Abstract
Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory ...diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
Studies conducted in drug addiction suggest a transition in processing of drug‐related cues from the ventral to the dorsal component of the striatum. However, this process has not been studied in a ...behavioral addiction. Assessment of this process in a non‐drug addiction can provide insight into the pathophysiology of both substance and behavioral addictions. Thirty‐nine male Internet gaming disorder (IGD) subjects and 23 male matched healthy controls (HCs) participated in functional magnetic resonance imaging during performance of a cue‐reactivity task involving alternating presentation of Internet gaming‐related stimuli (game cues) and general Internet surfing‐related stimuli (control cues). Cue‐induced neural activations in the ventral and dorsal striatum (DS) were compared between IGD and HC participants. Associations between cue‐reactivity within these regions and cue‐induced craving and severity and duration of IGD were also explored. IGD participants exhibited higher cue‐induced activations within both the ventral and DS when compared with HCs. Within the IGD group, activity within the left ventral striatum (VS) was correlated negatively with cue‐induced craving; positive associations were found between activations within the DS (right putamen, pallidum and left caudate) and duration of IGD. Cue‐induced activity within the left putamen was negatively associated with right VS volumes among IGD participants. Consistent with studies in substance addictions, our results suggest that a transition from ventral to dorsal striatal processing may occur among individuals with IGD, a condition without the impact of substance intake.
For the individuals with Internet gaming disorder (IGD), cue‐induced activity within the left ventral striatum was correlated negatively with cue‐induced craving, whereas positive associations were found between activations within the dorsal striatum (right putamen, pallidum, and left caudate) and duration of IGD.
Internet gaming disorder (IGD) is characterized by cognitive and emotional deficits. Previous studies have reported the co-occurrence of IGD and depression. However, extant brain imaging research has ...largely focused on cognitive deficits in IGD. Few studies have addressed the comorbidity between IGD and depression symptoms and underlying neural mechanisms. Here, we systematically investigated this issue by combining a longitudinal survey study, a cross-sectional resting-state functional connectivity (rsFC) study and an intervention study. Autoregressive cross-lagged modeling on a longitudinal dataset of college students showed that IGD severity and depression are reciprocally predictive. At the neural level, individuals with IGD exhibited enhanced rsFC between the left amygdala and right dorsolateral prefrontal cortex (DLPFC), inferior frontal and precentral gyrus, compared with control participants, and the amygdala-frontoparietal connectivity at the baseline negatively predicted reduction in depression symptoms following a psychotherapy intervention. Further, following the intervention, individuals with IGD showed decreased connectivity between the left amygdala and left middle frontal and precentral gyrus, as compared with the non-intervention group. These findings together suggest that IGD may be closely associated with depression; aberrant rsFC between emotion and executive control networks may underlie depression and represent a therapeutic target in individuals with IGD. Registry name: The behavioral and brain mechanism of IGD; URL: https://www.clinicaltrials.gov/ct2/show/NCT02550405; Registration number: NCT02550405.
Psychobehavioral intervention is an effective treatment of Internet addiction, including Internet gaming disorder (IGD). However, the neural mechanisms underlying its efficacy remain unclear. ...Cortical‐ventral striatum (VS) circuitry is a common target of psychobehavioral interventions in drug addiction, and cortical‐VS dysfunction has been reported in IGD; hence, the primary aim of the study was to investigate how the VS circuitry responds to psychobehavioral interventions in IGD. In a cross‐sectional study, we examined resting‐state functional connectivity of the VS in 74 IGD subjects (IGDs) and 41 healthy controls (HCs). In a follow‐up craving behavioral intervention (CBI) study, of the 74 IGD subjects, 20 IGD subjects received CBI (CBI+) and 16 IGD subjects did not (CBI−). All participants were scanned twice with similar time interval to assess the effects of CBI. IGD subjects showed greater resting‐state functional connectivity of the VS to left inferior parietal lobule (lIPL), right inferior frontal gyrus and left middle frontal gyrus, in positive association with the severity of IGD. Moreover, compared with CBI−, CBI+ showed significantly greater decrease in VS‐lIPL connectivity, along with amelioration in addiction severity following the intervention. These findings demonstrated that functional connectivity between VS and lIPL, each presumably mediating gaming craving and attentional bias, may be a potential biomarker of the efficacy of psychobehavioral intervention. These results also suggested that non‐invasive techniques such as transcranial magnetic or direct current stimulation targeting the VS‐IPL circuitry may be used in the treatment of Internet gaming disorders.
