bluuebunny/crossref_metadata_2025_split huggingface dataset:
Making the MOSTest of imaging genetics
Authors: van der Meer Dennis , Frei Oleksandr , Kaufmann Tobias , Shadrin Alexey A. , Devor Anna , Smeland Olav B. , Thompson Wes , Fan Chun Chieh , Holland Dominic , Westlye Lars T. , Andreassen Ole A. , Dale Anders M. 
Published: September 2019

ABSTRACTRegional brain morphology has a complex genetic architecture, consisting of many common polymorphisms with small individual effects, which has proven challenging for genome-wide association studies to date, despite its high heritability1,2. Given the distributed nature of the genetic signal across brain regions, joint analysis of regional morphology measures in a multivariate statistical framework provides a way to enhance discovery of genetic variants with current sample sizes. While several multivariate approaches to GWAS have been put forward over the past years3–5, none are optimally suited for complex, large-scale data. Here, we applied the Multivariate Omnibus Statistical Test (MOSTest), with an efficient computational design enabling rapid and reliable permutation-based inference, to 171 subcortical and cortical brain morphology measures from 26,502 participants of the UK Biobank (mean age 55.5 years, 52.0% female). At the conventional genome-wide significance threshold of α=5×10−8, MOSTest identifies 347 genetic loci associated with regional brain morphology, more than any previous study, improving upon the discovery of established GWAS approaches more than threefold. Our findings implicate more than 5% of all protein-coding genes and provide evidence for gene sets involved in neuron development and differentiation. As such, MOSTest, which we have made publicly available, enhances our understanding of the genetic determinants of regional brain morphology.
3D Exploration of the Brainstem in 50-micron Resolution MRI
Authors: Makris N , Rushmore RJ , Wilson-Braun P , Papadimitriou G , Ng I , Rathi Y N , Zhang F , O’Donnell LJ , Kubicki M , Yeterian E , Lemaire JJ , Calabrese E , Johnson GA , Kikinis R 
Published: September 2019

AbstractThe brainstem, a structure of vital importance in the mammals, is currently becoming a principal focus in cognitive, affective and clinical neuroscience. Midbrain, pontine and medullar structures are the epicenter of conduit, cranial nerve and such integrative functions as consciousness, emotional processing, pain and motivation. In this study, we parcellated the nuclear masses and the principal fiber pathways that were visible in a high resolution T2-weighted MRI dataset of 50-micron isotropic voxels of a postmortem human brainstem. Based on this analysis, we generated a detailed map of the human brainstem. To assess the validity of our maps, we compared our observations with histological maps of traditional human brainstem atlases. Moreover, we reconstructed the motor, sensory and integrative neural systems of the brainstem and rendered them in 3D representations. We anticipate the utilization of these maps by the neuroimaging community at large for applications in basic neuroscience as well as in neurology, psychiatry and neurosurgery, due to their versatile computational nature in 2D and 3D representations in a publicly available capacity.
Anxious and obsessive-compulsive traits are independently associated with valuation of non-instrumental information
Authors: Bennett Daniel , Sutcliffe Kiran , Tan Nicholas Poh-Jie , Smillie Luke D. 
Published: September 2019

AbstractAversion to uncertainty about the future has been proposed as a transdiagnostic trait underlying psychiatric diagnoses including obsessive-compulsive disorder and generalised anxiety. This association might explain the frequency of pathological information-seeking behaviours such as compulsive checking and reassurance-seeking in these disorders. Here we tested the behavioural predictions of this model using a non-instrumental information-seeking task that measured preferences for unusable information about future outcomes in different payout domains (gain, loss, and mixed gain/loss). We administered this task, along with a targeted battery of self-report questionnaires, to a general-population sample of 146 adult participants. Using computational cognitive modelling of choices to test competing theories of information valuation, we found evidence for a model in which preferences for costless and costly information about future outcomes were independent, and in which information preference was modulated by both outcome mean and outcome variance. Critically, we also found positive associations between a model parameter controlling preference for costly information and individual differences in latent traits of both anxiety and obsessive-compulsion. These associations were invariant across different payout domains, providing evidence that individuals high in obsessive-compulsive and anxious traits show a generalised increase in willingness-to-pay for unusable information about uncertain future outcomes, even though this behaviour reduces their expected future reward.
Delta-1 functionalized hydrogel promotes hESC-cardiomyocyte graft proliferation and maintains heart function post-injury
Authors: Gerbin Kaytlyn A , Mitzelfelt Katie A , Guan Xuan , Martinson Amy M , Murry Charles E 
Published: September 2019

