Biology subjects

Wu, Y.

Publications and source records attributed to Wu, Y..

At least 469 records · Page 26Linked to original sources

bioRxiv2024

A vacuolar invertase gene SlVI modulates sugar metabolism and postharvest fruit quality and resistance in tomato

Sugars act as signaling molecules to modulate various growth processes and enhance plant tolerance to various abiotic and biotic stresses. Moreover, sugars contribute to the post-harvest flavor in fleshy fruit crops. To date, the regulation of sugar metabolism and its effect in plant growth, fruit ripening, postharvest quality and resistance remains not fully understood. In this study, we investigated the role of tomato gene encoding a vacuolar invertase, hydrolyzing sucrose to glucose and fructose. SlVI is specifically expressed during the tomato fruit ripening process. We found that overexpression of SlVI resulted in increased leaf size and early flowering, while knockout of SlVI led to increased fruit sucrose content, enhanced fruit firmness, elevated resistance of postharvest fruit to Botrytis cinerea. Moreover, the content of naringenin and total soluble solids was significantly increased in SlVI knockout fruit at postharvest stage. Transcriptome analysis showed a negative feedback regulation triggered by sucrose accumulation in SlVI knockout fruit resulting in a downregulation of BAM3 and AMY2, which are critical for starch degradation. Moreover, genes associated with cell wall, cutin, wax, and flavonoid biosynthesis and pathogen resistance were upregulated in SlVI knockout fruit. Conversely, the expression levels of genes involved in cell wall degradation were decreased in knockout fruit. These results are consistent with the enhanced postharvest quality and resistance. Our findings not only provide new insights into the relationship between tomato fruit sucrose content and postharvest fruit quality, but also suggest new strategies to enhance fruit quality and extend postharvest shelf life.

plant biology↗

bioRxiv2024

ProBASS: a language model with sequence and structural features for predicting the effect of mutations on binding affinity

Protein-protein interactions (PPIs) govern virtually all cellular processes. Even a single mutation within PPI can significantly influence overall protein functionality and potentially lead to various types of diseases. To date, numerous approaches have emerged for predicting the change in free energy of binding ({Delta}{Delta}Gbind) resulting from mutations, yet the majority of these methods lack precision. In recent years, protein language models (PLMs) have been developed and shown powerful predictive capabilities by leveraging both sequence and structural data from protein-protein complexes. Yet, PLMs have not been optimized specifically for predicting {Delta}{Delta}Gbind. We developed an approach to predict effects of mutations on PPI binding affinity based on two most advanced protein language models ESM2 and ESM-IF1 that incorporate PPI sequence and structural features, respectively. We used the two models to generate embeddings for each PPI mutant and subsequently fine-tuned our model by training on a large dataset of experimental {Delta}{Delta}Gbind values. Our model, ProBASS (Protein Binding Affinity from Structure and Sequence) achieved a correlation with experimental {Delta}{Delta}Gbind values of 0.83 {+/-} 0.05 for single mutations and 0.69 {+/-} 0.04 for double mutations when model training and testing was done on the same PDB. Moreover, ProBASS exhibited very high correlation (0.81 {+/-} 0.02) between prediction and experiment when training and testing was performed on a dataset containing 2325 single mutations in 132 PPIs. ProBASS surpasses the state-of-the-art methods in correlation with experimental data and could be further trained as more experimental data becomes available. Our results demonstrate that the integration of extensive datasets containing {Delta}{Delta}Gbind values across multiple PPIs to refine the pre-trained PLMs represents a successful approach for achieving a precise and broadly applicable model for {Delta}{Delta}Gbind prediction, greatly facilitating future protein engineering and design studies.

bioinformatics↗

bioRxiv2024

Central nucleus of the amygdala to medial prefrontal cortex 5-HTergic neural circuit modulates the recovery of consciousness during sevoflurane anesthesia

