Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing.

BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

YOLO-Weld: A Modified YOLOv5-Based Weld Feature Detection Network for Extreme Weld Noise.

Weld feature point detection is a key technology for welding trajectory planning and tracking. Existing two-stage detection methods and conventional convolutional neural network (CNN)-based approaches encounter performance bottlenecks under extreme welding noise conditions. To better obtain accurate weld feature point locations in high-noise environments, we propose a feature point detection network, YOLO-Weld, based on an improved You Only Look Once version 5 (YOLOv5). By introducing the reparameterized convolutional neural network (RepVGG) module, the network structure is optimized, enhancing detection speed. The utilization of a normalization-based attention module (NAM) in the network enhances the network's perception of feature points. A lightweight decoupled head, RD-Head, is designed to improve classification and regression accuracy. Furthermore, a welding noise generation method is proposed, increasing the model's robustness in extreme noise environments. Finally, the model is tested on a custom dataset of five weld types, demonstrating better performance than two-stage detection methods and conventional CNN approaches. The proposed model can accurately detect feature points in high-noise environments while meeting real-time welding requirements. In terms of the model's performance, the average error of detecting feature points in images is 2.100 pixels, while the average error in the world coordinate system is 0.114 mm, sufficiently meeting the accuracy needs of various practical welding tasks.

The risk of perchlorate and iodine on the incidence of thyroid tumors and nodular goiter: a case-control study in southeastern China.

BACKGROUND: The incidence rates of thyroid tumors and nodular goiter show an upward trend worldwide. There are limited reports on the risk of perchlorate and iodine on thyroid tumors, but evidence from population studies is scarce, and their impact on thyroid function is still uncertain. Therefore, the objective of this study was to investigate the association of perchlorate and iodine with the risk of nodular goiter (NG), papillary thyroid microcarcinoma (PTMC), and papillary thyroid carcinoma (PTC) and to assess the correlation between perchlorate and iodine with thyroid function indicators. METHODS: A case-control population consisting of 184 pairs of thyroid tumors and nodular goiter matched by gender and age (±2 years) was recruited in this study. Serum and urine samples were collected from each participant. Thyroid function indicators in serum were tested by automatic chemical immunofluorescence, and perchlorate and iodine levels in urine were determined by ultra-high performance liquid chromatography tandem-mass spectrometry and inductively coupled plasma-mass spectrometry, respectively. Conditional logistic regressions and multiple linear regressions were used to analyze the associations. RESULTS: Urinary perchlorate concentration was significantly higher in total cases, NG and PTC than in the corresponding controls (P < 0.05). Perchlorate was positively associated with PTC (OR = 1.058, 95% CI: 1.009, 1.110) in a non-linear dose-response relationship, but there was no association between perchlorate and NG or PTMC. Iodine was not associated with the risk of thyroid tumors and NG and did not correlate with the thyroid function indicators. Furthermore, perchlorate showed a positive correlation with thyroid stimulating hormone (TSH) at iodine adequate levels (P < 0.05), and a negative correlation with free triiodothyronine (FT3) and a positive correlation with thyroglobulin antibody (TgAb) at iodine more than adequate or excess levels (P < 0.05). CONCLUSIONS: Perchlorate can increase the risk of PTC in a non-linear dose-response relationship and disturb the thyroid hormone homeostasis and thyroid autoantibody levels.

A Study on Fatigue Crack Propagation for Friction Stir Welded Plate of 7N01 Al-Zn-Mg Alloy by EBSD.

