bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of an Adapted Project Connect Community-based Intervention Among Professionals Serving Young Minority Men
Authors: Perin Jamie , Jennings Jacky M. , Arrington-Sanders Renata , Page Kathleen R. , Loosier Penny S. , Dittus Patricia J. , Marcell Arik V.
Published: January 2019

Background

To address sexual and reproductive health (SRH) needs of young minority urban males, we developed and evaluated Project Connect Baltimore (Connect), which was adapted from a program with demonstrated effectiveness among young females. The objectives were to determine (1) the feasibility of Connect as adapted for young minority men, (2) whether the program increased SRH knowledge and resource sharing of youth-serving professionals (YSPs) working with young men, and (3) whether the program improved awareness and use of resources for young minority men in Baltimore City, an urban environment with high rates of sexually transmitted diseases.

Methods

Connect developed a clinic referral guide for male youth-friendly resources for SRH. The YSPs working with partners and organizations serving young minority men were trained to use Connect materials and pretraining, immediate, and 3-month posttraining surveys were conducted to evaluate program effects. A before-after evaluation study was conducted among young men attending five urban Connect clinics where sexually transmitted disease/human immunodeficiency virus rates are high, recruiting young men in repeated cross-sectional surveys from April 2014 to September 2017.

Results

Two hundred thirty-five YSPs were trained to use Connect materials, including a website, an article-based pocket guide, and were given information regarding SRH for young men. These professionals demonstrated increased knowledge about SRH for young men at immediate posttest (60.6% to 86.7%, P < 0.05), and reported more sharing of websites for SRH (23% to 62%, P < 0.05) from pretraining to 3-month posttraining. 169 young minority men were surveyed and reported increased awareness of Connect over 3 and a half years (4% to 11%, P = 0.015), although few young men reported using the website to visit clinics.

Conclusions

Project Connect Baltimore increased knowledge of SRH needs among youth-serving professionals and sharing of SRH resources by these professionals with young men. This program also demonstrated increases in awareness of SRH resources among young minority urban men.
Repetitive Transcranial Magnetic Stimulation in the Treatment of a Difficult to Treat Condition, Borderline Personality Disorder
Authors: RACHID FADY
Published: January 2019

Background:

Borderline personality disorder (BPD) is a serious mental disorder characterized by a pervasive pattern of instability in affect regulation and interpersonal relationships, poor self-image and behavioral control, self-injurious behavior, suicidality, and other high-risk behaviors. It is also characterized by a high mortality rate by suicide.

Methods:

The published literature on repetitive transcranial magnetic stimulation (TMS), theta-burst stimulation (TBS), and deep TMS in the treatment of BPD were reviewed.

Results:

Four clinical studies (2 randomized trials and 2 case studies) with limited sample sizes found that TMS and TBS were safe and potentially effective in the reduction of symptoms of BPD.

Conclusions:

Given the limited clinical evidence for efficacy on the basis of the results of these studies, future controlled studies involving larger samples and optimal stimulus parameters should be designed to confirm the short-term and long-term safety and efficacy of repetitive TMS and TBS in the treatment of BPD.
The Association Between Psychotropic Drug Use and Fertility Problems Among Male Subjects
Authors: SOLOMON RONNIE , SHVARTSUR RACHEL , AZAB ABED N.
Published: January 2019

Mental disorders affect a high percentage of the general population and are associated with a significant burden. One major component of treatment for mental illnesses is pharmacotherapy. Various psychotropic medications are used in the treatment of psychiatric disorders and these are often associated with a plethora of side effects. The many side effects of psychotropic drugs can severely impair patients’ quality of life and decrease their adherence to treatment. Among the relatively neglected and less-studied potential side effects of psychotropic drugs are impairment of sperm parameters and fertility problems among male patients. This article summarizes the data with regard to the effects of 6 widely used psychotropic drugs—lithium, valproate, haloperidol, olanzapine, imipramine, and fluoxetine—on sexual function and sperm parameters in male subjects. In general, the reviewed data suggest that these medications can be associated with sexual function problems and negative effects on sperm parameters among male subjects. It is important to note that most of the data are based on preclinical studies and nonrandomized clinical trials with relatively small sample sizes, so that it is not possible to draw unequivocal conclusions with regard to the clinical relevance of the findings. Prospective, randomized clinical trials are necessary to elucidate the effects of psychotropic drugs on men’s sperm parameters and fertility indices per se.
Coronary Artery Spasm as Related to Anxiety and Depression: A Nationwide Population-Based Study
Authors: Hung Ming-Yow , Mao Chun-Tai , Hung Ming-Jui , Wang Jiunn-Kae , Lee Hsin-Chien , Yeh Chi-Tai , Hu Patrick , Chen Tien-Hsing , Chang Nen-Chung
Published: January 2019

Objective

Anxiety and depression are risk factors for obstructive coronary artery disease (CAD), but their effects on coronary artery spasm (CAS) remain unestablished.

