bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Outcomes of a High-Resolution Anoscopy-Based Anal Cancer Screening Program Among People With HIV Enrolled in an Integrated Health Care System
Authors: Barnell Gregory M. , Merchant Maqdooda , Lam Jennifer O. , Silverberg Michael J.
Published: April 2019

Background:

Few studies have examined outcomes of high-resolution anoscopy (HRA)-based screening for people with HIV infection (PWH), a population at increased risk for anal cancer.

Setting:

Large integrated health care system.

Methods:

Cohort study of 13,552 people with HIV infection, comparing incidences of anal cancer and advanced anal cancer (higher stage, recurrence, death, or surgical salvage) before and after HRA became available (2008). Calendar time was divided as 1998–2007, 2008–2010, and 2011–2012. Rate ratios (RRs) were obtained from Poisson regression models with adjustment for baseline demographic and health variables. Cohort cases during 2008–2012 were included in a nested case–control study, evaluating association of screening with anal cancer (33 cases, 330 controls) and advanced anal cancer (19 cases, 190 controls). Odds ratios (ORs) for receipt of screening were obtained from conditional logistic regression models with adjustment for baseline demographic and health history variables.

Results:

Compared with 1998–2007 (pre-HRA), 2008–2010 adjusted RRs were 1.32 [95% confidence intervals (CI): 0.77 to 2.27; P = 0.31] for anal cancer and 2.11 (95% CI: 0.99 to 4.48; P = 0.053) for advanced anal cancer; and 2011–2012 adjusted RRs were 0.35 (95% CI: 0.12 to 0.99; P = 0.048) for anal cancer and 0.23 (95% CI: 0.03 to 1.77; P = 0.16) for advanced anal cancer. Individual history of screening did not reach statistical significance for anal cancer (OR 1.7; 0.6–4.6) or advanced anal cancer (OR 0.44; 0.1–3.8).

Conclusions:

Despite the possible effect of secular trends, we found 2008–2012 incidence trends for anal cancer and advanced anal cancer that seem consistent with expected findings of a beneficial screening program.
Cognitive and Motor Impairment Severity Related to Signs of Subclinical Wernicke's Encephalopathy in HIV Infection
Authors: Le Berre Anne-Pascale , Fama Rosemary , Sassoon Stephanie A. , Pfefferbaum Adolf , Sullivan Edith V. , Zahr Natalie M.
Published: April 2019

Background:

Wernicke's encephalopathy (WE) is a neurological condition resulting from thiamine deficiency. Although commonly associated with alcoholism, nonalcoholic WE has been described in individuals with HIV infection, but subclinical WE may be underdiagnosed. The current study questioned whether the presence of subclinical WE signs underlies cognitive and motor deficits in HIV individuals as observed in alcoholism.

Setting:

Fifty-six HIV-positive individuals (HIV+) and 53 HIV-negative controls (HIV−) were assessed on 6 cognitive and motor domains: attention/working memory, production, immediate and delayed episodic memory, visuospatial abilities, and upper-limb motor function.

Methods:

Based on a rating scheme by Caine et al, HIV+ individuals were categorized by subclinical WE risk factors (dietary deficiency, oculomotor abnormality, cerebellar dysfunction, and altered mental state). Performance was expressed as age- and education-corrected Z-scores standardized on controls.

Results:

Sorting by Caine criteria yielded 20 HIV+ as Caine 0 (ie, meeting no criteria), 22 as Caine 1 (ie, meeting one criterion), and 14 as Caine 2 (ie, meeting 2 criteria). Comparison among HIV+ Caine subgroups revealed a graded effect: Caine 0 performed at control levels, Caine 1 showed mild to moderate deficits on some domains, and Caine 2 showed the most severe deficits on each domain.

Conclusion:

This graded severity pattern of performance among Caine subgroups suggests that signs of subclinical WE can partly explain the heterogeneity in HIV-related cognitive and motor impairment. This study highlights the utility of Caine criteria in identifying potential causes of HIV-related neurocognitive disorders and has implications for disease management.
In Vivo Flattening of the Central Aponeurosis of the Rectus Femoris Due to Knee Extension Torque in Healthy Young and Elderly Individuals With Knee Osteoarthritis
Authors: Takahashi Yusuke , Saito Akira , Sato Hiromichi , Shibata Kazuyuki , Okura Kazuki , Kinoshita Kazuo , Seto Arata , Osawa Shinjiro , Wakasa Masahiko , Kimoto Minoru , Okada Kyoji
Published: April 2019

