Biology subjects

Xiong, B.

Publications and source records attributed to Xiong, B..

At least 19 recordsLinked to original sources

bioRxiv2025

Brain Preparedness for Active Forgetting: Cortisol Awakening Response Proacts Prefrontal Control Over Hippocampal-Striatal Circuitry

Stress-related psychiatric pathologies (e.g., rumination in depression, intrusive memories in PTSD) involve impaired inhibitory control over emotional memories and disrupted cortisol circadian rhythms. However, how these mechanisms interact to support adaptive forgetting remains unclear. Here, by integrating multi-modal neuroendocrine profiling with fMRI-based memory suppression in 90 participants, we demonstrate that the cortisol awakening response (CAR)--a circadian surge priming the brain for daily demands--proactively and selectively enhances suppression of recently acquired but not overnight-consolidated emotional memories. This time-dependent facilitation manifests through dual neural mechanisms: Robust CAR broadly amplifies dorsolateral prefrontal cortex (dlPFC) engagement during suppression attempts and specifically strengthens top-down dlPFC control over hippocampal-striatal circuits exclusively for recent traces. Our findings bridge circadian biology, systems neuroscience, and clinical psychopathology to establish CAR as a neuroendocrine preparedness mechanism that proactively configures adaptive forgetting circuits across sleep-wake cycles, thereby informing circadian-based interventions for stress disorders.

neuroscience↗

bioRxiv2025

Exposing the Molecular Reaction Blind Spots of LLMs with PathwayQA

Proteins mediate a large portion of cellular activity, and understanding protein pathways can yield novel biological insights. Large language models (LLMs) have become increasingly adept at performing inference tasks across different fields of science and engineering. These models could facilitate the analysis of protein networks and help generate hypotheses about protein interactions in a scalable and accessible manner. However, the performance of LLMs in inferring protein-mediated biochemical reactions remains understudied. Here, we evaluate nine LLMs in reasoning over protein pathways included in the curated Reactome database. We find that all nine models struggle to infer products of a reaction when given reactants and enzymes. GPT-4o mini performed the best with a median recovery score of 0.6667, but no model surpassed the baseline strategy of parroting reactants back as predicted products. Most LLMs also performed poorly when inferring whether a protein pathway is associated with a human disease, with an average accuracy of 0.5980. DeepSeek 7B Chat performed the best with an accuracy of 0.9100. This study highlights an area where LLMs still struggle to make correct inferences and provides an opportunity for further work in developing biological LLMs. We also provide a novel question-answer dataset, PathwayQA, which is based on the Reactome database. PathwayQA can be used to benchmark and improve model performance on reasoning over protein-interaction networks. PathwayQA is available at https://github.com/Helix-Research-Lab/PathwayQA.

bioinformatics↗

bioRxiv2025

A single-cell transcriptomic atlas maps cerebellar astrocyte diversity and uncovers the transcriptional code underlying their maturation trajectories

Astrocytes are increasingly recognized as key regulators of neural circuit development and function, with mounting evidence revealing substantial heterogeneity within and across brain regions. Yet, the full extent of this diversity and its developmental mechanisms remain poorly understood. To address this, we leveraged the uniqueness of the mouse cerebellum, which hosts well-defined astrocyte types and established progenitor pools. Through complementary multi-modal omic approaches, including single-cell RNA sequencing, spatial transcriptomics, trajectory inference, clonal lineage reconstruction, and gene expression and regulatory network analyses, we systematically dissected the molecular diversity and ontogenesis of cerebellar astrocytes. We identified known types and uncovered new subtypes with functional specialization, inferring their developmental trajectories from multiple embryonic niches and postnatal progenitor sources with fate divergence, convergence, and restriction. We further predicted a hierarchical transcriptional regulator code governing this diversification, operating at multiple levels: distinct regulatory modules i) reflect embryonic regionalization and lineage; ii) determine broad astroglial identity; specify iii) Bergmann versus non-Bergmann fates; and guide iv) astrocyte type and v) subtype acquisition. Our findings map and temporally organize transcriptional programs that capture key determinants of astrocyte fate, integrating them along defined trajectories toward diverse astrocyte identities. This high-resolution framework for cerebellar glial diversification offers a model to be challenged across other brain regions.

