bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Perspectives on Alcohol use Disorder Pharmacotherapy and Integration of Treatment into Primary Care Settings
Authors: Haley Sean J. , Pinsker Erika A. , Gerould Heather , Wisdom Jennifer P. , Hagedorn Hildi J.
Published: March 2019

Background

Evidence-based pharmacotherapies for alcohol use disorders (AUDs) are underutilized. This mixed-methods study reports supplementary findings from the alcohol use disorder pharmacotherapy and treatment in primary care (ADaPT-PC) implementation study at 3 Veterans Health Administration (VHA) hospital sites to understand why prescription rates did not increase following the ADaPT-PC intervention.

Methods

Qualitative interviews ( N = 30) were conducted in advance of the ADaPT-PC intervention to understand patients’ pharmacotherapy attitudes among those in AUD treatment, with previous treatment experience, or who needed assistance with their alcohol use. Following the ADaPT-PC intervention, chart reviews from a random sample of patients with AUD or a most recent Alcohol Use Disorders Identification Test consumption questions (AUDIT-C) score >8, and no active AUD prescription, were conducted to determine the frequency of alcohol-related conversations ( N = 455).

Results

Most interviewed patients welcomed a discussion about their alcohol use and pharmacotherapy. Of the 15 medication-naïve patients interviewed, 6 stated that they would be willing to try pharmacotherapy, 5 stated that they were unlikely, 2 identified reservations, 1 said no, and 1 was not asked. Fifteen patients were either currently taking medications ( n = 10) or had taken medication in the past ( n = 7; 2 patients had past and current experience). Chart reviews indicated that although 66% of charts ( n = 299) documented a discussion of their alcohol use with the provider, only 7.5% ( n = 22) of individuals with an AUD diagnosis had a documented discussion of AUD pharmacotherapy, and only 5 received pharmacotherapy.

Conclusion

Most interviewed patients were open to discussing AUD treatment, including discussions of pharmacotherapy, with their provider. From documented conversations about alcohol use to treatment options, medical records suggests a continuous narrowing of the number of patients engaged in alcohol-related consultations. Although some interviewed patients expressed reticence about initiating pharmacotherapy, these findings suggest that the treatment cascade may have a greater influence on the number of pharmacotherapy prescriptions than patients’ preferences.
The FIFA 11 programme reduces the costs associated with ankle and hamstring injuries in amateur Spanish football players: A retrospective cohort study
Authors: Nouni‐Garcia Rauf , Asensio‐Garcia María Rosario , Orozco‐Beltran Domingo , Lopez‐Pineda Adriana , Gil‐Guillen Vicente F. , Quesada Jose A. , Bernabeu Casas Roberto Carlos , Carratala‐Munuera Concepcion
Published: March 2019

This study aimed to assess the cost‐effectiveness of the “Fédération Internationale de Football Association (FIFA) 11” injury prevention programme for ankle and hamstring injuries. This retrospective cohort study included eighty‐four male amateur football players aged 18–40 years. The exposed group performed the FIFA 11 protocol twice a week throughout the 2010–2011 and 2011–2012 seasons; the unexposed group performed the usual training during the 2008–2009 and 2009–2010 seasons. Lateral ankle ligament and hamstring injuries were recorded over the whole study period. We compared the mean costs associated with lateral ankle ligament and hamstring injuries in the two groups. The mean cost per player and lateral ankle injury was EUR 928 in the unexposed group versus EUR 647 in the exposed group (p = 0.19). The mean cost of hamstring injury per player was EUR 1271 in the unexposed group versus EUR 742 in the exposed group (p = 0.028). The mean total cost per player was EUR 2199 in the unexposed group versus EUR 1273 in the exposed group (p = 0.008). We concluded that the use of the FIFA 11 injury prevention programme reduced both the direct and indirect costs associated with lateral ankle ligament and hamstring injuries.
Higher order expansions for the probabilistic local Cauchy theory of the cubic nonlinear Schrödinger equation on ℝ³
Authors: Bényi Árpád , Oh Tadahiro , Pocovnicu Oana
Published: March 2019

We consider the cubic nonlinear Schrödinger equation (NLS) on

R

3

\mathbb {R}^3

with randomized initial data. In particular, we study an iterative approach based on a partial power series expansion in terms of the random initial data. By performing a fixed point argument around the second order expansion, we improve the regularity threshold for almost sure local well-posedness from our previous work. We further investigate a limitation of this iterative procedure. Finally, we introduce an alternative iterative approach, based on a modified expansion of arbitrary length, and prove almost sure local well-posedness of the cubic NLS in an almost optimal regularity range with respect to the original iterative approach based on a power series expansion.
Both/And
Authors: Felski Rita
Published: March 2019

