bluuebunny/crossref_metadata_2025 huggingface dataset:
Constraining the IMF at Pluto Using New Horizons SWAP Data and Hybrid Simulations
Authors: Barnes N. P. , Delamere P. A. , Strobel D. F. , Bagenal F. , McComas D. J. , Elliott H. A. , Valek P. , Weaver H. A. , Ennico K. , Young L. A. , Stern S. A.
Published: February 2019

New Horizons did not carry a magnetometer, so there is no direct way to know the strength of the Interplanetary Magnetic Field (IMF) at the time of the flyby. Using a hybrid model together with a detailed model of the Solar Wind Around Pluto (SWAP) instrument (McComas et al., 2007, https://doi.org/10.1007/s11214-007-9205-3) we have identified three observables that are sensitive to IMF strength: the width of Pluto's heavy ion tail, the energy of heavy ions, and the profile of thermal pressure along the New Horizons trajectory. By comparing simulation to data we infer that the IMF strength was most likely near or below ∼0.1 nT. We also show that the shell distribution of Interstellar Pickup Ions is important for reproducing these observations due to its effect on global pressure balance.
Acyl Peroxy Nitrates Link Oil and Natural Gas Emissions to High Ozone Abundances in the Colorado Front Range During Summer 2015
Authors: Lindaas Jakob , Farmer Delphine K. , Pollack Ilana B. , Abeleira Andrew , Flocke Frank , Fischer Emily V.
Published: February 2019

We present measurements of ozone (O3), acyl peroxy nitrates (APNs), and a suite of O3precursors made at the Boulder Atmospheric Observatory in Erie, Colorado, during summer 2015. We employ an empirical analysis of the APNs and a previously described positive matrix factorization of the volatile organic compounds (VOCs) to investigate the contribution of different VOC sources to high O3abundances at Boulder Atmospheric Observatory. Based on the ratio of peroxypropionyl nitrate (PPN) to peroxyacetyl nitrate (PAN), we find that anthropogenic VOC precursors dominate APN production when O3is most elevated. Propane and larger alkanes, primarily from oil and natural gas emissions in the Colorado Front Range, drive these elevated PPN to PAN ratios during high O3events. The percentage of OH reactivity associated with oil and gas emissions is also positively correlated with O3and PPN/PAN. Idealized box model simulations are used to probe the chemical mechanisms potentially responsible for these observations. We find that observed abundances of long‐lived oil and natural gas‐related VOCs are likely high enough such that the oxidation of these VOCs in a single photochemical day produces sufficient peroxy radicals to contribute to O3formation in the northern Colorado Front Range. Based on our empirical observations and box model simulations, we conclude that oil and natural gas emissions contribute to O3production on high O3days in this region during summer 2015.
Inconsistent Wind Speed Trends in Current Twentieth Century Reanalyses
Authors: Wohland Jan , Omrani Nour‐Eddine , Witthaut Dirk , Keenlyside Noel S.
Published: February 2019

Reanalysis data underpin much research in atmospheric and related sciences. While most reanalysis only cover the last couple of decades, National Oceanic and Atmospheric Administration (20CR) and European Centre for Medium‐Range Weather Forecasts (ERA20C and CERA20C) also developed reanalyses for the entire twentieth century that theoretically allow investigation of multidecadal variability. However, the approaches adopted to handle the massively evolving number of observations can cause spurious signals. Here we focus on wind speeds, as its assimilation is a key difference among these two products. We show that ERA20C and CERA20C feature significant trends in the North Atlantic and North Pacific wind speeds of up to 3 m/s per century. We show that there is a good relation between the trends in the reanalysis and assimilated wind speeds. In contrast, 20CR and the European Centre for Medium‐Range Weather Forecasts free model run ERA20CM do not show positive trends in the same regions. As a consequence, conclusions drawn from any single twentieth century reanalysis should be treated cautiously in particular in sectors with a strong wind dependency (e.g., wind energy).
Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland
Authors: Arnau-Soler Aleix , Macdonald-Dunlop Erin , Adams Mark J. , Clarke Toni-Kim , MacIntyre Donald J. , Milburn Keith , Navrady Lauren ,   Generation Scotland,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hayward Caroline , McIntosh Andrew M. , Thomson Pippa A.
Published: February 2019

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10−6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10−9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10−8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10−8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10−6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10−3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
Structural neuroimaging correlates of social deficits are similar in autism spectrum disorder and attention-deficit/hyperactivity disorder: analysis from the POND Network
Authors: Baribeau Danielle A. , Dupuis Annie , Paton Tara A. , Hammill Christopher , Scherer Stephen W. , Schachar Russell J. , Arnold Paul D. , Szatmari Peter , Nicolson Rob , Georgiades Stelios , Crosbie Jennifer , Brian Jessica , Iaboni Alana , Kushki Azadeh , Lerch Jason P. , Anagnostou Evdokia
Published: February 2019