We aimed to elucidate the relationship between active force production and the curvature of the central aponeurosis (CA) of the rectus femoris in young healthy participants as fundamental data and compare the muscle CA curvature before and after straight leg raising (SLR) training in participants with knee osteoarthritis (OA). Central aponeurosis curvature was determined during submaximal and maximal voluntary contractions (MVCs) using ultrasonography. Twenty-five young healthy female volunteers underwent ultrasonographic measurements under conditions of isometric MVC. They were divided into a flat shaped CA group (flat) and an incompletely flat shaped CA group (remnant). Central aponeurosis curvature was calculated as the ratio of CA height and length in the axial view. Central aponeurosis shape and muscular strength before and after muscle training were measured in 11 participants with knee OA. In the young healthy individuals, maximal voluntary torque and changes in CA curvature were significantly higher in the flat group than in the remnant group (2.15 Nm/kg and − 17.7% vs 1.75 Nm/kg and −9.8%, respectively; P = 0.005). The rate of change of the CA curvature during contraction was significantly correlated with maximal voluntary torque corrected for body mass (r = 0.512). The CA curvature progressively decreased as %MVC increased. In the OA group, CA curvature during MVC after SLR training was significantly lower than that before SLR training (3.2% vs 7.2%; P = 0.031). Central aponeurosis curvature was associated with muscle strength, and the results supported our hypothesis that geometric observation of CA changes during contractions may reflect muscle fiber function. We aim to develop a new ultrasonographic skeletal muscle evaluation method based on our present findings.
Injury-specific variables improve risk adjustment and hospital quality assessment in severe traumatic brain injury
Authors: Dawes Aaron J. , Sacks Greg D. , Needleman Jack , Brook Robert H. , Mittman Brian S. , Ko Clifford Y. , Cryer H. Gill
Published: April 2019

BACKGROUND

Hospital benchmarking is essential to quality improvement, but its usefulness depends on the ability of statistical models to adequately control for inter-hospital differences in patient mix. We explored whether the addition of injury-specific clinical variables to the current American College of Surgeons-Trauma Quality Improvement Program (TQIP) algorithm would improve model fit.

METHODS

We analyzed a prospective registry containing all adult patients who presented to a regional consortium of 14 trauma centers between 2010 and 2011 with severe traumatic brain injury (TBI). We used hierarchical logistic regression and stepwise forward selection to develop two novel risk-adjustment models. We then tested our novel models against the current TQIP model and ranked hospitals by their risk-adjusted mortality rates under each model to determine how model selection affects quality benchmarking.

RESULTS

Seven hundred thirty-four patients met inclusion criteria. Stepwise selection resulted in two distinct models: one that added three TBI-specific variables (pupil reactivity, cerebral edema, loss of basal cisterns) to the model specification currently used by TQIP and another that combined two TBI-specific variables (pupil reactivity, cerebral edema) with a three-variable subset of TQIP (age, Abbreviated Injury Scale score for the head region, Glasgow Coma Scale motor score). Both novel models outperformed TQIP. Although rankings remained largely unchanged across model configurations, several hospitals moved across quality terciles.

CONCLUSION

The inclusion of injury-specific variables improves risk adjustment for patients with severe TBI. Trauma Quality Improvement Program should consider replacing several of its general patient characteristics with injury-specific clinical predictors to increase efficiency, reduce the risk of overfitting, and improve the accuracy of hospital benchmarking.

LEVEL OF EVIDENCE

Prognostic and epidemiological, level II.
Cognitive Complaints in Nondemented Parkinson’s Disease Patients and Their Close Contacts do not Predict Worse Cognitive Outcome
Authors: AlDakheel Amaal , Gasca-Salas Carmen , Armstrong Melissa J. , Duff-Canning Sarah , Marras Connie
Published: April 2019

Objectives:

The main purpose of this study was to investigate 4 methods of eliciting subjective cognitive complaints (SCCs) in Parkinson’s disease (PD) patients without dementia and determine the relationship between their SCC and cognitive performance.

Design:

This study was a retrospective analysis of a prospective cohort study.

Setting:

Six North American movement disorder clinics.

Measurements:

SCCs were elicited through a modified Neurobehavioral Inventory administered to patients and close contacts, a general complaint question, and Movement Disorders Society Unified Parkinson's Disease Rating Scale item question 1.1 administered to patients. Clinical evaluation, formal neuropsychological testing and Disability Assessment for Dementia were conducted in Ontario state. Agreement between SCCs eliciting methods was calculated. Associations between SCC, cognitive testing, and mild cognitive impairment (MCI) were assessed.

Results:

Of 139 participating nondemented PD patients, 42% had PD-MCI at baseline. Agreement between SCC eliciting methods was low. Neither patient-reported nor close contact-reported SCCs were associated with impaired baseline cognitive testing or PD-MCI nor were they associated with cognitive decline over time. In PD patients with normal baseline cognition, 26% of patients with 1-year follow-up and 20% of patients with 2-year follow-up met MCI criteria.

Conclusions:

Agreement between SCC eliciting methods is poor and no SCC method was associated with cognitive testing or decline over time. With no clear superior method for eliciting SCCs, clinicians should consider performing regular screening.
Which MCI Patients Should be Included in Prodromal Alzheimer Disease Clinical Trials?
Authors: Grill Joshua D. , Nuño Michelle M. , Gillen Daniel L.
Published: April 2019

Background:

Prodromal Alzheimer disease (AD) clinical trials enroll patients with mild cognitive impairment (MCI) meeting biomarker criteria, but specific enrollment criteria vary among trials.

Methods:

We used data from AD Neuroimaging Initiative (ADNI) MCI participants to assess AD biomarker eligibility, variation in trial outcome measures, and statistical power.

Results:

Most (65%) participants meet eligibility criteria based on low cerebrospinal fluid amyloid beta (Aβ). Relative to trials enrolling exclusively based on low cerebrospinal fluid Aβ, trials including participants with a high ratio of phosphorylated tau to Aβ would include an additional 15% of participants. Fewer (34% to 62%) participants met criteria for Aβ and tau. Differences in clinical and demographic characteristics of modeled trial samples were minimal. Those with low Aβ and high tau showed the greatest change over time on outcome measures.

