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Abstract The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity. Specifically, FAM92A1 deficiency impairs diverse neuronal membrane morphology, including the mitochondrial inner membrane, myelin sheath, and synapses, indicating its roles in membrane remodeling and maintenance. By determining the crystal structure of the FAM92A1 BAR domain, combined with atomistic molecular dynamics simulations, we uncover that FAM92A1 interacts with phosphoinositide- and cardiolipin-containing membranes to induce lipid-clustering and membrane curvature. Altogether, these findings reveal the physiological role of FAM92A1 in the brain, highlighting its impact on synaptic plasticity and neural function through the regulation of membrane remodeling and endocytic processes.

The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.

Introduction: Methamphetamine (METH) abuse by pregnant drug addicts causes toxic effects on fetal neurodevelopment; however, the mechanism underlying such effect of METH is poorly understood.Methods: In the present study, we applied three-dimensional (3D) neurospheres derived from the embryonic rat hippocampal tissue to investigate the effect of METH on neurodevelopment. Through the combination of whole genome transcriptional analyses, the involved cell signalings were identified and investigated.Results: We found that METH treatment for 24 h significantly and concentration-dependently reduced the size of neurospheres. Analyses of genome-wide transcriptomic profiles found that those down-regulated differentially expressed genes (DEGs) upon METH exposure were remarkably enriched in the cell cycle progression. By measuring the cell cycle and the expression of cell cycle-related checkpoint proteins, we found that METH exposure significantly elevated the percentage of G0/G1 phase and decreased the levels of the proteins involved in the G1/S transition, indicating G0/G1 cell cycle arrest. Furthermore, during the early neurodevelopment stage of neurospheres, METH caused aberrant cell differentiation both in the neurons and astrocytes, and attenuated migration ability of neurospheres accompanied by increased oxidative stress and apoptosis.Conclusion: Our findings reveal that METH induces an aberrant cell cycle arrest and neuronal differentiation, impairing the coordination of migration and differentiation of neurospheres.

BackgroundHand-transmitted vibration is one of the most common occupational hazards and is closely related to symptoms of fingertip terminal nerve damage. ObjectiveTo analyze the effects of hand-transmitted vibration on the terminal nerve of fingertips. MethodsWe systematically searched literature about the effects of hand-transmitted vibration on fingertip terminal nerve at home and abroad. The outcome index was the number (rate) of fingertip terminal nerve symptoms reported by the vibration group and the control group, such as finger numbness and finger tingling, and the search period was from database inception to December 2021. The quality of cross-sectional studies was assessed using the criteria recommended by the Agency for Healthcare Research and Quality (AHRQ), and the quality of cohort studies was assessed by the Newcastle-Ottawa Scale (NOS). NoteExpress 3.2 was used for literature management, and Excel 2003 was used for data collection and extraction. RevMan 5.4.1 software was used for statistical analysis, and random effect model was used to calculate the OR value of pooled effects and to draw forest plots. Subgroup analysis was carried out according to the working years with vibration exposure. At the same time, sensitivity analysis was performed after excluding studies with the largest weight and funnel plots were generated to evaluate publication bias. ResultsA total of 3619 articles were retrieved, and 39 articles were finally included, including 29 Chinese articles and 10 English articles; 36 cross-sectional studies and 3 cohort studies. In total, 8399 subjects were studied, including 5673 cases in the vibration exposure group and 2726 cases in the control group. Random effect model was used to merge the included literature. The results of meta-analysis showed that compared with the control group, hand-transmitted vibration was significantly associated with the self-reported occurrence of finger numbness (OR=8.29, 95%CI: 5.43-12.66), finger tingling (OR=7.50, 95%CI: 4.78-11.77), finger swelling (OR=8.25, 95%CI: 4.06-16.76), finger stiffness (OR=10.71, 95%CI: 3.60-31.87), finger trembling (OR=5.11, 95%CI: 2.60-10.04), hand weakness (OR=11.05, 95%CI: 3.98-30.68), hand sweating (OR=2.70, 95%CI: 1.64-4.43), hand coldness (OR=3.54, 95%CI: 2.42-5.18) (P

