Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future.

Müller glia, as prominent glial cells within the retina, plays a significant role in maintaining retinal homeostasis in both healthy and diseased states. In lower vertebrates like zebrafish, these cells assume responsibility for spontaneous retinal regeneration, wherein endogenous Müller glia undergo proliferation, transform into Müller glia-derived progenitor cells, and subsequently regenerate the entire retina with restored functionality. Conversely, Müller glia in the mouse and human retina exhibit limited neural reprogramming. Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders. Müller glia reprogramming in mice has been accomplished with remarkable success, through various technologies. Advancements in molecular, genetic, epigenetic, morphological, and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice. Nevertheless, there remain issues that hinder improving reprogramming efficiency and maturity. Thus, understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency, and for developing novel Müller glia reprogramming strategies. This review describes recent progress in relatively successful Müller glia reprogramming strategies. It also provides a basis for developing new Müller glia reprogramming strategies in mice, including epigenetic remodeling, metabolic modulation, immune regulation, chemical small-molecules regulation, extracellular matrix remodeling, and cell-cell fusion, to achieve Müller glia reprogramming in mice.

Associations of prenatal exposure to individual and mixed organophosphate esters with ADHD symptom trajectories in preschool children: The modifying effects of maternal Vitamin D.

BACKGROUND: Organophosphate esters (OPEs) are a class of environmental chemicals with endocrine-disrupting properties. Epidemiologic studies have demonstrated that prenatal OPEs exposure is associated with neurodevelopmental disorders in offspring. However, studies assessing the effects of prenatal OPEs exposure on the dynamic changes in attention deficit hyperactivity disorder (ADHD) symptoms in preschoolers are scarce. Since vitamin D has been demonstrated to have a "neuroprotective" effect, the modifying effects of maternal vitamin D were estimated. METHODS: The present study included 2410 pregnant women from the Ma'anshan Birth Cohort. The levels of OPEs in the mothers' urine were examined in the three trimesters. The Chinese version of the Conners Abbreviated Symptom Questionnaire was used to examine preschoolers' ADHD symptoms at 3, 5, and 6 years of age. ADHD symptom trajectories were fitted via group-based trajectory modeling. We used multinomial logistic regression, Bayesian kernel machine regression, quantile-based g-computation, and generalized linear models to assess individual and mixed relationships between OPEs during pregnancy and preschoolers' ADHD symptoms and trajectories. RESULTS: Preschoolers' ADHD symptom scores were fitted to 3 trajectories, including the low-score, moderate-score, and high-score groups. First-trimester dibutyl phosphate (DBP), second-trimester bis(2-butoxyethyl) phosphate (BBOEP), and third-trimester diphenyl phosphate (DPHP) were associated with an increased risk in the high-score group (p < 0.05). BBOEP in the third trimester was associated with decreased risk in the moderate-score group (OR = 0.89, 95% CI: 0.79, 1.00). For mothers with 25(OH)D deficiency, a positive relationship was observed between OPEs during pregnancy and symptom trajectories. Our results did not reveal any mixed effects of OPEs on ADHD symptom trajectories. CONCLUSION: Prenatal exposure to OPEs had heterogeneous associations with ADHD symptom trajectories in preschoolers. Additionally, the effect of individual OPEs on symptom trajectories was intensified by vitamin D deficiency.

Prevalence of infection and reinfection among healthcare workers in a hospital of Northern China between BA.5/BF. 7 and XBB.1.5 wave.

