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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 48,100 bioRxiv papers from 215,661 authors.

Most tweeted bioRxiv papers, last 24 hours

390 results found. For more information, click each entry to expand.

81: miR-9 mediated noise optimization of the her6 oscillator is needed for cell state progression in the Zebrafish hindbrain
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Posted to bioRxiv 15 Apr 2019

miR-9 mediated noise optimization of the her6 oscillator is needed for cell state progression in the Zebrafish hindbrain
3 tweets developmental biology

Ximena Soto, Veronica Biga, Jochen Kursawe, Robert Lea, Parnian Doostdar, Nancy Papalopulu

Ultradian oscillations of key transcription factors, such as members of the Hes family, are thought to be important in Neural Progenitor Cell (NPC) maintenance and miR-9 acts as a tuner of these oscillations in vitro. However, the existence and the role of such dynamic oscillatory expression in vivo is poorly understood. Here, we have generated a Zebrafish CRISPR knock-in Her6::venus fusion (Hes1 orthologue) to study endogenous dynamic gene expression in the embryonic hindbrain. We show that Her6 undergoes a transition from irregular, noisy, fluctuations to periodic oscillations as neurogenesis proceeds. In the absence of miR-9 input, noise in the Her6 oscillator increases and NPCs are unable to transit away from an intermediary state where they co-express progenitor and early differentiation markers. Thus, Her6 oscillations are facilitated by noise optimization mediated by miR-9 and this noise-tuning step is functionally important for cells to transition to differentiation.

82: Characterising the vocal repertoire of the Indian wolf (Canis lupus pallipes)
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Posted to bioRxiv 18 Apr 2019

Characterising the vocal repertoire of the Indian wolf (Canis lupus pallipes)
3 tweets animal behavior and cognition

Sougata Sadhukhan, Lauren Hennelly, Bilal Habib

Vocal communication in social animals plays a crucial role in mate choice, maintaining social structure, and foraging strategy. The Indian grey wolf, among the less studied subspecies, is a social carnivore that lives in groups called packs and has many types of vocal communication. In this study, we characterise harmonic vocalisation types in the Indian wolf using howl survey responses and opportunistic recordings from captive and nine packs (each pack contains 2-9 individuals) of free-ranging Indian wolves. Using principal component analysis, hierarchical clustering, and discriminant function analysis, we found four vocal types using 270 recorded vocalisations (Average Silhouette width Si = 0.598) which include howls and howl-bark (N=238), whimper (N=2), social squeak (N=28), and whine (N=2). Although having a smaller body size, Indian wolf howls have an average mean fundamental frequency of 0.422KHz (±0.126), which is similar to other Holarctic clade subspecies. The whimper showed the highest frequency modulation (37.296±4.601 KHz) and the highest mean fundamental frequency (1.708±0.524 KHz) compared to other call types. Less information is available on the third vocalisation type, i.e. ‘Social squeak’ or ‘talking’ (Mean fundamental frequency =0.461±0.083 KHz), which is highly variable (coefficient of frequency variation = 18.778±3.587 KHz). Our study’s characterisation of the Indian wolf’s harmonic vocal repertoire provides a first step in understanding the function and contextual use of vocalisations in this social mammal.

83: Modeling implicates inhibitory network bistability as an underpinning of seizure initiation
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Posted to bioRxiv 18 Apr 2019

Modeling implicates inhibitory network bistability as an underpinning of seizure initiation
3 tweets neuroscience

Scott Rich, Homeira Moradi Chameh, Marjan Rafiee, Katie Ferguson, Frances K Skinner, Taufik Valiante

A plethora of recent experimental literature implicates the abrupt, synchronous activation of GABAergic interneurons in driving the sudden change in brain activity that heralds seizure initiation. However, the mechanisms predisposing an inhibitory network toward sudden coherence specifically during ictogenesis remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyper-excitable interneurons modeled to mimic treatment with 4-Aminopyridine (4-AP), an agent commonly used to model seizures \textit{in vivo} and \textit{in vitro}. Our \textit{in silico} study demonstrates that model inhibitory networks with 4-AP interneurons are more prone than their control counterparts to exist in a bistable state in which asynchronously firing networks can abruptly transition into synchrony due to a brief perturbation. We further show that perturbations driving this transition could reasonably arise \textit{in vivo} based on models of background excitatory synaptic activity in the cortex. Thus, these results propose a mechanism by which an inhibitory network can transition from incoherent to coherent dynamics in a fashion that may precipitate seizure as a downstream effect. Moreover, this mechanism specifically explains why inhibitory networks containing hyper-excitable interneurons are more vulnerable to this state change, and how such networks can undergo this transition without a permanent change in the drive to the system. This, in turn, potentially explains such networks' increased vulnerability to seizure initiated by GABAergic activity.

