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OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024.
ABSTRACT
Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clockflox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clockflox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.
Subject(s)
Epilepsy , Animals , Mice , Anxiety , Disease Susceptibility/metabolism , Epilepsy/genetics , Epilepsy/metabolism , Mice, Knockout , Neurons/metabolism , Seizures/metabolismABSTRACT
Enhancing phosphoric acid (PA) doping in polybenzimidazole (PBI) membranes is crucial for improving the performance of high-temperature proton exchange membrane fuel cells (HT-PEMFCs). However, excessive PA uptake often leads to drawbacks such as PA loss and compromised mechanical properties when surpassing PA capacity of PBI basic functionality. Herein, a new strategy that integrates high PA uptake, mechanical strength, and acid retention is proposed by embedding linear PBI chains into a crosslinked poly(N-vinylimidazole) (PVIm) backbone via in-situ polymerization. The imidazole (Im)-riched semi-interpenetrating polymer network (sIPN) membrane with high-density nitrogen moieties, significantly enhancing the PA doping degree to 380% shows an excellent conductivity (0.108 S cm-1). Meanwhile, the crosslinking structure in the sIPN membrane ensures adequate mechanical properties, low hydrogen permeability, and a relatively low swelling ratio. As a result, the single cell based on the membrane achieves the highest power density of 1060 mW cm-2 with a low Pt loading (0.6 mg cm-2) up to now and exhibits excellent fuel cell stability.
ABSTRACT
Broadband amplified spontaneous emission (ASE) light sources are recognized for their cost-effective generation. However, their inherent high-intensity noise and the stringent requirement for time delay matching limits their widespread application in coherent optical telecommunication. Here we propose a broadband ASE source-enabled digital-analog radio-over-fiber (DA-RoF) mobile fronthaul architecture, leveraging semiconductor optical amplifiers (SOAs) and multicore fiber in tandem. Our proposed system uses SOAs to suppress the intensity noise of the ASE carrier and transmits the DA-RoF signal alongside an unmodulated carrier through distinct cores of an 8-core, 1-km fiber. This setup significantly enhances the signal-to-noise ratio (SNR) by 19.4 dB, boosts capacity, and enables self-homodyne detection at the receiver end. We achieve an aggregated bandwidth of 35 GHz (7 cores × 5 GHz), supporting a 2.05-Tb/s CPRI-equivalent data rate with 1024-ary quadrature-amplitude-modulated (1024-QAM) signals. Additionally, we analyze the impact of chromatic dispersion on signal-to-noise ratio for broadband source coherent detection systems. This innovative scheme offers a pragmatic solution for integrating low-cost broadband sources into cost-sensitive fronthaul systems, providing both high capacity and fidelity in massive deployment scenarios.
ABSTRACT
Microwave signals can be generated by photodetecting the repetition frequencies of the soliton microcombs. In comparison to other methods, the dual-pumped method allows for the stable generation of the soliton microcombs even with resonators having lower Q-factors. However, introducing an additional pump laser may affect the phase noise of the generated microwave signals when using these dual-pumped soliton microcombs. Here, we investigate the factors that could influence the phase noise of microwave signals generated with dual-pumped soliton microcombs, including the polarization, amplitude noise, and phase noise of the two pumps. We demonstrate a 25.25 (12.63) GHz microwave with phase noise reaching -112(-118) dBc/Hz at a 10 kHz offset frequency, surpassing the performance of previous reports on microwave generation using free-running Si3N4 soliton microcombs, even those generated with higher Q microresonators. We analyze the noise floor of the generated microwave signals and establish a phase noise simulation model to study the limiting factors in our system. Our work highlights the potential of generating low-phase-noise microwave signals using free-running dual-pumped soliton microcombs.