Preoperative anxiety and depression are significant risk factors for prolonged general anesthesia emergence, raising postoperative complications and mortality. However, the neural mechanisms underlying this association remain unclear, limiting effective interventions and development of effective preventive and therapeutic strategies. Previous studies have shown that sleep-wakefulness neural circuit is closely related to neural circuitry of anesthesia recovery, with 5-Hydroxytryptamine (5-HT) playing a pivotal role of anesthesia arousal. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry and retrograde tracing to demonstrate that activation of the 5-HTergic neural circuit between the central amygdala (CeA) and medial prefrontal cortex (mPFC) accelerates recovery from sevoflurane anesthesia. Particularly for individuals with anxiety- and depression-like symptoms, who exhibit more severe delayed emergence, it is necessary to enhance 5-HT neuronal activity by further optimizing parameters. To further validate the reliability of our findings and the specificity of viral tools, we successfully bred TPH2-Cre transgenic mice and repeated key experiments, which robustly confirmed all original conclusions. Pharmacological experiments further demonstrated that both 5-HTA and 5-HT2A receptors mediate the pro-arousal function of this circuit. Collectively, our study identifies a key CeA-mPFC serotonergic pathway linking emotional disorders to abnormal anesthetic emergence, providing potential targets for optimizing anesthesia management in vulnerable patients. HighlightsO_LIBoosting the 5-HTergic neural circuit between the CeA and mPFC promotes emergence from sevoflurane anesthesia, with 5-HT1A and 5-HT2A receptors playing a critical role in modulating consciousness transitions. C_LIO_LIPreoperative anxiety and depression exacerbate delayed emergence from anesthesia, highlighting the need for targeted interventions. C_LIO_LIDeciphering the aberrant neurocircuitry mechanisms underlying delayed emergence to inversely deduce the neurocircuitry principles of normal physiology represents a pathological-to-physiological research paradigm. C_LIO_LIStepwise enhancement of intervention parameters reverses delayed emergence in pathological states. C_LIO_LITailored activation of the 5-HTergic circuit offers a novel approach to mitigate complications from delayed emergence in vulnerable patient populations. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/599720v3_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@589b26org.highwire.dtl.DTLVardef@13204fforg.highwire.dtl.DTLVardef@e6374dorg.highwire.dtl.DTLVardef@38cac0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Head dopaminergic and serotonergic neurons monitor alterations in gut bacterial activity through a gut-brain-gut axis

The brain is suggested to monitor gut microbial changes to critically maintain health, whereas the particular bacterial alterations and the mechanisms involved are largely unclear. Here, through a genome-wide screen, we identified 29 E. coli genes whose inactivation can be surveilled by C. elegans head dopaminergic and serotonergic neurons through increasing host neuronal dopamine and serotonin biosynthesis. Mechanistically, we found that these head neurons respond to the E. coli lack of respiratory chain genes by detecting the bacteria-caused reductions in host labile iron levels that impair intestinal mitochondria, and the intestine-expressed mitochondrial stress sensor ATFS-1 is critically involved. Furthermore, this neuronal response in turn promotes intestinal ferritin-1 expression to counteract bacteria-caused labile iron reduction and thereby maintaining mitochondrial function. Our findings systematically identify bacterial activity changes that elevate brain dopamine and serotonin levels and unveil an unexpected gut-brain-gut axis in which the head neurons inspect bacterial activity-mediated changes in host iron metabolism and mitochondrial function, enlightening crucial roles and mechanisms of brain in surveilling microbial activity alterations.

developmental biology↗

bioRxiv2024

The up-regulation of TGF-beta1 by miRNA-132-3p/WT1 is involved in inducing leukemia cells to differentiate into macrophages

