bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutionary puzzle: discussing the evolution of sentience in Metazoa through a phylogenetic perspective
Authors: Andrade Michaella P. , Santos Charles Morphy D. 
Published: May 2021

AbstractSentience is the capacity of organisms to feel and experience through subjective states. During the last years, several investigations have indicated that response mechanisms to harmful stimuli can be highly conserved among the Metazoa. However, there is a research bias towards vertebrates in the available studies. Here we discuss the evolution of the nervous and sensory system, pain and nociception in animals through a phylogenetic perspective testing the hypothesis of common ancestry of sentience. Our results indicate that characteristics related to sentience - morphological and molecular and behavioural -, were already present in the common ancestors of Metazoa, Eumetazoa and Bilateria. Our phylogenetic hypotheses positioned Porifera as the sister-group to all the other Metazoa, corroborating the hypothesis of a single origin of the nervous system. Our results also depict Urbilateria as the ancestor of the metazoan toolkit related to the sentience. These scenarios suggest that some attributes of the sensory system may have appeared even before the emergence of the nervous system, through possible cooptations of sensory modules of the first Metazoa.
Histone H3K27 methylation perturbs transcriptional robustness and underpins dispensability of highly conserved genes in fungi
Authors: Tralamazza Sabina Moser , Abraham Leen Nanchira , Corrêa Benedito , Croll Daniel 
Published: May 2021

AbstractEpigenetic modifications are key regulators of gene expression and underpin genome integrity. Yet, how epigenetic changes affect the evolution and transcriptional robustness of genes remains largely unknown. Here, we show how the repressive histone mark H3K27me3 influences the trajectory of highly conserved genes in fungi. We first performed transcriptomic profiling on closely related species of the plant pathogen Fusarium graminearum species complex. We determined transcriptional responsiveness of genes across environmental conditions to determine expression robustness. To infer evolutionary conservation of coding sequences, we used a comparative genomics framework of 23 species across the Fusarium genus. We integrated histone methylation data from three Fusarium species across the phylogenetic breadth of the genus. Gene expression variation is negatively correlated with gene conservation confirming that highly conserved genes show higher expression robustness. Furthermore, we show that highly conserved genes marked by H3K27me3 deviate from the typical housekeeping gene archetype. Compared to the genomic background, H3K27me3 marked genes encode smaller proteins, exhibit lower GC content, weaker codon usage bias, higher levels of hydrophobicity and are enriched for functions related to regulation and membrane transport. The evolutionary age of conserved genes with H3K27me3 histone marks falls typically within the origins of the Fusarium genus. We show that highly conserved genes marked by H3K27me3 are more likely to be dispensable for survival. Lastly, we show that conserved genes exposed to repressive H3K27me3 marks across distantly related fungi predict transcriptional perturbation at the microevolutionary scale in Fusarium fungi. In conclusion, we establish how repressive histone marks determine the evolutionary fate of highly conserved genes across evolutionary timescales.
Meclizine and metabotropic glutamate receptor agonists attenuate severe pain and primary sensory neuron Ca2+activity in chemotherapy-induced peripheral neuropathy
Authors: Shannonhouse John , Bernabucci Matteo , Gomez Ruben , Son Hyeonwi , Zhang Yan , Ishida Hirotake , Kim Yu Shin 
Published: May 2021

AbstractChemotherapy-induced peripheral neuropathy (CIPN) affects about 68% of patients undergoing chemotherapy and causes severe neuropathic pain which is debilitating health problem and greatly reduces quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing. Meclizine is an H1 histamine receptor antagonist which is known to have neuroprotective effects including anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN to test agonists of mGluR8 and group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests andin vivoentire DRG neurons Ca2+imaging using genetically-encoded Ca2+indicator, Pirt-GCaMP3 to monitor different drug interventions on a populational ensemble level. CIPN induced increased spontaneous Ca2+activity in DRG neurons, increased Ca2+transient amplitudes, and hyperresponses to mechanical, thermal, and chemical stimuli. We found mGluR8 agonist, DCPG, group II mGluR agonist, LY379268, and Histamine1 receptor antagonist, meclizine all significantly attenuated mechanical and thermal pain caused by CIPN. LY379268 and meclizine, but not DCPG, attenuated DRG neuronal Ca2+activity elevated by CIPN. Furthermore, meclizine attenuated cisplatin-induced weight loss. These results suggest group II mGluR agonist, mGluR8 agonist, and meclizine are excellent candidates to study for mechanisms and new treatment option for CIPN.
Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment
Authors: Huang Yanqing , Garcia Garcia Carolina J. , Lin Daniel , Nguyen Nicholas D. , Fujimoto Tara N. , Zhao Jun , Lee Jaewon J. , Bernard Vincent , Yu Meifang , Delahoussaye Abagail M. , Phan Jae L. , Deorukhkar Amit , Molkentine Jessica M. , Fuentes Natividad R. , Turner Madeleine C. , Saur Dieter , Maitra Anirban , Taniguchi Cullen M. 
Published: May 2021