Conclusions:

Eligibility rates for prodromal trials vary depending on the specific biomarker criteria, though differences in demographics and the variation associated with outcome measures are minimal. Broadening inclusion criteria beyond amyloid alone may facilitate recruitment but include patients showing slower progression over time. Biomarker criteria selection should be informed by the goal of enrolling individuals most likely to utilize and benefit from the intervention under investigation in a particular setting.
Awareness in Dementia
Authors: Dourado Marcia C.N. , Laks Jerson , Mograbi Daniel C.
Published: April 2019

Awareness of disease is defined as the recognition of changes caused by the deficits related to the disease process. We aimed to examine the psychometric properties of the short versions of the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD-s), a multidimensional awareness scale. Using a cross-sectional design, we included 201 people with dementia and their family caregivers. The creation of the short versions was based on items with higher loadings on each factor, the correlations between the short versions and demographic or clinical variables and the relevance of the item to the respondent population. Three short versions were created: version 1 and 3, with 12 items and version 2, with 16 items. The short versions correlated very strongly with the full scale and with the 4 factors of the original scale, maintaining the multidimensional nature of the ASPIDD. Loss of awareness was associated with worse quality of life, decreased functionality and cognitive level, and higher caregiver burden across the short versions. Considering the appropriateness of the items and their clinical relevance, we recommend version 3 for use. With only 12 items, the time required for the completion of the scale is short, while maintaining robust psychometric properties.
Women and Men Presenting to a Rural and Remote Memory Clinic in Saskatchewan, Canada Show Similar Cognitive Findings for Dementia
Authors: Robertson Olivia , Kirk Andrew , Karunanayake Chandima , Morgan Debra , O’Connell Megan E.
Published: April 2019

Introduction:

The course of dementia may differ between men and women. Men, for example, are more likely to exhibit aggression. It is unclear if sex differences are present at initial presentation. The present study examines sex differences among patients at initial referral to a memory clinic.

Materials and Methods:

Three hundred seventy-five (159 males, 216 females) patients referred to the University of Saskatchewan’s Rural and Remote Memory Clinic participated. Data were collected from patients and caregivers at initial assessment. Cognitive, functional, and demographic information were compared between males and females.

Results:

Males and females presented to the clinic at similar ages. Females were more likely to have a son or daughter caregiver and to live alone. Males were more likely to be currently working. No statistically significant differences were found for cognitive or functional assessment scores.

Discussion:

Within this rural and remote sample, there was equivalence between male and female level of cognitive decline, function and neuropsychiatric symptoms at initial referral. Both sexes were of similar ages at the time of initial presentation. These findings may provide reassurance to patients and their family members as it does not appear that patients of one sex were referred later than the other.
Kelch13 and MDR1 Polymorphisms, and Drug Effectiveness at Day 3 after Dihydroartemisinin-Piperaquine Treatment for Plasmodium falciparum Malaria on Bioko Island, Equatorial Guinea: 2014-2017
Authors: Zheng Yu-Zhong , Chen Jiang-Tao , Liang Xue-Yan , Ehapo Carlos Salas , Eyi Urbano Monsuy , Huang Hui-Ying , Chen Wei-Zhong , Lin Li-Yun , Xie Dong-De , Wang Yu-Ling , Chen Guo-Wei , Liu Xiang-Zhi , Zha Guang-Cai , Mo Huan-Tong , Chen Xin-Yao , Li Jian , Jiang Ting-Ting , Lin Min
Published: April 2019

Artemisinin (ART) combination therapies were introduced on malaria endemic Bioko Island in 2004 through Bioko Island Malaria Control Project. Recently, ART-resistant Plasmodium falciparum strain with Kelch13 (K13) propeller M579I mutation originating from Equatorial Guinea was observed as an increased parasite clearance time on day 3 after dihydroartemisinin-Piperaquine (DHA-PIP) treatment (D3 positivity). Here, we surveyed DHA-PIP effectiveness and molecular markers of drug resistance at D3 after DHA-PIP treatment on Bioko Island from 2014 to 2017. Among the 371 uncomplicated P. falciparum patients, 86.3% (320/471) were successfully followed up at D3. 5.9% (19/320) of patients showed D3 positivity. K13 and MDR1 gene were successfully sequenced from 46 patients collected at D0 (baseline population) and 19 D3-positivity patients. Five non-synonymous K13 mutations (H136N; K189N; K248N; K326E; K332N) were found. There was no statistical difference in the frequency of these K13 mutations between baseline population and D3-positivity samples (p>0.05). Additionally, none of the K13 propeller polymorphisms known to be involved in ART-resistance in Asia or Africa were detected. For MDR1 gene, 38.5% (25/65) carried N86Y mutation; 73.8% (48/65) the Y184F mutation. Parasites surviving DHA-PIP at D3 post-treatment were significantly more likely than the baseline population to carry the N86Y (p <0.05). These results suggest that K13 is not the best predictive molecular marker for ART resistance in Africa. More isolates from cases with delayed parasite clearance after DHA-PIP treatment indicated that in vitro and in vivo monitoring for ART derivatives and ACT partner drugs should be regularly performed on Bioko Island, Equatorial Guinea.
Genetic Contributions To Health Literacy
Authors: Fawns-Ritchie Chloe , Davies Gail , Hagenaars Saskia P , Deary Ian J
Published: April 2019

