bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal and daily activity patterns by Eleonora’s FalconFalco eleonoraebased on GPS telemetry: a contribution to the species’ movement ecology at its breeding grounds
Authors: KASSARA C. , EVANGELIDIS A. , TSIOPELAS N. , BARBOUTIS C. , GIOKAS S.
Published: February 2021

Eleonora’s FalconFalco eleonoraeis a migratory raptor, well-known for its delayed breeding period. Owing to its great mobility, current information on its distribution pattern during the pre-breeding period is rather sporadic, mainly based on field observations and only one telemetry study. Likewise, the species’ ranging activity during the breeding period has not been thoroughly investigated due to methodological limitations of the approaches implemented in previous studies, again amounting to only two telemetry studies in recent years. In this study we aimed to provide a comprehensive overview of the species’ ranging activity at its breeding grounds based on telemetry. Utilizing GPS data from six adult females originating from the core of the species’ breeding range we explored broad- and fine-scale activity patterns while at their breeding grounds. Our results indicated that during the pre-breeding period the falcons visited high biodiversity areas lying hundreds of kilometres away from their colonies, exhibiting site-fidelity, as shown for falcons from other breeding colonies in the past. During the breeding period the falcons roamed at an average distance of 17 km from their nesting sites, but their ranging activity could be observed up to 130 km. In accordance with the species’ breeding biology, the falcons tended to perform longer trips as the nestlings became more independent. The temporal pattern of ranging activity fitted well with the diurnal variability of the autumn migration flux. Furthermore, nest attendance tended to decrease in windy conditions and as the season progressed, and to increase when southerly winds blew. Despite the low number of tracked falcons, our study set a reference basis for future studies highlighting the importance of specific (protected) areas during the pre-breeding period and providing the first assessment of the movement ecology of the species during the pre-breeding and breeding period in Greece.
Chromosomal microarray detects genetic risks of neurodevelopmental disorders in newborns with congenital heart disease
Authors: Gill Kamalvir , Sasaki Jun , Jayakar Parul , Sosa Lisa , Welch Elizabeth
Published: February 2021

Objective:

To compare the genetic testing results of neonates with CHD by chromosomal microarray to karyotyping and fluorescence in situ hybridisation analysis.

Methods:

This was a single-centre retrospective comparative study of patients with CHD and available genetic testing results admitted to the cardiac ICU between January, 2004 and December, 2017. Patients from 2004 to 2010 were tested by karyotyping and fluorescence in situ hybridisation analysis, while patients from 2012 to 2017 were analysed by chromosomal microarray.

Results:

Eight-hundred and forty-nine neonates with CHD underwent genetic testing, 482 by karyotyping and fluorescence in situ hybridization, and 367 by chromosomal microarray. In the karyotyping and fluorescence in situ hybridisation analysis group, 86/482 (17.8%) had genetic abnormalities detected, while in the chromosomal microarray group, 135/367 (36.8%) had genetic abnormalities detected (p < 0.00001). Of patients with abnormal chromosomal microarray results, 41/135 (30.4%) had genetic abnormality associated with neurodevelopmental disorders that were exclusively identified by chromosomal microarray. Conotruncal abnormalities were the most common diagnosis in both groups, with karyotyping and fluorescence in situ hybridisation analysis detecting genetic abnormalities in 26/160 (16.3%) patients and chromosomal microarray detecting abnormalities in 41/135 (30.4%) patients (p = 0.004). In patients with d-transposition of the great arteries, 0/68 (0%) were found to have genetic abnormalities by karyotyping and fluorescence in situ hybridisation compared to 7/54 (13.0%) by chromosomal microarray.