84: G-protein coupled receptor 88 knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson's disease.
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Posted to bioRxiv 24 Apr 2019

G-protein coupled receptor 88 knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson's disease.
3 tweets neuroscience

Benjamin Galet, Manuela Ingallinesi, Jonathan Pegon, Anh Do Thi, Philippe Ravassard, Nicole Faucon Biguet, Rolando Meloni

Beyond the motor disability, Parkinson's disease (PD) is also characterized by an early appearance of psychiatric symptoms such as apathy, depression, anxiety and cognitive deficits, which can entail dementia and psychosis in later stages. While current treatments may provide some level of symptomatic relief, their use is limited by the development of adverse effects such as impulse-control disorders. There is thus a medical need for targets with novel modes of action to treat these aspects of PD. In this context, we investigated GPR88, an orphan G-protein coupled receptor that is associated with psychiatric disorders and highly enriched in the striatum, where it exerts an inhibitory control over neurotransmitter systems that are compromised in PD. To evaluate the potential of GPR88 as a target for the treatment of the psychiatric symptoms of PD, we knocked-down (KD) its expression in sensorimotor (dorsolateral, DLS) or associative (dorsomedial, DMS) striatal areas in a translational rat model of early PD. Our findings indicate that Gpr88-KD in the DMS, but not DLS, reduced the alterations in mood, motivation and cognition that characterized the model, through modulation of the expression of regulator of G-protein signaling 4 (Rgs4) and of transcription factor ∆FosB. Furthermore, the rat model of PD exhibited allostatic changes in striatal activity markers that may be related to patterns observed in patients, and which were reduced by Gpr88-KD. Taken together, these results thus highlight the relevance of GPR88 as a therapeutic target for the psychiatric symptoms of PD.

85: Extensive splicing across the Saccharomyces cerevisiae genome
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Posted to bioRxiv 10 Jan 2019

Extensive splicing across the Saccharomyces cerevisiae genome
3 tweets molecular biology

Stephen Douglass, Calvin S Leung, Tracy L Johnson

Pre-mRNA splicing is vital for the proper function and regulation of eukaryotic gene expression. Saccharomyces cerevisiae has been used as a model organism for studies of RNA splicing because of the striking conservation of the spliceosome components and its catalytic activity. Nonetheless, there are relatively few annotated alternative splice forms, particularly when compared to higher eukaryotes. Here, we describe a method to combine large scale RNA sequencing data to accurately discover novel splice isoforms in Saccharomyces cerevisiae. Using our method, we find extensive evidence for novel splicing of annotated intron-containing genes as well as genes without previously annotated introns and splicing of transcripts that are antisense to annotated genes. By incorporating several mutant strains at varied temperatures, we find conditions which lead to differences in alternative splice form usage. Despite this, every class and category of alternative splicing we find in our datasets is found, often at lower frequency, in wildtype cells under normal growth conditions. Together, these findings show that there is widespread splicing in Saccharomyces cerevisiae, thus expanding our view of the regulatory potential of RNA splicing in yeast.

86: Genomics In The Jungle: Using Portable Sequencing As A Teaching Tool In Field Courses
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Posted to bioRxiv 29 Mar 2019

Genomics In The Jungle: Using Portable Sequencing As A Teaching Tool In Field Courses
3 tweets scientific communication and education