ABSTRACTCurrent cell transplantation techniques are hindered by small graft size, requiring high cell doses to achieve therapeutic cardiac remuscularization. Enhancing the proliferation of transplanted human stem cell-derived cardiomyocytes (hESC-CMs) could address this, allowing an otherwise subtherapeutic cell dose to prevent disease progression after myocardial infarction. Here, we designed a hydrogel that activates Notch signaling through 3D presentation of the Notch ligand Delta-1 to use as an injectate for transplanting hESC-CMs into the infarcted rat myocardium. After four weeks, hESC-CM proliferation increased 2-fold and resulted in a 3-fold increase in graft size with the Delta-1 hydrogel compared to controls. To stringently test the effect of Notch-mediated graft expansion on long-term heart function, a normally subtherapeutic dose of hESC-CMs was implanted into the infarcted myocardium and cardiac function was evaluated by echocardiography. Transplantation of the Delta-1 hydrogel + hESC-CMs augmented heart function and was significantly higher at three months compared to controls. Graft size and hESC-CM proliferation were also increased at three months post-implantation. Collectively, these results demonstrate the therapeutic approach of a Delta-1 functionalized hydrogel to reduce the cell dose required to achieve functional benefit after myocardial infarction by enhancing hESC-CM graft size and proliferation.
A dynamic interaction between CD19 and the tetraspanin CD81 controls B cell co-receptor trafficking
Authors: Susa Katherine J. , Seegar Tom C. M. , Blacklow Stephen C. , Kruse Andrew C. 
Published: September 2019

SUMMARYCD81 and its binding partner CD19 are core subunits of the B cell co-receptor complex. While CD19 is a single-pass transmembrane protein belonging to the extensively studied Ig superfamily, CD81 belongs to a conserved but poorly understood family of four-pass transmembrane proteins called tetraspanins. These functionally diverse proteins play important roles in a wide variety of different organ systems by controlling protein trafficking and other cellular processes. Here, we show that CD81 relies on its ectodomain to control trafficking of CD19 to the cell surface. Moreover, the anti-CD81 antibody 5A6, which binds selectively to activated B cells, recognizes a conformational epitope on CD81 that is masked when CD81 is in complex with CD19. Mutations of CD81 in this contact interface suppress its CD19 surface-export activity. Taken together, these data indicate that the CD81 - CD19 interaction is dynamically regulated upon B cell activation, suggesting that this dynamism can be exploited to regulate B cell function. These results are not only important for understanding B cell biology, but also have important implications for understanding tetraspanin function more generally.
TRAF6 controls spinogenesis instructing synapse density and neuronal activity through binding neuroplastin
Authors: Vemula Sampath Kumar , Malci Ayse , Junge Lennart , Lehmann Anne-Christin , Rama Ramya , Hradsky Johannes , Matute Ricardo A. , Weber André , Prigge Matthias , Naumann Michael , Kreutz Michael R. , Seidenbecher Constanze I. , Gundelfinger Eckart D. , Herrera-Molina Rodrigo 
Published: September 2019

AbstractSynaptogenic mechanisms and their relevance to achieve a correct synapse density and activity in mature neurons are poorly understood. Here, we show that the tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early spinogenesis by binding the cell adhesion molecule neuroplastin which is has been related to synapse formation in vivo. TRAF6-neuroplastin co-precipitations from brain samples and co-transfected HEK cells is explained by direct interaction of the proteins based on three-dimensional modelling and biochemical identification of intracellular amino acids of neuroplastin binding the TRAF-C domain of TRAF6 with micromolar affinity. TRAF6 was not only required for normal spinogenesis but also was strictly necessary to restore failed spinogenesis in neuroplastin-deficient neurons. Independently from neuroplastin’s extracellular adhesive properties or interaction with another known partner i.e. the plasma membrane Ca2+ ATPases, TRAF6 mediated formation of new postsynapses by neuroplastin overexpression in rat hippocampal neurons. Furthermore, TRAF6-controlled spinogenesis was required for the establishment of a correct synapse density as well as proper synaptic activity and intrinsic neuronal activity as demonstrated with intracellular and extracellular electrophysiological recordings. These findings provide a novel mechanism for early synapse formation that shapes connectivity and functioning of hippocampal neurons.
Frameshift mutations of YPEL3 alter sensory circuit function in Drosophila
Authors: Kim Jung Hwan , Singh Monika , Pan Geng , Lopez Adrian , Zito Nicholas , Bosse Benjamin , Ye Bing 
Published: September 2019