The hand-arm vibration disease due to widespread hand-transmitted vibration operations is difficult to cure and seriously affects the health and quality of life of patients. Focusing on the prevention and control of hand-transmitted vibration and its occupational hazards, advances in occupational health relevant to hand-transmitted vibration were reviewed from the aspects of occupational hazard status, health impact, exposure monitoring, prevention and control of hand-transmitted vibration, as well as health surveillance, diagnosis, and treatment of hand-arm vibration disease. In addition, further suggestions on prevention and control of occupational hazards related with hand-transmitted vibration were prospected.

Hand-transmitted vibration is one of the most common physical harmful factors in the workplace，and the hand-arm vibration syndrome caused by it lacks effective treatment, and seriously affects the physical and mental health of the involved workers. As an important target for hand-transmitted vibration, the nervous system has attracted increasing attention from scholars, and much progress has been made in recent years in studying the effects of hand-transmitted vibration on nervous system function. Based on related literature at home and abroad, this paper introduced the hand-transmitted vibration-associated damage in peripheral, autonomic, and central nervous systems, and then explored the associated influence factors, like vibration frequency, environment temperature, and individual factors. The potential directions for further research were also proposed.

AIM: To investigate the effect of microRNA-373(miR-373)by targeting vascular endothelial growth factor A(VEGFA)on diabetic retinopathy(DR)rats.METHODS: Totally 40 rats were randomly divided into control group(n=10)and DR group(n=30). The rats after successful modeling in DR group were divided into model group(n=10), miR-373 agomir group(n=10), and agomir-NC group(n=10). The right eyes vitreous cavity separately were injected with 200μL normal saline, miR-373 agomir(200nmol)and agomir-NC(200nmol)were treated once a week for 12wk. The expression levels of miR-373 and VEGFA mRNA in each group were detected by RT-qPCR. Dual luciferase experiment was used to verify the targeting relationship between miR-373 and VEGFA. Western-blot was used to detect VEGFA, Bcl-2 related X protein(Bax), b-cell lymphoma-2(Bcl-2), phosphatidylinositol 3-kinase(PI3K)and phospho phosphatidylinositol 3-kinase(p-PI3K), serine threonine protein kinase(AKT), phospho serine protein kinase(p-AKT)protein expression levels.RESULTS: Compared with the control group, the expression levels of miR-373 and Bcl-2 protein in the retina tissue of model group and agomir-NC group were significantly decreased, and the expression levels of VEGFA mRNA, Bax, p-PI3K and p-AKT protein were significantly increased. Compared with the agomir-NC group, the expression levels of miR-373 and Bcl-2 protein in the retina tissue of miR-373 agomir group were significantly increased(all P

Abstract Peritumoral cysts are commonly detected in the central nervous system tumors, especially hemangioblastomas (HBs). However, the molecular mechanisms driving their formation and propagation are still unknown. We conducted an integrated lipidomics and transcriptomics analysis on solid and cystic HB samples in order to elucidate the changes in the lipid profile and expression of lipid metabolism-related genes during cyst formation. Transcriptomic analysis revealed differential expression of several genes between the solid and cystic HBs, and those associated with lipid metabolism, such as ADCY4, MGLL, ACOT2, DGKG, SHC1 and LPAR2, were markedly dysregulated in the cystic HBs. The lipidomic analysis further showed a significant reduction in the abundance of triacylglycerol, ceramide, lysophosphatidylcholine and lysophosphatidylethanolamine, and an increase in phosphatidylcholine and phosphatidylethanolamine levels in the cystic HBs. Furthermore, bioinformatics analysis revealed altered lipid biosynthesis, glycerophospholipid metabolism and phospholipase activity in the cystic HBs. Taken together, our findings indicate that cyst formation in HBs is related with aberrant lipid metabolism.