Methods

Patient records in this population-based study were retrospectively collected from the Taiwan National Health Insurance Research Database. Using propensity score matching, we used 1:1:1 ratio stratification into a control group of 10,325 individuals without CAS or CAD, a CAS group comprising 10,473 patients, and a CAD group comprising 10,473 patients during 2000–2012.

Results

The prevalence of CAS and CAD was 0.067% and 8.7%, respectively, in the general population. The prevalence of anxiety and depression diagnoses was significantly higher in patients with new-onset CAS than in those with new-onset CAD and controls without CAS/CAD, even after propensity score matching. Compared with CAD, anxiety and depression diagnoses conferred a higher risk of developing CAS (odds ratio [OR] = 2.29, 95% confidence interval [CI], 2.14–2.45,p< .001, and OR = 1.34, 95% CI, 1.08–1.66,p= .007, respectively). The association was even stronger when comparing CAS with the control group without CAD or CAS (OR = 5.20, 95% CI, 4.72–5.74,p< .001, and OR = 1.98, 95% CI, 1.50–2.62,p< .001, respectively). The increased risk of new-onset CAS as related to previous anxiety and depression diagnoses was comparable between males and females.

Conclusions

Compared with CAD or the general population, anxiety and depression diagnoses confer a higher risk of developing CAS. No sex differences are found for the association of anxiety and depression with CAS.
Analyzing Our International Facial Reconstructive Mission Work: A Review of Patients Treated by American Academy of Facial Plastic and Reconstructive Surgery Sanctioned Trips
Authors: Rousso Joseph J. , Abraham Manoj T. , Rozanski Collin
Published: January 2019

Importance:

To identify ways to improve care to underserved international populations.

Objective:

To analyze the authors’ data in hopes of meeting further needs.

Design:

This is a retrospective review of medical missions using data from the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS) Face to Face) Database.

Setting:

International sites of AAFPRS approved surgical mission trips.

Participants:

One thousand six hundred forty-six patients who were seen by an AAFPRS mission trip between January 12, 2010 and April 27, 2017.

Outcomes/Measures:

Patient and mission data, procedure data, characteristics of cleft patients, patient follow-up data, repeat patient data, and factors affecting whether a patient was provided service were all evaluated.

Results:

Patients were seen over the course of 26 trips to 6 different countries. Patients (n, mean, median age) who underwent a primary cleft lip repair only (175, 2.5 years, 0.6 years) and those who underwent a primary cleft palate repair only (268, 6.4 years, 3.6 years) were significantly older than what is identified as the upper range of normal in surgical literature
13,14
(Wilcoxon Signed-Rank test Z = −4.3, P < 0.001 for lip and Z = −10.1, P < 0.001 for palate). Patients (n, median, mean rank) receiving a primary cleft palate repair were significantly younger in Peru (160, 3.0 years, 126) compared with patients in other countries (108, 5.0 years, 147) (Z = −2.1, P < 0.05). The odds of a patient returning unplanned were 2.8 (OR, 95% CI 1.52–4.98; P < 0.01) times higher if they were diagnosed with a cleft palate only and 0.91 (OR, 95% CI 0.90–0.93; P < 0.05) times lower if they were diagnosed with combined cleft lip with cleft palate at their first visit. Patients (median age, mean rank) who were provided a service (6.0 years, 724.70) were younger than patients who were not provided a service (8.0 years, 637.23) at their first visit (Mann–Whitney, U = 164,275; P < 0.001).

Conclusion/Relevance:

This data indicates that disparities exist among patients treated on mission trips compared with those in higher income countries. Furthermore, the authors’ data indicate that multiple mission trips to the same country within the same year decrease some of these disparities. Additionally, isolated cleft palate patients are most likely to return unplanned indicating need for standardized postoperative visits. The preferential care of younger patients with unrepaired clefts as compared with older patients and those with palatal fistulas indicates a need for additional resource allocation.
Multi-trait meta-analyses reveal 25 quantitative trait loci for economically important traits in Brown Swiss cattle
Authors: Fang Zih-Hua , Pausch Hubert
Published: January 2019

Background

The Brown Swiss dual-purpose cattle breed is renowned for high milk and protein yield and long productive lifetime under different production conditions. However, little is known about the genetic architecture of those traits because only few genome-wide association studies (GWAS) have been carried out in this breed. Moreover, most GWAS had been performed for single traits, thus preventing insights into potentially existing pleiotropic effects of trait-associated loci.

