Biology subjects

Qi, Z.

Publications and source records attributed to Qi, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

Cerebral ischaemia-reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA-miRNA-mRNA ceRNA mechanism and that 3UTR methylation of mRNAs can hinder miRNA-mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

neuroscience↗

bioRxiv2022

Regulation of Nuclear Transcription by Mitochondrial RNA

Chromatin-associated RNAs (caRNAs) form a relatively poorly recognized layer of the epigenome. The caRNAs reported to date are transcribed from the nuclear genome. Here, leveraging a recently developed assay for detection of caRNAs and their genomic association, we report that mitochondrial RNAs (mtRNAs) are attached to the nuclear genome and constitute a subset of caRNA, which we termed mt-caRNA. In four human cell types analyzed, mt-caRNAs preferentially attach to promoter regions. In human endothelial cells (ECs), the level of mt-caRNA-promoter attachment changes in response to environmental stress that mimics diabetes. Suppression of a non-coding mt-caRNA in ECs attenuates stress-induced nascent RNA transcription from the nuclear genome, including that of critical genes regulating cell adhesion, and abolishes stress-induced monocyte adhesion, a hallmark of dysfunctional ECs. Finally, we report increased nuclear localization of multiple mtRNAs in the ECs of human diabetic donors, suggesting many mtRNA translocate to the nucleus in a cell stress and disease-dependent manner. These data nominate mt-caRNAs as messenger molecules responsible for mitochondrial-nuclear communication and connect the immediate product of mitochondrial transcription with the transcriptional regulation of the nuclear genome.

genomics↗

bioRxiv2022

A Novel Gene REPTOR2 Activates the Autophagic Degradation of Wing Disc in pea aphid

Wing dimorphism is an evolutionarily adaptive trait to maximize insect fitness under various environments, by which the population could be balanced between migration and reproduction. Most studies concern the regulatory mechanisms underlying the stimulation of wing morph in aphids, but relatively little research addresses the molecular basis of wing loss. Here, we found that the wing disc of wingless-destined pea aphids degenerated 30 h post birth by autophagic rather than apoptotic degeneration, whereas winged-destined aphids developed normally. Activation of autophagy in 1st instar nymphs reduced the proportion of winged aphids, and suppression of autophagy increased the proportion. The REPTOR2 gene associated with TOR signaling pathway was identified by RNA-seq as a differentially expressed gene between the two morphs, with higher expression in the thorax of wingless-destined aphids. Further genetic analysis indicated that REPTOR2 could be a novel gene derived from a gene duplication event exclusively in pea aphid on autosome A1 but translocated to the sex chromosome. Knockdown of REPTOR2 reduced autophagy in the wing disc and increased the proportion of winged aphids. In agreement with REPTORs canonical negative regulatory role of TOR on autophagy, winged-destined aphids had higher TOR expression in the wing disc. Suppression of TOR activated autophagy of the wing disc and decreased the proportion of winged aphids, and vice versa. These results revealed that the TOR signaling pathway controlled degradation of the wing disc in pea aphids, and that REPTOR2 could modulate this autophagic degradation.

developmental biology↗

bioRxiv2022

Angiotensin II regulates the neural expression of subjective fear in humans

BackgroundRodent models and pharmacological neuroimaging studies in humans have been employed to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear which represents the key symptom why patients seek treatment. We here employed a novel precision pharmacological fMRI approach that is based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (ATR1) antagonist losartan on the subjective experience of fear. MethodsIn a double-blind, placebo-controlled randomized pharmacological fMRI design n = 87 healthy participants were administered 50mg losartan or placebo before they underwent an oddball paradigm which included neutral, novel and fear oddballs. Losartan effects on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined. ResultsAT1R blockade selectively reduces the neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate (vACC) communication. Neurofunctional decoding further demonstrates fear-specific effects given that ATR1 blockade (1) reduces the neural expression of subjective fear, but not threat or non-specific negative expressions, and (2) does not affect reactivity to novel oddballs. ConclusionsThese results show a specific role of the AT1R in regulating subjective fear experience and demonstrate the feasibility of a precision pharmacological fMRI approach to the affective characterization of novel receptor targets for fear in humans.

neuroscience↗

bioRxiv2022

Human statistical learning dynamically shapes the hippocampal processing of temporal associations

