate, in part due to difficulties in designing robust models and approaches. Here we review some of the evidence, concepts, and potential mechanisms of non–DNA sequence–based transgenerational inheritance. We highlight model systems and discuss whether phenotypes are replicated or reconstructed over successive generations, as well as whether mechanisms operate at transcriptional and/or posttranscriptional levels. Finally, we explore the short- and long-term implications of non–DNA sequence–based inheritance. Understanding the effects of non–DNA sequence–based mechanisms is key to a full appreciation of heritability in health and disease.
The MIFstep in parthanatos
Authors: Jonas Elizabeth
Published: October 2016

Preventing cells from killing themselves may save tissues from damage during disease

[Also see Research Article by

Yingfei
et al.

]
Roger Y. Tsien (1952–2016)
Authors: Lippard Stephen J.
Published: October 2016

An exceptionally creative scientist shed light (of many colors) on biological mysteries
Gene-environment interplay
Authors: Berg Jeremy
Published: October 2016

The advent of increasingly powerful and inexpensive DNA sequencing methods is changing many aspects of genetics research. In particular, human genome sequencing is transforming our understanding of many aspects of human biology and medicine. However, we must be careful to remember that genes alone do not determine our futures—environmental factors and chance also play important roles.
Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax
Authors: Chen Wilbur H. , Pasetti Marcela F. , Adhikari Rajan P. , Baughman Holly , Douglas Robin , El-Khorazaty Jill , Greenberg Nancy , Holtsberg Frederick W. , Liao Grant C. , Reymann Mardi K. , Wang Xiaolin , Warfield Kelly L. , Aman M. Javad
Published: October 2016

Staphylococcus aureus
produces several enterotoxins and superantigens, exposure to which can elicit profound toxic shock. A recombinant staphylococcal enterotoxin B (rSEB) containing 3 distinct mutations in the major histocompatibility complex class II binding site was combined with an alum adjuvant (Alhydrogel) and used as a potential parenteral vaccine named STEBVax. Consenting healthy adult volunteers (age range, 23 to 38 years) participated in a first-in-human open-label dose escalation study of parenteral doses of STEBVax ranging from 0.01 μg up to 20 μg. Safety was assessed by determination of the frequency of adverse events and reactogenicity. Immune responses to the vaccination were determined by measurement of anti-staphylococcal enterotoxin B (anti-SEB) IgG by enzyme-linked immunosorbent assay and a toxin neutralization assay (TNA). Twenty-eight participants were enrolled in 7 dosing cohorts. All doses were well tolerated. The participants exhibited heterogeneous baseline antibody titers. More seroconversions and a faster onset of serum anti-SEB IgG toxin-neutralizing antibodies were observed by TNA with increasing doses of STEBVax. There was a trend for a plateau in antibody responses with doses of STEBVax of between 2.5 and 20 μg. Among the participants vaccinated with 2.5 μg to 20 μg of STEBVax, ∼93% seroconverted for SEB toxin-neutralizing antibody. A strong correlation between individual SEB-specific serum IgG antibody titers and the neutralization of gamma interferon production was found
in vitro
. STEBvax appeared to be safe and immunogenic, inducing functional toxin-neutralizing antibodies. These data support its continued clinical development. (This study has been registered at ClinicalTrials.gov under registration no. NCT00974935.)
The Intracellular Cholesterol Transport Inhibitor U18666A Inhibits the Exosome-Dependent Release of Mature Hepatitis C Virus
Authors: Elgner Fabian , Ren Huimei , Medvedev Regina , Ploen Daniela , Himmelsbach Kiyoshi , Boller Klaus , Hildt Eberhard
Published: October 2016

Hepatitis C virus (HCV) particles are described as lipoviroparticles which are released similarly to very-low-density lipoproteins (VLDLs). However, the release mechanism is still poorly understood; the canonical endoplasmic reticulum-Golgi intermediate compartment (ERGIC) pathway as well as endosome-dependent release has been proposed. Recently, the role of exosomes in the transmission of HCV has been reported. Only a minor fraction of the
de novo
-synthesized lipoviroparticles is released by the infected cell. To investigate the relevance of multivesicular bodies (MVBs) for viral morphogenesis and release, the MVB inhibitor U18666A was used. Intracellular trafficking was analyzed by confocal microscopy and electron microscopy. Moreover, an mCherry-tagged HCV variant was used. Conditions were established that enable U18666A-dependent inhibition of MVBs without affecting viral replication. Under these conditions, significant inhibition of the HCV release was observed. The assembly of viral particles is not affected. In U18666A-treated cells, intact infectious viral particles accumulate in CD63-positive exosomal structures and large dysfunctional lysosomal structures (multilamellar bodies). These retained particles possess a lower density, reflecting a misloading with lipids. Our data indicate that at least a fraction of HCV particles leaves the cell via the endosomal pathway. Endosomes facilitate the sorting of HCV particles for release or degradation.

