Biology subjects

Qiao, Z.

Publications and source records attributed to Qiao, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

A polysynaptic hypothalamuspelvic-ganglion circuit regulates prostate tumor growth via WNT3A

Brain-tumor communication is increasingly recognized. Peripheral autonomic nerves regulate prostate cancer progression, yet how the brain influences local nerve-tumor interactions remains unclear. We identify a polysynaptic circuit linking the hypothalamic paraventricular nucleus (PVN), dorsal motor nucleus of the vagus (DMV), major pelvic ganglion (MPG) and prostate tumor in mice. Although both nuclei were activated during tumor growth, PVN activity restrained, whereas DMV activity promoted tumor growth. MPG ablation abolished DMV-induced tumor promotion. Combining LMD with Smart-seq2 revealed transcriptional remodeling and increased Wnt3a expression in tumor-innervating, activated MPG neurons under upstream neural control. MPG explants released WNT3A, whose neutralization suppressed explant-induced cancer-cell proliferation. Together, our findings identify a polysynaptic PVN-DMV-MPG circuit that regulates prostate tumor growth and implicate WNT3A as a mediator of the pro-tumor effects of the MPG, highlighting the therapeutic potential of targeting the neural circuit and downstream molecular pathway.

cancer biology↗

bioRxiv2026

Oxidized protein states define metastatic fitness in lung cancer

AbstractReactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10*Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo. These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.

Cancer Biology↗

bioRxiv2026

OpenBase: a universal framework for high-accuracy single-molecule detection of diverse non-canonical DNA bases using nanopore sequencing

Nanopore sequencing holds great potential for the direct detection of non-canonical DNA bases from electrical signals, yet current approaches remain limited to a few classical epigenetic marks. Here we present OpenBase, an open and universal framework that standardizes training-data generation and deep learning based-modeling for single-molecule identification of diverse non-canonical DNA bases. OpenBase transforms nanopore sequencing into a broadly accessible platform for exploring the chemical diversity of DNA.

bioinformatics↗

bioRxiv2026

The Impact of Dysregulated Lipid Metabolism on the Gut-Brain Axis in Patients with Intracerebral Hemorrhage

BACKGROUNGBisphenol A (BPA) has been linked to hypertension and disturbances in lipid metabolism; however, limited evidence is available regarding its association with hypertensive intracerebral hemorrhage (ICH). METHODSA multicenter, retrospective case-control study was conducted involving 129 participants, including individuals from an ICH group and healthy controls. Standard assays were employed to assess serum thyroid function, lipid profiles, serum fatty acid-binding [x]protein 4 (FABP4), oxidative stress markers, gap junction proteins, Wnt/{beta}-catenin signaling pathway activity, and expression changes of S100A8-mediated inflammatory cytokines involved in gut-brain interactions. Correlation analyses using Pearson and Spearman methods revealed that both BPA exposure and low T3 levels were significantly associated with elevated diastolic blood pressure, altered lipid metabolism, gut microbiota composition, and microglial activation. RESULTSGender-based disparities in lipid metabolism were identified. Changes in {beta}3-adrenergic receptor and neuromodulin-1 expression appear to influence fat regulation and attenuate oxidative stress responses. Subsequently, increased expression of gap junction proteins and activation of the Wnt/{beta}-catenin signaling pathway contribute to metabolic reprogramming and alterations in biochemical kinetics. Gut microbiota analysis demonstrated that, compared to controls, the ICH group exhibited significant dysbiosis and reduced alpha diversity. Further correlation analyses indicated that BPA levels were positively associated with FABP4 and oxidative stress markers, while S100A8 showed a strong dependence on microglial expression. CONCLUSIONThe interplay between lipid metabolism dysfunction and pro-inflammatory cytokines enhances vascular vulnerability. Collectively, BPA exposure, oxidative stress, and microglia-mediated neuroinflammation are significantly associated with an elevated risk of hypertensive ICH. China Clinical Trial Registry registration noticeFrom: China Clinical Trials Registry +To:guopingwang60a yunyanshuangfei FUNDINGThis work was supported by the Natural Science Foundation of Shanxi Province (grant no. 201701D121177) Key informationGender-specific differences were observed in lipid metabolism and oxidative stress parameters; BPA exposure was shown to induce lipid metabolic disturbances, promote excessive production of oxidative stress byproducts, and consequently elevate oxidative stress responses; BPA was associated with stress-induced alterations in thyroid hormone function, further exacerbating dysregulation of lipid metabolism and oxidative stress; Fatty acid binding protein 4 (FABP4), a key adipokine implicated in metabolic disorders and adipose tissue inflammation, exhibited a significant positive correlation with serum BPA levels, whereas low levels of triiodothyronine (T3) were negatively correlated with FABP4. These findings suggest that serum FABP4 may serve as a biochemical marker for chronic low-grade adipose tissue inflammation and metabolic dysfunction; Gap junction proteins and the Wnt/{beta}-catenin signaling pathway may contribute to microglial activation and mediate neuroinflammatory responses, nerve injury, and secondary pathological processes in obesity-related cerebral hemorrhage.

