Genetic causality between modifiable risk factors and the risk of rheumatoid arthritis: Evidence from Mendelian randomization.

OBJECTIVES: Emerging research has investigated the potential impact of several modifiable risk factors on the risks of rheumatoid arthritis (RA), but the findings did not yield consistent results. This study aimed to comprehensively explore the genetic causality between modifiable risk factors and the susceptibility of RA risk using the Mendelian randomization (MR) approach. METHODS: Genetic instruments for modifiable risk factors were selected from several genome-wide association studies at the genome-wide significance level (p < 5 × 10-8), respectively. Summary-level data for RA were sourced from a comprehensive meta-analysis. The causal estimates linking modifiable risk factors to RA risk were assessed using MR analysis with inverse variance weighting (IVW), MR-Egger, weighted, and weighted median methods. RESULTS: After Bonferroni correction for multiple tests, we found the presence of causality between educational attainment and RA, where there were protective effects of educational attainment (college completion) (odds ratio [OR] = 0.50, 95% CI = 0.36, 0.69, p = 2.87E-05) and educational attainment (years of education) (OR = 0.93, 95% CI = 0.90, 0.96, p = 4.18E-06) on the lower RA risks. Nevertheless, smoking initiation was observed to be associated with increased RA risks (OR = 1.27, 95% CI = 1.09, 1.47, p = .002). Moreover, there was no indication of horizontal pleiotropy of genetic variants during causal inference between modifiable risk factors and RA. CONCLUSIONS: Our study reveals the genetic causal impacts of educational attainment and smoking on RA risks, suggesting that the early monitoring and recognition of modifiable risk factors would be beneficial for the preventive counseling/treatment strategies for RA.

Global burden of osteoarthritis: Prevalence and temporal trends from 1990 to 2019.

OBJECTIVE: To investigate the age-standardized prevalence rate (ASPR) and temporal trends for hip, knee, hand, and other osteoarthritis (OA) at a global, continental, and national level. DESIGN: The estimates and 95% uncertainty intervals (UIs) for case number and ASPR of OA were derived from the Global Burden of Diseases Study (GBD) 2019. The joinpoint regression analysis was utilized to examine the temporal trends from 1990 to 2019. RESULTS: In 2019, the global ASPR of hip, knee, hand, and other OA was 400.95 (95% UI: 312.77-499.41), 4375.95 (95% UI: 3793.04-5004.9), 1726.38 (95% UI: 1319.91-2254.85), and 745.62 (95% UI: 570.16-939.8). As for the ASPR of hip OA, hand OA, and other OA, Europe and America had higher rates than Asia and Africa, and Asia was second only to America in knee OA ASPRs. The period 1990-2019, the ASPR at global level dropped significantly for hand OA (AAPC = -0.4%, 95% CI: -0.47 to -0.34) and increased significantly for hip OA (AAPC = 0.43%, 95% CI: 0.39-0.46), knee OA (AAPC = 0.17%, 95% CI: 0.09-0.24) and other OA (AAPC = 0.16%, 95% CI: 0.15-0.17). Different continents, countries, and periods demonstrated significant changes. CONCLUSIONS: Globally, America has the highest OA burden and Asia has a higher knee OA burden. Appropriate prevention and control measures to reduce modifiable risk factors are needed to reduce the burden of OA.

Global burden of musculoskeletal disorders in children and adolescents from 1990 to 2021: a joint point regression and decomposition analysis.

