Biology subjects

Yuan, W.

Publications and source records attributed to Yuan, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections

Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also its N6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1{beta}, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1{beta}, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections. IMPORTANCEInnate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found that N6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.

microbiology↗

bioRxiv2022

Targeting the BAG-1 family of co-chaperones in lethal prostate cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR drives transcriptional activity in CRPC but is intrinsically disordered and remains a challenging therapeutic target. Therefore, inhibiting critical co-chaperones, such as BAG-1L, is an attractive alternative strategy. We performed druggability analyses demonstrating the BAG domain to be a challenging drug target. Thio-2, a tool compound, has been reported to bind the BAG domain of BAG-1L and inhibit BAG-1L-mediated AR transactivation. However, despite these data, the mechanism of action of Thio-2 is poorly understood and the BAG domain which is present in all BAG-1 isoforms has not been validated as a therapeutic target. Herein, we demonstrate growth inhibiting activity of Thio-2 in CRPC cell lines and patient derived models with decreased AR genomic binding and AR signaling independent of BAG-1 isoform function. Furthermore, genomic abrogation of BAG-1 isoforms did not recapitulate the described Thio-2 phenotype, and NMR studies suggest that Thio-2 may bind the AR NTD, uncovering a potential alternative mechanism of action, although in the context of low compound solubility. Furthermore, BAG-1 isoform knockout mice are viable and fertile, in contrast to previous studies, and when crossed with prostate cancer mouse models, BAG-1 deletion does not significantly impact prostate cancer development and growth. Overall, these data demonstrate that Thio-2 inhibits AR signaling and growth in CRPC independent of BAG-1 isoforms, and unlike previous studies of the activated AR, therapeutic targeting of the BAG domain requires further validation before being considered a therapeutic strategy for the treatment of CRPC.

molecular biology↗

bioRxiv2022

High-throughput TCRB enrichment sequencing of human cord blood exhibited a distinct fetal T cell repertoire in the third trimester of pregnancy

Study questionWhat are the molecular characteristics during the maturation process of the human fetal immune system in the third trimester of pregnancy? Summary answerBoth the diversity and length of complementarity determining region 3 (CDR3s) in the fetal TCRB repertoire were less than those of adult CDR3s, and the fetal CDR3 length increased with gestation weeks in late pregnancy. What is known alreadyThe adaptive immune system recognizes various pathogens based on a large repertoire of T-cell receptors (TCR repertoire), but the maturation dynamics of the fetal TCR repertoire in the third trimester are largely unknown. The CDR3is the most diversified segment in the T-cell receptor {beta} chain (TCRB) that binds and recognizes the antigen. Study design, size, and durationThis was a basic research to assess the composing characteristics of TCRBs in core blood and the dynamic pattern with fetal development in the third trimester of pregnancy. Participants/materials, setting methodsHigh-throughput TCRB-enrichment sequencing was utilized to characterize the TCRB repertoire of cord blood at 24~38 weeks of gestational age (WGA) with nonpreterm fetuses and to investigate their difference compared with that of adult peripheral blood. Main results and the role of chanceCompared to the adult control, the fetal TCRB repertoire had a 4.8-fold lower number of unique CDR3s, a comparable Shannon diversity index (p=0.7387), a lower mean top clone rate (p < 0.001) and a constrictive top 1000 unique clone rates. Although all kinds of TCRBV and TCRBJ genes present in adult CDR3s were identified in fetuses, nearly half of these fragments showed a significant difference in usage. Moreover, the fetal TCRB repertoire held a shorter CDR3 length, and the CDR3 length showed a progressive increase with fetal development. Jensen-Shannon (JS) divergences of TCRBV and TCRBJ gene usage in dizygotic twins were much lower than those in unrelated pairs. In the parental-fetal pair, JS divergence of TCRBV gene usage was not obviously different, while that of TCRBJ gene usage was only slightly lower. Limitations, reasons for cautionThe sample size is limited due to the limited accessibility to cord blood in late pregnancy with healthy nonpreterm fetuses. Wider implications of the findingsOur findings reveal the unique properties of fetal TCRB repertoires in the third trimester, fill the gap in our understanding of the maturation process of prenatal fatal immunity, and deepen our understanding of the immunologically relevant problems in neonates. Study funding/competing interest(s)This work was supported by the National Natural Science Foundation of China (82171661) and Tianjin Municipal Science and Technology Special Funds for Enterprise Development (NO. 14ZXLJSY00320). The authors declare that they have no competing interests.