Higher health literacy is associated with higher cognitive function and better health. Despite its wide use in medical research, no study has investigated the genetic contributions to health literacy. Using 5,783 English Longitudinal Study of Ageing (ELSA) participants (mean age=65.49, SD=9.55) who had genotyping data and had completed a health literacy test at wave 2 (2004-2005), we carried out a genome-wide association study (GWAS) of health literacy. We estimated the proportion of variance in health literacy explained by all common single nucleotide polymorphisms (SNPs). Polygenic profile scores were calculated using summary statistics from GWAS of 21 cognitive and health measures. Logistic regression was used to test whether polygenic scores for cognitive and health-related traits were associated with having adequate, compared to limited, health literacy. No SNPs achieved genome-wide significance for association with health literacy. The proportion of variance in health literacy accounted for by common SNPs was 8.5% (SE=7.2%). Greater odds of having adequate health literacy were associated with a 1SD higher polygenic score for general cognitive ability (OR=1.34, 95% CI 1.26-1.42), verbal-numerical reasoning (OR=1.30, 1.23-1.39), and years of schooling (OR=1.29, 1.21-1.36). Reduced odds of having adequate health literacy were associated with higher polygenic profiles for poorer self-rated health (OR=0.92, 0.87-0.98) and schizophrenia (OR=0.91, 0.85-0.96). The well-documented associations between health literacy, cognitive function and health may partly be due to shared genetic aetiology. Larger studies are required to obtain accurate estimates of SNP-based heritability, and to discover specific health literacy-associated genetic variants.
A three-years assessment of Ixodes ricinus-borne pathogens in a French peri-urban forest
Authors: Lejal Emilie , Marsot Maud , Chalvet-Monfray Karine , Cosson Jean-François , Moutailler Sara , Vayssier-Taussat Muriel , Pollet Thomas
Published: April 2019

Background

Ixodes ricinus is the predominant tick species in Europe and the primary pathogen vector for both humans and animals. These ticks are frequently involved in the transmission of Borrelia burgdorferi sensu lato, the causative agents of Lyme borreliosis. While much more is known about I. ricinus tick-borne pathogen composition, information about temporal tick-borne pathogen patterns remain scarce. These data are crucial for predicting seasonal/annual patterns which could improve understanding and prevent tick-borne diseases.

Methods

We examined tick-borne pathogen (TBPs) dynamics in I. ricinus collected monthly in a peri-urban forest over three consecutive years. In total, 998 nymphs were screened for 31 pathogenic species using high-throughput microfluidic real-time PCR.

Results

We detected DNA from Anaplasma phagocytophilum (5.3%), Rickettsia helvetica (4.5%), Borrelia burgdorferi s.l. (3.7%), Borrelia miyamotoi (1.2%), Babesia venatorum (1.5%) and Rickettsia felis (0.1%). Among all analysed ticks, 15.9% were infected by at least one of these microorganisms, and 1.3% were co-infected. Co-infections with B. afzeli/B. garinii and B. garinii/B. spielmanii were significantly over-represented. Moreover, significant variations in seasonal and/or inter-annual prevalence were observed for several pathogens (R. helvetica, B. burgdorferi s.l., B. miyamotoi, and A. phagocytophilum).

Conclusions

Analysing TBPs prevalence in monthly sampled tick over three years allowed us to assess seasonal and inter-annual fluctuations of the prevalence of TBPs known to circulate in the sampled area, but also to punctually detect less common species. All these data emphasize that sporadic tick samplings are not sufficient to determine TBPs prevalence and that regular monitoring is necessary.
Inhibiting TG2 sensitizes lung cancer to radiotherapy through interfering TOPOIIα-mediated DNA repair
Authors: Lei Xiao , Liu Zhe , Cao Kun , Chen Yuanyuan , Cai Jianming , Gao Fu , Yang Yanyong
Published: April 2019

Radiotherapy is an indispensable strategy for lung cancer, however, treatment failure or reoccurrence is often found in patients due to the developing radioresistance. Novel approaches are required for radiosensitizing to improve the therapeutic efficacy. In present study, we found that transglutaminase 2 (TG2) confers radioresistance in non-small cell lung cancer (NSCLC) cells through regulating TOPOIIα and promoting DNA repair. Our data showed that TG2 inhibitor or knockdown increased NSCLC radiosensitivity in vivo and in vitro. We found that TG2 translocated into nucleus and located to DSB sites, surprisingly, knockdown TG2 or glucosamine inhibited the phosphorylation of ATM, ATR and DNA-Pkcs. Through IP-MS assay and functional experiments, we identified that TOPOIIα as an downstream factor of TG2. Moreover, we found that TGase domain account for the interaction with TOPOIIα. Finally, we found that TG2 expression was correlated with poor survival in lung adenocarcinoma instead of squamous cell carcinoma. In conclusion, we demonstrated that inhibiting TG2 sensitize NSCLC to IR through interfere TOPOIIα mediated DNA repair, suggesting TG2 as a potential radiosensitizing target in NSCLC.
Decoys and dilution: the impact of incompetent hosts on prevalence of Chagas disease
Authors: Zahid Mondal Hasan , Kribs Christopher M.
Published: April 2019