This essay responds to Winfried Fluck’s review of The Limits of Critique (2015). While appreciating the care and attention with which Fluck reads my book, I do not see the book as displaying a “corporeal bias.” While it addresses the role of mood and disposition, it also stresses the importance of interpretation, thought, and meaning. I also clarify that The Limits of Critique is not an argument against routine as such—quite the opposite—but seeks to clarify the specific contradictions that arise from the routinization of critique. How does the status of critique change when the rhetoric of defamiliarization becomes all too familiar and a discourse of transgression and resistance is a required academic methodology?
Time for a change: patterns of sex expression, health and mortality in a sex-changing tree
Authors: Blake-Mahmud Jennifer , Struwe Lena
Published: March 2019

Background and Aims

The ability of individuals to change sex during their lifetime is known as environmental sex determination (ESD). This represents a unique life history trait, allowing plants to allocate resources differentially to male and female functions across lifetimes, potentially maximizing fitness in response to changing environmental or internal cues. In this study, Acer pensylvanicum, a species with an unconfirmed sex determination system, was investigated to see what patterns in sex expression existed across multiple years, if there were sex-based differences in growth and mortality, and whether this species conformed to theoretical predictions that females are larger and in better condition.

Methods

Patterns of sex expression were documented over 4 years in a phenotypically subdioecious A. pensylvanicum population located in New Jersey, USA, and data on size, mortality, health and growth were collected. A machine-learning algorithm known as a boosted classification tree was used to develop a model to predict the sex of a tree based on its condition, size and previous sex.

Results

In this study, 54 % of the trees switched sex expression during a 4-year period, with 26 % of those trees switching sex at least twice. Consistently monoecious trees could change relative sex expression by as much as 95 %. Both size and condition were influential in predicting sex, with condition exerting three times more relative influence than size on expressed sex. Contrary to theoretical predictions, the model showed that full female sex expression did not increase with size. Healthy trees were more likely to be male; predicted female sex expression increased with deteriorating health. Growth rate negatively correlated with multiple years of female sex expression. Populations maintained similar male-skewed sex ratios across years and locations and may result from differential mortality: 75 % of dead trees flowered female immediately before death.

Conclusions

This study shows conclusively that A. pensylvanicum exhibits ESD and that femaleness correlates with decreased health, in contrast to prevailing theory. The mortality findings advance our understanding of puzzling non-equilibrium sex ratios and life history trade-offs resulting from male and female sex expression.
Lower Respiratory Tract Infections in Children in a Well-vaccinated South African Birth Cohort: Spectrum of Disease and Risk Factors
Authors: le Roux David M , Nicol Mark P , Myer Landon , Vanker Aneesa , Stadler Jacob A M , von Delft Eckart , Zar Heather J
Published: March 2019

Background

Childhood lower respiratory tract infections (LRTIs) cause substantial morbidity and under-5 child mortality. The epidemiology of LRTI is changing in low- and middle-income countries with expanding access to conjugate vaccines, yet there are few data on the incidence and risk factors for LRTI in these settings.

Methods

A prospective birth cohort enrolled mother–infant pairs in 2 communities near Cape Town, South Africa. Active surveillance for LRTI was performed for the first 2 years of life over 4 respiratory seasons. Comprehensive data collection of risk factors was done through 2 years of life. World Health Organization definitions were used to classify clinical LRTI and chest radiographs.

Results

From March 2012 to February 2017, 1143 children were enrolled and followed until 2 years of age. Thirty-two percent of children were exposed to antenatal maternal smoking; 15% were born at low birth weights. Seven hundred ninety-five LRTI events occurred in 429 children by February 2017; incidence of LRTI was 0.51 and 0.25 episodes per child-year in the first and second years of life, respectively. Human immunodeficiency virus (HIV)–exposed, uninfected infants (vs HIV-unexposed infants) were at increased risk of hospitalized LRTI in the first 6 months of life. In regression models, male sex, low birth weight, and maternal smoking were independent risk factors for both ambulatory and hospitalized LRTI; delayed or incomplete vaccination was associated with hospitalized LRTI.

Conclusions

LRTI incidence was high in the first year of life, with substantial morbidity. Strategies to ameliorate harmful exposures are needed to reduce LRTI burden in vulnerable populations.
Comparative urbanization of birds in China and Europe based on birds associated with trees
Authors: Møller Anders Pape , Xia Canwei , ZHou Bo , Che Xianli , CHu Xingzhi , Feng Changzhang , Laursen Karsten , Morelli Federico , Li Wangming , Liu Jianping , Quan Qing , Zhang Min , Zhang Qiang , ZHan Qiangwen , Ma Laikun , Wang Haitao , Zou Fasheng , Liang Wei
Published: March 2019

