Abnormal metabolism in melanocytes participates in the activation of dendritic cell in halo nevus.

A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation.

Comprehensive genetic analysis of facioscapulohumeral muscular dystrophy by Nanopore long-read whole-genome sequencing.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a high-prevalence autosomal dominant neuromuscular disease characterized by significant clinical and genetic heterogeneity. Genetic diagnosis of FSHD remains a challenge because it cannot be detected by standard sequencing methods and requires a complex diagnosis workflow. METHODS: We developed a comprehensive genetic FSHD detection method based on Oxford Nanopore Technologies (ONT) whole-genome sequencing. Using a case-control design, we applied this procedure to 29 samples and compared the results with those from optical genome mapping (OGM), bisulfite sequencing (BSS), and whole-exome sequencing (WES). RESULTS: Using our ONT-based method, we identified 59 haplotypes (35 4qA and 24 4qB) among the 29 samples (including a mosaic sample), as well as the number of D4Z4 repeat units (RUs). The pathogenetic D4Z4 RU contraction identified by our ONT-based method showed 100% concordance with OGM results. The methylation levels of the most distal D4Z4 RU and the double homeobox 4 gene (DUX4) detected by ONT sequencing are highly consistent with the BSS results and showed excellent diagnostic efficiency. Additionally, our ONT-based method provided an independent methylation profile analysis of two permissive 4qA alleles, reflecting a more accurate scenario than traditional BSS. The ONT-based method detected 17 variations in three FSHD2-related genes from nine samples, showing 100% concordance with WES. CONCLUSIONS: Our ONT-based FSHD detection method is a comprehensive method for identifying pathogenetic D4Z4 RU contractions, methylation level alterations, allele-specific methylation of two 4qA haplotypes, and variations in FSHD2-related genes, which will all greatly improve genetic testing for FSHD.

Total and Out-of-Pocket Costs Surrounding Emergency Department Care Among Older Adults Enrolled in Traditional Medicare and Medicare Advantage.

STUDY OBJECTIVE: We sought to quantify differences in total and out-of-pocket health care costs associated with treat-and-release emergency department (ED) visits among older adults with traditional Medicare and Medicare Advantage. METHODS: We conducted a repeated cross-sectional analysis of treat-and-release ED visits using 2015 to 2020 data from the Medicare Current Beneficiary Survey. We measured total and out-of-pocket health care spending during 3 time periods: the 30 days prior to the ED visit, the treat-and-release ED visit itself, and the 30 days after the ED visit. Stratified by traditional Medicare or Medicare Advantage status, we determined median total costs and the proportion of costs that were out-of-pocket. RESULTS: Among the 5,011 ED visits by those enrolled in traditional Medicare, the weighted median total (and % out-of-pocket) costs were $881.95 (13.3%) for the 30 days prior to the ED visit, $419.70 (10.1%) for the ED visit, and $809.00 (13.8%) for the 30 days after the ED visit. For the 2,595 ED visits by those enrolled in Medicare Advantage, the weighted median total (and % out-of-pocket) costs were $484.92 (24.0%) for the 30 days prior to the ED visit, $216.66 (21.9%) for the ED visit, and $439.13 (22.4%) for the 30 days after the ED visit. CONCLUSION: Older adults insured by Medicare Advantage incur lower total health care costs and face similar overall out-of-pocket expenses in the time period surrounding emergency care. However, a higher proportion of expenses are out-of-pocket compared with those insured by traditional Medicare, providing evidence of greater cost sharing for Medicare Advantage plan enrollees.

MiR-26a-5p exerts its influence by targeting EP300, a molecule known for its role in activating the PI3K/AKT/mTOR signaling pathway in CD8+tumor-infiltrating lymphocytes of colorectal cancer.

