bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variation and evolutionary history of a mycorrhizal fungus regulate the currency of exchange in symbiosis with the food security crop cassava
Authors: Savary Romain , Dupuis Cindy , Masclaux Frédéric G , Mateus Ivan D , Rojas Edward C , Sanders Ian R 
Published: February 2020

AbstractMost land plants form symbioses with arbuscular mycorrhizal fungi (AMF). Diversity of AMF increases plant community productivity and plant diversity. For decades, it was known that plants trade carbohydrates for phosphate with their fungal symbionts. However, recent studies show that plant-derived lipids probably represent the most essential currency of exchange. Understanding the regulation of plant genes involved in the currency of exchange is crucial to understanding stability of this mutualism. Plants encounter many different AMF genotypes that vary greatly in the benefit they confer to plants. Yet the role that fungal genetic variation plays in the regulation of this currency has not received much attention. We used a high-resolution phylogeny of one AMF species (Rhizophagus irregularis) to show that fungal genetic variation drives the regulation of the plant fatty acid pathway in cassava (Manihot esculenta); a pathway regulating one of the essential currencies of trade in the symbiosis. The regulation of this pathway was explained by clearly defined patterns of fungal genome-wide variation representing the precise fungal evolutionary history. This represents the first demonstrated link between the genetics of AMF and reprogramming of an essential plant pathway regulating the currency of exchange in the symbiosis. The transcription factor RAM1 was also revealed as the dominant gene in the fatty acid plant gene co-expression network. Our study highlights the crucial role of variation in fungal genomes in the trade of resources in this important symbiosis and also opens the door to discovering characteristics of AMF genomes responsible for interactions between AMF and cassava that will lead to optimal cassava growth.
Phylogenomic analysis of novel Diaforarchaea is consistent with sulfite but not sulfate reduction in volcanic environments on early Earth
Authors: Colman Daniel R , Lindsay Melody R , Amenabar Maximiliano J , Fernandes-Martins Maria C , Roden Eric R , Boyd Eric S 
Published: February 2020

Abstract
The origin(s) of dissimilatory sulfate and/or (bi)sulfite reducing organisms (SRO) remains enigmatic despite their importance in global carbon and sulfur cycling since at least 3.4 Ga. Here, we describe novel, deep-branching archaeal SRO populations distantly related to other Diaforarchaea from two moderately acidic thermal springs. Dissimilatory (bi)sulfite reductase homologs, DsrABC, encoded in metagenome assembled genomes (MAGs) from spring sediments comprise one of the earliest evolving Dsr lineages. DsrA homologs were expressed in situ under moderately acidic conditions. MAGs lacked genes encoding proteins that activate sulfate prior to (bi)sulfite reduction. This is consistent with sulfide production in enrichment cultures provided sulfite but not sulfate. We suggest input of volcanic sulfur dioxide to anoxic spring-water yields (bi)sulfite and moderately acidic conditions that favor its stability and bioavailability. The presence of similar volcanic springs at the time SRO are thought to have originated (&gt;3.4 Ga) may have supplied (bi)sulfite that supported ancestral SRO. These observations coincide with the lack of inferred SO42− reduction capacity in nearly all organisms with early-branching DsrAB and which are near universally found in hydrothermal environments.
Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios
Authors: Zhang Lingli , Huang Chu-Chung , Dai Yuan , Luo Qiang , Ji Yiting , Wang Kai , Deng Shining , Yu Juehua , Xu Mingyu , Du Xiujuan , Tang Yun , Shen Chun , Feng Jianfeng , Sahakian Barbara J , Lin Ching-Po , Li Fei 
Published: February 2020

AbstractBumetanide has been reported to alter synaptic excitation–inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.
Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice
Authors: Guarnieri Leonardo O. , Pereira-Caixeta Ana Raquel , Medeiros Daniel C. , Aquino Nayara S. S. , Szawka Raphael E. , Mendes Eduardo M. A. M. , Moraes Márcio F. D. , Pereira Grace S. 
Published: February 2020

AbstractAlthough loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.
Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden
Authors: Mooney Michael A. , Ryabinin Peter , Wilmot Beth , Bhatt Priya , Mill Jonathan , Nigg Joel T. 
Published: February 2020