Conclusions:

Chromosomal microarray identified patients with CHD at genetic risk of neurodevelopmental disorders, allowing earlier intervention with multidisciplinary care and more accurate pre-surgical prognostic counselling.
Individualism and attitudes towards reporting corruption: evidence from post-communist economies
Authors: Amini Chiara , Douarin Elodie , Hinks Tim
Published: February 2021

Individualistic values are often presented as promoting economic development; however, their links to relevant behaviour and preferences at the micro-level remain under-explored. Here we investigate the relationship between individualistic values and personal attitudes towards reporting corruption. Unlike much of the previous research which focuses on attitudes towards corruption, we analyse the micro-level mechanisms relating to one's willingness to escape the status quo and act against corruption. We also focus on a region associated with persistently high levels of perceived corruption. Our findings indicate that individualism is associated with a greater likelihood to act against corruption. The effect estimated is small but highly significant and robust to changes in estimators and specifications. We also find evidence that institutional trust and individualism strengthen each other to generate greater willingness to report corruption.
Experience vs. knowledge in comparative law: critical notes on Pierre Legrand's ‘sensitive epistemology’
Authors: Siliquini-Cinelli Luca
Published: February 2021

This paper expounds some critical reflections on Pierre Legrand's recent account of James Gordley's and James Whitman's comparative methodologies. Pushing his unconventional writing style to the limits and labelling Gordley's ‘positivist’ and Whitman's ‘cultural’ comparative law, Legrand's piece appears to be taking the first step towards a new, more sensitive phase for the comparative study of law and legal cultures. The paper argues that, contrary to what might be first thought, Legrand's ‘sensitive epistemology’ cannot act as a gateway to cultural otherness. This is because it is wholly in line with the constructivist objectification of life that characterises the study and practice of law both within and outside the comparative-law dimension.
What is the Role of Technology in Recruitment and Selection?
Authors: Nikolaou Ioannis
Published: February 2021

We explore a number of new developments in the field of employee recruitment and selection with a focus on recent technological developments. We discuss examples of technological developments across the four stages of the recruitment and selection process. In the attraction stage we discuss how on-line/internet recruitment and especially social networking websites have changed dramatically the focus of attracting candidates effectively. In the next stage of screening, we discuss how cybervetting and applicant tracking systems offer opportunities but also threats for recruiters and candidates. In the third stage of employee selection, we focus especially on two new selection methods; the asynchronous/digital interview and gamification/games-based assessment, along with the critical role and impact applicant reactions have on the selection process. Finally, we briefly discuss the main technological developments in on-boarding and socialization, and we conclude with a few suggestions for future research in this field.
Spontane Koronararteriendissektion
Authors: Würdinger Michael , Templin-Ghadri Jelena-Rima
Published: February 2021

Zusammenfassung. Die spontane Koronararteriendissektion (SCAD) ist eine zunehmend diagnostizierte Ätiologie des akuten Koronarsyndroms und eine wichtige Ursache des Myokardinfarktes bei Frauen. Sie wurde zum ersten Mal bereits 1931 beschrieben und ist definiert als ein spontaner Einriss einer Koronararterie, welcher weder die Folge einer Atherosklerose, eines Traumas oder einer Intervention ist. Die spontane Koronararteriendissektion betrifft vor allem jüngere Frauen und wird inzwischen als Ursache von 4 % aller und 25 % der akuten Koronarsyndrome bei Frauen unter 50 Jahren angenommen. Sie ist die häufigste Ursache des Myokardinfarktes in der Schwangerschaft. Risikofaktoren sind weibliches Geschlecht, Schwangerschaft, emotionaler und physischer Stress sowie einige Bindegewebserkrankungen, Arteriopathien und chronische Entzündungszustände. Diagnostischer Goldstandard ist die Koronarangiographie, da die klinische Präsentation identisch zu der des atherosklerotischen akuten Koronarsyndroms ist. Dennoch ist die Diagnose oft schwierig. Die Behandlung besteht im Gegensatz zum atherosklerotischen Myokardinfarkt meist aus konservativen Massnahmen, da interventionelle Therapien häufig komplikationsreich verlaufen oder erfolglos sind. Die Prognose ist gekennzeichnet durch ein häufiges Auftreten von Rezidiven, insbesondere in den ersten Jahren nach dem Ereignis.
Community-Augmented Meta-Analyses (CAMAs) in Psychology
Authors: Burgard Tanja , Bošnjak Michael , Studtrucker Robert
Published: February 2021