Surgical resection remains the primary approach for treating colorectal cancer, which is among the prevalent types of cancers affecting the digestive system. Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a prominent area of study in the field of tumor immunotherapy in recent times, with the potential to serve as a supplementary treatment for colorectal cancer. For this investigation, we employed single-cell sequencing data to assess the manifestation extent of miR-26a-5p exists in healthy colon tissue, tissue affected by colorectal cancer, and tissue adjacent to the tumor. According to our findings, tumor-infiltrating T lymphocytes express comparatively less miR-26a-5p in comparison to normal T lymphocytes, the role of it in modulating the function of tumor-infiltrating T lymphocytes is suggested. Studies on miR-26a-5p's involvement in tumor-infiltrating T lymphocytes is limited, despite previous evidence indicating its ability to facilitate the development and advancement of cancerous cells. As a result of our experiments, we concluded that miR-26a-5p hindered the PI3K/AKT/mTOR(PAM) signaling pathway, reducing the ability of CD8+ tumor-infiltrating cells eradicate tumors. Using bioinformatics tools, we utilized prediction methods to identify EP300 as the specific gene targeted by miR-26a-5p. Subsequent research understood that downregulation of EP300 counteracted the suppressive impact exerted by miR-26a-5p on the stimulation of PAM signaling pathway, while it also diminishes the viability and cytotoxicity of CD8+ tumor-infiltrating lymphocytes. Therefore, miR-26a-5p emerges as a compelling option for the effective control of TIL therapy.

Disease Awareness and Treatment Preferences in Vitiligo: A Cross-sectional Study in China.

In China, there is a lack of data regarding the awareness and treatment preferences among patients with vitiligo and their families. To address this gap, a cross-sectional questionnaire-based study was conducted to investigate disease awareness and treatment preferences in Chinese patients with vitiligo. The study also evaluated willingness to pay, using 2 standardized items, and assessed quality of life, using the Dermatology Life Quality Index (DLQI) score. Data from 307 patients with vitiligo (59.3% women, mean age 28.98 years, range 2-73 years) were analysed. Of these patients, 44.7% had insufficient knowledge of vitiligo, particularly those from rural areas or with low levels of education. Mean DLQI total score was 4.86 (5.24 for women and 4.30 for men). Among the most accepted treatments were topical drugs, phototherapy, and systemic therapy. Patients were relatively conservative about the duration and cost of treatment, with only 27.7% willing to pay more than 10,000 Chinese yuan renminbi (CNY) for complete disease remission. High level of education, high income, skin lesions in specific areas, and skin transplantation therapy predicted higher willingness to pay. Insufficient knowledge was associated with a higher burden of disease. In order to reduce the disease burden and improve treatment adherence it is crucial to enhance disease awareness and take into account patient preferences.

Using recycled coffee grounds for the synthesis of ZIF-8@BC to remove Congo red in water.

Around 6.6 million tons of spent coffee is produced per year, resulting in resources loss and potential environmental risks. Hence, a green technique is required to reuse the spent coffee grains. In this study, coffee grounds were burnt at 900 °C to generate the biochar (BC) for the synthesis of the porous adsorbent (ZIF-8 @BC) by growing ZIF-8 on the surface of BC. We applied the well-prepared ZIF-8 @BC to remove Congo red (CR) in water. The maximum adsorption capacity of ZIF-8 @BC on Congo red in water was up to 1080.4 mg/g, which was significantly higher than that of many different types of BCs reported in previous studies. The reasons for its highly efficient adsorption of CR probably was attributed to metal ions and coordinatively unsaturated sites in the material. Also, BC enabled the less aggregation of ZIF-8 to provide sufficient specific surface area for CR adsorption. From the analysis of the pseudo-second-order kinetic model and Langmuir model, the adsorption of ZIF-8 @BC on CR was a homogeneously chemical adsorption process regulated by electrostatic interaction, π-π stacking and metal coordination.

Preparation of UiO-66-NH2 and UiO-66-NH2/sponge for adsorption of 2,4-dichlorophenoxyacetic acid in water.

MOFs are usually used as efficient adsorbents to remove specific pollutants in water. However, because of their poor water stability relatively small particle size, their application in adsorbing and removing pollutants from water is limited. In this paper, with nitrile rubber sponge as the substrate, UiO-66-NH2/sponge composites were firstly in-situ synthesized and systematically evaluated UiO-66-NH2 as an adsorbent to remove 2,4-dichlorophenoxyacetic acid from water. This composite could not only remain the adsorption capacity for 2,4-dichlorophenoxyacetic acid of UiO-66-NH2, but also was much more convenient for separation after the adsorption compared to UiO-66-NH2. In addition, the mechanism of the adsorption of UiO-66-NH2 for 2,4-dichlorophenoxyacetic acid were discussed in detail. Electrostatic interaction between UiO-66-NH2 and 2,4-dichlorophenoxyacetic acid was the main adsorption mechanism. The adsorption was mainly suitable for Langmuir isotherm models, and its maximum adsorption capacity of 2,4-dichlorophenoxyacetic acid was 72.99 mg g-1.