We investigated the neural basis of chunking during statistical learning (SL). Behavioral evidence suggests that a common mechanism in learning and memory can serve to combine smaller units into larger ones to facilitate sensory and higher-level processing. And yet, the neural underpinnings of this mechanism remain unclear. Drawing insights from previous findings of neural codes in the hippocampus, we propose a computational model to account for the temporal chunking process in SL for sequential inputs. We operationalize chunking into a hidden Markov model (HMM) that incorporates two core principles: (1) the hidden states represent serial order rather than specific visual features, and (2) the formation of temporal chunks leads to autocorrelated brain activity. We show with numeric simulations that the HMM can decode embedded triplet representations when both assumptions hold. Applying the HMM to functional neuroimaging data from subjects performing a visual SL task, we show that decoding was successful (1) for triplet sequences but not random sequences, (2) at the later stage but not earlier stage of learning, and (3) in the hippocampus but not in the early visual cortex. These results provide evidence for a hippocampal representation of generalized temporal structure emerged from sequential visual input, shedding light on the chunking mechanism for SL. SignificanceIn statistical learning (SL), individuals develop internal representations of patterns after brief exposure to structured stimuli. People tend to recognize frequently co-occurring items as a single unit. This process, known as "chunking", is understood to play an important role in facilitating sensory processing for learning. However, its neural underpinnings remain unclear. In this study we draw insights from hippocampal coding theories and introduce a chunking model focusing on generalized presentations for SL. With functional neuroimaging data from human subjects performing a visual learning task, the chunking model successfully decoded the temporal regularities embedded in the sequential inputs. This model and related findings provide critical evidence for a chunking process underlying SL as well as its representation in the human hippocampus.

neuroscience↗

bioRxiv2022

A Neuropsin-based Optogenetic Tool for Precise Control of Gq signaling

Gq-coupled receptors regulate numerous physiological processes by activating enzymes and inducing intracellular Ca2+ signals. There is a strong need for an optogenetic tool that enables powerful experimental control over Gq signaling. Here, we present chicken opsin 5 (cOpn5) as the long sought-after, single-component optogenetic tool that mediates ultra-sensitive optical control of intracellular Gq signaling with high temporal and spatial resolution. Expressing cOpn5 in mammalian cells enables blue light-triggered, Gq-dependent Ca2+ release from intracellular stores and protein kinase C activation. Strong Ca2+ transients were evoked by brief light pulses of merely 10 ms duration and at 3 orders lower light intensity of that for common optogenetic tools. Photostimulation of cOpn5-expressing cells at the subcellular and single-cell levels generated intracellular and intercellular Ca2+ wave propagation, respectively, thus demonstrating the high spatial precision of cOpn5 optogenetics. The cOpn5-mediated optogenetics could also be applied to activate neurons and control animal behavior in a circuit-dependent manner. We further revealed that optogenetic activation of cOpn5-expressing astrocytes induced massive ATP release and modulation neuronal activation in the brain of awake, behaving mice. cOpn5 optogenetics may find broad applications in studying the mechanisms and functional relevance of Gq signaling in both non-excitable cells and excitable cells in all major organ systems.

neuroscience↗

bioRxiv2021

Landscape, complexity and regulation of a filamentous fungal transcriptome

Alternative splicing (AS) and alternative polyadenylation (APA) of pre-mRNAs contribute greatly to transcriptome complexity and gene expression regulation in higher eukaryotes. Their biological impact in filamentous fungi, however, has been poorly studied. Here we combine PacBio Isoform Sequencing and strand-specific RNA-Seq of multiple tissues together with mutant characterization to reveal the landscape, complexity and regulation of AS and APA in the filamentous plant pathogenic fungus Fusarium graminearum. We updated the reference genome and generated a comprehensive annotation comprising 51,617 transcript isoforms from 17,189 genes. Majority of the transcripts represent novel isoforms, including 2,998 undiscovered protein-coding genes. In total, 42.7% of multi-exonic genes and 64.8% of genes have AS and APA isoforms, respectively, suggesting AS and APA increase previously unrecognized transcriptome complexity in fungi. Nonsense-mediated mRNA decay factor FgUPF1 may not degrade AS transcripts with premature-stop codons but regulate ribosome biogenesis. Distal polyadenylation sites have a strong signal but proximal polyadenylation isoforms are high expressed. The core 3-end processing factors FgRNA15, FgHRP1, and FgFIP1 play important roles in promoting proximal polyadenylation site usage and also intron splicing. Genome-wide increase in the abundance of transcripts with retained introns and long 3-UTRs and downregulation of the spliceosomal and 3-end processing factors are found in older tissues and quiescent conidia, indicating that intron retention and 3-UTR lengthening may be a transcriptional signature of aging and dormancy in fungi. Overall, our study generates a comprehensive full-length transcript annotation for F. graminearum and provides new insights into the complexity and regulation of transcriptome in filamentous fungi.