The study aimed to investigate the pattern and trend of Musculoskeletal (MSK) disorders in people aged 5-19 years from 1990 to 2021. The data was sourced from the Global Burden of Disease study 2021. The Age-standardized DALYs rates (ASDR), age-standardized mortality rate (ASMR), age-standardized prevalence rate (ASPR), and age-standardized incidence rate (ASIR) and their corresponding average annual percent change (AAPC) for MSK disorders were evaluated by sex, region, and sociodemographic index (SDI) quintiles. Globally, the ASPR of MSK disorders among children and adolescents increased per 100,000 population from 3048.66 (95% confidence interval [CI]: 2336.68-3887.02) in 1990 to 3105.46 (95% CI: 2421.09-3904.95) in 2021 (AAPC 0.06 [95% CI: 0.05-0.07]). In 2021, individuals aged 15-19 experienced the highest burden compared to those aged 5-9 and 10-14. In 2021, high SDI countries had the highest ASIR, ASPR, ASDR of MSK disorders. The AAPC of ASPR in high SDI countries showed a stark contrast to that in low SDI countries for the same period (AAPC 0.48 vs. AAPC -0.03). From 1990 to 2021, in low SDI and low-middle SDI countries, the increase in DALYs was primarily due to population growth. However, in middle SDI, high-middle, and high SDI countries, the increases were mainly due to epidemiological changes. Globally, patients aged 10-14 experienced better care compared to those in the 5-9 and 15-19 age groups. Specific preventive health measures are needed for females and adolescents aged 15-19 in high SDI countries.

Exploring the association between ambient air pollution and COVID-19 risk: A comprehensive meta-analysis with meta-regression modelling.

Introduction: Air pollution is speculated to increase the risk of Coronavirus disease-2019 (COVID-19). Nevertheless, the results remain inconsistent and inconclusive. This study aimed to explore the association between ambient air pollution (AAP) and COVID-19 risks using a meta-analysis with meta-regression modelling. Methods: The inclusion criteria were: original studies quantifying the association using effect sizes and 95 % confidence intervals (CIs); time-series, cohort, ecological or case-crossover peer-reviewed studies in English. Exclusion criteria encompassed non-original studies, animal studies, and data with common errors. PubMed, Web of Science, Embase and Google Scholar electronic databases were systemically searched for eligible literature, up to 31, March 2023. The risk of bias (ROB) was assessed following the Agency for Healthcare Research and Quality parameters. A random-effects model was used to calculate pooled risk ratios (RRs) and their 95 % CIs. Results: A total of 58 studies, between 2020 and 2023, met the inclusion criteria. The global representation was skewed, with major contributions from the USA (24.1 %) and China (22.4 %). The distribution included studies on short-term (43.1 %) and long-term (56.9 %) air pollution exposure. Ecological studies constituted 51.7 %, time-series-27.6 %, cohorts-17.2 %, and case crossover-3.4 %. ROB assessment showed low (86.2 %) and moderate (13.8 %) risk. The COVID-19 incidences increased with a 10 µg/m3 increase in PM2.5 [RR = 4.9045; 95 % CI (4.1548-5.7895)], PM10 [RR = 2.9427: (2.2290-3.8850)], NO2 [RR = 3.2750: (3.1420-3.4136)], SO2 [RR = 3.3400: (2.7931-3.9940)], CO [RR = 2.6244: (2.5208-2.7322)] and O3 [RR = 2.4008: (2.1859-2.6368)] concentrations. A 10 µg/m3 increase in concentrations of PM2.5 [RR = 3.0418: (2.7344-3.3838)], PM10 [RR = 2.6202: (2.1602-3.1781)], NO2 [RR = 3.2226: (2.1411-4.8504)], CO [RR = 1.8021 (0.8045-4.0370)] and O3 [RR = 2.3270 (1.5906-3.4045)] was significantly associated with COVID-19 mortality. Stratified analysis showed that study design, exposure period, and country influenced exposure-response associations. Meta-regression model indicated significant predictors for air pollution-COVID-19 incidence associations. Conclusion: The study, while robust, lacks causality demonstration and focuses only on the USA and China, limiting its generalizability. Regardless, the study provides a strong evidence base for air pollution-COVID-19-risks associations, offering valuable insights for intervention measures for COVID-19.

Epigenetic regulation of immune cells in systemic lupus erythematosus: insight from chromatin accessibility.

