Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 42,904 bioRxiv papers from 193,370 authors.
Most tweeted bioRxiv papers, last 24 hours
258 results found. For more information, click each entry to expand.
9 tweets genomics
DNA synthesis is a fundamental requirement for cell proliferation and DNA repair, but no tools exist to identify the location, direction and speed of replication forks with base pair resolution. Mammalian cells have the ability to incorporate thymidine analogs along with the natural A, T, G and C bases during DNA synthesis, which allows for labelling of replicating or repaired DNA. Most sequencing platforms rely on base-pairing to identify the four canonical nucleotides, and are thus unable to distinguish them from these analogs. In contrast, the Oxford Nanopore Technologies (ONT) MinION infers nucleotide identity from changes in the ionic current as DNA strands are pulled through nanopores and can in principle differentiate noncanonical nucleotides from natural ones. Here, we demonstrate the use of the ONT MinION to detect 11 different thymidine analogs including CldU, BrdU, IdU, as well as, EdU alone or coupled to Biotin and other bulky adducts in synthetic DNA templates. We also show detection of IdU in the genome of mouse pluripotent stem cells. We find that different modifications generate variable shifts in ionic signals, providing a method of using analog combinations to identify the location and direction of DNA synthesis and repair at high resolution. We conclude that this novel method has the potential for single-base, genome-wide examination of DNA replication in stem cell differentiation or cell transformation.
9 tweets microbiology
Evidence suggests many marine bacteria are cosmopolitan, with widespread but sparse strains poised to seed abundant populations upon conducive growth conditions. However, studies supporting this 'microbial seed bank' hypothesis have analyzed taxonomic marker genes rather than whole genomes/metagenomes, leaving open the possibility that disparate ocean regions harbor endemic gene content. The Red Sea is isolated geographically from the rest of the ocean and has a combination of high irradiance, high temperature, and high salinity that is unique among the ocean; we therefore asked whether it harbors endemic gene content. We sequenced and assembled single-cell genomes of 21 SAR11 (subclades Ia, Ib, Id, II) and 5 Prochlorococcus (ecotype HLII) cells from the Red Sea and combined them with globally-sourced reference genomes to cluster genes into ortholog groups (OGs). Ordination of OG composition could distinguish clades, including phylogenetically cryptic Prochlorococcus ecotypes LLII and LLIII. Compared with reference genomes, 1% of Prochlorococcus and 17% of SAR11 OGs were unique to the Red Sea genomes (RS-OGs). Most (83%) RS-OGs had no annotated function, but 65% of RS-OGs were expressed in diel Red Sea metatranscriptomes, suggesting they could be functional. Searching Tara Oceans metagenomes, RS-OGs were as likely to be found as non-RS-OGs; nevertheless, Red Sea and other warm samples could be distinguished from cooler samples using the relative abundances of OGs. The results suggest that the prevalence of OGs in these surface ocean bacteria is largely cosmopolitan, with differences in population metagenomes manifested by differences in relative abundance rather than complete presence-absence of OGs.
8 tweets epidemiology
Ari V Ahola-Olli, Linda Mustelin, Maria Kalimeri, Johannes Kettunen, Jari Jokelainen, Juha Auvinen, Katri Puukka, Aki S Havulinna, Terho Lehtimaki, Mika Kahonen, Markus Juonala, Sirkka Keinanen-Kiukaanniemi, Veikko Salomaa, Markus Perola, Marjo-Riitta Jarvelin, Mika Ala-Korpela, Olli Raitakari, Peter Würtz
Objective: Advances in metabolomics now allow high-throughput biomarker profiling of large population studies. We aimed to identify circulating metabolic biomarkers predictive of type 2 diabetes in young adults. Methods: Nuclear magnetic resonance metabolomics was used to quantify 229 metabolic measures in 11,896 individuals from four Finnish cohorts (mean age 33 years, range 24-45). Associations between baseline metabolites and risk of type 2 diabetes onset during 8-15 years of follow-up (392 incident cases) were assessed by logistic regression adjusted for sex, age, body mass index, and fasting glucose. Results: Out of 229 metabolic measures, 113 were associated with incident diabetes in meta-analysis of the four cohorts (P<0.0009; odds ratios per 1-SD: 0.59-1.50). Among the strongest predictors of diabetes risk were branched-chained and aromatic amino acids (odds ratios 1.31-1.33), triglyceride fractions within the largest very-low-density lipoprotein particles (VLDL; odds ratios 1.33-1.50)), as well as linoleic omega-6 fatty acids (odds ratio 0.75) and free cholesterol in large high-density lipoprotein particles (HDL; odds ratio 0.59). A biomarker score comprised of phenylalanine, free cholesterol in large HDL, and the ratio of cholesteryl esters to total lipids in large VLDL was predictive of the risk for future diabetes in an independent validation cohort (odds ratio 10.1 [95% confidence intervals 4.2-24.1] comparing individuals in upper vs lower fifth of biomarker score). Adjustment for routine lipids and insulin attenuated the odds ratio to 5.8 [2.2-15.1]. Conclusions: Metabolic aberrations across multiple molecular pathways are predictive of the long-term risk of type 2 diabetes in young adults. Comprehensive metabolic profiling may potentially help targeting preventive interventions for young asymptomatic individuals at increased risk for type 2 diabetes.
