Biology subjects

Zhou, S.

Publications and source records attributed to Zhou, S..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

Systematic Identification of Post-Transcriptional Regulatory Modules

In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we performed a systematic annotation of RBP combinatorial interactions via multimodal data integration. We built a large-scale map of RBP protein neighborhoods by generating in vivo proximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we used CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generated an integrated map of functional RBP interactions. We then used this map to match RBPs to their context-specific functions and validated the predicted functions biochemically for four RBPs. This study highlights the previously underappreciated scale of the inter-RBP interactions, be it genetic or physical, and is a first step towards a more comprehensive understanding of post-transcriptional regulatory processes and their underlying molecular grammar.

systems biology↗

bioRxiv2023

Signaling from the C. elegans Hypodermis Non-autonomously Facilitates Short-term Associative Memory

Memory loss is one of the most debilitating symptoms of aging. While we normally think of memory regulation as autonomous to the brain, other factors outside of the brain can also affect neuron function. We have shown that the longevity insulin/IGF-1 signaling (IIS) pathway regulates neuron-specific activity, but whether the maintenance of memory through the IIS pathway is completely autonomous to the nervous system, or if there are systemic inputs, is unknown. We address this question using the auxin-inducible degradation (AID) system to degrade the IIS receptor, DAF-2, in specific tissues. Surprisingly, DAF-2 degradation specifically in the hypodermis improves memory in both young and aged C. elegans through the hypodermal expression of the diffusible Notch ligand, OSM-11. The Notch receptor LIN-12 is required for OSM-11s effect on memory, as are the downstream transcription factor LAG-1 and co-activator SEL-8. Furthermore, mid-life overexpression of the Notch ligand OSM-11 improves memory and slows cognitive decline. Hypodermal DAF-2 degradation suppresses the expression of ins-19, whose downregulation extends memory. Together, our data suggest a model in which the hypodermis, a metabolic tissue, can non-autonomously regulate neuronal activity and function, indicating a systemic connection between metabolism and memory regulation.

genetics↗

bioRxiv2023

Ex vivo tissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with scRNAseq and induced a multi-lineage circuit of fibrogenic cell states in hPCLS, which we show to be highly similar to the in vivo cell circuit in a multi-cohort lung cell atlas from pulmonary fibrosis patients. Using micro-CT staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the ex vivo hPCLS model provides evidence that the basaloid cell state was derived from alveolar type-2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in the hPCLS model and anti-fibrotic drug treatments showed highly cell type specific effects. Our work provides an experimental framework for perturbational single cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration and pathology. We further demonstrate that hPCLS offers novel avenues for scalable, high-resolution drug testing to accelerate anti-fibrotic drug development and translation.

cell biology↗

bioRxiv2023

HPC-Atlas: Computationally Constructing A Comprehensive Atlas of Human Protein Complexes

A fundamental principle of biology is that proteins tend to form complexes to play significant roles in the core functions of cells. For a complete understanding of human cellular functions, it is crucial to have a comprehensive atlas of human protein complexes. Unfortunately, we still lack such a comprehensive atlas of experimentally validated protein complexes, which prevents us from gaining a complete understanding of the compositions and functions of human protein complexes and biological mechanisms. To fill this gap, we built HPC-Atlas, as far as we know, the most accurate and comprehensive atlas of human protein complexes available to date. We integrated two latest protein interaction networks, and developed a novel computational method to identify nearly 9000 protein complexes, including many previously uncharacterized complexes. Compared with the existing works, our method achieves outstanding performance on both test and independent sets. Furthermore, with HPC-Atlas we identified 751 SARS-CoV-2 affected human protein complexes, and 456 multifunctional proteins that contain many potential moonlighting proteins. These results suggest that HPC-Atlas can serve as not only a computing framework to effectively identify biologically meaningful protein complexes by integrating multiple protein data sources, but also a valuable resource for exploring new biological findings. The HPC-Atlas webserver is freely available at http://www.yulpan.top/HPC-Atlas.

bioinformatics↗

bioRxiv2022

Promoting Axon Regeneration By Inhibiting RNA N6-methyladenosine Demethylase ALKBH5

A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral (PNS) and central nervous system (CNS). Previous studies have identified axon regeneration regulators that act on gene expression in injured neurons. However, it is less known if RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in DRG neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.

neuroscience↗

bioRxiv2022

Scoring thermal limits in small insects using open-source, computer assisted motion detection.

