bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent ultra-rare inherited mutations identify novel autism candidate risk genes
Authors: Wilfert Amy B , Turner Tychele N , Murali Shwetha C , Hsieh PingHsun , Sulovari Arvis , Wang Tianyun , Coe Bradley P , Guo Hui , Hoekzema Kendra , Bakken Trygve E , Winterkorn Lara H , Evani Uday S , Byrska-Bishop Marta , Earl Rachel K , Bernier Raphael A ,   The SPARK Consortium, Zody Michael C , Eichler Evan E 
Published: February 2020

AbstractAutism is a highly heritable, complex disorder wherede novomutation (DNM) variation contributes significantly to disease risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare mutations. We report and replicate a transmission disequilibrium of private likely-gene disruptive (LGD) mutations in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport, and Erb signaling protein networks. We estimate these mutations are ~2.5 generations old and significantly younger than other mutations of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and act on a distinct set of genes not yet associated with autism.One sentence summaryUltra-rare autism variants preferentially transmitted to probands are younger and identify distinct gene candidates and functional networks.
The induciblelacoperator-repressor system is functional in zebrafish cells
Authors: Nishizaki Sierra S. , McDonald Torrin L. , Farnum Gregory A. , Holmes Monica J. , Drexel Melissa L. , Switzenberg Jessica A. , Boyle Alan P. 
Published: February 2020

AbstractBackgroundZebrafish are a foundational model organism for studying the spatio-temporal activity of genes and their regulatory sequences. A variety of approaches are currently available for editing genes and modifying gene expression in zebrafish, including RNAi, Cre/lox, and CRISPR-Cas9. However, thelacoperator-repressor system, a component of theE. coli lacoperon which has been adapted for use in many other species and is a valuable, flexible tool for studying the inducible modulation of gene expression, has not previously been tested in zebrafish.ResultsHere we demonstrate that thelacoperator-repressor system robustly decreases expression of firefly luciferase in cultured zebrafish fibroblast cells. Our work establishes thelacoperator-repressor system as a promising tool for the manipulation of gene expression in whole zebrafish.ConclusionsOur results lay the groundwork for the development oflac-based reporter assays in zebrafish, and adds to the tools available for investigating dynamic gene expression in embryogenesis. We believe that this work will catalyze the development of new reporter assay systems to investigate uncharacterized regulatory elements and their cell-type specific activities.
Parallel mechanisms of visual memory formation across distinct regions of the honey bee brain
Authors: Avalos Arián , Traniello Ian M. , Claudio Eddie Perez , Giray Tugrul 
Published: February 2020

AbstractVisual learning is vital to the behavioral ecology of the Western honey bee (Apis mellifera). Honey bee workers forage for floral resources, a behavior that requires the learning and long-term memory of visual landmarks, but how these memories are mapped to the brain remains poorly understood. To address this gap in our understanding, we collected bees that successfully learned visual associations in a conditioned aversion paradigm and compared gene expression correlates of memory formation in the mushroom bodies, a higher-order sensory integration center classically thought to contribute to learning, as well as the optic lobes, the primary visual neuropil responsible for sensory transduction of visual information. We quantitated expression ofCREBandCaMKii, two classical genetic markers of learning andfen-1, a gene specifically associated with punishment learning in vertebrates. As expected, we report substantial involvement of the mushroom bodies for all three markers but additionally demonstrate an unexpected involvement of the optic lobes across a similar time course. Our findings imply the molecular involvement of a sensory neuropil during visual associative learning parallel to a higher-order brain region, furthering our understanding of how a tiny brain processes environmental signals.
Shaping Brain Structure: Genetic and Phylogenetic Axes of Macro Scale Organization of Cortical Thickness
Authors: Valk Sofie L. , Xu Ting , Margulies Daniel S. , Masouleh Shahrzad Kahrabian , Paquola Casey , Goulas Alexandros , Kochunov Peter , Smallwood Jonathan , Yeo B.T. Thomas , Bernhardt Boris C. , Eickhoff Simon B. 
Published: February 2020