IMPORTANCE
There are still a variety of open questions regarding morphogenesis and release of hepatitis C virus. The HCV-infected cell produces significant more viral particles that are released, raising the question about the fate of the nonreleased particles. Moreover, the relevance of the endosomal pathway for the release of HCV is under debate. Use of the MVB (multivesicular body) inhibitor U18666A enabled a detailed analysis of the impact of MVBs for viral morphogenesis and release. It was revealed that infectious, fully assembled HCV particles are either MVB-dependently released or intracellularly degraded by the lysosome. Our data indicate that at least a fraction of HCV particles leaves the cell via the endosomal pathway independent from the constitutive secretory pathway. Our study describes a so-far-unprecedented cross talk between two pathways regulating on the one hand the release of infectious viral particles and on the other hand the intracellular degradation of nonreleased particles.
Repression of the Chromatin-Tethering Domain of Murine Leukemia Virus p12
Authors: Brzezinski Jonathon D. , Modi Apexa , Liu Mengdan , Roth Monica J.
Published: October 2016

Murine leukemia virus (MLV) p12, encoded within Gag, binds the viral preintegration complex (PIC) to the mitotic chromatin. This acts to anchor the viral PIC in the nucleus as the nuclear envelope re-forms postmitosis. Mutations within the p12 C terminus (p12 PM13 to PM15) block early stages in viral replication. Within the p12 PM13 region (p12
60
PSPMA
65
), our studies indicated that chromatin tethering was not detected when the wild-type (WT) p12 protein (M63) was expressed as a green fluorescent protein (GFP) fusion; however, constructs bearing p12-I63 were tethered. N-terminal truncations of the activated p12-I63-GFP indicated that tethering increased further upon deletion of p12
25
DLLTEDPPPY
34
, which includes the late domain required for viral assembly. The p12 PM15 sequence (p12
70
RREPP
74
) is critical for wild-type viral viability; however, virions bearing the PM15 mutation (p12
70
AAAAA
74
) with a second M63I mutant were viable, with a titer 18-fold lower than that of the WT. The p12 M63I mutation amplified chromatin tethering and compensated for the loss of chromatin binding of p12 PM15. Rescue of the p12-M63-PM15 nonviable mutant with prototype foamy virus (PFV) and Kaposi's sarcoma herpesvirus (KSHV) tethering sequences confirmed the function of p12
70–74
in chromatin binding. Minimally, full-strength tethering was seen with only p12
61
SPIASRLRGRR
71
fused to GFP. These results indicate that the p12 C terminus alone is sufficient for chromatin binding and that the presence of the p12
25
DLLTEDPPPY
34
motif in the N terminus suppresses the ability to tether.

IMPORTANCE
This study defines a regulatory mechanism controlling the differential roles of the MLV p12 protein in early and late replication. During viral assembly and egress, the late domain within the p12 N terminus functions to bind host vesicle release factors. During viral entry, the C terminus of p12 is required for tethering to host mitotic chromosomes. Our studies indicate that the p12 domain including the PPPY late sequence temporally represses the p12 chromatin tethering motif. Maximal p12 tethering was identified with only an 11-amino-acid minimal chromatin tethering motif encoded at p12
61–71
. Within this region, the p12-M63I substitution switches p12 into a tethering-competent state, partially rescuing the p12-PM15 tethering mutant. A model for how this conformational change regulates early versus late functions is presented.
Protective Capacity of the Human Anamnestic Antibody Response during Acute Dengue Virus Infection
Authors: Xu Meihui , Züst Roland , Toh Ying Xiu , Pfaff Jennifer M. , Kahle Kristen M. , Davidson Edgar , Doranz Benjamin J. , Velumani Sumathy , Tukijan Farhana , Wang Cheng-I , Fink Katja
Published: October 2016

Half of the world's population is exposed to the risk of dengue virus infection. Although a vaccine for dengue virus is now available in a few countries, its reported overall efficacy of about 60% is not ideal. Protective immune correlates following natural dengue virus infection remain undefined, which makes it difficult to predict the efficacy of new vaccines. In this study, we address the protective capacity of dengue virus-specific antibodies that are produced by plasmablasts a few days after natural secondary infection. Among a panel of 18 dengue virus-reactive human monoclonal antibodies, four groups of antibodies were identified based on their binding properties. While antibodies targeting the fusion loop of the glycoprotein of dengue virus dominated the antibody response, two smaller groups of antibodies bound to previously undescribed epitopes in domain II of the E protein. The latter, largely serotype-cross-reactive antibodies, demonstrated increased stability of binding at pH 5. These antibodies possessed weak to moderate neutralization capacity
in vitro
but were the most efficacious in promoting the survival of infected mice. Our data suggest that the cross-reactive anamnestic antibody response has a protective capacity despite moderate neutralization
in vitro
and a moderate decrease of viremia
in vivo
.

IMPORTANCE
Antibodies can protect from symptomatic dengue virus infection. However, it is not easy to assess which classes of antibodies provide protection because
in vitro
assays are not always predictive of
in vivo
protection. During a repeat infection, dengue virus-specific immune memory cells are reactivated and large amounts of antibodies are produced. By studying antibodies cloned from patients with heterologous secondary infection, we tested the protective value of the serotype-cross-reactive “recall” or “anamnestic” response. We found that results from
in vitro
neutralization assays did not always correlate with the ability of the antibodies to reduce viremia in a mouse model. In addition, a decrease of viremia in mice did not necessarily improve survival. The most protective antibodies were stable at pH 5, suggesting that antibody binding in the endosomes, after the antibody-virus complex is internalized, might be important to block virus spread in the organism.