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal–parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.
Prefrontal networks dynamically related to recovery from major depressive disorder: a longitudinal pharmacological fMRI study
Authors: Meyer Bernhard M. , Rabl Ulrich , Huemer Julia , Bartova Lucie , Kalcher Klaudius , Provenzano Julian , Brandner Christoph , Sezen Patrick , Kasper Siegfried , Schatzberg Alan F. , Moser Ewald , Chen Gang , Pezawas Lukas
Published: February 2019

Due to lacking predictors of depression recovery, successful treatment of major depressive disorder (MDD) is frequently only achieved after therapeutic optimization leading to a prolonged suffering of patients. This study aimed to determine neural prognostic predictors identifying non-remitters prior or early after treatment initiation. Moreover, it intended to detect time-sensitive neural mediators indicating depression recovery. This longitudinal, interventional, single-arm, open-label, phase IV, pharmacological functional magnetic resonance imaging (fMRI) study comprised four scans at important stages prior (day 0) and after escitalopram treatment initiation (day 1, 28, and 56). Totally, 22 treatment-free MDD patients (age mean ± SD: 31.5 ± 7.7; females: 50%) suffering from a concurrent major depressive episode without any comorbid DSM-IV axis I diagnosis completed the study protocol. Primary outcome were neural prognostic predictors of depression recovery. Enhanced de-activation of anterior medial prefrontal cortex (amPFC, single neural mediator) indicated depression recovery correlating with MADRS score and working memory improvements. Strong dorsolateral PFC (dlPFC) activation and weak dlPFC-amPFC, dlPFC-posterior cingulate cortex (PCC), dlPFC-parietal lobe (PL) coupling (three prognostic predictors) hinted at depression recovery at day 0 and 1. Preresponse prediction of continuous (dlPFC-PL: R2day1 = 55.9%, 95% CI: 22.6–79%, P < 0.005) and dichotomous (specificity/sensitivity: SP/SNday1 = 0.91/0.82) recovery definitions remained significant after leave-one-out cross-validation. Identified prefrontal neural predictors might propel the future development of fMRI markers for clinical decision making, which could lead to increased response rates and adherence during acute phase treatment periods. Moreover, this study underscores the importance of the amPFC in depression recovery.
Effects of familial risk and stimulant drug use on the anticipation of monetary reward: an fMRI study
Authors: Just Alanna L. , Meng Chun , Smith Dana G. , Bullmore Edward T. , Robbins Trevor W. , Ersche Karen D.
Published: February 2019

The association between stimulant drug use and aberrant reward processing is well-documented in the literature, but the nature of these abnormalities remains elusive. The present study aims to disentangle the separate and interacting effects of stimulant drug use and pre-existing familial risk on abnormal reward processing associated with stimulant drug addiction. We used the Monetary Incentive Delay task, a well-validated measure of reward processing, during fMRI scanning in four distinct groups: individuals with familial risk who were either stimulant drug-dependent (N = 41) or had never used stimulant drugs (N = 46); and individuals without familial risk who were either using stimulant drugs (N = 25) or not (N = 48). We first examined task-related whole-brain activation followed by a psychophysiological interaction analysis to further explore brain functional connectivity. For analyses, we used a univariate model with two fixed factors (familial risk and stimulant drug use). Our results showed increased task-related activation in the putamen and motor cortex of stimulant-using participants. We also found altered task-related functional connectivity between the putamen and frontal regions in participants with a familial risk (irrespective of whether they were using stimulant drugs or not). Additionally, we identified an interaction between stimulant drug use and familial risk in task-related functional connectivity between the putamen and motor-related cortical regions in potentially at-risk individuals. Our findings suggest that abnormal task-related activation in motor brain systems is associated with regular stimulant drug use, whereas abnormal task-related functional connectivity in frontostriatal brain systems, in individuals with familial risk, may indicate pre-existing neural vulnerability for developing addiction.
Do polygenic risk and stressful life events predict pharmacological treatment response in obsessive compulsive disorder? A gene–environment interaction approach
Authors: Alemany-Navarro María , Costas Javier , Real Eva , Segalàs Cinto , Bertolín Sara , Domènech Laura , Rabionet Raquel , Carracedo Ángel , Menchón Jose M. , Alonso Pino
Published: February 2019