AbstractStructural and functional characteristics of the cortex systematically vary along global axes as a function of cytoarchitecture, gene expression, and connectivity. The topology of the cerebral cortex has been proposed to be a prerequisite for the emergence of human cognition and explain both the impact and progression of pathology. However, the neurogenetic origin of these organizational axes in humans remains incompletely understood. To address this gap in the literature our current study assessed macro scale cortical organization through an unsupervised machine learning analysis of cortical thickness covariance patterns and used converging methods to evaluate its genetic basis. In a large-scale sample of twins (n=899) we found structural covariance of thickness to be organized along both an anterior-to-posterior and inferior-to-superior axis. We found that both axes showed a high degree of correspondence in pairs of identical twins, suggesting a strong heritable component in humans. Furthermore, comparing these dimensions in macaques and humans highlighted similar organizational principles in both species demonstrating that these axes of cortical organization are phylogenetically conserved within primate species. Finally, we found that in both humans and macaques the inferior-superior dimension of cortical organization was aligned with the predictions of the dual-origin theory, highlighting the possibility that the macroscale organization of primate brain structure is subject to multiple distinct neurodevelopmental trajectories. Together, our study establishes the genetic basis of natural axes in the cerebral cortex along which structure is organized and so provides important insights into the organization of human cognition that will inform both our understanding of how structure guides function and for the progression of pathology in diseases.
unCOVERApp: an interactive graphical application for clinical assessment of sequence coverage at the base-pair level
Authors: Iovino Emanuela , Seri Marco , Pippucci Tommaso 
Published: February 2020

AbstractMotivationNext Generation Sequencing (NGS) is increasingly adopted in the clinical practice largely thanks to concurrent advancements in bioinformatic tools for variant detection and annotation. Despite improvements in available approaches, the need to assess sequencing quality down to the base-pair level still poses challenges for diagnostic accuracy. One of the most popular quality parameters of diagnostic NGS is the percentage of targeted bases characterized by low depth of coverage (DoC). These regions potentially hide a clinically-relevant variant, but no annotation is usually returned for them.However, visualizing low-DoC data with their potential functional and clinical consequences may be useful to prioritize inspection of specific regions before re-sequencing all coverage gaps or making assertions about completeness of the diagnostic test.To meet this need we have developed unCOVERApp, an interactive application for graphical inspection and clinical annotation of low-DoC genomic regions containing genes.ResultsunCOVERApp is a suite of graphical and statistical tools to support clinical assessment of low-DoC regions. Its interactive plots allow to display gene sequence coverage down to the base-pair level, and functional and clinical annotations of sites below a user-defined DoC threshold can be downloaded in a user-friendly spreadsheet format. Moreover, unCOVERApp provides a simple statistical framework to evaluate if DoC is sufficient for the detection of somatic variants, where the usual 20x DoC threshold used for germline variants is not adequate. Amaximum credible allele frequencycalculator is also available allowing users to set allele frequency cut-offs based on assumptions about the genetic architecture of the disease instead of applying a general one (e.g. 5%). In conclusion, unCOVERApp is an original tool designed to identify sites of potential clinical interest that may be hidden in diagnostic sequencing data.AvailabilityunCOVERApp is a freely available application written in R and developed with Shiny packages and available in GitHub.
Drosophila SWR1 and NuA4 complexes are defined by DOMINO isoforms
Authors: Scacchetti Alessandro , Schauer Tamas , Reim Alexander , Apostolou Zivkos , Sparr Aline Campos , Krause Silke , Heun Patrick , Wierer Michael , Becker Peter B. 
Published: February 2020

