Biology subjects

Zhou, F.

Publications and source records attributed to Zhou, F..

At least 163 records · Page 9Linked to original sources

bioRxiv2021

Anxiolytic effects of chronic intranasal oxytocin on neural responses to threat are dose-frequency dependent

Anxiety disorders are prevalent psychiatric conditions characterized by exaggerated anxious arousal and threat reactivity. Animal and human studies suggest an anxiolytic potential of the neuropeptide oxytocin (OT), yet, while a clinical application will require chronic administration protocols previous studies in humans have exclusively focused on single-dose (acute) intranasal OT effects. We aimed at determining whether the anxiolytic effects of OT are maintained with repeated (chronic) administration or are influenced by dose frequency and trait anxiety. A double-blind randomized, placebo-controlled pharmaco-fMRI trial (n=147) determined acute (single-dose) as well as chronic effects of two different dose frequencies of OT (OT administered daily for 5 days or every other day) on emotional reactivity in healthy subjects with high versus low trait anxiety. OT produced valence, dose frequency and trait anxiety specific effects, such that the low-frequency (intermittand) chronic dosage specifically attenuated neural reactivity in amygdala-insula-prefrontal regions in high anxious subjects in response to threatening but not positive stimuli. The present trial provides evidence that low dose frequency chronic oxytocin nasal spray has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels underscoring a treatment potential for anxiety disorders.

neuroscience↗

bioRxiv2021

Correlated Functional Connectivity and Glucose Metabolism in Brain White Matter Revealed by Simultaneous MRI/PET

Blood oxygenation level-dependent (BOLD) signals in white matter (WM) have usually been ignored or undetected, consistent with the lower vascular density and metabolic demands in WM than in gray matter (GM). Despite converging evidence demonstrating the reliable detection of BOLD signals in WM evoked by neural stimulation and in a resting state, few studies have examined the relationship between BOLD functional signals and tissue metabolism in WM. By analyzing simultaneous recordings of MRI and PET data, we found that the correlations between low frequency resting state BOLD signals in WM are spatially correlated with local glucose uptake, which also covaried with the amplitude of spontaneous low frequency fluctuations in BOLD signals. These results provide further evidence that BOLD signals in WM reflect variations in metabolic demand associated with neural activity, and suggest they should be incorporated into more complete models of brain function.

neuroscience↗

bioRxiv2021

Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein

The COVID-19 pandemic has demonstrated the need for exploring different diagnostic and therapeutic modalities to tackle future viral threats. In this vein, we propose the idea of sentinel cells, cellular biosensors capable of detecting viral antigens and responding to them with customizable responses. Using SARS-CoV-2 as a test case, we developed a live cell sensor (SARSNotch) using a de novo-designed protein binder against the SARS-CoV-2 Spike protein. SARSNotch is capable of driving custom genetically-encoded payloads in immortalized cell lines or in primary T lymphocytes in response to purified SARS-CoV-2 Spike or in the presence of Spike-expressing cells. Furthermore, SARSNotch is functional in a cellular system used in directed evolution platforms for development of better binders or therapeutics. In keeping with the rapid dissemination of scientific knowledge that has characterized the incredible scientific response to the ongoing pandemic, we extend an open invitation for others to make use of and improve SARSNotch sentinel cells in the hopes of unlocking the potential of the next generation of smart antiviral therapeutics.