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is a multi-dimensional autoimmune disease involving numerous tissues throughout the body. The chromatin accessibility landscapes in immune cells play a pivotal role in governing their activation, function, and differentiation. Aberrant modulation of chromatin accessibility in immune cells is intimately associated with the onset and progression of SLE. AREAS COVERED: In this review, we described the chromatin accessibility landscapes in immune cells, summarized the recent evidence of chromatin accessibility related to the pathogenesis of SLE, and discussed the potential of chromatin accessibility as a valuable option to identify novel therapeutic targets for this disease. EXPERT OPINION: Dynamic changes in chromatin accessibility are intimately related to the pathogenesis of SLE and have emerged as a new direction for exploring its epigenetic mechanisms. The differently accessible chromatin regions in immune cells often contain binding sites for transcription factors (TFs) and cis-regulatory elements such as enhancers and promoters, which may be potential therapeutic targets for SLE. Larger scale cohort studies and integrating epigenomic, transcriptomic, and metabolomic data can provide deeper insights into SLE chromatin biology in the future.

Recently, there has been a growing body of studies that explore the influence of epigenetic factors including DNA methylation, histone post-translational modifications, and non-coding RNA regulation on Systemic Lupus Erythematosus (SLE). Unusual regulation of these common epigenetic modifications would change the chromatin accessibility landscapes in SLE immune cells. Many studies have mapped the chromatin accessibility of various immune cells in SLE patients to uncover potential regulators like transcription factors (TFs) and cis-regulatory elements. Higher chromatin accessibility of immune cells in SLE patients compared to healthy individuals provides new avenues for diagnosing this disease. TFs identified in differentially accessible chromatin regions and their regulated genes might serve as novel targets for therapies, where the phenotypes affected by these genes, like inflammatory cytokine release and immune activation, are reliable bases for evaluating the prognosis of such targeted therapies.In this review, we described the chromatin accessibility landscape in immune cells, summarized the recent evidence of chromatin accessibility related to the process by which SLE develops, and discussed the potential of chromatin accessibility as a valuable option to identify novel therapeutic targets for this disease. Larger scale studies and combining epigenomic, transcriptomic, and metabolomic data can provide deeper insights into SLE chromatin biology in the future.

Single-cell analysis and machine learning identify psoriasis-associated CD8+ T cells serve as biomarker for psoriasis.

Psoriasis is a chronic inflammatory skin disease, the etiology of which has not been fully elucidated, in which CD8+ T cells play an important role in the pathogenesis of psoriasis. However, there is a lack of in-depth studies on the molecular characterization of different CD8+ T cell subtypes and their role in the pathogenesis of psoriasis. This study aims to further expound the pathogenesy of psoriasis at the single-cell level and to explore new ideas for clinical diagnosis and new therapeutic targets. Our study identified a unique subpopulation of CD8+ T cells highly infiltrated in psoriasis lesions. Subsequently, we analyzed the hub genes of the psoriasis-specific CD8+ T cell subpopulation using hdWGCNA and constructed a machine-learning prediction model, which demonstrated good efficacy. The model interpretation showed the influence of each independent variable in the model decision. Finally, we deployed the machine learning model to an online website to facilitate its clinical transformation.

Two Decades of Publications in Journals Dedicated to Autoimmunity: A Bibliometric Analysis of the Autoimmunity Field from 2004 to 2023.

To carry out an in-depth analysis of the scientific research on autoimmunity, we performed the first bibliometric analysis focusing on publications in journals dedicated to autoimmunity (JDTA) indexed by science citation index during the period 2004-2023. Using bibliometric analysis, we quantitatively and qualitatively analyzed the country, institution, author, reference and keywords information of publications in JDTA, so as to understand the quantity, publication pattern and publication characteristics of these publications. The co-occurrence networks, clustering map and timeline map were created by CiteSpace and VOSviewer software to visualize the results. The CiteSpace was also used to analyze the strongest citation burst of keywords, which could describe the frequency, intensity and time period of high-frequency keywords, and indicate the research hotspots in the field. A total of 5 710 publications were analyzed, and their annual distribution number was basically stable from 2004 to 2023, fluctuating around 300. The United States and Italy led the way in terms of the number of publications, followed by France and China. For international cooperation, the developed countries represented by the United States cooperate more closely, but the cooperation was localized, reflecting that there was no unified model of autoimmunity among countries. UDICE-French Research Universities had the greatest number of publications. Subsequently, the number of publications decreased slowly with the ranking, and the gradient was not large. Eric Gershwin and Yehuda Shoenfeld stood out among the authors. They had an excellent academic reputation and great influence in the field of autoimmunity. The results of keyword analysis showed that JDTA publications mainly studied a variety of autoimmune diseases, especially SLE and RA. At the same time, JDTA publications also paid special attention to the research of cell function, autoantibody expression, animal experiments, disease activity, pathogenesis and treatment. This study is the first to analyze the publications in JDTA from multiple indicators by bibliometrics, thus providing new insights into the research hotspots and development trends in the field of autoimmunity.