EBSD (electron backscattered diffraction) was used to study the fatigue crack propagation mechanism in a friction stir welding joint of a 15 mm-thick 7N01 aluminum alloy plate. Crack tips with detailed features were clearly characterized by EBSD images. The plastic zone caused by crack was small in the stir zone. Due to the fine grain strengthening in the stir zone, there were several lattice distortion regions which were observed in the BC (band contrast) map but disappeared in the SEI (secondary electron image). In the stir zone, fatigue crack tends to awake and grow along grain boundaries, and propagate with little deformation of the grains. When the crack tries to grow across a boundary, the deformation of the plastic zone at the crack tip shows little correlation to the cyclic loading direction. However, the plastic zone in base metal, the rolled plate, is large and continuous, and no obvious lattice distortion region was found. According to Schmidt factor, the base metal near crack is fully deformed, lots of low angle boundaries parallel to the cyclic force can be observed. The base metal showed a better ability for fatigue crack propagation resistance.

Hexabromocyclododecanes in breast milk from residents in Shenzhen, China: Implications for infant exposure.

Hexabromocyclododecanes (HBCDs) are widely used as flame retardants for various products and have become ubiquitous pollutants in environmental media. However, little is known about HBCD exposure for humans, especially in China. This study aimed to investigate the levels and profiles of hexabromocyclododecanes (HBCDs) in human breast milk and to estimate the daily HBCD intake for infants in Shenzhen, China. Levels of the HBCD diastereoisomers α-, ß-, and γ-HBCD in 180 breast milk samples collected from primiparas in Shenzhen were measured. The concentrations of α-, ß-, and γ-HBCD (ΣHBCDs) ranged within 0.103-15.1ng/g lipid and had a median of 1.82ng/g lipid. ΣHBCDs levels in milk in the present study are comparable to those in milk from other countries and regions but are markedly higher than those for most populations in other regions of China. Among the diastereoisomers, α-HBCD was predominant, accounting for 97.6% of the concentration of ΣHBCDs. The estimated daily intake of ΣHBCDs via breast milk for infants in Shenzhen ranged from 0.481 to 100ng/kgbw/day with a median of 8.40ng/kgbw/day, however, which was unlikely to raises a health concern based on the margin of exposure (MOE) approach. The duration of residence was found to have a significant positive correlation with the HBCD levels in the human breast milk (p<0.05). To our knowledge, this is the first report on HBCD levels in breast milk from Shenzhen residents.

Spatiotemporal variability of polybrominated diphenyl ether concentration in atmospheric fine particles in Shenzhen, China.

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants for various products and have become ubiquitous pollutants in environmental media. However, little is known about PBDE levels in Shenzhen, a manufacturing center of electronic products. This study aimed to investigate spatiotemporal variability of PBDE concentration in atmospheric fine particles (PM2.5) and to estimate the daily inhalation exposure doses for local residents in Shenzhen, China. A total of 36 samples were collected and 8 PBDE compounds (BDE-28, 47, 99, 100, 153, 154, 183 and 209) were analyzed by isotope dilution high-resolution gas chromatograph/high-resolution mass spectrometer (HRGC/HRMS). Mean concentrations of Σ8PBDEs and BDE-209 in PM2.5 in Shenzhen were 33.47 pg/m3 and 24.75 pg/m3, respectively, which were lower than those for other reported cities from China. The mean concentration of Σ8PBDEs was higher in the winter + spring than that in summer + autumn, and both concentrations of BDE-28 and BDE-47 in PM2.5 were significantly higher in winter + spring than those in summer + autumn. Among the 8 congeners, BDE-209 was predominant, accounting for 73.9% of the Σ8PBDEs concentrations. Traffic area, industrial area, residential area and discharge of electronic industries had significant positive influences on PBDE concentrations in PM2.5. Both vegetation area and water area were significantly negatively correlated with PBDE levels in PM2.5. Significantly negative correlation was also found between PBDE concentrations in PM2.5 and the relative humidity. The ranking of estimated inhalation exposure doses of PBDEs via PM2.5 inhalation were toddlers (1.74 pg/kg b.w./day) > children (1.33 pg/kg b.w./day) > adults (1.26 pg/kg b.w./day) > teenagers (0.64 pg/kg b.w./day), and toddlers had a highest risk to expose to PBDEs by PM2.5. To our knowledge, the present study is the first to reveal the spatiotemporal variability of PBDEs in PM2.5 of Shenzhen, China.