Urbanization effects on living organisms are spatially heterogeneous. Here we quantified the abundance of birds per tree in forested urban and rural habitats for 85,829 trees mainly in China and Europe. A population model was based on the assumption that: 1) birds have a normally distributed habitat preference; 2) an increase in population size linked to the habitat preference; 3) a population size dependent on the habitat preference; and 4) the removal of a certain fraction of individuals giving rise to extinction. We tested for large-scale differences in the impact of urbanization on the frequency distribution of the difference in abundance between urban and rural habitats in China and parts of Europe. The difference in the frequency distribution of urban population density of birds in trees minus rural population density of birds in trees in China and Europe was statistically significant, suggesting that the abundance of birds differed between trees in urban and rural habitats, but more so in China than in Europe. We hypothesize that more pronounced differences in China than in Europe may have arisen due to the Four Pests Campaign in 1958–1962 that resulted in death of hundreds of millions of birds (mainly tree sparrows Passer montanus, but also numerous other less common species that were starting to become urbanized around 1960). Species that were less common in 1960 could not sustain reductions in population size in urban areas and hence these species are still rare or absent in urban areas today 60 years later.
Evaluating Forest Biomass Recovery in South Central Alabama Pine Plantations
Authors: Grace J Mcfero , Klepac J F , Taylor Steve E
Published: March 2019

Improved use of forest biomass has been presented as a viable option to satisfy a portion of the demand for sustainable alternative sources of energy. Yet, there are considerable gaps in our understanding related to the efficiencies of current state-of-the-art forest biomass recovery systems. Southern pine plantation biomass stands typically exhibit higher stand densities and smaller-diameter trees than conventional stands, which, in turn, may result in reduced recovery efficiencies. In this study, the impact of new harvest systems for biomass recovery was investigated in typical southern pine plantation biomass harvests. Specifically, spatial and temporal effects on residue distribution were examined following biomass harvest of 14- and 24-year-old loblolly pine plantations. Preharvest total standing biomass for the younger site at 90 t ac–1 (220 t hectare–1) was half that of the older site at 160 t ac–1 (390 t hectare–1). Although the analysis detected no significant temporal effects on residue distributions, the preharvest condition exhibited 100 percent ground cover, whereas postharvest conditions had nearly 20 percent of the area designated as bare. Two of the five residue classifications, light debris and litter-herbaceous, were found to have a significantly higher incidence of occurrence than the other residue classifications on the sites based on a multinomial regression. In general, we found recovery efficiencies for both sites of 80 percent or greater for both methods of determination, by destructive sampling and based on load tickets.
Population structure and spatial distribution of porbeagles (Lamna nasus) in Irish waters
Authors: Cameron Luke W J , Roche William K , Houghton Jonathan D R , Mensink Paul J
Published: March 2019

Porbeagles throughout the North Atlantic have experienced severe population decline through overfishing, with the northeastern population listed as critically endangered. Management of this population is constrained by the paucity of data on porbeagle population structure, distribution and behaviour in this region. Here we use a long-term (47 year) Irish capture-mark-recapture dataset to investigate the population structure, spatial distribution and seasonal movements of this species. From 1970–2017, a total of 268 sharks (9 recaptures) were ID tagged, with most individuals likely being juvenile based on length at maturity estimates (mean total length = 143.9 cm, SD = 35.4). Almost all captures were recorded at three distinct locations near angling hubs along the south, west and north coasts with catches peaking in August. Long-term trends in capture date indicated a shift towards earlier capture dates in the northern site (n = 153). Our findings suggest Irish waters may act as a persistent summer aggregation site for juveniles, which show evidence for seasonal site fidelity, returning to nearby locations between years. These findings demonstrate the utility of such programmes, which can be implemented, with minimal expense by engaging with the angling sector, to elucidate the population structure and distribution of wide-ranging fish species.
What Is the Dose-Response Relationship Between Exercise and Cardiorespiratory Fitness After Stroke? A Systematic Review
Authors: Galloway Margaret , Marsden Dianne L , Callister Robin , Erickson Kirk I , Nilsson Michael , English Coralie
Published: March 2019

Background

Exercise after stroke improves cardiorespiratory fitness and walking capacity; however, the effect of altering exercise dose (via frequency, intensity, time, and type) on fitness or walking capacity is unclear.

Purpose

The purpose of this study was to synthesize the current evidence for the effects of different doses of exercise on cardiorespiratory fitness and walking capacity in people after stroke.

Data Sources

Seven relevant electronic databases were searched using keywords relating to stroke and cardiorespiratory fitness.

Study Selection

Trials that compared more than 1 dose of exercise for people (≥ 18 years old) after stroke and measured peak oxygen consumption or 6-minute walk test distance as an outcome were included. Two reviewers independently appraised all trials.

Data Extraction

Two reviewers independently extracted data from included articles. Intervention variables were extracted in accordance with the Template for Intervention Description and Replication checklist.

Data Synthesis

Data were synthesized narratively. Nine trials involving 279 participants were included. Three of 5 trials comparing exercise intensity showed that higher-intensity training was associated with greater improvements in cardiorespiratory fitness. The effects of other exercise dose components (frequency, time, and type) on fitness were not determined. Overall, walking capacity improved as program length increased.

Limitations

All trials had a high risk of bias, and most had a high rate of attrition. Most trials included people more than 6 months after stroke and who walked independently, limiting the generalizability of the findings.