biochemistry↗

bioRxiv2026

Protein Language Modeling and Evolutionary Analysis Reveal an N-terminal Determinant of Functional Divergence in Cytochrome P450s from Sophora. tonkinensis

The N-terminal membrane anchor of cytochrome P450s is essential for function yet exceptionally variable--a paradox resistant to alignment-based analysis. Using an alignment-free protein language model (ESM2) pipeline on 345 Sophora tonkinensis P450s, we show the N-terminal 50 residues evolve under pervasive neutral relaxation (mean dispersion 0.62), punctuated by a single constrained island: a PxxG structural hinge (P21, G24 conserved at 98%/99%). Despite lacking sequence-level constraint, embedding-space decomposition resolves this scaffold into two separable channels. DIVA (unsupervised) captures a topological template encoding membrane-anchoring architecture, validated by physicochemical correlations recapitulating ER signal-anchor insertion and confirmed by DeepLoc- 2.1. PIVOT (supervised ablation) captures a family-associated signal whose peak position distinguishes CYP families ({varepsilon}2 = 0.44, permutation p < 0.0001) despite label-free training. The channels are largely separable: PIVOT peaks lie downstream of DIVA peaks in 84.4% of proteins, with mutually exclusive signal-loss sets. The P450 N-terminus thus integrates membrane-topological and family-identity information within a single relaxed region. Neutral evolution is reframed not as absence of information, but as the condition enabling multiplexed functional encoding--a mechanistic rationale for the functional importance of this variable anchor.

plant biology↗

bioRxiv2025

Drug-like antibody design against challenging targets with atomic precision

Computational antibody design has seen rapid progress, with high success rates enabling direct translation to characterization without any high-throughput screening required. In this work, we markedly expand the scope of de novo antibody design by applying our state-of-the-art Chai-2 platform to design drug-like antibodies in full-length monoclonal format. We find that >86% of these full-length mAbs have strong developability profiles on par with therapeutic antibodies. We further show that experimentally determined structures of Chai-2 designs closely match their in silico predictions, demonstrating that Chai-2 produces atomically accurate models of designed antibodies. Building on these foundational capabilities, we showcase two potential applications of Chai-2 against different targets: designing functional antibodies mediating GPCR agonism, and highly specific antibodies selectively binding tumor-specific neoepitopes. Taken together, this work brings new flexibility to modern discovery pipelines, accelerating the path from in silico design to functional validation across both conventional and challenging targets. Beyond reducing the cost and timelines associated with large screening campaigns, in silico design can now open new frontiers for creative, targeted therapeutics that address unmet clinical needs.

molecular biology↗

bioRxiv2025

Yuanyang allele pairs enable engineered obligate co-inheritance for population replacement and suppression