The rate of response to pharmacological treatment in Obsessive-compulsive disorder (OCD) oscillates between 40 and 70%. Genetic and environmental factors have been associated with treatment response in OCD. This study analyzes the predictive ability of a polygenic risk score (PRS) built from OCD-risk variants, for treatment response in OCD, and the modulation role of stressful life events (SLEs) at the onset of the disorder. PRSs were calculated for a sample of 103 patients. Yale–Brown Obsessive Compulsive Scale (YBOCS) scores were obtained before and after a 12-week treatment. Regression analyses were performed to analyze the influence of the PRS and SLEs at onset on treatment response. PRS did not predict treatment response. The best predictive model for post-treatment YBOCS (post YBOCS) included basal YBOCS and age. PRS appeared as a predictor for basal and post YBOCS. SLEs at onset were not a predictor for treatment response when included in the regression model. No evidence for PRS predictive ability for treatment response was found. The best predictor for treatment response was age, agreeing with previous literature specific for SRI treatment. Suggestions are made on the possible role of neuroplasticity as a mediator on this association. PRS significantly predicted OCD severity independent on pharmacological treatment. SLE at onset modulation role was not evidenced. Further research is needed to elucidate the genetic and environmental bases of treatment response in OCD.
An implicit and reliable neural measure quantifying impaired visual coding of facial expression: evidence from the 22q11.2 deletion syndrome
Authors: Leleu Arnaud , Favre Emilie , Yailian Alexandre , Fumat Hugo , Klamm Juliette , Amado Isabelle , Baudouin Jean-Yves , Franck Nicolas , Demily Caroline
Published: February 2019

Although various psychiatric disorders present with social-cognitive impairment, a measure assessing social-cognitive processes implicitly and reliably, with high selectivity and with enough signal-to-noise ratio (SNR) for individual evaluation of any population at any age, is lacking. Here we isolate a neural marker quantifying impaired visual coding of facial expression in individuals with 22q11.2 deletion syndrome (22q11DS) using frequency-tagging with electroencephalography (EEG). Twenty-two 22q11DS participants and 22 healthy controls were presented with changes of facial expression displayed at low, moderate, and high intensities every five cycles in a stream of one neutral face repeating 6 times per second (i.e., at a 6 Hz base rate). The brain response to expression changes tagged at the 1.2 Hz (i.e., 6 Hz/5) predefined frequency was isolated over occipito-temporal regions in both groups of participants for moderate- and high-intensity facial expressions. Neural sensitivity to facial expression was reduced by about 36% in 22q11DS, revealing impaired visual coding of emotional facial signals. The significance of the expression-change response was estimated for each single participant thanks to the high SNR of the approach. Further analyses revealed the high reliability of the response and its immunity from other neurocognitive skills. Interestingly, response magnitude was associated with the severity of positive symptoms, pointing to a potential endophenotype for psychosis risk. Overall, the present study reveals an objective, selective, reliable, and behavior-free signature of impaired visual coding of facial expression implicitly quantified from brain activity with high SNR. This novel tool opens avenues for clinical practice, providing a potential early biomarker for later psychosis onset and offering an alternative for individual assessment of social-cognitive functioning in even difficult-to-test participants.
What do DNA methylation studies tell us about depression? A systematic review
Authors: Li Muzi , D’Arcy Carl , Li Xintong , Zhang Tieyuan , Joober Ridha , Meng Xiangfei
Published: February 2019

There has been a limited number of systematic reviews conducted to summarize the overview of the relationship between DNA methylation and depression, and to critically appraise the roles of major study characteristics in the accuracy of study findings. This systematic review aims to critically appraise the impact of study characteristics on the association between DNA methylation and depression, and summarize the overview of this association. Electronic databases and gray literatures until December 2017 were searched for English-language studies with standard diagnostic criteria of depression. A total of 67 studies were included in this review along with a summary of their study characteristics. We grouped the findings into etiological and treatment studies. Majority of these selected studies were recently published and from developed countries. Whole blood samples were the most studied common tissues. Bisulfite conversion, along with pyrosequencing, was widely used to test the DNA methylation level across all the studies. High heterogeneity existed among the studies in terms of experimental and statistical methodologies and study designs. As recommended by the Cochrane guideline, a systematic review without meta-analysis should be undertaken. This review has, in general, found that DNA methylation modifications were associated with depression. Subgroup analyses showed that most studies found BDNF and SLC6A4 hypermethylations to be associated with MDD or depression in general. In contrast, studies on NR3C1, OXTR, and other genes, which were tested by only few studies, reported mixed findings. More longitudinal studies using standardized experimental and laboratory methodologies are needed in future studies to enable more systematical comparisons and quantitative synthesis.
The genomics of major psychiatric disorders in a large pedigree from Northern Sweden
Authors: Szatkiewicz Jin , Crowley James J. , Adolfsson Annelie Nordin , Åberg Karolina A. , Alaerts Maaike , Genovese Giulio , McCarroll Steven , Del-Favero Jurgen , Adolfsson Rolf , Sullivan Patrick F.
Published: February 2019