Abstract. The limits of static snapshot meta-analyses and the relevance of reproducibility and data accessibility for cumulative meta-analytic research are outlined. A publication format to meet these requirements is presented: Community-augmented meta-analyses (CAMA). We give an overview of existing systems implementing this approach and compare these in terms of scope, technical implementation, data collection and augmentation, data curation, tools available for analysis, and methodological flexibility.
Gender Differences in the Intention to Start a Business
Authors: Steinmetz Holger , Isidor Rodrigo , Bauer Corinna
Published: February 2021

Abstract. The present study updates and extends the meta-analysis by Haus et al. (2013) who applied the theory of planned behavior (TPB) to analyze gender differences in the motivation to start a business. We extend this meta-analysis by investigating the moderating role of the societal context in which the motivation to start a business emerges and proceeds. The results, based on 119 studies analyzing 129 samples with 266,958 individuals from 36 countries, show smaller gender differences than the original study and reveal little differences across cultural regions in the effects of the tested model. A meta-regression analyzing the role of specific cultural dimensions and economic factors on gender-related correlations reveals significant effects only of gender egalitarianism and in the opposite direction as expected. In summary, the study contributes to the discussion on gender differences, the importance of study replications and updates of meta-analyses, and the generalizability of theories across cultural contexts.
Models of Maghematization: Observational Evidence in Support of a Magnetic Unstable Zone
Authors: Ge Kunpeng , Williams Wyn , Nagy Lesleis , Tauxe Lisa
Published: February 2021

Recent micromagnetic simulations predict that particles have an abnormal region of low magnetic stability for grain sizes near the domain state transitions from single domain to single vortex. The implications of this zone are not yet fully understood, but if the size range of this window changes as a function of applied field and temperature then it is likely to contribute to observational uncertainties in paleomagnetic recordings. The narrow size range of this zone means that its effects are difficult to identify when integrated across the much wider distribution of grain sizes present in a sample. Here we report a method of examining the unstable region using low temperature oxidation of magnetite. The rock magnetic experiments on partially oxidized particles with a median diameter close to the unstable zone are reinterpreted using micromagnetic simulations of a multilayer core‐shell structure. The predicted magnetic properties exhibit significantly improved agreement with experimental data than that of the previously reported single core‐shell coupled geometry. The observed changes in remanence and coercivity are associated with predicted domain structure changes near a proposed magnetic unstable zone (∼80–∼120 nm), and so provide the first experimental indication of the existence of such a region. We also demonstrate that magnetic remanence in particles with grain sizes outside this size range were stable to maghemitization. The research provides ideas for the experimental study of the “magnetic unstable zone” and is significant to the correct interpretation of magnetic recordings. Finally, the partially oxidized magnetite particles are able to record paleomagnetic signals.
Compactive Deformation of Sandstone Under Crustal Pressure and Temperature Conditions
Authors: Jefferd Mark , Brantut Nicolas , Meredith Philip G. , Mitchell Thomas M. , Plümper Oliver
Published: February 2021

The transition from macroscopically brittle to macroscopically ductile deformation in porous sandstones is known to be pressure dependent, with compactive, ductile behavior occurring only once significant effective pressures have been reached. Within the crust, such effective pressures are associated with burial depths in the range 0.5–6 km, where the temperature is likely 35°C–200°C. To test the importance of such elevated temperature on the strength and deformability of sandstone, a series of constant strain rate, triaxial deformation experiments were performed on three different water saturated sandstones at either ambient temperature or 150°C. For each sandstone, an effective pressure range was used which spanned both the brittle and ductile deformation regimes, up to a maximum of 120 MPa. In the brittle regime, we observed a temperature‐dependent lowering of the yield stress of between 8% and 17%. Within the ductile regime, we observed an even greater reduction in the yield stress of between 9% and 37%. A further notable observation is that the transition from dilatant, brittle behavior to compactive, ductile behavior tends to occur at a lower effective pressure at elevated temperature. The weakening observed at elevated temperature can be explained by a reduction in fracture toughness, which is shown mathematically to cause greater weakening in the ductile regime than in the brittle regime. The apparent reduction in fracture toughness at elevated temperature is potentially driven by a combination of a reduction in surface energy and, to a minor extent, an increase in subcritical crack growth rate.
The Thermal Diffusivity of Sedimentary Rocks: Empirical Validation of a Physically Based α − φ Relation
Authors: Fuchs Sven , Förster Hans‐Jürgen , Norden Ben , Balling Niels , Miele Roberto , Heckenbach Esther , Förster Andrea
Published: February 2021