Results

To compile a comprehensive catalogue of large-effect QTL segregating in Brown Swiss cattle, we carried out association tests between partially imputed genotypes at 598,016 SNPs and daughter-derived phenotypes for more than 50 economically important traits, including milk production, growth and carcass quality, body conformation, reproduction and calving traits in 4,578 artificial insemination bulls from two cohorts of Brown Swiss cattle (Austrian-German and Swiss populations). Across-cohort multi-trait meta-analyses of the results from the single-trait GWAS revealed 25 quantitative trait loci (QTL;P< 8.36 x 10−8) for economically relevant traits on 17Bos taurusautosomes (BTA). Evidence of pleiotropy was detected at five QTL located on BTA5, 6, 17, 21 and 25. Of these, two QTL at BTA6:90,486,780 and BTA25:1,455,150 affect a diverse range of economically important traits, including traits related to body conformation, calving, longevity and milking speed. Furthermore, the QTL at BTA6:90,486,780 seems to be a target of ongoing selection as evidenced by an integrated haplotype score of 2.49 and significant changes in allele frequency over the past 25 years, whereas either no or only weak evidence of selection was detected at all other QTL.

Conclusions

Our findings provide a comprehensive overview of QTL segregating in Brown Swiss cattle. Detected QTL explain between 2 and 10% of the variation in the daughter-derived phenotypes and thus may be considered as the most important QTL segregating in the Brown Swiss cattle breed. Multi-trait association testing boosts the power to detect pleiotropic QTL and assesses the full spectrum of phenotypes that are affected by trait-associated variants.
Adapting genotyping-by-sequencing and variant calling for heterogeneous stock rats
Authors: Gileta Alexander F. , Gao Jianjun , Chitre Apurva S. , Bimschleger Hannah V. , St. Pierre Celine L. , Gopalakrishnan Shyam , Palmer Abraham A.
Published: January 2019

The heterogeneous stock (HS) is an outbred rat population derived from eight inbred rat strains. HS rats are ideally suited for genome wide association studies; however, only a few genotyping microarrays have ever been designed for rats and none of them are currently in production. To address the need for an efficient and cost effective method of genotyping HS rats, we have adapted genotype-by-sequencing (GBS) to obtain genotype information at large numbers of single nucleotide polymorphisms (SNPs). In this paper, we have outlined the laboratory and computational steps we took to optimize double digest genotype-by-sequencing (ddGBS) for use in rats. We also evaluate multiple existing computational tools and explain the workflow we have used to call and impute over 3.7 million SNPs. We also compared various rat genetic maps, which are necessary for imputation, including a recently developed map specific to the HS. Using our approach, we obtained concordance rates of 99% with data obtained using data from a genotyping array. The principles and computational pipeline that we describe could easily be adapted for use in other species for which reliable reference genome sets are available.
Human discrimination and categorization of emotions in voices: a functional Near-Infrared Spectroscopy (fNIRS) study
Authors: Gruber T. , Debracque C. , Ceravolo L. , Igloi K. , Marin Bosch B. , Frühholz S. , Grandjean D.
Published: January 2019

Variations of the vocal tone of the voice during speech production, known as prosody, provide information about the emotional state of the speaker. In recent years, functional imaging has suggested a role of both right and left inferior frontal cortices in attentive decoding and cognitive evaluation of emotional cues in human vocalizations. Here, we investigated the suitability of functional Near-Infrared Spectroscopy (fNIRS) to study frontal lateralization of human emotion vocalization processing during explicit and implicit categorization and discrimination. Participants listened to speech-like but semantically meaningless words spoken in a neutral, angry or fearful tone and had to categorize or discriminate them based on their emotional or linguistic content. Behaviorally, participants were faster to discriminate than to categorize and they processed the linguistic content of stimuli faster than their emotional content, while an interaction between condition (emotion/word) and task (discrimination/categorization) influenced accuracy. At the brain level, we found a four-way interaction in the fNIRS signal between condition, task, emotion and channel, highlighting the involvement of the right hemisphere to process fear stimuli, and of both hemispheres to treat anger stimuli. Our results show that fNIRS is suitable to study vocal emotion evaluation in humans, fostering its application to study emotional appraisal.
Accurate estimation of SNP-heritability from biobank-scale data irrespective of genetic architecture
Authors: Hou Kangcheng , Burch Kathryn S. , Majumdar Arunabha , Shi Huwenbo , Mancuso Nicholas , Wu Yue , Sankararaman Sriram , Pasaniuc Bogdan
Published: January 2019

The proportion of phenotypic variance attributable to the additive effects of a given set of genotyped SNPs (i.e. SNP-heritability) is a fundamental quantity in the study of complex traits. Recent works have shown that existing methods to estimate genome-wide SNP-heritability often yield biases when their assumptions are violated. While various approaches have been proposed to account for frequency- and LD-dependent genetic architectures, it remains unclear which estimates of SNP-heritability reported in the literature are reliable. Here we show that genome-wide SNP-heritability can be accurately estimated from biobank-scale data irrespective of the underlying genetic architecture of the trait, without specifying a heritability model or partitioning SNPs by minor allele frequency and/or LD. We use theoretical justifications coupled with extensive simulations starting from real genotypes from the UK Biobank (N=337K) to show that, unlike existing methods, our closed-form estimator for SNP-heritability is highly accurate across a wide range of architectures. We provide estimates of SNP-heritability for 22 complex traits and diseases in the UK Biobank and show that, consistent with our results in simulations, existing biobank-scale methods yield estimates up to 30% different from our theoretically-justified approach.
Mitigative effects of Alpha-lipoic acid for the toxicity of Dimethoate in male rats
Authors: Abdelsalam Hani M.
Published: January 2019

Background

Organophosphates are widely used by human nowadays, but these compounds have tremendous negative effect on the man health. So this study aims to use of Alpha-lipoic acid (ALA) to alleviates the negative effects of Dimethoate (DM).