genomics↗

bioRxiv2021

Losartan shifts social reward motivation and punishment feedback sensitivity via modulating midbrain-striato-frontal circuits

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that interactions between the dopamine and renin-angiotensin system may modulate learning and reward-related processes. The present study therefore examined the behavioral and neural effects of the angiotensin II type 1 receptor (AT1R) antagonist Losartan on social reward and punishment processing in humans. A pre-registered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay fMRI paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of Losartan (50mg, n=43) or placebo (n=44). Reaction times and emotional ratings served as behavioral outcomes, on the neural level activation and connectivity were modelled. Relative to placebo, Losartan modulated the reaction time and arousal differences between social punishment and social reward. On the neural level the Losartan-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation. Losartan increased the reward-neutral difference in the ventral tegmental area (VTA) and attenuated VTA associated connectivity with the bilateral insula in response to punishment during the outcome phase. Losartan modulated approach-avoidance motivation and emotional salience during social punishment versus social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations. Significance StatementSocial deficits and anhedonia characterize several mental disoders and have been linked to the midbrain-striato-frontal circuits of the brain. Based on initial findings from animal models we here combine the pharmacological blockade of the angiotensin II type 1 receptor (AT1R) via Losartan with functional MRI to demonstrate that AT1R blockade enhances the motivational salience of social rewards and attenuates the negative impact of social punishment via modulating the communication in the midbrain-striato-frontal circuits in humans. The findings demonstrate for the first time an important role of the AT1R in social reward processing in humans and render the AT1R as promising novel treatment target for social and motivational deficits in mental disoders.

neuroscience↗

bioRxiv2021

Three-dimensional organization of chromatin associated RNAs and their role in chromatin architecture in human cells

The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization.

genomics↗

bioRxiv2021

The cortical hubs related to recovery of consciousness

Background and ObjectivesThe neural mechanism that enables the recovery of consciousness in patients with unresponsive wakefulness syndrome (UWS) remains unclear. The aim of the current study is to characterize the cortical hub regions related to the recovery of consciousness in patients with UWS. MethodsVoxel-wise degree centrality analysis was adopted to identify the cortical hubs related to the recovery of consciousness, for which a total of 27 UWS patients were used, including 13 patients who emerged from UWS (UWS-E), and 14 patients who remained in UWS (UWS-R) at least three months after the experiment performance. Furthermore, other recoverable unconscious states including three independent deep sleep datasets (n = 12, 9, 9 respectively) and three independent anesthesia datasets (n = 27, 14, 6 respectively) were adopted as validation groups. Spatial similarity of the hub characteristic with the validation groups between the UWS-E and UWS-R was compared using the dice coefficient. Finally, with the cortical regions persistently shown as hubs across UWS-E and validation states, functional connectivity analysis was further performed to explore the connectivity patterns underlying the recovery of consciousness. ResultsFour cortical hubs were identified with significantly higher degree centrality for UWS-E than UWS-R, including the anterior precuneus, left inferior parietal lobule, left inferior frontal gyrus, and left middle frontal gyrus, of which the degree centrality value also positively correlated with the patients Glasgow Outcome Scale (GOS) score. Furthermore, the anterior precuneus was found to show significantly higher similarity of hub characteristics as well as functional connectivity pattern between UWS-E and validation groups, compared with UWS-R. DiscussionThe results suggest that the recovery of consciousness may be relevant to the integrity of cortical hubs, especially the anterior precuneus. The identified cortical hub regions could serve as potential targets for noninvasive stimulation aimed at promoting the patients consciousness recovery.

neuroscience↗

bioRxiv2021

Location, location, location- choice of Voxel-Based Morphometry processing pipeline drives variability in the location of neuroanatomical brain markers

