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Most tweeted bioRxiv papers, last 7 days
386 results found. For more information, click each entry to expand.
35 tweets biophysics
The computation of tautomer rations of druglike molecules is enormously important in computer-aided drug discovery, as over a quarter of all approved drugs can populate multiple tautomeric species in solution. Unfortunately, accurate calculations of aqueous tautomer ratios\---|the degree to which these species must be penalized in order to correctly account for tautomers in modeling binding for computer-aided drug discovery\---|is surprisingly difficult. While quantum chemical approaches to computing aqueous tautomer ratios using continuum solvent models and rigid-rotor harmonic-oscillator thermochemistry are currently state of the art, these methods are still surprisingly inaccurate despite their enormous computational expense. Here, we show that a major source of this inaccuracy lies in the breakdown of the standard approach to accounting for quantum chemical thermochemistry using rigid rotor harmonic oscillator (RRHO) approximations, which are frustrated by the complex conformational landscape introduced by the migration of double bonds, creation of stereocenters, and introduction of multiple conformations separated by low energetic barriers induced by migration of a single proton. Using quantum machine learning (QML) methods that allow us to compute potential energies with quantum chemical accuracy at a fraction of the cost, we show how rigorous alchemical free energy calculations can be used to compute tautomer ratios in vacuum free from the limitations introduced by RRHO approximations. Furthermore, since the parameters of QML methods are tunable, we show how we can train these models to correct limitations in the underlying learned quantum chemical potential energy surface using free energies, enabling these methods to learn to generalize tautomer free energies across a broader range of predictions. ### Competing Interest Statement The authors have declared no competing interest.
33 tweets neuroscience
Recent developments in reinforcement learning, cognitive control, and systems neuroscience highlight the complimentary roles in learning of valenced reward prediction errors (RPEs) and non-valenced salience prediction errors (PEs) driven by the magnitude of surprise. A core debate in reward learning focuses on whether valenced and non-valenced PEs can be isolated in the human electroencephalogram (EEG). Here, we combine behavioral modeling and single-trial EEG regression revealing a sequence of valenced and non-valenced PEs in an interval timing task dissociating outcome valence, magnitude, and probability. Multiple regression across temporal, spatial, and frequency dimensions revealed a spatio-tempo-spectral cascade from valenced RPE value represented by the feedback related negativity event-related potential (ERP) followed by non-valenced RPE magnitude and outcome probability effects indexed by subsequent P300 and late frontal positivity ERPs. The results show that learning is supported by a sequence of multiple PEs evident in the human EEG. ### Competing Interest Statement The authors have declared no competing interest.
32 tweets molecular biology
Jimmy Lee, Tom Hughes, Mei-Ho Lee, Hume Field, Jeffrine Japning Rovie-Ryan, Frankie Thomas Sitam, Symphorosa Sipangkui, Senthilvel KSS Nathan, Diana Ramirez, Subbiah Vijay Kumar, Helen Lasimbang, Jonathan H Epstein, Peter Daszak
The legal and illegal trade in wildlife for food, medicine and other products is a globally significant threat to biodiversity that is also responsible for the emergence of pathogens that threaten human and livestock health and our global economy. Trade in wildlife likely played a role in the origin of COVID-19, and viruses closely related to SARS-CoV-2 have been identified in bats and pangolins, both traded widely. To investigate the possible role of pangolins as a source of potential zoonoses, we collected throat and rectal swabs from 334 Sunda pangolins (Manis javanica) confiscated in Peninsular Malaysia and Sabah between August 2009 and March 2019. Total nucleic acid was extracted for viral molecular screening using conventional PCR protocols used to routinely identify known and novel viruses in extensive prior sampling (>50,000 mammals). No sample yielded a positive PCR result for any of the targeted viral families: Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae and Paramyxoviridae. In light of recent reports of coronaviruses including a SARS-CoV-2 related virus in Sunda pangolins in China, the lack of any coronavirus detection in our "upstream" market chain samples suggests that these detections in "downstream" animals more plausibly reflect exposure to infected humans, wildlife or other animals within the wildlife trade network. While confirmatory serologic studies are needed, it is likely that Sunda pangolins are incidental hosts of coronaviruses. Our findings further support the importance of ending the trade in wildlife globally. ### Competing Interest Statement The authors have declared no competing interest.