Mendels law of segregation, which dictates independent assortment of alleles, is a cornerstone of genetics. Here, we present the Yuanyang allele pair (YYAP), an engineered underdominance gene drive system that enforces obligate co-dependency between homologous alleles via synthetic toxin-antitoxin circuits. This design produces a striking deviation from classical Mendelian segregation: YYAP alleles cannot segregate independently, reshaping inheritance outcomes without altering the physical mechanics of meiosis. In Drosophila melanogaster, optimized YYAP strain K711 exhibits >99% hemizygous lethality when crossed with wild type, while maintaining stable transmission and high fitness in transheterozygotes. Cage experiments demonstrate efficient population replacement, positioning YYAP as a confined, resistance-proof alternative to CRISPR homing gene drives. Release of only males represents a self-limiting suppression strategy that was also successful in cage experiments. By imposing a near-complete postzygotic incompatibility, YYAP establishes a programmable framework that not only supports pest management, but also enables modeling of reproductive isolation and allelic co-dependency, thereby creating opportunities to explore speciation and broader synthetic inheritance systems in ecology and evolution.

molecular biology↗

bioRxiv2025

Population density triggers wing dimorphism via NlNompC-mediated insulin signaling in Nilaparvata lugens

The Nilaparvata lugens employs wing dimorphism as a key adaptive strategy to environmental heterogeneity. While hormonal pathways and transcription factors governing nutrient-induced wing plasticity are known, how population density triggers developmental divergence remains unresolved. Here, we mechanistically dissect density-dependent wing morph determination, revealing tactile inter-individual contact as the primary signal. High-density conditions amplify gentle-touch frequency, which is detected by mechanosensitive ion channels NlNompC and NlNMDARs. Genetic silencing or pharmacological inhibition of these channels abolished density-induced long-winged morphogenesis. The conserved role of NlNompC in gentle-touch sensation was validated by rescuing tactile perception deficits in Drosophila nompC mutants. Crucially, NlNompC integrates tactile cues into insulin/insulin-like growth factor signaling (IIS): crowding-driven mechanical stimuli upregulate NlIlp3, while suppressing NlInR2, to activate wing elongation programs. Epistasis experiments confirmed IIS as the key downstream pathway, with co-silencing NlInR2 or NlFoxO rescuing the short-winged phenotype induced by NlNompC knockdown or low population density, silencing NlIlp3 or NlInR1 rescuing the long-winged phenotype induced by high population density. Our work uncovers a mechano-endocrine axis linking tactile perception to developmental plasticity, bridging ecological cues with molecular pathways. These findings redefine density sensing beyond chemical modalities and offer actionable targets for disrupting pest dispersal strategies, advancing sustainable agriculture.

molecular biology↗

bioRxiv2025

Insect-derived long non-coding RNAs function as epigenetic effectors to reprogram plant immunity

Cross-kingdom RNAs are emerging as critical mediators of interspecies interactions, yet the functions of long RNAs such as mRNAs and long non-coding RNAs (lncRNAs) in recipient organisms remain largely unexplored. Here, we show that the brown planthopper (Nilaparvata lugens, BPH), a major rice pest, translocates mRNAs and lncRNAs into rice plants, where they migrate systemically from feeding sites to distal tissues. Compared with BPH mRNAs, BPH Salivary gland Cross-kingdom LncRNA (BSCLs) exhibit markedly higher stability in rice. Among them, BSCL1 functions as a virulence factor that promotes BPH feeding and reproduction by suppressing host defense. Mechanistically, BSCL1 associates with the HIRA histone chaperone complex and displaces histone H3.3 from the promoters of transcription factors, including bHLH genes central to jasmonic acid signaling, thereby repressing transcriptional immunity. Our results identify BSCLs as systemic, RNA-based effectors that reprogram host defense at the epigenetic level, revealing a previously unrecognized mode of insect-mediated manipulation of plant immunity and highlighting lncRNAs as cross-kingdom regulators. Significance StatementPlant-herbivore interactions are traditionally viewed as battles over nutrients and defense signaling, mediated largely by proteins and small RNAs. Here, we demonstrate that long non-coding RNAs from brown planthopper saliva are translocated into rice, migrate systemically, and function as epigenetic effectors that suppress key transcription factors in jasmonic acid-mediated defense. Unlike insect mRNAs, these lncRNAs persist in the plant and reprogram immunity by interfering with histone deposition. This discovery uncovers a new class of mobile, RNA-based virulence factors, expands our understanding of cross-kingdom regulation, and suggests innovative strategies for pest control targeting RNA effectors.