Biodiversity is commonly believed to reduce risk of vector-borne zoonoses. However, researchers already showed that the effect of biodiversity on disease transmission is not that straightforward. This study focuses on the effect of biodiversity, specifically on the effect of the decoy process (additional hosts distracting vectors from their focal host), on reducing infections of vector-borne diseases in humans. Here, we consider the specific case of Chagas disease and use mathematical population models to observe the impact on human infection of the proximity of chickens, which are incompetent hosts for the parasite but serve as a preferred food source for vectors. We consider three cases as the distance between the two host populations varies: short (when farmers bring chickens inside the home to protect them from predators), intermediate (close enough for vectors with one host to detect the presence of the other host type), and far (separate enclosed buildings such as a home and hen-house). Our analysis shows that the presence of chickens reduces parasite prevalence in humans only at an intermediate distance under the condition that the vector birth rate from feeding on chickens is sufficiently low.
A New European Species of The Opportunistic Pathogenic GenusSaksenaea–S. dorisiaeSp. Nov.
Authors: Labuda Roman , Bernreiter Andreas , Hochenauer Doris , Schüller Christoph , Kubátová Alena , Strauss Joseph , Wagner Martin
Published: April 2019

A new speciesSaksenaea dorisiae(Mucoromycotina, Mucorales), recently isolated from a water sample originating from a private well in a rural area of Serbia (Europe), is described and illustrated. The new taxon is well supported by phylogenetic analysis of the internal transcribed spacer region (ITS), domains D1 and D2 of the 28S rRNA gene (LSU), and translation elongation factor-1α gene (TEF-1α), and it is resolved in a clade withS. oblongisporaandS. trapezispora. This fungus is characteristic by its moderately slow growth at 15 and 37°C, sparse rhizoids, conical-shaped sporangia and short-cylindrical sporangiospores.S. dorisiaeis a member of the opportunistic pathogenic genus often involved in severe human and animal mucormycoses encountered in tropical and subtropical regions. Despite its sensitivity to several conventional antifungals (terbinafine and ciclopirox), the fungus is potentially causing clinically challenging infections. This is the first novel taxon of the genusSaksenaeadescribed from the moderately continental climate area of Europe.
Sagittal abdominal diameter and waist circumference are equally good as identifiers of cardiometabolic risk
Authors: Møller Grith , Ritz Christian , Kjølbæk Louise , Vuholm Stine , Korndal Sanne Kellebjerg , Larsen Thomas Meinert , Pedersen Oluf , Saris Wim , Astrup Arne , Lauritzen Lotte , Kristensen Mette , Lind Mads Vendelbo
Published: April 2019

Background

Body mass index (BMI) and waist circumference (WC) are commonly used markers of cardiometabolic risk. However, sagittal abdominal diameter (SAD) has been proposed to be a better marker of intra-abdominal obesity compared to WC and might better associate with metabolic disturbances in high-risk populations. The objective of this study was to compare SAD, WC, and BMI as determinants of an adverse metabolic phenotype.

Method

Anthropometric and metabolic measures of 1516 overweight or obese individuals with features of the metabolic syndrome were included to examine differences between SAD, WC and BMI as measures of an adverse metabolic phenotype. Multiple linear regression and logistic regression models were used to investigate the association between SAD, WC, and BMI and markers of metabolic syndrome, insulin resistance, blood lipids, and low grade inflammation.

Results

Both SAD and WC correlated with BMI, but as BMI increased, SAD proportionately estimated higher abdominal adiposity compared to WC (slope = 0.0037 (0.0029; 0.0046), p<0.0001). We did not find major differences between SAD, WC and BMI in explained variance in models with the different markers of metabolic risk. Furthermore, we did not find differences between SAD and WC in the ability to identify individuals with metabolic syndrome according to the International Diabetes Federation (IDF) cut-offs, but a few differences from BMI were indicated but mostly before adjustments. Moreover, the differences between SAD and WC associations were not modified by sex or degree of adiposity, but identification of individuals with a metabolic phenotype was generally better in women.

Conclusion

These data indicate that SAD and WC are equally good indicators of an adverse metabolic phenotype. Thus, from a public health perspective choice of anthropometric measure may depend only on what is the most practical method in a given situation.
Specific Disruption of EstablishedP. aeruginosaBiofilms Using Polymer-Attacking Enzymes
Authors: Kovach Kristin N. , Fleming Derek , Rumbaugh Kendra P. , Gordon Vernita D.
Published: April 2019