Scoring large amounts of thermal tolerance traits live or with recorded video can be time consuming and susceptible to investigator bias, and as with many physiological measurements, there can be trade-offs between accuracy and throughput. Recent studies show that particle tracking is a viable alternative to manually scoring videos, although it may not detect subtle movements, and many of the software options are proprietary and costly. In this study, we present a novel strategy for automated scoring of thermal tolerance videos by inferring motor activity with motion detection using an open-source Python command line application called DIME (Detector of Insect Motion Endpoint). We apply our strategy to both dynamic and static thermal tolerance assays, and our results indicate that DIME can accurately measure thermal acclimation responses, generally agrees with visual estimates of thermal limits, and can significantly increase the throughput over manual methods. Summary statementMotion detection algorithm for reliable, automatic scoring of thermal limits in insects with open-source tool

physiology↗

bioRxiv2022

Integrated proteomics reveals the landscape of autophagy degradation in human neurons and autophagy receptors regulating neuronal activity

Autophagy is a catabolic and self-degradative process crucial for maintaining cellular homeostasis. Malfunctional autophagy is implicated in neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we reported a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and LC3-interactome uncovers a role of neuronal autophagy in targeting primarily endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) proteins, and cAMP-PKA pathway, for degradation. Tubular ER and specific SV proteins are significant autophagy cargos in the axons. Functional validation identified calumenin as an ER resident autophagy receptor and illuminated a role of autophagy in regulating PKA and neuronal activity through AKAP11-mediated degradation. Our study thus reveals the landscape of autophagy degradation in human neurons and offers molecular insight into mechanisms of neurological disorders linked to autophagy deficiency. HighlightO_LIIntegrated proteomics reveals the landscape of autophagy degradation in human neurons C_LIO_LIAutophagy clears tubular ER and selective ER and synaptic vesicle proteins in neurons C_LIO_LICalumenin is an ER resident autophagy receptor C_LIO_LIAutophagy controls PKA pathway and neuronal activity through autophagy receptor AKAP11 C_LI

neuroscience↗

bioRxiv2022

Engineering CAR-NK cells targeting CD33 with concomitant extracellular secretion of anti CD16 antibody revealed superior antitumor effects toward myeloid leukemia

Acute myeloid leukemia (AML) is a common form of acute leukemia and current drugs are overall unsatisfactory. In the present study, we report an immune cell therapy strategy by employing genetically-modified bifunctional CAR-NK cells that combines efficient targeting of AML cells via the CD33 molecule with the concomitant stimulation of NK cell cytotoxicity through the expression and extracellular secretion of anti-CD16 antibody (B16) that binds back to the FC receptor of NK cells. Comparing to CAR-NK cells that target CD33 only, the bifunctional CD33/B16 CAR-NK cells showed superior killing efficiency toward AML cells in vitro, which increased about 4 times based on the number of cells needed to achieve 80% killing activity. In vivo study with xenograft model also revealed effective clearance of leukemic cells and much longer survival - no relapse or death for at least 60 days. In addition, the safety of CAR-NK is not changed with additional expression of B16 as determined by the release of cytokines. These data revealed a promising CAR-NK approach to treat AML patients, which may improve CAR-NK based treatment in general and have potential applications to deal with other tumors as well.

immunology↗

bioRxiv2022

Single-cell imaging based prognosis prediction identifies new breast cancer survival subtypes

