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Biology subjects

Yuan, X.

Publications and source records attributed to Yuan, X..

At least 91 records · Page 5Linked to original sources

Identification and classification of the genomes of novel Microviruses in a poultry slaughterhouse

Microviridae is a family of phages with circular ssDNA genomes and they are widely found in various environments and organisms. In this study, Virome techniques were employed to explore potential members of Microviridae in poultry slaughterhouse, leading to the identification of 98 novel and complete microvirus genomes. Using a similarity clustering network classification approach, these viruses were found to belong to at least 6 new subfamilies within Microviridae and 3 higher-level taxonomic units. Analysis of their genomes found that the genome size, GC content and genome structure of these new taxa showed evident regularities, validating the rationality of our classification method. Compared with the 19 families classified by previous researchers for microviruses dataset, our method can divide microviruses into about 45 more detailed clusters, which may serve as a new standard for classifying Microviridae members. Furthermore, addressing the scarcity of host information for microviruses, this study significantly broadened their host range and discovered over 20 possible new hosts, including important pathogenic bacteria such as Helicobacter pylori and Vibrio cholerae, as well as different taxa demonstrated differential host specificity. The findings of this study effectively expand the diversity of the Microviridae, providing new insights for their classification and identification. Additionally, it offers a novel perspective for monitoring and controlling pathogenic microorganisms in poultry slaughterhouse environments.

microbiology↗

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development

Within the adult rodent hippocampus, opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting local micro-circuits. However, it is unknown if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in hippocampus proper but not primary neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate early population activity. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

neuroscience↗

High-fidelity, high-resolution light-field reconstruction with physics-informed neural representation learning

Light-field microscopy (LFM) captures 3D biological dynamics by single 2D snapshots but suffers from limited resolution and artifacts during 2D-to-3D inversion. Here, we introduce light-field meta neural representation (LFMNR), a novel self-supervised paradigm that utilizes physics-informed light-field implicit neural representation (LFINR) and meta learning for high-quality 3D reconstruction in Fourier-LFM. By developing a physics-based hybrid-rendering model, LFINR achieves artifact-free light-field reconstruction with enhanced spatial resolution (>1.4-fold improvement). Additionally, the integration of meta-learning and progressive sampling strategies mitigates INRs intrinsic limitations in low reconstruction speed caused by scene-specific optimization, enabling a [~]100-fold acceleration in the representation of consecutive volumes and facilitating the visualization of sustained 3D dynamics. These advancements enable LFMNR to deliver superior imaging with high spatiotemporal resolution and low phototoxicity, as demonstrated by capturing instantaneous voltage signals in C. elegans at 100 volumes per second and recording 6000 time points of organelle dynamics over 25 hours.

cell biology↗

Universal protection against SARS-CoV-2 viruses by multivalent mRNA vaccine in mice

The continual emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges available SARS-CoV-2 vaccines for adequate control of outbreaks. Currently, universal vaccines capable of obviating the need for exact strain matching between mRNA vaccines and circulating viruses are absent. In this study, we designed, manufactured, and evaluated a nucleoside-modified lipid nanoparticle mRNA vaccine, aimed for offering broad-spectrum protection against recent SARS-CoV-2 variants. Additionally, the protection efficiency of monovalent, bivalent, quadrivalent, and XBB.1.5 mRNA vaccines was compared with the proposed universal vaccine. The neutralizing antibody activity against wuhan-1, BA.4/5, XBB.1.5, B.1.1.529, BQ.1.1, EG.5.1 and JN.1 was assessed using enzyme-linked immunosorbent assay, rapid fiber-optic biolayer interferometry-based biosensor, and pseudovirus neutralization test. Our results reveal that the proposed multivalent vaccine affords comprehensive protection against previously circulating, current and previously unidentified SARS-CoV-2 strains.

immunology↗

Neurophysiological Features of STN LFP underlying Sleep Fragmentation in Parkinson's Disease