genetics↗

bioRxiv2022

Canalization of genome-wide transcriptional activity in Arabidopsis thaliana accessions by MET1-dependent CG methylation

BACKGROUNDEukaryotes employ epigenetic marks such as DNA methylation at cytosines both for gene regulation and genome defense. In Arabidopsis thaliana, a central role is played by methylation in the CG context, with profound effects on gene expression and transposable element (TE) silencing. Nevertheless, despite its conserved role, genome-wide CG methylation differs substantially between wild A. thaliana accessions. RESULTSWe hypothesized that global reduction of CG methylation would reduce epigenomic, transcriptomic and phenotypic diversity in A. thaliana accessions. To test our hypothesis, we knocked out MET1, which is required for CG methylation, in 18 early-flowering A. thaliana accessions. Homozygous met1 mutants in all accessions suffered from a range of common developmental defects such as dwarfism and delayed flowering, in addition to accession-specific abnormalities in rosette leaf architecture, silique morphology and fertility. Integrated analysis of genome-wide methylation, chromatin accessibility and transcriptomes confirmed that inactivation of MET1 greatly reduces CG methylation and alters chromatin accessibility at thousands of loci. While the effects on TE activation were similarly drastic in all accessions, the quantitative effects on non-TE genes varied greatly. The expression profiles of accessions became considerably more divergent from each other after genome-wide removal of CG methylation, although the expression of genes with diverse expression profiles across wild-type accessions tended to become more similar in mutants. CONCLUSIONSOur systematic analysis of MET1 requirement for genome function in different A. thaliana accessions revealed a dual role for CG methylation: for many genes, CG methylation appears to canalize expression levels, with methylation masking regulatory divergence. However, for a smaller subset of genes, CG methylation increases expression diversity beyond genetically encoded differences.

plant biology↗

bioRxiv2022

Balancing p38 MAPK Signaling with Proteostasis Mechanisms Supports Tissue Integrity during Aging in C. elegans

Like other p38 MAPKs, C. elegans PMK-1 is activated by phosphorylation during stress responses and inactivated by phosphatases. PMK-1 initiates immune response and blocks development when hyperactivated. Here we show that PMK-1 signaling is essential for tissue homeostasis during aging. Loss of PMK-1 accelerates progressive declines in neuronal integrity and lysosome function compromising longevity. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. The cleavage-resistant PMK-1 mutant behaves oppositely to the pmk-1 null in regulating both transcriptional and protein degradation programs supporting tissue homeostasis. PMK-1 activates a complex transcriptional program and requires UNC-62 (MEIS), FOS/JUN, and DAF-16 (FOXO) transcription factors to regulate lysosome formation which is both cell autonomous and non-cell autonomous. We show that during early aging the absolute phospho-p38 amount is nearly constant but maintained at a small percentage of total p38. The reservoir of non-phospho-p38 diminishes during early aging to enhance signaling without hyperactivation. CED-3 caspase cleavage limits phosphorylated PMK-1 and truncated PMK-1 is rapidly degraded by the proteasome. Modulating phospho-p38 ratio confers dynamic control for tissue-homeostasis without activating stress response to support longevity.

molecular biology↗

bioRxiv2022

The asymmetric ABA response on both sides of root tip is important for tomato root hydrotropism by mediating proton efflux and cell elongation