ABSTRACTA frameshift mutation in Yippee-like (YPEL) 3 was recently found from a rare human disorder with peripheral neurological conditions including hypotonia and areflexia. The YPEL gene family is highly conserved from yeast to human, but their functions are poorly defined. Moreover, the pathogenicity of the human YPEL3 variant is completely unknown. To tackle these issues, we generated a Drosophila model of human YPEL3 variant by CRISPR-mediated In-del mutagenesis. Gene-trap analysis suggests that Drosophila YPEL3 (dYPEL3) is predominantly expressed in subsets of neurons, including nociceptors. Analysis on chemical nociception induced by allyl-isothiocyanate (AITC), a natural chemical stimulant, revealed a reduced nociceptive response in dYPEL3 mutants. Subsequent circuit analysis showed a reduction in the activation of second-order neurons (SONs) in the pathway without affecting nociceptor activation upon AITC treatment. Although the gross axonal and dendritic development of nociceptors was not affected, the synaptic contact between nociceptors and SONs were decreased by dYPEL3 mutations. Together, these suggest that the frameshift mutation in human YPEL3 causes neurological conditions by weakening synaptic connection through presynaptic mechanisms.
Predicting the genetic ancestry of 2.6 million New York City patients using clinical data
Authors: Ramlall Vijendra , Quinnies Kayla M. , Vanguri Rami , Lorberbaum Tal , Goldstein David B. , Tatonetti Nicholas P. 
Published: September 2019

AbstractAncestry is an essential covariate in clinical genomics research. When genetic data are available, dimensionality reduction techniques, such as principal components analysis, are used to determine ancestry in complex populations. Unfortunately, these data are not always available in the clinical and research settings. For example, electronic health records (EHRs), which are a rich source of temporal human disease data that could be used to enhance genetic studies, do not directly capture ancestry. Here, we present a novel algorithm for predicting genetic ancestry using only variables that are routinely captured in EHRs, such as self-reported race and ethnicity, and condition billing codes. Using patients that have both genetic and clinical information at Columbia University/ New York-Presbyterian Irving Medical Center, we developed a pipeline that uses only clinical data to predict the genetic ancestry of all patients of which more than 80% identify as other or unknown. Our ancestry estimates can be used in observational studies of disease inheritance, to guide genetic cohort studies, or to explore health disparities in clinical care and outcomes.
Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis
Authors: Katsara Olga , Attur Mukundan , Kolupaeva Victoria 
Published: September 2019

ABSTRACTAs world population growing older, burden of age-related conditions soars. One of them is osteoarthritis (OA), a debilitating joint disease with no effective treatment. Articular cartilage degeneration is a central event in OA, and changes in expression of many genes in OA cartilage are well-documented. Still, the specific mechanisms are rarely known. We showed that in OA cartilage the increased abundance of many proteins, including extracellular matrix protein Fibronectin (Fn1) and an orphan nuclear receptor Nr4a1 is translationally controlled and requires inactivation of 4EBP, an inhibitor of cap-dependent translation. Importantly, intra-articular injection of the translation inhibitor 4E1RCat reduces Fn1 and Nr4a upregulation in a rodent OA model and delays cartilage degeneration. Our results support the hypothesis that maintaining proper translational control is an important homeostatic mechanism, the loss of which contributes to OA development.
Xmas ESC: A new female embryonic stem cell system that reveals the BAF complex as a key regulator of the establishment of X chromosome inactivation
Authors: Keniry Andrew , Jansz Natasha , Gearing Linden J. , Wanigasuriya Iromi , Chen Joseph , Nefzger Christian M. , Hickey Peter F. , Gouil Quentin , Liu Joy , Breslin Kelsey A. , Iminitoff Megan , Beck Tamara , Tapia del Fierro Andres , Whitehead Lachlan , Kinkel Sarah A. , Taberlay Phillippa C. , Willson Tracy , Pakusch Miha , Ritchie Matthew E. , Hilton Douglas J. , Polo Jose M. , Blewitt Marnie E. 
Published: September 2019