BackgroundSleep fragmentation is a persistent problem throughout the course of Parkinsons disease (PD). However, the related neurophysiological patterns and the underlying mechanisms remained unclear. MethodWe recorded subthalamic nucleus (STN) local field potentials (LFPs) using DBS with real-time wireless recording capacity from thirteen PD patients undergoing a one-night polysomnography recording, one month after DBS surgery before initial programming and when the patients were Off-Medication. The STN LFP features that characterized different sleep stages, correlated with arousal and sleep fragmentation index, and preceded stage transitions during N2 and REM sleep were analyzed. ResultsBoth beta and low gamma oscillations in NREM sleep increased with the severity of sleep disturbance (arousal index (ArI)-betaNREM: r=0.9,p=0.0001) and sleep fragmentation index (SFI)-betaNREM: r=0.6,p=0.0301; SFI-gammaNREM: r=0.6,p=0.0324). We next examined the low-to-high power ratio, which was the power ratio of theta oscillations to beta and low gamma oscillations, and found it to be an indicator of sleep fragmentation (ArI-LHPRNREM: r=-0.8,p=0.0053; ArI-LHPRREM: r=-0.6,p=0.0373; SFI-LHPRNREM: r=-0.7,p=0.0204; SFI-LHPRREM: r=-0.6,p=0.0428). In addition, long beta bursts (>0.25s) during NREM stage 2 were found preceding the completion of transition to stages with more cortical activities (towards Wake/N1/REM compared with towards N3 (p<0.01)) and negatively correlated with STN spindles, which were detected in STN LFPs with peak frequency distinguishable from long beta bursts (STN spindle: 11.5Hz, STN long beta bursts: 23.8Hz), in occupation during NREM sleep ({beta} = -0.24,p<0.001). ConclusionFeatures of STN LFPs help explain neurophysiological mechanisms underlying sleep fragmentations in PD, which can inform new intervention for sleep dysfunction. What is already known on this topicBeta oscillation, which is a biomarker for rigidity and bradykinesia during awake, significantly reduced during NREM sleep compared to REM or awake. Researches from MPTP non-human primate model suggested increased beta oscillation in basal ganglia contributed to insomnia in PD, however evidence in human patients is still lacking. What this study addsBeta and low gamma band activities in STN LFPs during sleep recorded from human PD patients correlated with severity of sleep impairment. The low-high power ratio can serve as a biomarker for sleep fragmentation. Besides, pathological beta bursts and physiological sleep spindles can be detected in STN LFP during NREM sleep and distinguishable from each other. How this study might affect research, practice or policyThese findings enhance our understanding of the electrophysiological mechanisms that underlie sleep fragmentation in Parkinsons disease. The study also has implications on the design of closed-loop DBS: we may need to take multiple frequency band activities into consideration and differentiate pathological beta oscillation from the sleep spindles.

physiology↗

Immune landscape of tertiary lymphoid structures in hepatocellular carcinoma (HCC) treated with neoadjuvant immune checkpoint blockade

Neoadjuvant immunotherapy is thought to produce long-term remissions through induction of antitumor immune responses before removal of the primary tumor. Tertiary lymphoid structures (TLS), germinal center-like structures that can arise within tumors, may contribute to the establishment of immunological memory in this setting, but understanding of their role remains limited. Here, we investigated the contribution of TLS to antitumor immunity in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy. We found that neoadjuvant immunotherapy induced the formation of TLS, which were associated with superior pathologic response, improved relapse free survival, and expansion of the intratumoral T and B cell repertoire. While TLS in viable tumor displayed a highly active mature morphology, in areas of tumor regression we identified an involuted TLS morphology, which was characterized by dispersion of the B cell follicle and persistence of a T cell zone enriched for ongoing antigen presentation and T cell-mature dendritic cell interactions. Involuted TLS showed increased expression of T cell memory markers and expansion of CD8+ cytotoxic and tissue resident memory clonotypes. Collectively, these data reveal the circumstances of TLS dissolution and suggest a functional role for late-stage TLS as sites of T cell memory formation after elimination of viable tumor. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/562104v2_fig0.gif" ALT="Figure 0"> View larger version (30K): org.highwire.dtl.DTLVardef@859572org.highwire.dtl.DTLVardef@169ed2org.highwire.dtl.DTLVardef@11510f0org.highwire.dtl.DTLVardef@b39a4_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LSTHighlightsC_LSTO_LIIn patients with hepatocellular carcinoma (HCC), tertiary lymphoid structures (TLS) are induced by neoadjuvant immunotherapy and are associated with favorable clinical outcomes. C_LIO_LITLS within the same tumor demonstrate extensive sharing of expanded granzyme K and granzyme B-expressing CD8+ T effector memory clonotypes, but the B cell repertoires of individual TLS are almost wholly distinct, consistent with independent germinal center reactions. C_LIO_LIWithin areas of viable tumor, mature TLS are characterized by high expression of CD21 and CD23, BCL6+ germinal center B cells, and close interactions between DCLAMP+ mature dendritic cells and CXCR5-CXCR3+ CD4 T peripheral helper cells within a T cell zone adjacent to the B cell follicle. C_LIO_LIWithin areas of tumor regression, an involuted TLS morphology is identified that is notable for dissolution of the B cell germinal center, retention of the T cell zone, and increased T cell memory. C_LI

immunology↗

Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig.