ABSTRACT
As the optical communication industry advances, metropolitan area networks (MANs) and radio access networks (RANs) are extensively deployed on a large scale, demanding energy-efficient integrated light sources and simplified digital signal processing (DSP) technologies. The emergence of thin-film lithium niobate (TFLN) has given rise to high-performance, energy-efficient on-chip modulators, making on-chip optical frequency comb (OFC) more appealing. Owing to the phase uniformity and stability of this chip-scale device, it has been possible to eliminate the carrier frequency phase estimation (CPE) in DSP stacks using comb-clone-enabled self-homodyne detection. Here we report the first use, to our knowledge, of a TFLN on-chip electro-optic (EO) frequency comb to realize comb cloning and self-homodyne coherent detection. We transmit three optical pilot tones and eight data channels encoded with 20 Gbaud polarization-multiplexed 16-ary quadrature amplitude modulation (PM-16-QAM) over 10 km and 80 km standard single-mode fibers. The bit error ratios (BERs) of the eight channels reach below 10-3, a result made possible by our on-chip comb. The scalability and mass producibility of on-chip EO combs, combined with the simplified DSP, show potential in our proposed fifth-generation (5G) RAN and MAN transmission scheme.
ABSTRACT
BACKGROUND: Cancer-related depression is a well-documented condition that significantly impacts long-term quality of life. Brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neurogenesis and neuronal plasticity, has been implicated in various neuropsychological disorders including depression associated with cancer. Cytokines, on the other hand, play a crucial role in regulating depression, potentially by influencing BDNF expression. Transforming growth factor-ß (TGF-ß), a key immune regulator within the tumor microenvironment, has been found to elevate BDNF levels, establishing a link between peripheral immune responses and depression. The study aims to investigate the correlation of TGF-ß and BDNF in cancer-related depression. METHODS: This study involved a cohort of 153 gynecological patients, including 61 patients with gynecological cancer and 92 patients without cancer. Depression levels were assessed using the subscale of Hospital Anxiety and Depression Scale (HADS-D), and TGF-ß and BDNF plasma levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The study revealed elevated plasma TGF-ß levels in patients with cancer (32.24 ± 22.93 ng/ml) compared to those without cancer (25.24 ± 19.72 ng/ml) (P = 0.046). Additionally, reduced levels of BDNF were observed in patients presenting depression symptoms (44.96 ± 41.06 pg/ml) compared to those without depression (133.5 ± 176.7 pg/ml) (P = 0.036). Importantly, a significant correlation between TGF-ß and BDNF was found in patients without cancer but with depression (correlation coefficient = 0.893, **P < 0.01). Interestingly, cancer appeared to influence the association between TGF-ß and BDNF in patients with depression, as evidenced by a significant difference in the correlation of TGF-ß and BDNF between cancer and non-cancer groups (P = 0.041). CONCLUSIONS: These findings underscore the active involvement of TGF-ß and BDNF crosstalk in the context of cancer-related depression.
Subject(s)
Brain-Derived Neurotrophic Factor , Depression , Transforming Growth Factor beta , Humans , Brain-Derived Neurotrophic Factor/blood , Female , Cross-Sectional Studies , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/metabolism , Depression/etiology , Middle Aged , Adult , Genital Neoplasms, Female/complications , Genital Neoplasms, Female/psychology , Quality of Life , Enzyme-Linked Immunosorbent Assay , Aged , Psychiatric Status Rating Scales , Case-Control StudiesABSTRACT
BACKGROUND: The body image during pregnancy potentially affects both short- and long-term maternal and child health outcomes, including pregnancy mood, postpartum weight recovery, and the quality of mother-child interactions. However, research on the impact of body changes during pregnancy in the Chinese population is scarce. A comprehensive, practical, and reliable tool for assessing pregnant women is needed to detect, intervene in, and implement the reduction of physical dissatisfaction risk. This study translated the Prenatal Body Image Questionnaire (PBIQ) into the Chinese version (PBIQ-C) to assess the body image of pregnant women and evaluated its reliability and validity. METHODS: An improved Brislin translation model was used for the translation. A panel of experts determined the content validity. A convenience sample of 429 pregnant women was chosen from three third-class hospitals in different regions of Fujian Province, China. Factor analysis, Pearson's correlation, retest reliability, and Cronbach's alpha were employed to evaluate structural validity and reliability. RESULTS: The final PBIQ-C had five dimensions with 21 items. Exploratory factor analysis obtained a five-factor solution, which accounted for a total of 60.34%. Confirmatory factor analysis showed that the model fit of the five-factor model also reached a satisfactory model fit after modifying: The Comparative Fit Index was 0.93, and the Tucker-Lewis Index was 0.92; the Root Mean Square Error of Approximation was 0.079. The content validity index of the scale ranged from 0.63 ~ 1.00. The Cronbach's alpha coefficient was 0.95 for the total scale, and the test-retest reliability was 0.80. CONCLUSIONS: The findings indicated that the PBIQ-C is a valid and reliable instrument for assessing women's body image during pregnancy, which helps in the early identification of body dissatisfaction during pregnancy and enables the early prevention of postpartum depression.