Metal-Free ortho C-H Borylation of Thiobenzamides.

A BBr3-mediated S-directed ortho C-H borylation of thiobenzamides was developed. A variety of ortho-borylated thiobenzamides were obtained in moderate to good yields with a wide functional group tolerance under simple and metal-free conditions. This transformation provided a convenient and practical route to important functionalized thiobenzamides.

Exosomes-mediated transmission of standard bovine viral diarrhea strain OregonC24Va in bovine trophoblast cells.

Bovine viral diarrhoea virus (BVDV) can infect cows on days 30-110 of gestation and crossing the placental barrier, resulting in persistently infected (PI) and causing significant economic losses to dairy farming. Bovine placental trophoblast cells (BTCs) are the major cells in the early chorionic tissue of the placenta and play important roles in placental resistance to viral transmission. In this study, we have confirmed that BTCs is among a groups of cell types those could be infected by BVDV in vivo, and BVDV infection stimulates the autophagic responses in BTCs and promotes the release of exosomes. Meanwhile, the exosomes derived from BTCs can be used by BVDV to spread between placental trophoblast cells, and this mode of transmission cannot be blocked by antibodies against the BVDV E2 protein, whereas the replication and spread of BVDV in BTCs can be blocked by inhibiting autophagy and exosomogenesis. Our study provides a theoretical and practical basis for scientific prediction and intervention of reproductive disorders caused by BVDV infection in cows of different gestation periods from a novel perspective.

Organic diffusive gradients in thin films (o-DGT) for determining environmental behaviors of antibiotics: A review.

Antibiotics are recognized as effective medicine that has been extensively used in human and veterinary. Since the rate of releasing into the environment is stronger than the rate of elimination, antibiotics are regarded as persistent or "pseudo-persistent" organic compounds that result in the development of microbial antibiotic resistance. Therefore, assessment for their ecological risks to the environment are essential. Diffusive gradients in thin films for organic compounds (o-DGT) have been adapted to investigate the environmental behaviors of antibiotics. Currently, more than 20 compounds have been tested by o-DGT in waters and soil environments. In this review, we explained the theoretical reason that o-DGT is feasible to determine the labile fraction of antibiotics in different environmental media. The most used agarose diffusive gel, and various binding agents such as resin, porous carbon and nano-scale materials have been compared to optimize the sampling of antibiotics by o-DGT. Results of deploying o-DGT devices in waters and soils from previous studies were discussed to understand the bioavailability and dynamic transport of antibiotics. Also, we provided the feasibility analysis of using o-DGT in sediments for antibiotics measurements, which is required to be carried out in future studies. To have a deep view on the development of o-DGT, its technical limitations and viable improvements were summarized in this study for further applications on antibiotics research.

Pollution and Distribution of Microplastics in Grassland Soils of Qinghai-Tibet Plateau, China.

Microplastics (MPs) are plastic fragments with particle sizes smaller than 5 mm that have potentially harmful effects on ecosystems and human health. The soil environment is not only the source but also the sink of MPs. Thus, it is necessary to fully understand the pollution and distribution of MPs in soils. In this study, Qinghai Province, northeast of the Qinghai-Tibet Plateau, was selected as the research area, and 22 soil samples were collected and analyzed to study the levels and distribution characteristics of MPs in grassland soils. MPs were obtained from the soils by using density separation, and a laser confocal micro Raman spectrometer was used for MP identification. The results showed that MPs were detected in all of the soil samples. The total abundances of MPs ranged from 1125 to 1329 items/kg, with a mean abundance of 1202 items/kg. Various types, shapes, sizes, and colors of MPs were observed. Polyethylene terephthalate (PET) was the dominant polymer in all the grassland soil samples. The size range of 10-50 µm accounted for 50% of all identified MPs. Pellets were the dominant MP shape, and colored MPs accounted for 64% of all MPs. The results revealed the presence of large quantities of MPs in the grassland soils of remote areas as well. This study can act as a reference for further studies of MPs in terrestrial systems. At the end of the paper, the prospects and suggestions for pollution control by soil MPs are given.

