bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stress adaptation is associated with insulin resistance in women with gestational diabetes mellitus
Authors: Feng Yan , Feng Qi , Qu Hongmei , Song Xinna , Hu Jianwei , Xu Xiaomeng , Zhang Li , Yin Shaohua 
Published: February 2020

Abstract
Aim
Oxidative stress is known to increase the risk of insulin resistance (IR). The aim of this study was to investigate the association between stress hormones and IR in women with gestational diabetes mellitus (GDM), in an attempt to gain insights into the pathogenesis of GDM.

Methods
Recruited in this study were 70 GDM women and 70 healthy pregnant women as control. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), plasma epinephrine (E), noradrenaline (NE), glucagon, and cortisol levels were detected. IR was assessed by homeostasis model assessment of IR (HOMA-IR) in both groups. Correlations among stress hormones, oxidative stress, and IR were analyzed by Pearson’s correlation after log transformation.

Results
Compared with the Control group, MDA was increased and anti-oxidative enzymes SOD and GSH were decreased significantly in the GDM group. Glucagon, E, and NE in the GDM group were increased by 22.42%, 36.82%, and 35.09%, respectively, as compared with those in the Control group. MDA showed a significant positive correlation, and SOD showed a negative correlation with HOMA-IR in the GDM group. In addition, HOMA-IR was positively related to glucagon, E, NE, and cortisol.

Conclusions
Elevation of stress hormones and stress adaptation disturbance may be associated with the pathogenesis of GDM in pregnant women.
EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma
Authors: Struve Nina , Binder Zev A. , Stead Lucy F. , Brend Tim , Bagley Stephen J. , Faulkner Claire , Ott Leonie , Müller-Goebel Justus , Weik Anna-Sophie , Hoffer Konstantin , Krug Leonie , Rieckmann Thorsten , Bußmann Lara , Henze Marvin , Morrissette Jennifer J. D. , Kurian Kathreena M. , Schüller Ulrich , Petersen Cordula , Rothkamm Kai , O´ Rourke Donald M. , Short Susan C. , Kriegs Malte 
Published: February 2020

AbstractThe oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR.
Genomic prediction of alcohol-related morbidity and mortality
Authors: Kiiskinen Tuomo , Mars Nina J. , Palviainen Teemu , Koskela Jukka , Rämö Joel T. , Ripatti Pietari , Ruotsalainen Sanni ,   FinnGen, GSCAN Consortium, Palotie Aarno , Madden Pamela A. F. , Rose Richard J. , Kaprio Jaakko , Salomaa Veikko , Mäkelä Pia , Havulinna Aki S. , Ripatti Samuli 
Published: February 2020

AbstractWhile polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85–12.58 g, p = 2.3 × 10–58). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66–2.01, p = 1.6 × 10–36). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26–1.99, p = 8.2 × 10–5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20–1.47, p = 4.5 × 10–8) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.
Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders
Authors: Erli Filippo , Palmos Alish B. , Raval Pooja , Mukherjee Jayanta , Sellers Katherine J. , Gatford Nicholas J. F. , Moss Stephen J. , Brandon Nicholas J. , Penzes Peter , Srivastava Deepak P. 
Published: February 2020

AbstractLoss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia 1 (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number.
Delayed sleep timing and circadian rhythms in pregnancy and transdiagnostic symptoms associated with postpartum depression
Authors: Obeysekare Jessica L. , Cohen Zachary L. , Coles Meredith E. , Pearlstein Teri B. , Monzon Carmen , Flynn E. Ellen , Sharkey Katherine M. 
Published: February 2020

AbstractLater sleep timing, circadian preference, and circadian rhythm timing predict worse outcomes across multiple domains, including mood disorders, substance use, impulse control, and cognitive function. Disturbed sleep is common among pregnant and postpartum women. We examined whether sleep timing during third trimester of pregnancy predicted postpartum symptoms of mania, depression, and obsessive-compulsive disorder (OCD). Fifty-one women with a previous, but not active, episode of unipolar or bipolar depression had symptoms evaluated and sleep recorded with wrist actigraphy at 33 weeks of gestation and 2, 6, and 16 weeks postpartum. Circadian phase was measured in a subset of women using salivary dim light melatonin onset (DLMO). We divided the sample into “early sleep” and “late sleep” groups using average sleep onset time at 33 weeks of gestation, defined by the median-split time of 11:27 p.m. The “late sleep” group reported significantly more manic and depressive symptoms at postpartum week 2. Longer phase angle between DLMO and sleep onset at 33 weeks was associated with more manic symptoms at postpartum week 2 and more obsessive-compulsive symptoms at week 6. Delayed sleep timing in this sample of at-risk women was associated with more symptoms of mania, depression, and OCD in the postpartum period. Sleep timing may be a modifiable risk factor for postpartum depression.
Genome-wide association study of dietary intake in the UK biobank study and its associations with schizophrenia and other traits
Authors: Niarchou Maria , Byrne Enda M. , Trzaskowski Maciej , Sidorenko Julia , Kemper Kathryn E. , McGrath John J. , O’ Donovan Michael C. , Owen Michael J. , Wray Naomi R. 
Published: February 2020