Understanding the thermal behavior of nonsteady state subsurface geosystems, when temperature changes over time, requires knowledge on the speed of heat propagation and, thus, of the rock's thermal diffusivity as essential thermo‐physical parameter. Mixing models are commonly used to describe thermo‐physical properties of polymineralic rocks. A thermal diffusivity‐porosity relation is known from literature that incorporates common mixing models into the heat equation and properly works for unconsolidated, clastic clayey, and sandy marine sediments of high porosity (35%–80%). We have proofed the relation's applicability for consolidated, isotropic sedimentary rocks of low porosity (<35%). The performance of this approach was evaluated for consolidated quartz‐dominated sandstones containing air, water, and heptane as pore‐ and/or fracture‐filling medium. For these rocks, the reliability of the relation was confirmed for the entire range of porosity and all three media, with water‐saturated rocks displaying an almost perfect fit between measured and modeled thermal diffusivity. Additional measurements conducted on a larger suite of low‐porous siliciclastic and carbonate rocks imply that it is also suitable to acceptably good to infer the thermal diffusivity of mineralogically more diverse sedimentary rocks. In contrast to other common mixing models, this relation is appropriate to convert thermal‐diffusivity data obtained on air‐saturated samples into such reflecting water‐saturated conditions. This is of particular importance for handling data acquired from methods limited to the measurement of dry samples, for example, laser‐flash analysis. In conclusion, the applied relation is suited to model thermal‐diffusivity data of isotropic sedimentary rocks of different porosity and independent of the pore fluid.
Influence of Hydraulic Connectivity on Carbon Burial Efficiency in Mackenzie Delta Lake Sediments
Authors: Lattaud J. , Bröder L. , Haghipour N. , Rickli J. , Giosan L. , Eglinton T. I.
Published: February 2021

The Arctic is undergoing accelerated changes in response to ongoing modifications to the climate system, and there is a need for local to regional scale records of past climate variability in order to put these changes into context. The Mackenzie Delta region in northern Canada is populated by numerous small shallow lakes. They are classified as no‐, low‐, and high‐closure (NC, LC, and HC, respectively) lakes, reflecting varying degrees of connection to the river main stem, and have different sedimentation characteristics. This study examines sedimentological (mineral surface area, grain size), carbon isotopic (bulk and molecular‐level) and inorganic isotopic (neodymium) characteristics of sediment cores from three lakes representing each class. We find that HC lake sediments exhibit strikingly different properties from the other lake sediments. Specifically, they are characterized by higher organic carbon loadings per unit mineral surface area and with relatively minor influence from allochthonous, petrogenic (rock‐derived) organic carbon. In contrast, LC and NC lakes have the potential to record basin‐scale climatic changes at a high resolution by virtue of enhanced detrital sedimentation. Overall the delta lakes have the capacity to bury about 2 MtC year−1, with little changes in the last 200 years. However, in the (near) future, an increased number of high closure lakes might change the carbon burial efficiency of the Mackenzie Delta as they seem to retain less carbon than NC and LC lakes.
Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia
Authors: Wei Andrew H. , Ribera Josep-Maria , Larson Richard A. , Ritchie David , Ghobadi Armin , Chen Yuqi , Anderson Abraham , Dos Santos Cedric E. , Franklin Janet , Kantarjian Hagop
Published: February 2021