Methods

This study is designed as follows, Thirty adult male Wistar albino rats were utilized, further subdivided into control, DM and DM+ALA groups. Liver and renal cortex sections from all groups were processed for histopathological examination, biochemical estimation of liver function tests, serum Urea, Creatinine, BUN, testosterone and lipid profile were performed.

Results

This study clarified the improvement effects of ALA against the negative effects of DM where ALA caused a significant recovery of the hepatic (ALT, AST, ALP and total protein) and renal functions by normalizing them in DM + ALA group and to some extent improvement of lipid profile and testosterone levels. Also, ALA restored normal hepatic and renal histomorphology.

Conclusion

It is concluded that ALA therapy can ameliorate the negative effects of DM that affect the vital organs as the liver and kidney. Also ALA can reduce the occurrence of atherogensis by reducing the levels of bad cholesterol in the blood. ALA boosts the levels of testosterone so it augments the male sexual characters.
Phenotypic evolution is more constrained in simpler food webs
Authors: Barbour Matthew A. , Greyson-Gaito Christopher J. , Sootodeh Arezoo , Locke Brendan , Bascompte Jordi
Published: January 2019

Global change is simplifying the structure of ecological networks; however, we are currently in a poor position to predict how these simplified communities will affect the evolutionary potential of remaining populations. Theory on adaptive landscapes provides a framework for predicting how selection constrains phenotypic evolution, but often treats the community context of evolving populations as a “black box”. Here, we integrate ecological networks and adaptive landscapes to examine how changes in food-web complexity shape evolutionary constraints. We conducted a field experiment that manipulated the diversity of insect parasitoids (food-web complexity) that were able to impose selection on an insect herbivore. We then measured herbivore survival as a function of three key phenotypic traits. We found that more traits were under selection in simpler vs. more complex food webs. The adaptive landscape was more neutral in complex food webs because different parasitoid species impose different selection pressures, minimizing relative fitness differences among phenotypes. Our results suggest that phenotypic evolution becomes more constrained in simplified food webs. This indicates that the simplification of ecological communities may constrain the adaptive potential of remaining populations to future environmental change. “What escapes the eye, however, is a much more insidious kind of extinction: the extinction of ecological interactions.” Janzen (1974)
Microbial regulation of enteric eosinophils and its impact on tissue remodeling and Th2 immunity
Authors: Jiménez-Saiz Rodrigo , Anipindi Varun C. , Galipeau Heather , Ellenbogen Yosef , Chaudhary Roopali , Koenig Joshua F. , Gordon Melissa E. , Walker Tina D. , Mandur Talveer S. , Abed Soumeya , Humbles Alison , Chu Derek K. , Ask Kjetil , Verdú Elena F. , Jordana Manel
Published: January 2019

Eosinophils have emerged as multifaceted cells that contribute to tissue homeostasis. However, the factors that control their frequency and function at mucosal sites remain unclear. Here, we investigated the role of the microbiota in regulating enteric eosinophils. We found that small intestinal (SI) eosinophilia was significantly greater in germ-free (GF) mice compared to specific pathogen free (SPF) controls. This phenomenon was associated with enteric overexpression of signals that mediate attraction, retention and survival of eosinophils, and was reversed by colonization. Additionally, we generated a novel strain of eosinophil-deficient GF mice. These mice displayed intestinal fibrosis and were less prone to allergic sensitization as compared to GF controls. Overall, our study demonstrates that commensal microbes regulate intestinal eosinophil frequency and function, which impacts tissue repair and allergic sensitization to food antigens. These data support a critical interplay between the commensal microbiota and intestinal eosinophils in shaping homeostatic, innate and adaptive immune processes in health and disease.
The number of spaced-word matches between twoDNAsequences as a function of the underlying pattern weight
Authors: Röhling Sophie , Morgenstern Burkhard
Published: January 2019

We study the numberNkof (spaced) word matches between pairs of evolutionarily related DNA sequences depending on the word length or pattern weightk, respectively. We show that, under theJukes-Cantormodel, the number of substitutions per site that occurred since two sequences evolved from their last common ancestor, can be esti-mated from the slope of a certain function ofNk. Based on these considerations, we implemented a software program for alignment-free sequence comparison calledSlope-SpaM. Test runs on simulated sequence data show thatSlope-SpaMcan estimate phylogenetic dis-tances with high accuracy for up to around 0.5 substitutions per po-sitions. The statistical stability of our results is improved if spaced words are used instead of contiguousk-mers. Unlike previous methods that are based on the number of (spaced) word matches, our approach can deal with sequences that share only local homologies.
Partitioning stable and unstable expression level variation in cell populations: a theoretical framework with application to the T cell receptor
Authors: Guzella Thiago S. , Barreto Vasco M. , Carneiro Jorge
Published: January 2019