31 tweets evolutionary biology
Genes for which homologs can be detected only in a limited group of evolutionarily related species, called "lineage-specific genes," are pervasive: essentially every lineage has them, and they often comprise a sizable fraction of the group's total genes. Lineage-specific genes are often interpreted as "novel" genes, representing genetic novelty born anew within that lineage. Here, we develop a simple method to test an alternative null hypothesis: that lineage-specific genes do have homologs outside of the lineage that, even while evolving at a constant rate in a novelty-free manner, have merely become undetectable by search algorithms used to infer homology. We show that this null hypothesis is sufficient to explain the lack of detected homologs of a large number of lineage-specific genes in fungi and insects. However, we also find that a minority of lineage-specific genes in both clades are not well-explained by this novelty-free model. The method provides a simple way of identifying which lineage-specific genes call for special explanations beyond homology detection failure, highlighting them as interesting candidates for further study. ### Competing Interest Statement The authors have declared no competing interest.
31 tweets genomics
While the size of chromosomes can be measured under a microscope, the size of genomes cannot be measured precisely. Biochemical methods and k-mer distribution-based approaches allow only estimations. An alternative approach to predict the genome size based on high contiguity assemblies and short read mappings is presented here and optimized on Arabidopsis thaliana and Beta vulgaris. Brachypodium distachyon, Solanum lycopersicum, Vitis vinifera, and Zea mays were also analyzed to demonstrate the broad applicability of this approach. Mapping-based Genome Size Estimation (MGSE) and additional scripts are available on github: https://github.com/bpucker/MGSE.
30 tweets evolutionary biology
Tracking genetic changes of populations through time allows a more direct study of the evolutionary processes acting on the population than a single contemporary sample. Several statistical methods have been developed to characterize the demography and selection from temporal population genetic data. However, these methods are usually developed under the assumption of outcrossing reproduction and might not be applicable when there is substantial selfing in the population. Here, we focus on a method to detect loci under selection based on a genome scan of temporal differentiation, adapting it to the particularities of selfing populations. Selfing reduces the effective recombination rate and can extend hitch-hiking effects to the whole genome, erasing any local signal of selection on a genome scan. Therefore, selfing is expected to reduce the power of the test. By means of simulations, we evaluate the performance of the method under scenarios of adaptation from new mutations or standing variation at different rates of selfing. We find that the detection of loci under selection in predominantly selfing populations remains challenging even with the adapted method. Still, selective sweeps from standing variation on predominantly selfing populations can leave some signal of selection around the selected site thanks to historical recombination before the sweep. Under this scenario, ancestral advantageous alleles at low frequency leave the strongest local signal, while new advantageous mutations leave no local footprint of the sweep. ### Competing Interest Statement The authors have declared no competing interest.
29 tweets neuroscience
Successful self-control requires the ability to stop unwanted actions or thoughts. Stopping is regarded as a central function of inhibitory control, a mechanism enabling the suppression of diverse mental content, and strongly associated with the prefrontal cortex. A domain-general inhibitory control capacity, however, would require the region or regions implementing it to dynamically shift top-down inhibitory connectivity to diverse target regions in the brain. Here we show that stopping unwanted thoughts and stopping unwanted actions engage common regions in the right anterior dorsolateral and right ventrolateral prefrontal cortex, and that both areas exhibit this dynamic targeting capacity. Within each region, pattern classifiers trained to distinguish stopping actions from making actions also could identify when people were suppressing their thoughts (and vice versa) and could predict which people successfully forgot thoughts after inhibition. Effective connectivity analysis revealed that both regions contributed to action and thought stopping, by dynamically shifting inhibitory connectivity to motor area M1 or to the hippocampus, depending on the goal, suppressing task-specific activity in those regions. These findings support the existence of a domain-general inhibitory control mechanism that contributes to self-control and establish dynamic inhibitory targeting as a key mechanism enabling these abilities. ### Competing Interest Statement The authors have declared no competing interest.