We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.
Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
Authors: Gottschalk Michael G. , Richter Jan , Ziegler Christiane , Schiele Miriam A. , Mann Julia , Geiger Maximilian J. , Schartner Christoph , Homola György A. , Alpers Georg W. , Büchel Christian , Fehm Lydia , Fydrich Thomas , Gerlach Alexander L. , Gloster Andrew T. , Helbig-Lang Sylvia , Kalisch Raffael , Kircher Tilo , Lang Thomas , Lonsdorf Tina B. , Pané-Farré Christiane A. , Ströhle Andreas , Weber Heike , Zwanzger Peter , Arolt Volker , Romanos Marcel , Wittchen Hans-Ulrich , Hamm Alfons , Pauli Paul , Reif Andreas , Deckert Jürgen , Neufang Susanne , Höfler Michael , Domschke Katharina
Published: February 2019

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma
Authors: Stewart A. Keith , Krishnan Amrita Y. , Singhal Seema , Boccia Ralph V. , Patel Manish R. , Niesvizky Ruben , Chanan-Khan Asher A. , Ailawadhi Sikander , Brumm Jochen , Mundt Kirsten E. , Hong Kyu , McBride Jacqueline , Shon-Nguyen Quyen , Xiao Yuanyuan , Ramakrishnan Vanitha , Polson Andrew G. , Samineni Divya , Leipold Douglas , Humke Eric W. , McClellan James Scott , Berdeja Jesus G.
Published: February 2019

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.
Mycobacterium tuberculosis antigens repress Th1 immune response suppression and promotes lung cancer metastasis through PD-1/PDl-1 signaling pathway
Authors: Cao Shuhui , Li Jingwen , Lu Jun , Zhong Runbo , Zhong Hua
Published: February 2019

Given one-third of the world’s population is infected with Mycobacteriumtuberculosis (MTB), it is important to identify the underling molecular mechanism between development of TB and lung cancer. This study investigated the immune response to MTB infection on lung metastasis in lung cancer cells via T cell-mediated immune response. To clarify this problem, we analyzed the expression levels of PD-1, PD-L1, and PD-L2 and immune function in antigen-specific T cell as derived from MTB patients or spleen lymphocytes derived from wild-type and PD-1 knockout mice with MTB antigen stimulation and Lewis lung cancer cells injection. Our data indicate that the expression levels of PD-1, PD-L1, and PD-L2 were elevated in active pulmonary TB patients, as well as in mice received MTB and lung cancer cells treatment. We also observed the T cell-mediated cellular immune response were inhibited by MTB while MTB significantly promote tumor metastasis in lung. In conclusion, the PD-1/PD-L pathway is required MTB repressed T-cell immune response and promotes tumor metastasis. This study provides evidence that blockade of PD-1/PD-L1 signaling pathway may benefit patients with MTB or other chronic infection and even prevent them from development of cancer.
Inflammation-induced endothelial to mesenchymal transition promotes brain endothelial cell dysfunction and occurs during multiple sclerosis pathophysiology
Authors: Derada Troletti Claudio , Fontijn Ruud D. , Gowing Elizabeth , Charabati Marc , van Het Hof Bert , Didouh Imad , van der Pol Susanne M. A. , Geerts Dirk , Prat Alexandre , van Horssen Jack , Kooij Gijs , de Vries Helga E.
Published: February 2019

The blood-brain barrier (BBB) has a major role in maintaining brain homeostasis through the specialized function of brain endothelial cells (BECs). Inflammation of the BECs and loss of their neuroprotective properties is associated with several neurological disorders, including the chronic neuro-inflammatory disorder multiple sclerosis (MS). Yet, the underlying mechanisms of a defective BBB in MS remain largely unknown. Endothelial to mesenchymal transition (EndoMT) is a pathophysiological process in which endothelial cells lose their specialized function and de-differentiate into mesenchymal cells. This transition is characterized by an increase in EndoMT-related transcription factors (TFs), a downregulation of brain endothelial markers, and an upregulation of mesenchymal markers accompanied by morphological changes associated with cytoskeleton reorganization. Here, we postulate that EndoMT drives BEC de-differentiation, mediates inflammation-induced human BECs dysfunction, and may play a role in MS pathophysiology. We provide evidence that stimulation of human BECs with transforming growth factor (TGF)-β1 and interleukin (IL)-1β promotes EndoMT, a process in which the TF SNAI1, a master regulator of EndoMT, plays a crucial role. We demonstrate the involvement of TGF-β activated kinase 1 (TAK1) in EndoMT induction in BECs. Finally, immunohistochemical analysis revealed EndoMT-associated alterations in the brain vasculature of human post-mortem MS brain tissues. Taken together, our novel findings provide a better understanding of the molecular mechanisms underlying BECs dysfunction during MS pathology and can be used to develop new potential therapeutic strategies to restore BBB function.
Generation and characterization of novel anti-DR4 and anti-DR5 antibodies developed by genetic immunization
Authors: Dubuisson Agathe , Favreau Cécile , Fourmaux Eric , Lareure Sabrina , Rodrigues-Saraiva Rafael , Pellat-Deceunynck Catherine , El Alaoui Said , Micheau Olivier
Published: February 2019