8 tweets bioinformatics
The open-source de-novo Protein-Level ASSembler Plass (https://plass.mmseqs.org) assembles six-frame-translated sequencing reads into protein sequences. It recovers 2 to 10 times more protein sequences from complex metagenomes and can assemble huge datasets. We assembled two redundancy-filtered reference protein catalogs, 2 billion sequences from 640 soil samples (SRC) and 292 million sequences from 775 marine eukaryotic metatranscriptomes (MERC), the largest free collections of protein sequences.
8 tweets immunology
Effective vaccines inducing lifelong protection against many important infections such as respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), influenza and Epstein-Barr virus (EBV) are not yet available despite decades of research. As an alternative to a protective vaccine we developed a genetic engineering strategy in which CRISPR/Cas9 was utilized to replace endogenously-encoded antibodies with antibodies protective against RSV, HIV, influenza or EBV in primary human or murine B cells. The engineered antibodies were expressed in up to 59% of primary B cells under the control of endogenous regulatory elements, which maintained normal antibody expression and secretion. Importantly, a single transfer of murine B cells engineered to express an antibody protective against RSV resulted in potent and durable protection against RSV infection in immunocompromised hosts. This approach offers the opportunity to achieve sterilizing immunity against pathogens for which traditional vaccination has failed to induce or maintain protective antibody responses.
8 tweets genetics
Supernumerary B chromosomes (Bs), which are often preferentially inherited, deviating from usual Mendelian segregation. This chromosome drive is one of the most important features of Bs. Here we analyzed the drive mechanism of Aegilops speltoides Bs and provide direct insight into its cellular mechanism. Comparative genomics resulted in the identification of the tandem repeat AesTR-183 of Ae. speltoides Bs, which also can be found on the Bs of Ae. mutica and rye, was used to track Bs during microgametogenesis. Nondisjunction of CENH3-positive, tubulin interacting B sister chromatids and an asymmetric spindle during first pollen grain mitosis are likely components of the accumulation process. A quantitative flow cytometric approach revealed, that independent on the number of Bs present in the mother plant Bs accumulate in the generative nuclei with more than 93%. Nine of eleven tested (peri)centromeric repeats were shared by A and B chromosomes. A common origin of the drive process in Poaceae is likely.
8 tweets evolutionary biology
The skin is the largest human organ, functioning to serve as the protective barrier to the harsh, outside world. Recent studies have revealed that large numbers of somatic mutations accumulate in normal tissue, which can be used to infer skin cell dynamics. Here we present the first realistic, cell-genome mechanistic epidermal model that shows homeostasis imposes a characteristic log-linear subclone size distribution for both neutral and oncogenic driver mutations, where the largest skin subclones are the oldest subclones. Because homeostasis inherently limits proliferation and therefore clonal sweeps, selection for driver mutations (NOTCH1 and TP53) in normal epidermis is instead conferred by greater persistence, which leads to larger subclone sizes. These results highlight how the integration of mechanistic modeling with genomic data provide novel insights into the evolutionary cell dynamics of normal human homeostatic tissues.
8 tweets genetics
Mark James Adams, David M. Howard, Michelle Luciano, Gail M Davies, William David Hill, 23andMe Research Team, Major Depressive Disorder Working Group of the Psy, Daniel J Smith, Ian J Deary, David J Porteous, Andrew M McIntosh
Major depressive disorder and neuroticism share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression. We analysed two sets of summary statistics from genome-wide association studies of depression (from the Psychiatric Genomics Consortium and 23andMe) and compared them to GWAS of neuroticism (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only neuroticism, or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with neuroticism. We found evidence that most genetic variants associated with depression are likely to be shared with neuroticism. The overlapping common genetic variance of depression and neuroticism was negatively genetically correlated with cognitive function and positively genetically correlated with several psychiatric disorders. We found that the genetic contributions unique to depression, and not shared with neuroticism, were correlated with inflammation, cardiovascular disease, and sleep patterns. Our findings demonstrate that, while genetic risk factors for depression are largely shared with neuroticism, there are also non-neuroticism related features of depression that may be useful for further patient or phenotypic stratification.
