bluuebunny/crossref_metadata_2025 huggingface dataset:
The Diabetes Prevention Impact Tool Kit: An Online Tool Kit to Assess the Cost-Effectiveness of Preventing Type 2 Diabetes
Authors: Lanza Andrew , Soler Robin , Smith Bryce , Hoerger Thomas , Neuwahl Simon , Zhang Ping
Published: February 2019

The National Diabetes Prevention Program lifestyle change program demonstrated health benefits and potential for health care cost-savings. For many states, employers, and insurers, there is a strong business case for paying for type 2 diabetes prevention, which will likely result in medical and nonmedical cost-savings as well as improved quality of life after a few years. Using an iterative feedback process with multiple stakeholders, the Centers for Disease Control and Prevention developed the Diabetes Prevention Impact Tool kit, https://nccd.cdc.gov/toolkit/diabetesimpact, which forecasts the cost impact the lifestyle change program can have for states, employers, and health insurers. We conducted key informant interviews and a qualitative analysis to evaluate the tool kit. We found that end users recognized its utility for decision making. They valued the detail of the tool kit's underlying calculations and appreciated the option of either using the default settings or revising assumptions based on their own data. The Diabetes Prevention Impact Tool kit can be a helpful tool for organizations that wish to forecast the economic costs and benefits of implementing or covering the National Diabetes Prevention Program lifestyle change program.
Inframammary Fold Reconstruction in the Previously Reconstructed Breast: A Comprehensive Review
Authors: Kraft Casey T. , Rendon Juan L. , Koutz Cynthia A. , Miller Michael J.
Published: February 2019

The inframammary fold presents a reconstructive challenge once disrupted during total mastectomy or inadequately restored during breast reconstruction. Various methods of recreating the inframammary fold have been proposed, but reports are generally based on small sample sizes and lack long-term analyses and patient-reported outcomes. The authors herein review the literature on inframammary fold anatomy and reconstructive techniques, highlighting the need for more critical analysis of methodology to develop more predictable and durable outcomes.
The Use of the Restricted Mean Survival Time as a Treatment Measure in HIV/AIDS Clinical Trial: Reanalysis of the ACTG A5257 Trial
Authors: Abulizi Xianmixikemaier , Ribaudo Heather J. , Flandre Philippe
Published: February 2019

Background:

The restricted mean survival time (RMST) measures have not been used as primary measure of efficacy in HIV/AIDS clinical trials. In this work, we aim to compare analysis based on the difference in RMST (Δ-RMST) measure and 2 other treatment-effect measures in a recent HIV equivalence trial, and to investigate the performance and characteristics of Δ-RMST–based analysis in a simulation study.

Setting and Methods:

We reanalyzed a recent HIV equivalence trial (ACTG A5257 trial) with hazard ratio and Δ-RMST, and then compared the results with the original analysis based on risk difference estimated by Kaplan–Meier curves (RDKM). In a simulation study, we investigated the performance and operating characteristics of Δ-RMST–based analysis in the setting of non-proportional hazards (PH) ratio.

Results:

In the ACTG A5257 trial, analyses based on Δ-RMST globally led to similar conclusions as the published finding based on RDKM. By contrast, analyses based on hazard ratio provided some discordant equivalence conclusions compared both with the initial analyses based on RDKM and the Δ-RMST. Results of simulation study indicate that the violation of the PH assumption has an impact on Δ-RMST–based analysis regarding the probability of declaring equivalence.

Conclusions:

Although the RMST-based analysis is an alternative measure of efficacy in HIV/AIDS, clinical trials such an analysis can be strongly impacted by departures from the PH assumption.
High Plasma Soluble CD163 During Infancy Is a Marker for Neurocognitive Outcomes in Early-Treated HIV-Infected Children
Authors: Benki-Nugent Sarah F. , Martopullo Ira , Laboso Tony , Tamasha Nancy , Wamalwa Dalton C. , Tapia Kenneth , Langat Agnes , Maleche-Obimbo Elizabeth , Marra Christina M. , Bangirana Paul , Boivin Michael J. , John-Stewart Grace C.
Published: February 2019

Background:

Monocyte activation may contribute to neuronal injury in aviremic HIV-infected adults; data are lacking in children. We examined the relation between monocyte activation markers and early and long-term neurodevelopmental outcomes in early-treated HIV-infected children.

Setting:

Prospective study of infant and child neurodevelopmental outcomes nested within a randomized clinical trial (NCT00428116) and extended cohort study in Kenya.

Methods:

HIV-infected infants (N = 67) initiated antiretroviral therapy (ART) at age <5 months. Plasma soluble (s) CD163 (sCD163), sCD14, and neopterin were measured before ART (entry) and 6 months later. Milestone attainment was ascertained monthly during 24 months, and neuropsychological tests were performed at 5.8–8.2 years after initiation of ART (N = 27). The relationship between neurodevelopment and sCD163, sCD14, and neopterin at entry and 6 months after ART was assessed using Cox proportional hazards models and linear regression.