Development of therapeutic antibodies in oncology has attracted much interest in the past decades. More than 30 of them have been approved and are being used to treat patients suffering from cancer. Despite encouraging results, and albeit most clinical trials aiming at evaluating monoclonal antibodies directed against TRAIL agonist receptors have been discontinued, DR4 or DR5 remain interesting targets, since these receptors are overexpressed by tumour cells and are able to trigger their death. In an effort to develop novel and specific anti-DR4 and anti-DR5 antibodies with improved properties, we used genetic immunization to express native proteins in vivo. Injection of DR4 and DR5 cDNA into the tail veins of mice elicited significant humoral anti-DR4 and anti-DR5 responses and fusions of the corresponding spleens resulted in numerous hybridomas secreting antibodies that could specifically recognize DR4 or DR5 in their native forms. All antibodies bound specifically to their targets with a very high affinity, from picomolar to nanomolar range. Among the 21 anti-DR4 and anti-DR5 monoclonal antibodies that we have produced and purified, two displayed proapoptotic properties alone, five induced apoptosis after cross-linking, four were found to potentiate TRAIL-induced apoptosis and three displayed antiapoptotic potential. The most potent anti-DR4 antibody, C#16, was assessed in vivo and was found, alone, to inhibit tumour growth in animal models. This is the first demonstration that DNA-based immunization method can be used to generate novel monoclonal antibodies targeting receptors of the TNF superfamily that may constitute new therapeutic agents.
CHD1L contributes to cisplatin resistance by upregulating the ABCB1–NF-κB axis in human non-small-cell lung cancer
Authors: Li Yang , He Li-Ru , Gao Ying , Zhou Ning-Ning , Liu Yurong , Zhou Xin-Ke , Liu Ji-Fang , Guan Xin-Yuan , Ma Ning-Fang , Xie Dan
Published: February 2019

Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified gene associated with malignant tumor progression and patient chemotherapy resistance in human hepatocellular carcinoma (HCC). Previously, we found an association between CHD1L overexpression and poor patient survival in non-small-cell lung cancer (NSCLC). However, little is known about the relationship between CHD1L expression and chemotherapy resistance of NSCLC. By employing immunohistochemistry, we analyzed the expression of CHD1L in NSCLC samples and elucidated the roles and mechanism of CHD1L in NSCLC chemoresistance. We found that the increased expression of CHD1L is positively correlated with a shorter survival time of patients who had received chemotherapy after surgery. We also found that the expression of CHD1L was increased after cisplatin treatment in A549 cells. Conversely, the depletion of CHD1L in cisplatin-resistance cells increased the cell sensitivity to cisplatin, indicating that CHD1L plays a critical role in cisplatin resistance of NSCLC cells. Importantly, we identified the ATP-Binding Cassette Sub-Family B Member (ABCB1) gene as a potential downstream target of CHD1L in NSCLC cells. Knocking down ABCB1 coupled with ectopic expression of CHD1L enhanced the effect of cisplatin on NSCLC cells apoptosis. In addition, overexpressed CHD1L increase the transcription of c-Jun which targeted directly to the promoter of ABCB1. Our data demonstrate that CHD1L could induce cisplatin resistance in NSCLC via c-Jun-ABCB1–NF-κB axis, and may serve as a novel predictive marker and the potential therapeutic target for cisplatin resistance in NSCLC.
Resveratrol enhances pluripotency of mouse embryonic stem cells by activating AMPK/Ulk1 pathway
Authors: Suvorova Irina I. , Knyazeva Aleksandra R. , Petukhov Alexey V. , Aksenov Nicolay D. , Pospelov Valery A.
Published: February 2019