PRRSV infection activates NLRP3 inflammasome through inducing cytosolic mitochondrial DNA stress.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe interstitial pneumonia and inflammatory response in piglets and growing pigs. IL-1ß is implicated in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection. Mitochondria are critical intracellular organelles which is served as signaling platform for antiviral immunity response to participate in immune response of virus infection. The role of mitochondria in PRRSV-mediated inflammatory response and the pathogenesis of PRRSV infection has not been elucidated. Here, our data suggested that PRRSV infection facilitates mitochondrial dysfunction, which induces cytosolic mitochondrial DNA (mtDNA) stress and ROS accumulation, severally activates the NLRP3 inflammasome and NF-κB signaling pathway, and consequently stimulates IL-1ß production in PAMs. Furthermore, mtDNA degradation by DNase I abrogates the activation of NLRP3 inflammasome and IL-1ß secretion during PRRSV infection. Scavenging ROS significantly inhibits NF-κB signaling activation and the subsequently transcription and secretion of IL-1ß. In conclusion, our results indicate that cytosolic mtDNA stress and ROS accumulation after PRRSV infection-induced mitochondrial dysfunction activate NLRP3 inflammasome and NF-κB signaling pathway to promote IL-1ß production, revealing a new strategy for vaccine and drug development to PRRSV.

Dihydrotestosterone mediates the inflammation effect under lipopolysaccharides in bovine endometrial epithelial cells via AR blockading TLR4/MyD88 signaling pathway.

Dihydrotestosterone (DHT) is a potent nonaromatizable 5α-reduced androgen with both positive and negative effect on inflammation process. However, it remains unknown whether DHT can regulate Lipopolysaccharides (LPS)-induced inflammation in bovine endometrial epithelial cells (bEECs). Here, we demonstrated that the DHT biosynthesis ability and androgen receptors (AR) expression is defective in bovine endometrial with endometritis, which aggravates endometrial inflammation. In vitro study, we established a LPS-induced inflammation model in bEECs, and found that DHT inhibited the TLR4 and MyD88 protein as well as TNF-α, IL-1ß, and IL-6 mRNA of bEECs in a dose-dependent manner. Moreover, the anti-inflammation effect of DHT was blocked by AR inhibitor flutamide. Together, we demonstrated that supplementing DHT can alleviate the inflammation response of bEECs caused by LPS, which is associated with AR regulating the inhibition of TLR4/MyD88 signaling pathway.

Medical Marijuana for Pain Management in Hospice Care as a Complementary Approach to Scheduled Opioids: A Single Arm Study.

Background: Opioid therapy is critical for pain relief for most hospice patients but may be limited by adverse side effects. Combining medical cannabis with opioids may help mitigate adverse effects while maintaining effective pain relief. Aim: This single-arm study investigated the impact of combined medical cannabis/opioid therapy on pain relief, opioid dose, appetite, respiratory function, well-being, nausea, and adverse events in hospice inpatients. Design: Adult hospice inpatients using scheduled oral, parenteral, or transdermal opioids for pain were administered standardized oral medical cannabis, 40 mg CBD/1.5 mg THC or 80 mg CBD/3 mg THC. Descriptive statistics detailed demographic and clinical baseline characteristics, the Mann-Whitney test compared outcomes, and the longitudinal mixed effects regression model analyzed longitudinal effects of combined therapy. Setting/Participants: Sixty-six inpatients at The Connecticut Hospital, Inc. were assessed over 996 treatment days; average age was 68.2 ± 12.9 years, 90.9% were white. Cancer was the most common diagnosis. Results: The medical cannabis/opioid combination showed a significant longitudinal reduction in pain intensity (P = .0029) and a non-significant trend toward lower opioid doses. Well-being, appetite, nausea, and respiratory function showed non-statistically significant changes. Three patients (4.5%) experienced minor, reversible adverse events potentially related to medical cannabis. No serious or life-threatening adverse events were seen. Conclusion: Combination medical cannabis/opioid therapy showed statistically significant pain relief and may have the potential for reducing opioid dose and mitigating opioid toxicity, offering a safe pain management alternative to opioids alone for patients in end-of-life care settings, and warrants further investigation in larger controlled trials.

AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.

AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD+. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.

Highly efficient removal of quinolones by using the easily reusable MOF derived-carbon.