Results:

Infants with high entry sCD163 had unexpected earlier attainment of supported sitting (5 vs 6 months; P = 0.006) and supported walking (10 vs 12 months; P = 0.02) with trends in adjusted analysis. Infants with high 6-month post-ART sCD163 attained speech later (17 vs 15 months; P = 0.006; adjusted hazard ratio, 0.47; P = 0.02), threw toys later (18 vs 17 months; P = 0.01; adjusted hazard ratio, 0.53; P = 0.04), and at median 6.8 years after ART, had worse neuropsychological test scores (adj. mean Z-score differences, cognition, −0.42; P = 0.07; short-term memory, −0.52; P = 0.08; nonverbal test performance, −0.39, P = 0.05).

Conclusions:

Before ART, monocyte activation may reflect transient neuroprotective mechanisms in infants. After ART and viral suppression, monocyte activation may predict worse short- and long-term neurodevelopment outcomes.
18F-FDG PET/CT Demonstrates Renal Cell Cancer in a Transplant With Synchronous Intestinal Infection
Authors: Kavanal Anwin Joseph , Bharati Joyita , Vadi Shelvin Kumar , Gupta Krishan Lal , Kumar Rajender , Mittal Bhagwant Rai
Published: February 2019

We present a case of a 22-year-old man with history of allogenic renal transplantation on immunosuppression, who underwent 18F-FDG-PET/CT to characterize a lesion in the transplanted kidney on ultrasonogram and contrast-enhanced computed tomography imaging. PET/CT revealed FDG avid lesion in the transplanted kidney and mural thickening involving the distal ileum, ileocecal junction, and ileocolic lymph nodes. Subsequent histopathological examination from the renal lesion revealed renal cell carcinoma in the transplanted kidney. Additionally, endoscopic biopsy from the ileal thickening revealed granulomatous inflammation, suggesting tuberculosis, which was missed on both ultrasonogram and contrast-enhanced CT imaging.
Oral immunization with a probiotic cholera vaccine induces broad protective immunity againstVibrio choleraecolonization and disease in mice
Authors: Sit Brandon , Zhang Ting , Fakoya Bolutife , Akter Aklima , Biswas Rajib , Ryan Edward T. , Waldor Matthew K.
Published: February 2019

Oral cholera vaccines (OCVs) are being increasingly employed, but current killed formulations generally require multiple doses and lack efficacy in young children. We recently developed a new live-attenuated OCV candidate (HaitiV) derived from aVibrio choleraestrain isolated during the 2010 Haiti cholera epidemic. HaitiV exhibited an unexpected probiotic-like activity in infant rabbits, preventing intestinal colonization and disease by wild-typeV. choleraebefore the onset of adaptive immunity. However, it remained unknown whether HaitiV would behave similarly to other OCVs to stimulate adaptive immunity againstV. cholerae.Here, we orally immunized adult germ-free female mice to test HaitiV’s immunogenicity. HaitiV safely and stably colonized vaccinated mice and induced known adaptive immune correlates of cholera protection within 14 days of administration. Pups born to immunized mice were protected against lethal challenges of both homologous and heterologousV. choleraestrains. Cross-fostering experiments revealed that protection was not dependent on vaccine colonization in or transmission to the pups. These findings demonstrate the protective immunogenicity of HaitiV and support its development as a new tool for limiting cholera.

Author summary

Vaccines for cholera are gaining acceptance as public health tools for prevention of cholera and curtailing the spread of outbreaks. However, current killed vaccines provide minimal protection in young children, who are especially susceptible to this diarrheal disease, and do not stimulate immunity against antigens that may only be expressed by live bacteria during infection. We recently developed HaitiV, an extensively engineered live-attenuated oral cholera vaccine candidate, derived from a clinical isolate from the Haiti cholera outbreak. Here, we found that the HaitiV induces immunological correlates of protection against cholera in germ free mice and leads to protection against disease in their offspring. Protection in this model was dependent on passively acquired factors in the milk of immunized dams and not transmission or colonization of HaitiV. Coupling the immunogenicity data presented here with our previous observation that HaitiV can protect from cholera prior to the induction of adaptive immunity, suggests that HaitiV may provide both rapid-onset short-term protection from disease while eliciting stable and long-lasting immunity against cholera.
Pancreas patch-seq links physiologic dysfunction in diabetes to single-cell transcriptomic phenotypes
Authors: Camunas-Soler Joan , Dai Xiaoqing , Hang Yan , Bautista Austin , Lyon James , Suzuki Kunimasa , Kim Seung K , Quake Stephen R , MacDonald Patrick E
Published: February 2019

Pancreatic islet cells regulate glucose homeostasis through insulin and glucagon secretion; dysfunction of these cells leads to severe diseases like diabetes. Prior single-cell transcriptome studies have shown heterogeneous gene expression in major islet cell-types; however it remains challenging to reconcile this transcriptomic heterogeneity with observed islet cell functional variation. Here we achieved electrophysiological profiling and single-cell RNA sequencing in the same islet cell (pancreas patch-seq) thereby linking transcriptomic phenotypes to physiologic properties. We collected 1,369 cells from the pancreas of donors with or without diabetes and assessed function-gene expression networks. We identified a set of genes and pathways that drive functional heterogeneity in β-cells and used these to predict β-cell electrophysiology. We also report specific transcriptional programs that correlate with dysfunction in type 2 diabetes (T2D) and extend this approach to cryopreserved cells from donors with type 1 diabetes (T1D), generating a valuable resource for understanding islet cell heterogeneity in health and disease.