Subject(s)
Body Image , Pregnant Women , Humans , Female , Pregnancy , Psychometrics , Reproducibility of Results , Surveys and Questionnaires , China , Factor Analysis, StatisticalABSTRACT
BACKGROUND: To analyze the vessel density (VD) of the retina and choriocapillaris (CC) layer and the structure of the foveal avascular zone (FAZ) in the fellow eyes of central serous chorioretinopathy (CSC) patients by using optical coherence tomography angiography (OCTA). METHODS: This was a case-control study. Unilateral CSC patients and age-matched healthy subjects were recruited from the Affiliated Eye Hospital of Wenzhou Medical University between July 2016 and July 2021. All eyes were divided into three groups: acute CSC (aCSC), chronic CSC (cCSC), and healthy controls. Both aCSC and cCSC were again divided into two subgroups: the affected eyes and the fellow eyes. In this study, all parameters of VD and FAZ were measured by self-software of OCTA. RESULTS: A total of 231 eyes of 137 subjects were included, with 47 aCSC patients, 47 cCSC patients, and 43 healthy controls. In the fellow eyes of CSC, the retinal VD was significantly lower (all P < 0.05), and the FAZ was significantly larger (all P < 0.05) in the cCSC group than in healthy controls, while no difference was detected in the CC layer. There was no significant difference between the aCSC group and healthy controls in all OCTA parameters. In the affected eyes of CSC, the superficial retinal vessel density (SRVD) was significantly higher (all P < 0.05) in healthy controls than in the aCSC and cCSC groups, while the deep retinal vessel density (DRVD) was significantly lower (all P < 0.05) and the FAZ was larger (all P < 0.05) in the cCSC group than in the aCSC group and healthy controls. A liner regression equation was established: Y (BCVA, best corrected visual acuity) = 3.692-0.036â±X1 (DRVD-Fovea)-0.031â±X2 (FD-300, vessel density around the 300 µm width of the FAZ), R2 = 0.427. CONCLUSION: Based on OCTA measurements, this study revealed that the retinal microvascular network was impaired even in the fellow eyes of those with cCSC, which should arouse attention to the observation of unilateral CSC.
Subject(s)
Central Serous Chorioretinopathy , Fluorescein Angiography , Retinal Vessels , Tomography, Optical Coherence , Visual Acuity , Humans , Central Serous Chorioretinopathy/diagnosis , Central Serous Chorioretinopathy/physiopathology , Tomography, Optical Coherence/methods , Male , Female , Fluorescein Angiography/methods , Case-Control Studies , Retinal Vessels/diagnostic imaging , Retinal Vessels/pathology , Adult , Middle Aged , Visual Acuity/physiology , Choroid/blood supply , Choroid/diagnostic imaging , Fundus OculiABSTRACT
OBJECTIVE: This study aims to investigate the occurrence of postoperative kinesiophobia in patients with CSM and compare the postoperative recovery of patients with and without kinesiophobia to understand its influence on clinical outcomes in CSM. METHODS: Between November 2020 and November 2022, surgical treatment was performed in the neurosurgical wards of 2 Grade III Class A general public hospitals in the Fujian Province. The demographic and disease data of the patients were collected, and patients were divided into a kinesiophobia group and non-kinesiophobia group according to the Tampa kinesiophobia Scale (TSK). The cervical dysfunction index, cervical Japanese Orthopaedic Association (JOA) rating, self-anxiety rating, and activity of daily living rating scales were collected three months postoperatively. The influence of postoperative kinesiophobia on early rehabilitation was also analysed. RESULTS: A total of 122 patients were an average age of (55.2 ± 10.3) years included in this study. The average score of kinesophobia after surgery was 41.2 ± 4.5, with an incidence of 75.4%. Multivariate logistic regression analysis showed that age (OR = 1.105, 95% CI = 1.014-1.204), neck disability index (NDI) (OR = 1.268, 95% CI = 1.108-1.451), diabetes mellitus (OR = 0.026, 95% CI = 0.001-0.477), and Japanese Orthopaedic Association (JOA) score (OR = 0.698, 95% CI = 0.526-0.927) were associated with the occurren. CONCLUSION: Doctors should be aware of kinesiophobia in patients with CSM. Education regarding kinesiophobia, strategies to avoid it, and treatment strategies using a multidisciplinary approach can improve recovery outcomes.