neuroscience↗

bioRxiv2025

N'-(1-phenylethylidene)-benzohydrazide cytotoxicity is LSD1 independent and linked to Fe-S cluster disruption in Ewing sarcoma

The noncompetitive LSD1 inhibitors SP-2509 and SP-2577 are N-(1-phenylethylidene)-benzohydrazides that display potent activity in Ewing sarcoma. They block transcriptional regulation of the causative oncogenic fusion protein, EWSR1::FLI1, and cause cell death. However, SP-2509 and SP-2577 are the only LSD1 inhibitors active in Ewing sarcoma; other LSD1 inhibitors have little effect. Studies from our group and others suggest SP-2509 activity may result from off-target activity affecting the mitochondria. Here we identified potential off-target mechanisms of N-(1-phenylethylidene)-benzohydrazides using an unbiased approach, cellular thermal shift assay coupled to mass spectrometry (CETSA-MS). Interestingly, this revealed significant destabilization of the electron transport chain complex III protein ubiquinol-cytochrome c reductase (UQCRFS1). We find that UQCRFS1 destabilization is likely linked to impaired iron-sulfur (Fe-S) cofactor binding, and that SP-2509 broadly destabilizes cellular Fe-S proteins. Using both chemical and genetic tools, we show that SP-2509 mediated cell death is LSD1 independent and instead requires a N-(2-hydroxybenzylidene)hydrazide. Our studies suggest this core moiety alters iron metabolism in the cell. Importantly, we also find that the reversal of EWSR1::FLI1 transcriptional regulation by SP-2509 is independent from LSD1 inhibition. This unique activity is instead associated with the N-(2-hydroxybenzylidene)-hydrazide core and destabilization of Fe-S proteins. These findings reveal a novel mechanism of action for this class of compounds and raise additional questions regarding how EWSR1::FLI1 transcriptional regulation is linked to Fe-S biogenesis, the precise mechanisms of cell death, the biological features of susceptible cancer cells, and strategies for clinical translation.

pharmacology and toxicology↗

bioRxiv2025

N-Orbit: towards a universal model and metric for comparing tissue microenvironments

Advances in spatial omics technologies have greatly expanded our ability to explore tissue microenvironments (TMEs) across development and disease. Yet a theoretical framework for modeling and comparing tissue architecture in diverse biological contexts remains lacking. We introduce, N-Orbit, a mathematical model that captures both cell type composition and spatial relationships within tissue cellular neighborhoods, encoding this information in a vector format for computationally efficient distance metric calculations. While not a neighborhood detection method itself, N-Orbit enhances insights gleaned from the neighborhood generated by the plethora of recently developed methods. We benchmarked the N-Orbit-based neighborhood distance metric on spatial omics datasets containing ground truth neighborhoods and patient clinical outcomes. We demonstrated that the N-Orbit outperforms cell type enrichment (CTE)-based metrics in discriminating neighborhood types, predicting clinical variables, and identifying homologous structures across species. Additionally, N-Orbit enhances model interpretability by allowing neighborhoods to be traced back to their enriched N-Orbit structures. N-Orbit holds significant potential for deepening our understanding of how TMEs remodel during development, disease, and evolution.