Internet gaming disorder subjects showed greater resting‐state functional connectivity of ventral striatum to left inferior parietal lobule, right inferior frontal gyrus, and left middle frontal gyrus. The strength of ventral striatum‐left inferior parietal lobule connectivity was reduced, along with amelioration in addiction severity following the craving behavioral intervention.
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•Hierarchical CuCo2O4 nanowire arrays wrapped with metal oxides nanosheets have been successfully fabricated.•The CuCo2O4@NiO electrode exhibits high areal capacitance of 2.3 F/cm2 at ...2 mA/cm2 and excellent cycling stability.•The asymmetric supercapacitor shows a high energy density of 38.9 Wh/kg at 750 W/kg.
Herein, we report the rational design and fabrication of multicomponent, hierarchical CuCo2O4 nanowire arrays wrapped with metal oxides (NiO, Co3O4 and MnO2) nanosheets for use in high-performance supercapacitors. Among all the composite electrodes prepared, the CuCo2O4@NiO electrode exhibits the best electrochemical behavior with a high areal capacitance of 2.3 F/cm2 at 2 mA/cm2 and excellent cycling stability. The asymmetric supercapacitor with CuCo2O4@NiO as the positive electrode shows a superior specific capacitance of 124.6 F/g at 1 A/g, exceptional energy density of 38.9 Wh/kg at 750 W/kg, and long cycle life with ∼81.3% capacitance retention after 6000 cycles. The results indicate that the CuCo2O4@NiO electrode shows great potential for high-performance electrochemical energy storage.
•IGD is associated with alterations in fronto-striatal and fronto-cingulate regions.•IGD may share similar neural mechanisms with other addictive disorders.•Studies in different domains reveal ...different aspects of neural alterations in IGD.•Multi-domain assessment is encouraged for IGD to improve intervention efficacy.
This meta-analytic study aimed to identify the common and specific neural alterations in Internet gaming disorder (IGD) across different domains and modalities. Two separate meta-analyses for functional neural activation and gray-matter volume were conducted. Sub-meta-analyses for the domains of reward, cold-executive, and hot-executive functions were also performed, respectively. IGD subjects, compared with healthy controls, showed: (1) hyperactivation in the anterior and posterior cingulate cortices, caudate, posterior inferior frontal gyrus (IFG), which were mainly associated with studies measuring reward and cold-executive functions; and, (2) hypoactivation in the anterior IFG in relation to hot-executive function, the posterior insula, somatomotor and somatosensory cortices in relation to reward function. Furthermore, IGD subjects showed reduced gray-matter volume in the anterior cingulate, orbitofrontal, dorsolateral prefrontal, and premotor cortices. These findings suggest that IGD is associated with both functional and structural neural alterations in fronto-striatal and fronto-cingulate regions. Moreover, multi-domain assessments capture different aspects of neural alterations in IGD, which may be helpful for developing effective interventions targeting specific functions.
Hydrogen sulfide (H2S) has antifibrotic activity in the kidneys, heart, lungs, and other organs. The present study investigated the protective activity of exogenous H2S against myocardial fibrosis in ...a rat model of diabetes. Animals were assigned to normal control, diabetes mellitus (DM), DM + sodium hydrosulfide (NaHS; DM + NaHS) and NaHS groups. Fasting blood glucose (FBG), cardiac function and hydroxyproline were monitored. Heart histomorphology and ultrastructure were additionally evaluated. Wnt1‑inducible signaling pathway protein (WISP)‑1 protein expression in the myocardium was determined by immunohistochemical staining. Matrix metalloprotease (MMP)‑2, tissue inhibitor of metalloproteinase (TIMP)‑2, collagens, and canonical Wnt and transforming growth factor (TGF)‑β1/SMAD family member 3 (Smad3) pathway‑related proteins were assessed by western blotting. Cardiac function was decreased, and myocardial injury, hypertrophy and fibrosis were increased in the diabetes model rats. MMP‑2 expression was decreased, and the expressions of WISP‑1, TIMP‑2, collagens, and canonical Wnt and TGF‑β1/Smad3 pathway‑related proteins were increased in the myocardia of the diabetes model rats. The present results indicated that the canonical Wnt pathway promoted diabetic myocardial fibrosis by upregulating the TGF‑β1/Smad3 pathway. Except for FBG, exogenous H2S ameliorated the changes in diabetes‑associated indices in rats in the DM + NaHS group. The results are consistent with H2S protection of streptozotocin‑induced myocardial fibrosis in the diabetes model rats by downregulation of the canonical Wnt and TGF‑β1/Smad3 pathway and decreased myocardial collagen deposition.