AbstractBackground & AimsPancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown.MethodsWe used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade.ResultsCAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models.ConclusionsTogether, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
Capsaicin pretreatment alleviates postoperative pain and reduces primary sensory neuron Ca2+ activity
Authors: Ishida Hirotake , Zhang Yan , Gomez Ruben , Shannonhouse John , Son Hyeonwi , Kim Yu Shin 
Published: May 2021

AbstractAfter surgeries, especially thoracotomy incision, patients develop unbearable pain. Opioids are used for reducing pain but often cause serious side effects. Previously, we found that capsaicin pretreatment of the incision area alleviated spontaneous and thermal pain in a postoperative pain animal model. In the present study, we aimed to monitor primary sensory neuron Ca2+ activity in in vivo dorsal root ganglia (DRG) in a postoperative pain model using Pirt-GCaMP3 treated with capsaicin or controls. Intraplantar injection of capsaicin (0.05%) alleviated spontaneous, mechanical, and thermal postoperative pain. The Ca2+ response in in vivo DRG and in in situ spinal cord was significantly enhanced in the ipsilateral side compared to contralateral side or naive control. Primary sensory nerve fiber length was significantly decreased in the incision skin area in capsaicin-pretreated animals detected by immunohistochemistry and placental alkaline phosphatase (PLAP) staining. Thus, capsaicin pretreatment alleviates postoperative pain by suppressing Ca2+ response due to degeneration of primary sensory nerve fibers in the skin.
Imaging sensory transmission and neuronal plasticity in primary sensory neurons with genetically-encoded voltage indicator, ASAP4.4-Kv
Authors: Zhang Yan , Shannonhouse John , Gomez Ruben , Son Hyeonwi , Ishida Hirotake , Evans Stephen , Chavarha Mariya , Shi Dongqing , Zhang Guofeng , Lin Michael Z , Kim Yu Shin 
Published: May 2021

AbstractDetection of somatosensory inputs requires conversion of external stimuli into electrical signals by activation of primary sensory neurons. The mechanisms by which heterogeneous primary sensory neurons encode different somatosensory inputs remains unclear. In vivo dorsal root ganglia (DRG) imaging using genetically-encoded Ca2+ indicators (GECIs) is currently the best technique for this purpose by providing an unprecedented spatial and populational resolution. It permits the simultaneous imaging of >1800 neurons/DRG in live mice. However, this approach is not ideal given that Ca2+ is a second messenger and has inherently slow response kinetics. In contrast, genetically-encoded voltage indicators (GEVIs) have the potential to track voltage changes in multiple neurons in real time but often lack the brightness and dynamic range required for in vivo use. Here, we used soma-targeted ASAP4.4-Kv, a novel GEVI, to dissect the temporal dynamics of noxious and non-noxious neuronal signals during mechanical, thermal, or chemical stimulation in DRG of live mice. ASAP4.4-Kv is sufficiently bright and fast enough to optically characterize individual neuron coding dynamics. Notably, using ASAP4.4-Kv, we uncovered cell-to-cell electrical synchronization between adjacent DRG neurons and robust dynamic transformations in sensory coding following tissue injury. Finally, we found that a combination of GEVI and GECI imaging empowered in vivo optical studies of sensory signal processing and integration mechanisms with optimal spatiotemporal analysis.HighlightsIn vivo ultra fast and sensitive dynamic voltage imaging of peripheral primary sensory neurons by a newly generated genetically-encoded voltage indicator.Identification of mechanical, thermal, or chemical stimuli-evoked voltage signals with superior temporal resolution.Single-cell detection of changes in sub- and suprathreshold voltage dynamics across different disease conditions.Combination of voltage (by ASAP4.4-Kv) and Ca2+ (by Pirt-GCaMP3) signals to facilitate the understanding of signal processing and integration of primary sensory neurons, especially for noxious versus non-noxious sensation.
Noninvasive genetic surveys before and after a megafire detect displacement of migratory mule deer
Authors: Brazeal Jennifer L. , Sollmann Rahel , Sacks Benjamin N. 
Published: May 2021