Although it has been shown that abnormal expression of Wilms tumor gene 1 (WT1) is associated with the occurrence of leukemia, the specific mechanism via which it induces leukemia cells to differentiate into macrophages remains poorly understood. Based on the prediction that the microRNA miRNA-132-3p is the miRNA that possibly lies upstream of the WT1 gene, we hypothesized that miRNA-132-3p may participate in the polarization process of macrophages through regulating expression of the WT1 gene. The focus of the present study was therefore to investigate the role of the miRNA-132-3p/WT1 signaling axis in the differentiation of THP-1 leukemia cells into macrophages induced by PMA. The results obtained indicated that, compared with the control group, the proliferation of THP-1 cells was clearly inhibited by PMA, and the cell cycle was arrested at G0/G1 phase, associated with an upregulation of CD11b and CD14 expression. Induced by PMA, the expression level of miRNA-132-3p was increased, WT1 expression was decreased, and the expression level of TGF-{beta}1 was increased. Following transfection with miRNA-132-3p mimics, however, the expression of WT1 in the THP-1 cells was downregulated, with upregulation of the CD11b and CD14 antigens, whereas this downregulation of WT1 mediated by miRNA-132-3p mimics could be reversed by co-transfection with WT1 vector, which was accompanied by downregulation of the CD11b and CD14 antigens. The luciferase activity of the co-transfected miRNA-132-3p mimic + WT1-wild-type (WT) group was found to be statistically significantly lower compared with that of the co-transfected miRNA-132-3p mimic + WT1-mutated (MUT) group. Furthermore, chromatin immunoprecipitation experiments showed that WT1 was able to directly target the promoter of the downstream target gene TGF-{beta}1, which led to the negative modulation of TGF-{beta}1 expression, whereas downregulation of WT1 led to an upregulation of the expression of TGF-{beta}1, which thereby promoted the differentiation of THP-1 cells into macrophages. Taken together, the present study has provided evidence, to the best of the authors knowledge for the first time, that the miRNA-132-3p/WT1/TGF-{beta}1 axis is able to regulate the committed differentiation of leukemia cells into macrophages.

immunology↗

bioRxiv2024

Calorie Restriction Induces Degeneration of Neurons with Mitochondrial DNA Depletion by Altering ER-Mitochondria Calcium Transfer

Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model where in mtDNA depletion induced by Herpes Simplex Virus Type 1 (HSV-1) protein-UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neurons in vitro (rho-) causes epilepsy-like abnormal EEG. Caloric restriction (CR) is a strategy proven to reduce epileptic activity, however CR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating CR-induced mitochondrial calcium overload. Rho- neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho- neuron model. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that CR may not be a viable clinical intervention in patients with mtDNA depletion.

cell biology↗

bioRxiv2024

Local adaptation of both plant and pathogen: an arms-race compromise in switchgrass rust

O_LIIn widespread species, parasites can locally adapt to host populations, or hosts can locally adapt to resist parasites. Parasites with rapid life cycles locally adapt more quickly, but host diversity, selective pressure, and climatic factors impact coevolution. C_LIO_LITo better understand local adaptation in co-evolved host-parasite systems, we examined switchgrass (Panicum virgatum), and its leaf rust pathogen (Puccinia novopanici) across a latitudinal range in North America. We grew diverse switchgrass genotypes in ten replicated common gardens spanning 16.78{degrees} latitude for three years, measuring rust severity from natural infection. We conducted genome wide association mapping to identify genetic loci associated with rust severity. C_LIO_LIGenetically differentiated rust populations were locally adapted to northern and southern switchgrass, despite host local adaptation in the same regions. Rust resistance was highly polygenic, and distinct loci were associated with rust severity in the north and south. We narrowed a previously identified large-effect QTL for rust severity to a candidate YSL3-like gene, and linked numerous other loci to immunity-related genes. C_LIO_LIBoth hosts and parasites can be locally adapted when parasites have a lower impact on fitness than other local selection pressures. In switchgrass, our results suggest variation in fungal resistance mechanisms between locally adapted regions. C_LI

evolutionary biology↗

bioRxiv2024

Metabolic imprint of an intracellular pathogen drives histone hypermethylation and tunes the host transcriptional response to infection