Conclusions

Exercising at an intensity greater than 70% of heart rate reserve can be more effective in increasing cardiorespiratory fitness after stroke than exercising at lower intensities. More trials that compare exercise doses by manipulating only 1 dose parameter at a time for people after stroke are needed.
Medication adherence among patients with chronic diseases: a survey-based study in pharmacies
Authors: Jüngst C , Gräber S , Simons S , Wedemeyer H , Lammert F
Published: March 2019

Background

Poor adherence to medication leads to worsening of the disease, increased mortality and substantial rise in health care costs.

Aim

It was our aim to evaluate drug adherence and influencing factors in a cohort of non-selected adult pharmacy customers with various chronic diseases and following long-term treatment.

Design and Methods

We conducted an 8 week anonymized survey in 152 German pharmacies using the Morisky Medication Adherence Scale to measure medication adherence and a questionnaire comprising questions on multiple factors with potential impact on adherence. Depression was assessed applying the Patient Health Questionnaire-9.

Results

In total, 1192 patients were included showing an overall adherence rate of 59.1%. A positive association to drug adherence was found in univariate analysis for non-smoking status, retirement, less disease related complaints, positive belief in drug effects, comprehensive knowledge about the disease and high quality of care by the physician and pharmacist. Multivariate regression analysis revealed that no or minimal depression (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.7–3.0), higher patient age (>63 years) (OR 2.2, CI 1.7–2.8), high perceived importance of the medication (OR 2.0, CI 1.5–2.6), good tolerability of the medication (OR 2.0, CI 1.2–3.5) and drug effect as expected or better (OR 1.6, CI 1.1–2.3) were positively correlated with adherence.

Conclusions

Suboptimal adherence to medication is common in pharmacy customers with chronic diseases. The determined factors influencing adherence may help to identify patients at risk for nonadherence and support the need of improvement in physicians’ communication with patients to achieve adequate adherence rates.
The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency
Authors: Thomas Russell S , Bahadori Tina , Buckley Timothy J , Cowden John , Deisenroth Chad , Dionisio Kathie L , Frithsen Jeffrey B , Grulke Christopher M , Gwinn Maureen R , Harrill Joshua A , Higuchi Mark , Houck Keith A , Hughes Michael F , Hunter E Sidney , Isaacs Kristin K , Judson Richard S , Knudsen Thomas B , Lambert Jason C , Linnenbrink Monica , Martin Todd M , Newton Seth R , Padilla Stephanie , Patlewicz Grace , Paul-Friedman Katie , Phillips Katherine A , Richard Ann M , Sams Reeder , Shafer Timothy J , Setzer R Woodrow , Shah Imran , Simmons Jane E , Simmons Steven O , Singh Amar , Sobus Jon R , Strynar Mark , Swank Adam , Tornero-Valez Rogelio , Ulrich Elin M , Villeneuve Daniel L , Wambaugh John F , Wetmore Barbara A , Williams Antony J
Published: March 2019

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA’s Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.
Disease Incidence in Sugar Beet Fields Is Correlated with Microbial Diversity and Distinct Biological Markers
Authors: Kusstatscher Peter , Cernava Tomislav , Harms Karsten , Maier Johann , Eigner Herbert , Berg Gabriele , Zachow Christin
Published: March 2019

Sugar beets (Beta vulgaris), which are one of the major sources for sugar, alternative energy, and fuel, are affected by several fungal pathogens at harvest time. In order to identify correlations between the microbiome of field-grown sugar beets and their health status before harvest, we studied 2,200 antifungal antagonists together with 73 amplicon datasets obtained with 16S rRNA gene fragments as well as the fungal internal transcribed spacer region in samples from 13 different field sites in Austria and Germany. Overall, a substantial loss of microbial diversity (bacteriome H’: 8 versus 6.5; mycobiome H’: 4.5 versus 3.5) as well as a substantially different taxonomic composition was observed in root rot-affected sugar beets when compared with healthy beets. The Gram-positive Lactobacillales as well as distinct fungal taxa such as Candida, Penicillium, and Fusarium were identified as indicators of root rot on the microbiome level. In contrast, higher microbial diversity as well as distinct fungal genera assigned to Vishniacozyma and Plectosphaerella were associated with the microbiome of healthy plants. The taxonomic shifts in the fungal microbiome were accompanied by trophic specialization; pathotrophic and symbiotrophic fungi were replaced by saprotrophic fungi in diseased sugar beets. Moreover, samples with high proportions of antagonistic bacteria were not vulnerable to shifts in the fungal microbiome. The overall findings show implications between microbial antagonists and plant health as well as key taxa that are indicative for the health status in beets. They provide the basis for the development of improved disease management systems and preventive counteractions.
Effects of nonlinear growth rates of spherical crystals and their withdrawal rate from a crystallizer on the particle-size distribution function
Authors: Makoveeva Eugenya V. , Alexandrov Dmitri V.
Published: March 2019

In this paper, we show that the nonlinear growth rate of particles in a supersaturated solution or supercooled melt, as well as the rate of removal of crystals from the metastable liquid of a crystallizer, significantly change the size-distribution function of crystals. Taking these rates into account, we present a complete analytical solution of the integro-differential model describing the transient nucleation of solid particles and their evolution in a metastable liquid. The distribution function and metastability degree (supersaturation or supercooling) are found by means of the separation of variables and saddle-point methods. The nonlinear growth rates of crystals in supersaturated solutions and supercooled melts (single-component and binary) are summarized and compared with experimental data.