Phenotypic variation in the copy number of gene products expressed by cells or tissues has been the focus of intense investigation. To what extent the observed differences in cellular expression levels are persistent or transient is an intriguing question. Here, we develop a quantitative framework that resolves the expression variation into stable and unstable components. The difference between the expression means in two cohorts isolated from any cell population is shown to converge to an asymptotic value, with a characteristic time,τT, that measures the timescale of the unstable dynamics. The asymptotic difference in the means, relative to the initial value, measures the stable proportion of the original population variance. Empowered by this insight, we analysed the T-cell receptor (TCR) expression variation in CD4 T cells. About 70% of TCR expression variance is stable in a diverse polyclonal population, while over 80% of the variance in an isogenic TCR transgenic population is volatile. In both populations the TCR levels fluctuate with a characteristic time of 32 hours. This systematic characterisation of the expression variation dynamics, relying on time series of cohorts’ means, can be combined with technologies that measure gene or protein expression in single cells or in bulk.
Mobile genetic element insertions drive antibiotic resistance across pathogens
Authors: Durrant Matthew G. , Li Michelle M. , Siranosian Ben , Bhatt Ami S.
Published: January 2019

Mobile genetic elements contribute to bacterial adaptation and evolution; however, detecting these elements in a high-throughput and unbiased manner remains challenging. Here, we demonstrate ade novoapproach to identify mobile elements from short-read sequencing data. The method identifies the precise site of mobile element insertion and infers the identity of the inserted sequence. This is an improvement over previous methods that either rely on curated databases of known mobile elements or rely on ‘split-read’ alignments that assume the inserted element exists within the reference genome. We apply our approach to 12,419 sequenced isolates of nine prevalent bacterial pathogens, and we identify hundreds of known and novel mobile genetic elements, including many candidate insertion sequences. We find that the mobile element repertoire and insertion rate vary considerably across species, and that many of the identified mobile elements are biased toward certain target sequences, several of them being highly specific. Mobile element insertion hotspots often cluster near genes involved in mechanisms of antibiotic resistance, and such insertions are associated with antibiotic resistance in laboratory experiments and clinical isolates. Finally, we demonstrate that mutagenesis caused by these mobile elements contributes to antibiotic resistance in a genome-wide association study of mobile element insertions in pathogenicEscherichia coli. In summary, by applying ade novoapproach to precisely identify mobile genetic elements and their insertion sites, we thoroughly characterize the mobile element repertoire and insertion spectrum of nine pathogenic bacterial species and find that mobile element insertions play a significant role in the evolution of clinically relevant phenotypes, such as antibiotic resistance.
Parallel control of mechanosensory hair cell orientation by the PCP and Wnt pathways
Authors: Acedo Joaquin Navajas , Voas Matthew G. , Alexander Richard , Woolley Thomas , Unruh Jay R. , Li Hua , Moens Cecilia , Piotrowski Tatjana
Published: January 2019

Cell polarity plays a crucial role during development of vertebrates and invertebrates. Planar Cell Polarity (PCP) is defined as the coordinated polarity of cells within a tissue axis and is essential for processes such as gastrulation, neural tube closure or hearing. Wnt ligands can be instructive or permissive during PCP-dependent processes, and Wnt pathway mutants are often classified as PCP mutants due to the complexity and the similarities between their phenotypes. Our studies of the zebrafish sensory lateral line reveal that disruptions of the PCP and Wnt pathways have differential effects on hair cell orientations. While mutations in PCP genes cause random orientations of hair cells, mutations in Wnt pathway members induce hair cells to adopt a concentric pattern. We show that PCP signaling is normal in hair cells of Wnt pathway mutants and that the concentric hair cell phenotype is due to altered organization of the surrounding support cells. Thus, the PCP and Wnt pathways work in parallel, as separate pathways to establish proper hair cell orientation. Our data suggest that coordinated support cell organization is established during the formation of lateral line primordia, much earlier than the appearance of hair cells. Together, these finding reveal that hair cell orientation defects are not solely explained by defects in PCP signaling and that some hair cell phenotypes warrant reevaluation.
Metabolic landscape of the tumor microenvironment
Authors: Xiao Zhengtao , Dai Ziwei , Locasale Jason W.
Published: January 2019