Chlamydia trachomatis, an intracellular bacterium, highjacks metabolites from the host cell for its own proliferation. We provide evidence of global hypermethylation of the host proteome, including histones, during the late stages of infection. Single cell analyses revealed co-occurrence of several methylated residues on histones. Histone hypermethylation correlated with bacterial load and was prevented by antibiotic treatment. Mapping of trimethylation of histone 3 at residues K4 and K9 revealed a broad distribution throughout the chromatin. Nuclear fractions of infected cells exhibited a four-fold decrease of demethylase activity towards H3K4me3 and a two-fold increase in succinate concentration, a competitive inhibitor for the demethylase co-factor -ketoglutarate. Supplementation of the culture medium with dimethyl-ketoglutarate (DMKG) or with iron, a second co-factor of histone lysine demethylases, reduced histone hypermethylation. DMKG supplementation modified the transcription of about one third of the infection-responsive genes, indicating that histone hypermethylation contributes to modulating the transcriptional response of the host to infection. Finally, chemical inhibition of histone demethylases in a mouse model of infection showed a moderate benefit regarding the outcome of infection. Overall, our data show that the metabolic pressure exerted by a pathogen with an intracellular lifestyle drives epigenetic changes in infected cells.

cell biology↗

bioRxiv2024

Acetyl-CoA Synthetase Mutations S868G and V949I Do Not Confer Resistance to Antimalarial Drugs in vitro in Plasmodium falciparum.

Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.

microbiology↗

bioRxiv2024

Post-flowering photoperiod sensitivity of soybean in pod-setting responses

The development of soybean (Glycine max) is regulated by photoperiod, with genes related to photoperiod sensitivity primarily focused on flowering time. However, their roles in post-flowering reproductive development and the mechanisms by which photoperiod affects them are not yet determined. In this study, we found that pod formation is sensitive to photoperiod. Long-day (LD) conditions tend to extend the time from flowering to pod formation (R1 to R3 stage), and the first wave of flowers tends to fall off. Additionally, photoperiod affects pistil morphology; under short-day (SD) conditions, the stigma has a curved hook-like structure that facilitates better interaction with the filaments when pollen is released, ultimately influencing the timing of pod formation. Photoperiod-insensitive mutants, lacking E1 family and Evening Complex genes, showed no difference in pod formation time under LD or SD conditions. Hormone content analysis and transcriptome data analysis indicated that various hormones, ROS signals, and the application of sucrose solution in vitro might influence floral organ abscission. HighlightPhotoperiod sensitivity after flowering affects the pod-setting time in soybean.

plant biology↗

bioRxiv2024

scRNA-seq revealed the rules for CDR3 length pairing in TCR beta and alpha chains and BCR heavy and light chains in human and mice