This article is part of the theme issue ‘Heterogeneous materials: metastable and non-ergodic internal structures’.
Discontinuous shear thickening in concentrated suspensions
Authors: Bossis Georges , Volkova Olga , Grasselli Yan , Gueye Oumar
Published: March 2019

The flow of concentrated suspensions of solid particles can be suddenly blocked by the formation of a percolated network of frictional contacts above a critical value of the applied stress. Suspensions of magnetic particles coated with a superplastifier molecule were shown to produce a strong jamming transition. We find that, for these suspensions with an abrupt discontinuous shear thickening, a model using the divergence of the viscosity at a volume fraction that depends on the applied stress does not well describe the observed behaviour both below and above the critical stress. At a constant applied stress above the critical one, we have a stick–slip behaviour of the shear rate whose period can be predicted and scaled as the square root of the relaxation time of the frictional contacts. The application of a small magnetic field allows us to continuously decrease the critical shear rate, and it appears that the yield stress induced by the magnetic field does not contribute to the jamming transition. Finally, it is shown that this jamming transition also appears in the extrusion of a suspension through a die, but with a much slower dynamics than in the case of stress imposed on a rotational geometry.

This article is part of the theme issue ‘Heterogeneous materials: metastable and non-ergodic internal structures’.
Systematic identification of regulators of antibody-drug conjugate toxicity using CRISPR-Cas9 screens
Authors: Tsui C. Kimberly , Barfield Robyn M. , Fischer Curt R. , Morgens David W. , Li Amy , Smith Benjamin A. H. , Bertozzi Carolyn R. , Rabuka David , Bassik Michael C.
Published: March 2019

Antibody-drug conjugates (ADCs) selectively deliver highly toxic chemotherapeutic agents to target antigen-expressing cells and have become an important cancer treatment in recent years. However, the molecular mechanisms by which ADCs are internalized and activated within cells remain unclear. Here we use CRISPR-Cas9 screens to identify genes that control the toxicity of ADCs. Our results demonstrate critical roles for a range of known and novel endolysosomal trafficking regulators in ADC toxicity. We identify and characterize C18orf8/RMC1 as a regulator of ADC toxicity through its role in endosomal maturation. Through comparative analysis of CRISPR screens with ADCs bearing a noncleavable linker versus a cleavable valine-citrulline (VC) linker, we show that a subset of late endosomal and lysosomal regulators are selectively essential for toxicity of noncleavable linker ADCs. We further show that cleavable VC linkers are rapidly processed upon internalization and therefore surprisingly appear to bypass the requirement of lysosomal delivery. Lastly, we show that inhibition of sialic acid biosynthesis sensitizes cells to ADC treatment by increasing the rate of ADC internalization. This sensitization was observed using several ADCs targeting different antigens in diverse cancer cell types, including the FDA-approved ADC trastuzumab emtansine (T-DM1) in Her2-positive breast cancer cells. Together, these results reveal novel regulators of endolysosomal trafficking, provide important insights to guide future ADC design, and identify candidate combination therapy targets as well as potential mechanisms of ADC resistance.
Single particle trajectory statistic to reconstruct chromatin organization and dynamics
Authors: Shukron O. , Seeber A. , Amitai A. , Holcman D.
Published: March 2019

Chromatin organization remains complex and far from understood. We discuss here recent statistical methods to extract biophysical parameters from in vivo single particle trajectories of loci to reconstruct chromatin reorganization in response to cellular stress such as DNA damages. We look at the methods to analyze both single loci as well as multiple loci tracked simultaneously and explain how to quantify and describe chromatin motion using a combination of extractable parameters. These parameters can be converted into information about chromatin dynamics and function. Furthermore, we discuss how the time scale of recurrent motion of a locus can be extracted and converted into local chromatin dynamics. We also discuss the effect of various sampling rates on the estimated parameters. Finally, we discuss polymer methods based on cross-linkers that account for minimal loop constraints hidden in tracked loci, that reveal chromatin organization at the 250nmspatial scale. We list and refer to some algorithm packages that are now publicly available. To conclude, chromatin organization and dynamics at hundreds of nanometers can be reconstructed from locus trajectories and predicted based on polymer models.
Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ
Authors: Law Pui-Pik , Chan Ping-Kei , McEwen Kirsten , Zhi Huihan , Liang Bing , Naruse Chie , Asano Masahide , Tan-Un Kian-Cheng , Chan Godfrey Chi-Fung , Festenstein Richard
Published: March 2019