SUMMARYHistone acetylation and deposition of H2A.Z variant are integral aspects of active transcription. InDrosophila, the single DOMINO chromatin regulator complex is thought to combine both activitiesviaan unknown mechanism. Here we show that alternative isoforms of the DOMINO nucleosome remodeling ATPase, DOM-A and DOM-B, directly specify two distinct multi-subunit complexes. Both complexes are necessary for transcriptional regulation but through different mechanisms. The DOM-B complex incorporates H2A.V (the fly ortholog of H2A.Z) genome-wide in an ATP-dependent manner, like the yeast SWR1 complex. The DOM-A complex, instead, functions as an ATP-independent histone acetyltransferase complex similar to the yeast NuA4, targeting lysine 12 of histone H4. Our work provides an instructive example of how different evolutionary strategies lead to similar functional separation. In yeast and humans, nucleosome remodeling and histone acetyltransferase complexes originate from gene duplication and paralog specification.Drosophilagenerates the same diversity by alternative splicing of a single gene.HighlightsIsoforms of DOMINO dictate the formation of distinct complexesDOM-B complex is theDrosophilaSWR1 and incorporates H2A.V genome-wideDOM-A complex acetylates H4K12 and is theDrosophilaNuA4
Anthropogenic factors influence the occupancy of an invasive carnivore in a suburban preserve system
Authors: Vanek John P. , Rutter Andrew U. , Preuss Timothy S. , Jones Holly P. , Glowacki Gary A. 
Published: February 2020

AbstractDomestic cats (Felis catus) are one of the world’s most damaging invasive species. Free-ranging cats kill billions of wild animals every year, spread parasites and diseases to both wildlife and humans, and are responsible for the extinction or extirpation of at least 63 species. While the ecology and conservation implications of free-ranging cats have well studied in some locations, relatively little is known about cats inhabiting urban nature preserves in the United States. To address this knowledge gap, we used camera traps to study the occupancy and activity patterns of free-ranging cats in 55 suburban nature preserves in the Chicago, IL metropolitan area. From 2010–2018 (4,440 trap days), we recorded 355 photos of free-ranging cats across 26 preserves (ψnaïve= 0.45) and 41 randomly distributed monitoring points (ψnaïve= 0.18). Cats were detected every year, but rarely at the same point or preserve, and cats were largely crepuscular/diurnal. Using single-season occupancy models and a “stacked” design, we found that cat occupancy increased with building density and detectability was highest near the urban/preserve boundary. Based on our top-ranked model, predicted occupancy within individual preserves ranged from 0.09 to 0.28 (ψmean= 0.11) and was poorly correlated with preserve size or shape. Overall, our results suggest that free-ranging cats are rare within suburban preserves in our study area, and that these cats are most likely owned or heavily subsidized by people (which pose different risks and management challenges than truly feral cats). We discuss the conservation and management implications for urban natural areas.HighlightsWe surveyed for domestic cats across 55 suburban preserves from 2010-2018.We modeled occupancy and detectability as a function of urban covariates.Cat occupancy was low overall and best predicted by building density.The risk to native species is highest near preserve boundaries bordered by built environments.
Measuring aptamer folding energy using a molecular clamp
Authors: Qu Hao , Ma Qihui , Wang Lu , Mao Yu , Eisenstein Michael , Soh Hyongsok Tom , Zheng Lei 
Published: February 2020

AbstractFolding energy offers a useful metric for characterizing the stability and function of aptamers. However, experimentally measuring the folding energy is challenging and there is currently no general technique to measure this parameter directly. In this work, we present a simple approach for measuring aptamer folding energy. First, the aptamer is stretched under equilibrium conditions with a double-stranded DNA “molecular clamp” that is coupled to the aptamer ends. We then measure the total internal energy of stressed DNA molecules using time-lapse gel electrophoresis and compare the folding and unfolding behavior of molecular clamp-stressed molecules that incorporate either the aptamer or unstructured random single-stranded DNA in order to derive the aptamer folding energy. Using this approach, we measured a folding energy of 10.40 kJ/mol for the HD22 thrombin aptamer, which is consistent with other predictions and estimates. We also analyzed a simple hairpin structure, generating a folding energy result of 9.05 kJ/mol, consistent with the value predicted by computational models (9.24 kJ/mol). We believe our strategy offers an accessible and generalizable approach for obtaining such measurements with virtually any aptamer.
Transcriptomic and Proteomic analysis of clear cell foci (CCF) in the human non-cirrhotic liver identifies several differentially expressed genes and proteins with functions in cancer cell biology and glycogen metabolism
Authors: Metzendorf Christoph , Wineberger Katharina , Rausch Jenny , Cigliano Antonio , Calvisi Diego F. , Peters Kristin , Sun Baodong , Mennerich Daniela , Kietzmann Thomas , Dombrowski Frank , Ribback Silvia 
Published: February 2020