7 tweets cell biology
To increase our understanding of cells, there is a need for specific markers to identify biomolecules, cellular structures and compartments. One type of markers comprises genetically encoded fluorescent probes that are linked with protein domains, peptides and/or signal sequences. These markers are encoded on a plasmid and they allow straightforward, convenient labeling of cultured mammalian cells by introducing the plasmid into the cells. Ideally, the fluorescent marker combines favorable spectroscopic properties (brightness, photostability) with specific labeling of the structure or compartment of interest. Here, we report on our ongoing efforts to generate robust and bright genetically encoded fluorescent markers for highlighting structures and compartments in living cells.
7 tweets developmental biology
Rationale: Accurate and efficient quantification of heartbeats in small fish models is an important readout to study cardiovascular biology, disease states and pharmacology at large scale. However, dependence on anesthesia, laborious sample orientation or requirement for fluorescent reporters have hampered the establishment of high-throughput heartbeat analysis. Objective: To overcome these limitations, we aimed to develop a high-throughput assay with automated heart rate scoring in medaka (Oryzias latipes) and zebrafish (Danio rerio) embryos under physiological conditions designed for genetic screens and drug discovery and validation. Methods and Results: We established an efficient screening assay employing automated label-free heart rate determination of randomly oriented, non-anesthetized specimen in microtiter plates. Automatically acquired bright-field data feeds into an easy-to-use HeartBeat software, a MATLAB algorithm with graphical user interface developed for automated quantification of heart rate and rhythm. Sensitivity of the assay and algorithm was demonstrated by profiling heart rates during entire embryonic development. Our analysis pipeline revealed acute temperature changes triggering rapid adaption of heart rates, which has implications for standardization of experimental layout. The approach is scalable and allows scoring of multiple embryos per well resulting in a throughput of >500 embryos per 96-well plate. In a proof of principle screen for compound testing, our assay captured concentration-dependent effects of nifedipine and terfenadine over time. Conclusion: A novel workflow and HeartBeat software provide efficient means for reliable and direct quantification of heart rate and rhythm of small fish in a physiological environment. Importantly, confounding factors such as anesthetics or laborious mounting are eliminated. We provide detailed profiles of embryonic heart rate dynamics in medaka and zebrafish as reference for future assay development. Ease of sample handling, automated imaging, physiological conditions and software-assisted analysis now facilitate various large-scale applications ranging from phenotypic screening, interrogation of gene functions to cardiovascular drug development pipelines.
7 tweets evolutionary biology
Qiaowei Pan, Romain Feron, Ayaka Yano, Rene Guyomard, Elodie Jouanno, Estelle Vigouroux, Ming Wen, Jean-Mickael Busnel, Julien Bobe, Jean-Paul Concordet, Hugues Parrinello, Laurent Journot, Christophe Klopp, Jerome Lluch, Celine Roques, John Postlethwait, Manfred Schartl, Amaury Herpin, Yann Guiguen
Teleost fishes, thanks to their rapid evolution of sex determination mechanisms, provide remarkable opportunities to study the formation of sex chromosomes and the mechanisms driving the birth of new master sex determining (MSD) genes. However, the evolutionary interplay between the sex chromosomes and the MSD genes they harbor is rather unexplored. We characterized a male-specific duplicate of the anti-Müllerian hormone (amh) as the MSD gene in Northern Pike (Esox lucius), using genomic and expression evidences as well as by loss-of-function and gain-of-function experiments. Using RAD-Sequencing from a family panel, we identified Linkage Group (LG) 24 as the sex chromosome and positioned the sex locus in its sub-telomeric region. Furthermore, we demonstrated that this MSD originated from an ancient duplication of the autosomal amh gene, which was subsequently translocated to LG24. Using sex-specific pooled genome sequencing and a new male genome sequence assembled using Nanopore long reads, we also characterized the differentiation of the X and Y chromosomes, revealing a small male-specific insertion containing the MSD gene and a limited region with reduced recombination. Our study depicts an unexpected level of limited differentiation within a pair of sex chromosomes harboring an old MSD gene in a wild population of teleost fish, highlights the pivotal role of genes from the amh pathway in sex determination, as well as the importance of gene duplication as a mechanism driving the turnover of sex chromosomes in this clade.
