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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 59,974 bioRxiv papers from 266,630 authors.

Most tweeted bioRxiv papers, last 24 hours

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

1: Precision calcium imaging of dense neural populations via a cell body-targeted calcium indicator
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Posted to bioRxiv 17 Sep 2019

Precision calcium imaging of dense neural populations via a cell body-targeted calcium indicator
74 tweets neuroscience

Or A. Shemesh, Changyang Linghu, Kiryl D. Piatkevich, Daniel Goodwin, Howard Gritton, Michael F. Romano, Cody A Siciliano, Ruixuan Gao, Chi-Chieh (Jay) Yu, Hua-an Tseng, Seth Bensussen, Sujatha Narayan, Chao-Tsung Yang, Limor Freifeld, Ishan Gupta, Habiba Noamany, Nikita Pak, Young-Gyu Yoon, Jeremy F.P. Ullmann, Burcu Guner-Ataman, Zoe R. Sheinkopf, Won Min Park, Shoh Asano, Amy Keating, James Trimmer, Jacob Reimer, Andreas Tolias, Kay M Tye, Xue Han, Misha B Ahrens, Edward S Boyden

Methods for one-photon fluorescent imaging of calcium dynamics in vivo are popular due to their ability to simultaneously capture the dynamics of hundreds of neurons across large fields of view, at a low equipment complexity and cost. In contrast to two-photon methods, however, one-photon methods suffer from higher levels of crosstalk between cell bodies and the surrounding neuropil, resulting in decreased signal-to-noise and artifactual correlations of neural activity. Here, we address this problem by engineering cell body-targeted variants of the fluorescent calcium indicator GCaMP6f. We screened fusions of GCaMP6f to both natural as well as engineered peptides, and identified fusions that localized GCaMP6f to within approximately 50 microns of the cell body of neurons in live mice and larval zebrafish. One-photon imaging of soma-targeted GCaMP6f in dense neural circuits reported fewer artifactual spikes from neuropil, increased signal-to-noise ratio, and decreased artifactual correlation across neurons. Thus, soma-targeting of fluorescent calcium indicators increases neuronal signal fidelity and may facilitate even greater usage of simple, powerful, one-photon methods of population imaging of neural calcium dynamics.

2: Most cancers carry a substantial deleterious load due to Hill-Robertson interference
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Posted to bioRxiv 14 Sep 2019

Most cancers carry a substantial deleterious load due to Hill-Robertson interference
70 tweets evolutionary biology

Susanne Tilk, Christina Curtis, Dmitri Petrov, Christopher Dennis McFarland

Introduction Cancer genomes exhibit surprisingly weak signatures of negative selection[1][1],[2][2]. This may be because tumors evolve either under very weak selective pressures (‘weak selection’) or under conditions that prevent the elimination of many deleterious passenger mutations (‘poor efficacy of selection’)xs. Rationale The weak selection model argues that the majority of genes are only important for multicellular function. The poor efficacy of selection model argues, in contrast, that genome-wide linkage in cancer prevents many deleterious mutations from being removed via Hill-Robertson interference[3][3]. Since these linkage effects weaken as mutation rates decrease, we predict that cancers with lower mutational burdens should exhibit stronger signals of negative selection. Furthermore, because linkage affects driver mutations as well, low mutational burden cancers should also show stronger evidence of positive selection in driver genes. Neither pattern — in drivers or passengers — is expected under the weak selection model. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. Results We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, and are present in clonal and subclonal mutations. Two additional orthogonal lines of evidence support the weak efficacy model: passengers are less damaging in low mutational burden cancers, and patterns of attenuated selection also emerge in Copy Number Alterations. Finally, we find that an evolutionary model incorporating Hill-Robertson interference can reproduce both patterns of attenuated selection in drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. Conclusion Collectively, our findings suggest that the lack of signals of negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost) and succeed due to acquisition of additional strong drivers (~5 with an overall benefit of ~130%). Understanding how this deleterious load is overcome may help identify cancer vulnerabilities that may be targeted by new and existing therapies. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3

3: Selection of representative genomes for 24,706 bacterial and archaeal species clusters provide a complete genome-based taxonomy
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Posted to bioRxiv 18 Sep 2019

Selection of representative genomes for 24,706 bacterial and archaeal species clusters provide a complete genome-based taxonomy
67 tweets microbiology