plant biology↗

bioRxiv2025

Zero-shot antibody design in a 24-well plate

Despite breakthroughs in protein design enabled by artificial intelligence, reliably designing functional antibodies from scratch has remained an elusive challenge. Recent works show promise but still require large-scale experimental screening of thousands to millions of designs to reliably identify hits. In this work, we introduce Chai-2, a multimodal generative model that achieves a 16% hit rate in fully de novo antibody design, representing an over 100-fold improvement compared to previous computational methods. We prompt Chai-2 to design[≤] 20 antibodies or nanobodies to 52 diverse targets, completing the workflow from AI design to wet-lab validation in under two weeks. Crucially, none of these targets have a preexisting antibody or nanobody binder in the Protein Data Bank. Remarkably, in just a single round of experimental testing, we find at least one successful hit for 50% of targets, often with strong affinities and favorable drug-like profiles. Beyond antibody design, Chai-2 achieves a 68% wet-lab success rate in miniprotein design - routinely yielding picomolar binders. The high success rate of Chai-2 enables rapid experimental validation and characterization of novel antibodies in under two weeks, paving the way toward a new era of rapid and precise atomic-level molecular engineering. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/663018v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@69655borg.highwire.dtl.DTLVardef@17d44dborg.highwire.dtl.DTLVardef@133b7ddorg.highwire.dtl.DTLVardef@6c4319_HPS_FORMAT_FIGEXP M_FIG 52 antigens targeted by Chai-2. Blue boxes indicate targets with at least one successful binder out of [≤]20 assayed designs, representing 50% of the tested targets. Date: June 30, 2025 C_FIG

synthetic biology↗

bioRxiv2024

Sleep patterns predicting stress resilience are dependent on sex

Sleep disturbances and stress have a well-established link with neuropsychiatric illness; however, the nature of this relationship remains unclear. Recently, studies using the mouse social-defeat stress model revealed a causal role for non-rapid eye movement (NREM) sleep in the maladaptive behavioral responses to stress. These results suggest a novel function for NREM sleep; as a response by cortical neurons to mitigate the maladaptive effects of stress. A major limitation in many social defeat studies has been the exclusion of females. Women exhibit a greater prevalence of both affective disorders and sleep disturbances compared to men, thus there is a clear need to understand sleep - stress interactions in females. The present study adapts recently developed female social-defeat stress models to allow social-defeat and EEG in male - female pairs. Our findings duplicate the behavioral responses that occur in other female, nondiscriminatory, and male models of social-defeat stress. Analysis of electroencephalographic (EEG) recordings, before exposure to stress, reveal that resilience is associated with differences in both NREM and REM sleep that are dependent on sex. After social defeat stress, NREM sleep was increased only in resilient males. In females, susceptibility to stress was associated with increased durations in NREM-sleep bouts. A potential cause of these sleep differences was also identified prior to stress exposure, sex differences in recovery from NREM-sleep loss; thus, suggesting an underlying sex-difference in the homeostatic process regulating sleep interactions with social-defeat stress. These findings suggest that NREM sleep quality is lower in resilient females, whereas the amount of REM sleep is decreased in susceptible females--when compared to males of the same behavioral phenotype. Overall, our findings reveal sexual dimorphism in both the sleep characteristics predicting resilience and sleep changes induced by social-defeat stress.