6 tweets bioinformatics
Motivation: Discovery of genetic variants by whole genome sequencing has proven a powerful approach to study the etiology of complex genetic disorders. Elucidation of all variants is a necessary step in identifying causative variants and disease genes. In particular, there is an increased interest in detection of de novo variation and investigation of its role in various disorders. State-of-the-art methods for variant discovery rely on mapping reads from each individual to a reference genome and predicting variants from difference observed between the mapped reads and the reference genome. This process typically results in millions of variant predictions, most of which are inherited and irrelevant to the phenotype of interest. To distinguish between inherited variation and novel variation resulting from de novo germline mutation, whole-genome sequencing of close relatives (especially parents and siblings) is commonly used. However, standard mapping-based approaches tend to have a high false-discovery rate for de novo variant prediction, which in many cases arises from problems with read mapping. This is a particular challenge in predicting de novo indels and structural variants. Results: We have developed a mapping-free method, Kevlar, for de novo variant discovery based on direct comparison of sequence content between related individuals. Kevlar identifies high-abundance k-mers unique to the individual of interest and retrieves the reads containing these k-mers. These reads are easily partitioned into disjoint sets by shared k-mer content for subsequent locus-by-locus processing and variant calling. Kevlar also utilizes a novel probabilistic approach to score and rank the variant predictions to identify the most likely de novo variants. We evaluated Kevlar on simulated and real pedigrees, and demonstrate its ability to detect both de novo SNVs and indels with high sensitivity and specificity. Availability: https://github.com/dib-lab/kevlar
6 tweets neuroscience
How does the brain combine information predictive of the value of a visually guided task (incentive value) with information predictive of where task relevant stimuli may occur (spatial certainty)? Human behavioural evidence indicates that these two predictions are combined additively to bias visual selection (additive hypothesis), whereas neuroeconomic studies posit that they may be multiplicatively combined (expected value hypothesis). We sought to arbitrate between these two alternatives, and to test the possibility that both operations are available to visual prioritization mechanisms, but that their use is context dependent (mixed operations hypothesis). Participants viewed two coloured placeholders that specified the potential value of correctly identifying an imminent letter target if it appeared in that placeholder. Then, prior to the target's presentation, an endogenous spatial cue was presented indicating the target's more likely location. Spatial cues were parametrically manipulated with regard to the information gained (in bits). Across two experiments, response time and accuracy were greater for targets appearing in high versus low value placeholders and higher when targets appeared in validly cued locations, even under conditions designed to impinge the optimality of an additive operation. Interestingly, these factors did not interact; Bayesian model selection showed that the additive hypothesis clearly outperformed the expected value and mixed operations hypotheses in accounting for the observed data from both experiments. These findings refute theories that expected value computations are the singular mechanism driving the deployment of endogenous spatial attention. Instead, incentive value and spatial certainty seem to act independently to influence visual selection.
6 tweets evolutionary biology
Larger populations generally adapt faster to their existing environment. However, it is unknown if the population size experienced during evolution influences the ability to face sudden environmental changes. To investigate this issue, we subjected replicate Escherichia coli populations of different sizes to experimental evolution in an environment containing a cocktail of three antibiotics. In this environment, the ability to actively efflux molecules outside the cell is expected to be a major fitness-affecting trait. We found that all the populations eventually reached similar fitness in the antibiotic cocktail despite adapting at different speeds, with the larger populations adapting faster. Surprisingly, whereas efflux activity enhanced in the smaller populations, it decayed in the larger ones. The evolution of efflux activity was largely shaped by pleiotropic responses to selection and not by drift. This demonstrates that quantitative differences in population size can lead to qualitative differences (decay/enhancement) in the fate of a character during adaptation to identical environments. Furthermore, the larger populations showed inferior fitness upon sudden exposure to several alternative stressful environments. These observations provide a novel link between population size and vulnerability to environmental changes. Counter-intuitively, adapting in larger numbers can render bacterial populations more vulnerable to abrupt environmental changes.
6 tweets neuroscience
Can humans be trained to make strategic use of unconscious representations in their own brains? We investigated how one can derive reward-maximizing choices from latent high-dimensional information represented stochastically in neural activity. In a novel decision-making task, reinforcement learning contingencies were defined in real-time by fMRI multivoxel pattern analysis; optimal action policies thereby depended on multidimensional brain activity that took place below the threshold of consciousness. We found that subjects could solve the task, when their reinforcement learning processes were boosted by implicit metacognition to estimate the relevant brain states. With these results we identified a frontal-striatal mechanism by which the brain can untangle tasks of great dimensionality, and can do so much more flexibly than current artificial intelligence.