SummaryAlthough female pluripotency significantly differs to male, complications within vitroculture of female embryonic stem cells (ESC) have severely limited the use and study of these cells. We report a replenishable female ESC system, Xmas, that has enabled us to optimise a protocol for preserving the XX karyotype. Our protocol also improves male ESC fitness. We utilised our Xmas ESC system to screen for regulators of the female-specific process of X chromosome inactivation, revealing chromatin remodellers Smarcc1 and Smarca4 as key regulators of establishment of X inactivation. The remodellers create a nucleosome depleted region at gene promotors on the inactive X during exit from pluripotency, without which gene silencing fails. Our female ESC system provides a tractable model for XX ESC culture that will expedite study of female pluripotency and has enabled us to discover new features of the female-specific process of X inactivation.
Genome and community-level interaction insights on wide carbon utilizing and element cycling function of Hydrothermarchaeota from hydrothermal sediment
Authors: Zhou Zhichao , Liu Yang , Xu Wei , Pan Jie , Luo Zhu-Hua , Li Meng 
Published: September 2019

AbstractHydrothermal vents release reduced compounds and small organic carbons into surrounding seawaters, providing essential substrates for microbial-derived biosynthesis and bioenergy transformations. Despite the wide distribution of Marine Benthic Group-E archaea (referred to as Hydrothermarchaeota) in hydrothermal environments, little is known on their genome blueprints and ecofunctions. Here, we studied four relatively high-completeness (> 80%) metagenome-assembled genomes (MAGs) from a black smoker chimney and surrounding sulfide sediments in the Mid-Atlantic Ridge of the South Atlantic Ocean (BSmoChi-MAR) as well as publicly available datasets. Comparative genomics suggest that Hydrothermarchaeota members have versatile carbon metabolism, including assimilating proteins, lactate and acetate, degrading aromatics anaerobically, oxidizing C1compounds (CO, formate, and formaldehyde), utilizing methyl-compounds, and incorporating CO2by tetrahydromethanopterin-based Wood–Ljungdahl (WL) pathway and Calvin–Benson–Bassham (CBB) cycle with type III Ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO). They could oxidize sulfur, arsenic, and hydrogen, and respire anaerobically via sulfate reduction and denitrification based on genomic evidence. The redundancy of carbon utilizing and element cycling functions, and the interactive processes of syntrophic and sequential utilization of substrates from community-level metabolic prediction, enable wide accessibility of carbon and energy sources to microorganisms. Hydrothermarchaeota members derived important functional components from the community through lateral gene transfer, and became clade-distinctive on genome content, which might serve as a niche-adaptive strategy to metabolize potential heavy metals, C1compounds, and reduced sulfur compounds.ImportanceThis study provides comprehensive metabolic insights on Hydrothermarchaeota from comparative genomics, evolution and community-level aspects. Hydrothermarchaeota synergistically participates in a wide range of carbon utilizing and element cycling processes with other microbes in the community. We expand the current understanding of community interactions within hydrothermal sediment environments, suggesting that microbial interactions driven by functions are essential to nutrient and element cycling.
Diverse flanking sequence types ofblaNDMin IncX3 and IncB/O/K/Z plasmids inEscherichia coliisolated from poultry
Authors: Zhu Jia-Hang , Cai Run-Mao , Zhang Li-Juan , Zheng Xing-Run , Lu Yue-Wei , Zhao Qiu-Yun , Chang Man-Xia , Jiang Hong-Xia 
Published: September 2019

AbstractWe identified 33blaNDM-harboringEscherichia coliin 470 poultry samples from Shandong and Guangdong provinces during 2016 to 2017 and included the subtypesblaNDM-1,blaNDM-5andblaNDM-9.TheblaNDMgene possessed by all strains was plasmid-borne and ranged in size from 46 to 265 kb. The plasmids included the replicon types IncX3, IncY, IncB/O/K/Z and IncHI2 and most were transferable and stable in recipient host bacteria. Sequences flankingblaNDMin IncX3 and IncB/O/K/Z plasmids were diverse and the mobile element IS26played an important role in the evolution of the IncB/O/K/ZblaNDMplasmids.
Plasmid transmitted small multidrug resistant (SMR) efflux pumps differ in gene regulation and enhance tolerance to quaternary ammonium compounds (QAC) when grown as biofilms
Authors: Slipski Carmine J. , Jamieson Taylor R. , Lam Amy , Shing Vanessa Leung , Bell Kelli , Zhanel George G. , Bay Denice C. 
Published: September 2019