neuroscience↗

bioRxiv2024

Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tandem repeats (TRs) - highly polymorphic, repetitive sequences across the human genome - are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here, we generate new whole genome and single-cell RNA sequencing from >5.4 million blood-derived cells across 1,925 individuals in two cohorts [Cuomo et al., accompanying manuscript], and perform meta-analysis to characterize the impact of variation in >1.7 million TR loci on immune cell type-specific gene expression. We identify >69,000 single-cell expression TR loci (sc-eTRs), 30.7% of which are specific to one of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell ATAC sequencing profiles from >3.4 million nuclei in 922 individuals [Xue et al., accompanying manuscript]. uncover chromatin accessibility QTLs for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight >200 genes in which TRs likely mediate genetic associations with immune and hematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

genomics↗

bioRxiv2024

Temporal Dynamics and Adaptive Mechanisms of Microbial Communities: Divergent Responses and Network Interactions

Microbial communities are integral to aquatic ecosystems, playing key roles in biogeochemical cycles, nutrient recycling, and ecosystem functioning. Despite their importance, the temporal dynamics of these communities, especially in response to short-term environmental changes, remain inadequately understood. This study utilizes high-throughput amplicon sequencing and Co-occurrence network analysis to elucidate how prokaryotic and eukaryotic microbial communities dynamically respond to short-term environmental fluctuations, and dynamics of networks. Our results reveal distinct temporal patterns, with eukaryotic communities showing consistent increases in diversity, while prokaryotic communities exhibited more pronounced fluctuations and directional changes. Co-occurrence network analysis further highlighted the differences in community structure between phases of homogenization and heterogenization. Specifically, we observed a shift from a more modular network during the homogenization phase to a more centralized network in the heterogenization phase, resulting in increased network fragility. Environmental factors, such as nutrient levels and climatic conditions, were found to play pivotal roles in shaping these dynamics. This study provides critical insights into the resilience and adaptability of microbial communities, emphasizing the intricate interplay between biodiversity, network structure, and ecosystem stability under varying environmental conditions.

microbiology↗

bioRxiv2024

The Origin and Evolution of Orphan Genes: A Case Study in Tea Plant Family

Orphan genes and transcription factor genes (TFs) are pervasive across genomes, play pivotal roles as regulators in a myriad of biological processes. Despite their ubiquity, the evolutionary trajectories and functional divergence of these genes remain largely unexplored. Theaceae family, encompassing the economically and culturally significant tea plant, presents a unique opportunity to study these dynamics. Here, we decoded a nearly complete, chromosome-scale reference genome of Stewartia gemmata spanning 2.95 Gb. This study is enhanced by integrating the genome of S. gemmata, an early-diverging species within Theaceae, crucial for phylogenomic analyses and understanding the functional dynamics of orphan genes in this family. Our analysis confirmed the absence of a recent specific whole-genome duplication (WGD) event, with tandem duplications emerging as the predominant mechanism for gene duplication at ancestral nodes within Theaceae. By conducting an extensive comparative genomics analysis across 13 Theaceae and comparing these with a wide array of eukaryotic and prokaryotic proteins, we identified 37,618 orphan genes and 25,884 TFs in Theaceae. Interestingly, some orphan genes appear to have ancient origins in tea plant ancestors, suggesting relatively early origins with frequent gains and losses, conversely, many others seem more specific and recent. Notably, the orphan genes are characterized by shorter lengths, fewer exons and functional domains than TFs, implying relatively simpler functional roles. These orphan genes demonstrate diverse cellular localization and functions as predicted by GO/KEGG analysis, and are implicated in environmental response and flavor formation in tea plants. This study not only sheds light on the distinct evolutionary histories and functional divergences between orphan genes and TFs in Theaceae, but also contributes to our understanding of the genetic complexity and adaptability of this economically and culturally valuable plant family. Short summary: The nearly complete genome of an early-diverging species Stewartia gemmata and phylogenomic studies provide insights into new gene evolution in Theaceae.

bioinformatics↗

bioRxiv2022

Non-rapid eye movement sleep determines resilience to social stress

Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience--demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that is both necessary and sufficient for promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.

neuroscience↗

bioRxiv2021

SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1 kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1 as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1 through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1 was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1, perhaps as a strategy to eliminate detection by the host immune system. IMPORTANCESARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1 (IRE1) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1 kinase and RNase activities, SARS-CoV-2 only partially activates IRE1, promoting its kinase activity but not RNase activity. Based on IRE1-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1 RNase activation as a strategy to limit detection by the host immune system.