Dynamic status of metabolically healthy overweight/obesity and metabolically unhealthy and normal weight and the risk of type 2 diabetes mellitus: A cohort study of a rural adult Chinese population.

OBJECTIVE: We aimed to determine dynamic status of metabolically healthy overweight or obesity (MHO) and metabolically unhealthy and normal weight (MUNW) and the risk of incident type 2 diabetes mellitus (T2DM). METHODS: Body mass index and metabolic health were assessed on 11,865 eligible participants ≥18 years from 6-year follow-up cohort study of a rural Chinese population. Participants were classified as metabolically healthy and normal weight (MHNW), MHO, MUNW and metabolically unhealthy overweight or obesity (MUO) at both baseline and follow-up examinations. Hazard ratio (HR) and 95% confidence interval (CI) were used to assess baseline and their changes of BMI-metabolic status and the risk of incident T2DM. RESULTS: Risk of T2DM was increased for all participants with baseline MHO, MUNW, and MUO (adjusted HR 1.94, 95% CI 1.33-2.81; 3.10, 95% CI 2.19-4.39; and 6.63, 95% CI 4.94-8.90, all P<0.001, respectively). However, risk of T2DM was increased for participants with transformation from MHO to MUO (4.52, 95% CI 2.42-8.47, P<0.001) as compared with stable MHNW, but not stable MHO (0.53, 95CI 0.20-1.40, P=0.20). Risk of T2DM did not differ between participants with transformation from MUNW to metabolically healthy and those with stable MHNW (P>0.05), but was increased with stable MUNW (5.78, 95% CI 3.15-10.62, P<0.001). The results were consistent when analyses were restricted to participants without baseline impaired fasting glucose level. CONCLUSIONS: Our findings provide understanding for differentiating high-risk individuals for incident T2DM in Chinese population.

Association of type 2 diabetes mellitus with the interaction between low-density lipoprotein receptor-related protein 5 (LRP5) polymorphisms and overweight and obesity in rural Chinese adults.

BACKGROUND: Low-density lipoprotein receptor-related protein 5 (LRP5) plays an important role in glucose and cholesterol metabolism. The present cohort study evaluated associations of LRP5 variants with the incidence of type 2 diabetes mellitus (T2DM) in a rural adult Chinese population. METHODS: In all, 7751 subjects aged ≥18 years without T2DM underwent genotyping at baseline; 6326 subjects (81.62%) were followed-up, and 5511 with a clear disease outcome were eligible for analysis. The same questionnaire was administered and the same anthropometric and blood biochemical examinations were performed at baseline and follow-up. Association analysis was performed for five single nucleotide polymorphisms and haplotypes of LRP5. RESULTS: Cox proportional hazards testing of three different genetic models found no significant association between T2DM and LRP5 after adjusting for potential risk factors (P > 0.05). However, the incidence of T2DM in subjects with LRP5 mutational genotypes was higher in the overweight/obese than normal weight population. Under the dominant model, the risk of T2DM was increased with an interaction between rs11228303 and the waist-to-height ratio adjusted for baseline age, sex, and family history of T2DM (synergy index [SI] = 4.172; 95% confidence interval [CI] 1.014-17.166)], and body mass index (SI = 3.237; 95% CI 1.102-9.509). Furthermore, the A allele of rs3758644 was related to decreased fasting plasma insulin and homeostatic model assessment of ß-cell function levels, whereas the T allele of rs12363572 was related to increased high-density lipoprotein cholesterol levels in new-onset diabetes patients (P < 0.05). CONCLUSIONS: The risk of T2DM may be associated with interactions between the LRP5 gene and overweight and obesity. Polymorphisms of LRP5 are related to ß-cell function and lipid metabolism.