Subject(s)
Cervical Vertebrae , Spondylosis , Humans , Middle Aged , Female , Male , Cross-Sectional Studies , Spondylosis/surgery , Spondylosis/psychology , Spondylosis/rehabilitation , Aged , Treatment Outcome , Cervical Vertebrae/surgery , Phobic Disorders/psychology , Phobic Disorders/etiology , Phobic Disorders/epidemiology , Adult , Spinal Cord Diseases/surgery , Spinal Cord Diseases/psychology , Spinal Cord Diseases/rehabilitation , Postoperative Period , Postoperative Complications/psychology , Postoperative Complications/etiology , Postoperative Complications/epidemiology , KinesiophobiaABSTRACT
The aim of this study was to investigate the potential drug-drug interactions (DDIs) between ticagrelor and other drugs as well as their underlying mechanisms. Rat liver microsome (RLM) reaction system was used to screen potential DDIs in vitro, and ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to detect the levels of ticagrelor and AR-C124910XX, the main metabolite of ticagrelor. A total of 68 drugs were screened, 11 of which inhibited the production of AR-C124910XX to 20% or less, especially two flavonoids (myricetin and quercetin). The half-maximal inhibitory concentration (IC50) of myricetin on ticagrelor was 11.51 ± 0.28 µM in RLM and 17.96 ± 0.54 µM in human liver microsome (HLM). The IC50 of quercetin in inhibiting ticagrelor in RLM and HLM was 16.92 ± 0.49 µM and 60.15 ± 0.43 µM, respectively. They all inhibited the metabolism of ticagrelor through a mixed mechanism. In addition, Sprague-Dawley (SD) rats were used to study the interactions of ticagrelor with selected drugs in vivo. We found that the main pharmacokinetic parameters including AUC (0-t), AUC (0-∞) and Cmax of ticagrelor were significantly increased when ticagrelor was combined with these two flavonoids. Our results suggested that myricetin and quercetin of flavonoids both had significant effects on the metabolism of ticagrelor, providing reference data for the clinical individualized medication of ticagrelor.
Subject(s)
Quercetin , Tandem Mass Spectrometry , Humans , Rats , Animals , Ticagrelor/pharmacology , Ticagrelor/metabolism , Quercetin/pharmacology , Chromatography, Liquid/methods , Rats, Sprague-Dawley , Tandem Mass Spectrometry/methods , Flavonoids/pharmacology , Flavonoids/metabolism , Microsomes, Liver/metabolismABSTRACT
BACKGROUND: Loneliness has a significant impact on the physical and psychological well-being of patients with cancer. However, the specific factors contributing to loneliness among patients with cancer within the context of Chinese culture remain poorly understood. OBJECTIVE: The objective of this study was to identify the factors associated with loneliness among patients with cancer in China. METHODS: A cross-sectional study was conducted using convenience sampling, involving a sample of 205 patients with cancer from a tertiary hospital in Guangzhou, China. Participants completed several validated questionnaires, including the Cancer Loneliness Scale (CLS), Hospital Anxiety and Depression Scale (HADS), Cancer-Related Negative Social Expectations Scale (C-rNSES), and Social Support Rating Scale (SSRS). Multiple linear stepwise regression analysis was employed to explore the relationships between loneliness and psychosocial factors. RESULTS: The median score for loneliness among patients with cancer was 13, with an interquartile range of 8. The multiple linear stepwise regression analysis revealed that negative social expectations, social support, and depression were significantly associated with loneliness in this population. Collectively, these factors accounted for 50.1% (R2 = .501) of the variance in loneliness. CONCLUSIONS: The findings of this study highlight the importance of addressing negative social expectations and depression and improving social support to prevent or reduce loneliness among patients with cancer. Health care providers should consider these factors when developing interventions aimed at preventing or alleviating loneliness in this population.