An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.

Many multi-spanning membrane proteins contain poorly hydrophobic transmembrane domains (pTMDs) protected from phospholipid in mature structure. Nascent pTMDs are difficult for translocon to recognize and insert. How pTMDs are discerned and packed into mature, muti-spanning configuration remains unclear. Here, we report that pTMD elicits a post-translational topogenesis pathway for its recognition and integration. Using six-spanning protein adenosine triphosphate-binding cassette transporter G2 (ABCG2) and cultured human cells as models, we show that ABCG2's pTMD2 can pass through translocon into the endoplasmic reticulum (ER) lumen, yielding an intermediate with inserted yet mis-oriented downstream TMDs. After translation, the intermediate recruits P5A-ATPase ATP13A1, which facilitates TMD re-orientation, allowing further folding and the integration of the remaining lumen-exposed pTMD2. Depleting ATP13A1 or disrupting pTMD-characteristic residues arrests intermediates with mis-oriented and exposed TMDs. Our results explain how a "difficult" pTMD is co-translationally skipped for insertion and post-translationally buried into the final correct structure at the late folding stage to avoid excessive lipid exposure.

The Role of Regulatory Cell Death in Vitiligo.

Vitiligo is one of the common chronic autoimmune skin diseases in clinic, which is characterized by localized or generalized depigmentation and seriously affects the physical and mental health of patients. At present, the pathogenesis of vitiligo is not clear; mainly, heredity, autoimmunity, oxidative stress, melanocyte (MC) self-destruction, and the destruction, death, or dysfunction of MCs caused by various reasons are always the core of vitiligo. Regulatory cell death (RCD) is an active and orderly death mode of cells regulated by genes, which widely exists in various life activities, plays a pivotal role in maintaining the homeostasis of the organism, and is closely related to the occurrence and development of many diseases. With the deepening of the research and understanding of RCD, people gradually found that there are many different forms of RCD in the lesions and perilesional skin of vitiligo patients, such as apoptosis, autophagy, pyroptosis, ferroptosis, and so on. Different cell death modes have different mechanisms in vitiligo, and different RCDs can interact and regulate each other. In this article, the mechanism related to RCD in the pathogenesis of vitiligo is reviewed, which provides new ideas for exploring the pathogenesis and targeted treatment of vitiligo.

Serum albumin mediates the associations between heavy metals and two novel systemic inflammation indexes among U.S. adults.

BACKGROUND: The effects of heavy metal exposure on immunological function have sparked widespread concern, but unequivocal evidence on the association between mixed metal exposure and novel systemic inflammatory indexes remains scarce. OBJECTIVES: This study aimed to analyze the associations of heavy metals with two novel systemic inflammation indexes and the mediated effects of serum albumin. METHODS: Nineteen metals were detected among 4082 U.S. adults based on the NHANES. A linear regression, restricted cubic splines (RCS) regression, weighted quantile sum (WQS), Quantile-based Gcomputation (qgcomp), and Bayesian kernel machine regression (BKMR) were conducted to evaluate the associations of single metal and mixed metals with systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) levels, respectively. A series of subgroup analyses were used to identify potentially vulnerable populations. Furthermore, we conducted mediation analyses to investigate the mediated effects of serum albumin on the associations of metals with SII and SIRI. RESULTS: In the single-exposure model, exposure to various metals such as urinary Co, As, and serum Zn, Cu was associated with SII and SIRI (PFDR<0.05). Simultaneously, the above metals were linear positively correlated with SII and SIRI. Mixed-exposure analyses consistently showed that overall mixed urinary metal levels were positively pertinent for SII and SIRI levels, and the metal Co played a significant role in the urinary metal mixtures. Subgroup analyses showed that exposure to urinary Cd in men and elderly people increased SII and SIRI levels. The results of mediation analyses suggested the association of urinary metal mixture with SII and SIRI was mediated by albumin, and the proportion of mediation was 14.45% and 9.49%, respectively. CONCLUSIONS: Our findings suggested that metal exposure is strongly associated with the levels of system inflammation indexes and that serum albumin is, in part, a mediator of this association.