Fundamental and clinical neuroscience has benefited from the development of automated computational analyses of Magnetic Resonance Imaging (MRI) data, such as Voxel-based Morphometry (VBM). VBM determines regional gray matter variations with high spatial resolution and results are commonly interpreted in a regional-specific manner, for instance with respect to which specific brain regions differ in volume between women and men. In excess of 600 papers using VBM are now published every year and a number of different automated VBM processing pipelines are frequently used in analyses although it remains to be fully and systematically assessed whether they come up with the same answers. Here we have therefore examined variability between four commonly used VBM pipelines in two large brain structural datasets. Spatial similarity, reproducibility and reliability of the processed gray matter brain maps was generally low between pipelines. Examination of sex-differences and age-related changes in gray matter volumes revealed considerable differences between the pipelines in terms of the specific regions identified as well as meta-analytic characterization of their function. In contrast, applying machine learning-based multivariate analyses allowed an accurate prediction of sex or age based on the gray matter maps across pipelines, although prediction accuracy differed strongly between them. Together the findings suggest that the choice of pipeline alone leads to considerable variability in brain structural analyses which poses a serious challenge for reproducibility as well as interpretation.

neuroscience↗

bioRxiv2021

Abnormal function in dentate nuclei precedes the onset of psychosis: a resting-state fMRI study in high-risk individuals

ObjectiveThe cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into three functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN precede the onset of psychosis in individuals at risk of developing schizophrenia. MethodsWe used the MRI dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N=144), with longitudinal follow-up to determine which subjects developed a psychotic episode within one year of their fMRI scan (converters N=23). Analysis used the three functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. ResultsRsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the three functional territories of the DN that were evaluated. ConclusionsWe show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

neuroscience↗

bioRxiv2020

SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators

The identity and functions of specialized cell types are dependent on the complex interplay between signaling and transcriptional networks. We present SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network), a computational method to link cell-surface receptors to transcription factors (TFs) by exploiting cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets with cis-regulatory information. SPaRTAN is applied to immune cell types in the blood to predict the coupling of signaling receptors with cell context-specific TFs. The predictions are validated by prior knowledge and flow cytometry analyses. SPaRTAN is then used to predict the signaling coupled TF states of tumor infiltrating CD8+ T cells in malignant peritoneal and pleural mesotheliomas. SPaRTAN greatly enhances the utility of CITE-seq datasets to uncover TF and cell-surface receptor relationships in diverse cellular states. SignificanceRecently single-cell technologies such as CITE-seq have been developed that enable simultaneous quantitative analysis of cell-surface receptor expression with transcriptional states. To date, these datasets have not been used to systematically develop cell-context-specific maps of the interface between signaling and transcriptional regulators orchestrating cellular identity and function. We developed a computational framework, SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network) that integrates single-cell proteomic and transcriptomic data based on CITE-seq with cis-regulatory information. We applied our method to publicly available (PBMCs) and new CITE-seq datasets (mesothelioma). Our predicted TF activity and cell-surface receptor relationships are validated by prior knowledge as well as experimental testing. SPaRTAN reveals many previously unidentified surface-receptor associated TFs.

bioinformatics↗

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

Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by sequential intermittent anti-PI3Ka/b/δ and anti-PD-1 treatment

Prostate cancers generally lack T cell infiltration and display resistance to immune checkpoint therapies (ICT). We found that intermittent but not daily dosing of PI3K/{beta}/{delta} inhibitor BAY1082439 on a Pten-null spontaneous prostate cancer model could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts Pten-null cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFN/{gamma} pathway activation, {beta}2-microglubin expression and CXCL10/CCL5 secretion. Together with its preferential Treg inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells. Once primed, tumors remain as T cell-inflamed and become responsive to anti-PD-1 therapy. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT. SignificanceThe combination of ICT and targeted therapies holds great promises for broad and long-lasting therapeutic effects for cancers. However, combining ICT with anti-PI3K inhibitors have been difficult because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we show a carefully designed anti-PI3K treatment, both in its specificity and dosing schedule, to inhibit cancer cell growth while promoting anti-tumor immunity, is critically important for successful ICT. Since the PI3K pathway is one of the most frequently altered signaling pathways in human cancers, our work may shed light on treating those cancers with PI3K activation and overcome resistance to ICT. HighlightsO_LIIntermittent PI3K/{beta}/{delta} inhibitor BAY1082439 treatment overcomes ICT resistance C_LIO_LIBAY1082439 turns Pten-null prostate cancer from "cold" to T cell-inflamed C_LIO_LIBAY1082439 inhibits cancer cell-intrinsic immunosuppressive activity and Treg C_LIO_LIBAY1082439 promotes clonal expansion and immunity of tumor-associated CD8+ T cells C_LI

cancer biology↗

bioRxiv2020

Higher-order sensorimotor circuit of the brain' global network supports human consciousness