Resveratrol, a natural polyphenolic compound, shows many beneficial effects in various animal models. It increases efficiency of somatic cell reprograming into iPSCs and contributes to cell differentiation. Here, we studied the effect of resveratrol on proliferation and pluripotency of mouse embryonic stem cells (mESCs). Our results demonstrate that resveratrol induces autophagy in mESCs that is provided by the activation of the AMPK/Ulk1 pathway and the concomitant suppression of the activity of the mTORC1 signaling cascade. These events correlate with the enhanced expression of pluripotency markers Oct3/4, Sox2, Nanog, Klf4, SSEA-1 and alkaline phosphatase. Pluripotency is retained under resveratrol-caused retardation of cell proliferation. Given that the Ulk1 overexpression enhances pluripotency of mESCs, the available data evidence that mTOR/Ulk1/AMPK-autophagy network provides the resveratrol-mediated regulation of mESC pluripotency. The capability of resveratrol to support the mESC pluripotency provides a new approach for developing a defined medium for ESC culturing as well as for better understanding signaling events that govern self-renewal and pluripotency.
Molecular interactions between Hel2 and RNA supporting ribosome-associated quality control
Authors: Winz Marie-Luise , Peil Lauri , Turowski Tomasz W. , Rappsilber Juri , Tollervey David
Published: February 2019

Ribosome-associated quality control (RQC) pathways monitor and respond to ribosome stalling. Using in vivo UV-crosslinking and mass spectrometry, we identified a C-terminal region in Hel2/Rqt1 as an RNA binding domain. Complementary crosslinking and sequencing data for Hel2 revealed binding to 18S rRNA and translated mRNAs. Hel2 preferentially bound mRNAs upstream and downstream of the stop codon. C-terminal truncation of Hel2 abolished the major 18S crosslink and polysome association, and altered mRNA binding. HEL2 deletion caused loss of RQC and, we report here, no-go decay (NGD), with comparable effects for Hel2 truncation including the RNA-binding site. Asc1 acts upstream of Hel2 in RQC and asc1∆ impaired Hel2 binding to 18S and mRNA. In conclusion: Hel2 is recruited or stabilized on translating 40S ribosomal subunits by interactions with 18S rRNA and Asc1. This 18S interaction is required for Hel2 function in RQC and NGD. Hel2 probably interacts with mRNA during translation termination.
Enabling low voltage losses and high photocurrent in fullerene-free organic photovoltaics
Authors: Yuan Jun , Huang Tianyi , Cheng Pei , Zou Yingping , Zhang Huotian , Yang Jonathan Lee , Chang Sheng-Yung , Zhang Zhenzhen , Huang Wenchao , Wang Rui , Meng Dong , Gao Feng , Yang Yang
Published: February 2019

Despite significant development recently, improving the power conversion efficiency of organic photovoltaics (OPVs) is still an ongoing challenge to overcome. One of the prerequisites to achieving this goal is to enable efficient charge separation and small voltage losses at the same time. In this work, a facile synthetic strategy is reported, where optoelectronic properties are delicately tuned by the introduction of electron-deficient-core-based fused structure into non-fullerene acceptors. Both devices exhibited a low voltage loss of 0.57 V and high short-circuit current density of 22.0 mA cm−2, resulting in high power conversion efficiencies of over 13.4%. These unconventional electron-deficient-core-based non-fullerene acceptors with near-infrared absorption lead to low non-radiative recombination losses in the resulting organic photovoltaics, contributing to a certified high power conversion efficiency of 12.6%.
Labrador Sea freshening at 8.5 ka BP caused by Hudson Bay Ice Saddle collapse
Authors: Lochte Annalena Antonia , Repschläger Janne , Kienast Markus , Garbe-Schönberg Dieter , Andersen Nils , Hamann Christian , Schneider Ralph
Published: February 2019

A significant reduction in the Atlantic Meridional Overturning Circulation and rapid northern Hemisphere cooling 8200 years ago have been linked to the final melting of the Laurentide Ice Sheet. Although many studies associated this cold event with the drainage of Lake Agassiz-Ojibway, recent model simulations have shown that the Hudson Bay Ice Saddle collapse would have had much larger effects on the Atlantic Meridional Overturning Circulation than the lake outburst itself. Based on a combination of Mg/Ca and oxygen isotope ratios of benthic foraminifera, this study presents the first direct evidence of a major Labrador shelfwater freshening at 8.5 ka BP, which we associate with the Hudson Bay Ice Saddle collapse. The freshening is preceded by a subsurface warming of the western Labrador Sea, which we link to the strengthening of the West Greenland Current that could concurrently have accelerated the ice saddle collapse in Hudson Bay.
Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites
Authors: Liu Xianzhuang , Guo Xiangyang , Niu Liling , Li Xixia , Sun Fei , Hu Junjie , Wang Xiangming , Shen Kang
Published: February 2019