Characteristics of vitiligo patients with versus without associated autoimmune thyroid disease.

BACKGROUND: Clinical data are limited in patients with vitiligo with or without autoimmune thyroid disease. OBJECTIVES: The objective of the study was to investigate the clinical features and basic data of patients with vitiligo, especially those with autoimmune thyroid disease. METHODS: The study was a single-center retrospective study. A total of 1305 patients with vitiligo from June 2018 to May 2023 were included, and the clinical characteristics and basic information of the patients were recorded in detail. RESULTS: We identified an association between sex (odds ratio [OR]: 2.380; 95% confidence interval [CI]: 1.772-1.198), vitiligo duration (OR: 1.449; 95% CI: 1.076-1.952), skin involvement exceeding 5% of the body surface area (OR: 3.764; 95% CI: 2.134-6.640), negative emotions (OR: 3.076; 95% CI: 2.292-4.127), vitiligo type (OR: 1.974; 95% CI: 1.096-3.555), family history of AITD (OR: 4.979; 95% CI: 2.687-9.225), and family history of AD (OR: 2.418; 95% CI: 1.410-4.146) and patients with vitiligo. CONCLUSIONS: For patients with statistically significant associated risk factors, differential diagnosis and early intervention should be performed.

UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage.

The transcription factor nuclear factor erythroid 2 like 1 (NFE2L1 or NRF1) regulates constitutive and inducible expression of proteasome subunits and assembly chaperones. The precursor of NRF1 is integrated into the endoplasmic reticulum (ER) and can be retrotranslocated from the ER to the cytosol where it is processed by ubiquitin-directed endoprotease DDI2. DDI2 cleaves and activates NRF1 only when NRF1 is highly polyubiquitinated. It remains unclear how retrotranslocated NRF1 is primed with large amount of ubiquitin and/or very long polyubiquitin chain for subsequent processing. Here, we report that E3 ligase UBE4A catalyzes ubiquitination of retrotranslocated NRF1 and promotes its cleavage. Depletion of UBE4A reduces the amount of ubiquitin modified on NRF1, shortens the average length of polyubiquitin chain, decreases NRF1 cleavage efficiency and causes accumulation of non-cleaved, inactivated NRF1. Expression of a UBE4A mutant lacking ligase activity impairs the cleavage, likely due to a dominant negative effect. UBE4A interacts with NRF1 and the recombinant UBE4A can promote ubiquitination of retrotranslocated NRF1 in vitro. In addition, knocking out UBE4A reduces transcription of proteasomal subunits in cells. Our results indicate that UBE4A primes NRF1 for DDI2-mediated activation to facilitate expression of proteasomal genes.

Research on dynamic characteristics of large deformation shearer cable based on absolute node coordinate formulation method.

The development of intelligent and unmanned coal mining has put forward higher requirements on the service life and dynamic reliability of shearer cables. However, it is difficult to comprehensively consider the complexity of hosting conditions of coal mining working face and the dynamic characteristics of cables in different towing systems in the design and development of cables. The cables are periodized by pitch and have the same cross-sectional structure and properties. Based on the homogenization theory and volume average principle, the cable was assumed to be an orthotropic elastomer, and the tensile experimental method and finite element method were combined to calibrate the cable equivalent mechanical parameters. Based on the Absolute Node Coordinate Formulation (ANCF) method, the rigid-flexible coupled virtual prototype co-simulation model of shearer cable towing system was constructed to obtain the kinetic and kinematic parameters of each node of the cable and study the dynamic gradual change characteristics of the cable in different working areas. This research method has an important theoretical significance and engineering application value for the acquisition of dynamic characteristic parameters of shearer cables and the optimal design and dynamic reliability of cables.