The tumor milieu consists of numerous cell types with each cell existing in a different nutritional environment. However, a characterization of intratumoral metabolic heterogeneity at the single-cell level in human cancer is not established. Here, we develop a computational pipeline to analyze metabolic gene expression programs of single cells within human tumors. In two representative cancer types, melanoma and head and neck, we apply this algorithm to define the single-cell metabolic landscape of human tumors. We find that malignant cells in general have higher metabolic activity and higher metabolic variation than previously observed from studies of bulk tumor comparisons. Indeed, most of the observed metabolic variation of single tumor and normal cells were found to be inconsistent with comparisons with bulk tumor samples. Variation in the expression of mitochondrial programs is the major contributor to intratumoral metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in almost all cell types. Immune and stromal cells could also be distinguished by their metabolic features. Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of intratumoral metabolic heterogeneity.
Investigating Genetic Heterogeneity in Major Depression Through Item-level Genetic Analyses of the PHQ-9
Authors: Thorp Jackson G. , Marees Andries T. , Ong Jue-Sheng , An Jiyuan , MacGregor Stuart , Derks Eske M.
Published: January 2019

Background

Major Depressive Disorder (MDD) is a clinically heterogeneous disorder. Previous large-scale genetic studies of MDD have explored genetic risk factors of MDD case-control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity.

Aim

In this study, we present the results of symptom-level genetic analyses and compare SNP-based heritability (h2SNP) and genetic correlations across major depression symptoms. We further investigate genetic correlations with a range of psychiatric disorders and other associated traits. Methods: We have analysed data from the UK biobank and included 148,752 subjects of white British ancestry with genotype data who completed nine items of a self-rated measure of depression: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD score regression analysis was used to calculate SNP-based heritability (h2SNP) and genetic correlations (rg) across symptoms and to investigate genetic correlations with 25 external phenotypes. Confirmatory factor analyses were applied to test whether one, two, or three-factor models best fit the pattern of genetic correlations across the nine symptoms.

Results

We identified 9 novel genome-wide significant genomic loci, with no overlap in loci across depression symptoms. h2SNP ranged from 3% (suicidal ideation) to 11% (fatigue). Genetic correlations range from 0.54 to 0.96 (all p < 1.39×10−3) with 30 of 36 correlations being significantly smaller than 1. A 3-factor model provided the best fit to the genetic correlation matrix, with factors representing “psychological”, “neurovegetative”, and “psychomotor / concentration” symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms.

Discussion

Patterns of h2SNP and genetic correlations differed across the nine symptoms of depression. Our findings suggest that the large phenotypic heterogeneity observed for MDD is recapitulated at a genetic level. Future studies should investigate how genetic heterogeneity in MDD influences the efficacy of clinical interventions.
Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen
Authors: Zamith-Miranda Daniel , Heyman Heino M. , Cleare Levi G. , Couvillion Sneha , Clair Geremy , Bredeweg Erin , Gacser Attila , Nimrichter Leonardo , Nakayasu Ernesto S. , Nosanchuk Joshua D.
Published: January 2019

Candida aurisis a recently described pathogenic fungus that is causing invasive outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-resistant strains that have been isolated in distinct sites across the globe. The fact that its diagnosis is still problematic suggests that the spreading of the pathogen remains underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance employed by this new species are largely unknown. In the present work, we compared two clinical isolates ofC. auriswith distinct drug susceptibility profiles and aCandida albicansreference strain using a multi-omics approach. Our results show that, despite the distinct drug-resistance profile, bothC. aurisstrains appear to be very similar, albeit with a few notable differences. However, when compared toC. albicansbothC. aurisstrains have major differences regarding their carbon utilization and downstream lipid and protein content, suggesting a multi-factorial mechanism of drug resistance. The molecular profile displayed byC. aurishelps to explain the antifungal resistance and virulence phenotypes of this new emerging pathogen.

Importance

Candida auriswas firstly described in Japan in 2009 and has now been the cause of significant outbreaks across the globe. The high number of isolates that are resistant to one or more antifungals, as well as the high mortality rates from patients with bloodstream infections, has caught the attention of the medical mycology, infectious disease and public health communities to this pathogenic fungus. In the current work, we performed a broad multi-omics approach on two clinical isolates isolated in New York, the most affected area in the USA and found that the omic profile ofC. aurisdiffers significantly fromC. albicans. Besides our insights intoC. auriscarbon utilization and lipid and protein content, we believe that the availability of these data will enhance our ability to combat this rapidly emerging pathogenic yeast.
RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma
Authors: Naert Thomas , Dimitrakopoulou Dionysia , Tulkens Dieter , Demuynck Suzan , Noelanders Rivka , Eeckhout Liza , Isterdael Gert van , Deforce Dieter , Vanhove Christian , Dorpe Jo Van , Creytens David , Vleminckx Kris
Published: January 2019