AbstractEpigenetic variation in peripheral tissues is being widely studied as a molecular biomarker of complex disease and disease-related exposures. To date, few studies have examined differences in DNA methylation associated with attention-deficit hyperactivity disorder (ADHD). In this study, we profiled genetic and methylomic variation across the genome in saliva samples from children (age 7–12 years) with clinically established ADHD (N = 391) and nonpsychiatric controls (N = 213). We tested for differentially methylated positions (DMPs) associated with both ADHD diagnosis and ADHD polygenic risk score, by using linear regression models including smoking, medication effects, and other potential confounders in our statistical models. Our results support previously reported associations between ADHD and DNA methylation levels at sites annotated to VIPR2, and identify several novel disease-associated DMPs (p < 1e–5), although none of them were genome-wide significant. The two top-ranked, ADHD-associated DMPs (cg17478313 annotated to SLC7A8 and cg21609804 annotated to MARK2) are also significantly associated with nearby SNPs (p = 1.2e–46 and p = 2.07e–59), providing evidence that disease-associated DMPs are under genetic control. We also report a genome-wide significant association between ADHD polygenic risk and variable DNA methylation at a site annotated to the promoter of GART and SON (p = 6.71E–8). Finally, we show that ADHD-associated SNPs colocalize with SNPs associated with methylation levels in saliva. This is the first large-scale study of DNA methylation in children with ADHD. Our results represent novel epigenetic biomarkers for ADHD that may be useful for patient stratification, reinforce the importance of genetic effects on DNA methylation, and provide plausible molecular mechanisms for ADHD risk variants.
Emotional remodeling with oxytocin durably rescues trauma-induced behavioral and neuro-morphological changes in rats: a promising treatment for PTSD
Authors: Le Dorze Claire , Borreca Antonella , Pignataro Annabella , Ammassari-Teule Martine , Gisquet-Verrier Pascale 
Published: February 2020

AbstractRecent evidence indicates that reactivated memories are malleable and can integrate new information upon their reactivation. We injected rats with oxytocin to investigate whether the delivery of a drug which dampens anxiety and fear before the reactivation of trauma memory decreases the emotional load of the original representation and durably alleviates PTSD-like symptoms. Rats exposed to the single prolonged stress (SPS) model of PTSD were classified 15 and 17 days later as either resilient or vulnerable to trauma on the basis of their anxiety and arousal scores. Following 2 other weeks, they received an intracerebral infusion of oxytocin (0.1 µg/1 µL) or saline 40 min before their trauma memory was reactivated by exposure to SPS reminders. PTSD-like symptoms and reactivity to PTSD-related cues were examined 3–14 days after oxytocin treatment. Results showed that vulnerable rats treated with saline exhibited a robust PTSD syndrome including increased anxiety and decreased arousal, as well as intense fear reactions to SPS sensory and contextual cues. Exposure to a combination of those cues resulted in c-fos hypo-activation and dendritic arbor retraction in prefrontal cortex and amygdala neurons, relative to resilient rats. Remarkably, 83% of vulnerable rats subjected to oxytocin-based emotional remodeling exhibited a resilient phenotype, and SPS-induced morphological alterations in prelimbic cortex and basolateral amygdala were eliminated. Our findings emphasize the translational potential of the present oxytocin-based emotional remodeling protocol which, when administered even long after the trauma, produces deep re-processing of traumatic memories and durable attenuation of the PTSD symptomatology.
Predicting treatment dropout after antidepressant initiation
Authors: Pradier Melanie F. , McCoy Jr Thomas H. , Hughes Michael , Perlis Roy H. , Doshi-Velez Finale 
Published: February 2020

AbstractAntidepressants exhibit similar efficacy, but varying tolerability, in randomized controlled trials. Predicting tolerability in real-world clinical populations may facilitate personalization of treatment and maximize adherence. This retrospective longitudinal cohort study aimed to determine the extent to which incorporating patient history from electronic health records improved prediction of unplanned treatment discontinuation at index antidepressant prescription. Clinical data were analyzed from individuals from health networks affiliated with two large academic medical centers between March 1, 2008 and December 31, 2014. In total, the study cohorts included 51,683 patients with at least one International Classification of Diseases diagnostic code for major depressive disorder or depressive disorder not otherwise specified who initiated antidepressant treatment. Among 70,121 total medication changes, 16,665 (23.77%) of them were followed by failure to return; maximum risk was observed with paroxetine (27.71% discontinuation), and minimum with venlafaxine (20.78% discontinuation); Mantel–Haenzel χ2 (8 df) = 126.44, p = 1.54e–23 <1e–6. Models incorporating diagnostic and procedure codes and medication prescriptions improved per-medication Areas Under the Curve (AUCs) to a mean of 0.69 [0.64–0.73] (ranging from 0.62 for paroxetine to 0.80 for escitalopram), with similar performance in the second, replication health system. Machine learning applied to coded electronic health records facilitates identification of individuals at high-risk for treatment dropout following change in antidepressant medication. Such methods may assist primary care physicians and psychiatrists in the clinic to personalize antidepressant treatment on the basis not solely of efficacy, but of tolerability.
Sex differences in the association of body mass index with symptoms and cognitive deficits in Chinese patients with chronic schizophrenia
Authors: Wei Chang Wei , Chen Ying Qi , Ma Mi , Xiu Mei Hong , Zhang Xiang Yang 
Published: February 2020