25 tweets genomics
William L Hwang, Karthik A. Jagadeesh, Jimmy A. Guo, Hannah I Hoffman, Payman Yadollahpour, Rahul Mohan, Eugene Drokhlyansky, Nicholas Van Wittenberghe, Orr Ashenberg, Samouil Farhi, Denis Schapiro, Jason W Reeves, Daniel R. Zollinger, George Eng, Jason M Schenkel, William A Freed-Pastor, Clifton Rodrigues, Joshua Gould, Conner Lambden, Caroline Porter, Alexander Tsankov, Danielle Dionne, Domenic Abbondanza, Julia Waldman, Michael S Cuoco, Lan Nguyen, Toni Delorey, Devan Phillips, Debora Ciprani, Marina Kern, Arnav Mehta, Kit Fuhrman, Robin Fropf, Joseph M. Beechem, Jay S Loeffler, David P Ryan, Colin D Weekes, David T. Ting, Cristina R Ferrone, Jennifer Y Wo, Theodore S Hong, Andrew J. Aguirre, Orit Rozenblatt-Rosen, Mari Mino-Kenudson, Carlos Fernandez-del Castillo, Andrew S Liss, Tyler Jacks, Aviv Regev
Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease. Characterizing PDAC by mRNA profiling remains particularly challenging. Previously identified bulk expression subtypes were influenced by contaminating stroma and have not yet informed clinical management, whereas single cell RNA-seq (scRNA-seq) of fresh tumors under-represented key cell types. Here, we developed a robust single-nucleus RNA-seq (snRNA-seq) technique for frozen archival PDAC specimens and used it to study both untreated tumors and those that received neoadjuvant chemotherapy and radiotherapy (CRT). Gene expression programs learned across untreated malignant cell and fibroblast profiles uncovered a clinically relevant molecular taxonomy with improved prognostic stratification compared to prior classifications. Moreover, in the increasingly-adopted neoadjuvant treatment context, there was a depletion of classical-like phenotypes in malignant cells in favor of basal-like phenotypes associated with TNF-NFkB and interferon signaling as well as the presence of novel acinar and neuroendocrine classical-like states, which may be more resilient to cytotoxic treatment. Spatially-resolved transcriptomics revealed an association between malignant cells expressing these basal-like programs and higher immune infiltration with increased lymphocytic content, whereas those exhibiting classical-like programs were linked to sparser macrophage-predominant microniches, perhaps pointing to susceptibility to distinct therapeutic strategies. Our refined molecular taxonomy and spatial resolution can help advance precision oncology in PDAC through informative stratification in clinical trials and insights into differential therapeutic targeting leveraging the immune system. ### Competing Interest Statement A.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov. From August 1, 2020, A.R. is an employee of Genentech. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J. laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative, but this funding did not support the research described in this manuscript. D.T.T. has received consulting fees from ROME Therapeutics, Foundation Medicine, Inc., EMD Millipore Sigma, and Pfizer that are not related to this work. D.T.T. is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. D.T.T. receives research support from ACD-Biotechne, PureTech Health LLC, Ribon Therapeutics, which was not used in this work. M.M.K. has served as a compensated consultant for H3 Biomedicine and AstraZeneca and received a research grant (to institution) from Novartis that is not related to this work. The interests of D.T.T. and M.M.K. were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. J.R., D.R.Z., K.F., R.F., and J.B. are employees of NanoString Technologies. A.R., W.L.H., K.A.J., J.A.G., and T.J. submitted a provisional patent application based on this work. All other authors declare no competing interests.