Alterations of the retinoblastoma and/or the p53 signaling network are associated with specific cancers such as high-grade astrocytoma/glioblastoma, small cell lung cancer (SCLC), choroid plexus tumors and small-cell pancreatic neuroendocrine carcinoma (SC-PaNEC). However, the intricate functional compensation between RB1 and the related pocket proteins RBL1/p107 and RBL2/p130 in suppressing tumorigenesis remains poorly understood. Here we performed lineage-restricted parallel inactivation ofrb1andrbl1by multiplex CRISPR/Cas9 genome editing in the true diploidXenopus tropicalisto gain insight into thesein vivocompensatory mechanisms. We show that whilerb1inactivation is sufficient to induce choroid plexus papilloma, combinedrb1andrbl1inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimickingtp53mutantX. tropicalisline, we demonstrate increased malignancy of retinoblastoma-mutant neural malignancies upon concomitant inactivation oftp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, thetp53status had little effect on the establishment and growth of SC-PaNEC, but may rather be essential for maintaining chromosomal stability. SCLC was only rarely observed in our experimental set-up, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1 and generate new insights in functional compensation within the retinoblastoma protein family in suppressing pancreatic and specific neural cancers.
Habitat loss does not always entail negative genetic consequences
Authors: Carvalho Carolina S. , Lanes Éder C. M. , Silva Amanda R. , Caldeira Cecilio F. , Carvalho-Filho Nelson , Gastauer Markus , Imperatriz-Fonseca Vera L. , Júnior Wilson Nascimento , Oliveira Guilherme , Siqueira José O. , Viana Pedro L. , Jaffé Rodolfo
Published: January 2019

Although habitat loss has large, consistently negative effects on biodiversity, its genetic consequences are not yet fully understood. In this paper, we assess the genetic consequences of extreme habitat loss driven by mining in two endemic plants from Amazonian Savannas. Our analyses are the first to overcome major methodological limitations like the confounding effect of habitat fragmentation, historical processes underpinning genetic differentiation, time-lags between the onset of disturbances and genetic outcomes, and the need for large numbers of samples, genetic markers and replicated landscapes to ensure sufficient statistical power. We found that both species are remarkably resilient, as genetic diversity and gene flow patterns were unaffected by habitat loss. Our study unambiguously demonstrates that it is not possible to generalize about the genetic consequences of habitat loss, and imply that future conservation efforts need to consider species-specific genetic information.
Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice
Authors: Huysmans Hanne , Zhong Zifu , De Temmerman Joyca , Mui Barbara L. , Tam Ying K. , Mc Cafferty Séan , Gitsels Arlieke , Vanrompay Daisy , Sanders Niek N.
Published: January 2019

In this work we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid nanoparticle (LNP) mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression with the plateau between day 3 and 10. The overall protein expression of sa-RNA was significant higher than that obtained after electroporation of pDNA or non-replication mRNAs. Moreover, intradermal electroporation of sa-RNA induced a short-lived innate immune response that did not affect the expression of the sa-RNA. A complete different expression profile and innate immune response was observed when LNPs were used. The expression peaked 24h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop can be explained by the strong innate immune response elicited by the sa-RNA-LNPs 4h after injection. Interestingly, sa-RNA-LNPs were able to transfection the draining lymph nodes after intradermal injection.
Verticillium dahliae strains that infect the same host plant display highly divergent effector catalogs
Authors: Gibriel Hesham A.Y. , Li Jinling , Zhu Longfu , Seidl Michael F. , Thomma Bart P.H.J.
Published: January 2019

Originality and significance statement

During host colonization, plant pathogens secrete molecules that enable host colonization, also known as effector proteins. Here, we show that strains of the fungal plant pathogen Verticillium dahliae that are able to infect the same host plant harbour highly divergent LS effector repertoires. Our study outlines the variability within LS effector gene repertoires of V. dahliae strains, which may allow the various strains to be competitive in the co-evolution with their hosts.

Effectors are proteins secreted by pathogens to support colonization of host plants, often by deregulating host immunity. Effector genes are often localized within dynamic lineage-specific (LS) genomic regions, allowing rapid evolution of effector catalogues. Such localization permits pathogens to be competitive in the co-evolutionary arms races with their hosts. For a broad host-range pathogen such as Verticillium dahliae it is unclear to what extent single members of their total effector repertoires contribute to disease development on multiple hosts. Here, we determined the core and LS effector repertoires of a collection of V. dahliae strains, as well as the ability of these strains to infect a range of plant species comprising tomato, cotton, Nicotiana benthamiana, Arabidopsis, and sunflower to assess whether the presence of particular LS effectors correlates with the ability to infect particular plant species. Surprisingly, we found that V. dahliae strains that are able to infect the same host plant harbor highly divergent LS effector repertoires. Furthermore, we observed differential V. dahliae core effector gene expression between host plants. Our data suggest that different V. dahliae lineages utilise divergent effector catalogs to colonize the same host plant, suggesting considerable redundancy among the activities of effector catalogs between lineages.
Scale dependent patterns in interaction diversity maintain resiliency in a frequently disturbed ecosystem
Authors: Dell Jane E. , Salcido Danielle M. , Lumpkin Will , Richards Lora A. , Pokswinski Scott M. , Loudermilk E. Louise , O’Brien Joseph J. , Dyer Lee A.
Published: January 2019