Causal Relationships between Air Pollutant Exposure and Bone Mineral Density and the Risk of Bone Fractures: Evidence from a Two-Stage Mendelian Randomization Analysis.

A number of studies from the literature have suggested that exposure to air pollutants is associated with a declined bone mineral density (BMD), and increased risks of osteoporosis (OP) and bone fractures. This study was performed to systemically assess the genetically causal associations of air pollutants with site-/age-specific BMD and risk of bone fractures with the implementation of two-sample Mendelian randomization (TSMR) and multivariate Mendelian randomization (MVMR). The TSMR analysis was implemented to infer the causal associations between air pollutants and BMD and the risk of bone fractures, additional MVMR analysis was used to further estimate the direct causal effects between air pollutants and BMD, the occurrence of OP, and bone fractures. The results showed that NOx exposure contributed to lower femoral neck BMD (FN-BMD) (ß = -0.71, 95%CI: -1.22, -0.20, p = 0.006) and total body BMD (TB-BMD) (ß = -0.55, 95%CI: -0.90, -0.21, p = 0.002). Additionally, exposure to PM10 was found to be associated with a decreased TB-BMD (B ß = -0.42, 95%CI: -0.66, -0.18, p = 0.001), further age-specific subgroup analysis demonstrated the causal effect of PM10 exposure on the decreased TB-BMD in a subgroup aged 45 to 60 years (ß = -0.70, 95%CI: -1.12, -0.29, p = 0.001). Moreover, the findings of the MVMR analysis implied that there was a direct causal effect between PM10 exposure and the decreased TB-BMD (45 < age < 60), after adjusting for PM2.5 and PM2.5 -10 exposure. Our study provides additional evidence to support the causal associations of higher concentrations of air pollutant exposure with decreased BMD, especially in those populations aged between 45 to 60 years, suggesting that early intervention measures and public policy should be considered to improve public health awareness and promote bone health.

TMUB1 is an endoplasmic reticulum-resident escortase that promotes the p97-mediated extraction of membrane proteins for degradation.

Membrane protein clients of endoplasmic reticulum (ER)-associated degradation must be retrotranslocated from the ER membrane by the AAA-ATPase p97 for proteasomal degradation. Before direct engagement with p97, client transmembrane domains (TMDs) that have partially or fully crossed the membrane must be constantly shielded to avoid non-native interactions. How client TMDs are seamlessly escorted from the membrane to p97 is unknown. Here, we identified ER-anchored TMUB1 as a TMD-specific escortase. TMUB1 interacts with the TMD of clients within the membrane and holds ∼10-14 residues of a hydrophobic sequence that is exposed out of membrane, using its transmembrane and cytosolic regions, respectively. The ubiquitin-like domain of TMUB1 recruits p97, which can pull client TMDs from bound TMUB1 into the cytosol. The disruption of TMUB1 escortase activity impairs retrotranslocation and stabilizes retrotranslocating intermediates of client proteins within the ER membrane. Thus, TMUB1 promotes TMD segregation by safeguarding the TMD movement from the membrane to p97.

Hispolon Methyl Ether, a Hispolon Analog, Suppresses the SRC/STAT3/Survivin Signaling Axis to Induce Cytotoxicity in Human Urinary Bladder Transitional Carcinoma Cell Lines.

Bladder cancer is a leading human malignancy worldwide. Signal transducer and activator of transcription (STAT) 3 is an oncogenic transcription factor commonly hyperactivated in most human cancers, including bladder cancer. Notably, preclinical evidence has validated STAT3 blockade as a promising therapeutic strategy for bladder cancer. Hispolon Methyl Ether (HME) is a structural analog of hispolon, an anticancer component of the medicinal mushroom Phellinus linteus. Thus far, HME's anticancer activity and mechanisms remain largely unknown. We herein report HME was cytotoxic, more potent than cisplatin, and proapoptotic to various human bladder transitional carcinoma cell lines. Of note, HME blocked STAT3 activation, evidenced by HME-elicited reduction in tyrosine 705-phosphorylated STAT3 levels constitutively expressed or induced by interleukin-6. Significantly, HME-induced cytotoxicity was abrogated in cells expressing a dominant-active STAT3 mutant (STAT3-C), confirming STAT3 blockage as a pivotal mechanism of HME's cytotoxic action. We further revealed that survivin was downregulated by HME, while its levels were rescued in STAT3-C-expressing cells. Moreover, survivin overexpression abolished HME-induced cytotoxicity, illustrating survivin as a central downstream mediator of STAT3 targeted by HME. Lastly, HME was shown to lower tyrosine 416-phosphorylated SRC levels, suggesting that HME inhibits STAT3 by repressing the activation of SRC, a STAT3 upstream kinase. In conclusion, we present the first evidence of HME's anti-bladder cancer effect, likely proceeding by evoking apoptosis through suppression of the antiapoptotic SRC/STAT3/survivin signaling axis.