ABSTRACTClear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen-overload and activation of AKT/mTOR-signaling.Here we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We mainly found genes and proteins with lower expression in CCF compared to control samples. Of 14 differentially expressed transcripts only 3 were overexpressed and belong to previously uncharacterized long non-coding RNAs. At the protein level, 3 proteins were at least 1.5-fold higher expressed in CCF than in control samples, while 22 proteins were at least 1.5-fold less abundant. Using immunohistochemistry, the reduced expressions of STBD1, USP28, monad/WDR92, CYB5B and HSPE1 were validated in CCF. Knockout ofSTBD1, the gene coding for Starch-binding domain-containing protein 1, in mice did not have an effect on liver glycogen levels. Similiarly,Usp28knockout in mice did not affect glycogen storage in diethylnitrosamine-induced liver carcinoma. Thus, these data indicate that reduced expression of STBD1 or USP28 in CCF is unlikely to explain glycogen overload.Our study revealed several novel proteins and RNAs that are differentially expressed in CCF and have functions relevant for carcinogenesis or the glycogen metabolism.
Acetylation of isoniazid - a novel mechanism of isoniazid resistance inMycobacterium tuberculosis
Authors: Arun K. B. , Madhavan Aravind , Abraham Billu , Balaji M. , Sivakumar K. C. , Nisha P. , Kumar R. Ajay 
Published: February 2020

AbstractIsoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a pro-drug which is converted into its active form by the intracellular KatG enzyme ofMycobacterium tuberculosis. The activated drug hinders cell wall biosynthesis by inhibiting InhA protein. INH resistant strains ofM. tuberculosisusually have mutations inkatG,inhA,ahpC,kasA, andndhgenes. However, INH resistant strains which do not have mutations in any of these genes are reported, suggesting that these strains may adopt some other mechanism to become resistant to INH. In the present study we characterized Rv2170, a putative acetyltransferase inM. tuberculosis, to elucidate its role in inactivating isoniazid. The purified recombinant protein was able to catalyze transfer of acetyl group to INH from acetyl CoA. HPLC and LC-MS analyses showed that following acetylation by Rv2170, INH is broken down into isonicotinic acid and acetylhydrazine. Drug susceptibility assay and confocal analysis showed thatM. smegmatis, which is susceptible to INH, is not inhibited by INH acetylated with Rv2170. RecombinantM. smegmatisandM. tuberculosisH37Ra overexpressing Rv2170 were found to be resistant to INH at minimum inhibitory concentrations that inhibited wildtype strains. In addition, intracellularM. tuberculosisH37Ra overexpressing Rv2170 survived better in macrophages when treated with INH. Our results strongly indicate that Rv2170 acetylates INH, and this could be one of the strategies adopted by at least someM. tuberculosisstrains to overcome INH toxicity.
Autosomal Recessive Alzheimer’s disease (arAD): homozygosity mapping of genomic regions containing arAD loci
Authors: Moreno-Grau Sonia , Fernández Maria Victoria , de Rojas Itziar , Hernández Isabel , Farias Fabiana , Budde John P , Quintela Inés , Madrid Laura , González-Perez Antonio , Montrreal Laura , Garcia-Gonzalez Pablo , Alarcón-Martín Emilio , Alegret Montserrat , Maroñas Olalla , Pineda Juan Antonio , Macías Juan ,   GR@ACE & DEGESCO consortia,   Alzheimer’s Disease Neuroimaging Initiative, Marquié Marta , Valero Sergi , Benaque Alba , Clarimón Jordi , Bullido Maria Jesus , García-Ribas Guillermo , Pástor Pau , Sánchez-Juan Pascual , Álvarez Victoria , Piñol-Ripoll Gerard , García-Alberca Jose María , Royo José Luis , Franco-Macías Emilio , Mir Pablo , Calero Miguel , Medina Miguel , Rábano Alberto , Ávila Jesús , Antúnez Carmen , Real Luis Miguel , Orellana Adelina , Carracedo Ángel , Sáez María Eugenia , Tárraga Lluis , Boada Mercè , Cruchaga Carlos , Ruiz Agustín 
Published: February 2020