Mrinalini Watsa, Gideon A. Erkenswick, Aaron Pomerantz, Stefan Prost

Genetic research is a rapidly evolving field of study that is increasingly being utilized as a tool for wildlife conservation. However, researchers and science educators in remote areas can often find it difficult to access the latest genetic technologies, often due to a combination of high costs, bulky equipment, and lack of infrastructure. Recent technological innovations are resulting in portable, low-cost instruments that enable next-generation sequencing in remote environments, offering new opportunities to generate a more widespread network of trained conservation scientists, particularly within regions of high biodiversity. What is currently lacking are formalized educational efforts to teach participants in biodiverse areas with hands-on training in molecular biology and real-time DNA sequencing techniques. To address this challenge, we report the design and summarized feedback/outcomes of a conservation genetics field course, called 'Genomics in the Jungle', that took place at a field research station in the Amazon rainforest of southeastern Peru. The program was established by a small US-based NGO, Field Projects International, and facilitated by a local eco-tourism company in Peru, Inkaterra. We utilized portable sequencing technologies from Oxford Nanopore Technologies, and in-kind support from the manufacturers MiniPCR, MiniOne Systems, Promega, and New England Biolabs. Participants included a mix of non-Peruvian students and local/regional students, some of which had no prior exposure to a genetics laboratory. Overall, we maintain that portable sequencing technology is democratizing scientific research and conservation efforts, and is a major step forward for science educators and conservationists.

87: Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design
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Posted to bioRxiv 06 Mar 2019

Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design
3 tweets genomics

Jo Lynne Rokita, Komal S. Rathi, Maria F. Cardenas, Kristen A. Upton, Joy Jayaseelan, Katherine L. Cross, Jacob Pfeil, Laura E. Ritenour, Apexa Modi, Alvin Farrel, Gregory P Way, Nathan M. Kendsersky, Khushbu Patel, Gonzalo Lopez, Zalman Vaksman, Chelsea Mayoh, Jonas Nance, Kristyn McCoy, Michelle Haber, Kathryn Evans, Hannah McCalmont, Katerina Bendak, Julia W. Bohm, Glenn M. Marshall, Vanessa Tyrrell, Karthik Kalletla, Frank K. Braun, Lin Qi, Yunchen Du, Huiyuan Zhang, Holly B Lindsay, Sibo Zhao, Jack Shu, Patricia Baxter, Christopher Morton, Dias Kurmashev, Siyuan Zheng, Yidong Chen, Jay Bowen, Anthony C. Bryan, Kristen M. Leraas, Sara E. Coppens, HarshaVardhan Doddapaneni, Zeineen Momin, Wendong Zhang, Gregory I. Sacks, Lori S. Hart, Kateryna Krytska, Yael P. Mosse, Gregory J. Gatto, Yolanda Sanchez, Casey S. Greene, Sharon J. Diskin, Olena M. Vaske, David Haussler, Julie M Gastier-Foster, E. Anders Kolb, Richard Gorlick, Xiao-Nan Li, C. Patrick Reynolds, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Pichai Raman, David A Wheeler, John M. Maris

Accelerating cures for children with cancer remains an immediate challenge due to extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs) from high-risk childhood cancers, many refractory to current standard-of-care treatments. Here, we genomically characterize 261 PDX models from 29 unique pediatric cancer malignancies and demonstrate faithful recapitulation of histologies, subtypes, and refine our understanding of relapsed disease. Expression and mutational signatures are used to classify tumors for TP53 and NF1 inactivation, as well as impaired DNA repair. We anticipate that these data will serve as a resource for pediatric oncology drug development and guide rational clinical trial design for children with cancer.

88: Multi-immersion open-top light-sheet microscope for high-throughput imaging of cleared tissues
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Posted to bioRxiv 13 Feb 2019

Multi-immersion open-top light-sheet microscope for high-throughput imaging of cleared tissues
3 tweets bioengineering

Adam K Glaser, Nicholas P. Reder, Ye Chen, Chengbo Yin, Linpeng Wei, Soyoung Kang, Lindsey A. Barner, Weisi Xie, Erin F. McCarty, Chenyi Mao, Aaron R. Halpern, Caleb R. Stoltzfus, Jonathan S. Daniels, Michael Y. Gerner, Philip R Nicovich, Joshua C Vaughan, Lawrence D. True, Jonathan T.C. Liu

Recent advances in optical clearing and light-sheet microscopy have provided unprecedented access to structural and molecular information from intact tissues. However, current light-sheet microscopes have imposed constraints on the size, shape, number of specimens, and compatibility with various clearing protocols. Here we present a multi-immersion open-top light-sheet microscope that enables simple mounting of multiple specimens processed with a variety of protocols, which will facilitate wider adoption by preclinical researchers and clinical laboratories.