Donovan H Parks, Maria Chuvochina, Pierre-Alain Chaumeil, Christian Rinke, Aaron J. Mussig, Philip Hugenholtz

We recently introduced the Genome Taxonomy Database (GTDB), a phylogenetically consistent, genome-based taxonomy providing rank normalized classifications for nearly 150,000 genomes from domain to genus. However, nearly 40% of the genomes used to infer the GTDB reference tree lack a species name, reflecting the large number of genomes in public repositories without complete taxonomic assignments. Here we address this limitation by proposing 24,706 species clusters which encompass all publicly available bacterial and archaeal genomes when using commonly accepted average nucleotide identity (ANI) criteria for circumscribing species. In contrast to previous ANI studies, we selected a single representative genome to serve as the nomenclatural type for circumscribing each species with type strains used where available. We complemented the 8,792 species clusters with validly or effectively published names with 15,914 de novo species clusters in order to assign placeholder names to the growing number of genomes from uncultivated species. This provides the first complete domain to species taxonomic framework which will improve communication of scientific results.

4: DolphinNext: A graphical user interface for creating Nextflow pipelines
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Posted to bioRxiv 02 Jul 2019

DolphinNext: A graphical user interface for creating Nextflow pipelines
49 tweets bioinformatics

Onur Yukselen, Osman Turkyilmaz, Ahmet Rasit Ozturk, Manuel Garber, Alper Kucukural

The emergence of high throughput technologies that produce vast amounts of genomic data, such as next-generation sequencing (NGS) are transforming biological research. The dramatic increase in the volume of data makes analysis the main bottleneck for scientific discovery. The processing of high throughput datasets typically involves many different computational programs, each of which performs a specific step in a pipeline. Given the wide range of applications and organizational infrastructures, there is a great need for a highly-parallel, flexible, portable, and reproducible data processing frameworks. Flexibility ensures that pipelines can support a variety of applications without requiring one-off modifications. Portability ensures that users can leverage computationally available resources and work within economic constraints. Reproducibility warrants credibility to the results, and is particularly challenging in the face of the sheer volume of data and the complexity of processing pipelines that vary widely between users. Several platforms currently exist for the design and execution of complex pipelines (e.g. Galaxy, GenePattern, GeneProf). Unfortunately, these platforms lack the necessary combination of parallelism, portability, flexibility and/or reproducibility that are required by the current research environment. To address these shortcomings, Nextflow was implemented to simplify portable, scalable, and reproducible scientific pipelines using containers. We have used Nextflow capabilities as a leverage and developed a user interface, DolphinNext, for creating, deploying, and executing complex Nextflow pipelines for high throughput data processing. The guiding principle of DolphinNext is to facilitate the building and deployment of complex pipelines using a modular approach implemented in a graphical interface. DolphinNext provides: 1. A drag and drop user interface that abstracts pipelines and allows users to create pipelines without familiarity in underlying programming languages. 2. A user interface to monitor pipeline execution that allows the re-initiation of pipelines at intermediate steps 3. Reproducible pipelines with version tracking and stand-alone versions that can be run independently. 4. Seamless portability to distributed computational environments such as high performance clusters or cloud computing environments.

5: Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life
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Posted to bioRxiv 17 Sep 2019

Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life
40 tweets genetics

Joshua A Bell, Caroline J. Bull, Marc J Gunter, David Carslake, George Davey Smith, Nicholas J. Timpson, Emma E Vincent