ABSTRACTLong runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of recent inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD). However, the search for recessive variants has been poorly assessed to date. To investigate homozygosity in AD, we performed a fine-scale ROH analysis including 21,100 individuals from 10 cohorts of European ancestry (11,919 AD cases and 9,181 controls). We detected an increase of homozygosity in AD cases compared to controls [βFROH(CI95%) = 0.051 (0.023 – 0.078); P = 3.25 x 10-4]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 x 10-16). The top associated ROH with AD risk (β (CI95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 x 10-4) was detected upstream theHS3ST1locus (chr4:11,189,482‒11,305,456), previously related to AD. Next, to construct a homozygosity map of AD cases, we selected ROHs shared by inbred AD cases extracted from an outbred population. We used whole-exome sequencing data from 1,449 individuals from the Knight-ADRC-NIA-LOAD (KANL) cohort to identify potential recessive variants in candidate ROHs. We detected a candidate marker, rs117458494, mapped in theSPON1locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
Tissue-specific transcriptome profiling of theArabidopsis thalianainflorescence stem reveals local cellular signatures
Authors: Shi Dongbo , Jouannet Virginie , Agustí Javier , Kaul Verena , Levitsky Victor , Sanchez Pablo , Mironova Victoria V , Greb Thomas 
Published: February 2020

AbstractGenome-wide gene expression maps with a high spatial resolution have substantially accelerated molecular plant science. However, the number of characterized tissues and growth stages is still small because of the limited accessibility of most tissues for protoplast isolation. Here, we provide gene expression profiles of the mature inflorescence stem ofArabidopsis thalianacovering a comprehensive set of distinct tissues. By combining fluorescence-activated nucleus sorting and laser-capture microdissection with next generation RNA sequencing, we characterize transcriptomes of xylem vessels, fibers, the proximal and the distal cambium, phloem, phloem cap, pith, starch sheath, and epidermis cells. Our analyses classify more than 15,000 genes as being differentially expressed among different stem tissues and reveal known and novel tissue-specific cellular signatures. By determining transcription factor binding regions enriched in promoter regions of differentially expressed genes, we furthermore provide candidates for tissue-specific transcriptional regulators. Our datasets predict expression profiles of an exceptional amount of genes and allow generating hypotheses toward the spatial organization of physiological processes. Moreover, we demonstrate that information on gene expression in a broad range of mature plant tissues can be established with high spatial resolution by nuclear mRNA profiling.One sentence summaryA genome-wide high-resolution gene expression map of the Arabidopsis inflorescence stem is established.
Abundance and Distribution ofHeterelmis cf. glabra(Coleoptera: Elmidae) within Dolan Falls Preserve and the Devils River State Natural Area, Texas, USA
Authors: Diaz Peter H. , Gibson J. Randy , Norris Chad W. , Thompson Carrie L. 
Published: February 2020

AbstractThe Devils River watershed in south-central Texas has baseflows entirely attributable to groundwater primarily sourced from the Edwards-Trinity and Edwards Aquifers. The largest known populations of a species of riffle beetle,Heterelmis cf. glabra, are located in springs associated with the upper Devils River. The focus of this study was to 1) determine site-level abundances ofH. cf. glabrausing open system N-mixture models, 2) test mesohabitat associations of members in the riffle beetle family Elmidae and, 3) measure and examine abiotic and habitat associations for adult and larval beetles within the study area. We sampled 32 spring sources to determine occupancy and abundance of adult and larval riffle beetles (Elmidae) within the study area. Spring sources were mapped and categorized by type (orifice, upwelling, group of springs, or seep). Basic water chemistry and flow rate categorization were also performed at each site. Model results suggest that rainfall, flow and site are important for detection ofH. cf. glabra. Based on our results, regular monitoring of these 32 sites using these methods, is recommended to conduct hypotheses tests on covariates influencing abundance. Such baseline information will be important in measuring impacts to this and other spring-associated species as the habitats of this region are impacted by natural or anthropogenic phenomena.