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression of UGT2B31 in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.

genetics↗

Single-cell impedance cytometry of anticancer drug-treated tumor cells exhibiting mitotic arrest state to apoptosis using low-cost silver-PDMS microelectrodes

Chemotherapeutic drugs such as paclitaxel and vinblastine interact with the microtubules, and thus induce complex cell states of mitosis arrest at the G2/M phase followed by apoptosis dependent on drug exposure time and concentration. Microfluidic impedance cytometry (MIC) as a label-free and high-throughput technology for single-cell analysis, has been applied for viability assay of cancer cells post drug exposure at fixed time and dosage, yet verification of this technique for varied tumor cell states after anticancer drug treatment remains vacant. Here we present a novel MIC device and for the first time perform impedance cytometry on carcinoma cells exhibiting progressive states of G2/M arrest followed by apoptosis related to drug concentration and exposure time, after treatments by paclitaxel and vinblastine, respectively. Our results from impedance cytometry reveal increased amplitude and negative phase shift at low frequency, as well as higher opacity for the Hela cells under G2/M mitotic arrest compared to the untreated cells. The cells under apoptosis, on the other hand, exhibit opposite changes in these electrical parameters. Therefore, the impedance features differentiate the Hela cells under progressive states post anticancer drug treatment. We also demonstrate that vinblastine poses a more potent drug effect than paclitaxel especially at low concentrations. Our device is fabricated with a unique sacrificial layer-free soft lithography process as compared to the existing MIC device, which gives rise to readily aligned parallel microelectrodes made of silver-PDMS embedded in PDMS channel sidewalls with one molding step. Our results uncover the potential of the MIC device, with a fairly simple and low-cost fabrication process, for cellular state screening in anticancer drug therapy.

cell biology↗

Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon response uniformly across models. The induction of an interferon response is partially due to the inhibition of Sox4 translation by Zotatifin. A similar induction of interferon-stimulated genes was observed in breast cancer patient biopsies following Zotatifin treatment. Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC. One Sentence SummaryTargeting EIF4A sensitizes TNBC to immune therapy and chemotherapy by suppressing Sox4, inducing an interferon response, and reprograming the tumor immune microenvironment.

cancer biology↗

HEARTSVG: a fast and accurate method for spatially variable gene identification in large-scale spatial transcriptomic data

Identifying spatially variable genes (SVGs) is crucial for understanding the spatiotemporal characteristics of diseases and tissue structures, posing a distinctive challenge in spatial transcriptomics research. We propose HEARTSVG, a distribution-free, test-based method for fast and accurately identifying spatially variable genes in large-scale spatial transcriptomic data. Extensive simulations demonstrate that HEARTSVG outperforms state-of-the-art methods with higher F1 scores (average F1 score=0.903), improved computational efficiency, scalability, and reduced false positives (FPs). Through analysis of twelve real datasets from various spatial transcriptomic technologies, HEARTSVG identifies a greater number of biologically significant SVGs (average recall=0.985, average AUC=0.788) than other comparative methods without prespecifing spatial patterns. Furthermore, by clustering SVGs, we uncover two distinct tumor spatial domains characterized by unique spatial expression patterns, spatial-temporal locations, and biological functions in human colorectal cancer data, unraveling the complexity of tumors.

bioinformatics↗

Predicting Gene Spatial Expression and Cancer Prognosis: An Integrated Graph and Image Deep Learning Approach Based on HE Slides