synthetic biology↗

bioRxiv2021

Lag structure of BOLD signals within white matter in resting-state fMRI

PurposePrevious studies have demonstrated that BOLD signals in gray matter in resting-state functional MRI (RSfMRI) have variable time lags, representing apparent propagations of fMRI BOLD signals in gray matter. We complemented existing findings and explored the corresponding variations of signal latencies in white matter. MethodsWe used data from the Brain Genomics Superstruct Project, consisting of 1412 subjects (both sexes included) and divided the dataset into ten equal groups to study both the patterns and reproducibility of latency estimates within white matter. We constructed latency matrices by computing cross-correlations between voxel pairs. We also applied a clustering analysis to identify functional networks within white matter, based on which latency analysis was also performed to investigate lead/lag relationship at network level. A dataset consisting of various sensory states (eyes closed, eyes open and eyes open with fixation) was also included to examine the relationship between latency structure and different states. ResultsProjections of voxel latencies from the latency matrices were highly correlated (average Pearson correlation coefficient = 0.89) across the subgroups, confirming the reproducibility and structure of signal lags in white matter. Analysis of latencies within and between networks revealed a similar pattern of inter- and intra-network communication to that reported for gray matter. Moreover, a dominant direction, from inferior to superior regions, of BOLD signal propagation was revealed by higher resolution clustering. The variations of lag structure within white matter are associated with different sensory states. ConclusionsThese findings provide additional insight into the character and roles of white matter BOLD signals in brain functions.

neuroscience↗

bioRxiv2021

AIM-CICs: automatic identification method for Cell-in-cell structures based on convolutional neural network

Whereas biochemical markers are available for most types of cell death, current studies on non-autonomous cell death by entosis relays strictly on the identification of cell-in-cell structure (CICs), a unique morphological readout that can only be quantified manually at present. Moreover, the manual CICs quantification is generally over-simplified as CICs counts, which represents a major hurdle against profound mechanistic investigations. In this study, we take advantage of artificial intelligence (AI) technology to develop an automatic identification method for CICs (AIM-CICs), which performs comprehensive CICs analysis in an automated and efficient way. The AIM-CICs, developed on the algorithm of convolutional neural network (CNN), can not only differentiate between CICs and non-CICs (AUC > 0.99), but also accurately categorize CICs into five subclasses based on CICs stages and cell number involved (AUC > 0.97 for all subclasses). The application of AIM-CICs would systemically fuel researches on CICs-mediated cell death such as high-throughput screening.

cell biology↗

bioRxiv2021

Optogenetic silencing of neurotransmitter release with a naturally occurring invertebrate rhodopsin

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways in cognitive and behavioral processes requires temporally precise manipulation of their activity in vivo. However, existing optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro as well as in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents leads to an ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at synaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo.

neuroscience↗

bioRxiv2021

Pkd1 mutation has no apparent effects on peroxisome structure or lipid metabolism

BackgroundMultiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. MethodsUsing control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific {beta}-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies. ResultsPeroxisome abundance, morphology and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal {beta}-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers. ConclusionsOur studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisomedependent fatty acid metabolism. Key points- While mitochondrial abnormalities and fatty acid oxidation impairment have been reported in ADPKD, no studies have investigated if peroxisome dysfunction contributes to these defects. - We investigated peroxisome morphology, biogenesis and function in cell and animal models of ADPKD and investigated whether polycystin-1 co-localized with peroxisome proteins. - Our studies show that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.

genetics↗

bioRxiv2021

Archaeal extracellular vesicles are produced in an ESCRT-dependent manner and promote gene transfer and nutrient cycling in extreme environments

Membrane-bound extracellular vesicles (EVs), secreted by cells from all three domains of life, transport various molecules and act as agents of intercellular communication in diverse environments. Here we demonstrate that EVs produced by a hyperthermophilic and acidophilic archaeon Sulfolobus islandicus carry not only diverse proteins but also chromosomal and plasmid DNA, and can transfer this DNA to recipient cells. Furthermore, we show that EVs can support the heterotrophic growth of Sulfolobus in minimal medium, implicating EVs in carbon and nitrogen fluxes in extreme environments. Finally, our results suggest that, similar to eukaryotes, production of EVs in S. islandicus depends on the archaeal ESCRT machinery. Using synchronized S. islandicus cultures, we show that EV production is linked to cell division and appears to be triggered by increased expression of ESCRT proteins during this cell cycle phase. Using a CRISPR-based knockdown system, we show that archaeal ESCRT-III and AAA+ ATPase Vps4 are required for EV production, whereas archaea-specific component CdvA appears to be dispensable. Collectively, our results suggest that ESCRT-mediated EV biogenesis has deep evolutionary roots, likely predating the divergence of eukaryotes and archaea, and that EVs play an important role in horizontal gene transfer and nutrient cycling in extreme environments.