The binding of T cell receptor (TCR)/B cell receptor (BCR) CDR3 with linear or conformational epitopes is a prerequisite for the adaptive immune response. The rules for CDR3 length pairing and the amino acid (AA) distributions in the prioritized rearrangement of the {beta} chain (or heavy chain) and subsequent rearrangement of the chain (or light chain) during the process of germline V(D)J gene rearrangement and self-tolerance selection to form the T- or B-cell CDR3 repertoire are currently unknown. Single-cell VDJ sequencing can provide abundant information on CDR3 sequences in paired chains. In this study, the paired-chain CDR3 sequences of central and peripheral T and B cells in humans and mice were analyzed according to single-cell VDJ sequencing data. This is the first study to find that T cells with {beta} chains longer than paired chains and B cells with heavy chains longer than paired light chains have absolute advantages. The proportion of T cells with length differences of three or more AAs between paired chains in CDR3 in humans was significantly higher than that in mice, and the proportion of B cells with length differences of six or more AAs between paired chains in CDR3 in humans was significantly higher than that in mice. The CDR3 length range of the {beta} chain was narrower than that of the chain, while the heavy chain had a much wider range than the light chain. The CDR3 length in human TCRs and BCRs was greater than that in mice. Extreme length differences were found between paired chains in both human and mouse T and B cells. There were significant differences in the range of pairing length, AA distribution, hydrophobicity, and polarity of the paired-chain CDR3 region in 5 chains ({beta}, , H, {kappa}, and {lambda}). Human TCR and BCR paired CDR3 sequences exhibited greater plasticity than those of mice. This study reveals new ideas about the molecular mechanisms of TCR and BCR responses to different antigenic epitopes. Our innovative findings offer novel perspectives and techniques for examining V(D)J rearrangement and selection mechanisms in T and B cells. These advancements enable us to analyze antigenic epitopes targeted by TCRs and BCRs, and further, to explore the genetic evolution of T and B cell responses across diverse animal species. Graphical AbstractscRNA-seq the TCR and BCR CDR3 repertoires of 35 samples from the central and peripheral tissues of humans and mice. It provides an opportunity to reveal the rules for CDR3 length pairing in TCR beta and alpha chains and BCR heavy and light chains. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=45 SRC="FIGDIR/small/596201v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@11982edorg.highwire.dtl.DTLVardef@1e2d1aaorg.highwire.dtl.DTLVardef@33200dorg.highwire.dtl.DTLVardef@7d61b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Upregulation of FasII underlies synergistic neuropathological and behavioral defects in a Drosophila model of myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. In this study, we characterized a novel model of DM1 neuropathology by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, both pre- and postsynaptic expression of CUG repeats participate to induce reduction of synaptic boutons, increase of arbor disassembly and impairment of larval locomotor activity. We found that the expression of CUG repeats caused an upregulation of the cell adhesion molecule, FasII (NCAM1 in mammals), in both the motor neurons and the body wall muscles. Knockdown of fasII was sufficient to rescue bouton numbers and locomotor impairment in this model. Further analyses identified the upregulation of the FasII-C isoform as a major contributor of these phenotypes. Remarkably, overexpressing the FasII-A-PEST+ isoform rescued the synaptic and behavioral defects, likely by outcompeting the upregulated FasII-C. Our study provided the foundation for a basic mechanism of synapse dysregulation in DM1.

neuroscience↗

bioRxiv2024

Overlapping role of synaptophysin and synaptogyrin family proteins in determining the small size of synaptic vesicles

Members of the synaptophysin and synaptogyrin family are vesicle proteins with four transmembrane domains. In spite of their abundance in synaptic vesicle (SV) membranes, their role remains elusive and only mild defects at the cellular and organismal level are observed in mice lacking one or more family members. Here, we show that co-expression with synapsin of each of the four brain-enriched members of this family - synaptophysin, synaptoporin, synaptogyrin1 and synaptogyrin3 - in fibroblasts is sufficient to generate clusters of small vesicles in the same size range of SVs. Moreover, mice lacking all these four proteins have larger SVs. We conclude that synaptophysin and synaptogyrin family proteins play an overlapping function in the biogenesis of SVs and in determining their small size.

neuroscience↗

bioRxiv2024

Chlamydia-driven ISG15 expression dampens the immune response of epithelial cells independently of ISGylation

Excessive inflammation upon C. trachomatis infection can cause severe damages in the female genital tract. This obligate intracellular bacterium develops mainly in epithelial cells, whose innate response contributes to the overall inflammatory response to infection. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) stimulates interferon {gamma} (IFN{gamma}) production and is required for bacterial clearance in several infectious contexts. Here, we describe and investigate the consequences of the increase in ISG15 expression by epithelial cells infected with C. trachomatis. Infection of HeLa cells and primary ecto-cervical epithelial cells resulted in a transcriptional up-regulation of ISG15 expression. This did not involve the canonical IFN-I signaling pathway and depended instead on the activation of the STING/TBK1/IRF3 pathway. Absence or reduction of ISG15 synthesis led to increased production of several cytokines and chemokines including interleukin (IL) 6 and IL8, implicating that ISG15 normally dampens the immune response induced by C. trachomatis infection in epithelial cells. ISG15 exerted its control from an intracellular location, but without involving ISGylation. Finally, higher levels of inflammation and delayed bacterial clearance were observed in the genital tracts of ISG15-KO mice infected by C. trachomatis compared to wild type animals, however IFN{gamma} production was unchanged. Altogether, our data show that ISG15 expression acts as a brake on the immune response to C. trachomatis infection in epithelial cells and limits bacterial burden and inflammation in mice.