89: Simple study designs in ecology produce inaccurate estimates of biodiversity responses
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Posted to bioRxiv 23 Apr 2019

Simple study designs in ecology produce inaccurate estimates of biodiversity responses
3 tweets ecology

Alec P Christie, Tatsuya Amano, Philip A Martin, Gorm E Shackelford, Benno I Simmons, William J Sutherland

Ecologists use a wide range of study designs to estimate the impact of interventions or threats but there are no quantitative comparisons of their accuracy. For example, while it is accepted that simpler designs, such as After (sampling sites post-impact without a control), Before-After (BA) and Control-Impact (CI), are less robust than Randomised Controlled Trials (RCT) and Before-After Control-Impact (BACI) designs, it is not known how much less accurate they are. We simulate a step-change response of a population to an environmental impact using empirically-derived estimates of the major parameters. We use five ecological study designs to estimate the effect of this impact and evaluate each one by determining the percentage of simulations in which they accurately estimate the direction and magnitude of the environmental impact. We also simulate different numbers of replicates and assess several accuracy thresholds. We demonstrate that BACI designs could be 1.1-1.5 times more accurate than RCTs, 2.9-4.1 times more accurate than BA, 3.8-5.6 times more accurate than CI, and 6.8-10.8 times more accurate than After designs, when estimating to within ±30% of the true effect (depending on the sample size). We also found that increasing sample size substantially increases the accuracy of BACI designs but only increases the precision of simpler designs around a biased estimate; only by using more robust designs can accuracy increase. Modestly increasing replication of both control and impact sites also increased the accuracy of BACI designs more than substantially increasing replicates in just one of these groups. We argue that investment into using more robust designs in ecology, where possible, is extremely worthwhile given the inaccuracy of simpler designs, even when using large sample sizes. Based on our results we propose a weighting system that quantitatively ranks the accuracy of studies based on their study design and the number of replicates used. We hope these accuracy weights enable researchers to better account for study design in evidence synthesis when assessing the reliability of a range of studies using a variety of designs.

90: Predicting cognitive and mental health traits and their polygenic architecture using large-scale brain connectomics
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Posted to bioRxiv 16 Apr 2019

Predicting cognitive and mental health traits and their polygenic architecture using large-scale brain connectomics
3 tweets neuroscience

Luigi A. Maglanoc, Tobias Kaufmann, Dennis van der Meer, Andre F. Marquand, Thomas Wolfers, Rune Jonassen, Eva Hilland, Ole A Andreassen, Nils Inge Landrø, Lars T. Westlye

Cognitive abilities and mental disorders are complex traits sharing a largely unknown neuronal basis and aetiology. Their genetic architectures are highly polygenic and overlapping, which is supported by heterogeneous phenotypic expression and substantial clinical overlap. Brain network analysis provides a non-invasive means of dissecting biological heterogeneity yet its sensitivity, specificity and validity in clinical applications remains a major challenge. We used machine learning on static and dynamic temporal synchronization between all brain network nodes in 10,343 healthy individuals from the UK Biobank to predict (i) cognitive and mental health traits and (ii) their genetic underpinnings. We predicted age and sex to serve as our reference point. The traits of interest included individual level educational attainment and fluid intelligence (cognitive) and dimensional measures of depression, anxiety, and neuroticism (mental health). We predicted polygenic scores for educational attainment, fluid intelligence, depression, anxiety, and different neuroticism traits, in addition to schizophrenia. Beyond high accuracy for age and sex, permutation tests revealed above chance-level prediction accuracy for educational attainment and fluid intelligence. Educational attainment and fluid intelligence were mainly negatively associated with static brain connectivity in frontal and default mode networks, whereas age showed positive correlations with a more widespread pattern. In comparison, prediction accuracy for polygenic scores was at chance level across traits, which may serve as a benchmark for future studies aiming to link genetic factors and fMRI-based brain connectomics.

91: Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes
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Posted to bioRxiv 19 Dec 2018

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes
3 tweets neuroscience

Sarah E. Morgan, Jakob Seidlitz, Kirstie Whitaker, Rafael Romero-Garcia, Nicholas E Clifton, Cristina Scarpazza, Therese van Amelsvoort, Machteld Marcelis, Jim van Os, Gary Donohoe, David Mothersill, Aiden Corvin, Andrew Pocklington, Armin Raznahan, Philip McGuire, The PSYSCAN Consortium, Petra E. Vértes, Edward T. Bullmore