BACKGROUND: Healthcare workers (HCWs) play a crucial role as frontline responders during the COVID-19 pandemic. This study aimed to analyze the epidemiological characteristics of the first SARS-CoV-2 infection and reinfection associated with the emergence of Omicron variant in HCWs. METHODS: We enrolled 760 HCWs who received 2-4 vaccination doses of COVID-19 and followed by BA.5/BF.7 and/or XBB.1.5 breakthrough infections between December 2022 and July 2023. Serum sample from each individual were collected approximately 1,3 and 6 months after last exposure. IgM, IgG and Total antibodies against SARS-CoV-2 were measured by chemiluminescent immunoassay. Meanwhile, we created an Enterprise WeChat link for HCWs to self-report SARS-CoV-2 infections, symptoms and post COVID-19 conditions. RESULTS: Our study revealed that the reinfection rate among HCWs reached 26.1%. The main symptoms were fever (91.2% vs. 60.1%), cough (78.8% vs. 58.0%), and sore throat (75.4% vs. 59.6%) during infection and reinfection in Omicron BA.5/BF.7 and XBB.1.5 wave, and the interval for reinfection ranged from 91 to 210 days (median 152 days). Fatigue (23.6%), memory loss (18.8%) and coughing (18.6%) were the most prevalent long COVID symptoms in HCWs, with a higher prevalence among female HCWs. CONCLUSIONS: HCWs reinfection with SARS-CoV-2 causes milder symptoms, but high reinfection rate and short intervals. Enhancing prevention strategies, protection and training is crucial to mitigating HCW infection risk and improving health services.

Identification and validation of aging-related genes in neuropathic pain using bioinformatics.

Background: Neuropathic pain (NP) is a debilitating and refractory chronic pain with a higher prevalence especially in elderly patients. Cell senescence considered a key pathogenic factor in NP. The objective of this research is to discover genes associated with aging in peripheral blood of individuals with NP using bioinformatics techniques. Methods: Two cohorts (GSE124272 and GSE150408) containing peripheral blood samples of NP were downloaded from the GEO database. By merging the two cohorts, differentially expressed aging-related genes (DE-ARGs) were obtained by intersection with aging-related genes. The potential biological mechanisms of DE-ARGs were further analyzed through GO and KEGG. Three machine learning methods, namely, LASSO, SVM-RFE, and Random Forest, were utilized to identify diagnostic biomarkers. A Nomogram model was developed to assess their diagnostic accuracy. The validation of biomarker expression and diagnostic effectiveness was conducted in three distinct pain cohorts. The CIBERSORT algorithm was employed to evaluate the immune cell composition in the peripheral blood of patients with NP and investigate its association with the expression of diagnostic biomarkers. Results: This study identified a total of 24 DE-ARGs, mainly enriched in "Chemokine signaling pathway," "Inflammatory mediator regulation of TRP channels," "HIF-1 signaling pathway" and "FOXO signaling pathway". Three machine learning algorithms identified a total of four diagnostic biomarkers (CEBPA, CEACAM1, BTG3 and IL-1R1) with good diagnostic performance and the similar expression difference trend in different types of pain cohorts. The expression levels of CEACAM1 and IL-1R1 exhibit a positive correlation with the percentage of neutrophils. Conclusion: Using machine learning techniques, our research identified four diagnostic biomarkers related to aging in peripheral blood, providing innovative approaches for the diagnosis and treatment of NP.

Finite immune imprinting on neutralizing antibody responses to Omicron subvariants by repeated vaccinations.

OBJECTIVE: To investigate the effects of repeated vaccination with ancestral SARS-CoV-2 (Wuhan-hu-1)-based inactivated, recombinant protein subunit or vector-based vaccines on the neutralizing antibody response to Omicron subvariants. METHODS: Individuals who received four-dose vaccinations with the Wuhan-hu-1 strain, individuals who were infected with the BA.5 variant alone without prior vaccination, and individuals who experienced a BA.5 breakthrough infection following receiving 2-4 doses of the Wuhan-hu-1 vaccine were enrolled. Neutralizing antibodies against D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 were detected using a pseudovirus-based neutralization assay. Antigenic cartography was used to analyze cross-reactivity patterns among D614G, BA.5, XBB.1.5, EG.5.1, and BA.2.86 and sera from individuals. RESULTS: The highest neutralizing antibody titers against D614G were observed in individuals who only received four-dose vaccination and those who experienced BA.5 breakthrough infection, which was also significantly higher than the antibody titers against XBB.1.5, EG.5.1, and BA.2.86. In contrast, only BA.5 infection elicited comparable neutralizing antibody titers against the tested variants. While neutralizing antibody titers against D614G or BA.5 were similar across the cohorts, the neutralizing capacity of antibodies against XBB.1.5, EG.5.1, and BA.2.86 was significantly reduced. BA.5 breakthrough infection following heterologous booster induced significantly higher neutralizing antibody titers against the variants, particularly against XBB.1.5 and EG.5.1, than uninfected vaccinated individuals, only BA.5 infected individuals, or those with BA.5 breakthrough infection after primary vaccination. CONCLUSIONS: Our findings suggest that repeated vaccination with the Wuhan-hu-1 strain imprinted a neutralizing antibody response toward the Wuhan-hu-1 strain with limited effects on the antibody response to the Omicron subvariants.

