bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression
Authors: Kautzky Alexander , James Gregory M. , Philippe Cecile , Baldinger-Melich Pia , Kraus Christoph , Kranz Georg S. , Vanicek Thomas , Gryglewski Gregor , Hartmann Annette M. , Hahn Andreas , Wadsak Wolfgang , Mitterhauser Markus , Rujescu Dan , Kasper Siegfried , Lanzenberger Rupert 
Published: January 2019

AbstractAlterations of the 5-HT1A receptor and BDNF have consistently been associated with affective disorders. Two functional single nucleotide polymorphisms (SNPs), rs6295 of the serotonin 1A receptor gene (HTR1A) and rs6265 of brain-derived neurotrophic factor gene (BDNF), may impact transcriptional regulation and expression of the 5-HT1A receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT1A receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. Genotyping was performed for rs6265 and rs6295. Subjects showing a genotype with at least three risk alleles (G of rs6295 or A of rs6265) were compared to control genotypes. Cortical surface binding potential (BPND) was computed for 32 cortical regions of interest (ROI). Mixed model was applied to study main and interaction effects of ROI and genotype. ANOVA was used for post hoc analyses. Individuals with the risk genotypes exhibited an increase in 5-HT1A receptor binding by an average of 17% (mean BPND 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BPND and differences could be demonstrated in 10 ROI post hoc. The combination of disadvantageous allelic expression of rs6295 and rs6265 may result in a 5-HT1A receptor profile comparable to affective disorders as increased 5-HT1A receptor binding is a well published phenotype of depression. Thus, epistasis between BDNF and HTR1A may contribute to the multifactorial risk for affective disorders and our results strongly advocate further research on this genetic signature in affective disorders.
Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice
Authors: Schob Claudia , Morellini Fabio , Ohana Ora , Bakota Lidia , Hrynchak Mariya V. , Brandt Roland , Brockmann Marco D. , Cichon Nicole , Hartung Henrike , Hanganu-Opatz Ileana L. , Kraus Vanessa , Scharf Sarah , Herrmans-Borgmeyer Irm , Schweizer Michaela , Kuhl Dietmar , Wöhr Markus , Vörckel Karl J. , Calzada-Wack Julia , Fuchs Helmut , Gailus-Durner Valérie , Hrabě de Angelis Martin , Garner Craig C. , Kreienkamp Hans-Jürgen , Kindler Stefan 
Published: January 2019

AbstractIn humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice. Our study reveals that the loss of SAPAP4 triggers profound behavioural abnormalities, including cognitive deficits combined with impaired vocal communication and social interaction, phenotypes reminiscent of ASD in humans. These behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in synapse morphology, function and plasticity, indicating that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders.
Behavioral training rescues motor deficits in Cyfip1 haploinsufficiency mouse model of autism spectrum disorders
Authors: Bachmann Sven O. , Sledziowska Monika , Cross Ellen , Kalbassi Shireene , Waldron Sophie , Chen Fangli , Ranson Adam , Baudouin Stéphane J. 
Published: January 2019

AbstractDeletions in the 15q11.2 region of the human genome are associated with neurobehavioral deficits, and motor development delay, as well as in some cases, symptoms of autism or schizophrenia. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) is one of the four genes contained within this locus and has been associated with other genetic forms of autism spectrum disorders (ASD). In mice, Cyfip1 haploinsufficiency leads to alteration of dendritic spine morphology and defects in synaptic plasticity, two pathophysiological hallmarks of mouse models of ASD. At the behavioral level, however, Cyfip1 haploinsufficiency leads to minor phenotypes, not directly relevant for 15q11.2 deletion syndrome or ASD. A fundamental question is whether neuronal phenotypes caused by the mutation of Cyfip1 are relevant for the human condition. Here, we describe a synaptic cluster of ASD-associated proteins centered on CYFIP1 and the adhesion protein Neuroligin-3. Cyfip1 haploinsufficiency in mice led to decreased dendritic spine density and stability associated with social behavior and motor learning phenotypes. Behavioral training early in development resulted in alleviating the motor learning deficits caused by Cyfip1 haploinsufficiency. Altogether, these data provide new insight into the neuronal and behavioral phenotypes caused by Cyfip1 mutation and proof-of-concept for the development of a behavioral therapy to treat phenotypes associated with 15q11.2 syndromes and ASD.
Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene
Authors: Patowary Ashok , Won So Yeon , Oh Shin Ji , Nesbitt Ryan R , Archer Marilyn , Nickerson Debbie , Raskind Wendy H. , Bernier Raphael , Lee Ji Eun , Brkanac Zoran 
Published: January 2019