Hydrotropism is an important adaptation of plant roots to the uneven distribution of water, and the current research on hydrotropism is mainly focused on Arabidopsis thaliana. We examined hydrotropism in tomato (Solanum lycopersicum) primary roots. We used RNA sequencing to detect the gene expression on both sides (dry and wet side) of root tips (5 mm from the root cap junction) by splitting root tips longitudinally into two halves. We found that hydrostimulation induced the asymmetric cell elongation between the dry side (lower water potential) and wet side of root tips (higher water potential). ABA biosynthesis gene ABA4 was induced on the dry side as compared to the wet side of root tips. Chemical inhibitors that block ABA biosynthesis can disrupt hydrotropism, and ABA biosynthesis mutant not showed significantly reduced hydrotropism. Furthermore, asymmetric H+ efflux was found in wild-type but not in root tips of ABA biosynthesis mutant not after hydrostimulation. Our results suggest that the asymmetric ABA response on both sides of root tip mediate asymmetric H+ efflux, and then drive the asymmetric cell elongation, which allows the root to bend towards the wet side to take up more water. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/483958v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1f8132dorg.highwire.dtl.DTLVardef@1b30b09org.highwire.dtl.DTLVardef@199955corg.highwire.dtl.DTLVardef@1cfd13_HPS_FORMAT_FIGEXP M_FIG Involvement of ABA-mediated asymmetric H+ efflux in root hydrotropism. Compared to the wet side of root tip (higher water potential), the dry side (lower water potential) induces the expression of ABA biosynthesis gene ABA4, thus enhancing proton efflux to promoting cell elongation on the dry side. Because H+ efflux and cell elongation on the dry side of the root tip are higher than that on the wet side, the asymmetric growth of cells on both sides allows the root to bend towards the wet side for taking up more water. C_FIG In BriefThe asymmetric ABA response on both sides of root tip (dry side and wet side) sequently mediates root asymmetric H+ efflux, and then drives the asymmetric cell elongation on both sides of root tip, which allows the root to bend towards the wet side for absorbing more water. HighlightsHydrotropic bending requires asymmetric cell elongation on the root two sides. Asymmetric expression of ABA biosynthesis gene ABA4 is required for root hydrotropism. The H+ efflux on the dry side of the root is increased. ABA-associated asymmetric H+ efflux driven root hydrotropic bending.

ecology↗

bioRxiv2022

Oxidative phosphorylation pathway disruption is an alternative pathological mechanism leading to Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a rare congenital disorder characterized by the failure of erythroid progenitor differentiation; however, the molecular mechanisms leading to erythroid defects remain unclear. By analyzing the transcriptomic profiles of bone marrow from patients with DBA (n = 10), we identified the dysfunction of the oxidative phosphorylation (OXPHOS) pathway as a possible cause of DBA. We established a DBA cell model using differentiating hematopoietic stem progenitor cells in which the OXPHOS pathway was suppressed to completely recapitulate the defects in erythroid progenitor differentiation, ribosome biogenesis, and heme biosynthesis, which are representative characteristics of patients with DBA. Disruption of the OXPHOS pathway led to ribosomal defects and associated erythroid defects via abolishment of the Ran GTPase activating protein RanGAP1, which is pivotal in the RNA transport pathway. The composition of the ribosomal proteins in the established DBA cells was unchanged, but an overall reduction in ribosomal protein levels was observed, leading to an alteration in the translation of a subset of transcripts specific to erythropoiesis. We revealed that the OXPHOS pathway participates in erythropoiesis, particularly at an early stage, and reinforced the relationship between the OXPHOS pathway and erythropoiesis. Coenzyme Q10, an activator of OXPHOS, largely rescued the erythroid defects in DBA cells. Our results reveal that OXPHOS repression is an alternative pathological mechanism leading to DBA, demonstrating its potential as a therapeutic pathway. Key PointsO_LIOxidative phosphorylation (OXPHOS) pathway disruption is an alternative pathological mechanism underlying Diamond-Blackfan anemia (DBA). C_LIO_LISuppression of OXPHOS leads to defects in erythropoiesis and ribosomal biogenesis via the RanGAP1 protein. C_LI

cell biology↗

bioRxiv2022

Rapid phenotypic differentiation and local adaptation in Japanese knotweed s.l. (Reynoutria japonica and R. x bohemica, Polygonaceae) invading novel habitats