25 tweets cancer biology
Srivatsan Raghavan, Peter S. Winter, Andrew W. Navia, Hannah L Williams, Alan DenAdel, Radha L. Kalekar, Jennyfer Galvez-Reyes, Kristen E. Lowder, Nolawit Mulugeta, Manisha S. Raghavan, Ashir A. Borah, Sara A. Vayrynen, Andressa Dias Costa, Raymond W.S. Ng, Junning Wang, Emma Reilly, Dorisanne Y. Ragon, Lauren K. Brais, Alex M. Jaeger, Liam F. Spurr, Yvonne Y. Li, Andrew D. Cherniack, Isaac Wakiro, Asaf Rotem, Bruce E. Johnson, James M. McFarland, Ewa T. Sicinska, Tyler E. Jacks, Thomas E. Clancy, Kimberly Perez, Douglas A. Rubinson, Kimmie Ng, James M. Cleary, Lorin Crawford, Scott Manalis, Jonathan A. Nowak, Brian M. Wolpin, William C. Hahn, Andrew J. Aguirre, Alex K. Shalek
In pancreatic ductal adenocarcinoma (PDAC), the basal-like and classical transcriptional subtypes are associated with differential chemotherapy sensitivity and patient survival. These phenotypes have been defined using bulk transcriptional profiling, which can mask underlying cellular heterogeneity and the biologic mechanisms that distinguish these subtypes. Furthermore, few studies have interrogated metastases, which are the cause of mortality in most patients with this highly lethal disease. Using single-cell RNA-sequencing of metastatic needle biopsies and matched organoid models, we demonstrate intra-tumoral subtype heterogeneity at the single-cell level and define a continuum for the basal-like and classical phenotypes that includes hybrid cells that co-express features of both states. Basal-like tumors show enrichment of mesenchymal and stem-like programs, and demonstrate immune exclusion and tumor cell crosstalk with specific macrophage subsets. Conversely, classical tumors harbor greater immune infiltration and a relatively pro-angiogenic microenvironment. Matched organoid models exhibit a strong bias against the growth of basal-like cells in standard organoid media, but modification of culture conditions can rescue the basal-like phenotype. This study reframes the transcriptional taxonomy of PDAC, demonstrates how divergent transcriptional subtypes associate with unique tumor microenvironments, and highlights the importance of evaluating both genotype and transcriptional phenotype to establish high-fidelity patient-derived cancer models. ### Competing Interest Statement B.M.W. reports research support from Celgene, Eli Lilly and consulting for BioLineRx, Celgene, G1 Therapeutics, GRAIL. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, Tyra Biosciences, iTeos, Frontier Medicines, and Paraxel. W.C.H. is a founder and a member of the scientific advisory board (SAB) for KSQ Therapeutics. A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics, Orche Bio, and Dahlia Biosciences. A.J.A. has consulted for Oncorus, Inc., Arrakis Therapeutics, and Merck & Co., Inc, and has research funding from Mirati Therapeutics, Deerfield, Inc. and Novo Ventures that are unrelated to this project. S.R.M. is a founder of Travera. J.M.C. has received research funding from Merck, Tesaro, Astrazeneca, and Esperas Pharma, has served as a consultant to Bristol Myers Squib, and has received travel funding from Bristol Myers Squib. A.R. is a consultant to eGenesis, a member of the SAB for NucleAI, and an equity holder in Celsius Therapeutics. Y.Y.L. reports equity from g.Root Biomedical Services. A.D.C. reports research support from Bayer. K.N. reports research support from Revolution Medicines, Evergrande Group, Genentech, Gilead Sciences, Celgene, Trovagene, Pharmavite, and Tarrex Biopharma, is a member of SABs for Bayer, Seattle Genetics, and Array Biopharma, and has consulted for X-Biotix Therapeutics.
25 tweets cancer biology
Jaewon J. Lee, Vincent Bernard, Alexander Semaan, Maria E. Monberg, Jonathan Huang, Bret M. Stephens, Daniel Lin, Brian R Weston, Manoop S Bhutani, Cara L. Haymaker, Chantale Bernatchez, Cullen M. Taniguchi, Anirban Maitra, Paola A. Guerrero
Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployed ex vivo preclinical platforms, such as patient-derived organoids (PDOs) remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast (CAF) subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. While PDOs continue to enable prospective therapeutic prediction, our analysis also demonstrates the complementarity of using orthogonal de novo biopsies from PDAC patients paired with scRNA-seq to inform clinical decision-making. ### Competing Interest Statement A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology, and this financial relationship is managed and monitored by the UTMDACC Conflict of Interest Committee. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection. C.L.H. is on the Scientific Advisory Board of BriaCell and has no conflict of interest relevant to this study.
19 tweets cancer biology
Initiation and progression of cancers reflect the underlying process of somatic evolution, which follows a Darwinian logic, i.e ., diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination – a key diversification mechanism throughout all strata of life. Based on observations of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions could serve as a source of parasexual recombination in cancer cell populations. Using differentially labelled tumor cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo . While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modeling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumor cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape, relative to strictly asexual populations, which may substantially accelerate a tumor’s ability to adapt to new selective pressures. ### Competing Interest Statement The authors have declared no competing interest.