Biofilms are communities of bacteria embedded in an extracellular matrix of self-produced polymeric substances. This polymer matrix lends the bacteria protection against a wide array of chemical and mechanical stresses that they may experience in their environment, which might be a location in the human body in the case of a biofilm infection, or a surface immersed in fluid in an industrial setting. Breaking down the matrix network renders biofilms more susceptible to physical disruption and to treatments. Different species of bacteria, and different strains within the same species, produce different types of matrix polymers – this suggests that targeting specific polymers for disruption may be more effective than non-specific approaches to disrupting biofilm matrices. In this study, we treatedPseudomonas aeruginosabiofilms with enzymes that are specific to different matrix polymers. We used bulk rheology to measure the resulting alteration in biofilm mechanics, and scanning electron microscopy to visualize the alteration in the matrix network upon treatment. Different lab strains ofP. aeruginosaform biofilms that can be dominated by one of three main extracellular polysaccharides: Psl, alginate, and Pel, which binds electrostatically to extracellular DNA in the matrix. We applied enzymes to biofilms dominated by different extracellular polysaccharides and found that, for biofilms grownin vitro, the effect of enzymatic treatment is maximized when the enzyme is specific to a dominant matrix polymer – for such a case, specifically-matched enzymatic treatment tends to: reduce yield strain and yield stress; reduce or eliminate long-range structure and shorten or eliminate connecting network fibers in the biofilm as seen under scanning electron microscopy; and increase the rate of biofilm drying, most likely due to increased diffusivity as a result of network compromise. However, forex vivobiofilms grown in murine wounds, we find that generic glycoside hydrolases have more profound disruptive effects than specifically-matched enzymes, even though they had no measurable effect for biofilms grownin vitro. This highlights the importance of the environment in which the biofilms are grown, the need to take this into account when developing treatments for biofilms, and the possibility that effective approaches to eradicating biofilms in environmental or industrial settings may need to be very different from effective treatments of infection.
Evolutionary contingency’s impact on laboratory evolution ofEscherichia coliunder fluctuating environments
Authors: Pechuan Ximo , Biro Daniel , Lambros Maryl , Bergman Aviv
Published: April 2019

1

The adaptation of biological organisms to fluctuating environments is one major determinant of their structural and dynamical complexity. Organisms have evolved devoted adaptations to ensure the robust performance of physiological functions under environmental fluctuations. To further our understanding of particular adaptation strategies to different environmental fluctuations, we perform laboratory evolution experiments ofEscherichia coliunder three temperature fluctuation regimes alternating between 15°C and 43°C. Two of these regimes are determined by the population’s growth, while the third regime switches stochastically. To address evolutionary contingencies, the experiments are performed on two lineages departing from different genetic backgrounds. The two lineages display distinct evolutionary trajectories, demonstrating dependency on the starting strain’s genetic background. Several genes exhibit a high degree of parallelism, suggesting their potential adaptive nature. The growth increase of the representative clones from each final population relative to their ancestor at 15°C and 43°C demonstrated no correlation between both temperatures, insinuating an absence of a strong trade-off between these two temperatures. Some had a growth rate decrease at 15°C unless exposed to a 43°C epoch, indicating some degree of internalization of the structure of the environment fluctuations. The phenotypic response of the evolved clones at 15°C and 43°C was assessed by a phenotype array method. The resulting responses reveal a general tendency to move closer to the phenotypic response of our starting strains at the optimum of 37°C. This observation expands the documented restorative responses, even when facing complex environmental conditions.

2

Author Summary

Laboratory evolution experiments have been widely employed to test hypotheses from evolutionary theory. To assess the dynamics of adaptation under environmental fluctuations, we evolved 24Escherichia colipopulations under different regimes of temperature switching between 15°C and 43°C for about 600 generations. At the final point of the evolution experiment, the evolved populations were genome sequenced and clones were isolated and sequenced for phenotypic characterization. Fitness measurements revealed adaptation to both environmental conditions and some strains internalized the environmental fluctuation. Array phenotypic measurements showed that the majority of evolved strains tended to restore the phenotypic signature of the perturbed environments to that of the optimal temperature condition. This observation expands the documented restorative responses, even when facing complex environmental conditions.
Prediction of antiviral drugs against African Swine Fever Viruses based on protein-protein interaction analysis
Authors: Zhu Zhaozhong , Fan Yunshi , Cai Zena , Zhang Zheng , Lu Congyu , Jiang Taijiao , Zhang Gaihua , Peng Yousong
Published: April 2019

The African swine fever virus (ASFV) has severely influenced the swine industry of the world. Unfortunately, there is no effective antiviral drug or vaccine against the virus until now. Identification of new anti-ASFV drugs is urgently needed. Here, an up-to-date set of protein-protein interactions (PPIs) between ASFV and swine were curated by integration of PPIs from multiple sources. Thirty-two swine proteins were observed to interact with ASFVs and were defined as AIPs. They were found to play a central role in the swine PPI network, with significant larger degree, betweenness and smaller shortest path length than other swine proteins. Some of AIPs also interacted with several other viruses and could be taken as potential targets of drugs for broad-spectrum effect, such as HSP90AB1. Finally, the antiviral drugs which targeted AIPs and ASFV proteins were predicted. Several drugs with either broad-spectrum effect or high specificity on AIPs were identified, such as Polaprezinc. This work could not only deepen our understanding towards the ASFV-swine interactions, but also help for the development of effective antiviral drugs against the ASFVs.
Homeostasis in the Central Dogma of Molecular Biology: the importance of mRNA instability
Authors: Pérez-Ortín José E. , Tordera Vicente , Chávez Sebastián
Published: April 2019

Cell survival requires the control of biomolecule concentration, i.e. biomolecules should approach homeostasis. With information-carrying macromolecules, the particular concentration variation ranges depend on each type: DNA is not buffered, but mRNA and protein concentrations are homeostatically controlled, which leads to the ribostasis and proteostasis concepts. In recent years, we have studied the particular features of mRNA ribostasis and proteostasis in the model organismS. cerevisiae. Here we extend this study by comparing published data from three other model organisms:E. coli, S. pombeand cultured human cells. We describe how mRNA ribostasis is less strict than proteostasis. A constant ratio appears between the average decay and dilution rates during cell growth for mRNA, but not for proteins. We postulate that this is due to a trade-off between the cost of synthesis and the response capacity. This compromise takes place at the transcription level, but is not possible at the translation level as the high stability of proteins,versusthat of mRNAs, precludes it. We hypothesize that the middle-place role of mRNA in theCentral Dogmaof Molecular Biology and its chemical instability make it more suitable than proteins for the fast changes needed for gene regulation.