Background: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to detailed metabolic traits across early life. Methods and Findings: Data were from up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children cohort. Linear models were used to examine effects of a genetic risk score (GRS, including 162 variants) for adult type 2 diabetes on 4 repeated measures of 229 traits from targeted nuclear magnetic resonance (NMR) metabolomics. These traits included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, inflammatory glycoprotein acetyls, and others, and were measured in childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y). For replication, two-sample Mendelian randomization (MR) was conducted using summary data from genome-wide association studies of metabolic traits from NMR in an independent sample of adults (N range 13,476 to 24,925; mean (SD) age range 23.9y (2.1y) to 61.3y (2.9y)). Among ALSPAC participants (49.7% male), the prevalence of type 2 diabetes was very low across time points (< 5 cases when first assessed at age 16y; 7 cases (0.4%) when assessed at age 25y). At age 8y, type 2 diabetes liability (per SD-higher GRS) was associated with lower lipids in high-density lipoprotein (HDL) particle subtypes - e.g. -0.03 SD (95% CI = -0.06, -0.003; P = 0.03) for total lipids in very-large HDL. At age 16y, associations remained strongest with lower lipids in HDL and became stronger with pre-glycemic traits including citrate (-0.06 SD, 95% CI = -0.09, -0.02; P = 1.41x10-03) and with glycoprotein acetyls (0.05 SD, 95% CI = 0.01, 0.08; P = 0.01). At age 18y, associations were stronger with branched chain amino acids including valine (0.06 SD; 95% CI = 0.02, 0.09; P = 1.24x10-03), while at age 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Results of two-sample MR in an independent sample of adults indicated persistent patterns of effect of type 2 diabetes liability, with higher type 2 diabetes liability positively associated with VLDL lipids and branched chain amino acid levels, and inversely associated with HDL lipids - again for large and very large HDL particularly (-0.004 SD (95% CI = -0.007, -0.002; P = 8.45x10-04) per 1 log odds of type 2 diabetes for total lipids in large HDL). Study limitations include modest sample sizes for ALSPAC analyses and limited coverage of protein and hormonal traits; insulin was absent as it is not quantified by NMR and not consistently available at each time point. Analyses were restricted to white-Europeans which reduced confounding by population structure but limited inference to other ethnic groups. Conclusions: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability which precedes higher branched chain amino acid and inflammatory glycoprotein acetyl levels. This feature is apparent in childhood as early as age 8y, decades before the clinical onset of disease.

6: Thinking small: next-generation sensor networks close the size gap in vertebrate biologging
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Posted to bioRxiv 18 Sep 2019

Thinking small: next-generation sensor networks close the size gap in vertebrate biologging
32 tweets animal behavior and cognition

Simon Ripperger, Gerald Carter, Rachel Page, Niklas Duda, Alexander Koelpin, Robert Weigel, Markus Hartmann, Thorsten Nowak, Joern Thielecke, Michael Schadhauser, Joerg Robert, Sebastian Herbst, Klaus Meyer-Wegener, Peter Waegemann, Wolfgang Schroeder-Preikschat, Bjoern Cassens, Ruediger Kapitza, Falko Dressler, Frieder Mayer

Recent advances in animal tracking technology have ushered in a new era in biologging. However, the considerable size of sophisticated biologging devices restricts their application to larger animals, while old-fashioned techniques still represent the state-of-the-art for studying small vertebrates. In industrial applications, low-power wireless sensor networks fulfill requirements similar to those needed to monitor animal behavior at high resolution and at low tag weight. We created a wireless biologging network (WBN), which enables simultaneous direct proximity sensing, high-resolution tracking and long-range remote data download at tag weights of one to two grams. Deployments to study wild bats created data of unprecedented quality and demonstrate the high potential of WBNs for studying (social) behavior. Our developments highlight the vast capabilities of WBNs and their potential to close an important gap in biologging: fully automated tracking and proximity sensing of small animals, even in closed habitats, at high spatial and temporal resolution.

7: Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases
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Posted to bioRxiv 16 Sep 2019

Non-Coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases
31 tweets neuroscience

J Nicholas Cochran, Ethan G. Geier, Luke W. Bonham, J. Scott Newberry, Michelle D. Amaral, Michelle L. Thompson, Brittany N. Lasseigne, Anna M. Karydas, Erik D Roberson, Gregory M Cooper, Gil D. Rabinovici, Bruce L Miller, Richard M. Myers, Jennifer S. Yokoyama

We conducted genome sequencing to search for rare variation contributing to early onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 493 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than 1 in 10,000 or private), computational prediction of deleteriousness (CADD 10 or 15 thresholds), and molecular function (protein loss-of-function only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,871 independent cases and 15,941 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p=6.5x10-8, genome-wide corrected p=0.0037). Most of these variants were canonical loss-of-function or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of AD and FTD (replication only p=0.0071). The combined analysis odds ratio was 2.2 (95% CI 1.5-3.2) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 2.1 (95% CI 1.2-3.9). For loss-of-function variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.2 (95% CI 2.0-5.3). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.