AbstractSmall multidrug resistance (SMR) efflux pump genes are commonly identified from integrons carried by multidrug-resistant (MDR) plasmids. SMR pumps are annotated as ‘qac’ for their ability to confer resistance to quaternary ammonium compounds (QACs) but few qac are characterized to date. Hence, we have examined SMR sequence diversity, antimicrobial susceptibility, and gene expression from >500 sequenced proteobacterial plasmids. SMR sequence diversity from plasmid database surveys identified 20 unique SMR sequences annotated as qacE/EΔ1/F/G/H/I/L, or sugE. Phylogenetic analysis shows ‘Qac’ sequences are homologous to archetypical SMR member EmrE, and share a single sequence origin. In contrast, SugE sequences are homologous to archetypical member Gdx/SugE and likely originate from different species. SMR genes, qacE, qacEΔ1, qacF, qacG, qacH, and sugE(p), were over-expressed in Escherichia coli to determine their QAC antimicrobial susceptibility as planktonic, colony, and biofilms. SMRs (except qacEΔ1/sugE) expressed in biofilms significantly increased its QAC tolerance as compared to planktonic and colony growth. Analysis of upstream SMR nucleotide regions indicate sugE(p) genes are regulated by type II guanidinium riboswitches, whereas qacE and qacEΔ1 have a conserved class I integron Pq promoter, and qacF/G/H are regulated by integron Pc promoter in variable cassettes region. Beta-galactosidase assays were used to characterize growth conditions regulating Pq and Pc promoters and revealed that Pq and Pc have different expression profiles during heat, peroxide, and QAC exposure. Altogether, this study reveals that biofilm growth methods are optimal for SMR-mediated QAC susceptibility testing and suggests SMR gene regulation on plasmids is similar to chromosomally inherited SMR members.
Screening the Medicines for Malaria Venture Pathogen Box for invasion and egress inhibitors of the blood stage of Plasmodium falciparum reveals several inhibitory compounds
Authors: Dans Madeline G. , Weiss Greta E. , Wilson Danny W. , Sleebs Brad E. , Crabb Brendan S. , de Koning-Ward Tania F. , Gilson Paul R. 
Published: September 2019

AbstractTo identify potential inhibitors of egress and invasion in the asexual blood stage of Plasmodium falciparum, we screened the Medicines for Malaria Venture (MMV) Pathogen Box. This compound library comprises of 400 drugs against neglected tropical diseases, including 125 with antimalarial activity. For this screen, we utilised transgenic parasites expressing a bioluminescent reporter, Nanoluciferase (Nluc), to measure inhibition of parasite egress and invasion in the presence of the Pathogen Box compounds. At a concentration of 2 µM, we found 15 compounds that inhibited parasite egress by >40% and 24 invasion-specific compounds that inhibited invasion by >90%. We further characterised 11 of these inhibitors through cell-based assays and live cell microscopy and found two compounds that inhibited merozoite maturation in schizonts, one compound that inhibited merozoite egress, one compound that directly inhibited parasite invasion and one compound that slowed down invasion and arrested ring formation. The remaining compounds were general growth inhibitors that acted during the egress and invasion phase of the cell cycle. We found the sulfonylpiperazine, MMV020291, to be the most invasion-specific inhibitor, blocking successful merozoite internalisation within human RBCs and having no substantial effect on other stages of the cell cycle. This has greater implications for the possible development of an invasion-specific inhibitor as an antimalarial in a combination based therapy, in addition to being a useful tool for studying the biology of the invading parasite.ImportancePlasmodium falciparum causes the most severe form of malaria and with emerging resistance to frontline treatments, there is the need to identify new drug targets in the parasite. One of the most critical processes during the asexual blood stage in the parasite’s lifecycle is the egress from old red blood cells (RBCs) and subsequent invasion of new RBCs. Many unique parasite ligands, receptors and enzymes are employed during egress and invasion that are essential for parasite proliferation and survival, therefore making these processes druggable targets. Identifying novel compounds that inhibit these essential processes would further their development into possible antimalarials that would be highly effective at killing asexual RBC stage parasites when used in combination with drugs that target the intraerythrocytic growth phase. These compounds potentially may also be used as novel tools to study the complex biology of parasites to gain further insight into the mechanisms behind egress and invasion.