Quantitative models that explicitly capture single-cell resolution cell-cell interaction features to predict patient survival at population scale are currently missing. Here, we computationally extracted hundreds of features describing single-cell based cell-cell interactions and cellular phenotypes from a large, published cohort of cyto-images of breast cancer patients. We applied these features to a neural-network based Cox-nnet survival model and obtained high accuracy in predicting patient survival in test data (Concordance Index > 0.8). We identified seven survival subtypes using the top survival features, which present distinct profiles of epithelial, immune, fibroblast cells, and their interactions. We identified atypical subpopulations of TNBC patients with moderate prognosis (marked by GATA3 over-expression) and Luminal A patients with poor prognosis (marked by KRT6 and ACTA2 over-expression and CDH1 under-expression). These atypical subpopulations are validated in TCGA-BRCA and METABRIC datasets. This work provides important guidelines on bridging single-cell level information towards population-level survival prediction. STATEMENT OF TRANSLATIONAL RELEVANCEOur findings from a breast cancer population cohort demonstrate the clinical utility of using the single-cell level imaging mass cytometry (IMC) data as a new type of patient prognosis prediction marker. Not only did the prognosis prediction achieve high accuracy with a Concordance index score greater than 0.8, it also enabled the discovery of seven survival subtypes that are more distinguishable than the molecular subtypes. These new subtypes present distinct profiles of epithelial, immune, fibroblast cells, and their interactions. Most importantly, this study identified and validated atypical subpopulations of TNBC patients with moderate prognosis (GATA3 over-expression) and Luminal A patients with poor prognosis (KRT6 and ACTA2 over-expression and CDH1 under-expression), using multiple large breast cancer cohorts.

bioinformatics↗

bioRxiv2022

Normalized Semi-Covariance Co-Efficiency Analysis of Spike Proteins from SARS-CoV-2 variant Omicron and Other Coronaviruses for their Infectivity and Virulence

Spectrum-based Mass-Charge modeling is increasingly used in biological analysis. To explain statistical phenomenon with positive and negative fluctuations of amino acid charges in spike protein sequences from Omicron and other coronaviruses, we propose calculation-based Mass-Charge modeling, a normalized derivation algorithm with exact Excel and MATLAB tool involving separate quadrant extension to normalized covariance, which is still compatible with Pearson covariance co-efficiency. The number of amino acids, molecular weight, isoelectric point, amino acid composition, charged residues, mass-charge ratio, hydropathicity of the proteins were taken into consideration in the analyses, and the relative peak and dip of the average with spike protein sequences based on hydrophobic mass to isoelectric charges of amino acids were also examined. The analyses with the algorithm provide more clear insights leading to revealing underline evolving trends of the viral proteins. Spike proteins from SARS-CoV-2 variants, seasonal and murine coronaviruses were taken as representative examples in this study. The analyses demonstrate that the Mass-Charge covariance co-efficiency can distinguish subtle differences between biological properties of spike proteins and correlate well with viral infectivity and virulence.

bioinformatics↗

bioRxiv2022

Unified control of temporal and spatial scales of sensorimotor behavior through neuromodulation of short-term synaptic plasticity

Neuromodulators such as dopamine have been shown to modulate short-term synaptic plasticity (STP). Here we propose that the neuromodulation of STP provides a general mechanism to scale neural dynamics and motor outputs in time and space. We trained RNNs that incorporated STP to produce complex motor trajectories--handwritten digits--with different temporal (speed) and spatial (size) scales. The learned dynamics underwent temporal and spatial scaling when higher synaptic release probabilities corresponded to higher speed/size. Neuromodulation of STP enhanced temporal or spatial generalization compared to weight modulation alone. The model accounted for the data of two experimental studies involving flexible sensorimotor timing. Our results address a long-standing debate regarding the role of dopamine in timing and predict novel mechanisms by which dopamine may slow down neural dynamics and thus slow "clock" speed.

neuroscience↗

bioRxiv2022

Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration

Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.

cell biology↗

bioRxiv2022

Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1

Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that the CAR-T cell mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSC caused an increase of CD4+ T cells and Treg cells but decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) that contribute to the immune-suppressive function of tumor. Moreover, MSCs suppressed key components of NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from excessive immune response.

cancer biology↗

bioRxiv2022

1 Natural Genetic Variation in a Dopamine Receptor is Associated With Variation in Female Fertility in Drosophila melanogaster