18 tweets developmental biology
The mammalian brain develops through a complex interplay of spatial cues generated by diffusible morphogens, cell-cell interactions, and intrinsic genetic programs that result in the generation of likely more than a thousand distinct cell types. Therefore, a complete understanding of mammalian brain development requires systematic mapping of cell states covering the entire relevant spatiotemporal range. Here we report a comprehensive single-cell transcriptome atlas of mouse brain development spanning from gastrulation to birth. We identified almost a thousand distinct cellular states, including the initial emergence of the neuroepithelium, a rich set of region-specific secondary organizers and a complete developmental program for the functional elements of the brain and its enclosing membranes. We used the atlas to directly test the hypothesis that human glioblastoma reflects a return to a developmental cell state. In agreement, most aneuploid tumor cells matched embryonic rather than adult types, while karyotypically normal cells predominantly matched adult immune cell types. ### Competing Interest Statement The authors have declared no competing interest.
17 tweets genomics
Multiple publications have independently described pangolin CoV genomes from the same batch of smuggled pangolins confiscated in Guangdong province in March, 2019. We analyzed the three metagenomic datasets that sampled this batch of pangolins and found that the two complete pangolin CoV genomes, GD_1 by Xiao et al. Nature and MP789 by Liu et al. PLoS Pathogens, were both built primarily using the 2019 dataset first described by Liu et al. Viruses. Other publications, such as Zhang et al. Current Biology and Lam et al. Nature, have also relied on this same dataset by Liu et al. Viruses for their assembly of the Guangdong pangolin CoV sequences and comparisons to SARS-CoV-2. To our knowledge, all of the published pangolin CoV genome sequences that share a highly similar Spike receptor binding domain with SARS-CoV-2 originate from this singular batch of smuggled pangolins. This raises the question of whether pangolins are truly reservoirs or hosts of SARS-CoV-2-related coronaviruses in the wild, or whether the pangolins may have contracted the CoV from another host species during trafficking. Our observations highlight the importance of requiring authors to publish their complete genome assembly pipeline and all contributing raw sequence data, particularly those supporting epidemiological investigations, in order to empower peer review and independent analysis of the sequence data. This is necessary to ensure both the accuracy of the data and the conclusions presented by each publication. ### Competing Interest Statement The authors have declared no competing interest.
14 tweets evolutionary biology
Marc Tollis, Elliot Ferris, Michael S. Campbell, Valerie K. Harris, Shawn M. Rupp, Tara M. Harrison, Wendy K. Kiso, Dennis L. Schmitt, Michael M. Garner, C. A. Aktipis, Carlo C. Maley, Amy M. Boddy, Mark Yandell, Christopher Gregg, Joshua D. Schiffman, Lisa M. Abegglen
Disease susceptibility and resistance comprise important factors in conservation, particularly in elephants. To determine genetic mechanisms underlying disease resistance and other unique elephant traits, we estimated 862 and 1,017 potential regulatory elements in Asian and African elephants, respectively. These elements are significantly enriched in both species with differentially expressed genes involved in immunity pathways, including tumor-necrosis factor which plays a role in the response to elephant endotheliotropic herpesvirus (EEHV). Population genomics analyses indicate that amplified TP53 retrogenes are maintained by purifying selection and may contribute to cancer resistance in elephants, including less malignancies in African vs. Asian elephants. Positive selection scans across elephant genomes revealed genes that may control iconic elephant traits such as tusk development, memory, and somatic maintenance. Our study supports the hypothesis that interspecies variation in gene regulation contributes to differential inflammatory responses leading to increased infectious disease and cancer susceptibility in Asian versus African elephants. Genomics can inform functional immunological studies which may improve both conservation for elephants and human therapies. ### Competing Interest Statement Dr. Schiffman is co-founder, shareholder, and employed by PEEL Therapeutics, Inc., a company developing evolution-inspired medicines based on cancer resistance in elephants. Dr. Abegglen is share-holder and consultant to PEEL Therapeutics, Inc.