AbstractDue to climate change and past logging and fire suppression, the western US are experiencing increasingly large and frequent wildfires. Understanding how wildlife respond to these mega-fires is becoming increasingly relevant to protect and manage these populations. However, the lack of predictability inherent in such events makes studies difficult to plan. We took advantage of a large high-severity wildfire that burned adjacent to an ongoing study of mule deer (Odocoileus hemionus) on their summer range upslope of the fire to investigate their displacement onto our study area both immediately and upon their return to summer range the following year. We used spatial capture-recapture models in conjunction with noninvasive fecal DNA sampling to estimate density and non-spatial Pradel robust-design models to estimate apparent survival and recruitment rates. Compared to density before the fire, we observed an increase in deer density and an increase in per-capita recruitment rates one month after the fire. These findings suggest that the immediate response of at least some deer was to flee the fire upslope onto the study area rather than to downslope toward their winter range. These changes did not carry over into the following year, however, suggesting that deer formerly using the burned area as summer range may have returned there despite the high severity of the fire, or may have chosen new areas for their summer range. This suggests that, at least in the short term, the fire did not negatively affect the deer population.
Intrapopulation adaptive variance supports selective breeding in a reef-building coral
Authors: Drury Crawford , Bean Nina , Harris Casey , Hancock Josh , Hucekba Joel , Christian Martin H. , Roach Ty , Quinn Robert , Gates Ruth D. 
Published: May 2021

AbstractThe long-term persistence of coral reefs under climate change requires heritable drivers of thermal tolerance which support adaptation. The genomic basis of thermal tolerance has been evaluated across strong spatial and environmental gradients, but this variation also exists within populations due to neutral evolutionary processes. Small scale heterogeneity in coral bleaching is ubiquitous, so we used corals from a single reef to examine genomic signatures of bleaching performance, their biochemical correlates and the downstream consequences of selective breeding. In the absence of directional selection due to environmental differences, adult corals from a single population exhibit strong genomic patterns related to natural bleaching tolerance and symbiosis state, including functional differentiation in signaling pathways, protein and amino acid modification and metabolism. Conversely, growth, development and innate immune responses did not distinguish bleaching tolerance in adult corals. The genomic signatures of these gene ontologies influence biochemical patterns in healthy corals, primarily via cell-signaling pathway impacts on peptides and amino acids. Thermal tolerance in this population is highly heritable, with significantly higher survivorship under temperature stress in larvae and juveniles reared from thermally tolerant parents than those from sensitive parents. Using a select and re-sequence approach, certain gene ontologies were reproducibly impacted, while antioxidant activity and cell signaling ontologies were disproportionately selected in thermally tolerant corals, demonstrating the genomic drivers of successful selective breeding. These data show that intrapopulation variance in the absence of historical selection supports the adaptive capacity of coral reefs under climate change.
Leveraging a founder population to identify novel rare-population genetic determinants of lipidome
Authors: Montasser May E. , Aslibekyan Stella , Srinivasasainagendra Vinodh , Tiwari Hemant K. , Patki Amit , Bagheri Minoo , Kind Tobias , Barupal Dinesh Kumar , Fan Sili , Perry James , Ryan Kathleen A. , Arnett Donna K. , Beitelshees Amber L. , Irvin Marguerite Ryan , O’Connell Jeffrey R. 
Published: May 2021

ABSTRACTIdentifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and new insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of novel biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a GWAS of 355 lipid species in 650 individuals from the Old Order Amish founder population including 127 lipid species not previously tested. We report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants:APOB_rs5742904 andAPOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus includingGLPTD2_rs536055318,CERS5_rs771033566, andAKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol withUGTlocus on chromosome 2 and estriol withSLC22A8/A24locus on chromosome 11. Our results show the power of founder populations to discover novel biology due to genetic drift that can increase the frequency of an allele from only few copies in large sample cohorts such as the UK Biobank to dozens of copies in sample size as small as 650.
Design and modular assembly of synthetic intramembrane proteolysis receptors for custom gene regulation in therapeutic cells
Authors: Zhu Iowis , Liu Raymond , Hyrenius-Wittsten Axel , Piraner Dan I. , Alavi Josef , Israni Divya V. , Khalil Ahmad S. , Roybal Kole T. 
Published: May 2021

SUMMARYSynthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors we call SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the potential transformative utility of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.
Demuxalot: scaled up genetic demultiplexing for single-cell sequencing
Authors: Rogozhnikov Alex , Ramkumar Pavan , Shah Kevan , Bedi Rishi , Kato Saul , Escola G. Sean 
Published: May 2021