AbstractAutism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. Although next-generation sequencing (NGS) technologies have been successfully applied to gene identification in de novo ASD, the genetic architecture of familial ASD remains largely unexplored. Our approach, which leverages the high specificity and sensitivity of NGS technology, has focused on rare variants in familial autism. We used NGS exome sequencing in 26 families with distantly related affected individuals to identify genes with private gene disrupting and missense variants of interest (VOI). We found that the genes carrying VOIs were enriched for biological processes related to cell projection organization and neuron development, which is consistent with the neurodevelopmental hypothesis of ASD. For a subset of genes carrying VOIs, we then used targeted NGS sequencing and gene-based variant burden case-control analysis to test for association with ASD. Missense variants in one gene, CEP41, associated significantly with ASD (p = 6.185e−05). Homozygous gene-disrupting variants in CEP41 were initially found to be responsible for recessive Joubert syndrome. Using a zebrafish model, we evaluated the mechanism by which the CEP41 variants might contribute to ASD. We found that CEP41 missense variants affect development of the axonal tract, cranial neural crest migration and social behavior phenotype. Our work demonstrates the involvement of CEP41 heterozygous missense variants in ASD and that biological processes involved in cell projection organization and neuron development are enriched in ASD families we have studied.
Dysconnectivity of the medio-dorsal thalamic nucleus in drug-naïve first episode schizophrenia: diagnosis-specific or trans-diagnostic effect?
Authors: Gong Qiyong , Puthusseryppady Vaisakh , Dai Jing , He Manxi , Xu Xin , Shi Yan , Zhou Baiwan , Ai Yuan , Yang Cheng , Zhang Feifei , Lui Su , Mechelli Andrea 
Published: January 2019

AbstractConverging lines of evidence implicate the thalamocortical network in schizophrenia. In particular, the onset of the illness is associated with aberrant functional integration between the medio-dorsal thalamic nucleus (MDN) and widespread prefrontal, temporal and parietal cortical regions. Because the thalamus is also implicated in other psychiatric illnesses including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), the diagnostic specificity of these alterations is unclear. Here, we determined whether aberrant functional integration between the MDN and the cortex is a specific feature of schizophrenia or a trans-diagnostic feature of psychiatric illness. Effective connectivity (EC) between the MDN and rest of the cortex was measured by applying psychophysiological interaction analysis to resting-state functional magnetic resonance imaging data of 50 patients with first episode schizophrenia (FES), 50 patients with MDD, 50 patients with PTSD and 122 healthy controls. All participants were medication-naïve. The only significant schizophrenia-specific effect was increased EC between the right MDN and the right pallidum (p < 0.05 corrected). In contrast, there were a number of significant trans-diagnostic alterations, with both right and left MDN displaying trans-diagnostic increased EC with several prefrontal and parietal regions bilaterally (p < 0.05 corrected). EC alterations between the MDN and the cortex are not specific to schizophrenia but are a trans-diagnostic feature of psychiatric disorders, consistent with emerging conceptualizations of mental illness based on a single general psychopathology factor. Therefore, dysconnectivity of the MDN could potentially be used to assess the presence of general psychopathology above and beyond traditional diagnostic boundaries.
Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes
Authors: Montalban Enrica , Al-Massadi Omar , Sancho-Balsells Anna , Brito Verónica , de Pins Benoit , Alberch Jordi , Ginés Silvia , Girault Jean-Antoine , Giralt Albert 
Published: January 2019