Toxaphene levels in retail food from the Pearl River Delta area of South China and an assessment of dietary intake.

Limited literature exists on toxaphene contamination in food worldwide, particularly in mainland China. In this study, three toxaphene congeners, Parlar 26 (B8-1413), Parlar 50 (B9-1679) and Parlar 62 (B9-1025), were analyzed in five different food categories from the Pearl River Delta Area in China using isotope dilution high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS), and toxaphene levels in food were reported and toxaphene dietary intake by local residents estimated. The results showed that fish contained the highest toxaphene level with a median of 12.87 pg/g wet weight (ww), followed by poultry meat, egg products, livestock meat and vegetable, which had median levels of 5.8, 2.2, 1.89 and 0.67 pg/g ww, respectively. Parlar 50 and Parlar 26 were the predominant characteristic congeners in fish, and Parlar 26 was the predominant congener not only in poultry products and eggs, but also in livestock and vegetable. The estimated average daily intake found by local residents was 35.57 pg/kg body weight/day. Overall toxaphene levels and estimated dietary intake in the Pearl River Delta Area of South China are far lower than the European Maximum Residue Limits (EU MRLs), the German MRL for fish, and other international literature data. Therefore, the risk of adverse health effects from dietary intakes of toxaphene for the local residents is not considerable at the current time, but follow-ups are warranted to study dynamic changes of toxaphene in food in this area.

Levels and profiles of polychlorinated dibenzo-p-dioxin and dibenzofurans in raw and treated water from water treatment plants in Shenzhen, China.

Levels and profiles of polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) were analyzed for the first time in raw and treated water from five water treatment plants in Shenzhen, South China. The average PCDD/Fs concentrations were 32.93 pg/L (0.057 pg international toxic equivalent quantity (I-TEQ)/L) and 0.64 pg/L (0.021 pg I-TEQ/L) in raw and treated water, respectively. The removal rate of PCDD/Fs in terms of mass concentration varied from 93.4% to 98.8%, whereas a negative removal rate was observed in one plant in terms of TEQ concentration. The PCDD/Fs concentration in raw water was lower than most of the published data from other countries and regions, and the PCDD/Fs concentration in treated water was below the Maximum Contaminants Level (MCL) of 30 pg/L for dioxin in drinking water set by the US EPA. Historical pentachlorophenol usage, local waste incineration and industrial emissions, as well as surface runoff or even soil erosion, might be the main sources for PCDD/F pollution in water. The daily intake of PCDD/Fs for local residents from drinking water was estimated to be 0.69 fg I-TEQ/kg/day, which is negligible compared with that from food consumption (1.23 pg WHO-TEQ/kg/day) in the local area.

Characterization of mycobacterial UDP-N-acetylglucosamine enolpyruvyle transferase (MurA).

The mycobacterial peptidoglycan has structure and biosynthetic pathways to similar those of other bacteria. UDP-N-acetylglucosamine enolpyruvyle transferase (MurA) catalyzes the first reaction in the biosynthesis of peptidoglycan. The MurA enzyme has been identified from various bacterial species, but the in-depth biochemical properties of mycobacterial MurA have not been characterized. In this study, both Mycobacterium tuberculosis MurA protein and Mycobacterium smegmatis MurA protein were overexpressed in Escherichia coli and purified by affinity chromatography. MurA activity was detected by HPLC. A colorimetric assay of MurA activity was also developed and the kinetic properties of Mtb MurA and Msm MurA were determined using this colorimetric assay. A conditional murA gene knockout strain was constructed by DNA homologous recombination. The disruption of murA in the genome of M. smegmatis led to loss of viability at a non-permissive temperature. Drastic morphological and structural alterations in the M. smegmatis murA knockout strain were observed by scanning electron microscopy and transmission electron microscopy. These results demonstrated that murA was an essential gene for growth of M. smegmatis. Therefore, MurA is a potential target for developing new anti-tuberculosis drugs.