Sex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1γ). To determine whether this sex-regulatory effect of HP1γ was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1γ. Strikingly, HP1γ was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1γ gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease.
Small RNA expression pattern in multiply inbred lines and their hybrids of maize embryo
Authors: Liu Yong-Xin
Published: March 2019

Heterosis, also known as hybrid vigor or transgression, is the phenomenon wherein an F1 hybrid produced from crossing two cultivars of the same or different species shows superior phenotypes. Heterosis in maize has been found and applied in breeding for more than one hundred years. However, its underlying molecular mechanisms are still poorly understood. To investigate whether small RNAs (sRNAs) participate in the regulation of heterosis, we profiled the sRNA expression patterns in the germ seeds of five inbred lines and theirs three F1 hybrids using high-throughput sequencing technology. The sequencing result show maize sRNAs are enriched in 22-nt length. Nearly 90% of 22-nt small RNA dominated clusters (SRCs) are in repeat regions, which mainly originated from Gypsy and Copia in retrotransposon. About 25% differentially expressed SRCs exist between parents, and hybrid gain almost all differentially expressed 22-nt SRCs. Twenty-four-nt sRNA also enriched in maize, which showed great sequence diversity and overall low expression across the genome. More than half of 24-nt SRCs originate from repeat, and 80% of them come from DNA transposon. Nearly 30% of 24-nt SRCs located in genes or their flanking regions, especially in flanking regions of “lipid metabolic process” and “macromolecule modification” related genes. Several thousands 24-nt SRCs are paternal or maternal specific expressed, and hybrids gain only half of differentially expressed 24-nt SRCs. Hundreds of 24-nt SRCs show high parent or above high parent expression pattern in different hybrids, and them mainly from Tourist, haT, and CACTA in DNA transposon and enrich nearby “tRNA aminoacylation for protein translation” related genes. Also, some 21-nt SRCs show conserved expression pattern in low parent. They were enriched in anti-sense region of some genes, which functions are about oxidative phosphorylation and translation. miRNAs have a global downregulated tendency in hybrids. zma-miR408-5p, zma-miR1432-5p and zma-miR528-5p are significant downregulated in each hybrid, and this phenomenon may cause their target genes more stable and contribute to hybrid vigor. Taken together, our results illustrated that sRNAs may contribute to heterosis at the very early stage of seed germination through repressing of retrotransposon activity, regulation gene activity at gene and genic flanking regions, and promotion some gene expressions by downregulated miRNAs.
Computational Design of Myristoylated Cell Penetrating Peptides Targeting Oncogenic K-Ras.G12D at the Effector Binding Membrane Interface
Authors: Li Zhenlu , Buck Matthias
Published: March 2019

A number of small inhibitors have been developed in the recent years to target the cancer driving protein, K-Ras. In this study we propose and design a novel way of targeting oncogenic K-Ras4B.G12D with myristoylated cell penetrating peptides which become membrane anchored and lock the protein into an inactive state. In all atom molecular dynamics simulations such peptides associate with K-Ras4B exclusively at the effector binding region, which, in turn, expected to hinder the binding of down-stream effector proteins (e.g. C-Raf). The myristoylated R9 (Arg9) peptide strongly locks K-Ras4B.G12D into orientations that are unfavorable for effector binding. After breaking the cyclic structure and myristoylation, a cell penetrating peptide cyclorasin 9A5, which was designed for targeting the Ras: Raf interface, is also found to be effective in targeting the Ras: membrane interface. The myristoylated peptides likely have high cell permeability due to their mixed cationic/hydrophobic character at the N-terminus, while simultaneously the subsequent multiple charges help to maintain a strong association of the peptide with the K-Ras4B.G12D effector binding lobe. Targeting protein-membrane interfaces is starting to attract attention very recently, thanks to our understanding of the signaling mechanism of an increased number of peripheral membrane proteins. The strategy used in this study has potential applications in the design of drugs against K-Ras4B driven cancers. It also provides insights into the general principles of targeting protein-membrane interfaces.
Vimentin protects the structural integrity of the nucleus and suppresses nuclear damage caused by large deformations
Authors: Patteson Alison E , Vahabikashi Amir , Pogoda Katarzyna , Adam Stephen A , Goldman Anne , Goldman Robert , Janmey Paul A
Published: March 2019

Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis or in pathological situations such as metastasis. The nucleus has recently emerged as an important factor in regulating 3D cell migration. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein which forms networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we used wild type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape, motility, and the ability of cells to resist large deformations. The results show that loss of VIFs alters nuclear shape, reduces perinuclear stiffness, and enhances motility in 3D. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous re-expression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration.
Structured Inhibitory Activity Dynamics During Learning
Authors: Arriaga Moises , Han Edward B.
Published: March 2019