Endoplasmic reticulum (ER) is characterized by interconnected tubules and sheets. Neuronal ER adopts specific morphology in axons, dendrites and soma. Here we study mechanisms underlying ER morphogenesis in a C. elegans sensory neuron PVD. In PVD soma and dendrite branch points, ER tubules connect to form networks. ER tubules fill primary dendrites but only extend to some but not all dendritic branches. We find that the Atlastin-1 ortholog, atln-1 is required for neuronal ER morphology. In atln-1 mutants with impaired GTPase activity, ER networks in soma and dendrite branch points are reduced and replaced by tubules, and ER tubules retracted from high-order dendritic branches, causing destabilized microtubule in these branches. The abnormal ER morphology likely causes defects in mitochondria fission at dendritic branch points. Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia (HSP) patients show similar ER phenotypes, suggesting that neuronal ER impairment contributes to HSP disease pathogenesis.
Exceptionally active iridium evolved from a pseudo-cubic perovskite for oxygen evolution in acid
Authors: Chen Yubo , Li Haiyan , Wang Jingxian , Du Yonghua , Xi Shibo , Sun Yuanmiao , Sherburne Matthew , Ager Joel W. , Fisher Adrian C. , Xu Zhichuan J.
Published: February 2019

Exploring robust catalysts for water oxidation in acidic electrolyte is challenging due to the limited material choice. Iridium (Ir) is the only active element with a high resistance to the acid corrosion during water electrolysis. However, Ir is rare, and its large-scale application could only be possible if the intrinsic activity of Ir could be greatly enhanced. Here, a pseudo-cubic SrCo0.9Ir0.1O3-δ perovskite, containing corner-shared IrO6 octahedrons, is designed. The Ir in the SrCo0.9Ir0.1O3-δ catalyst shows an extremely high intrinsic activity as reflected from its high turnover frequency, which is more than two orders of magnitude higher than that of IrO2. During the electrochemical cycling, a surface reconstruction, with Sr and Co leaching, over SrCo0.9Ir0.1O3-δ occurs. Such reconstructed surface region, likely contains a high amount of structural domains with corner-shared and under-coordinated IrOx octahedrons, is responsible for the observed high activity.
Publisher Correction: Early preclinical detection of prions in the skin of prion-infected animals
Authors: Wang Zerui , Manca Matteo , Foutz Aaron , Camacho Manuel V. , Raymond Gregory J. , Race Brent , Orru Christina D. , Yuan Jue , Shen Pingping , Li Baiya , Lang Yue , Dang Johnny , Adornato Alise , Williams Katie , Maurer Nicholas R. , Gambetti Pierluigi , Xu Bin , Surewicz Witold , Petersen Robert B. , Dong Xiaoping , Appleby Brian S. , Caughey Byron , Cui Li , Kong Qingzhong , Zou Wen-Quan
Published: February 2019

The original version of this Article contained errors in the author affiliations. Affiliation 2 incorrectly read ‘Department of Neurology, The First Hospital of Jilin University, Changchun 130021 Jilin Province, China.’Affiliation 5 incorrectly read ‘Department of Otolaryngology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061 Shanxi Province, China’Affiliation 9 incorrectly read ‘State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.’This has now been corrected in both the PDF and HTML versions of the Article.
Local-environment dependence of stacking fault energies in concentrated solid-solution alloys
Authors: Zhao Shijun , Osetsky Yuri , Stocks G. Malcolm , Zhang Yanwen
Published: February 2019

Concentrated solid-solution alloys (CSAs) based on 3d transition metals have demonstrated extraordinary mechanical properties and radiation resistance associated with their low stacking fault energies (SFEs). Owing to the intrinsic disorder, SFEs in CSAs exhibit distributions depending on local atomic configurations. In this work, the distribution of SFEs in equiatomic CSAs of NiCo, NiFe, and NiCoCr are investigated based on empirical potential and first-principles calculations. We show that the calculated distribution of SFEs in chemically disordered CSAs depends on the stacking fault area using empirical potential calculations. Based on electronic structure calculations, we find that local variations of SFEs in CSAs correlate with the charge density redistribution in the stacking fault region. We further propose a bond breaking and forming model to understand and predict the SFEs in CSAs based on the local structure alone. It is shown that the perturbation induced by a stacking fault is localized in the first-nearest planes for NiCo, but extends up to the third nearest planes for NiFe and NiCoCr because of partially filled d electrons in Fe and Cr.
Diffuse splenic FDG uptake is predictive of clinical outcomes in patients with rectal cancer
Authors: Kim Sang Yoon , Moon Chang Mo , Yoon Hai-Jeon , Kim Bom Sahn , Lim Ji Young , Kim Tae Oh , Choe A. Reum , Tae Chung Hyun , Kim Seong-Eun , Jung Hye-Kyung , Shim Ki-Nam , Jung Sung-Ae
Published: February 2019