Key findings

Pancreas patch-seq provides a single-cell survey of function-transcriptome pairing in 1,369 islet cells from donors with and without diabetes

Expression of a specific subset of genes predicts β-cell electrophysiology in transcriptome-function networks.

Compromised β-cell function in T2D correlates with altered ETV1 expression and inflammatory pathways

Functional heterogeneity in α-cells maps to ER stress and islet lineage markers

Application of patch-seq to cells from rare cryopreserved islets from donors with T1D
Nucleic Acid Cleavage with a Hyperthermophilic Cas9 from an Unculturable Ignavibacterium
Authors: Schmidt Stephanie Tzouanas , Yu Feiqiao Brian , Blainey Paul C. , May Andrew P. , Quake Stephen R.
Published: February 2019

CRISPR-Cas9 systems have been effectively harnessed to engineer the genomes of organisms from across the tree of life. Nearly all currently characterized Cas9 proteins are derived from mesophilic bacteria, and canonical Cas9 systems are challenged by applications requiring enhanced stability or elevated temperatures. We discovered IgnaviCas9, a Cas9 protein from a hyperthermophilic Ignavibacterium identified through mini-metagenomic sequencing of samples from a hot spring. IgnaviCas9 is active at temperatures up to 100 °C in vitro, which enables DNA cleavage beyond the 44 °C limit of Streptococcus pyogenes Cas9 (SpyCas9) and the 70 °C limit of both Geobacillus stearothermophilus Cas9 (GeoCas9) and Geobacillus thermodenitrificans T12 Cas9 (ThermoCas9). As a potential application of this enzyme, we demonstrated that IgnaviCas9 can be used in bacterial RNA-seq library preparation to remove unwanted cDNA from 16s ribosomal rRNA (rRNA) without increasing the number of steps, thus underscoring the benefits provided by its exceptional thermostability in improving molecular biology and genomic workflows. Taken together, IgnaviCas9 is an exciting addition to the CRISPR-Cas9 toolbox and expands its temperature range.
Disrupted Mechanobiology Links the Molecular and Cellular Phenotypes in Familial Dilated Cardiomyopathy
Authors: Clippinger Sarah R. , Cloonan Paige E. , Greenberg Lina , Ernst Melanie , Tom Stump W. , Greenberg Michael J.
Published: February 2019

Familial dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death and a major indicator for heart transplant. The disease is frequently caused by mutations of sarcomeric proteins; however, it is not well understood how these molecular mutations lead to alterations in cellular organization and contractility. To address this critical gap in our knowledge, we studied the molecular and cellular consequences of a DCM mutation in troponin-T, ΔK210. We determined the molecular mechanism of ΔK210 and used computational modeling to predict that the mutation should reduce the force per sarcomere. In mutant cardiomyocytes, we found that ΔK210 not only reduces contractility, but also causes cellular hypertrophy and impairs cardiomyocytes’ ability to adapt to changes in substrate stiffness (e.g., heart tissue fibrosis that occurs with aging and disease). These results link the molecular and cellular phenotypes and implicate alterations in mechanosensing as an important factor in the development of DCM.
Gene regulatory network of human GM-CSF secreting T helper cells
Authors: Éliás Szabolcs , Schmidt Angelika , Gomez-Cabrero David , Tegnér Jesper
Published: February 2019

GM-CSF produced by autoreactive CD4 positive T helper cells is involved in the pathogenesis of autoimmune diseases, such as Multiple Sclerosis. However, the molecular regulators that establish and maintain the features of GM-CSF positive CD4 T cells are unknown. In order to identify these regulators, we isolated human GM-CSF producing CD4 T cells from human peripheral blood by using a cytokine capture assay. We compared these cells to the corresponding GM-CSF negative fraction, and furthermore, we studied naïve CD4 T cells, memory CD4 T cells and bulk CD4 T cells from the same individuals as additional control cell populations. As a result, we provide a rich resource of integrated chromatin accessibility (ATAC-seq) and transcriptome (RNA-seq) data from these primary human CD4 T cell subsets, and we show that the identified signatures are associated with human autoimmune disease, especially Multiple Sclerosis. By combining information about mRNA expression, DNA accessibility and predicted transcription factor binding, we reconstructed directed gene regulatory networks connecting transcription factors to their targets, which comprise putative key regulators of human GM-CSF positive CD4 T cells as well as memory CD4 T cells. Our results suggest potential therapeutic targets to be investigated in the future in human autoimmune disease.
In Situ Electrochemical Studies of the Terrestrial Deep Subsurface Biosphere at the Sanford Underground Research Facility, South Dakota, USA
Authors: Jangir Yamini , Karbelkar Amruta A. , Beedle Nicole M. , Zinke Laura A. , Wanger Greg , Anderson Cynthia M. , Reese Brandi Kiel , Amend Jan P. , El-Naggar Mohamed Y.
Published: February 2019