Schizophrenia has been conceived as a disorder of brain connectivity but it is unclear how this network phenotype is related to the emerging genetics. We used morphometric similarity analysis of magnetic resonance imaging (MRI) data as a marker of inter-areal cortical connectivity in three prior case-control studies of psychosis: in total, N=185 cases and N=227 controls. Psychosis was associated with globally reduced morphometric similarity (MS) in all 3 studies. There was also a replicable pattern of case-control differences in regional MS which was significantly reduced in patients in frontal and temporal cortical areas, but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in MS was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally over-expressed in cortical areas with reduced MS were significantly up-regulated in a prior post mortem study of schizophrenia. We propose that this combination of neuroimaging and transcriptional data provides new insight into how previously implicated genes and proteins, as well as a number of unreported proteins in their vicinity on the protein interaction network, may interact to drive structural brain network changes in schizophrenia.

92: Phylogenomics clarifies biogeographic and evolutionary history, and conservation status of West Indian tremblers and thrashers (Aves: Mimidae)
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Posted to bioRxiv 05 Feb 2019

Phylogenomics clarifies biogeographic and evolutionary history, and conservation status of West Indian tremblers and thrashers (Aves: Mimidae)
3 tweets evolutionary biology

Jeffrey M DaCosta, Matthew J. Miller, Jennifer L Mortensen, J. Michael Reed, Robert L Curry, Michael D Sorenson

The West Indian avifauna has provided fundamental insights into island biogeography, taxon cycles, and the evolution of avian behavior. Our interpretations, however, rely on robust hypotheses of evolutionary relationships and consistent conclusions about taxonomic status in groups with many endemic island populations. Here we present a phylogenetic study of the West Indian thrashers, tremblers, and allies, an assemblage of at least 5 species found on 29 islands, which is considered the archipelago's only avian radiation. We improve on previous phylogenetic studies of this group by using double-digest restriction site-associated DNA sequencing (ddRAD-seq) to broadly sample loci scattered across the nuclear genome. A variety of analyses, based on either nucleotide variation in 2,223 loci that were recovered in all samples or on 13,282 loci that were confidently scored as present or absent in all samples, converged on a single well-supported phylogenetic hypothesis. In contrast to previous studies, we found that the resident West Indian taxa form a monophyletic group, exclusive of the Neotropical-Nearctic migratory Gray Catbird Dumetella carolinensis, which breeds in North America. Earlier studies indicated that the Gray Catbird was nested within a clade of island resident species. Instead, our findings imply a single colonization of the West Indies without the need to invoke a subsequent 'reverse colonization' of the mainland by West Indian taxa. Furthermore, our study is the first to sample both endemic subspecies of the endangered White-breasted Thrasher Ramphocinclus brachyurus. We find that these subspecies have a long history of evolutionary independence with no evidence of gene flow, and are as genetically divergent from each other as other genera in the group. These findings support recognition of R. brachyurus (restricted to Martinique) and the Saint Lucia Thrasher R. sanctaeluciae as two distinct, single-island endemic species, and indicate the need to re-evaluate conservation plans for these taxa. Our results demonstrate the utility of phylogenomic datasets for generating robust systematic hypotheses.

93: In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation
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Posted to bioRxiv 18 Apr 2019

In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation
3 tweets genetics

Daniel Andergassen, Zachary D Smith, Jordan P. Lewandowski, Chiara Gerhardinger, Alexander Meissner, John L. Rinn

Recent evidence has determined that the conserved X chromosome mega-structures controlled by the Firre and Dxz4 alleles are not required for X chromosome inactivation (XCI) in cell lines. Here we determined the in vivo contribution of these alleles by generating mice carrying a single or double deletion of Firre and Dxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and Firre locus dependent gene sets. The largest transcriptional effect was observed in all strains lacking the Firre locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.

94: β-lactamase Amplification and Porin Loss Drive Progressive β-lactam Resistance in Recurrent ESBL Enterobacteriaceae Bacteremia
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Posted to bioRxiv 23 Apr 2019

β-lactamase Amplification and Porin Loss Drive Progressive β-lactam Resistance in Recurrent ESBL Enterobacteriaceae Bacteremia
3 tweets genomics

William C Shropshire, Samuel L Aitken, Reed Pifer, Jiwoong Kim, Micah M Bhatti, Xiqi Li, Awdhesh Kalia, Jessica Galloway-Pena, Pranoti Sahasrabhojane, Cesar A Arias, David E Greenberg, Blake M. Hanson, Samuel Shelburne