Frequently disturbed ecosystems are characterized by resilience to ecological disturbances. For example, longleaf pine ecosystems are exposed to frequent fire disturbance, and this feature sustains biodiversity. We examined how fire frequency maintains beta diversity of multi-trophic interactions, as this community parameter provides a measure of functional redundancy of an ecosystem. We found that turnover in interaction diversity at small local scales is highest in the most frequently burned stands, conferring immediate resiliency to disturbance by fire. Interactions become more specialized and less resilient as fire frequency decreases. Local scale patterns of interaction diversity contribute to broader scale patterns and confer long-term ecosystem resiliency. Such natural disturbances are likely to be important for maintaining regional diversity of interactions for a broad range of ecosystems.
Environmental Consistency Modulation of Error Sensitivity During Motor Adaptation is Explicitly Controlled
Authors: Avraham Guy , Keizman Matan , Shmuelof Lior
Published: January 2019

Motor adaptation, the adjustment of sensorimotor representations in face of changes in the environment, may operate at different rates. When human participants encounter repeated or consistent perturbations, their corrections for the experienced errors are larger compared to when the perturbations are new or inconsistent. Such modulations of error sensitivity were traditionally considered to be an implicit process that does not require attentional resources. In recent years, the implicit view of motor adaptation is challenged by evidence showing a contribution of explicit strategies to learning. These findings raise a fundamental question regarding the nature of the error sensitivity modulation processes. We tested the effect of explicit control on error sensitivity in a series of experiments, in which participants controlled a screen cursor to virtual targets. We manipulated environmental consistency by presenting rotations in random (low consistency) or random walk (high consistency) sequences, and illustrated that perturbation consistency affects the rate of adaptation, corroborating previous studies. When participants were instructed to ignore the cursor and move directly to the target, thus, eliminating the contribution of explicit strategies, consistency-driven error sensitivity modulation was abolished. In addition, delaying the visual feedback, a manipulation that affects implicit learning, did not influence error sensitivity under consistent perturbations. These results suggest that increases of learning rate in consistent environments are attributable to an explicit rather than implicit process in sensorimotor adaptation.

Significant Statement

When experiencing an error in a motor task (e.g., missing a basketball shot in a windy day), the motor system modifies its next action based on environmental consistency (how frequent the changes in wind’s direction and strength are). It is unknown whether this process is driven by an implicit and automatic process, or by an explicit process that employs cognitive strategies. We examined these possibilities in a simple visuomotor task by perturbing the feedback in each trial with different consistency levels, and manipulating the use of implicit and explicit processes. We found that participants increase their sensitivity to errors in consistent environments when employing explicit strategies, and do not change their behavior when the implicit process is operating alone.
Cranial Bone Growth in Isolated Sagittal Craniosynostosis Compared to Normal Growth in the First Six Months of Age
Authors: Mercan Ezgi , Hopper Richard A. , Maga A. Murat
Published: January 2019

Background

Sagittal craniosynostosis (SCS), the most common type of premature perinatal cranial suture fusion, results in abnormal head shape that requires extensive surgery to correct. It is important to find objective and repeatable measures of severity and surgical outcome to examine the effect of timing and technique on different SCS surgeries. The purpose of this study was to develop statistical models of infant (0-6 months old) skull growth in both normative and SCS subjects (prior to surgery). Our goal was to apply these models to the assessment of differences between these two groups in overall post-natal growth patterns and sutural growth rates as a first step to develop methods for predictive models of surgical outcome.

Methods and Findings:

We identified 81 patients with isolated, non-syndromic SCS from Seattle Children’s Craniofacial Center patient database who had a pre-operative CT exam before the age of six months. As a control group, we identified 117 CT exams without any craniofacial abnormalities or bone fractures in the same age group. We first created population-level templates from the CT images of the SCS and normal groups. All CT images from both groups, as well as the canonical templates of both cohorts were annotated with anatomical landmarks, which were used in a growth model that predicted the locations of these landmarks at a given age based on each population. Using the template images and the landmark positions predicted by the growth models, we created 3D meshes for each week of age up to six months for both populations. To analyze the growth patterns at the suture sites, we annotated both templates with additional semi-landmarks equally spaced along the metopic, coronal, sagittal and lambdoidal cranial sutures. By transferring these semi-landmarks to meshes produced from the growth model, we measured the displacement of the bone borders and suture closure rates. We found that the growth at the metopic and coronal sutures were more rapid in the SCS cohort compared to the normal cohort. The antero-posterior displacement of the semi-landmarks indicated a more rapid growth in the sagittal plane in the SCS model compared to the normal model as well.

Conclusions:

Statistical templates and geometric morphometrics are promising tools for understanding the growth patterns in normal and synostotic populations and to produce objective and reproducible measurements of severity and outcome. Our study is the first of its kind to quantify the bone growth for the first six months of life in both normal and sagittal synostosis patients.