microbiology↗

bioRxiv2021

Molecular basis of ligand recognition and activation of human V2 vasopressin receptor

The V2 vasopressin receptor (V2R) is a class A G protein-coupled receptor (GPCR) and plays a vital role in controlling water homeostasis upon stimulation by the natural peptide arginine vasopressin (AVP). Thus, V2R has attracted intense interest as a drug target for diabetes insipidus, nocturia, and hyponatremia. However, how AVP recognizes and activates V2R remains elusive. Here, we report the 2.6 [A] resolution structure of V2R bound to AVP and the stimulatory G protein Gs, determined by cryo-electron microscopy (cryo-EM). In this complex, AVP presents a unique cyclic conformation formed by an intramolecular disulfide bond and engages the orthosteric binding pocket of V2R in a ligand-specific mode. Comparison of the AVP-V2R-Gs complex to previously reported Gs-coupled class A GPCRs reveals distinct structural features, including a smaller outward movement of TM5 and TM6 and the concomitant shift of Gs protein. Our detailed structural analysis provides a framework for understanding AVP recognition and V2R activation, thereby offering a structural template for drug design targeting V2R.

biophysics↗

bioRxiv2020

Segregating domain-general from emotional context-specific inhibitory control systems - ventral striatum and orbitofrontal cortex serve as emotion-cognition integration hubs

Inhibitory control hierarchically regulates cognitive and emotional systems in the service of adaptive goal-directed behavior across changing task demands and environments. While previous studies convergently determined the contribution of prefrontal-striatal systems to general inhibitory control, findings on the specific circuits that mediate the context-specific impact of inhibitory control remained inconclusive. Against this background we employed an evaluated emotional Go/No Go task with fMRI in a large cohort of subjects (N = 250) to segregate brain systems and circuits that mediate domain-general from emotion-specific inhibition control. Particularly during a positive emotional context, behavioral results showed a lower accuracy for No Go trials and a faster response time for Go trials. While the dorsal striatum and lateral frontal regions were involved in inhibitory control irrespective of emotional context, activity in the ventral striatum (VS) and medial orbitofrontal cortex (mOFC) varied as a function of emotional context. On the voxel-wise network level, limbic and striatal systems generally exhibited highest changes in global brain connectivity during inhibitory control, while global brain connectivity of the left mOFC was less suppressed during emotional contexts. Functional connectivity analyses moreover revealed that negative coupling between the VS with inferior frontal gyrus (IFG)/insula and mOFC varied as a function of emotional context. Together these findings indicated separable domain general systems as well emotional context-specific inhibitory brain systems which specifically encompass the VS and its connections with frontal regions.

neuroscience↗

bioRxiv2020

Spatial heterogeneity of glioblastoma cells reveals sensitivity to NAD+ depletion at tumor edge