Ketamine is used for sedation and treatment of depression, but is also a drug of abuse. Here the authors show that ketamine modulates the endocannabinoid system in mice, and that this may contribute to its psychoactive effects.

AIM: To discuss the effect of conbercept in the treatment of polypoid chorioretinopathy(PCV)and its influence on hemorheology.METHODS: From January 2017 to April 2018, 62 patients with PCV were enrolled in our hospital. According to the difference of treatment, the patients were divided into two groups, 31 cases in each group. The control group was treated with rapunzumab and the observation group with conbercept. Intraocular pressure, BCVA, CMT, SFCT, hemorheology and complications were compared between the two groups. RESULTS: There was no difference in intraocular pressure, BCVA, CMT and SFCT between the two groups before treatment(P>0.05). With the increase of time, BCVA increased, CMT and SFCT decreased in both groups(PPP>0.05). The whole blood high shear viscosity, whole blood low shear viscosity, plasma viscosity and RBC aggregation index in the observation group were lower than those before treatment and lower than those in the control group(PPvs 6%, P>0.05).CONCLUSION: The application of conbercept in PCV can improve the visual acuity, and have a good impact in the hemorheology, reduce the macular edema and other clinical symptoms, and it has high safety and no effect on intraocular pressure.

AIM: To investigate the changes of serum cytokines in patients with polypoid chorioretinopathy and analyze its risk factors. METHODS: Select 50 cases of PCV patients in our hospital from December 2018 to May 2019 served as observation group, 50 cases of senile cataract patients who want to undergo cataract surgery served as control group. The levels of inflammatory factors and angiogenic factors were compared between the two groups, and the general clinical data were analyzed by single factor and logistic regression. RESULTS: The levels of IL-8, MCP-1, VEGF and PEDF in the observation group were significantly higher than those in the control group(PPCONCLUSION: The serum levels of IL-8, MCP-1, VEGF and PEDF in PCV patients were all increased abnormally, which was closely related to smoking history and hypertension.

AIM: To investigate the effect of calcium oxybenzenesulfonate dispersible tablets combined with Mingmu Dihuang pills on clinical evaluation indexes, retinal angiogenesis factors and blood lipid levels in patients with non-value-added diabetic retinopathy. METHODS: Totally 100 cases of non-proliferative diabetic retinopathy(NPDR)patients treated in our hospital from January 2017 to March 2018 were selected as the study subjects. They were randomly divided into observation group(n=50)and control group(n=50). The control group was treated with calcium oxybenzosulfonate dispersible tablets, the observation group was treated with Mingmu Dihuang pills on the basis of the control group. The clinical evaluation indexes, retinal angiogenic factors and blood lipid levels of the two groups before and after treatment were observed and compared. RESULTS: Before treatment, there were no significant differences in clinical evaluation indexes, retinal angiogenic factor and blood lipid levels between the two groups(P>0.05).After treatment, the visual field gray value, hemangioma volume, macular thickness, hemorrhage area, vascular endothelial growth factor(VEGF), insulin-like growth factor-1(IGF-1), tissue factor(TF), total cholesterol(TC), triglyceride(TG)and low-density lipoprotein cholesterol(LDL-C)levels in the two groups were significantly lower than before treatment(PPPPCONCLUSION: Calcium oxybenzosulfonate dispersible tablets combined with Mingmu Dihuang pills can significantly improve the clinical evaluation index, inhibit angiogenesis and improve the level of blood lipid.

N-acetylneuraminic acid synthase (NANS), the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), is closely associated with infantile-onset severe developmental delay and skeletal dysplasia. However, the role and the involved mechanisms of NANS functioning have not been fully understood to date. Here, we generated a homozygous NANS-knockout human induced pluripotent stem cell (iPSC) line, NCCSEDi001-A-1, via the CRISPR/Cas9-based gene editing method. The NCCSEDi001-A-1 cell line does not express NANS protein, but maintains a normal karyotype, pluripotency, and trilineage differentiation potential.