Interpreting the tumor microenvironment (TME) heterogeneity within solid tumors presents a cornerstone for precise disease diagnosis and prognosis. However, while spatial transcriptomics offers a wealth of data, ranging from gene expression and spatial location to corresponding Hematoxylin and Eosin (HE) images, to explore the TME of various cancers, its high cost and demanding infrastructural needs significantly limit its clinical application, highlighting the need for more accessible alternatives. To bridge this gap, we introduce the Integrated Graph and Image Deep Learning (IGI-DL) model. This innovation, a fusion of Convolutional Neural Networks and Graph Neural Networks, is designed to predict gene spatial expression using HE images. The IGI-DL model outperforms its predecessors in analyzing colorectal cancer (CRC), breast cancer, and cutaneous squamous cell carcinoma (cSCC) by leveraging both pixel intensity and structural features in images. Significantly, across all cancer types, the IGI-DL model enhances the mean correlation of the top five genes by an average of 0.125 in internal and external test sets, rising from 0.306 to 0.431, surpassing existing state-of-the-art (SOTA) models. We further present a novel risk score derived from a super-patch graph, where gene expression predicted by IGI-DL serves as node features. Demonstrating superior prognostic accuracy, this risk score, with a C-index of 0.713 and 0.741 for CRC and breast cancer, supersedes traditional HE-based risk scores. In summary, the approach augments our understanding of the TME from the aspect of histological images, portending a transformation in cancer prognostics and treatment planning and ushering in a new era of personalized and precision oncology.

bioinformatics↗

Protein subcellular relocalization and function of duplicated flagellar calcium binding protein genes in honey bee trypanosomatid parasite

The honey bee trypanosomatid parasite, Lotmaria passim, contains two genes that encode the flagellar calcium binding protein (FCaBP) through tandem duplication in its genome. FCaBPs localize in the flagellum and cell body of L. passim through specific N-terminal sorting sequences. This finding suggests that this is an example of protein subcellular relocalization resulting from gene duplication, altering the intracellular localization of FCaBP. However, this phenomenon may not have occurred in Leishmania, as one or both of the duplicated genes have become pseudogenes. Multiple copies of the FCaBP gene are present in several Trypanosoma species and Leptomonas pyrrhocoris, indicating rapid evolution of this gene in trypanosomatid parasites. The N-terminal flagellar sorting sequence of L. passim FCaBP1 interacts with the BBSome complex, while those of Trypanosoma brucei and Leishmania donovani FCaBPs do not direct GFP to the flagellum in L. passim. These results suggest that the N-terminal flagellar sorting sequence of FCaBP1 has co-evolved with the BBSome complex in each trypanosomatid species. Deletion of the two FCaBP genes in L. passim affected growth and impaired flagellar morphogenesis and motility, but it did not impact host infection. Therefore, FCaBP represents a duplicated gene with a rapid evolutionary history that is essential for flagellar structure and function in a trypanosomatid parasite.

microbiology↗

A non-image-forming visual circuit mediates the innate fear of heights

The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naive mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to heights threat through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.

neuroscience↗

Carotenoid assembly regulates quinone diffusion and the Roseiflexus castenholzii reaction center-light harvesting complex architecture

Carotenoid (Car) pigments perform central roles in photosynthesis-related light harvesting (LH), photoprotection, and assembly of functional pigment-protein complexes. However, the relationships between Car depletion in the LH, assembly of the prokaryotic reaction center (RC)-LH complex, and quinone exchange are not fully understood. Here, we analyzed native RC-LH (nRC-LH) and Car-depleted RC-LH (dRC-LH) complexes in Roseiflexus castenholzii, a chlorosome-less filamentous anoxygenic phototroph that forms the deepest branch of photosynthetic bacteria. Newly identified exterior Cars functioned with the bacteriochlorophyll B800 to block the proposed quinone channel between LH{beta} subunits in the nRC-LH, forming a sealed LH ring that was disrupted by transmembrane helices from cytochrome c and subunit X to allow quinone shuttling. dRC-LH lacked subunit X, leading to an exposed LH ring with a larger opening, which together accelerated the quinone exchange rate. We also assigned amino acid sequences of subunit X and two hypothetical proteins Y and Z that functioned in forming the quinone channel and stabilizing the RC-LH interactions. This study reveals the structural basis by which Cars assembly regulates the architecture and quinone exchange of bacterial RC-LH complexes. These findings mark an important step forward in understanding the evolution and diversity of prokaryotic photosynthetic apparatus.

biochemistry↗

A human in vitro neuronal model for studying homeostatic plasticity at the network level