AbstractMajor depressive disorder (MDD) is a common disorder with a variety of symptoms including mood alterations, anhedonia, sleep and appetite disorders, and cognitive disturbances. Stressful life events are among the strongest risk factors for developing MDD. At the cellular level, chronic stress results in the modification of dendritic spine morphology and density. Here, we study the role of Pyk2 in the development of depressive-like symptoms induced by a model of chronic unpredictable mild stress (CUMS). Pyk2 is a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the forebrain principal neurons and involved in spine structure and density regulation. We show that Pyk2 knockout mice are less affected to anxiety-like and anhedonia-like phenotypes induced by the CUMS paradigm. Using region-specific knockout, we demonstrate that this phenotype is fully recapitulated by selective Pyk2 inactivation in the amygdala. We also show that in the absence of Pyk2 the spine alterations, PSD-95 clustering, and NMDA receptors changes induced by the CUMS paradigm are prevented. Our results reveal a possible role for Pyk2 in the response to stress and in synaptic markers expression and spine density regulation in the amygdala. We suggest that Pyk2 contributes to stress-induced responses through micro-structural changes and that its deficit may contribute to the resilience to chronic stress.
Constitutional mislocalization of Pten drives precocious maturation in oligodendrocytes and aberrant myelination in model of autism spectrum disorder
Authors: Lee Hyunpil , Thacker Stetson , Sarn Nicholas , Dutta Ranjan , Eng Charis 
Published: January 2019

AbstractThere is a strong genetic association between germline PTEN mutation and autism spectrum disorder (ASD), making Pten-mutant models exemplary for the study of ASD pathophysiology. We developed the Ptenm3m4 mouse, where Pten is largely restricted from the nucleus, which recapitulates patient-like, autism-related phenotypes: behavioral changes, macrocephaly, and white matter abnormalities. This study aimed to investigate the contribution of oligodendrocyte (OL) lineage differentiation and functional changes in myelination to the white matter phenotype. OL lineage differentiation and myelination in Ptenm3m4 mice was studied using immunohistochemical and electron microscopic analyses. We also used primary oligodendrocyte progenitor cells (OPCs) to determine the effect of the Ptenm3m4 mutation on OPC proliferation, migration and maturation. Finally, we assessed the myelinating competency of mutant OLs via co-culture with wildtype dorsal root ganglia (DRG) neurons. The in vivo analyses of Ptenm3m4/m3m4 murine brains showed deficits in proteolipid protein (Plp) trafficking in myelinating OLs. Despite the increased expression of myelin proteins in the brain, myelin deposition was observed to be abnormal, often occurring adjacent to, rather than around axons. Mutant primary OPCs showed enhanced proliferation and migration. Furthermore, mutant OPCs matured precociously, exhibiting aberrant myelination in vitro. Mutant OPCs, when co-cultured with wildtype DRG neurons, showed an inability to properly ensheath axons. Our findings provide evidence that the Ptenm3m4 mutation disrupts the differentiation and myelination programs of developing OLs. OL dysfunction in the Ptenm3m4 model explains the leukodystrophy phenotype, a feature commonly associated with autism, and highlights the growing importance of glial dysfunction in autism pathogenesis.
Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects
Authors: Rask-Andersen Mathias , Karlsson Torgny , Ek Weronica E. , Johansson Åsa 
Published: January 2019

AbstractBody mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested to be more pathogenic compared to fat stored in other compartments. In this study, we perform genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. 98 independent associations with body fat distribution are identified, 29 that have not previously been associated with anthropometric traits. A high degree of sex-heterogeneity is observed and the effects of 37 associated variants are stronger in females compared to males. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues as well as extracellular matrix maintenance and remodeling.
Ab initio predictions for polarized deuterium-tritium thermonuclear fusion
Authors: Hupin Guillaume , Quaglioni Sofia , Navrátil Petr 
Published: January 2019