This study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE® therapy, for 4 weeks (9 μg/day cycle 1 week 1, 28 μg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood samples were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival; lower tumor burden was prognostic for hematologic remission; and a higher percentage of CD3+ T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45+ CD3+ CD8+ T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.
Menin is necessary for long term maintenance of meningioma-1 driven leukemia
Authors: Libbrecht Clara , Xie Hongbo M. , Kingsley Molly C. , Haladyna Jessica N. , Riedel Simone S. , Alikarami Fatemeh , Lenard Alexandra , McGeehan Gerard M. , Ernst Patricia , Bernt Kathrin M.
Published: February 2021

Translocations of Meningioma-1 (MN1) occur in a subset of acute myeloid leukemias (AML) and result in high expression of MN1, either as a full-length protein, or as a fusion protein that includes most of the N-terminus of MN1. High levels of MN1 correlate with poor prognosis. When overexpressed in murine hematopoietic progenitors, MN1 causes an aggressive AML characterized by an aberrant myeloid precursor-like gene expression program that shares features of KMT2A-rearranged (KMT2A-r) leukemia, including high levels of Hoxa and Meis1 gene expression. Compounds that target a critical KMT2A–Menin interaction have proven effective in KMT2A-r leukemia. Here, we demonstrate that Menin (Men1) is also critical for the self-renewal of MN1-driven AML through the maintenance of a distinct gene expression program. Genetic inactivation of Men1 led to a decrease in the number of functional leukemia-initiating cells. Pharmacologic inhibition of the KMT2A–Menin interaction decreased colony-forming activity, induced differentiation programs in MN1-driven murine leukemia and decreased leukemic burden in a human AML xenograft carrying an MN1-ETV6 translocation. Collectively, these results nominate Menin inhibition as a promising therapeutic strategy in MN1-driven leukemia.
The placental lipidome of maternal antenatal depression predicts socio-emotional problems in the offspring
Authors: Wong Gerard , Weir Jacquelyn M. , Mishra Priti , Huynh Kevin , Nijagal Brunda , Gupta Varsha , Broekman Birit F. P. , Chong Mary Foong-Fong , Chan Shiao-Yng , Tan Kok Hian , Tull Dedreia , McConville Malcolm , Calder Philip C. , Godfrey Keith M. , Chong Yap Seng , Gluckman Peter D. , Meaney Michael J. , Meikle Peter J. , Karnani Neerja
Published: February 2021

While maternal mental health strongly influences neurodevelopment and health in the offspring, little is known about the determinants of inter-individual variation in the mental health of mothers. Likewise, the in utero biological pathways by which variation in maternal mental health affects offspring development remain to be defined. Previous studies implicate lipids, consistent with a known influence on cognitive and emotional function, but the relevance for maternal mental health and offspring neurodevelopment is unclear. This study characterizes the placental and circulatory lipids in antenatal depression, as well as socio-emotional outcomes in the offspring. Targeted liquid chromatography-mass spectrometry covering 470 lipid species was performed on placenta from 186 women with low (n = 70) or high (n = 116) levels of antenatal depressive symptoms assessed using the Edinburgh Postnatal Depression Scale at 26 weeks’ gestation. Child socio-emotional outcomes were assessed from the Child Behavior Check List (CBCL) at 48 months. Seventeen placental lipid species showed an inverse association with antenatal EPDS scores. Specifically, lower levels of phospholipids containing LC-PUFAs: omega-3 docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-6 arachidonic acid (AA) were significantly associated with depressive symptoms. Additional measurement of LC-PUFA in antenatal plasma samples at mid-gestation confirmed the reduced circulation of these specific fatty acids in mothers. Reduced concentration of the placental phospholipids also predicted poorer socio-emotional outcomes in the offspring. This study provides new insights into the role of the materno-fetal lipid cross-talk as a mechanism linking maternal mental health to that of the offspring. These findings show the potential utility of nutritional approaches among pregnant women with depressive symptoms to reduce offspring risk for later socio-emotional problems.
Disrupted-in-schizophrenia 1 enhances the quality of circadian rhythm by stabilizing BMAL1
Authors: Lee Su Been , Park Jihyun , Kwak Yongdo , Park Young-Un , Nhung Truong Thi My , Suh Bo Kyoung , Woo Youngsik , Suh Yeongjun , Cho Eunbyul , Cho Sehyung , Park Sang Ki
Published: February 2021

Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders. DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the circadian rhythm has not been determined yet. In this work, we revealed that Disc1 expression exhibits daily oscillating pattern and is regulated by binding of circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 deficiency increases the ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3β, which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally, Disc1-LI (Disc1 knockout) mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to the core circadian system by regulating BMAL1 stability.
Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior
Authors: Oguro-Ando Asami , Bamford Rosemary A. , Sital Wiedjai , Sprengers Jan J. , Zuko Amila , Matser Jolien M. , Oppelaar Hugo , Sarabdjitsingh Angela , Joëls Marian , Burbach J. Peter. H. , Kas Martien J.
Published: February 2021

Neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons.
DNA methylation differences associated with social anxiety disorder and early life adversity
Authors: Wiegand Ariane , Kreifelts Benjamin , Munk Matthias H. J. , Geiselhart Nadja , Ramadori Katia E. , MacIsaac Julia L. , Fallgatter Andreas J. , Kobor Michael S. , Nieratschker Vanessa
Published: February 2021

Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genesSLC43A2andTNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within theSLC17A3promoter region and theSIAH3gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions withinC2CD2LandMRPL28showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.
The psychiatric phenotypes of 1q21 distal deletion and duplication
Authors: Linden Stefanie C. , Watson Cameron J. , Smith Jacqueline , Chawner Samuel J. R. A. , Lancaster Thomas M. , Evans Ffion , Williams Nigel , Skuse David , Raymond F. Lucy , Hall Jeremy , Owen Michael J. , Linden David E. J. , Green-Snyder LeeAnne , Chung Wendy K. , Maillard Anne M. , Jacquemont Sébastien , van den Bree Marianne B. M.
Published: February 2021

Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4–40.1)], 55% for duplication carriers [8.3 (1.4–55.5)]) and anxiety disorders (24% [1.8 (0.4–8.4)] and 55% [10.0 (1.9–71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
The neuroprogressive nature of major depressive disorder: evidence from an intrinsic connectome analysis
Authors: Liu Jin , Fan Yiming , Ling-Li Zeng  , Liu Bangshan , Ju Yumeng , Wang Mi , Dong Qiangli , Lu Xiaowen , Sun Jinrong , Zhang Liang , Guo Hua , Futao Zhao  , Weihui Li  , Zhang Li , Li Zexuan , Liao Mei , Zhang Yan , Hu Dewen , Li Lingjiang
Published: February 2021

Major depressive disorder (MDD) is a prevailing chronic mental disorder with lifetime recurring episodes. Recurrent depression (RD) has been reported to be associated with greater severity of depression, higher relapse rate and prominent functioning impairments than first-episode depression (FED), suggesting the progressive nature of depression. However, there is still little evidence regarding brain functional connectome. In this study, 95 medication-free MDD patients (35 with FED and 60 with RD) and 111 matched healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (fMRI) scanning. After six months of treatment with paroxetine, 56 patients achieved clinical remission and finished their second scan. Network-based statistics analysis was used to explore the changes in functional connectivity. The results revealed that, compared with HCs, patients with FED exhibited hypoconnectivity in the somatomotor, default mode and dorsal attention networks, and RD exhibited hyperconnectivity in the somatomotor, salience, executive control, default mode and dorsal attention networks, as well as within and between salience and executive control networks. Moreover, the disrupted components in patients with current MDD did not change significantly when the patients achieved remission after treatment, and sub-hyperconnectivity and sub-hypoconnectivity were still found in those with remitted RD. Additionally, the hypoconnectivity in FED and hyperconnectivity in RD were associated with the number of episodes and total illness duration. This study provides initial evidence supporting that impairment of intrinsic functional connectivity across the course of depression is a progressive process.
Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study
Authors: Can Adem T. , Hermens Daniel F. , Dutton Megan , Gallay Cyrana C. , Jensen Emma , Jones Monique , Scherman Jennifer , Beaudequin Denise A. , Yang Cian , Schwenn Paul E. , Lagopoulos Jim
Published: February 2021

Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22–72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.
Multi-omic and multi-species meta-analyses of nicotine consumption
Authors: Palmer Rohan H. C. , Benca-Bachman Chelsie E. , Huggett Spencer B. , Bubier Jason A. , McGeary John E. , Ramgiri Nikhil , Srijeyanthan Jenani , Yang Jingjing , Visscher Peter M. , Yang Jian , Knopik Valerie S. , Chesler Elissa J.
Published: February 2021

Cross-species translational approaches to human genomic analyses are lacking. The present study uses an integrative framework to investigate how genes associated with nicotine use in model organisms contribute to the genetic architecture of human tobacco consumption. First, we created a model organism geneset by collecting results from five animal models of nicotine exposure (RNA expression changes in brain) and then tested the relevance of these genes and flanking genetic variation using genetic data from human cigarettes per day (UK BioBankN = 123,844; all European Ancestry). We tested three hypotheses: (1) DNA variation in, or around, the ‘model organism geneset’ will contribute to the heritability to human tobacco consumption, (2) that the model organism genes will be enriched for genes associated with human tobacco consumption, and (3) that a polygenic score based off our model organism geneset will predict tobacco consumption in the AddHealth sample (N = 1667; all European Ancestry). Our results suggested that: (1) model organism genes accounted for ~5–36% of the observed SNP-heritability in human tobacco consumption (enrichment: 1.60–31.45), (2) model organism genes, but not negative control genes, were enriched for the gene-based associations (MAGMA, H-MAGMA, SMultiXcan) for human cigarettes per day, and (3) polygenic scores based on our model organism geneset predicted cigarettes per day in an independent sample. Altogether, these findings highlight the advantages of using multiple species evidence to isolate genetic factors to better understand the etiological complexity of tobacco and other nicotine consumption.
Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice
Authors: Zhang Freddy , Rein Benjamin , Zhong Ping , Shwani Treefa , Conrow-Graham Megan , Wang Zi-Jun , Yan Zhen
Published: February 2021

Autism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of theSHANK3gene is causally linked to ASD, so adult (3–5 months old)Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adultShank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adultShank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.
The association of clinical correlates, metabolic parameters, and thyroid hormones with suicide attempts in first-episode and drug-naïve patients with major depressive disorder comorbid with anxiety: a large-scale cross-sectional study
Authors: Zhou Yongjie , Ren Wenchao , Sun Qianqian , Yu Katherine M. , Lang Xiaoe , Li Zezhi , Zhang Xiang Yang
Published: February 2021

The associated factors of suicide attempts in patients with major depressive disorder (MDD) comorbid with anxiety remains unclear. To the best of our knowledge, this is the first study with a large sample size that examines the risk factors of suicide attempts in first-episode drug-naïve (FEND) MDD patients comorbid with anxiety and includes clinical correlates, metabolic parameters, and thyroid hormone levels. A total of 1718 FEDN MDD patients were enrolled. The Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) were used to assess the symptoms of patients. Metabolic parameters and thyroid hormone levels were measured. The prevalence of suicide attempts in MDD patients comorbid anxiety symptoms was 24.28%, which was 9.51 times higher than that in MDD patients without anxiety symptoms (3.25%). Compared to non-attempters, MDD patients with anxiety symptoms who attempted suicide scored higher on HAMD and HAMA, and had higher systolic blood pressure, higher levels of thyroid stimulating hormone (TSH), and thyroid peroxidases antibody (TPOAb), which were also correlated with suicide attempts in MDD patients comorbid anxiety symptoms. The combination of HAMA score, HAMD score, and TSH could differentiate suicide attempters from non-suicide attempters. Further, the age of onset, illness duration, BMI, TSH, and TPOAb were associated with the times of suicide attempts in MDD patients comorbid anxiety symptoms. Our results demonstrate high prevalence of suicide attempts in MDD patients comorbid anxiety symptoms. Several clinical correlates, metabolic parameters, and thyroid hormones function contribute to the suicide attempts in MDD patients comorbid anxiety symptoms.
Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts
Authors: Pistis Giorgio , Milaneschi Yuri , Vandeleur Caroline L. , Lasserre Aurélie M. , Penninx Brenda W.J.H. , Lamers Femke , Boomsma Dorret I. , Hottenga Jouke-Jan , Marques-Vidal Pedro , Vollenweider Peter , Waeber Gérard , Aubry Jean-Michel , Preisig Martin , Kutalik Zoltán
Published: February 2021