Carbapenem resistant Enterobacteriaceae (CRE) are a critical public health issue. Recent studies indicate many CRE lack carbapenemases, but contain extended spectrum β-lactamases (ESBLs). We investigated 16 longitudinal, recurrent cases of extended spectrum B-lactamase (ESBL)-positive Enterobacteriaceae bacteremia to gain insights into mechanisms underlying the emergence of non-carbapenemase producing CRE (non-CP-CRE). Using a combination of short- and long-read sequencing technologies, we identified that non-CP-CRE emerges from an ESBL background through a combination of insertion sequence mediated β-lactamase translocation, subsequent amplification of β-lactamase encoding genes such as blaOXA-1 and blaCTX-M, and porin inactivation. Interestingly, the β-lactamase gene amplification occurred both on plasmids and on the chromosome, including in the middle of porin-encoding genes. Additionally, overexpression of blaOXA-1 increased resistance to the broad-spectrum β-lactam, piperacillin-tazobactam. This analysis shows mechanisms underlying non-CP-CRE emergence and demonstrates that copy number of β-lactamase genes needs to be considered to fully understand antimicrobial resistance amongst key human pathogens.

95: The role of lineage, hemilineage and temporal identity in establishing neuronal targeting and connectivity in the Drosophila embryo
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Posted to bioRxiv 24 Apr 2019

The role of lineage, hemilineage and temporal identity in establishing neuronal targeting and connectivity in the Drosophila embryo
3 tweets neuroscience

Brandon Mark, Sen-Lin Lai, Aref Arzan Zarin, Laurina Manning, Albert Cardona, James Truman, Chris Q Doe

The mechanisms specifying neuronal diversity are well-characterized, yet it remains unclear how these mechanisms are used to establish neuronal morphology and connectivity. Here we map the developmental origin of over 78 neurons from seven identified neural progenitors (neuroblasts) within a complete TEM reconstruction of the Drosophila larval CNS. This allowed us to correlate developmental mechanism with neuronal projection and synapse targeting. We find that clonally-related neurons from individual neuroblasts project widely in the neuropil without preferential circuit formation. In contrast, the two NotchON/NotchOFF hemilineages from each neuroblast project to restricted dorsal/motor neuropil domains (NotchON) and ventral/sensory neuropil domains (NotchOFF). Thus, each neuroblast contributes both motor and sensory processing neurons, although they share little connectivity. Lineage-specific constitutive Notch transforms sensory to motor hemilineages, showing hemilineage identity determines neuronal targeting. Within a hemilineage, neurons of different temporal cohorts target their synapses to different sub-domains of the neuropil. Importantly, neurons sharing a sub-domain defined by hemilineage and temporal identity preferentially connect to neurons of another hemilineage/temporal profile. We propose that the mechanisms that generate neural diversity are also determinants of neural circuit formation.

96: Stacks 2: Analytical Methods for Paired-end Sequencing Improve RADseq-based Population Genomics
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Posted to bioRxiv 22 Apr 2019

Stacks 2: Analytical Methods for Paired-end Sequencing Improve RADseq-based Population Genomics
2 tweets genomics

Nicolas C Rochette, Angel G Rivera-Colón, Julian M Catchen

For half a century population genetics studies have put type II restriction endonucleases to work. Now, coupled with massively-parallel, short-read sequencing, the family of RAD protocols that wields these enzymes has generated vast genetic knowledge from the natural world. Here we describe the first software capable of using paired-end sequencing to derive short contigs from de novo RAD data natively. Stacks version 2 employs a de Bruijn graph assembler to build contigs from paired-end reads and overlap those contigs with the corresponding single-end loci. The new architecture allows all the individuals in a meta population to be considered at the same time as each RAD locus is processed. This enables a Bayesian genotype caller to provide precise SNPs, and a robust algorithm to phase those SNPs into long haplotypes -- generating RAD loci that are 400-800bp in length. To prove its recall and precision, we test the software with simulated data and compare reference-aligned and de novo analyses of three empirical datasets. We show that the latest version of Stacks is highly accurate and outperforms other software in assembling and genotyping paired-end de novo datasets.