AIM:To explore the effects of Conbercept combined with laser on inflammatory factors, oxidative stress levels and retinal hemodynamics in diabetic retinopathy. METHODS: One hundred patients with diabetic retinopathy who were diagnosed and treated in our hospital from October 2015 to February 2017 were randomly divided into control group and observation group, 50 cases in each group. The control group was given laser treatment. The observation group was treated with conbercept on the basis of the control group. Afterwards, the clinical efficacy, inflammatory factors, oxidative stress and retinal hemodynamic level were tested before and after treatment of two groups of patients. RESULTS: There was no significant difference in LogMAR value and retinal thickness between the two groups before treatment(P>0.05). After treatment, both LogMAR values of visual acuity and retinal thickness decreased significantly in the two groups. After treatment, the LogMAR value of visual acuity of the observation group was 0.65±0.05, the thickness of retina was 157.97±15.51μm, which was significantly lower than that of the control group(PPPPCONCLUSION: Conbercept combined with laser can effectively improve the vision of patients with retinopathy, reduce retinal thickness, reduce the levels of inflammatory cytokines and oxidative stress, and improve retinal hemodynamics. The curative effect is reliable.

Abstract Background The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown. Methods The present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3−/− mice. The protein levels of phospho-NF-κB p65, IKKβ, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot. Results We showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3−/− mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKβ, and p-IκBα. Conclusions Taken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction.

Peanuts are a rich dietary source of lipids, which are essential for human health. In this study, the lipid contents of 13 peanut cultivars were analyzed using UPLC-Q-TOF-MS and GC–MS. The OXITEST reactor was used to test their lipid oxidation stabilities. A total of 27 subclasses, 229 individual lipids were detected. The combined analysis of lipid and oxidation stability showed that lipid unsaturation was inversely correlated with oxidation stability. Moreover, lipid profiles differed significantly among the different peanut cultivars. A total of 11 lipid molecules (TG 18:2/18:2/18:2, TG 24:0/18:2/18:3, TG 20:5/14:1/18:2, TG 18:2/14:1/18:2, PE 17:0/18:2, BisMePA 18:2/18:2, PG 38:5, PMe 18:1/18:1, PC 18:1/18:1, MGDG 18:1/18:1, TG 10:0/10:1/18:1) might be employed as possible indicators to identify high oleic acid (OA) and non-high OA peanut cultivars, based on the PLS-DA result of lipid molecules with a VIP value greater than 2. This comprehensive analysis will help in the rational selection and application of peanut cultivars.

Summary: Genome-edited human pluripotent stem cells (hPSCs) have broad applications in disease modeling, drug discovery, and regenerative medicine. We present and characterize a robust method for rapid, scarless introduction or correction of disease-associated variants in hPSCs using CRISPR/Cas9. Utilizing non-integrated plasmid vectors that express a puromycin N-acetyl-transferase (PAC) gene, whose expression and translation is linked to that of Cas9, we transiently select for cells based on their early levels of Cas9 protein. Under optimized conditions, co-delivery with single-stranded donor DNA enabled isolation of clonal cell populations containing both heterozygous and homozygous precise genome edits in as little as 2 weeks without requiring cell sorting or high-throughput sequencing. Edited cells isolated using this method did not contain any detectable off-target mutations and displayed expected functional phenotypes after directed differentiation. We apply the approach to a variety of genomic loci in five hPSC lines cultured using both feeder and feeder-free conditions. : In this article, Saha and colleagues describe a workflow for isolation of hPSC clones containing scarless, HDR-mediated, genome edits without the use of FACS or high-throughput sequencing technologies. They demonstrate that transient expression of a puromycin-resistance gene, from a non-integrated CRISPR/Cas9 plasmid, enables stringent selection for clones precisely edited with a single-stranded donor DNA template. Keywords: genome editing, human pluripotent stem cells, disease modeling, CRISPR/Cas9, scarless, transient selection, puromycin