8: Endogenous retroviruses are a source of oncogenic enhancers in acute myeloid leukemia
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Posted to bioRxiv 18 Sep 2019

Endogenous retroviruses are a source of oncogenic enhancers in acute myeloid leukemia
31 tweets genetics

Ozgen Deniz, Mamataz Ahmed, Christopher D Todd, Ana Rio-Machin, Mark A. Dawson, Miguel R Branco

Endogenous retroviruses (ERVs) and other transposons can act as tissue-specific regulators of gene expression in cis, with potential to affect biological processes. In cancer, epigenetic alterations and transcription factor misregulation may uncover the regulatory potential of typically repressed ERVs, which could contribute to tumour evolution and progression. Here, we asked whether transposons help to rewire oncogenic transcriptional circuits in acute myeloid leukemia (AML). Using epigenomic data from both primary cells and cell lines, we have identified six ERV families that are frequently found in an open chromatin state in AML when compared to differentiated healthy myeloid cells. A subset of these AML-associated ERVs harbour enhancer- specific histone modifications, and are bound by hematopoiesis-associated transcription factors that play key roles in haematopoiesis and in the pathogenesis of AML. Using CRISPR-mediated genetic editing and simultaneous epigenetic silencing of multiple ERV copies, we have established causal links between ERV deregulation in AML and expression changes of adjacent genes. Finally, we show that deletion and epigenetic silencing of an ERV, through modulating expression of APOC1 gene, leads to growth suppression by inducing apoptosis in leukemia cell lines. Our results suggest that ERV derepression provides an additional layer of gene regulation in AML that may be exploited by cancer cells to help drive oncogenic phenotypes.

9: Spatial transcriptional signatures define margin morphogenesis along the proximal-distal and medio-lateral axes in complex leaf species Solanum lycopersicum (tomato)
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Posted to bioRxiv 18 Sep 2019

Spatial transcriptional signatures define margin morphogenesis along the proximal-distal and medio-lateral axes in complex leaf species Solanum lycopersicum (tomato)
31 tweets plant biology

Ciera C Martinez, Siyu Li, Margaret R Woodhouse, Keiko Sugimoto, Neelima R Sinha

Plant morphogenesis is achieved by an interplay among the processes of cell differentiation, elongation, and specialization. During leaf development cells proceed through these processes at different rates depending on position along the medio-lateral and proximal-distal axes of the organ. The gene expression changes controlling cell fate along these axes remained elusive due to the difficulties in precise tissue isolation. This study combines rigorous early leaf characterization, laser capture microdissection, and transcriptomic sequencing to ask how patterns of gene expression regulate early leaf morphogenesis along the medio-lateral and proximal-distal axes in wild type Solanum lycopersium (tomato) and a leaf morphogenetic mutant trifoliate (tf-2). This work reveals transcriptional regulation of cell differentiation patterning along the proximal distal axis, and also identifies molecular signatures that delineate the classically defined marginal meristem / blastozone region early in leaf development. We describe and verify the importance of endoreduplication during leaf development, when and where photosynthetic competency is first achieved in the organ, regulation of auxin transport and signaling processes occurring along both the proximal-distal and medio-lateral axes, and narrow in on BLADE-ON-PETIOLE2 (BOP2) as a key regulator of margin tissue identity . CRISPR knockout mutants of BOP2 helped identify a unique phenotype of ectopic SAM formation on the complex leaf in tomato. Precise sampling practices allowed us to map gene expression signatures in specific domains of the leaf across multiple axes and evaluate the role of each domain in conferring indeterminacy and permitting blade outgrowth. This work also provides a global gene expression atlas of the early developing compound leaf.

10: A unifying framework for synaptic organization on cortical dendrites
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Posted to bioRxiv 18 Sep 2019

A unifying framework for synaptic organization on cortical dendrites
28 tweets neuroscience

Jan Hendrik Kirchner, Julijana Gjorgjieva

Dendritic synaptic inputs are organized into functional clusters with remarkable subcellular precision at the micron level. This organization emerges during early postnatal development through patterned spontaneous activity and manifests both locally where nearby synapses are significantly correlated, and globally with distance to the soma. We propose a biophysically motivated synaptic plasticity model to dissect the mechanistic origins of this organization during development, and elucidate synaptic clustering of different stimulus features in the adult. Our model captures local clustering of orientation in ferret vs. receptive field overlap in mouse visual cortex based on the cortical magnification of visual space. Including a back-propagating action potential explains branch clustering heterogeneity in the ferret, and produces a global retinotopy gradient from soma to dendrite in the mouse. Therefore, our framework suggests that sub-cellular precision in connectivity can already be established in development, and unifies different aspects of synaptic organization across species and scales.