Hippocampal network activity is tightly regulated by local inhibitory interneurons. Suppression of inhibition has been proposed to accelerate learning by enhancing network activity and plasticity; however, the activity dynamics of hippocampal interneurons during learning remain poorly understood. Furthermore, it is unknown if individual interneurons are stochastically suppressed across different learning episodes, mirroring the random remapping of place cells, or if instead they exhibit consistent patterns of activity suppression. These critical properties define how inhibition shapes and controls learning at a network level. To uncover the functional circuit dynamics of inhibition during novelty-induced learning, we recorded calcium activity from hippocampal CA1 interneurons using two-photon imaging as mice learned a virtual reality (VR) goal-directed spatial navigation task in new visual contexts. Here we focused on dendrite-targeting somatostatin-expressing interneurons (SOM-ints), which powerfully control burst firing and synaptic plasticity in excitatory neurons. We found robust activity suppression in SOM-ints upon exposure to novel virtual environments; activity then recovered over repeated exposures to the novel environment as the animal learned goal locations. At a population level, we found a continuum of activity suppression, from interneurons strongly suppressed to moderately activated during learning. Surprisingly, each interneuron exhibited a stable level of activity modulation: when animals were switched into a second novel environment, the magnitude of activity suppression was strongly correlated across remapping sessions. This work reveals dynamic inhibition suppression triggered by novel environments and the gradual return of inhibition with learning. Furthermore, unlike the stochastic remapping of place cells, inhibitory networks display a stable activity structure across learning episodes. This functional inhibitory circuit architecture suggests that individual interneurons play specialized and stereotyped roles during learning, perhaps by differentially regulating pyramidal subnetworks specialized for plasticity and stability.
Molecular evolution guided functional analyses reveals Nucleobindin-1 as a canonical E-box binding protein promoting Epithelial-to-Mesenchymal transition (EMT)
Authors: Sinha Sansrity , Pattnaik Siddhart , Aradhyam Gopala Krishna
Published: March 2019

Calcium binding proteins (CBPs) function in response to changes in intracellular calcium (Ca2+) levels by modulating intracellular signaling pathways. Calcium sensors, including Nucleobindins (Nucb1/2) undergo Ca2+-binding induced conformational changes and bind to target proteins. Nucleobindins possess additional uncharacterized domains including partly characterized EF-hands. We study the molecular evolution of Nucleobindins in eukaryotes emphasizing on the N-terminal DNA binding domain (DBD) that emerged as a result of domain insertion event in Nucb1/2 domain-scaffold in an ancestor to the opisthokonts. Our results fromin silicoanalyses and functional assays revealed that DBD of Nucb1 binds to canonical E-box sequences and triggers cell epithelial-mesenchymal transition (EMT). Thus, post gene duplication, Nucb1 has emerged as unconventional Ca2+-binding transcriptional regulators that can induce EMT.

Highlights

Nucleobindins emerged from prokaryotic EF-hand containing protein.

The DNA-binding domain was gained in these in opisthokonts.

Gene duplication in ancestor of euteleostomes, lead to emergence of Nucb1/2.

Nucb1 emerged as a canonical E-box binding protein promoting EMT
Probing Allosteric Coupling of a Constitutively Open Mutant of the Ion Channel KcsA using Solid State NMR
Authors: Sun Zhiyu , Xu Yunyao , Zhang Dongyu , McDermott Ann E
Published: March 2019

Transmembrane allosteric coupling is a feature of many critical biological signaling events. Here we test whether transmembrane allosteric coupling controls the mean open time of the prototypical potassium channel KcsA in the context of C-type inactivation. Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH. Numerous studies have suggested that this proton binding also prompts a conformational switch leading to a loss of affinity for potassium ions at the selectivity filter and therefore to channel inactivation. We tested this mechanism for inactivation using a KcsA mutant (H25R/E118A) that has the pH gate open across a broad range of pH values. We present solid-state NMR measurements of this open mutant at neutral pH to probe the affinity for potassium at the selectivity filter. The potassium binding affinity in the selectivity filter of this mutant, 81 mM, is about 4 orders of magnitude weaker than that of wild type KcsA at neutral pH and is comparable to the value for wild type KcsA at low pH (pH ∼ 3.5). This result strongly supports our assertion that the open pH gate allosterically effects the potassium binding affinity of the selectivity filter. In this mutant the protonation state of a glutamate residue (E120) in the pH sensor is sensitive to potassium binding, suggesting that this mutant also has flexibility in the activation gate and is subject to transmembrane allostery.

Significance statement

Inactivation of potassium channels controls mean open times and provides exquisite control over biological processes. In the highly conserved C-type inactivation process, opening of the activation gate causes subsequent inactivation. We test whether the open state of the channel simply has a poor ability to bind the K+ion. Previously, activated and inactivated states were stabilized using truncations or a significant pH drop. Here, we use the H25R/E118A constitutively open mutant of KcsA and also observe a large drop in potassium binding affinity. This provides strong evidence that channel opening causes an allosteric loss of ion affinity, and that the central feature of this universal channel inactivation process is loss of ion affinity at the selectivity filter.
The AAA+ ATPase TorsinA polymerizes into hollow tubes with a helical periodicity of 8.5 subunits per turn
Authors: Demircioglu F. Esra , Zheng Weili , McQuown Alexander J. , Maier Nolan , Watson Nicki , Cheeseman Iain M. , Denic Vladimir , Egelman Edward H. , Schwartz Thomas U.
Published: March 2019