As anthropogenic antibiotics, quinolones, e.g., ofloxacin have adverse impacts on ecological systems and human heaths. The removal of quinolones is of great importance, and adsorption techniques have been widely used to remove this hazardous contaminant. However, a robust and easy-operating adsorbent is still emergently required due to the complex chemical structure of quinolones. In this study, we successfully synthesized the promising metallic carbons (MCs) containing carbon nanotubes and cobalt nanoparticles by carbonizing Zn/Co-ZIF at 900 °C. Three different molar ratios of Co and Zn were applied to optimize the adsorption capacity on ofloxacin (OFL). Results showed MC with molar ratio of Co and Zn at 3:1 (Co-CNT/NPC3/1) achieved the maximal adsorption capacity to 118.3 mg g-1. Its adsorption performance was satisfied in the pH range from 5 to 9 and ionic strengths at 0.01 M. The main mechanisms for these adsorptions were identified as electrostatic attraction, metal coordination and π-π EDA. Removal efficiencies of quinolones higher than 68 mg g-1 indicated the strong feasibility of this adsorbent for wastewater treatments. The regeneration of Co-CNT/NPC3/1 at 600 °C allowed its at least 4-time reusability and its magnetic property enabled external magnets to recycle it from real environments.

Gut Microbial Metabolites in Parkinson's Disease: Implications of Mitochondrial Dysfunction in the Pathogenesis and Treatment.

The search for therapeutic targets for Parkinson's disease (PD) is hindered by the incomplete understanding of the pathophysiology of the disease. Mitochondrial dysfunction is an area with high potential. The neurobiological signaling connections between the gut microbiome and the central nervous system are incompletely understood. Multiple lines of evidence suggest that the gut microbiota participates in the pathogenesis of PD. Gut microbial dysbiosis may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The intervention of gut microbial metabolites via the microbiota-gut-brain axis may serve as a promising therapeutic strategy for PD. In this narrative review, we summarize the potential roles of gut microbial dysbiosis in PD, with emphasis on microbial metabolites and mitochondrial function. We then review the possible ways in which microbial metabolites affect the central nervous system, as well as the impact of microbial metabolites on mitochondrial dysfunction. We finally discuss the possibility of gut microbiota as a therapeutic target for PD.

Progressive Encephalomyelitis With Rigidity and Myoclonus With Thymoma: A Case Report and Literature Review.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is part of the variant type of the Stiff Person Syndrome (SPS) and is a rare neurological disease. We report here a patient with PERM who had thymoma and was positive for anti-glutamic acid decarboxylase (anti-GAD) antibodies. Her symptoms improved after treatment with hormones and gamma globulin. We also summarized the literature review of patients with PERM accompanied by tumors reported.

Ameliorating gut microenvironment through staphylococcal nuclease-mediated intestinal NETs degradation for prevention of type 1 diabetes in NOD mice.

AIMS: Recent studies have revealed that neutrophil extracellular traps (NETs) provide negative feedback in the progression to chronic inflammation and contribute to the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). In addition, accumulating evidences suggest that gut immunity play a key role in T1D pathogenesis. Our study aimed to evaluate whether staphylococcal nuclease (SNase) targeting intestinal NETs can ameliorate the intestinal inflammatory environment and protect against T1D development in non-obese diabetic(NOD) mice. MAIN METHODS: Degradation of NETs with SNase in vitro was examined using SYTOX green assay. NOD/LtJ mice were oral administration of Lactococcus lactisl (L. lactis) pCYT: SNase and blood glucose levels were monitored weekly. Several biomarkers of NETs formation, gut leakage and inflammation were determined using a commercial ELISA kit. T Cell phenotypes in peripheral immune system were analyzed in flow cytometry and fecal samples were isolated to investigate intestinal microbiota. KEY FINDINGS: The oral delivery of SNase by L. lactis can decrease the NETs levels and ameliorate inflammation both in the intestine and pancreatic islets and finally effectively regulate the blood glucose levels of NOD mice. Meanwhile, zonulin and lipopolysaccharide levels also reduced in SNase-fed NOD mice, suggesting SNase could improve gut barrier function via intestinal NETs degradation. Furthermore, the abundances of the intestinal microbiota and butyrate-producing gut bacteria were also increased with SNase treatment. SIGNIFICANCE: SNase shows potential for intestinal NETs to prevent T1D based on the gut-pancreas axis.