11: New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation
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Posted to bioRxiv 18 Sep 2019

New mutant mouse models clarify the role of NAIPs, phosphorylation, NLRP3, and tumors in NLRC4 inflammasome activation
28 tweets immunology

Jeannette Tenthorey, Roberto A Chavez, Thornton W Thompson, Katherine A Deets, Russell E Vance, Isabella Rauch

The NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new Nlrc4- deficient mouse line as well as mice encoding phosphomimetic S533D and non- phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.

12: Large-scale death of retinal astrocytes during normal development mediated by microglia
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Posted to bioRxiv 03 Apr 2019

Large-scale death of retinal astrocytes during normal development mediated by microglia
26 tweets neuroscience

Vanessa M. Puñal, Caitlin E Paisley, Federica S Brecha, Monica A Lee, Robin M Perelli, Emily G. O’Koren, Caroline R Ackley, Daniel R Saban, Benjamin E Reese, Jeremy N Kay

Naturally-occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the central nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type -- the astrocyte -- has rarely been studied. It is presently unclear whether astrocytes are subject to significant amounts of developmental death, or how it occurs. Here we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia kill and engulf astrocytes to mediate their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally-occurring cell death, and demonstrate its importance for formation and integrity of the retinal gliovascular network.

13: Extended Amygdala Kappa Opioid Receptor Signaling Gates Alcohol-induced Stress Impairments in Mice
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Posted to bioRxiv 18 Sep 2019

Extended Amygdala Kappa Opioid Receptor Signaling Gates Alcohol-induced Stress Impairments in Mice
24 tweets neuroscience

Lara S Hwa, Sofia Neira, Meghan E. Flanigan, Christina M Stanhope, Melanie M Pina, Dipanwita Pati, Olivia J Hon, Waylin Yu, Emily Kokush, Rachel Calloway, Kristen Boyt, Thomas L. Kash

Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor (KOR) signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate promoting a maladaptive behavioral phenotype following heavy alcohol drinking. Altered responses to an innate stressor were associated with enhanced PFC-driven excitation of prodynorphin-containing neurons in the BNST during protracted withdrawal from intermittent alcohol drinking. These findings suggest that corticolimbic connectivity may underlie impaired stress-coping during protracted withdrawal from heavy drinking and represents a target of potential therapeutic mediation.

14: Galactose-modified duocarmycin prodrugs as senolytics
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Posted to bioRxiv 24 Aug 2019

Galactose-modified duocarmycin prodrugs as senolytics
24 tweets cell biology

Ana Guerrero, Romain Guiho, Nicolás Herranz, Anthony Uren, Dominic J. Withers, Juan Pedro Martínez-Barbera, Lutz F. Tietze, Jesus Gil

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal b-galactosidase this has been exploited as a marker for senescence (senescence-associated b-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal b-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of b-catenin- positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.

15: Fluctuation-based Super-Resolution Traction Force Microscopy
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Posted to bioRxiv 18 Sep 2019

Fluctuation-based Super-Resolution Traction Force Microscopy
22 tweets cell biology

Aki Stubb, Romain F Laine, Camilo Guzmán, Ricardo Henriques, Guillaume Jacquemet, Johanna Ivaska

Cellular mechanics play a crucial role in tissue morphogenesis and homeostasis and are often misregulated in disease. Traction force microscopy (TFM) is one of the key methods that has enabled researchers to study fundamental aspects of mechanobiology; however, the power of TFM is limited by poor resolution and low throughput. Here, we propose a simplified protocol and imaging strategy, relying on super-resolution microscopy enabled by fluorophore fluctuation analysis, to enhance the output of TFM, by increasing both bead density as well as the accuracy of bead tracking in TFM gels. Our analysis pipeline can be used on either camera-based confocal or widefield microscopes and is fully compatible with available TFM analysis software. In addition, we demonstrate that our workflow can be used to gain biologically relevant information and is suitable for long-term live measurement of traction forces even in light-sensitive cells. Finally, we propose that our strategy could be used to considerably simplify the implementation of TFM screens. Our streamlined protocol can be performed with minimal hardware and software investment, and has the potential to standardize high-resolution TFM.