The terrestrial deep subsurface is host to significant and diverse microbial populations. However, these microbial populations remain poorly characterized, partially due to the inherent difficulty of sampling,in situstudies, and isolating of thein situmicrobes. Motivated by the ability of microbes to gain energy from redox reactions at mineral interfaces, we here presentin situelectrochemical colonization (ISEC) as a method to directly study microbial electron transfer activity and to enable the capture and isolation of electrochemically active microbes. We installed a potentiostatically controlled ISEC reactor containing four working electrodes 1500 m below the surface at the Sanford Underground Research Facility. The working electrodes were poised at different redox potentials, spanning anodic to cathodic, to mimic energy-yielding mineral reducing and oxidizing reactions predicted to occur at this site. We present a 16S rRNA analysis of thein situelectrode-associated microbial communities, revealing the dominance of novel bacterial lineages under cathodic conditions. We also demonstrate that thein situelectrodes can be further used for downstream electrochemical laboratory enrichment and isolation of novel strains. Using this workflow, we isolatedBacillus,Anaerospora,Comamonas,Cupriavidus, andAzonexusstrains from the electrode-attached biomass. Finally, the extracellular electron transfer activity of the electrode-oxidizingComamonasstrain (isolated at −0.19 V vs. SHE and designated WE1-1D1) and the electrode-reducingBacillusstrain (isolated at +0.53 V vs. SHE and designated WE4-1A1-BC) were confirmed in electrochemical reactors. Our study highlights the utility ofin situelectrodes and electrochemical enrichment workflows to shed light on microbial activity in the deep terrestrial subsurface.

SIGNIFICANCE

A large section of microbial life resides in the deep subsurface, but an organized effort to explore this deep biosphere has only recently begun. A detailed characterization of the resident microbes remains scientifically and technologically challenging due to difficulty in access, sampling, and emulating the complex interactions and energetic landscapes of subsurface communities with standard laboratory techniques. Here we describe an in situ approach that exploits the ability of many microbes to perform extracellular electron transfer to/from solid surfaces such as mineral interfaces in the terrestrial subsurface. By deploying and controlling the potential of in situ electrodes 4850 ft below the surface at the Sanford Underground Research Facility (South Dakota, USA), we highlight the promise of electrochemical techniques for studying active terrestrial subsurface microbial communities and enabling the isolation of electrochemically active microbes.
The influence of sex on the urogenital microbiome of rhesus monkeys
Authors: Hallmaier-Wacker L. K. , Lueert S. , Roos C. , Knauf S.
Published: February 2019

The vaginal microbiome of nonhuman primates (NHPs) differs substantially from humans in terms of Lactobacillus abundance, overall taxonomic diversity, and vaginal pH. Given these differences, it remains unclear in what way the NHP genital microbiome protects against pathogens, in particular sexually transmitted diseases. Considering the effect that microbiome variations can have on disease acquisition and outcome, we examined endogenous and exogenous factors that influence the urogenital microbiome of captive rhesus monkeys. The male urethral (n=37) and vaginal (n=194) microbiome of 11 breeding groups were examined in a cross-sectional study. During lactation and menstruation, the vaginal microbiome becomes significantly more diverse and more similar to the microbes observed in the male urethra. Group association and cage-mate (sexual partners) relationships were additionally associated with significant differences in the urogenital microbiome. Our results demonstrate that microbiome considerations are necessary in order to make informed selection of NHPs as translational animal models.
Brain gene expression in a novel mouse model of postpartum mood disorder
Authors: Humby Trevor , Davies William
Published: February 2019

Introduction

Steroid sulfatase (STS) is an enzyme which cleaves sulfate groups from a variety of steroid hormones, thereby altering their activity and solubility. The expression and activity of STS is increased in female mammalian tissues (including brain) during late pregnancy and into the postpartum period. STS-deficient human and mouse mothers (as a consequence of genetic mutation or acute pharmacological manipulation) show evidence for elevated psychopathology and abnormal behaviour respectively in the postpartum period. In mice, these behavioural effects can be partially normalised through administration of the antipsychotic ziprasidone.

Methods

To explore the neurobiology underlying these postpartum behavioural effects, we compared whole brain gene expression by microarray in behaviourally-defined new mouse mothers acutely administered the STS inhibitor 667-Coumate (10mg/kg p.o.) or vehicle solution (n=12 per group); significant changes were followed-up with pathway analysis and quantitative polymerase chain reaction (qPCR). Finally, the effects of combined 667-Coumate and antipsychotic (ziprasidone) administration (0, 0.3 and 1.0mg/kg i.p.) on the brain expression of the most robustly differentially-expressed candidate genes was examined (n≥7 per group).

Results

Surprisingly, no significant gene expression changes were detected between vehicle and 667-Coumate-treated brains at a False Discovery Rate (FDR) corrected p<0.1. 1,081 unique expression changes were detected at a less-stringent cut-off of p<0.05, just two top hits were verified by qPCR, and pathway analysis indicated a significant enrichment of genes involved in olfactory transduction (corrected p-value=1.8×10−3). The expression of the two most robust differentially-expressed genes (Stoml3 and Cyp2g1) was not affected by ziprasidone administration.