ABSTRACTDemultiplexing methods have facilitated the widespread use of single-cell RNA sequencing (scRNAseq) experiments by lowering costs and reducing technical variations. Here, we present demuxalot: a method for probabilistic genotype inference from aligned reads, with no assumptions about allele ratios and efficient incorporation of prior genotype information from historical experiments in a multi-batch setting. Our method efficiently incorporates additional information across reads originating from the same transcript, enabling up to 3x more calls per read relative to naive approaches. We also propose a novel and highly performant tradeoff between methods that rely on reference genotypes and methods that learn variants from the data, by selecting a small number of highly informative variants that maximize the marginal information with respect to reference single nucleotide variants (SNVs). Our resulting improved SNV-based demultiplex method is up to 3x faster, 3x more data efficient, and achieves significantly more accurate doublet discrimination than previously published methods. This approach renders scRNAseq feasible for the kind of large multi-batch, multi-donor studies that are required to prosecute diseases with heterogeneous genetic backgrounds.
Co-option of immune effectors by the hormonal signalling system triggering metamorphosis inDrosophila melanogaster
Authors: Nunes Catarina , Koyama Takashi , Sucena Élio 
Published: May 2021

AbstractInsect metamorphosis is regulated by the production, secretion and degradation of two peripheral hormones: 20-hydroxyecdysone (ecdysone) and juvenile hormone (JH). In addition to their roles in developmental regulation, increasing evidence suggests that these hormones are involved in innate immunity processes, such as phagocytosis and the induction of antimicrobial peptide (AMP) production. AMP regulation includes systemic responses as well as local responses at surface epithelia that contact with the external environment. At pupariation,Drosophila melanogasterincreases dramatically the expression of three AMP genes,drosomycin (drs), drosomycin-like 2 (drsl2)anddrosomycin-like 5 (drsl5). We show that the systemic action ofdrsat pupariation is dependent on ecdysone signalling in the fat body and operates via the ecdysone downstream target, Broad-Z4. In parallel, ecdysone also regulates local responses, specifically through the activation ofdrsl2expression in the gut. Finally, we confirm the relevance of this ecdysone dependent AMP expression for the control of bacterial persistence by showing that flies lackingdrsexpression in the fat body have higher bacterial persistence over metamorphosis. Together, our data emphasize the importance of the association between ecdysone signalling and immunity usingin vivostudies and establish a new role for ecdysone at pupariation, which impacts developmental success by regulating the immune system in a stage-dependent manner. We speculate that this co-option of immune effectors by the hormonal system may constitute a pre-emptive mechanism to control bacterial numbers in the pupa at the core of metamorphosis evolution.
Fast processing of environmental DNA metabarcoding sequence data using convolutional neural networks
Authors: Flück Benjamin , Mathon Laëtitia , Manel Stéphanie , Valentini Alice , Dejean Tony , Albouy Camille , Mouillot David , Thuiller Wilfried , Murienne Jérôme , Brosse Sébastien , Pellissier Loïc 
Published: May 2021

1AbstractThe intensification of anthropogenic pressures have increased consequences on biodiversity and ultimately on the functioning of ecosystems. To monitor and better understand biodiversity responses to environmental changes using standardized and reproducible methods, novel high-throughput DNA sequencing is becoming a major tool. Indeed, organisms shed DNA traces in their environment and this “environmental DNA” (eDNA) can be collected and sequenced using eDNA metabarcoding. The processing of large volumes of eDNA metabarcoding data remains challenging, especially its transformation to relevant taxonomic lists that can be interpreted by experts. Speed and accuracy are two major bottlenecks in this critical step. Here, we investigate whether convolutional neural networks (CNN) can optimize the processing of short eDNA sequences. We tested whether the speed and accuracy of a CNN are comparable to that of the frequently used OBITools bioinformatic pipeline. We applied the methodology on a massive eDNA dataset collected in Tropical South America (French Guiana), where freshwater fishes were targeted using a small region (60pb) of the 12S ribosomal RNA mitochondrial gene. We found that the taxonomic assignments from the CNN were comparable to those of OBITools, with high correlation levels and a similar match to the regional fish fauna. The CNN allowed the processing of raw fastq files at a rate of approximately 1 million sequences per minute which was 150 times faster than with OBITools. Once trained, the application of CNN to new eDNA metabarcoding data can be automated, which promises fast and easy deployment on the cloud for future eDNA analyses.