Graphical Abstract
Different Whole-Brain Functional Connectivity Correlates of Reactive-Proactive Aggression and Callous-Unemotional Traits in Disruptive Children and Adolescents
Authors: Werhahn Julia E , Mohl Susanna , Willinger David , Smigielski Lukasz , Roth Alexander , Naaijen Jilly , Mulder Leandra M , Glennon Jeffrey C , Hoekstra Pieter J , Dietrich Andrea , Deters Renee Kleine , Aggensteiner Pascal M , Holz Nathalie E , Baumeister Sarah , Banaschewski Tobias , Saam Melanie C , Schulze Ulrike M E , Lythgoe David J , Sethi Arjun , Craig Michael , Mastroianni Mathilde , Sagar-Ouriaghli Ilyas , Santosh Paramala J , Rosa Mireia , Bargallo Nuria , Castro-Fornieles Josefina , Arango Celso , Penzol Maria J , Zwiers Marcel P , Franke Barbara , Buitelaar Jan K , Walitza Susanne , Brandeis Daniel
Published: April 2019

Background

Disruptive behavior in children and adolescents can manifest itself in reactive (RA) and proactive (PA) aggression and is modulated by callous-unemotional (CU) traits and comorbidity. Research on aggression subtype-specific neural correlates is limited and the role of comorbid symptoms largely neglected.

Methods

The current multi-center study extended previous efforts by investigating unrestricted resting state functional connectivity (rsFC) alterations. The large sample (n = 207) of children and adolescents aged 8 – 18 years (mean age = 13.30 ± 2.60 years) included 118 cases with disruptive behavior (80 diagnosed with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptoms were added as covariates. We measured changes in global and local voxel-to-voxel rsFC using functional magnetic resonance imaging at 3T (mean acquisition time = 8 min 25 sec).

Results

Compared to controls, cases demonstrated altered rsFC including frontal areas when anxiety but not ADHD symptoms were considered. Within cases, RA and PA scores related to changes in global and local rsFC in central gyrus and precuneus previously linked to aggression-related impairments. CU trait severity correlated with global rsFC alterations including inferior and middle temporal gyrus implicated in empathy, emotion, and reward-related activity. Importantly, most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety problems were also accounted for.

Conclusions

The current study clarifies that distinct though overlapping brain connectivity measures can disentangle differing manifestations of aggressive behavior. Moreover, our results highlight the importance of considering comorbid symptoms for detecting aggression-related rsFC alterations.
Gene-level heritability analysis explains the polygenic architecture of cancer
Authors: Fanfani Viola , Citi Luca , Harris Adrian L. , Pezzella Francesco , Stracquadanio Giovanni
Published: April 2019

Genome-wide association studies (GWAS) have found hundreds of single nucleotide polymorphisms (SNPs) associated with increased risk of cancer. However, the amount of heritable risk explained by these variants is limited, thus leaving most of cancer heritability unexplained.

Recent studies have shown that genomic regions associated with specific biological functions explain a large proportion of the heritability of many traits. Since cancer is mostly triggered by aberrant genes function, we hypothesised that SNPs located in protein-coding genes could explain a significant proportion of cancer heritability.

To perform this analysis, we developed a new method, called Bayesian Gene HERitability Analysis (BAGHERA), to estimate the heritability explained by all the genotyped SNPs and by those located in protein coding genes directly from GWAS summary statistics.

By applying BAGHERA to the 38 cancers reported in the UK Biobank, we identified 1, 146 genes explaining a significant amount of cancer heritability. We found these genes to be tumour suppressors directly involved in the hallmark processes controlling the transformation from normal to cancer cell; moreover, these genes also harbour somatic driver mutation for many tumours, suggesting a two-hit model underpinning tumorigenesis.

Our study provides new evidence for a functional role of SNPs in cancer and identifies new targets for risk assessment and patients’ stratification.
The piRNA Response to Retroviral Invasion of the Koala Genome
Authors: Yu Tianxiong , Koppetsch Birgit S. , Chappell Keith , Pagliarani Sara , Johnston Stephen , Weng Zhiping , Theurkauf William E.
Published: April 2019