Fertility is a major component of fitness but its genetic architecture remains poorly understood. Using a full diallel cross of 50 Drosophila melanogaster Genetic Reference Panel inbred lines with full genome sequences, we found substantial genetic variation in fertility largely attributable to females. We mapped genes associated with variation in female fertility by genome-wide association analysis of common variants in the fly genome. Validation of candidate genes by RNAi knockdown confirmed the role of the dopamine 2-like receptor (Dop2R) in promoting egg laying. We replicated the Dop2R effect in an independently collected productivity dataset and showed that the effect of the Dop2R variant was mediated in part by regulatory gene expression variation. This study demonstrates the strong potential of genome-wide association analysis in this diverse panel of inbred strains and subsequent functional analyses for understanding the genetic architecture of fitness traits. Author SummaryIn evolutionary genetics, fitness is defined as the number of offspring an individual contributes to the next generation. This is determined by an individuals viability (its ability to survive past the reproductive age) and its fertility. Although understanding the genetic basis for natural variation in fitness is a major goal of evolutionary and population genetics, the genetic factors that contribute to variation in fertility in natural populations have remained largely unresolved. To address this issue, we took advantage of the Drosophila Genetic Reference Panel, a population of inbred, sequenced fly lines derived from a natural population. In this panel, there is minimal genetic variation among individuals within each line, whereas variation among the lines reflects the variation observed in the original population from which they were derived. We generated all possible pairwise crosses among 50 of these lines (2,500 distinct genotypes) and measured the productivity (number of offspring produced) for each genotype. We found considerable natural variation in productivity that was primarily determined by the female genotype. We performed a genome wide association as analysis and identified and functionally validated a dopamine receptor that plays a major role in determining variation in female fertility through an effect on egg-laying.

evolutionary biology↗

bioRxiv2022

Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single cell transcriptomics, software-guided segmentation of tissue damage, and in vivo lineage tracing, we have identified the grainyhead transcription factor Tfcp2l1 as a key regulator of this regenerative process. Tfcp2l1 expression is initiated late in lung development and restricted to the AT2 cell population in the postnatal lung. Loss of Tfcp2l1 in adult AT2 cells decreased self-renewal and enhanced AT2-AT1 differentiation during active tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute phase after injury. This ability of Tfcp2l1 to temporally regulate the balance of AT2 self-renewal and differentiation is spatially restricted to zones undergoing active alveolar regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics by balancing the traffic across the AT2-AT1 differentiation axis and restricting the inflammatory program in AT2 cells. Organoid modeling shows that these cell fate dynamics are controlled by Tfcp2l1 regulation of IL-1 receptor expression and activity in AT2 cells. Together, these studies reveal the critical importance of properly staging lung alveolar regeneration and the integral role of Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation in this process.

cell biology↗

bioRxiv2022

A systems biology-based identification and in vivo functional screening of Alzheimer's disease risk genes reveals modulators of memory function

Genome-wide association studies (GWAS) have uncovered over 40 genomic loci associated with risk for late-onset Alzheimers Disease (LOAD), but identification of the underlying causal genes remains challenging. While the role of glial biology in the mediation of LOAD genetic risk has been increasingly recognized, recent studies of induced pluripotent stem cell (iPSC)-derived neurons from LOAD patients have demonstrated the existence of neuronal cell-intrinsic functional defects, absent interactions with other brain cell types or exposure to neurotoxic insults. Here, we searched for genetic contributions to neuronal dysfunction in LOAD pathobiology, using an integrative systems approach that incorporated multi-evidence-based gene-mapping and network analysis-based prioritization. We found widespread dysfunction in neuronal gene co-expression networks in the LOAD brain and identified synaptic and endolysosomal function as being specifically impacted by LOAD-associated genetic variation. A systematic perturbation screening of candidate risk genes in C. elegans revealed that neuronal knockdown of the LOAD risk gene orthologs vha-10 (ATP6V1G2), cmd-1 (CALM3), amph-1 (BIN1), ephx-1 (NGEF), and pho-5 (ACP2) significantly alters short/intermediate-term memory function, the cognitive domain affected earliest during LOAD progression. These results highlight the impact of LOAD risk genes on evolutionarily conserved memory function, as mediated through neuronal endosomal dysfunction, and identify new targets for further mechanistic interrogation.