Conclusions

Behavioural abnormalities in new mothers in the postpartum period elicited as a result of STS deficiency are likely to be the culmination of many small gene expression changes. Our data are consistent with the idea that olfactory function is key to postpartum maternal behaviour in mice, and suggest that aberrant expression of olfactory system genes may partially underlie abnormal maternal behaviour in STS-deficient women.
The COMPARE Data Hubs
Authors: Amid Clara , Pakseresht Nima , Silvester Nicole , Jayathilaka Suran , Lund Ole , Dynovski Lukasz D. , Pataki Bálint Á. , Visontai Dávid , Cotten Matthew , Xavier Basil Britto , Alako Blaise , Belka Ariane , Cisneros Jose J. L. , Haringhuizen George B. , Harrison Peter W. , Höper Dirk , Holt Sam , Hundahl Camilla , Hussein Abdulrahman , Kaas Rolf S. , Malhotra-Kumar Surbhi , Leinonen Rasko , Nieuwenhuijse David F. , Rahman Nadim , Ribeiro Carolina dos S , Skiby Jeffrey E. , Stéger József , Szalai-Gindl János M. , Thomsen Martin C. F. , Csabai István , Koopmans Marion , Aarestrup Frank , Cochrane Guy
Published: February 2019

Data sharing enables research communities to exchange findings and build upon the knowledge that arises from their discoveries. Areas of public and animal health as well as food safety would benefit from rapid data sharing when it comes to emergencies. However, ethical, regulatory, and institutional challenges, as well as lack of suitable platforms which provide an infrastructure for data sharing in structured formats often lead to data not being shared, or at most shared in form of supplementary materials in journal publications. Here, we describe an informatics platform that includes workflows for structured data storage, managing and pre-publication sharing of pathogen sequencing data and its analysis interpretations with relevant stakeholders.
Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation
Authors: Sevilla-Montero J , Labrousse-Arias D , Fernández-Pérez C , Barreira B , Mondejar-Parreño G , Cogolludo A , Calzada MJ
Published: February 2019

Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies nowadays. Exposure to cigarette smoking is considered the chief leading cause of COPD. Current drugs therapies improve patient quality of life, however they do not revert the progression of the disease. Therefore, a deeper study of the cellular and molecular mechanisms that underlie this pathology is required to be able to carry out targeted and effective treatments. Although the effects of cigarette smoke in the progressive deterioration of the airway have been extensively studied in COPD patients, its effects on pulmonary vasculature have been unexplored, due to the classic conception that vascular damage is a consequence of alveolar hypoxia and loss of capillary bed. In this paper, we aimed to study the effects of cigarette smoke extract (CSE) in regulating pulmonary arterial cells phenotypic modulation, in particular the effects in fibroblasts (hPAFib) and smooth muscle cells (hPASMC), and in murine pulmonary arteries. Our results demonstrated that CSE exposure had direct effects on hPAFib and hPASMC, promoting a senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to increase the proliferative potential of non-exposed cells. CSE also increased total ROS levels in hPAFib and hPASMC, and upregulated NADPH oxidase subunits NOX1 and p22phox. Most importantly, CSE affected cell contractility and dysregulated the expression and activity of voltage-gated K+ channel Kv7.4. This contributed to limit vascular responses impairing vasoconstriction and endothelium-dependent and independent relaxation.
Genetic and shared couple environmental contributions to smoking and alcohol use in the UK population
Authors: Clarke Toni-Kim , Adams Mark J. , Howard David M. , Xia Charley , Davies Gail , Hayward Caroline , Campbell Archie , Padmanabhan Sandosh , Smith Blair H. , Murray Alison , Porteous David , Deary Ian J. , McIntosh Andrew M.
Published: February 2019

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18% and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use correlations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). Only couples’ smoking status PRSs were significantly associated (b=0.01, S.E=0.005, p=0.02). However, an individual’s alcohol PRS was associated with their partner’s phenotype (b=0.04, S.E=0.007, p < 2 x 10-7). In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.
Defined neuronal populations drive fatal phenotype in Leigh Syndrome
Authors: Bolea Irene , Gella Alejandro , Sanz Elisenda , Prada-Dacasa Patricia , Menardy Fabien , Machuca-Márquez Pablo , Bard Angela Michelle , Kalume Franck , Quintana Albert
Published: February 2019

Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energy-requiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death. While neural affectation is a critical component of the pathology, only discrete neuronal populations are susceptible. However, their molecular identity and their contribution to the disease remain unknown. Mice lacking the mitochondrial Complex I subunit NDUFS4 (Ndufs4KO mice) recapitulate the classical signs of Leigh Syndrome (LS), the most common presentation of mitochondrial disease with predominant CNS affectation. Here, we identify the critical role of two genetically-defined neuronal populations driving the fatal phenotype in Ndufs4KO mice. Selective inactivation of Ndufs4 in Vglut2-expressing glutamatergic neurons causes brainstem inflammation, motor and respiratory deficits, and early death. On the other hand, Ndufs4 deletion in GABAergic neurons leads to basal ganglia inflammation without motor or respiratory involvement, but accompanied by severe refractory epileptic seizures preceding premature death. These results provide novel insight in the cell type-specific contribution to LS pathology and open new avenues to understand the underlying cellular mechanisms of mitochondrial disease.
Considerations for clinical curation, classification and reporting of low-penetrance and low effect size variants associated with disease risk
Authors: Senol-Cosar Ozlem , Schmidt Ryan J. , Qian Emily , Hoskinson Derick , Mason-Suares Heather , Funke Birgit , Lebo Matthew S.
Published: February 2019

Purpose

Clinically relevant variants exhibit a wide range of penetrance. Medical practice has traditionally focused on highly penetrant variants with large effect sizes and, consequently, classification and clinical reporting frameworks are tailored to that variant type. At the other end of the penetrance spectrum, where variants are often referred to as “risk alleles”, traditional frameworks are no longer appropriate. This has led to inconsistency in how such variants are interpreted and classified. Here, we describe a conceptual framework to begin addressing this gap.

Methods

We used a set of risk alleles to define data elements that can characterize the validity of reported disease associations. We assigned weight to these data elements and established classification categories expressing confidence levels. This framework was then expanded to develop criteria for inclusion of risk alleles on clinical reports.

Results

Foundational data elements include cohort size, quality of phenotyping, statistical significance, and replication of results. Criteria for determining inclusion of risk alleles on clinical reports include presence of clinical management guidelines, effect size, severity of the associated phenotype, and effectiveness of intervention.

Conclusions

This framework represents an approach for classifying risk alleles and can serve as a foundation to catalyze community efforts for refinement.
Adrenergic signaling in muscularis macrophages limits neuronal death following enteric infection
Authors: Matheis Fanny , Muller Paul A. , Graves Christina , Gabanyi Ilana , Kerner Zachary J. , Costa-Borges Diego , Mucida Daniel
Published: February 2019

Enteric–associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility. Bidirectional interactions between immune and neuronal cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated how infection-induced inflammation affects intrinsic EANs and the role of intestinalmuscularismacrophages (MMs) in this process. Using murine model of bacterial infection, we observed long-term gastrointestinal symptoms including reduced motility and subtype-specific neuronal loss. Neuronal-specific translational–profiling uncovered a caspase 11–dependent EAN cell–death mechanism induced by enteric infections. MMs responded to luminal infection by upregulating a neuroprotective program; gain– and loss–of-function experiments indicated that β2-adrenergic receptor (β2-AR) signaling in MMs mediates neuronal protection during infection via an arginase 1-polyamine axis. Our results identify a mechanism of neuronal cell death post–infection and point to a role for tissue–resident MMs in limiting neuronal damage.
Ovarian cancer G protein-coupled receptor 1 inhibits A549 cells Migration through Casein kinase 2α intronless gene
Authors: Sharma Adhikarimayum Lakhikumar , Meitei Puyam Milan , Singh Naorem Tarundas , Singh Thiyam Ramsing , Singh Lisam Shanjukumar
Published: February 2019

We have previously reported that ovarian cancer G protein-coupled receptor 1 (OGR1) is a new metastasis suppressor gene. We have also reported for the first time that a new intronless gene for casein kinase 2α (CSNK2A3) is expressed in human cells. The promoter of the well-known casein kinase 2α (CSNK2A1) displays characteristics of housekeeping gene whereas CSNK2A3 has a characteristic of a regulated promoter with two TATA boxes and a CAAT box. In this study, we found that OGR1 up-regulates expression of CSNK2A3 by about 3 folds in A549 cells but not CSNK2A1. OGR1 also up-regulates expression of neutral endopeptidase (NEP). The OGR1 induced inhibition of A549 cell migration is completely abrogated by inhibition of casein kinase 2α activity, whereas partial abrogation (~ 30%) was observed in the presence of NEP inhibition. The results also revealed that OGR1 regulates CSNK2A3 via activation of Rac1/cdc42 and MAPKs pathways. CK2 is ubiquitously expressed and in contrast it is believed to be a constitutively active enzyme and its regulation appears to be independent of known second messengers. There is no previous report on how expression of CK2α in cancer cells is regulated although many studies have report of aberrant expression of the kinase in cancer. In the current study, we are reporting for the first time the regulation of intronless casein kinase 2α gene, CSNK2A3 in cancer cells. Our findings suggest that the aberrantly casein kinase 2α expression found in various cancer cells may the due to CSNK2A3 expression which is potentially regulated by several master regulators of the developmental pathways rather than well-known casein kinase 2α gene, CSNK2A1.
Positive selection in the Ebola virus proteome
Authors: Dasmeh Pouria
Published: February 2019