AbstractAccumulating studies have revealed gender differences in many aspects of schizophrenia (SZ), including obesity and cognitive function. The relationship between obesity and cognitive impairment in SZ has been studied before; however, the results are inconsistent. This study was designed to examine the sex differences in the relationship between body mass index (BMI) and cognitive deficits in Chinese patients with chronic SZ, which have not been investigated yet. 176 chronic patients with SZ (male/female = 108/68) and 200 controls (male/female = 120/80) were enrolled to compare the sex differences in cognitive functions measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), BMI, and their associations. The clinical symptoms were evaluated using the positive and negative syndrome scales (PANSS). Our results showed that male patients had lower BMI and more negative symptoms but fewer positive symptoms than female patients (all p < 0.05). However, there was no significant sex difference in RBANS scores. In male patients, BMI was correlated with age of onset, PANSS general psychopathology, total score, negative symptom, together with RBANS language, visuospatial/construction, and attention. Further regression analysis showed that in male patients, BMI was significantly associated with RBANS language, PANSS general psychopathology, PANSS total score, and age of onset, with adjusted R2 = 0.22. These findings revealed significant sex differences in BMI, cognitive dysfunctions and their association in SZ. Nonetheless, these results should only be considered as preliminary because of the cross-sectional design, which will deserve further replication in first-episode patients using a prospective longitudinal design.
A clinical staging model for bipolar disorder: longitudinal approach
Authors: de la Fuente-Tomás Lorena , Sierra Pilar , Sanchez-Autet Mónica , Arranz Belén , García-Blanco Ana , Safont Gemma , García-Portilla Maria P. 
Published: February 2020

AbstractBipolar disorder (BD) has been identified as a life-course illness with different clinical manifestations from an at-risk to a late stage, supporting the assumption that it would benefit from a staging model. In a previous study, we used a clustering approach to stratify 224 patients with a diagnosis of BD into five clusters based on clinical characteristics, functioning, cognition, general health, and health-related quality of life. This study was design to test the construct validity of our previously developed k-means clustering model and to confirm its longitudinal validity over a span of 3 years. Of the 224 patients included at baseline who were used to develop our model, 129 (57.6%) reached the 3-year follow-up. All life domains except mental health-related quality of life (QoL) showed significant worsening in stages (p < 0.001), suggesting construct validity. Furthermore, as patients progressed through stages, functional decline (p < 0.001) and more complex treatment patterns (p = 0.002) were observed. As expected, at 3 years, the majority of patients remained at the same stage (49.6%), or progressed (20.9%) or regressed (23.3%) one stage. Furthermore, 85% of patients who stayed euthymic during that period remained at the same stage or regressed to previous stages, supporting its longitudinal validity. For that reason, this study provides evidence of the construct and longitudinal validity of an empirically developed, comprehensive staging model for patients with BD. Thus, it may help clinicians and researchers to better understand the disorder and, at the same time, to design more accurate and personalized treatment plans.
Genetic associations with clozapine-induced myocarditis in patients with schizophrenia
Authors: Lacaze Paul , Ronaldson Kathlyn J. , Zhang Eunice J. , Alfirevic Ana , Shah Hardik , Newman Leah , Strahl Maya , Smith Melissa , Bousman Chad , Francis Ben , Morris Andrew P. , Wilson Trevor , Rossello Fernando , Powell David , Vasic Vivien , Sebra Robert , McNeil John J. , Pirmohamed Munir 
Published: February 2020

AbstractClozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10−6), with odds ratios ranging 5.5–13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10−7; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11–7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05–1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10−5). Combining clinical and genetic factors together increased the proportion of variability accounted for (r2 0.73, P = 9.8 × 10−9). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.
Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging
Authors: Barbu Miruna C. , Spiliopoulou Athina , Colombo Marco , McKeigue Paul , Clarke Toni-Kim , Howard David M. , Adams Mark J. , Shen Xueyi , Lawrie Stephen M. , McIntosh Andrew M. , Whalley Heather C. 
Published: February 2020

AbstractExpression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritable in vivo measures of human brain structural connectivity. Using large-scale eQTL mapping studies, we computed 6457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (NFA = 14,518) and mean diffusivity (NMD = 14,485), representing white matter structural integrity. We found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (βabsolute FA = 0.0339–0.0453; MD = 0.0308–0.0381) and individual tracts (βabsolute FA = 0.0320–0.0561; MD = 0.0295–0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson’s disease (DCAKD, SLC35A4, SEC14L4, SRA1, NMT1, CPNE1, PLEKHM1, UBE3C). Our findings indicate that eQTL scores are associated with measures of in vivo brain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these results suggest it may be possible, in future, to map potential trait- and disease-associated eQTL to in vivo brain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.