97: Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
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Posted to bioRxiv 07 Jul 2018

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
2 tweets cell biology

Ashley J. Earle, Tyler J. Kirby, Gregory R. Fedorchak, Philipp Isermann, Jineet Patel, Sushruta Iruvanti, Steven A Moore, Gisele Bonne, Lori L. Wallrath, Jan Lammerding

Mutations in the human LMNA gene, which encodes the nuclear envelope proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive nuclear envelope damage, consisting of chromatin protrusions and transient rupture of the nuclear envelope, in skeletal muscle cells in vitro and in vivo. The nuclear envelope damage was associated with progressive DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, nuclear envelope damage resulted from nuclear movement in maturing skeletal muscle cells, rather than actomyosin contractility, and was reversed by either depletion of kinesin-1 or stabilization of microtubules. Depletion of kinesin-1 also rescued DNA damage, indicating that DNA damage is the result of nuclear envelope damage. The extent of nuclear envelope damage and DNA damage in the different Lmna mouse models strongly correlated with the disease onset and severity in vivo, and inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA associated muscular dystrophy similarly revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for these skeletal muscle diseases.

98: Phigaro: high throughput prophage sequence annotation
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Posted to bioRxiv 22 Apr 2019

Phigaro: high throughput prophage sequence annotation
2 tweets bioinformatics

Elizaveta V. Starikova, Polina O. Tikhonova, Nikita A. Prianichnikov, Chris M Rands, Evgeny M Zdobnov, Vadim M Govorun

Phigaro is a standalone command-line application that is able to detect prophage regions taking raw genome and metagenome assemblies as an input. It also produces dynamic annotated "prophage genome maps" and marks possible transposon insertion spots inside prophages. It provides putative taxonomic annotations that can distinguish tailed from non-tailed phages. It is applicable for mining prophage regions from large metagenomic datasets.

99: DeepGOPlus: Improved protein function prediction from sequence
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Posted to bioRxiv 23 Apr 2019

DeepGOPlus: Improved protein function prediction from sequence
2 tweets bioinformatics

Maxat Kulmanov, Robert Hoehndorf

Protein function prediction is one of the major tasks of bioinformatics that can help in wide range of biological problems such as understanding disease mechanisms or finding drug targets. Many methods are available for predicting protein functions from sequence based features, protein--protein interaction networks, protein structure or literature. However, other than sequence, most of the features are difficult to obtain or not available for many proteins thereby limiting their scope. Furthermore, the performance of sequence-based function prediction methods is often lower than methods that incorporate multiple features and predicting protein functions may require a lot of time. We developed a novel method for predicting protein functions from sequence alone which combines deep convolutional neural network (CNN) model with sequence similarity based predictions. Our CNN model scans the sequence for motifs which are predictive for protein functions and combines this with functions of similar proteins. We evaluate the performance of DeepGOPlus on the CAFA3 dataset and significantly improve the performance of predictions of biological processes and cellular components with F_max of 0.47 and 0.70, respectively, using only the amino acid sequence of proteins as input. DeepGOPlus can annotate around 40 protein sequences per second, thereby making fast and accurate function predictions available for a wide range of proteins.

100: GWAS of brain volume on 54,407 individuals and cross-trait analysis with intelligence identifies shared genomic loci and genes
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Posted to bioRxiv 19 Apr 2019

GWAS of brain volume on 54,407 individuals and cross-trait analysis with intelligence identifies shared genomic loci and genes
2 tweets genetics

Philip R Jansen, Mats Nagel, Kyoko Watanabe, Yongbin Wei, Jeanne E Savage, Christiaan A de Leeuw, Martijn van den Heuvel, Sophie van der Sluis, Danielle Posthuma

The phenotypic correlation between human intelligence and brain volume (BV) is considerable (r≈0.40), and has been shown to be due to shared genetic factors. To further examine specific genetic factors driving this correlation, we present genomic analyses of the genetic overlap between intelligence and BV using genome-wide association study (GWAS) results. First, we conducted the largest BV GWAS meta-analysis to date (N=54,407 individuals), followed by functional annotation and gene-mapping. We identified 35 genomic loci (27 novel), implicating 362 genes (346 novel) and 23 biological pathways for BV. Second, we used an existing GWAS for intelligence (N=269,867 individuals), and estimated the genetic correlation (rg) between BV and intelligence to be 0.23. We show that the rg is driven by physical overlap of GWAS hits in 5 genomic loci. We identified 67 shared genes between BV and intelligence, which are mainly involved in important signaling pathways regulating cell growth. Out of these 67 we prioritized 32 that are most likely to have functional impact. These results provide new information on the genetics of BV and provide biological insight into BV's shared genetic etiology with intelligence.

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