Subject(s)
Loneliness , Neoplasms , Humans , Cross-Sectional Studies , Depression/psychology , Loneliness/psychology , Neoplasms/complications , Neoplasms/psychology , Social Support , East Asian PeopleABSTRACT
BACKGROUND: The correlation between the endocrine system and bipolar disorder(BD) has been well recognized, yet the influence of neuroendocrine hormones on readmission risk post-hospitalization for BD remains largely unexplored. This retrospective cohort study was to scrutinize the impact of neuroendocrine functionality on the readmission of patients with BD post-hospitalization for mental disorders. METHODS: The dataset was derived from the electronic medical records of the First Affiliated Hospital of Jinan University in Guangzhou, China. Both univariate and multivariate logistic regression analysis were conducted on all patients hospitalized for BD, and from 1 January 2017 to October 2022. RESULTS: Of the 1110 eligible patients, 83 and 141 patients experienced psychiatric readmissions within 90 and 180 days post-discharge, respectively. Multivariate analysis revealed that high serum TSH levels (aOR = 1.079; 95%CI = 1.003-1.160) and thyroid disease comorbidities (aOR = 2.899; 95%CI = 1.303-6.452) were independently correlated with the risk of 90-day readmission; while increased serum TSH levels (aOR = 1.179; 95%CI = 1.081-1.287) represented a risk factor for 180-day readmission. These results indicate that high serum TSH levels and thyroid disease comorbidities may contribute to an elevated readmission risk in patients with BD following hospitalization. CONCLUSION: Routinely evaluating and intervening in thyroid function is crucial in the treatment of BD, as it may aid in preventing re-hospitalization.
Subject(s)
Bipolar Disorder , Thyroid Diseases , Humans , Retrospective Studies , Patient Readmission , Aftercare , Patient Discharge , Hospitalization , Neurosecretory Systems , Risk Factors , Thyrotropin , Thyroid Diseases/epidemiologyABSTRACT
INTRODUCTION: Obesity has been identified as a significant risk factor for several chronic conditions, including diabetes, tumours and cardiovascular disease, and has been associated with increased mortality rates. Despite the well-established clinical practice of electroacupuncture (EA) as a potential treatment option for obesity, its efficacy remains questionable, primarily due to the paucity of empirical evidence supporting its therapeutic benefits. METHODS AND ANALYSIS: The present study aims to investigate the efficacy and safety of EA for weight loss in obese individuals with pre-diabetes, using a randomised, placebo-controlled clinical trial design. A total of 256 eligible patients will be randomly assigned to one of two groups: EA (comprising EA treatment with health education) or superficial acupuncture (SA) (comprising SA treatment with health education). The intervention will be administered three times per week for the initial 12 weeks, two times per week for the subsequent 8 weeks and one time per week for the final 4 weeks, with a 24-week follow-up period. The primary outcome measure will be the percentage of patients who achieve a reduction of 10% or more in their body weight at week 24. Secondary outcome measures will include changes in body weight and body mass index, blood test results, data collected by the body composition analyser, size of adipose tissue scanned by MRI of the abdomen and the Impact of Weight on Quality of Life, the 21-item Three-Factor Eating Questionnaire-Revised and the Food Craving Questionnaire-Trait. The Treatment Emergent Symptom Scale will be employed to monitor every adverse reaction from baseline to follow-up. ETHICS AND DISSEMINATION: This trial has received ethical clearance from the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine under the registration number 2021SHL-KY-74. All participants will provide their written informed consent prior to their enrolment. The findings of this investigation will be disseminated through peer-reviewed publications and scholarly conferences. TRIAL REGISTRATION NUMBER: NCT05237089.