PREMISEMany plant invaders like the Japanese knotweeds are thought to colonize new habitats with low genetic diversity. Such species provide an opportunity to study rapid adaptation to complex environmental conditions. METHODSUsing replicate reciprocal transplants of clones across three habitats, we described patterns of phenotypic response and assessed degree of local adaptation. KEY RESULTSWe found plants from beach habitats had decreased height, number of leaves, leaf area, and biomass allocation to roots and shoots compared to plants from marsh and roadside habitats when grown in their home habitat. In the marsh habitat, marsh plants were generally larger than beach plants, but not different from roadside plants. There were no differences among plants from different habitats grown in the roadside habitat. Despite this evidence of differentiation in beach and marsh habitats, we found mixed evidence for local adaptation. In their "home site" plants from the marsh habitat had greater biomass than plants from the beaches but not compared to plants from roadsides. Biomass comparisons in other habitats were either maladaptive or not significant. However, plants from the roadside had greater survival in their "home site" compared to foreign plants. There were no differences in survival in the other habitats. CONCLUSIONSWe found phenotypic differentiation associated with habitats despite the low reported genetic diversity for these populations. Our results partially support the hypothesis of local adaptation in marsh and roadside habitats. Identifying whether these patterns of differentiation result from genetic or heritable non-genetic mechanisms will require further work.

ecology↗

bioRxiv2022

Pervasive Under-Dominance in Gene Expression as Unifying Principle of Biomass Heterosis in Arabidopsis

Complex traits, such as growth and fitness, are typically controlled by a very large number of variants, which can interact in both additive and non-additive fashion. In an attempt to gauge the relative importance of both types of genetic interactions, we have turned to hybrids, which provide a facile means for creating many novel allele combinations. We focused on the interaction between alleles of the same locus and performed a transcriptomic study involving 141 random crosses between different accessions of the plant model species Arabidopsis thaliana. Additivity is rare, consistently observed for only about 300 genes enriched for roles in stress response and cell death. Regulatory rare-allele burden affects the expression level of these genes but does not correlate with F1 rosette size. Non-additive gene expression in F1 hybrids is much more common, with the vast majority of genes (over 90%) being expressed below parental average. Unlike in the additive genes, regulatory rare-allele burden in the non-additive gene set is strongly correlated with F1 rosette size, even though it only mildly covary with the expression level of these genes. Our study underscores under-dominance as the predominant gene action associated with emergence of rosette growth trajectories in the A. thaliana hybrid model. Our work lays the foundation for understanding molecular mechanisms and evolutionary forces that lead to dominance complementation of rare regulatory alleles.

genomics↗

bioRxiv2022

Metagenomics revealing molecular profiling of microbial community structure and metabolic capacity in Bamucuo, Tibet

We performed a survey of the microorganisms in Bamucuo, Tibet, resulting in 160,212 (soil) and 135,994 (water) contigs by shotgun metagenomic methods. We discovered 74 new bacterial species and reconstructed their draft genomes, which were obtained from the 75 reconstructed almost complete metagenomic assembly genomes (MAG) in the soil and water samples. Proteobacteria and Actinobacteria were found to be the most dominant bacterial phyla, while Euryarchaeota was the most dominant archaeal phylum. To our surprise, Pandoravirus salinus was found in the soil microbial community. We concluded that the microorganisms in Bamucuo fix carbon mainly through the 3-hydroxypropionic bi-cycle pathway. IMPORTANCEThe Qinghai-Tibet Plateau (QTP) is the highest plateau in the world, and the microorganisms there play vital ecological roles in the global biogeochemical cycle; however, detailed information on the microbial communities in QTP is still lacking, especially in high altitude areas above 4500 meters. This study, for the first time, characterized the microbial community composition and metabolic capacity in QTP high-altitude areas (with an altitude of 4,555 meters), confirmed that QTP is a huge and valuable resource bank in which more new non-resistant antibiotics and many other bioactive substances could be developed. In addition, the discovery of Pandoravirus salinus in the soil provides important information for further exploring this unique microorganism, and many draft genomes and the genome annotation information obtained in this study have laid the foundation for further in-depth study of the microbial ecology in Qinghai-Tibet Plateau.