This study aimed to investigate the correlations between diffuse splenic Fluorine-18-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT) and inflammatory markers and to evaluate the prognostic significance of splenic FDG uptake in rectal cancer patients who underwent curative surgery. We retrospectively analyzed the data from 161 patients who underwent splenic FDG PET/CT staging and subsequent curative surgical resection of rectal cancer between July 2006 and September 2014. The spleen-to-liver uptake ratio (S/L ratio) was calculated by dividing the spleen SUVmean by liver SUVmean. We found significant positive correlations between the S/L ratio and neutrophil-to-lymphocyte ratio (P = 0.013) and platelet-to-lymphocyte ratio (P = 0.007). In a Kaplan–Meier analysis, patients with S/L ratio ≤0.815 had a significantly higher recurrence-free survival rate than those with S/L ratio >0.815 (P = 0.028). Also, patients with S/L ratio ≤0.731 had a significantly higher overall survival rate than those with S/L ratio >0.731 (P = 0.036). In multivariate analysis, higher S/L ratio, as well as male, poor differentiation, higher TNM stage, perineural invasion, and larger tumor size, was independently predictive of cancer recurrence (>0.815 vs ≤0.815, hazard ratio [HR]: 2.04, P = 0.046). With regard to OS, S/L ratio was also an independent prognostic factor for death during follow-up (>0.731 vs ≤0.731, HR: 3.81, P = 0.017). Our results show significant correlations between S/L ratio on PET/CT and systemic inflammatory markers. Further, S/L ratio was an independent prognostic factor for predicting recurrence and death in patient with rectal cancer after curative surgery.
Autophagy induction and PDGFR-β knockdown by siRNA-encapsulated nanoparticles reduce chlamydia trachomatis infection
Authors: Yang Sidi , Traore Yannick , Jimenez Celine , Ho Emmanuel A.
Published: February 2019

C. trachomatis is the most common sexually transmitted bacterial infection in the world. Although the infection can be easily controlled by the use of antibiotics, several reports of clinical isolates that are resistant to antibiotics have prompted us to search for alternative strategies to manage this disease. In this paper, we developed a nanoparticle formulation (PDGFR-β siRNA-PEI-PLGA-PEG NP) that can simultaneously induce autophagy in human cells and knock down PDGFR-β gene expression, an important surface binding protein for C. trachomatis, as a strategy to reduce vaginal infection of C. trachomatis. PDGFR-β siRNA-PEI-PLGA-PEG NP significantly induced autophagy in human vaginal epithelial cells (VK2/E6E7) 48 hr post treatment by improving autophagic degradation activity without causing inflammation, apoptosis or any decrease in cell viability. Beclin-1, VPS34 (markers for initiation stage of autophagy), UVRAG, TECPR-1 (markers for degradation stage of autophagy) were found to be significantly upregulated after treatment with PDGFR-β siRNA-PEI-PLGA-PEG NP. Furthermore, PDGFR-β siRNA-PEI-PLGA-PEG NP decreased PDGFR-β mRNA expression by 50% and protein expression by 43% in VK2/E6E7 cells 48 hr post treatment. Treatment of cells with PDGFR-β siRNA-PEI-PLGA-PEG NP significantly decreased the intracellular C. trachomatis and extracellular release of C. trachomatis by approximately 65% and 67%, respectively, in vitro through augmenting autophagic degradation pathways and reducing bacterial binding simultaneously.
Distributed Acoustic Sensing Using Dark Fiber for Near-Surface Characterization and Broadband Seismic Event Detection
Authors: Ajo-Franklin Jonathan B. , Dou Shan , Lindsey Nathaniel J. , Monga Inder , Tracy Chris , Robertson Michelle , Rodriguez Tribaldos Veronica , Ulrich Craig , Freifeld Barry , Daley Thomas , Li Xiaoye
Published: February 2019

We present one of the first case studies demonstrating the use of distributed acoustic sensing deployed on regional unlit fiber-optic telecommunication infrastructure (dark fiber) for broadband seismic monitoring of both near-surface soil properties and earthquake seismology. We recorded 7 months of passive seismic data on a 27 km section of dark fiber stretching from West Sacramento, CA to Woodland, CA, densely sampled at 2 m spacing. This dataset was processed to extract surface wave velocity information using ambient noise interferometry techniques; the resulting VS profiles were used to map both shallow structural profiles and groundwater depth, thus demonstrating that basin-scale variations in hydrological state could be resolved using this technique. The same array was utilized for detection of regional and teleseismic earthquakes and evaluated for long period response using records from the M8.1 Chiapas, Mexico 2017, Sep 8th event. The combination of these two sets of observations conclusively demonstrates that regionally extensive fiber-optic networks can effectively be utilized for a host of geoscience observation tasks at a combination of scale and resolution previously inaccessible.