To gain insight into the recent evolution of EBOLA virus (EBOV) proteins and identify evolutionary hotspots, I investigated patterns of amino acid substitutions in the proteomes of 49 members of EBOV genus including EBOV, Bundibugyo virus (BDBV), Reston virus (RESTV), Sudan virus (SUDV) and Taï Forest virus (TAFV) spanning outbreaks from 1974 to 2014 in Democratic Republic of Congo (DRC), Uganda, Gabon, Sudan, Ivory Coast, Philippines, and Guinea among humans, non-human primates, and pigs. Of the seven genes of the Ebola genome, I found significant variations in evolutionary rates of Glycoprotein (GP), RNA/dependent RNA polymerase (L), and Nucleoprotein (NP) across different lineages. GP and NP were found to evolve at 5- and 3-fold higher rate than other EBOV genes. Several residues in GP and NP show significant dN/dS>1 along the internal branches of the phylogenetic tree leading to Philippines and Sudan outbreaks. Most of these residues are located in solvent exposed areas shown previously to be antigenic. We further identified significant changes in specific amino acid properties of GP, NP and L during the recent evolutionary history of EBOV outbreaks and in particular during the 2014 outbreak. The positively selected residues and chemical properties are consistent with changes in epitope interaction and could thus be important in detecting adaptation of EBOV to the host immune defense system.
Flooding and hydrologic connectivity modulate community assembly in a dynamic river-floodplain ecosystem
Authors: Larsen Stefano , Karaus Ute , Claret Cecile , Sporka Ferdinand , Hamerlík Ladislav , Tockner Klement
Published: February 2019

Braided river floodplains are highly dynamic ecosystems, where aquatic communities are strongly regulated by the hydrologic regime. So far, however, understanding of how flow variation influences assembly mechanisms remains limited.

We collected benthic chironomids and oligochaetes over a year across a lateral connectivity gradient in the semi-natural Tagliamento River (Italy). Four bankfull flood events occurred during the study, allowing the assessment of how flooding and hydrologic connectivity mediate the balance between stochastic and deterministic community assembly.

While invertebrate density and richness were positively correlated with connectivity, diversity patterns showed no significant correlation. Species turnover through time increased with decreasing connectivity. Contrary to expectations, hydrologic connectivity did not influence the response of community metrics (e.g. diversity, density) to floods.

Invertebrate composition was weakly related to connectivity, but changed predictably in response to floods. Multivariate ordinations showed that faunal composition diverged across the waterbodies during stable periods, reflecting differential species sorting across the lateral gradient, but converged again after floods. Stable hydrological periods allowed communities to assemble deterministically with prevalence of non-random beta-diversity and cooccurrence patterns and larger proportion of compositional variation explained by local abiotic features. These signals of deterministic processes clearly declined after flooding events. This occurred despite no apparent evidence of flood-induced homogenisation of habitat conditions.

This study is among the first to examine the annual dynamic of aquatic assemblages across a hydrologic connectivity gradient in a natural floodplain. Results highlight how biodiversity can exhibit complex relations with hydrologic connectivity. However, appraisal of the assembly mechanisms through time indicated that flooding shifted the balance from deterministic species sorting across floodplain habitats, towards stochastic processes related to organisms redistribution and the likely resetting of assembly to earlier stages.
The structure of CgnJ, a domain of unknown function protein from the crocagin gene cluster
Authors: Adam Sebastian , Klein Andreas , Surup Frank , Koehnke Jesko
Published: February 2019

Natural products often contain interesting new chemical entities that are introduced into the structure of a compound by the enzymatic machinery of the producing organism. The recently described crocagins are novel polycyclic peptides which belong to the class of ribosomally synthesized and post-translationally modified peptide natural products. They have been shown to bind to the conserved prokaryotic carbon-storage regulator Ain vitro. In efforts to understand crocagin biosynthesis, the putative biosynthetic genes were expressed and purified. Here, the first crystal structure of a protein from the crocagin-biosynthetic gene cluster, CgnJ, a domain of unknown function protein, is reported. Possible functions of this protein were explored by structural and sequence homology analyses. Even though the sequence homology to proteins in the Protein Data Bank is low, the protein shows significant structural homology to a protein with known function within the competency system ofBacillus subtilis, ComJ, leading to the hypothesis of a similar role of the protein within the producing organism.
Are students’ mindsets those of typical start-up founders?
Authors: Rungi Mait
Published: February 2019

Purpose

Studies have found that founders of start-up companies are similar to students in certain psychological characteristics. Confirming this similarity would have methodological and phenomenological implications. Phenomenologically, students are a main source for recruitment in start-up companies. Methodologically, students are a more convenient sample to study than start-up founders. The paper aims to discuss these issues.

Design/methodology/approach

The resemblance between students and start-up founders is tested by analyses of variance of the responses of 1,509 students and 53 start-up founders to a questionnaire survey.

Findings

The results indicate that, as a population, students are not entirely similar to start-up founders, though similarities were found to exist. The closest resemblance between students and founders was found for managerial, armed forces/police and medicine students; agricultural, humanities and natural science students had the least resemblance.