AbstractThe fusion of deuterium (D) with tritium (T) is the most promising of the reactions that could power thermonuclear reactors of the future. It may lead to even more efficient energy generation if obtained in a polarized state, that is with the spin of the reactants aligned. Here, we report first-principles predictions of the polarized DT fusion using nuclear forces from effective field theory. By employing the ab initio no-core shell model with continuum reaction method to solve the quantum mechanical five-nucleon problem, we accurately determine the enhanced fusion rate and angular distribution of the emitted neutron and 4He. Our calculations demonstrate in detail the small contribution of anisotropies, placing on a firmer footing the understanding of the rate of DT fusion in a polarized plasma. In the future, analogous calculations could be used to obtain accurate values for other, more uncertain thermonuclear reaction data critical to nuclear science applications.
Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration
Authors: Zhao Min , Mantel Irmela , Gelize Emmanuelle , Li Xinxin , Xie Xiaoyue , Arboleda Alejandro , Seminel Marie , Levy-Boukris Rinath , Dernigoghossian Marilyn , Prunotto Andrea , Andrieu-Soler Charlotte , Rivolta Carlo , Canonica Jérémie , Naud Marie-Christine , Lechner Sebastian , Farman Nicolette , Bravo-Osuna Irene , Herrero-Vanrell Rocio , Jaisser Frederic , Behar-Cohen Francine 
Published: January 2019

AbstractChoroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin. Intravitreal injections of spironolactone-loaded microspheres and systemic delivery lead to similar reductions in CNV. Together, our work suggests MR inhibition as a novel therapeutic option for wet AMD patients unresponsive to anti-VEGF drugs.
C1 CAGE detects transcription start sites and enhancer activity at single-cell resolution
Authors: Kouno Tsukasa , Moody Jonathan , Kwon Andrew Tae-Jun , Shibayama Youtaro , Kato Sachi , Huang Yi , Böttcher Michael , Motakis Efthymios , Mendez Mickaël , Severin Jessica , Luginbühl Joachim , Abugessaisa Imad , Hasegawa Akira , Takizawa Satoshi , Arakawa Takahiro , Furuno Masaaki , Ramalingam Naveen , West Jay , Suzuki Harukazu , Kasukawa Takeya , Lassmann Timo , Hon Chung-Chau , Arner Erik , Carninci Piero , Plessy Charles , Shin Jay W. 
Published: January 2019

AbstractSingle-cell transcriptomic profiling is a powerful tool to explore cellular heterogeneity. However, most of these methods focus on the 3′-end of polyadenylated transcripts and provide only a partial view of the transcriptome. We introduce C1 CAGE, a method for the detection of transcript 5′-ends with an original sample multiplexing strategy in the C1TM microfluidic system. We first quantifiy the performance of C1 CAGE and find it as accurate and sensitive as other methods in the C1 system. We then use it to profile promoter and enhancer activities in the cellular response to TGF-β of lung cancer cells and discover subpopulations of cells differing in their response. We also describe enhancer RNA dynamics revealing transcriptional bursts in subsets of cells with transcripts arising from either strand in a mutually exclusive manner, validated using single molecule fluorescence in situ hybridization.
Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells
Authors: Fenderico Nicola , van Scherpenzeel Revina C. , Goldflam Michael , Proverbio Davide , Jordens Ingrid , Kralj Tomica , Stryeck Sarah , Bass Tarek Z. , Hermans Guy , Ullman Christopher , Aastrup Teodor , Gros Piet , Maurice Madelon M. 
Published: January 2019