6 tweets bioinformatics
Identification of functional transcription factors that regulate a given gene set is an important problem in gene regulation studies. Conventional approaches for identifying transcription factors, such as DNA sequence motif analysis, are unable to predict functional binding of specific factors and not sensitive to detect factors binding at distal enhancers. Here we present Binding Analysis for Regulation of Transcription (BART), a novel computational method and software package for predicting functional transcription factors that regulate a query gene set or associate with a query genomic profile, based on more than 6,000 existing ChIP-seq datasets for over 400 factors in human or mouse. This method demonstrates the advantage of utilizing publicly available data for functional genomics research.
6 tweets genomics
We describe MULTI-seq: A rapid, modular, and universal scRNA-seq sample multiplexing strategy using lipid-tagged indices. MULTI-seq reagents can barcode any cell type from any species with an accessible plasma membrane. The method is compatible with enzymatic tissue dissociation, and also preserves viability and endogenous gene expression patterns. We leverage these features to multiplex the analysis of multiple solid tissues comprising human and mouse cells isolated from patient-derived xenograft mouse models. We also utilize MULTI-seq's modular design to perform a 96-plex perturbation experiment with human mammary epithelial cells. MULTI-seq also enables robust doublet identification, which improves data quality and increases scRNA-seq cell throughput by minimizing the negative effects of Poisson loading. We anticipate that the sample throughput and reagent savings enabled by MULTI-seq will expand the purview of scRNA-seq and democratize the application of these technologies within the scientific community.
5 tweets neuroscience
"Neural coding" is a popular metaphor in neuroscience, where objective properties of the world are communicated to the brain in the form of spikes. Here I argue that this metaphor is often inappropriate and misleading. First, when neurons are said to encode experimental parameters, the neural code depends on experimental details that are not carried by the coding variable. Thus, the representational power of neural codes is much more limited than generally implied. Second, neural codes carry information only by reference to things with known meaning. In contrast, perceptual systems must build information from relations between sensory signals and actions, forming a structured internal model. Neural codes are inadequate for this purpose because they are unstructured. Third, coding variables are observables tied to the temporality of experiments, while spikes are timed actions that mediate coupling in a distributed dynamical system. The coding metaphor tries to fit the dynamic, circular and distributed causal structure of the brain into a linear chain of transformations between observables, but the two causal structures are incongruent. I conclude that the neural coding metaphor cannot provide a basis for theories of brain function, because it is incompatible with both the causal structure of the brain and the informational requirements of cognition.
5 tweets systems biology
Although mRNAs are key molecules for understanding life, there exists no method to determine the full-length sequence of endogenous mRNAs including their poly(A) tails. Moreover, although poly(A) tails can be modified in functionally important ways, there also exists no method to accurately sequence them. Here, we present FLAM-seq, a rapid and simple method for high-quality sequencing of entire mRNAs. We report a cDNA library preparation method coupled to single-molecule sequencing to perform FLAM-seq. Using human cell lines, brain organoids, and C. elegans we show that FLAM-seq delivers high-quality full-length mRNA sequences for thousands of different genes per sample. We find that (a) 3' UTR length is correlated with poly(A) tail length, (b) alternative polyadenylation sites and alternative promoters for the same gene are linked to different tail lengths, (c) tails contain a significant number of cytosines. Thus, we provide a widely useful method and fundamental insights into poly(A) tail regulation.
5 tweets neuroscience
J. Edward van Veen, Laura G. Kammel, Patricia C. Bunda, Michael Shum, Michelle S Reid, Jae W. Park, Zhi Zhang, Megan G. Massa, Douglas Arneson, Haley Hrncir, Marc Liesa, Arthur P. Arnold, Xia Yang, Stephanie M Correa
Estrogen signaling in the central nervous system promotes weight loss by increasing thermogenesis and physical activity in the ventromedial hypothalamus (VMH), but the precise neuronal populations regulating these aspects of energy expenditure remain unclear. Here we define the molecular and functional heterogeneity of the VMH using single cell RNA sequencing, in situ hybridization, chemogenetic activation, and targeted gene knockdown. We describe six molecularly distinct neuron clusters in the VMH. In females, estrogen receptor alpha (ERα) is restricted to neurons expressing tachykinin-1 (Tac1) or reprimo (Rprm). Further, Tac1 and Rprm expression is enriched in females, a sex difference that is established by permanent effects of gonadal hormones early in life. Finally, while Tac1 ablation selectively impairs movement, here we show that silencing Rprm selectively dysregulates temperature without affecting physical activity. Together this work provides a novel architectural framework whereby distinct and sexually differentiated neuron populations within the VMH mediate sex-specific aspects of metabolic homeostasis.
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