Mechanisms that underlie homeostatic plasticity have been extensively investigated at single-cell levels in animal models, but are less well understood at the network level. Here, we used microelectrode arrays to characterize neuronal networks following induction of homeostatic plasticity in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with rat astrocytes. Chronic suppression of neuronal activity through tetrodotoxin (TTX) elicited a time-dependent network re-arrangement. Increased expression of AMPA receptors and the elongation of axon initial segments were associated with increased network excitability following TTX treatment. Transcriptomic profiling of TTX-treated neurons revealed up-regulated genes related to extracellular matrix organization, while down-regulated genes related to cell communication; also astrocytic gene expression was found altered. Overall, our study shows that hiPSC-derived neuronal networks provide a reliable in vitro platform to measure and characterize homeostatic plasticity at network and single-cell level; this platform can be extended to investigate altered homeostatic plasticity in brain disorders.

neuroscience↗

Aspartyl protease in the secretome of honey bee trypanosomatid parasite is essential for the efficient infection of host

Exoproteome represents the proteome consisting of all secreted proteins and proteins derived from the cell surface and lysed cell. The exoproteome of the trypanosomatid parasite should interact with the host cells and the associated microbiota; however, the roles of infecting insect hosts are not yet understood. To uncover the functions of exoproteome, we identified the exoproteome of honey bee trypanosomatid parasite, Lotmaria passim, and found that approximately 28 % are shared with that common between Leishmania spp. It demonstrates a core exoproteome with conserved functions exists in the Leishmaniinae lineage. The bioinformatic characterization suggests that L. passim exoproteome may interact with the host and its microbiota as well as their metabolites. Deletion of genes encoding two secretome proteins revealed that an aspartyl protease but not chitinase affects the development of L. passim under the culture condition and is necessary for the efficient infection in the honey bee gut. Our results demonstrate that the exoproteome represents a resource to uncover the mechanisms of trypanosomatid parasites to infect the insect host by interacting with the gut environment.

microbiology↗

Visualization and review of reads alignment on the graphical pan-genome with VAG

Recent advances in pangenomics have led to the rapid development of graph-based pangenomes that code genetic variant as nodes and edges preserve the contiguity of the sequence and structural variation between individuals. Data visualization is an essential component of genomic data analysis. However, the further application of the graph-based pangenome is still suffered from lacking bioinformatics tools to visualize graph format pangenomes and understand the reads alignment on graph pangenomes. In this research, we developed a novel bioinformatics platform, VAG (Visualizing read alignments in graph genomes), to overcome these challenges. VAG includes multifunctional modules integrated into a single command line and an online visualization platform supported through a web server. This tool can extract specific sequence regions from a graph pangenome and display read alignments on different paths of a graph pangenome. In addition, VAG provides population-level presence/absence variations frequency analysis and sequence path navigation to identify the population differentiation regions. To demonstrate the usage, we investigated genetic variations using a rice graph pangenome with population-level sequencing data to identify important genes and gene clusters underlying the indica-japonica differentiation with VAG. After investigating read alignments on the graph pangenome, we identified many false-positive alignments due to TE insertions. To reduce the impact of these misleading alignments, we developed a navigation module to determine and filter those false-positive alignments based on the pair-end alignment information. The utilization of mate-pair information in VAG provides a reliable reference for variation identification. Additionally, we developed a VAG web server to provide a user-friendly and interactive platform to visualize the read alignment data. VAG was also applied to SV discovery in the cucumber and soybean graph-based pangenome and details of VAG can be accessed by the following website (https://ricegenomichjx.xiaomy.net/VAG/sequenceextraction.php).

bioinformatics↗

Magnesium and the magnesium transporter UEX regulate sleep via Ca2+-dependent CREB signaling and a CNK-ERK pathway

Magnesium and its related preparations are already in medical use and have recognized therapeutic effects on sleep disorders. However, its underlying molecular mechanisms remain unclear. Here, using Drosophila as a model, we found that RNAi-mediated knockdown of Uex, the homologous gene of magnesium transporters of the Cyclin M family (CNNM) causes increased daily total sleep. Ectopic-expression of CNNM1 can rescue the sleep phenotype in Uex knockdown flies. UEX exhibits rhythmic oscillations in the brain and affects the efflux of cellular Mg2+. Knockdown of Uex in the nervous system influences Ca2+-mediated CREB signaling and neuroplasticity. Additionally, Uex physically interacts with CNK, the upstream regulator of ERK pathway. Similar effects on sleep are observed with knockdown of Cnk in flies. We propose that the UEX regulates sleep through its downstream Ca2+-dependent CREB signaling and a CNK-ERK pathway. Our findings may provide new insight into mechanisms of magnesium and magnesium transporter related sleep disorder.

genetics↗