Impact of chronic sleep deprivation on male reproductive health: Insights from testicular and epididymal responses in mice.

BACKGROUND: Sleep deprivation (SD) can cause damage to the male reproductive system. However, the duration required for such damage and the specific sequence and severity of damage to the testis and epididymis remain unclear. OBJECTIVE: To investigate the effects of different durations of SD on different parts of the testis and epididymis caput, corpus, and cauda. METHODS: Adult ICR mice were randomly assigned to five groups: the SD group (SD for 18 h/day for 1, 2, 3, or 4 weeks), the SD + Vit E group (supplemented with Vit E 50 mg/kg/d during 4 weeks of SD, the SD+NS group (saline supplementation during 4 weeks of SD), the SD + RS group (5 weeks of recovery sleep after 4 weeks of SD), and a normal sleep control (Ctrl) group. Following the interventions, sperm parameters, testicular and epididymal histopathology, inflammatory response, and oxidative stress markers were compared between the groups. RESULTS: Compared to the Ctrl group, the SD group showed a decrease in sperm motility and concentration from SD 2 W and SD 3 W, respectively. Decreases in sperm concentration and motility were more pronounced in the cauda compared to the caput and corpus. Pathological damage was less severe in the epididymis caput than in the corpus and cauda. After 4 weeks of SD, inflammation and oxidative stress increased in both testes and epididymis. Both sleep recovery and vitamin E supplementation showed significant improvements, though they did not fully reach the level of the Ctrl group. CONCLUSION: Chronic SD for more than 2 weeks causes varying degrees of damage to the testis, epididymis caput, corpus, and cauda in male mice. This damage is not fully reversible after 5 weeks of sleep recovery and antioxidant stress treatment. These findings help us to identify and prevent SD damage to the male reproduction at an early stage.

Co-exposure effects of urinary polycyclic aromatic hydrocarbons and metals on lung function: mediating role of systematic inflammation.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and metals were associated with decreased lung function, but co-exposure effects and underlying mechanism remained unknown. METHODS: Among 1,123 adults from National Health and Nutrition Examination Survey 2011-2012, 10 urinary PAHs, 11 urinary metals, and peripheral white blood cell (WBC) count were determined, and 5 lung function indices were measured. Least absolute shrinkage and selection operator, Bayesian kernel machine regression, and quantile-based g-computation were used to estimate co-exposure effects on lung function. Mediation analysis was used to explore mediating role of WBC. RESULTS: These models demonstrated that PAHs and metals were significantly associated with lung function impairment. Bayesian kernel machine regression models showed that comparing to all chemicals fixed at median level, forced expiratory volume in 1 s (FEV1)/forced vital capacity, peak expiratory flow, and forced expiratory flow between 25 and 75% decreased by 1.31% (95% CI: 0.72%, 1.91%), 231.62 (43.45, 419.78) mL/s, and 131.64 (37.54, 225.74) mL/s respectively, when all chemicals were at 75th percentile. In the quantile-based g-computation, each quartile increase in mixture was associated with 104.35 (95% CI: 40.67, 168.02) mL, 1.16% (2.11%, 22.40%), 294.90 (78.37, 511.43) mL/s, 168.44 (41.66, 295.22) mL/s decrease in the FEV1, FEV1/forced vital capacity, peak expiratory flow, and forced expiratory flow between 25% and 75%, respectively. 2-Hydroxyphenanthrene, 3-Hydroxyfluorene, and cadmium were leading contributors to the above associations. WBC mediated 8.22%-23.90% of association between PAHs and lung function. CONCLUSIONS: Co-exposure of PAHs and metals impairs lung function, and WBC could partially mediate this relationship. Our findings elucidate co-exposure effects of environmental mixtures on respiratory health and underlying mechanisms, suggesting that focusing on highly prioritized toxicants would effectively attenuate adverse effects.