microbiology↗

bioRxiv2021

Cell-adaptable dynamic hydrogel reinforced with stem cells improves the functional repair of spinal cord injury by alleviating neuroinflammation

Spinal cord injury (SCI) is one of the most challenging clinical issues. It is characterized by the disruption of neural circuitry and connectivity, resulting in neurological disability. Adipose-derived stem cells (ADSCs) serve as a promising source of therapeutic cells for SCI treatment. However, the therapeutic outcomes of direct ADSCs transplantation are limited in the presence of an inflammatory microenvironment. Herein, a cell-adaptable neurogenic (CaNeu) hydrogel was developed as a delivery vehicle for ADSCs to promote neuronal regeneration after SCI. The dynamic network of CaNeu hydrogel loaded with ADSCs provides a cell-infiltratable matrix that enhances axonal growth and eventually leads to improved motor evoked potential, hindlimb strength, and coordination of complete spinal cord transection in rats. Furthermore, the CaNeu hydrogel also establishes an anti-inflammatory microenvironment by inducing a shift in the polarization of the recruited macrophages toward the pro-regeneration (M2) phenotype. Our study showed that the CaNeu-hydrogel-mediated ADSCs delivery resulted in significantly suppressed neuroinflammation and apoptosis, and that this phenomenon involved the PI3K/Akt signaling pathway. Our findings indicate that the CaNeu hydrogel is a valuable delivery vehicle to assist stem cell therapy for SCI, providing a promising strategy for central nervous system diseases.

bioengineering↗

bioRxiv2021

Cryo-EM structures of human TMEM120A and TMEM120B

TMEM120A (Transmembrane protein 120A) was recently identified as a mechanical pain sensing ion channel named as TACAN, while its homologue TMEM120B has no mechanosensing property1. Here, we report the cryo-EM structures of both human TMEM120A and TMEM120B. The two structures share the same dimeric assembly, mediated by extensive interactions through the transmembrane domain (TMD) and the N-terminal coiled coil domain (CCD). However, the nearly identical structures cannot provide clues for the difference in mechanosensing between TMEM120A and TMEM120B. Although TMEM120A could mediate conducting currents in a bilayer system, it does not mediate mechanical-induced currents in a heterologous expression system, suggesting TMEM120A is unlikely a mechanosensing channel. Instead, the TMDs of TMEM120A and TMEM120B resemble the structure of a fatty acid elongase, ELOVL7, indicating their potential role of an enzyme in lipid metabolism.

biophysics↗

bioRxiv2021

Phage-Derived Depolymerase as an Antibiotic Adjuvant Against Multidrug-Resistant Acinetobacter Baumannii

Bacteriophage-encoded depolymerases are responsible for degrading capsular polysaccharides (CPS), lipopolysaccharides (LPS) and exopolysachcharides (EPS) of the host bacteria during phage invasion. They have been considered as promising antivirulence agents in controlling bacterial infections, including those caused by drug-resistant bacteria. This feature inspires a hope of utilizing these enzymes to disarm the polysaccharide capsid of the bacterial cells, which then strengthens the action of antibiotics. Here we have identified, cloned, and expressed a depolymerase Dpo71 from a bacteriophage specific for the gram-negative (G-ve) bacterium Acinetobacter baumannii in the heterologous host E. coli. Dpo71 sensitizes the multidrug-resistant (MDR) A. baumannii to the host immune attack, and also acts as an adjuvant to assist or boost the action of antibiotics, for example colistin. Specifically, Dpo71 at 10 {micro}g/ml enables a complete bacterial eradication by human serum at 50% volume ratio. Dpo71 inhibits biofilm formation and disrupts the pre-formed biofilm. Combination of Dpo71 could significantly enhance the antibiofilm activity of colistin, and improve the survival rate of A. baumannii infected Galleria mellonella. Dpo71 retains the strain-specificity of the parent phage from which Dpo71 is derived: the phage-sensitive A. baumannii strains respond to Dpo71 treatment, whereas the phage-insensitive strains do not. This indicates that Dpo71 indeed is responsible for the host specificity of bacteriophages. In summary, our work demonstrates the feasibility of using recombinant depolymerases as an antibiotic adjuvants to supplement the development of new antibacterials and to battle against MDR pathogens.