16: Odorant receptor inhibition is fundamental to odor encoding
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Posted to bioRxiv 05 Sep 2019

Odorant receptor inhibition is fundamental to odor encoding
22 tweets neuroscience

Patrick Pfister, Benjamin C. Smith, Barry J. Evans, Jessica H. Brann, Casey Trimmer, Mushhood Sheikh, Randy Arroyave, Gautam Reddy, Hyo-Young Jeong, Daniel A. Raps, Zita Peterlin, Massimo Vergassola, Matthew E. Rogers

Most natural odors are complex mixtures of many volatile components, competing to bind odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) of the nose. To date surprisingly little is known about how OR antagonism shapes neuronal representations in the periphery of the olfactory system. Here, we investigated its prevalence, the degree to which it disrupts OR ensemble activity, and its conservation across related ORs. Calcium imaging microscopy of dissociated OSNs revealed significant inhibition, often complete attenuation, of responses to indole, a commonly occurring volatile associated with both floral and fecal odors, by a set of 36 tested odorants. To confirm an OR mechanism for the observed inhibition, we performed single-cell transcriptomics on OSNs that exhibited specific response profiles to a diagnostic panel of odorants and identified the receptor Olfr743 which, when tested in vitro, recapitulated ex vivo responses. We screened ten ORs from the Olfr743 clade with 800 perfumery-related odorants spanning a range of chemical scaffolds and functional groups, over half of which (430) antagonized at least one of the ten ORs. Furthermore, OR activity outcomes were divergent rather than redundant, even for the most closely related paralogs. OR activity fitted a mathematical model of competitive receptor binding and suggests that normalization of OSN ensemble responses to odorant mixtures is the rule rather than the exception. In summary, we observed OR antagonism, inverse agonism and partial agonism occurring frequently and in a combinatorial manner. Thus, extensive receptor-mediated computation of mixture information appears to occur in the olfactory epithelium prior to transmission of odor information to the olfactory bulb.

17: A Systematic Evaluation of Single Cell RNA-Seq Analysis Pipelines
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Posted to bioRxiv 19 Mar 2019

A Systematic Evaluation of Single Cell RNA-Seq Analysis Pipelines
21 tweets bioinformatics

Beate Vieth, Swati Parekh, Christoph Ziegenhain, Wolfgang Enard, Ines Hellmann

The recent rapid spread of single cell RNA sequencing (scRNA-seq) methods has created a large variety of experimental and computational pipelines for which best practices have not been established, yet. Here, we use simulations based on five scRNA-seq library protocols in combination with nine realistic differential expression (DE) setups to systematically evaluate three mapping, four imputation, seven normalisation and four differential expression testing approaches resulting in ~ 3,000 pipelines, allowing us to also assess interactions among pipeline steps. We find that choices of normalisation and library preparation protocols have the biggest impact on scRNA-seq analyses. Specifically, we find that library preparation determines the ability to detect symmetric expression differences, while normalisation dominates pipeline performance in asymmetric DE-setups. Finally, we illustrate the importance of informed choices by showing that a good scRNA-seq pipeline can have the same impact on detecting a biological signal as quadrupling the sample size.

18: Over eight hundred cannabis strains characterized by the relationship between their psychoactive effects, perceptual profiles, and chemical compositions
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Posted to bioRxiv 08 Sep 2019

Over eight hundred cannabis strains characterized by the relationship between their psychoactive effects, perceptual profiles, and chemical compositions
21 tweets neuroscience

Laura Alethia de la Fuente, Federico Zamberlan, Andres Sanchez Ferran, Facundo Carrillo, Enzo Tagliazucchi, Carla Pallavicini