AbstractMotivated by observational studies that report associations between schizophrenia and traits, such as poor diet, increased body mass index and metabolic disease, we investigated the genetic contribution to dietary intake in a sample of 335,576 individuals from the UK Biobank study. A principal component analysis applied to diet question item responses generated two components: Diet Component 1 (DC1) represented a meat-related diet and Diet Component 2 (DC2) a fish and plant-related diet. Genome-wide association analysis identified 29 independent single-nucleotide polymorphisms (SNPs) associated with DC1 and 63 SNPs with DC2. Estimated from over 35,000 3rd-degree relative pairs that are unlikely to share close family environments, heritabilities for both DC1 and DC2 were 0.16 (standard error (s.e.) = 0.05). SNP-based heritability was 0.06 (s.e. = 0.003) for DC1 and 0.08 (s.e = 0.004) for DC2. We estimated significant genetic correlations between both DCs and schizophrenia, and several other traits. Mendelian randomisation analyses indicated a negative uni-directional relationship between liability to schizophrenia and tendency towards selecting a meat-based diet (which could be direct or via unidentified correlated variables), but a bi-directional relationship between liability to schizophrenia and tendency towards selecting a fish and plant-based diet consistent with genetic pleiotropy.
Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression
Authors: Zoubovsky Sandra P. , Hoseus Sarah , Tumukuntala Shivani , Schulkin Jay O. , Williams Michael T. , Vorhees Charles V. , Muglia Louis J. 
Published: February 2020

AbstractPostpartum depression (PPD) affects up to 20% of mothers and has negative consequences for both mother and child. Although exposure to psychosocial stress during pregnancy and abnormalities in the hypothalamic pituitary adrenal (HPA) axis have been linked to PPD, molecular changes in the brain that contribute to this disease remain unknown. This study utilized a novel chronic psychosocial stress paradigm during pregnancy (CGS) to investigate the effects of psychosocial stress on maternal behavior, neuroendocrine function, and gene expression changes in molecular regulators of the HPA axis in the early postpartum period. Postpartum female mice exposed to CGS display abnormalities in maternal behavior, including fragmented and erratic maternal care patterns, and the emergence of depression and anxiety-like phenotypes. Dysregulation in postpartum HPA axis function, evidenced by blunted circadian peak and elevation of stress-induced corticosterone levels, was accompanied by increased CRH mRNA expression and a reduction in CRH receptor 1 in the paraventricular nucleus of the hypothalamus (PVN). We further observed decreased PVN expression of nuclear steroid hormone receptors associated with CRH transcription, suggesting these molecular changes could underlie abnormalities in postpartum HPA axis and behavior observed. Overall, our study demonstrates that psychosocial stress during pregnancy induces changes in neuroendocrine function and maternal behavior in the early postpartum period and introduces our CGS paradigm as a viable model that can be used to further dissect the molecular defects that lead to PPD.
ADHD and ASD: distinct brain patterns of inhibition-related activation?
Authors: Albajara Sáenz Ariadna , Septier Mathilde , Van Schuerbeek Peter , Baijot Simon , Deconinck Nicolas , Defresne Pierre , Delvenne Véronique , Passeri Gianfranco , Raeymaekers Hubert , Salvesen Leila , Victoor Laurent , Villemonteix Thomas , Willaye Eric , Peigneux Philippe , Massat Isabelle 
Published: February 2020