Originality/value

Although student samples are commonly used in the study of management phenomena, the validity of this approach has not hitherto been tested, which indicates that the use of student subjects as stand-ins for start-up founders may be a practice without a solid foundation.
Board independence and internal control quality in Egypt: does CEO duality matter?
Authors: Khlif Hichem , Samaha Khaled
Published: February 2019

Purpose

This paper aims to examine the relationship between board independence and internal control quality (ICQ) in Egypt and investigate whether CEO duality moderates such an association.

Design/methodology/approach

A survey among external auditors is used to assess ICQ among Egyptian listed firms over the period of 2007-2010.

Findings

Findings show that board independence does not have a significant positive effect on ICQ. However, when testing for the moderating effect of CEO duality on such a relationship, the authors document that the association becomes positive and significant under combined board leadership structure, whereas it is negative under separated leadership structure.

Originality/value

The authors’ results demonstrate that CEO duality plays a governance role in weak legal environment like Egypt by strengthening board independence role in increasing ICQ.
Municipal charges on communal waste: do they compete with the immovable property tax?
Authors: Radvan Michal
Published: February 2019

Purpose

The purpose of this paper is to give a recommendation to the municipalities what local tax/taxes sensu largo (a waste charge or an immovable property tax increased by a local coefficient) are to be collected to achieve expected and necessary incomes and limit the administrative costs.

Design/methodology/approach

To reach the aim, it was necessary to analyze the number of municipalities increasing the property tax by the local coefficient and abolishing the charge on communal waste to save money for the waste charges administration. The evidence of municipalities applying the local coefficient was used as a basis for the research. To get the information on charges on communal waste collected in these municipalities with the local coefficient within the past at least five taxable periods, the information from Monitor was used. If there was any such a significant change, then it was necessary to use the bylaws and to do thorough analysis of the reasons.

Findings

The hypothesis that a high number of municipalities in the Czech Republic are replacing the charge on communal waste with the local coefficient applicable for the immovable property tax was rejected. In the opinion of the author, the ideal approach is to have just one local tax – immovable property tax. This tax is administered by the state tax office and the revenue should cover the cost of waste management. Adopting only the property tax increased by the local coefficient, it is necessary to explain the benefits to the taxpayers, that is, locals and voters.

Originality/value

The research on the given topic was never done in the Czech Republic, as there is no evidence of local charges collected in individual municipalities.
Social media and the police
Authors: Hu Xiaochen , Lovrich Nicholas P.
Published: February 2019

Purpose

Most police agencies in the USA make the claim that they use social media, and such use is drawing a great academic attention. Most studies on police use of social media focus on the content of police social media websites. Little research, however, has been conducted regarding what types of police agencies are in fact making use of social media. The purpose of this paper is to fill this gap in the knowledge.

Design/methodology/approach

The study reported here analyzes the 2013Law Enforcement Management and Administrative Statistics(LEMAS) data set to identify the principal organizational characteristics of police agencies associated with the use of social media. Binary logistic regression is used to identify significant independent predictors of police use of social media, viewed here as a form of innovation.

Findings

The findings indicate that the workforce size (commissioned and civilian personnel) of a police agency, the level of participation in multi-jurisdictional task forces and the early use of an official agency website to communicate with the public are the predictors of police use of social media.

Research limitations/implications

Three theories pertaining to organizational behavior (i.e. contingency theory, institutional theory, and resource dependency theory), as well as Maguire’s (2003) study, are used to establish the theoretical framework for the research reported here.

Originality/value

Viewed as a pioneering study testing organizational theories related to police use of social media, the current study sets forth findings that help deepen the collective understanding of contingency theory, institutional theory and resource dependency theory as frameworks for explaining organizational behavior in policing.
2D cooperative inversion of direct current resistivity and gravity data: A case study of uranium bearing target rock
Authors: Singh Anand , Mishra Pankaj K. , Sharma S.P.
Published: February 2019

Interpretation of a single geophysical data set is not sufficient to get complete subsurface information. Cooperative or joint inversion of geophysical data sets is the preferred method for most case studies. In the present study, we present the results of the cooperative inversion approach of direct current resistivity and gravity data. The algorithm uses fuzzy c‐means clustering to determine the petrophysical relationship between density and resistivity to obtain the similarity. Synthetic data set has demonstrated that the cooperative inversion approach can produce more reliable and better resistivity and density models of the subsurface as compared to those obtained through individual inversions. To utilize the presented cooperative inversion algorithm, the number of geologic units (number of clusters) in the study region must be known a priori. As a field study, the cooperative inversion approach was used to identify the extension of uranium‐bearing target rock around the Beldih open cast mine. We noted the inconsistencies in both resistivity and density models obtained from the individual inversions. However, the presented cooperative inversion approach was able to produce similar resistivity and density models while maintaining the same error level of the respective individual inversions. We have considered four geologic units in the presented cooperative inversion as a field case study. We have also compared our cooperative results with drilled borehole and found to be a reliable tool to differentiate between the target rocks (kaolinite and quartz–magnetite–apatite rocks) and the ultramafic rock (host rock quartzite/alkaline granite). However, this study is subject to certain limitations such as the inability to differentiate between closely spaced kaolinite and quartz–magnetite–apatite rocks.