14 tweets neuroscience
Stimulus perception is assumed to involve the (fast) detection of sensory inputs and their (slower) integration. The capacity of the brain to quickly adapt, at all times, to unexpected stimuli suggests that the interplay between the slow and fast processes happens at short timescales. We hypothesised that, even during resting-state, the flow of information across the brain regions should evolve quickly, but not homogeneously in time. Here we used high temporal-resolution Magnetoencephalography (MEG) signals to estimate the persistence of the information in functional links across the brain. We show that short- and long-lasting retention of the information, entailing different speeds in the update rate, naturally split the brain into two anatomically distinct subnetworks. The fast-updating network (FUN) is localized in the regions that typically belong to the dorsal and ventral streams during perceptive tasks, while the slow updating network (SUN) hinges classically associative areas. Finally, we show that only a subset of the brain regions, which we name the multi-storage core (MSC), belongs to both subnetworks. The MSC is hypothesized to play a role in the communication between the (otherwise) segregated subnetworks. ### Competing Interest Statement The authors have declared no competing interest.
14 tweets cell biology
Matthew D Martens, Nivedita Seshadri, Lucas Nguyen, Donald Chapman, Elizabeth S. Hensen, Bo Xiang, Arielys Mendoza, Sunil Rattan, Spencer B. Gibson, Ayesha D Saleem, Grant M. Hatch, Christine A. Doucette, Jason M. Karch, Vernon W Dolinsky, Ian M. Dixon, Adrian R West, Christof Rampitsch, Joseph W Gordon
Systemic hypoxia, a major complication associated with reduced gestational time, affects more 60% of preterm infants and is a known driver of hypoxia-induced Bcl-2-like 19kDa-interacting protein 3 (Bnip3) expression in the neonatal heart. At the level of the cardiomyocyte, Bnip3 activity plays a prominent role in the evolution of necrotic cell death, disrupting subcellular calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests both a cardioprotective role for protein kinase A (PKA) through stimulatory prostaglandin (PG) E1 signalling during prolonged periods of hypoxia, and a cytoprotective role for Bnip3 phosphorylation, indicating that post-translational modifications of Bnip3 may be a point of convergence for these two protective pathways. Using a combination of in vivo and multiple cell models, including human iPSC-derived cardiomyocytes, we tested if the PGE1 analogue misoprostol is cardioprotective during neonatal hypoxic injury by altering the phosphorylation status of Bnip3. Here we report that hypoxia exposure significantly increases Bnip3 expression, mitochondrial-fragmentation, -ROS, -calcium accumulation and -permeability transition, while reducing mitochondrial membrane potential, all of which were restored to control levels with the addition of misoprostol, despite elevated Bnip3 protein expression. Through both gain- and loss-of-function genetic studies we further show that misoprostol-induced protection directly affects Bnip3, preventing mitochondrial perturbations. We demonstrate that this is a result of PG EP4 receptor signalling, PKA activation, and direct Bnip3 phosphorylation at threonine-181. Furthermore, when this PKA phosphorylation site within Bnip3 is neutralized, the protective misoprostol effect is lost. We also provide evidence that misoprostol traffics Bnip3 away from the ER through a physical interaction with 14-3-3β, thereby preventing aberrant ER calcium release and MPT. In vivo studies further demonstrate that misoprostol treatment increases Bnip3 phosphorylation at threonine-181 in the mouse heart, preventing hypoxia-induced reductions in cardiac ejection fraction and fractional shortening. Taken together, our results demonstrate a foundational role for Bnip3 phosphorylation in the molecular regulation of cardiomyocyte contractile and metabolic dysfunction and identifies EP4 signaling as a potential pharmacological mechanism to prevent hypoxia-induced neonatal cardiac injury. ### Competing Interest Statement The authors have declared no competing interest.
13 tweets biophysics
Microtubule (MT)-associated proteins (MAPs) regulate intracellular transport by selectively recruiting or excluding kinesin and dynein motors from MTs. We used single-molecule and cryo-electron imaging to determine the mechanism of MAP-motor interactions in vitro. Unexpectedly, we found that the regulatory role of a MAP cannot be predicted based on whether it overlaps with the motor binding site or forms liquid condensates on the MT. Although the MT binding domain (MTBD) of MAP7 overlaps with the kinesin-1 binding site, tethering of kinesin-1 by the MAP7 projection domain supersedes this inhibition and results in biphasic regulation of kinesin-1 motility. Conversely, the MTBD of tau inhibits dynein motility without overlapping with the dynein binding site or by forming tau islands on the MT. Our results indicate that MAPs sort intracellular cargos moving in both directions, as neither dynein nor kinesin can walk on a MAP-coated MT without favorably interacting with that MAP. ### Competing Interest Statement The authors have declared no competing interest.