AbstractAttention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders often co-occur. In both cases, response inhibition deficits and inhibition-related atypical brain activation have been reported, although less consistently in ASD. Research exploring the overlap/distinctiveness between ADHD and ASD has significantly increased in recent years, but direct comparison of the inhibition-related neuronal correlates between these disorders are scarce in the literature. This study aimed at disentangling the shared and specific inhibitory brain dysfunctions in ASD and ADHD. Using functional magnetic resonance imaging (fMRI), brain activity was compared between children with ADHD, ASD and typically developing (TD) children aged 8–12 years during an inhibition stop-signal task, using stringent inclusion criteria. At the behavioural level, only children with ADHD exhibited inhibition deficits when compared with the TD group. Distinct patterns of brain activity were observed during successful inhibition. In children with ADHD, motor inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared with the ADHD and the TD groups. Our results evidence different patterns of activation during inhibition in these two disorders, recruiting different regions of the fronto-parietal network associated to inhibition. Besides brain activity differences, behavioural inhibition deficits found only in children with ADHD further suggest that reactive inhibition is one of the core deficits in ADHD, but not in ASD. Our findings provide further evidence contributing to disentangle the shared and specific inhibitory dysfunctions in ASD and ADHD.
Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease
Authors: Ray Balmiki , Maloney Bryan , Sambamurti Kumar , Karnati Hanuma K. , Nelson Peter T. , Greig Nigel H. , Lahiri Debomoy K. 
Published: February 2020

AbstractRivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer’s disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases– Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.
Genetic factors underlie the association between anxiety, attitudes and performance in mathematics
Authors: Malanchini Margherita , Rimfeld Kaili , Wang Zhe , Petrill Stephen A. , Tucker-Drob Elliot M. , Plomin Robert , Kovas Yulia 
Published: February 2020

AbstractStudents struggling with mathematics anxiety (MA) tend to show lower levels of mathematics self-efficacy and interest as well as lower performance. The current study addresses: (1) how MA relates to different aspects of mathematics attitudes (self-efficacy and interest), ability (understanding numbers, problem-solving ability, and approximate number sense) and achievement (exam scores); (2) to what extent these observed relations are explained by overlapping genetic and environmental factors; and (3) the role of general anxiety in accounting for these associations. The sample comprised 3410 twin pairs aged 16–21 years, from the Twins Early Development Study. Negative associations of comparable strength emerged between MA and the two measures of mathematics attitudes, phenotypically (~ −0.45) and genetically (~ −0.70). Moderate negative phenotypic (~ −0.35) and strong genetic (~ −0.70) associations were observed between MA and measures of mathematics performance. The only exception was approximate number sense whose phenotypic (−0.10) and genetic (−0.31) relation with MA was weaker. Multivariate quantitative genetic analyses indicated that all mathematics-related measures combined accounted for ~75% of the genetic variance in MA and ~20% of its environmental variance. Genetic effects were largely shared across all measures of mathematics anxiety, attitudes, abilities and achievement, with the exception of approximate number sense. This genetic overlap was not accounted for by general anxiety. These results have important implications for future genetic research concerned with identifying the genetic underpinnings of individual variation in mathematics-related traits, as well as for developmental research into how children select and modify their mathematics-related experiences partly based on their genetic predispositions.
Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome
Authors: Berg E. L. , Pride M. C. , Petkova S. P. , Lee R. D. , Copping N. A. , Shen Y. , Adhikari A. , Fenton T. A. , Pedersen L. R. , Noakes L. S. , Nieman B. J. , Lerch J. P. , Harris S. , Born H. A. , Peters M. M. , Deng P. , Cameron D. L. , Fink K. D. , Beitnere U. , O’Geen H. , Anderson A. E. , Dindot S. V. , Nash K. R. , Weeber E. J. , Wöhr M. , Ellegood J. , Segal D. J. , Silverman J. L. 
Published: February 2020

AbstractAngelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am−/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p− paternal transmission cohort. We also discovered Ube3am−/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am−/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p− did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.
Treatment-resistant psychotic symptoms and the 15q11.2 BP1–BP2 (Burnside-Butler) deletion syndrome: case report and review of the literature
Authors: Farrell Martilias , Lichtenstein Maya , Harner Matthew K. , Crowley James J. , Filmyer Dawn M. , Lázaro-Muñoz Gabriel , Dietterich Tyler E. , Bruno Lisa M. , Shaughnessy Rita A. , Biondi Tamara F. , Burkholder Stephan , Donmoyer Jane , Berg Jonathan S. , Szatkiewicz Jin , Sullivan Patrick F. , Josiassen Richard C. 
Published: February 2020

AbstractThe 15q11.2 BP1-BP2 (Burnside-Butler) deletion is a rare copy number variant impacting four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5), and carries increased risks for developmental delay, intellectual disability, and neuropsychiatric disorders (attention-deficit/hyperactivity disorder, autism, and psychosis). In this case report (supported by extensive developmental information and medication history), we present the complex clinical portrait of a 44-year-old woman with 15q11.2 BP1-BP2 deletion syndrome and chronic, treatment-resistant psychotic symptoms who has resided nearly her entire adult life in a long-term state psychiatric institution. Diagnostic and treatment implications are discussed.