Transposons are ubiquitous mobile elements with the potential to trigger genome instability and mutations linked to diseases1,2. Antisense piRNAs guide an adaptive genome immune system that silences established transposons during germline development3, but how the germline responds to new genome invaders is not understood. The KoRV retrovirus infects somatic and germline cells and is sweeping through wild koala populations by a combination of horizontal and vertical transfers, providing a unique opportunity to directly analyze the germline response to retroviral invasions of a mammalian genome4,5. We analyzed genome organization and long RNA and short RNA transcriptomes in testis, liver, and brain from two wild koalas infected with KoRV, while integrating our results with earlier genomic data. Consistent with data from other mammals6,7, koala piRNAs were detected in testis and mapped to both isolated transposon insertions and genic and intergenic piRNA clusters. Established transposon subfamilies produced roughly equal levels of antisense piRNAs, which are the effectors of trans-silencing, and sense piRNAs, which drive ping-pong amplification of these effectors8,9. KoRV piRNAs, in striking contrast, were strongly sense biased in both animals analyzed. These two koalas each carried 60 germline KoRV-A insertions, but only 14 of the insertions were shared, and none of the insertions mapped to piRNA clusters. The sense piRNAs thus appear to be produced by direct processing of the transcripts from isolated proviral insertions. A typical gammaretrovirus, KoRV produces spliced Env mRNAs and unspliced transcripts encoding Gag, Pol, and the viral genome. KoRV Env mRNAs were 5-fold more abundant than the unspliced pre-mRNAs, but 92% of piRNAs were derived from the unspliced pre-mRNAs. We show that this biased piRNA production from unspliced retrotransposon transcripts is conserved from flies to mice. Retroviruses must bypass splicing to replicate; thus, we propose that failed splicing produces a “molecular pattern” on transcripts from retroviral invaders that is recognized by an innate genome immune system, which silences transposons in cis by processing their transcripts into piRNAs. This innate immune response defends the germline until antisense piRNA production—from clusters or isolated insertions—is established to provide sequence-specific adaptive immunity and memory of the genome invader.
Dysregulation of M segment gene expression contributes to influenza A virus host restriction
Authors: Calderon Brenda M. , Danzy Shamika , Delima Gabrielle K. , Jacobs Nathan T. , Ganti Ketaki , Hockman Megan R. , Conn Graeme L. , Lowen Anice C. , Steel John
Published: April 2019

The M segment of the 2009 pandemic influenza A virus (IAV) has been implicated in its emergence into human populations. To elucidate the genetic contributions of the M segment to host adaptation, and the underlying mechanisms, we examined a panel of isogenic viruses that carry avian- or human-derived M segments. Avian, but not human, M segments restricted viral growth and transmission in mammalian model systems, and the restricted growth correlated with increased expression of M2 relative to M1. M2 overexpression was associated with intracellular accumulation of autophagosomes, which was alleviated by interference of the viral proton channel activity by amantadine treatment. As M1 and M2 are expressed from the M mRNA through alternative splicing, we separated synonymous and non-synonymous changes that differentiate human and avian M segments and found that dysregulation of gene expression leading to M2 overexpression diminished replication, irrespective of amino acid composition of M1 or M2. Moreover, in spite of efficient replication, virus possessing a human M segment that expressed avian M2 protein at low level did not transmit efficiently. We conclude that (i) determinants of transmission reside in the IAV M2 protein, and that (ii) control of M segment gene expression is a critical aspect of IAV host adaptation needed to prevent M2-mediated dysregulation of vesicular homeostasis.

Author summary

Influenza A virus (IAV) pandemics arise when a virus adapted to a non-human host overcomes species barriers to successfully infect humans and sustain human-to-human transmission. To gauge the adaptive potential and therefore pandemic risk posed by a particular IAV, it is critical to understand the mechanisms underlying viral adaptation to human hosts. Here, we focused on the role of one of IAV’s eight gene segments, the M segment, in host adaptation. Comparing the growth of IAVs with avian- and human-derived M segments in avian and mammalian systems revealed that the avian M segment restricts viral growth specifically in mammalian cells. We show that the mechanism underlying this host range phenotype is a dysregulation of viral gene expression when the avian IAV M segment is transcribed in mammalian cells. In particular, excess production of the M2 protein results in viral interference with cellular functions on which the virus relies. Our results therefore reveal that the use of cellular machinery to control viral gene expression leaves the virus vulnerable to over- or under-production of critical viral gene products in a new host species.
Cox regression increases power to detect genotype-phenotype associations in genomic studies using the electronic health record
Authors: Hughey Jacob J. , Rhoades Seth D. , Fu Darwin Y. , Bastarache Lisa , Denny Joshua C. , Chen Qingxia
Published: April 2019

Background

The growth of DNA biobanks linked to data from electronic health records (EHRs) has enabled the discovery of numerous associations between genomic variants and clinical phenotypes. Nonetheless, although clinical data are generally longitudinal, standard approaches for detecting genotype-phenotype associations in such linked data, notably logistic regression, do not naturally account for the times at which events occur. Here we explored the advantages of quantifying associations using Cox proportional hazards regression, which can account for the age at which a patient first visited the healthcare system (left truncation) and the age at which a patient either last visited the healthcare system or acquired a particular phenotype (right censoring).

Results

Using simulated data, we found that, compared to logistic regression, Cox regression had greater power at equivalent Type I error. We then scanned for genotype-phenotype associations using logistic regression and Cox regression on 50 phenotypes derived from the electronic health records of 49 792 genotyped individuals. In terms of effect sizes, the hazard ratios estimated by Cox regression were nearly identical to the odds ratios estimated by logistic regression. Consistent with the findings from our simulations, Cox regression had approximately 10% greater relative sensitivity for detecting known associations from the NHGRI-EBI GWAS Catalog.

Conclusions

As longitudinal health-related data continue to grow, Cox regression may improve our ability to identify the genetic basis for a wide range of human phenotypes.