microbiology↗

bioRxiv2021

Illustrating Potential Effects of Alternate Control Populations on Real-World Evidence-based Statistical Analyses

Case-control study designs are commonly used in retrospective analyses of Real-World Evidence (RWE). Due to the increasingly wide availability of RWE, it can be difficult to determine whether findings are robust or the result of testing multiple hypotheses. We investigate the potential effects of modifying cohort definitions in a case-control association study between depression and Type 2 Diabetes Mellitus (T2D). We found that small permutations to the criteria used to define the control population result in significant shifts in both the demographic structure of the identified cohort as well as the odds ratio of association. These differences remain present when testing against age and sex-matched controls. We believe this offers strong support for the need for robust guidelines, best practices and regulations around the use of observational RWE for clinical or regulatory decision making.

bioinformatics↗

bioRxiv2021

Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

p75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. However, the structural mechanism and physiological relevance of the adaptor protein TRADD in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the complex between p75NTR-DD and TRADD-DD and elucidate the structural basis of specific DD recognition in the p75NTR/TRADD signaling pathway. Furthermore, we identify spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and reveal the functional role of TRADD recruitment to p75NTR in the regulation of canonical NF-{kappa}B signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform to propagate downstream signaling in developing neurons.

biophysics↗

bioRxiv2020

A metabolic coincidence mechanism controls winter photoperiodism in plants

Plants have served as a preeminent study system for photoperiodism because of their propensity to flower in concordance with the seasons. A nearly singular focus on understanding seasonal flowering has been to the detriment of discovering other photoperiod measuring mechanisms that may be necessary for vegetative health. Here we use bioinformatics to identify a group of winter photoperiod-induced genes in Arabidopsis and show that one, PP2-A13, is critical for fitness and survival, exclusively in winter-like photoperiods. We create a real-time photoperiod reporter, using the PP2-A13 promoter driving luciferase, and show that winter photoperiod genes are regulated independent of the canonical CO/FT mechanism for photoperiodic flowering. The reporter then allows us to identify the first genetic and cellular drivers of winter photoperiodism and reveal a mechanism that relies on coincidence between light capture through photosynthesis and rhythmic metabolism. This work demonstrates that plants have distinct photoperiod measuring mechanisms that enact critical biological and developmental processes in different seasons.

plant biology↗

bioRxiv2020

Dorsal raphe nuclei to anterior cingulate cortex 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability in mandarin voles

Consolation is a common response to the distress of others in humans and some social animals, but the neural mechanisms underlying this behavior are not well characterized. By using socially monogamous mandarin voles, we found that optogenetic or chemogenetic inhibition of 5-HTergic neurons in the dorsal raphe nucleus (DR) or optogenetic inhibition of 5-HT terminals in the anterior cingulate cortex (ACC) significantly decreased allogrooming time in the consolation test and reduced sociability in the three-chamber test. The release of 5-HT within the ACC and the activity of DR neurons were significantly increased during allogrooming, sniffing and social approaching. Finally, we found that the activation of 5-HT1A receptors in the ACC was sufficient to reverse consolation and sociability deficits induced by the chemogenetic inhibition of 5-HTergic neurons in the DR. Our study provided first direct evidence that DR-ACC 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability.

neuroscience↗

bioRxiv2020

Temporally-Divergent Regulatory Mechanisms Govern Neuronal Development and Diversification in the Neocortex

Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling these early and late stages diverge: early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation, while programs active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. The data uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.

neuroscience↗