microbiology↗

bioRxiv2024

Phosphodiesterase 1A physically interacts with YTHDF2 and reinforces the progression of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of PDE1A in NSCLC. The RIP assay, mRNA stability assay and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. Phosphodiesterase 1A (PDE1A) has been shown to promote metastasis and EMT progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpresssed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of YTHDF2/PDE1A complex in regulating STAT3 pathway was predicted by overlapping YTHDF2-interacting-RNAs, and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated STAT3 pathway. The data not only uncovers a novel PDE1A/YTHDF2/STAT3 pathway in NSCLC progression but also provides therapeutic strategies for treating NSCLC patients with metastasis.

cancer biology↗

bioRxiv2024

A new approach to the challenging problem of mutational signature attribution

Mutational signatures are characteristic patterns of mutations caused by endogenous mutational processes or by exogenous mutational exposures. There has been little benchmarking of approaches for determining which signatures are present in a sample and estimating the number of mutations due to each signature. This problem is referred to as "signature attribution". We show that there are often many combinations of signatures that can reconstruct the patterns of mutations in a sample reasonably well, even after encouraging sparse solutions. We benchmarked thirteen approaches to signature attribution, including a new approach called Presence Attribute Signature Activity (PASA), on large synthetic data sets (2,700 synthetic samples in total). These data sets recapitulated the single-base, insertion-deletion, and doublet-base mutational signature repertoires of 9 cancer types. For single-base substitution mutations, PASA and MuSiCal outperformed other approaches on all the cancer types combined. However, the ranking of approaches varied by cancer type. For doublet-base substitutions and small insertions and deletions, while PASA outperformed the other approaches in most of the nine cancer types, the ranking of approaches again varied by cancer type. We believe this variation reflects inherent difficulties in signature attribution. These difficulties stem from the fact that there are often many attributions that can reasonably explain the pattern of mutations in a sample and from the combinatorial search space due to the need to impose sparsity. Tables herein can provide guidance on the selection of mutational signature attribution approaches that are best suited to particular cancer types and study objectives.

bioinformatics↗

bioRxiv2024

Kinship analysis and pedigree reconstruction by RAD sequencing in cattle

Kinship and pedigree information, used for estimating inbreeding, heritability, selection, and gene flow, is useful for breeding and animal conservation. However, as the size of the crossbred population increases, inaccurate generation and parentage recoding in livestock farms increases. Restriction-site-associated DNA sequencing (RAD-Seq) is a cost-effective platform for single nucleotide polymorphism (SNP) discovery and genotyping. Here, we performed a kinship analysis and pedigree reconstruction for Angus and Xiangxi yellow cattle, which benefit from good meat quality and yields, providing a basis for livestock management. A total of 975 cattle, including 923 offspring with 24 known sires and 28 known dams, were sampled and subjected to SNP discovery and genotyping. The identified SNPs panel included 7305 SNPs capturing the maximum difference between paternal and maternal genome information allowing us to distinguish between the F1 and F2 generation with 90% accuracy. In addition, parentage assignment software based on different strategies verified that the cross-assignments. In conclusion, we provided a low-cost and efficient SNP panel for kinship analyses and the improvement of local genetic resources, which are valuable for breed improvement, local resource utilization, and conservation.

genomics↗

bioRxiv2024

Norepinephrine Signals Through Astrocytes To Modulate Synapses

AbstractLocus coeruleus (LC)-derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and Ca2+ dynamics fully gate the effect of NE on synapses as the astrocyte-specific deletion of adrenergic receptors and three independent astrocyte-silencing approaches all render synapses insensitive to NE. Additionally, we find that NE suppression of synaptic strength results from an ATP-derived and adenosine A1 receptor-mediated control of presynaptic efficacy. An accompanying study from Chen et al. reveals the existence of an analogous pathway in the larval zebrafish and highlights its importance to behavioral state transitions. Together, these findings fuel a new model wherein astrocytes are a core component of neuromodulatory systems and the circuit effector through which norepinephrine produces network and behavioral adaptations, challenging an 80-year-old status quo.

neuroscience↗