High biological N fixation potential dominated by heterotrophic diazotrophs in alpine permafrost rivers on the Qinghai‒Tibet Plateau.

Biological nitrogen (N) fixation is a pivotal N source in N-deficient ecosystems. The Qinghai‒Tibet Plateau (QTP) region, which is assumed to be N limited and suboxic, is an ideal habitat for diazotrophs. However, the diazotrophic communities and associated N fixation rates in these high-altitude alpine permafrost QTP rivers remain largely unknown. Herein, we examined diazotrophic communities in the sediment and biofilm of QTP rivers via the nitrogenase (nifH) gene sequencing and assessed their N fixing activities via a 15N isotope incubation assay. Strikingly, anaerobic heterotrophic diazotrophs, such as sulfate- and iron-reducing bacteria, had emerged as dominant N fixers. Remarkably, the nifH gene abundance and N fixation rates increased with altitude, and the average nifH gene abundance (2.57 ± 2.60 × 108 copies g-1) and N fixation rate (2.29 ± 3.36 nmol N g-1d-1) surpassed that documented in most aquatic environments (nifH gene abundance: 1.31 × 105 ∼ 2.57 × 108 copies g-1, nitrogen fixation rates: 2.34 × 10-4 ∼ 4.11 nmol N g-1d-1). Such distinctive heterotrophic diazotrophic communities and high N fixation potential in QTP rivers were associated with low-nitrogen, abundant organic carbon and unique C:N:P stoichiometries. Additionally, the significant presence of psychrophilic bacteria within the diazotrophic communities, along with the enhanced stability and complexity of the diazotrophic networks at higher altitudes, clearly demonstrate the adaptability of diazotrophic communities to extreme cold and high-altitude conditions in QTP rivers. We further determined that altitude, coupled with organic carbon and phosphorus, was the predominant driver shaping diazotrophic communities and their N-fixing activities. Overall, our study reveals high N fixation potential in N-deficient QTP rivers, which provides novel insights into nitrogen dynamics in alpine permafrost rivers.

Ratiometric fluorescence probe based on carbon dots and p-phenylenediamine-derived nanoparticles for the sensitive detection of manganese ions.

A ratiometric fluorescence probe based on carbon quantum dots with 420 nm emission (bCQDs) and a p-phenylenediamine-derived fluorescence probe with 550 nm emission (yprobe) is constructed for the detection of Mn2+. The presence of Mn2+ results in the enhanced absorption band at 400 nm of yprobe, and the fluorescence of yprobe is significantly enhanced based on the chelation-enhanced fluorescence mechanism. The fluorescence of bCQDs is then quenched based on the inner filtration effect. The ratio (I550/I420) linearly increases with the increase of Mn2+ concentration within 2.00 × 10-7-1.50 × 10-6 M, and the limit of detection is 1.76 × 10-9 M. Given the fluorescence color changing from blue to yellow, the visual sensing of Mn2+ is feasible based on bCQDs/yprobe coupled with RGB value analysis. The practicability of the proposed method has been verified in tap water, lake water, and sparkling water beverage, indicating that bCQDs/yprobe has promising application in Mn2+ monitoring.

Assembly of Selenadiazine Scaffolds via Rh(III)-Catalyzed Amidine-Directed Cascade C-H Selenylation/[5 + 1] Annulation with Elemental Selenium.

By employing elemental selenium as the selenium source, we have realized the amidine-directed Rh(III)-catalyzed cascade C-H selenylation/[5 + 1] annulation for the direct construction of structurally novel selenadiazine, benzoselenadiazine, and benzoselenazol-3-amine frameworks with specific site selectivity and good functional group tolerance. Besides, the obtained products can serve as fundamental platforms for subsequent chemical transformations, and thus, the feasible SeNEx reaction, SeNEx/Michael addition, and simple conversion of the selenadiazine product into diverse other organoselenium molecules were demonstrated accordingly. Taken together, the developed methodology efficiently expands the chemical space of organoselenium species.