bioinformatics↗

bioRxiv2024

The Cryo-EM structure of TRPC1 and TRPC5 heterotetramer

Ion channel heteromers display distinct electrophysiological and ligand-binding properties, allowing precise modulation of cellular functions in specific tissues. Among the TRPC subtypes, the TRPC1/4/5 heteromers are the most abundant isoform in the human brain and represent a primary target for treating anxiety and depression. However, the structural organization of TRPC1/4/5 heteromers remain unclear, limiting the advancement of research on these channels. Here, we report the cryo-EM structure of TRPC1/5 heterotatramer at a resolution of 2.84 [A]. It consists of an asymmetric structure with three TRPC5 subunits and one TRPC1 subunit. Further structural and functional analysis revealed that the TRPC1 subunit contributes to an asymmetrical ion conduction pathway, a characteristic that differentiates it from TRPC5 homomers. The unique features of the TRPC1 pore loop and its interface interactions with TRPC5 were shown to play crucial roles in modulating the ion conduction properties and gating mechanisms of the heteromeric complex. In addition, we identified key residues within the gating regions that influence channel activation and ion permeability, elucidating the structural basis for the functional divergence between the TRPC1/C5 heterotetramer and TRPC5 homotetramer. Notably, TRPC5 residues were found to dominate gating mechanisms, underscoring the complex interplay between subunit composition and functional outcomes in TRPC channels. Our findings provide novel insights into the structural and functional dynamics of TRPC1/C5 heteromers, paving the way for targeted therapeutic strategies in TRPC5-related disorders.

biophysics↗

bioRxiv2024

Physics-Informed Ellipsoidal Coordinate Encoding Implicit Neural Representation for high-resolution volumetric wide-field microscopy

Wide-field fluorescence microscopy through axial scanning provides a simple way for volumetric imaging of cellular and intracellular activities, but the optical transfer function (OTF) of wide-field microscopy suffers from axial frequency deficiencies, leading to strong interference from out-of-focus fluorescence signals and reduced imaging quality. Richardson-Lucy (RL) deconvolution and its variants are commonly employed to reduce inter-plane signal interference of wide-field microscopy. However, these methods are still affected by the "missing cone" issue inherent in the OTF, compromising both the axial resolution and optical sectioning capability. Existing deep learning methods could realize high-fidelity 3D image stack restoration, but relying on high-quality paired datasets or specific assumptions about sample distributions. Here, we propose a novel method named physics-informed ellipsoidal coordinate encoding implicit neural representation (PIECE-INR), to tackle the challenges of background signal interference and resolution loss in axial scanning image stacks using the wide-field microscopy. In PIECE-INR, we integrate the wide-field fluorescence imaging model with the self-supervised INR network for high-fidelity reconstruction of 3D fluorescence data without the need of additional ground truth data for training. We further design a novel ellipsoidal coordinate encoding based on the systems OTF constraints and incorporate implicit priors derived from the physical model as the loss function into the reconstruction process. Our approach enables block-wise reconstruction of large-scale images by using localized physical information. We demonstrate state-of-the-art performance of our PIECE-INR method in volumetric imaging of live HeLa cells, large-volume C. elegans whole-embryo, and mitochondrial dynamics.

cell biology↗

bioRxiv2024

Mapping the Cellular Biogeography of Human Bone Marrow Niches Using Single-Cell Transcriptomics and Proteomic Imaging

The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.

cell biology↗

bioRxiv2024

Brain preparedness: The cortisol awakening response proacts dynamic organization of large-scale brain networks across emotional and executive functions

Emotion and cognition involve an intricate crosstalk of neural and endocrine systems that support allostatic processes for maintenance of dynamic equilibrium and rapid adaptation for upcoming challenges. As a hallmark of human endocrine activity, the cortisol awakening response (CAR) is recognized to play a critical role in modulating emotional and executive functions. Yet, the underlying mechanisms of such effects remain elusive. By leveraging pharmacological neuroimaging technique and Hidden Markov Modeling of brain state dynamics, we show that the CAR proactively modulates rapid reconfigurations (state) of large-scale brain networks across multi-task demands. Behaviorally, suppression of CAR proactively and selectively impaired accuracy for emotional discrimination task but not for working memory (WM). In parallel, suppressed CAR led to a decrease in the occurrence rate of brain state dominant to emotional processing, but an increase in brain state linking to executive control under high WM demand. Further energy-based analyses revealed an increase in transition frequency and sequence complexity along with an increased entropy during emotional tasks when suppressed CAR, suggesting a decreased energy supply. Moreover, an increased transition frequency was observed when shifting from neutral to emotional conditions, but an opposite pattern during WM task, with n decreased transition frequency shifts from low to high-executive demands. Our findings establish a causal link between CAR and dynamic allocation of neural resources for emotional and executive functions, suggesting a cognitive neuroendocrine account for CAR-mediated proactive effects and human allostasis.