Commercially available cannabis strains have multiplied in recent years as a consequence of regional changes in legislation for medicinal and recreational use. Lack of a standardized system to label plants and seeds hinders the consistent identification of particular strains with their elicited psychoactive effects. The objective of this work was to leverage information extracted from large databases to improve the identification and characterization of cannabis strains. Methods: We analyzed a large publicly available dataset where users freely reported their experiences with cannabis strains, including different subjective effects and flavour associations. This analysis was complemented with information on the chemical composition of a subset of the strains. Both supervised and unsupervised machine learning algorithms were applied to classify strains based on self reported and objective features. Results: Metrics of strain similarity based on self-reported effect and flavour tags allowed machine learning classification into three major clusters corresponding to Cannabis sativa, Cannabis indica, and hybrids. Synergy between terpene and cannabinoid content was suggested by significative correlations between psychoactive effect and flavour tags. The use of predefined tags was validated by applying semantic analysis tools to unstructured written reviews, also providing breed-specific topics consistent with their purported medicinal and subjective effects. While cannabinoid content was variable even within individual strains, terpene profiles matched the perceptual characterizations made by the users and could be used to predict associations between different psychoactive effects. Conclusions: Our work represents the first data-driven synthesis of self-reported and chemical information in a large number of cannabis strains. Since terpene content is robustly inherited and less influenced by environmental factors, flavour perception could represent a reliable marker to predict the psychoactive effects of cannabis. Our novel methodology contributes to meet the demands for reliable strain classification and characterization in the context of an ever-growing market for medicinal and recreational cannabis.

19: Temporal complexity of fMRI is reproducible and correlates with higher order cognition
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Posted to bioRxiv 16 Sep 2019

Temporal complexity of fMRI is reproducible and correlates with higher order cognition
20 tweets neuroscience

Amir Omidvarnia, Andrew Zalesky, Dimitri Van De Ville, Graeme Jackson, Mangor Pedersen

In 2014, McDonough and Nashiro derived multiscale entropy --a marker of signal complexity-- from resting state functional MRI data (rsfMRI), and found that functional brain networks displayed unique multiscale entropy fingerprints. This is a finding with potential impact as an imaging-based marker of normal brain function, as well as pathological brain dysfunction. Nevertheless, a limitation of this study was that rsfMRI data from only 20 healthy individuals was used for analysis. To overcome this limitation, we aimed to replicate McDonough and Nashiro's finding in a large cohort of healthy subjects. We used rsfMRI from the Human Connectome Project (HCP) comprising 936 gender-matched healthy young adults aged 22-35, each with 4 × 14.4-minute rsfMRI data from 100 brain regions. We quantified multiscale entropy of rsfMRI time series averaged at different cortical and sub-cortical regions. We also performed a test-retest analysis on the data of four recording sessions in 10 previously reported resting state networks (RSNs). Given that the morphology of multiscale entropy patterns is affected by the choice of the tolerance parameter (r), we performed the analyses at two r values: 0.5, similar to the original study and 0.15, a commonly used option in the literature. Our results were similar to previous findings by McDonough and Nashiro emphasizing high temporal complexity in the default mode network and frontoparietal networks, and low temporal complexity in the cerebellum. We also investigated the effect of temporal resolution (determined by fMRI repetition time) by downsampling rsfMRI time series. At a low temporal resolution, we observed increased entropy and variance across datasets likely due to fewer data points in the multiscale entropy analysis. Test-retest analysis showed that findings were likely reproducible across individuals over four rsfMRI runs, especially for r = 0.5. We also showed a positive relationship between temporal complexity of RSNs and fluid intelligence (people's capacity to reason and think flexibly), suggesting that complex dynamics is an important attribute of optimized brain function.

20: Derived Homo sapiens cis-eQTL regulation: implications for brain evolution
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Posted to bioRxiv 18 Sep 2019

Derived Homo sapiens cis-eQTL regulation: implications for brain evolution
20 tweets genetics

Alejandro Andirko, Cedric Boeckx

The high-quality sequence of the genomes of our extinct relatives, Neanderthals and Denisovans, became recently public. At the same time, we have seen the emergence of big databases of modern human genetic variation. However, linking human genetic variation, neuronal phenotypes and, eventually, behaviour, is only possible if we understand how variation and genetic regulation interact. We used two publicly available datasets, the GTEX cis-eQTL database (v7) and a catalog of high-frequency Homo sapiens specific alleles relative to the Neanderthals and Denisovan sequences, to understand how high-frequency Homo Sapiens derived alleles affect gene expression regulation. The resulting dataset shows that genes associated with brain development are affected by Homo sapiens-specific eQTL in brain areas key in human evolution such as the cerebellum. We also show that some of these eQTL overlap significantly with putative regions of positive selection relative to archaic humans [Peyregne et al., 2017]. Additionally, we tested whether any of the variants are associated with clinical conditions in modern human populations. These findings can inform future experimental work and enrich current venues of research of the Homo Sapiens brain evolution, such as the relationship between clinical and evolutionary research and the recent expansion of the cerebellum in Homo Sapiens [Gunz et al., 2010].

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