Subject(s)
Electroacupuncture , Prediabetic State , Humans , Electroacupuncture/methods , Prediabetic State/complications , Prediabetic State/therapy , Quality of Life , Treatment Outcome , China , Obesity/complications , Obesity/therapy , Weight Loss , Randomized Controlled Trials as TopicABSTRACT
Background: Alcoholic liver disease (ALD) is exacerbated by disruptions in intestinal microecology and immune imbalances within the gut-liver axis. The present study assesses the therapeutic potential of combining Akkermansia muciniphila (A. muciniphila) with inosine in alleviating alcohol-induced liver injury. Methods: Male C57BL/6 mice, subjected to a Lieber-DeCarli diet with 5% alcohol for 4 weeks, served as the alcoholic liver injury model. Various analyzes, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), ELISA, immunochemistry, 16S rRNA gene sequencing, and flow cytometry, were employed to evaluate liver injury parameters, intestinal barrier function, microbiota composition, and immune responses. Results: Compared to the model group, the A. muciniphila and inosine groups exhibited significantly decreased alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide (LPS) levels, reduced hepatic fat deposition and neutrophil infiltration, alleviated oxidative stress and inflammation, and increased expression of intestinal tight junction proteins (Claudin-1, Occludin, and ZO-1). These effects were further pronounced in the A. muciniphila and inosine combination group compared to individual treatments. While alcohol feeding induced intestinal dysbiosis and gut barrier disruption, the combined treatment reduced the abundance of harmful bacteria (Oscillibacter, Escherichia/Shigella, and Alistipes) induced by alcohol consumption, promoting the growth of butyrate-producing bacteria (Akkermansia, Lactobacillus, and Clostridium IV). Flow cytometry revealed that alcohol consumption reduced T regulatory (Treg) populations while increasing those of T-helper (Th) 1 and Th17, which were restored by A. muciniphila combined with inosine treatment. Moreover, A. muciniphila and inosine combination increased the expression levels of intestinal CD39, CD73, and adenosine A2A receptor (A2AR) along with enhanced proportions of CD4+CD39+Treg and CD4+CD73+Treg cells in the liver and spleen. The A2AR antagonist KW6002, blocked the beneficial effects of the A. muciniphila and inosine combination on liver injury in ALD mice. Conclusion: This study reveals that the combination of A. muciniphila and inosine holds promise for ameliorating ALD by enhancing the gut ecosystem, improving intestinal barrier function, upregulating A2AR, CD73, and CD39 expression, modulating Treg cells functionality, and regulating the imbalance of Treg/Th17/Th1 cells, and these beneficial effects are partly A2AR-dependent.
ABSTRACT
Hypoxic-ischemic encephalopathy (HIE) is a brain damage caused by perinatal hypoxia and blood flow reduction. Severe HIE leads to death. Available treatments remain limited. Oxidative stress and nerve damage are major factors in brain injury caused by HIE. Catalpol, an iridoid glucoside found in the root of Rehmannia glutinosa, has antioxidant and neuroprotective effects. This study examined the neuroprotective effects of catalpol using a neonatal rat HIE model and found that catalpol might protect the brain through inhibiting neuronal ferroptosis and ameliorating oxidative stress. Behavior tests suggested that catalpol treatment improved functions of motor, learning, and memory abilities after hypoxic-ischemic injury. Catalpol treatment inhibited changes to several ferroptosis-related proteins, including p-PI3K, p-AKT, NRF2, GPX4, SLC7A11, SLC3A2, GCLC, and GSS in HIE neonatal rats. Catalpol also prevented changes to several ferroptosis-related proteins in PC12 cells after oxygen-glucose deprivation. The ferroptosis inducer erastin reversed the protective effects of catalpol both in vitro and in vivo. We concluded that catalpol protects against hypoxic-ischemic brain damage (HIBD) by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis.
Subject(s)
Ferroptosis , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Rats , Animals , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/metabolism , Iridoid Glucosides/pharmacology , Iridoid Glucosides/therapeutic use , Animals, Newborn , NF-E2-Related Factor 2/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Hypoxia , Ischemia , Brain/metabolismABSTRACT
Intra- and inter-organismal interactions play a crucial role in the maintenance and function of individuals, as well as communities. Extracellular vesicles (EVs) have been identified as effective mediators for the communication both within and between species. They can carry and transport molecular cargoes to transmit biological messages. Several databases (ExoBCD, ExoCarta, EVpedia, EV-TRACK, Vesiclepedia) complied the cargoes information including DNA, RNA, protein, lipid and metabolite associated with EVs. Databases that refer to the complete records on both donor and recipient information are warranted to facilitate the understanding of the interaction across cells and species. In this study, we developed a database that compiled the records equipped with a structured process of EV-mediated interaction. The sources of donor and recipient were classified by cell type, tissues/organs and species, thus providing an extended knowledge of cell-cell, species-species interaction. The isolation and identification methods were presented for assessing the quality of EVs. Information on functional cargoes was included, where microRNA was linked to a prediction server to broaden its potential effects. Physiological and pathological context was marked to show the environment where EVs functioned. At present, a total of 1481 data records in our database, including 971 cell-cell interactions belonging to more than 40 different tissues/organs, and 510 cross-species records. The database provides a web interface to browse, search, visualize and download the interaction records. Users can search for interactions by selecting the context of interest or specific cells/species types, as well as functional cargoes. To the best of our knowledge, the database is the first comprehensive database focusing on interactions between donor and recipient cells or species mediated by EVs, serving as a convenient tool to explore and validate interactions. The Database, shorten as EV-COMM (EV mediated communication) is freely available at http://sdc.iue.ac.cn/evs/list/ and will be continuously updated.