neuroscience↗

bioRxiv2023

Large-scale lensless microscopy with fast acquisition and region-wise focusing

The imaging field of view (FOV) of lensless microscope is consistent with the size of image sensor in use, enabling the observation of sample areas larger than 20 mm2. Combined with high-performance and even super-resolution phase retrieval algorithms, micron and sub-micron resolution can be achieved, ultimately realizing wide-field and high-resolution imaging performance simultaneously. However, high-throughput lensless imaging poses significant challenges in terms of rapid data acquisition and large-scale phase retrieval. Additionally, when observing biological samples over a large FOV, the focus plane often exhibits inconsistency among different regions, necessitating further parameter calibration. In this study, we propose a fast acquisition and efficient reconstruction strategy for coherent lensless imaging based on a multi-height imaging model. Multiple measurements are manually modulated using an axial translation stage and continuously captured by an image sensor, facilitating rapid data acquisition within seconds and requiring no hardware synchronization. The efficiency and accuracy of phase retrieval are enhanced through precise parameter calibration algorithms, as well as techniques such as region-wise parallel computing and region-wise auto-focusing. Experimental results demonstrate 7.4x5.5 mm2 FOV and 1.55 m half-pitch resolution imaging of human skin and lung tumor sections with region-wise focusing, requiring only an approximate 0.5-s acquisition time and 44-s reconstruction time. Furthermore, by incorporating the pixel super-resolution principle, the 1.10 m half-pitch imaging resolution is demonstrated in full-FOV peripheral blood smears without additional data required, beneficial to the identification of hollow shape and segmentation of blood cells.

bioengineering↗

bioRxiv2023

Reprogramming an RNA-guided archaeal endonuclease for genome editing

RNA-guided endonucleases developed for genome editing have been identified exclusively from bacteria until now. Recently, the RNA-guided TnpB endonucleases encoded by bacterial IS200/IS605 and IS607 families have been reprogrammed for genome editing. In fact, these insertion sequence families are also widely distributed in archaea. However, whether archaea-derived TnpB could be used for genome editing remains unclear. Here, we found that TnpB derived from Sulfolobus islandicus REY15A (SisTnpB1) was an Mg2+/Mn2+-dependent RNA-guided endonuclease, and it could cleave DNA next to the 5 TTTAA transposon-associated motif (TAM) to generate double-stranded DNA breaks at the 3-end. We also found that SisTnpB1 was active at 37-85{degrees}C and tolerant to variations of TAM. Moreover, SisTnpB1 could be reprogrammed to edit bacterial cells with an editing efficiency of 100% at 37{degrees}C or 45{degrees}C. In summary, our finding expanded the resources of RNA-guided endonucleases for genome editing, especially those derived from archaea, the third domain of life.

molecular biology↗

bioRxiv2023

Aberration modeling in deep learning for volumetric reconstruction of light-field microscopy

Optical aberration is a crucial issue in optical microscopes, which fundamentally limits the practical imaging performance. As a commonly encountered one, spherical aberration is introduced by the refractive index mismatches between samples and environments, which will cause problems like low contrast, blurring, and distortion in imaging. Light-field microscopy (LFM) has recently emerged as a powerful tool for fast volumetric imaging. The appearance of spherical aberration in LFM will cause large changes of the point spread function (PSF) and thus greatly affects the imaging performance. Here, we propose the aberration-modeling view-channel-depth (AM-VCD) network for LFM reconstruction, which can well mitigate the influence of large spherical aberration. By quantitatively estimating the spherical aberration in advance and modeling it in the network training, the AM-VCD can obtain aberration-corrected high-speed visualization of three-dimensional (3D) processes with uniform spatial resolution and real-time reconstruction speed. Without any hardware modification, our method provides a convenient way to directly observe the 3D dynamics of samples in solution. We demonstrate the capability of AM-VCD under a large refractive index mismatch with volumetric imaging of a large-scale fishbone of largemouth bass. We further investigate the capability of AM-VCD in real-time volumetric imaging of dynamic zebrafish for tracking neutrophil migration.