Astrocytes play an important role in Rett syndrome (RTT) disease progression. Although the non-cell-autonomous effect of RTT astrocytes on neurons was documented, cell-autonomous phenotypes and mechanisms within RTT astrocytes are not well understood. We report that spontaneous calcium activity is abnormal in RTT astrocytes in vitro, in situ, and in vivo. Such abnormal calcium activity is mediated by calcium overload in the endoplasmic reticulum caused by abnormal store operated calcium entry, which is in part dependent on elevated expression of TRPC4. Furthermore, the abnormal calcium activity leads to excessive activation of extrasynaptic NMDA receptors (eNMDARs) on neighboring neurons and increased network excitability in Mecp2 knockout mice. Finally, both the abnormal astrocytic calcium activity and the excessive activation of eNMDARs are caused by Mecp2 deletion in astrocytes in vivo. Our findings provide evidence that abnormal calcium homeostasis is a key cell-autonomous phenotype in RTT astrocytes, and reveal its mechanism and consequence.

Studies have showed that prenatal cocaine exposure (PCOC) can impair cognitive function and social behavior of the offspring; however, the mechanism underlying such effect is poorly understood. Insulin-like growth factor II (Igf-II), an imprinted gene, has a critical role in memory consolidation and enhancement. We hypothesized that epigenetic regulation of hippocampal Igf-II may attribute to the cognitive deficits of PCOC offspring. We used Morris water maze and open-field task to test the cognitive function in PCOC offspring. The epigenetic alteration involved in hippocampal Igf-II expression deficit in PCOC offspring was studied by determining Igf-II methylation status, DNA methyltransferases (DNMT) expressions and l-methionine level. Moreover, IGF-II rescue experiments were performed and the downstream signalings were investigated in PCOC offspring. In behavioral tests, we observed impaired spatial learning and memory and increased anxiety in PCOC offspring; moreover, hippocampal IGF-II mRNA and protein expressions were significantly decreased. Hippocampal methylation of cytosine-phospho-guanine (CpG) dinucleotides in differentially methylated region (DMR) 2 of Igf-II was elevated in PCOC offspring, which may be driven by the upregulation of l-methionine and DNA methyltransferase (DNMT) 1. Importantly, intra-hippocampal injection of recombinant IGF-II reactivated the repressed calcium calmodulin kinase II α (CaMKIIα) and reversed cognitive deficits in PCOC offspring. Collectively, our findings suggest that cocaine exposure during pregnancy impairs cognitive function of offspring through epigenetic modification of Igf-II gene. Enhancing IGF-II signaling may represent a novel therapeutical strategy for cocaine-induced cognitive impairment.

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1)H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

Biallelic genetic variants in N-acetylneuraminic acid synthase (NANS), a critical enzyme in endogenous sialic acid biosynthesis, are clinically associated with neurodevelopmental disorders. However, the mechanism underlying the neuropathological consequences has remained elusive. Here, we found that NANS mutation resulted in the absence of both sialic acid and protein polysialylation in the cortical organoids and notably reduced the proliferation and expansion of neural progenitors. NANS mutation dysregulated neural migration and differentiation, disturbed synapse formation, and weakened neuronal activity. Single-cell RNA sequencing revealed that NANS loss of function markedly altered transcriptional programs involved in neuronal differentiation and ribosomal biogenesis in various neuronal cell types. Similarly, Nans heterozygous mice exhibited impaired cortical neurogenesis and neurobehavioral deficits. Collectively, our findings reveal a crucial role of NANS-mediated endogenous sialic acid biosynthesis in regulating multiple features of human cortical development, thus linking NANS mutation with its clinically relevant neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]