Subject(s)
Cell Communication , Extracellular Vesicles , Animals , Humans , Databases, Factual , Extracellular Vesicles/metabolism , MicroRNAs/metabolism , MicroRNAs/geneticsABSTRACT
The basic mechanism of heterosis has not been systematically and completely characterized. In previous studies, we obtained three economically important fishes that exhibit rapid growth, WR (WCC â × RCC â), WR-II (WR â × WCC â), and WR-III (WR-II â × 4nAU â), through distant hybridization. However, the mechanism underlying this rapid growth remains unclear. In this study, we found that WR, WR-II, and WR-III showed muscle hypertrophy and higher muscle protein and fat contents compared with their parent species (RCC and WCC). Candidate genes responsible for this rapid growth were then obtained through an analysis of 12 muscle transcriptomes. Notably, the mRNA level of mstnb (myostatin b), which is a negative regulator of myogenesis, was significantly reduced in WR, WR-II, and WR-III compared with the parent species. To verify the function of mstnb, a mstnb-deficient mutant RCC line was generated using the CRISPR-Cas9 technique. The average body weight of mstnb-deficient RCC at 12 months of age was significantly increased by 29.57% compared with that in wild-type siblings. Moreover, the area and number of muscle fibers were significantly increased in mstnb-deficient RCC, indicating hypertrophy and hyperplasia. Furthermore, the muscle protein and fat contents were significantly increased in mstnb-deficient RCC. The molecular regulatory mechanism of mstnb was then revealed by transcription profiling, which showed that genes related to myogenesis (myod, myog, and myf5), protein synthesis (PI3K-AKT-mTOR), and lipogenesis (pparγ and fabp3) were highly activated in hybrid fishes and mstnb-deficient RCC. This study revealed that low expression or deficiency of mstnb regulates somatic growth by promoting myogenesis, protein synthesis, and lipogenesis in hybrid fishes and mstnb-deficient RCC, which provides evidence for the molecular mechanism of heterosis via distant hybridization.
Subject(s)
Hybridization, Genetic , Muscle Development , Myostatin , Animals , Myostatin/genetics , Myostatin/metabolism , Muscle Development/genetics , Hybrid Vigor/genetics , Male , Fishes/genetics , Fishes/growth & development , Fishes/metabolism , Female , Transcriptome , Muscle Proteins/genetics , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/growth & development , Fish Proteins/genetics , Fish Proteins/metabolismABSTRACT
[This corrects the article DOI: 10.3389/fphar.2021.680351.].
ABSTRACT
Intricate cerebral cortex formation is orchestrated by the precise behavior and division dynamics of radial glial cells (RGCs). Endocytosis functions in the recycling and remodeling of adherens junctions (AJs) in response to changes in RGC activity and function. Here, we show that conditional disruption of ubiquitin-associated protein 1 (UBAP1), a component of endosomal sorting complex required for transport (ESCRT), causes severe brain dysplasia and prenatal ventriculomegaly. UBAP1 depletion disrupts the AJs and polarity of RGCs, leading to failure of apically directed interkinetic nuclear migration. Accordingly, UBAP1 knockout or knockdown results in reduced proliferation and precocious differentiation of neural progenitor cells. Mechanistically, UBAP1 regulates the expression and surface localization of cell adhesion molecules, and ß-catenin over-expression significantly rescues the phenotypes of Ubap1 knockdown in vivo. Our study reveals a critical physiological role of the ESCRT machinery in cortical neurogenesis by regulating AJs of RGCs.