Even after total resection of glioblastoma core lesions by surgery and aggressive post-surgical treatments, life-threatening tumors inevitably recur. A characteristic obstacle in effective treatment is high intratumoral heterogeneity, both longitudinally and spatially. Recurrence occurs predominantly at the brain parenchyma-tumor core interface, a region termed tumor edge. Given the difficulty of accessing it surgically, the composition of the tumor edge, harboring both cancerous and non-cancerous cells, remains largely unknown. Here, to identify phenotypic diversity among heterogeneous glioblastoma core and edge lesions, we uncovered the existence of three phenotypically-distinct clonal subpopulations within individual tumors from glioblastoma patients. Clones from the tumor core shared the same phenotype, exclusively generating tumor-core cells. In contrast, two distinct clonal subtypes were identified at the tumor edge: one generated only edge-lesion cells and the other expanded more broadly to establish both edge- and core-lesions. Using multiple xenograft experimental models in mouse brains, tumor edge development was found to require that both somatic and tumor cells express the NADase CD38, combinedly elevating glioblastoma malignancy. In vitro data suggested that intracellular NADase activity at the edge was provoked through intercellular communication between edge clones and normal astrocytes. Systemic treatment of tumor-bearing mice with 78c, a small-molecule CD38 inhibitor, attenuated the formation of glioblastoma edge lesions, suggesting its clinical potential to pharmacologically eliminate tumor-edge lesions. Collectively, these findings provide novel phenotypic and mechanistic insights into clonal heterogeneity within glioblastoma, particularly in the surgically unresectable, currently understudied tumor edge.

cancer biology↗

bioRxiv2020

Beyond fear centers: a distributed fMRI-based neuromarker for the subjective experience of fear

The specific neural systems underlying the subjective feeling of fear remain vigorously debated in affective neuroscience. Here, we combined functional MRI with machine learning to identify and evaluate a sensitive and generalizable neural signature predictive of the momentary self-reported subjective fear experience across discovery (n=67), validation (n=20) and generalization (n=31) cohorts. We systematically demonstrate that accurate fear prediction crucially requires distributed brain systems, with important contributions from cortical (e.g., prefrontal, midcingulate and insular cortices) and subcortical (e.g., thalamus, periaqueductal gray, basal forebrain and amygdala) regions. We further demonstrate that the neural representation of subjective fear is distinguishable from the representation of conditioned threat and general negative affect. Overall, our findings suggest that subjective fear, which exhibits distinct neural representation with some other aversive states, is encoded in distributed systems rather than isolated fear centers. This signature provides a neuromarker for monitoring fear-related neuropathology and evaluating novel treatments targeting pathological fear.

neuroscience↗

bioRxiv2020

ASPP2/PP1 complexes maintain the integrity of pseudostratified epithelia undergoing remodelling during morphogenesis

During development, pseudostratified epithelia undergo large scale morphogenetic events associated with increased mechanical stress. The molecular mechanisms that maintain tissue integrity in this context are poorly understood. Using a variety of genetic and imaging approaches, we uncover that the ASPP2/PP1 complex ensures proper epiblast and proamniotic cavity architecture via a mechanism that specifically prevents the most apical daughter cells from delaminating apically following cell division events. The ASPP2/PP1 complex achieves this by maintaining the integrity and organisation of the F-actin cytoskeleton at the apical surface of dividing cells. ASPP2/PP1 is also essential during gastrulation in the primitive streak, in somites and in the head fold region, suggesting that this complex is required across a wide range of pseudostratified epithelia during morphogenetic events that are accompanied by intense tissue remodelling and high cell proliferation. Finally, our study also suggests that the interaction between ASPP2 and PP1 is essential to the tumour suppressor function of ASPP2 which may be particularly relevant in the context of tissues that are subject to increased mechanical stress.

developmental biology↗

bioRxiv2020

Structural basis for repurpose and design of nucleoside drugs for treating COVID-19

SARS-CoV-2 has caused a global pandemic of COVID-19 that urgently needs an effective treatment. Nucleoside analog drugs including favipiravir have been repurposed for COVID-19 despite of unclear mechanism of their inhibition of the viral RNA polymerase (RdRp). Here we report the cryo-EM structures of the viral RdRp in complex with favipiravir and two other nucleoside inhibitor drugs ribavirin and penciclovir. Ribavirin and the ribosylated form of favipiravir share a similar ribose scaffold that is distinct from penciclovir. However, the structures reveal that all three inhibitors are covalently linked to the primer strand in a monophosphate form despite the different chemical scaffolds between favipiravir and penciclovir. Surprisingly, the base moieties of these inhibitors can form mismatched pairs with the template strand. Moreover, in view of the clinical disadvantages of remdesivir mainly associated with its prodrug form, we designed several orally-available remdesivir parent nucleoside derivatives, including VV16 that showed 5-fold more potent than remdesivir in inhibition of viral replication. Together, these results demonstrate an unexpected promiscuity of the viral RNA polymerase and provide a basis for repurpose and design of nucleotide analog drugs for COVID-19. One Sentence SummaryCryo-EM structures of the RNA polymerase of SARS-CoV-2 reveals the basis for repurposing of old nucleotide drugs to treat COVID-19.