TorsinA is an ER-resident AAA+ ATPase, whose single residue deletion of glutamate E303 results in the genetic neuromuscular disease primary dystonia. TorsinA is a highly unusual AAA+ ATPase in that it needs an external activator. Also, it appears not to thread a peptide substrate through a narrow central channel, in contrast to its closest structural homologs. Here, we examined the oligomerization of TorsinA to get closer to a molecular understanding of the still enigmatic function of it. We observe TorsinA to form helical filaments, which we analyzed by cryo-electron microscopy using helical reconstruction. The 4.4 Å structure reveals long hollow tubes with a helical periodicity of 8.5 subunits per turn, and an inner cavity of ∼4 nm diameter. We further show that the protein is able to induce tubulation of membranes in vitro, an observation that may reflect an entirely new characteristic of AAA+ ATPases. We discuss the implications of these observations for TorsinA function.
Novel Organ-Specific Genetic Factors for Quantitative Resistance to Late Blight in Potato
Authors: Juyo Rojas Deissy Katherine , Soto Sedano Johana Carolina , Ballvora Agim , Léon Jens , Mosquera Vásquez Teresa
Published: March 2019

Potato,Solanum tuberosum, is one of the highest consumed food in the world, being the basis of the diet of millions of people. The main limiting and destructive disease of potato is late blight, caused byPhytophtora infestans. Here, we present a multi-environmental analysis of the response toP. infestansusing an association panel of 150 accessions ofS. tuberosumGroup Phureja, evaluated in two localities in Colombia. Disease resistance data were merged with a genotyping matrix of 83,862 SNPs obtained by 2b-restriction site–associated DNA and Genotyping by sequencing approaches into a Genome-wide association study. We are reporting 16 organ-specific QTL conferring resistance to late blight. These QTL explain from 13.7% to 50.9% of the phenotypic variance. Six and ten QTL were detected for resistance response in leaves and stem, respectively.In silicoanalysis revealed 15 candidate genes for resistance to late blight. Four of them have no functional genome annotation, while eleven candidate genes code for diverse proteins, including one leucine-rich repeat kinase.
Chronic alcohol abuse affects the clinical course and outcome of community-acquired bacterial meningitis
Authors: Paciorek Marcin , Bednarska Agnieszka , Krogulec Dominika , Makowiecki Michał , Kowalska Justyna D , Bursa Dominik , Świderska Anna , Puła Joanna , Raczyńska Joanna , Skrzat-Klapaczyńska Agata , Radkowski Marek , Laskus Tomasz , Horban Andrzej
Published: March 2019

Background

The aim of the study was to determine the effect of chronic alcohol abuse on the course and outcome of bacterial meningitis (BM).

Materials/methods

We analyzed records of patients with BM who were hospitalized between January 2010 and December 2017 in the largest neuroinfection center in Poland.

Results

340 adult patients (211 men and 129 women) were analyzed. Forty-five (13.2%) patients were alcoholics (39 men and 6 women). Compared to non-alcoholics, alcoholics were more likely to present with seizures (33.3% vs 12.6%, p<0.001), scored higher on the Sequential Organ Failure Assessment (SOFA) (median 3 vs 2, p<0.001) and lower on the Glasgow Coma Scale (GCS) (median 10 vs 12, p<0.001) and had worse outcome as measured by the Glasgow Outcome Score (GOS) (median 3 vs 5, p<0.001). Furthermore, alcoholics were less likely to complain of headache (23.3% vs 52.3%, p<0.001) and nausea/vomiting (11.4% vs 33.6%, p=0.005) and had lower concentration of glucose in cerebrospinal fluid (CSF) (median 0,58 mmol/L vs 1,97, p=0.025). In the multiple logistic regression analysis, alcoholism was independently associated with lower GCS (OR 0.716, 95% CI 0.523-0.980, p=0.036), presence of seizures (OR 4.580, 95% CI 1.065-19.706, p=0.041), male gender (OR 4.617, 95% CI 1.060-20.113, p=0.042) and absence of nausea/vomiting (OR 0.205, 95%CI 0.045-0.930, p=0.040). Furthermore, alcoholism (regression coefficient [−0.636], 95% CI [− 1.21] – [−0.06], p=0.031), lower GCS score (regression coefficient 0.144, 95% CI 0.06-0.23, p=0.001) and higher urea blood concentration (regression coefficient [−0.052], 95% CI [−0.10] – [−0.01], p=0.018) were independently associated with worse outcome measured by GOS.

Conclusions

Compared to non-alcoholics, chronic alcohol abusers are more likely to present with seizures, altered mental status, higher SOFA score and have an increased risk of unfavorable outcome. In multivariate analysis seizures and low GCS were independently associated with alcoholism, while alcoholism was independently associated with worse outcome.