bioengineering↗

bioRxiv2023

Positive coping supports children's emotional wellness: Behavioral evidence and neuroendocrine mechanisms

A positive coping style is recognized as a stable disposition to foster emotional wellness and resilience, enabling an adaptive process of assessing and dealing with environmental challenges. Such an adaptive process is believed to rely on a nuanced interplay of the hippocampal system and the primary stress hormone cortisol activity. As a hallmark of diurnal cortisol rhythm, cortisol awakening response (CAR) is sensitive to upcoming stress and subserves the preparation of the hippocampal system for rapid behavioral adaption. Yet, little is known about how the hippocampal system and CAR contribute to the merit of positive coping on emotional wellness. By two studies, we investigate the effects of positive coping on childrens emotional wellness and CAR, as well as longitudinal changes in hippocampal-neocortical functional systems involved in emotional processing. Behaviorally, positive coping predicted better emotional regulation ability, but lower anxiety and lower response caution in emotional decision-making. At the endocrine and neurocognitive level, positive coping was associated with greater CAR, which further predicted higher connectivity of the hippocampus with ventrolateral prefrontal cortex (vlPFC) and stimulus-sensitive neocortex one year later. Furthermore, CAR mediated an indirect association between positive coping and longitudinal increases in hippocampal-neocortical connectivity. Positive coping and CAR together could account for the maturity of vlPFC through longitudinal changes in hippocampal-neocortical connectivity. Overall, our findings suggest a cognitive-neuroendocrinal framework in which positive coping shapes hippocampal-neocortical maturation via stress hormone response to support emotional wellness. SignificanceThe role of the hippocampal system in regulating stress response is well recognized, but its contribution to emotional well-being is not yet understood. Here we show that the protective effects of positive coping on emotional well-being are contingent on two factors: the cortisol awakening response (CAR), which is sensitive to upcoming stress, and hippocampal development. We found that positive coping practices promoted emotional wellness, enhanced emotional decision-making and increased CAR in young children. Longitudinal neuroimaging analysis revealed that positive coping-related CAR predicted greater hippocampal connectivity with stimulus-sensitive neocortex one year later. Importantly, CAR acted as a mediator of the promotive influence of positive coping on the longitudinal development of hippocampal-neocortical connectivity, which contributed to the maturity of prefrontal control systems. Our findings emphasize the importance of hippocampal-neocortical development in resilient coping and emotional wellness.

neuroscience↗

bioRxiv2022

Medial prefrontal-hippocampal concordance in child-parent dyads underlies children's psychological wellbeing

Family emotional climate is fundamental to childs emotional wellbeing and mental health. Negative family emotional climate may lead to heightened psychopathological symptoms via dysfunctional child-parent interactions. Single-brain paradigms have uncovered changes in brain systems and networks related to negative family environments, but how neurobiological reciprocity between child and parent brains is associated with childrens psychopathological symptoms remains unknown. In study1, we investigated the relationship between family emotional climate and childrens psychopathological symptoms in 395 child-parent dyads. In study2, using a naturalistic movie-watching functional magnetic imaging technique in a subsample of 100 children and parents, we investigate the neurobiological underpinnings of how family emotional climate is associated with childrens psychopathological symptoms through child-parent neural synchrony. Children from negative family emotional climate experienced more severe psychopathological symptoms. We revealed significantly higher inter-subject correlations in the dorsal and ventral portions of the medial prefrontal cortex (mPFC), and greater concordance of activity with widespread brain regions critical for socioemotional skills in child-parent than child-stranger dyads. Critically, negative family emotional climate was associated with decreased inter-subject functional correlation between the ventral mPFC and the hippocampus in child-parent dyads, which further accounted for higher childrens internalizing symptoms especially for anxious and depressed aspects. Family emotional climate might transmit into the brain of parent-child dyads, which may associate with child development outcomes. The present study identified that child-parent vmPFC-hippocampal circuitry is linked to childrens psychopathological symptoms. Our findings suggest a neurobiological mechanism of how negative family emotional climate affects childrens psychopathological symptoms through altered child-parent neural synchrony.