The neural correlates of consciousness, defined as the minimum neuronal mechanisms sufficient for any conscious percept, are usually subject to different interpretations depending on whether one uses measures of local or global brain activities. We argue that the local regions may support consciousness by serving as hubs within the brains global network. We adopt a unique functional magnetic resonance imaging resting state dataset that encompasses various conscious states, including non-rapid eye movement (NREM)-sleep, rapid eye movement (REM)-sleep, anesthesia, and brain injury patients. Using a graph-theoretical measure for detecting local hubs within the brains global network, we identify various higher-order sensory and motor regions as hubs with significantly reduced degree centrality during unconsciousness. Additionally, these regions form a sensorimotor circuit which correlates with levels of consciousness. Our findings suggest that integration of higher-order sensorimotor function may be a key mechanism of consciousness. This opens novel perspectives for therapeutic modulation of unconsciousness.

neuroscience↗

bioRxiv2020

Codon-optimized FAM132b prevents diet-induced obesity by modulating adrenergic response and insulin action

FAM132b, also known as myonectin, has been identified as a myokine produced by exercise. It is a secreted protein precursor that belongs to the adipolin/erythroferrone family, and has hormone activity in circulation to regulate cellular iron homeostasis and lipid metabolism via unknown receptors. Here, adeno-associated viral vectors (AAV9) were engineered to induce overexpression of FAM132b with 2 codon mutations (A136T and P159A). Treatment of mice under high-fat diet feeding with FAM132b gene transfer resulted in marked reductions in body weight, fat depot, adipocytes size, glucose intolerance and insulin resistance. Moreover, FAM132b overproduction reduced glycemic response to epinephrine (EPI) in whole body and increased lipolytic response to EPI in adipose tissues. This adrenergic response of adipose tissue led to the result that gene transfer reduced glycogen utilization and increased fat consumption in skeletal muscle during exercise. FAM132b knockdown by shRNA significantly increased glycemic response to EPI in vivo and reduced adipocytes response to EPI and adipose tissue browning. Structural analysis suggested that FAM132b mutants delivered by AAV9 may form a weak bond with ADRB2, and potentially bind to insulin against insulin receptor by blocking the receptor binding sites on insulin B-chain. Our study underscores the potential of FAM132b gene therapy with codon optimization to treat obesity by modulating adrenergic response and interfering insulin action. SignificanceWe show here that AAV9-mediated expression of FAM132b with A136T and P159A is a safe and effective therapeutic strategy for improving glucose homeostasis. This is the first demonstration of a therapeutic effect on metabolic disorders in mice with FAM132b codon optimization. These therapeutic effects indicate that FAM132b gene transfer with selective codon mutants in vivo might be a valid therapy for diabetes that can be extended to other metabolic disorders.

molecular biology↗

bioRxiv2020

Intrinsic neural timescales related to sensory processing: Evidence from abnormal behavioural states

The brain exhibits a complex temporal structure which translates into a hierarchy of distinct neural timescales. An open question is how these intrinsic timescales are related to sensory or motor information processing and whether these dynamics have common patterns in different behavioural states. We address these questions by investigating the brains intrinsic timescales in healthy controls, motor (amyotrophic lateral sclerosis, locked-in syndrome), sensory (anaesthesia, unresponsive wakefulness syndrome), and progressive reduction of sensory processing (from awake states over N1, N2, N3). We employed a combination of measures from EEG resting-state data: auto-correlation window (ACW), power spectral density (PSD), and power-law exponent (PLE). Prolonged neural timescales accompanied by a shift towards slower frequencies were observed in the conditions with sensory deficits, but not in conditions with motor deficits. Our results establish that the spontaneous activitys intrinsic neural timescale is related to specifically sensory rather than motor information processing in the healthy brain. HighlightsO_LIEEG resting-state shows a hierarchy of intrinsic neural timescales. C_LIO_LISensory deficits as in disorders of consciousness lead to prolonged intrinsic neuraltimescales. C_LIO_LIClinical conditions with motor deficits do not show changes in intrinsic neural timescales.20 C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/229161v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1893c45org.highwire.dtl.DTLVardef@d4176dorg.highwire.dtl.DTLVardef@4dfaa8org.highwire.dtl.DTLVardef@183621e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