genetics↗

bioRxiv2022

A reductase in the lipid metabolism at cross roads between cuticular wax production and jasmonic acid-mediated defenses in maize

Cuticular wax is the first physical layer to protect plants from herbivore infestations. Although wax and jasmonic acid (JA) biosynthesis are the two most studied branches of lipid metabolism, the mechanism how cuticular wax production modulates plant chemical defenses is unclear. Here, we show that the maize (Zea mays) GL8 gene, encoding 3-ketoacyl reductase during fatty acid elongation in the biosynthesis of very long chain fatty acids (VLCFA), functions as a turning point between wax production and JA-mediated defenses. The fall armyworm (Spodoptera frugiperda) larvae consumed more tissue but gained a lower performance on gl8/Ye478 mutant plants. gl8/Ye478 mutant displayed higher JA-mediated defenses constitutively, and also more inducible by herbivore stimulation. The comprehensive transcriptomic and lipidomic analyses further demonstrated that ZmGL8 mutation up-regulates the JA biosynthesis pathway by promoting the accumulation of lysophospholipids and modulation of galactolipid synthase genes ZmDGD and ZmMGD. The phenotypic and transcription comparisons of the maize and Arabidopsis wax-deficient mutants suggest a conserved wide-spread trade-off between wax production and chemical defense in both 18:3 and 16:3 plants. These results illustrate a critical role of VLCFA metabolism as a switch to control the balance between cuticular wax physical barrier and JA-mediated chemical defenses during plant-herbivore coevolution history.

plant biology↗

bioRxiv2022

Regulation of sleep quantity and intensity by long and short isoforms of SLEEPY kinase

In Sleepy (Sik3Slp) or Sik3S551A mice, deletion or mutation of inhibitory phosphorylation site serine551 (S551) from salt-inducible kinase 3 (SIK3) markedly increases daily non-rapid eye movement sleep (NREMS) amount, accompanied with constitutively elevated NREMS delta power density-a measure of sleep intensity or quality. Multiple SLP/SIK3 isoforms are expressed in mouse brain neurons, however, their respective roles in sleep regulation remain to be elucidated. Here, we identified a new and most abundant short isoform of SLP/SIK3 and examined sleep phenotypes resulted from isoform-specific expression of SLP-short (S) and long (L) isoforms. Adeno-associated virus-mediated adult brain chimeric (ABC)-expression of SLP-S in neurons, but not in astrocytes, significantly and constitutively elevates NREMS delta power, whereas slightly increases NREMS amount. The ability of SLP-S to regulate sleep quantity/intensity is abrogated by kinase-inactivating mutations, suggesting that the sleep-promoting activity of SLP-S is dependent on its kinase activity. In Sik3S551A-L knock-in mice, isoform-specific expression of SIK3S551A-L (or SLP-L) significantly increases NREMS amount with a modest effect on NREMS delta power. ABC-expression of SLP-S complements the sleep phenotypes of heterozygous Sik3S551A-L mice by further increasing NREMS amount and NREMS delta power to levels of Sik3Slp or Sik3S551A mice. Taken together, these results indicate that both SLP-L and SLP-S isoforms contribute critically to the increases of sleep quantity and intensity in Sik3Slp or Sik3S551A mice. Statement of SignificancePrevious studies have identified SIK3 as a key sleep regulatory kinase, of which gain-of-function mutations markedly increase sleep quantity and intensity in Sleepy mice. Multiple SLEEPY isoforms are expressed in mouse brain neurons, but their respective contributions to the hypersomnia phenotypes of Sleepy mice remain unclear. Here, we identified a new short isoform of SLP/SIK3 and examined sleep phenotypes resulted from specific expression of SLEEPY-short or long isoform. Our results indicate that both long and short isoforms of SLEEPY kinase contribute critically to increases of sleep quantity and intensity in Sleepy mice. Future studies are needed to identify downstream substrates of SLEEPY kinase that mediate regulation of sleep quantity/intensity, which should facilitate development of new treatments for human sleep disorders.

genetics↗