microbiology↗

bioRxiv2021

Arginine-Vasopressin Expressing Neurons in the Murine Suprachiasmatic Nucleus Exhibit a Circadian Rhythm in Network Coherence in vivo

The Suprachiasmatic Nucleus (SCN) is composed of functionally distinct sub-populations of GABAergic neurons which form a neural network responsible for synchronizing most physiological and behavioral circadian rhythms in mammals. To date, little is known regarding which aspects of SCN rhythmicity are generated by individual SCN neurons, and which aspects result from neuronal interaction within a network. Here, we utilize in vivo miniaturized microscopy to measure fluorescent GCaMP-reported calcium dynamics in AVP-expressing neurons in the intact SCN of awake, behaving mice. We report that SCN AVP neurons exhibit periodic, slow calcium waves which we demonstrate, using in vivo electrical recordings, likely reflect burst-firing. Further, we observe substantial heterogeneity of function in that AVP neurons exhibit unstable rhythms, and relatively weak rhythmicity at the population level. Network analysis reveals that correlated cellular behavior, or coherence, among neuron pairs also exhibited stochastic rhythms with about 33% of pairs rhythmic at any time. Unlike single-cell variables, coherence exhibited a strong rhythm at the population level with time of maximal coherence among AVP neuronal pairs at CT/ZT 6 and 9, coinciding with the timing of maximal neuronal activity for the SCN as a whole. These results demonstrate robust circadian variation in the coordination between stochastically rhythmic neurons and that interactions between AVP neurons in the SCN may be more influential than single-cell activity in the regulation of circadian rhythms. Furthermore, they demonstrate that cells in this circuit, like those in many other circuits imaged in vivo, exhibit profound heterogenicity of function over time and space. Significance StatementThis work is the first to employ two novel in vivo recording techniques, miniaturized calcium microscopy and optogentically-targeted single unit activity recording, to examine the rhythmic behavior of AVP expressing neurons both at the individual neuronal and network level. These results suggest that while AVP neurons are important for organismal rhythmicity, individual cellular rhythms are unstable and diverse. However, we observed correlated activity among these neurons which appears more reliably rhythmic, suggesting that emergent network properties of the SCN may be more relevant for organismal rhythmicity than individual neuronal characteristics.

neuroscience↗

bioRxiv2021

#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus ob-scure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized. ACM Reference FormatAbigail Dommer1{dagger}, Lorenzo Casalino1{dagger}, Fiona Kearns1{dagger}, Mia Rosenfeld1, Nicholas Wauer1, Surl-Hee Ahn1, John Russo,2 Sofia Oliveira3, Clare Morris1, AnthonyBogetti4, AndaTrifan5,6, Alexander Brace5,7, TerraSztain1,8, Austin Clyde5,7, Heng Ma5, Chakra Chennubhotla4, Hyungro Lee9, Matteo Turilli9, Syma Khalid10, Teresa Tamayo-Mendoza11, Matthew Welborn11, Anders Christensen11, Daniel G. A. Smith11, Zhuoran Qiao12, Sai Krishna Sirumalla11, Michael OConnor11, Frederick Manby11, Anima Anandkumar12,13, David Hardy6, James Phillips6, Abraham Stern13, Josh Romero13, David Clark13, Mitchell Dorrell14, Tom Maiden14, Lei Huang15, John McCalpin15, Christo- pherWoods3, Alan Gray13, MattWilliams3, Bryan Barker16, HarindaRajapaksha16, Richard Pitts16, Tom Gibbs13, John Stone6, Daniel Zuckerman2*, Adrian Mulholland3*, Thomas MillerIII11,12*, ShantenuJha9*, Arvind Ramanathan5*, Lillian Chong4*, Rommie Amaro1*. 2021. #COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy ofDeltaSARS-CoV-2 in a Respiratory Aerosol. In Supercomputing 21: International Conference for High Perfor-mance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages. https://doi.org/finalDOI

biophysics↗