Biscembranoids and Cembranoids from the Soft Coral Sarcophyton elegans.

Two novel biscembranoids, sarelengans A and B (1 and 2), five new cembranoids, sarelengans C-G (3-7), along with two known cembranoids (8 and 9) were isolated from the South China Sea soft coral Sarcophyton elegans. Their structures were determined by spectroscopic and chemical methods, and those of 1, 4, 5, and 6 were confirmed by single crystal X-ray diffraction. Compounds 1 and 2 represent the first example of biscembranoids featuring a trans-fused A/B-ring conjunction between the two cembranoid units. Their unique structures may shed light on an unusual biosynthetic pathway involving a cembranoid-∆8 rather than the normal cembranoid-∆¹ unit in the endo-Diels-Alder cycloaddition. Compounds 2 and 3 exhibited potential inhibitory effects on nitric oxide production in RAW 264.7 macrophages, with IC50 values being at 18.2 and 32.5 µM, respectively.

[Quantitative evaluation of inhibitory effects of epileptic spikes on theta rhythms in the network of hippocampal CA3 and entorhinal cortex in patients with temporal lobe epilepsy].

Epileptic spike is an indicator of hyper-excitability and hyper-synchrony in the neural networks. The inhibitory effects of spikes on theta rhythms (4-8 Hz) might be helpful to understand the mechanism of epileptic damage on the cognitive functions. To quantitatively evaluate the inhibitory effects of spikes on theta rhythms, intracerebral electroencephalogram (EEG) recordings with both sporadic spikes (SSs) and spike-free transient period between adjacent spikes were selected in 4 patients in the status of rapid eyes movement (REM) sleep with temporal lobe epilepsy (TLE) under the pre-surgical monitoring. The electrodes of hippocampal CA3 and entorhinal cortex (EC) were employed, since CA3 and EC built up one of key loops to investigate cognition and epilepsy. These SSs occurred only in CA3, only in EC, or in both CA3 and EC synchronously. Theta power was respectively estimated around SSs and during the spike-free transient period by Gabor wavelet transform and Hilbert transform. The intermittent extent was then estimated to represent for the loss of theta rhythms during the spike-free transient period. The following findings were obtained: (1) The prominent rhythms were in theta frequency band; (2) The spikes could transiently reduce theta power, and the inhibitory effect was severer around SSs in both CA3 and EC synchronously than that around either SSs only in EC or SSs only in CA3; (3) During the spike-free transient period, theta rhythms were interrupted with the intermittent theta rhythms left and theta power level continued dropping, implying the inhibitory effect was sustained. Additionally, the intermittent extent of theta rhythms was converged to the inhibitory extent around SSs; (4) The average theta power level during the spike-free transient period might not be in line with the inhibitory extent of theta rhythms around SSs. It was concluded that the SSs had negative effects on theta rhythms transiently and directly, the inhibitory effects aroused by SSs sustained during the spike-free transient period and were directly related to the intermittent extent. It was indicated that the loss of theta rhythms might qualify exactly the sustained inhibitory effects on theta rhythms aroused by spikes in EEG. The work provided an argumentation about the relationship between the transient negative impact of interictal spike and the loss of theta rhythms during spike-free activity for the first time, offered an intuitive methodology to estimate the inhibitory effect of spikes by EEG, and might be helpful to the analysis of EEG rhythms based on local field potentials (LFPs) in deep brain.