biophysics↗

bioRxiv2020

Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 in mice

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective preventive vaccination to reduce burden and spread of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) in humans. Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry before viral spread to the lung. Although SARS-CoV-2 vaccine development is rapidly progressing, the current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. Here, we show that AdCOVID, an intranasal adenovirus type 5 (Ad5)-vectored vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, elicits a strong and focused immune response against RBD through the induction of mucosal IgA, serum neutralizing antibodies and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. Therefore, AdCOVID, which promotes concomitant systemic and local mucosal immunity, represents a promising COVID-19 vaccine candidate.

immunology↗

bioRxiv2020

Putamen volume predicts real-time fMRI neurofeedback learning success across paradigms and neurofeedback target regions

Real-time fMRI guided neurofeedback training has gained increasing interest as a non-invasive brain regulation technique with the potential to normalize functional brain alterations in therapeutic contexts. Individual variations in learning success and treatment response have been observed, yet the neural substrates underlying the learning of self-regulation remain unclear. Against this background, we explored potential brain structural predictors for learning success with pooled data from three real-time fMRI datasets. Our analysis revealed that gray matter volume of the right putamen could predict neurofeedback learning success across the three datasets (n = 66 in total). Importantly, the original studies employed different neurofeedback paradigms during which different brain regions were trained pointing to a general association with learning success independent of specific aspects of the experimental design. Given the role of the putamen in associative learning the finding may reflect an important role of instrumental learning processes and brain structural variations in associated brain regions for successful acquisition of fMRI neurofeedback-guided self-regulation.

neuroscience↗

bioRxiv2020

Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

The COVID-19 pandemic by non-stop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report the discovery of suramin, a 100-year-old drug, as a potent inhibitor of the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) through blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for COVID-19. The 2.6 [A] cryo-EM structure of the viral RdRp bound to suramin reveals two binding sites of suramin, with one site directly blocking the binding of the RNA template strand and the other site clash with the RNA primer strand near the RdRp catalytic active site, therefore inhibiting the viral RNA replication. Furthermore, suramin potently inhibits SARS-CoV-2 duplication in Vero E6 cells. These results provide a structural mechanism for the first non-nucleotide inhibitor of the SARS-CoV-2 RdRp and a rationale for repurposing suramin for treating COVID-19. One Sentence SummaryDiscovery and mechanism of suramin as potent SARS-CoV-2 RNA polymerase inhibitor and its repurposing for treating COVID-19.

molecular biology↗

bioRxiv2020

Discrete escape responses are generated by neuropeptide-mediated circuit logic

Animals display a plethora of escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximize chances of survival. We uncovered a somatosensory network in Drosophila larvae that encodes two escape behaviors through input-specific neuropeptide action. Sensory neurons required for avoidance of noxious light and escape in response to harsh touch, each converge on discrete domains of the same neuromodulatory hub neurons. These gate harsh touch responses via short Neuropeptide F, but noxious light avoidance via compartmentalized, acute Insulin-like peptide 7 action and cognate Relaxin-family receptor signaling in connected downstream neurons. Peptidergic hub neurons can thus act as central circuit elements for first order processing of converging sensory inputs to gate specific escape responses. One Sentence SummaryCompartment-specific neuropeptide action regulates sensory information processing to elicit discrete escape behavior in Drosophila larvae.

neuroscience↗