Internet gaming disorder (IGD), a worldwide mental health issue, has been widely studied using neuroimaging techniques during the last decade. Although dysfunctions in resting‐state functional ...connectivity have been reported in IGD, mapping relationships from abnormal connectivity patterns to behavioral measures have not been fully investigated. Connectome‐based predictive modeling (CPM)—a recently developed machine‐learning approach—has been used to examine potential neural mechanisms in addictions and other psychiatric disorders. To identify the resting‐state connections associated with IGD, we modified the CPM approach by replacing its core learning algorithm with a support vector machine. Resting‐state functional magnetic resonance imaging (fMRI) data were acquired in 72 individuals with IGD and 41 healthy comparison participants. The modified CPM was conducted with respect to classification and regression. A comparison of whole‐brain and network‐based analyses showed that the default‐mode network (DMN) is the most informative network in predicting IGD both in classification (individual identification accuracy = 78.76%) and regression (correspondence between predicted and actual psychometric scale score: r = 0.44, P < 0.001). To facilitate the characterization of the aberrant resting‐state activity in the DMN, the identified networks have been mapped into a three‐subsystem division of the DMN. Results suggest that individual differences in DMN function at rest could advance our understanding of IGD and variability in disorder etiology and intervention outcomes.
We integrated the connectome‐based predictive modeling approach with the support vector machine to establish the link between brain connectivity profiles and behavior in internet gaming disorder. We found that the default‐mode network is the most informative network in predicting internet gaming disorder.
Difficulties in emotion regulation are commonly reported among individuals with alcohol and drug addictions and contribute to the acquisition and maintenance of addictive behaviors. Alterations in ...neural processing of negative affective stimuli have further been demonstrated among individuals with addictions. However, it is unclear whether these alterations are a general feature of addictions or are a result of prolonged exposure to drugs of abuse. To test the hypothesis of altered negative affect processing independent of drug effects, this study assessed neural function among drug-naïve youth with a behavioral addiction-Internet gaming disorder (IGD). Fifty-six young adults (28 with IGD, 28 matched controls) participated in fMRI scanning during performance of a well-validated emotion regulation task. Between-group differences in neural activity during task performance were assessed using a whole-brain, mixed-effects ANOVA with correction for multiple comparisons at currently recommended thresholds (voxel-level p<0.001, pFWE<0.05). Compared to controls, youth with IGD exhibited significantly blunted neural responses within distributed subcortical and cortical regions including the striatum, insula, lateral prefrontal cortex and anterior cingulate in response to negative affective cues, as well as during emotion regulation. Independent component analysis (ICA) further identified between-group differences in engagement of a fronto-cingulo-parietal network, involving decreased engagement in IGD youth relative to controls. Study findings are largely consistent with those from prior neuroimaging studies in substance-use disorders, thus raising the possibility that neural processing of negative affect may be blunted across drug and behavioral addictions independent of acute or chronic drug effects.
Summary
Tillering is a significant agronomic trait in wheat which shapes plant architecture and yield. Strigolactones (SLs) function in inhibiting axillary bud outgrowth. The roles of SLs in the ...regulation of bud outgrowth have been described in model plant species, including rice and Arabidopsis. However, the role of SLs genes in wheat remains elusive due to the size and complexity of the wheat genomes. In this study, TaD27 genes in wheat, orthologs of rice D27 encoding an enzyme involved in SLs biosynthesis, were identified. TaD27‐RNAi wheat plants had more tillers, and TaD27‐B‐OE wheat plants had fewer tillers. Germination bioassay of Orobanche confirmed the SLs was deficient in TaD27‐RNAi and excessive in TaD27‐B‐OE wheat plants. Moreover, application of exogenous GR24 or TIS108 could mediate the axillary bud outgrowth of TaD27‐RNAi and TaD27‐B‐OE in the hydroponic culture, suggesting that TaD27‐B plays critical roles in regulating wheat tiller number by participating in SLs biosynthesis. Unlike rice D27, plant height was not affected in the transgenic wheat plants. Transcription and gene coexpression network analysis showed that a number of genes are involved in the SLs signalling pathway and axillary bud development. Our results indicate that TaD27‐B is a key factor in the regulation of tiller number in wheat.
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