11 tweets genomics
Background: Despite their ecological and economical importance, conifers still have limited genomic resources, mainly due to the large size and complexity of their genomes. In addition, several of the available genomic resources lack complete structural and functional annotation. Transcriptomic resources have been commonly used to compensate for these deficiencies, though for most conifer species the currently available transcriptomes are limited to a small number of tissues, or capture only a fraction of the genes present in the genome. Results: Here we provide an atlas of gene expression patterns for conifer Pinus sylvestris grown under natural conditions across five tissues: embryo, megagametophyte, needle, phloem, and vegetative bud. Compared to previous studies, we used a wider range of tissues and focused our analyses on the expression profiles of genes at tissue level. We provide comprehensive information of the per-tissue normalized expression level, and indication of tissue preferential upregulation or tissue preferential expression. We identified a total of 48,001 tissue preferentially upregulated and tissue specifically expressed genes, of which 28% have annotation in the Swiss-Prot database. The annotated genes were associated with a total of 84,498 GO terms, of which 1,834 had significant enrichment in different processes and functions, for example glyoxylate cycle in megagametophyte and defense response in needle. Even though most of the genes originating from the transcriptome do not have functional information in current biological databases, the tissue-specific patterns identified here provide valuable information about their potential functions for further studies. Conclusions: The genes identified in this study will contribute to improve the annotation of the already available and forthcoming conifer genomes. This atlas of gene expression also provides ground to further the research in the areas of plant physiology, population genetics, and genomics in general. As we provide information on tissue specificity at both diploid and haploid life stages, our data will also contribute to the understanding of evolutionary rates of different tissue types and ploidy levels. ### Competing Interest Statement The authors have declared no competing interest.
10 tweets neuroscience
Neuroimaging has advanced our understanding of human psychology using reductionist stimuli that often do not resemble information the brain naturally encounters. It has improved our understanding of the network organization of the brain mostly through analyses of 'resting-state' data for which the functions of networks cannot be verifiably labelled. We make a 'Naturalistic Neuroimaging Database' (NNDb v1.0) publically available to allow for a more complete understanding of the brain under more ecological conditions during which networks can be labelled. Eighty-six participants underwent behavioural testing and watched one of 10 full-length movies while functional magnetic resonance imaging was acquired. Resulting timeseries data are shown to be of high quality, with good signal-to-noise ratio, few outliers and low movement. Data-driven functional analyses provide further evidence of data quality. They also demonstrate accurate timeseries/movie alignment and how movie annotations might be used to label networks. The NNDb can be used to answer questions previously unaddressed with standard neuroimaging approaches, progressing our knowledge of how the brain works in the real world. ### Competing Interest Statement The authors have declared no competing interest.
10 tweets neuroscience
Theoretically, working memory (WM) representations are encoded by population activity of neurons with distributed tuning across the stored feature. Here, we leverage computational neuroimaging approaches to map the topographic organization of human superior colliculus (SC) and model how population activity in SC encodes WM representations. We first modeled receptive field properties of voxels in SC, deriving a detailed topographic organization resembling that of the primate SC. Neural activity within male and female human SC persisted throughout a retention interval of several types of modified memory-guided saccade tasks. Assuming an underlying neural architecture of the SC based on its retinotopic organization, we used an encoding model to show that the pattern of activity in human SC represents locations stored in WM. Our tasks and models allowed us to dissociate the locations of visual targets and the motor metrics of memory-guided saccades from the spatial locations stored in WM, thus confirming that human SC represents true WM information. These data have several important implications. They add the SC to a growing number of cortical and subcortical brain areas that form distributed networks supporting WM functions. Moreover, they specify a clear neural mechanism by which topographically organized SC encodes WM representations. Significance Statement Using computational neuroimaging approaches, we mapped the topographic organization of human superior colliculus (SC) and modeled how population activity in SC encodes working memory (WM) representations, rather than simpler visual or motor properties that have been traditionally associated with the laminar maps in the primate SC. Together, these data both position the human SC into a distributed network of brain areas supporting WM and elucidate the neural mechanisms by which the SC supports WM. ### Competing Interest Statement The authors have declared no competing interest.
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