AbstractWnt-induced β-catenin-mediated transcription is a driving force for stem cell self-renewal during adult tissue homeostasis. Enhanced Wnt receptor expression due to mutational inactivation of the ubiquitin ligases RNF43/ZNRF3 recently emerged as a leading cause for cancer development. Consequently, targeting canonical Wnt receptors such as LRP5/6 holds great promise for treatment of such cancer subsets. Here, we employ CIS display technology to identify single-domain antibody fragments (VHH) that bind the LRP6 P3E3P4E4 region with nanomolar affinity and strongly inhibit Wnt3/3a-induced β-catenin-mediated transcription in cells, while leaving Wnt1 responses unaffected. Structural analysis reveal that individual VHHs variably employ divergent antigen-binding regions to bind a similar surface in the third β-propeller of LRP5/6, sterically interfering with Wnt3/3a binding. Importantly, anti-LRP5/6 VHHs block the growth of Wnt-hypersensitive Rnf43/Znrf3-mutant intestinal organoids through stem cell exhaustion and collective terminal differentiation. Thus, VHH-mediated targeting of LRP5/6 provides a promising differentiation-inducing strategy for treatment of Wnt-hypersensitive tumors.
A variable-stiffness tendril-like soft robot based on reversible osmotic actuation
Authors: Must Indrek , Sinibaldi Edoardo , Mazzolai Barbara 
Published: January 2019

AbstractSoft robots hold promise for well-matched interactions with delicate objects, humans and unstructured environments owing to their intrinsic material compliance. Movement and stiffness modulation, which is challenging yet needed for an effective demonstration, can be devised by drawing inspiration from plants. Plants use a coordinated and reversible modulation of intracellular turgor (pressure) to tune their stiffness and achieve macroscopic movements. Plant-inspired osmotic actuation was recently proposed, yet reversibility is still an open issue hampering its implementation, also in soft robotics. Here we show a reversible osmotic actuation strategy based on the electrosorption of ions on flexible porous carbon electrodes driven at low input voltages (1.3 V). We demonstrate reversible stiffening (~5-fold increase) and actuation (~500 deg rotation) of a tendril-like soft robot (diameter ~1 mm). Our approach highlights the potential of plant-inspired technologies for developing soft robots based on biocompatible materials and safe voltages making them appealing for prospective applications.
Correlative cryo-electron microscopy reveals the structure of TNTs in neuronal cells
Authors: Sartori-Rupp Anna , Cordero Cervantes Diégo , Pepe Anna , Gousset Karine , Delage Elise , Corroyer-Dulmont Simon , Schmitt Christine , Krijnse-Locker Jacomina , Zurzolo Chiara 
Published: January 2019

AbstractThe orchestration of intercellular communication is essential for multicellular organisms. One mechanism by which cells communicate is through long, actin-rich membranous protrusions called tunneling nanotubes (TNTs), which allow the intercellular transport of various cargoes, between the cytoplasm of distant cells in vitro and in vivo. With most studies failing to establish their structural identity and examine whether they are truly open-ended organelles, there is a need to study the anatomy of TNTs at the nanometer resolution. Here, we use correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structural organization of neuronal TNTs. Our data indicate that they are composed of a bundle of open-ended individual tunneling nanotubes (iTNTs) that are held together by threads labeled with anti-N-Cadherin antibodies. iTNTs are filled with parallel actin bundles on which different membrane-bound compartments and mitochondria appear to transfer. These results provide evidence that neuronal TNTs have distinct structural features compared to other cell protrusions.
A viral expression factor behaves as a prion
Authors: Nan Hao , Chen Hongying , Tuite Mick F. , Xu Xiaodong 
Published: January 2019

AbstractPrions are proteins that can fold into multiple conformations some of which are self-propagating. Such prion-forming proteins have been found in animal, plant, fungal and bacterial species, but have not yet been identified in viruses. Here we report that LEF-10, a baculovirus-encoded protein, behaves as a prion. Full-length LEF-10 or its candidate prion-forming domain (cPrD) can functionally replace the PrD of Sup35, a widely studied prion-forming protein from yeast, displaying a [PSI+]-like phenotype. Furthermore, we observe that high multiplicity of infection can induce the conversion of LEF-10 into an aggregated state in virus-infected cells, resulting in the inhibition of viral late gene expression. Our findings extend the knowledge of current prion proteins from cellular organisms to non-cellular life forms and provide evidence to support the hypothesis that prion-forming proteins are a widespread phenomenon in nature.