neuroscience↗

bioRxiv2022

Impact of fungal hyphae on growth and dispersal of obligate anaerobic bacteria in aerated habitats

Anoxic microsites arising in fungal biofilms may foster the presence of obligate anaerobes even in well-areated environments. Here, we analyzed whether and to which degree fractal hyphae of Coprinopsis cinerea thriving in oxic habitats enable the germination, growth, and dispersal of obligate anaerobic soil bacterium Clostridium acetobutylicum. Time-resolved optical oxygen mapping, microscopy and metabolite analysis revealed the formation and persistence of anoxic circum hyphal niches allowing for spore germination, growth and fermentative activity of the obligate anaerobe in an otherwise oxic environment. Hypoxic liquid films containing 80 {+/-} 10% of atmospheric oxygen saturation around single air-exposed hyphae thereby allowed for efficient clostridial dispersal amid spatially separated (>0.5 cm) anoxic sites. Our results suggest that fungal biomass typical in soil (<550 g g-1soil) may create anoxic microniches and enable activity as well as dispersal of obligate anaerobes near hyphae in an otherwise inhabitable environment.

microbiology↗

bioRxiv2021

A novel mechanism of Euonymine inhibits in-stent restenosis through enhancing contractile phenotype of VSMCs by targeting AKT1 and p38MAPK

This study aimed to examine the inhibitory effects of Euonymine on in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) and oxidized low-density lipoprotein (ox-LDL)-induced proliferation, migration, and pro-apoptotic of vascular smooth muscle cells (VSMCs) in vitro, and its potential mechanisms. Euonymine is a monomer component extracted from Tripterygium hypoglaucum (Levl) Hutch. Using in vitro models of rabbit carotid balloon injury and porcine atherosclerotic coronary implantation, we confirmed that Euonymine inhibited ISR after PCI. Furthermore, Euonymine inhibited VSMC phenotypic transformation by targeting AKT1 to regulate the PTEN/AKT1/m TOR signaling pathway, with exertion of anti-proliferative, anti-migratory, and pro-apoptotic effects on ox-LDL-induced cell injury model. Additionally, the study demonstrated that Euonymine induced apoptosis of VSMCs via the p38MAPK-related mitochondria-dependent apoptotic pathway. Collectively, these findings indicated that Euonymine drug-eluting stents inhibited ISR after PCI by targeting AKT1 and p38MAPK to enhance the contractile phenotype of VSMCs to prevent intimal hyperplasia development. This provides insights into a potential therapeutic strategy involving the beneficial effect of Euonymine drug-eluting stent on ISR. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/466441v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1582ef9org.highwire.dtl.DTLVardef@73e133org.highwire.dtl.DTLVardef@1c5f318org.highwire.dtl.DTLVardef@daca49_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

Brain preparedness: The proactive role of the cortisol awakening response

Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated preparation function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design using Dexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.

neuroscience↗

bioRxiv2020

Structure of SARS-CoV-2 main protease in the apo state reveals the inactive conformation

Mpro is of considerable interest as a drug target in the treatment of COVID-19 since the proteolytic activity of this viral protease is essential for viral replication. Here we report the first insight of the structure Mpro for SARS-CoV-2 in the inactive conformation under conditions close to the physiological state (pH 7.5) to an overall resolution of 1.9 [A]. The comparisons of Mpro in different states reveal that substrate binding site and the active site are more flexible in the inactive conformation than that in the active conformations. Notably, compared with the active conformation of the apo state structure in pH7.6 of SARS, the SARS-CoV-2 apo state is in the inactive conformation under condition close to physiological state (pH7.5). Two water molecules are present in the oxyanion hole in our apo state structure, whereas in the ligand-bound structure, water molecular is absence in the same region. This structure provides novel and important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational, structure-based, approaches for the design of specific SARS-CoV-2 ligands as new therapeutic agents.

biochemistry↗