Studies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23,p = 0.004), 0.77 (SE = 0.37,p = 0.036), and 1.11 (SE = 0.39,p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings.
In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing
Authors: Kou Juan , Lan Chunmei , Zhang Yingying , Wang Qianqian , Zhou Feng , Zhao Zhongbo , Montag Christian , Yao Shuxia , Becker Benjamin , Kendrick Keith M.
Published: February 2021

Intranasal oxytocin exerts wide-ranging effects on socioemotional behavior and is proposed as a potential therapeutic intervention in psychiatric disorders. However, following intranasal administration, oxytocin could penetrate directly into the brain or influence its activity via increased peripheral concentrations crossing the blood–brain barrier or influencing vagal projections. In the current randomized, placebo-controlled, pharmaco-imaging clinical trial we investigated effects of 24IU oral (lingual) oxytocin spray, restricting it to peripherally mediated blood-borne and vagal effects, on responses to face emotions in 80 male subjects and compared them with 138 subjects treated intranasally with 24IU. Oral, but not intranasal oxytocin administration increased both arousal ratings for faces and associated brain reward responses, the latter being partially mediated by blood concentration changes. Furthermore, while oral oxytocin increased amygdala and arousal responses to face emotions, after intranasal administration they were decreased. Thus, oxytocin can produce markedly contrasting motivational effects in relation to socioemotional cues when it influences brain function via different routes. These findings have important implications for future therapeutic use since administering oxytocin orally may be both easier and have potentially stronger beneficial effects by enhancing responses to emotional cues and increasing their associated reward.
Inhibition of long non-coding RNA XIST upregulates microRNA-149-3p to repress ovarian cancer cell progression
Authors: Jiang Rong , Zhang Hongyu , Zhou Jinhua , Wang Juan , Xu Yuejuan , Zhang He , Gu Yanzheng , Fu Fengqing , Shen Yu , Zhang Guangbo , Feng Lanlan , Zhang Xueguang , Chen Youguo , Shen Fangrong
Published: February 2021

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in human diseases. We aimed to clarify the role of lncRNA X-inactive specific transcript (XIST)/miR-149-3p/forkhead box P3 (FOXP3) axis in ovarian cancer (OC) cell growth. XIST, miR-149-3p and FOXP3 expression in OC tissues and cell lines was assessed, and the predictive role of XIST in prognosis of OC patients was analyzed. The OC cell lines were screened and accordingly treated with silenced/overexpressed XIST plasmid or miR-149-3p mimic/inhibitor, and then the proliferation, invasion, migration, colony formation ability, apoptosis, and cell cycle distribution of OC cells were measured. Effect of altered XIST and miR-149-3p on tumor growth in vivo was observed. Online website prediction and dual luciferase reporter gene were implemented to detect the targeting relationship of lncRNA XIST, miR-149-3p, and FOXP3. XIST and FOXP3 were upregulated, whereas miR-149-3p was downregulated in OC tissues and cells. High XIST expression indicated a poor prognosis of OC. Inhibition of XIST or elevation of miR-149-3p repressed proliferation, invasion, migration, and colony formation ability, and promoted apoptosis and cell cycle arrest of HO-8910 cells. In SKOV3 cells upon treatment of overexpressed XIST or reduction of miR-149-3p, there exhibited an opposite tendency. Based on online website prediction, dual luciferase reporter gene, and RNA pull-down assays, we found that there was a negative relationship between XIST and miR-149-3p, and miR-149-3p downregulated FOXP3 expression. This study highlights that knockdown of XIST elevates miR-149-3p expression to suppress malignant behaviors of OC cells, thereby inhibiting OC development.