Exploring noninvasive matrices for assessing long-term exposure to phthalates: a scoping review.

The phthalic acid esters (PAEs) are one class of the most abundant and frequently studied pseudo-persistent organic pollutants. Noninvasive urine is an effective substrate for evaluating PAE exposure, but repeated sampling is needed to overcome this bias. This adds much work to on-site collection and the cost of detection increases exponentially. Therefore, the aim of this study was to conduct a scope review to describe the detection methods and validity of the use of other noninvasive matrices, such as nails and hair, for assessing long-term exposure to PAEs. The PubMed, Web of Science and China National Knowledge Infrastructure (CNKI), electronic databases were searched from 1 January 2000 to 3 April 2024, and 12 studies were included. Nine and three studies used hair and nails, respectively, as noninvasive matrices for detecting PAE exposure. Five articles compared the results of nail or hair and urine tests for validity of the assessment of PAE exposure. The preprocessing and detection methods for these noninvasive samples are also described. The results of this review suggest that, compared with nails, hair may be more suitable as a noninvasive alternative matrix for assessing long-term exposure to PAEs. However, sample handling procedures such as the extraction and purification of compounds from hair are not uniform in various studies; therefore, further exploration and optimization of this process, and additional research evidence to evaluate its effectiveness, are needed to provide a scientific basis for the promotion and application of hair detection methods for assessing long-term PAE exposure levels.

Proteasome inhibition induces apoptosis through simultaneous inactivation of MCL-1/BCL-XL by NOXA independent of CHOP and JNK pathways.

Proteasome inhibitors have been employed in the treatment of relapsed multiple myeloma and mantle cell lymphoma. The observed toxicity caused by proteasome inhibitors is a universal phenotype in numerous cancer cells with different sensitivity. In this study, we investigate the conserved mechanisms underlying the toxicity of the proteasome inhibitor bortezomib using gene editing approaches. Our findings utilizing different caspase knocking out cells reveal that bortezomib induces classic intrinsic apoptosis by activating caspase-9 and caspase-3/7, leading to pore-forming protein GSDME cleavage and subsequent lytic cell death or called secondary necrosis, a phenotype also observed in many apoptosis triggers like TNFα plus CHX, DTT and tunicamycin treatment in HeLa cells. Furthermore, through knocking out of nearly all BH3-only proteins including BIM, BAD, BID, BMF and PUMA, we demonstrate that NOXA is the sole BH3-only protein responsible for bortezomib-induced apoptosis. Of note, NOXA is well known for selectively binding to MCL-1 and A1, but our studies utilizing different BH3 mimetics as well as immunoprecipitation assays indicate that, except for the constitutive interaction of NOXA with MCL-1, the accumulation of NOXA after bortezomib treatment allows it to interact with BCL-XL, then simultaneous relieving suppression on apoptosis by both anti-apoptotic proteins BCL-XL and MCL-1. In addition, though bortezomib-induced significant ER stress and JNK activation were observed in the study, further genetic depletion experiments prove that bortezomib-induced apoptosis occurs independently of ER stress-related apoptosis factor CHOP and JNK. In summary, these results provide a solid conclusion about the critical role of NOXA in inactivation of BCL-XL except MCL-1 in bortezomib-induced apoptosis.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Regulation of oxidative stress response and antioxidant modification in Corynebacterium glutamicum.

As an efficient and safe industrial bacterium, Corynebacterium glutamicum has extensive application in amino acid production. However, it often faces oxidative stress induced by reactive oxygen species (ROS), leading to diminished production efficiency. To enhance the robustness of C. glutamicum, numerous studies have focused on elucidating its regulatory mechanisms under various stress conditions such as heat, acid, and sulfur stress. However, a comprehensive review of its defense mechanisms against oxidative stress is needed. This review offers an in-depth overview of the mechanisms C. glutamicum employs to manage oxidative stress. It covers both enzymatic and non-enzymatic systems, including antioxidant enzymes, regulatory protein families, sigma factors involved in transcription, and physiological redox reduction pathways. This review provides insights for advancing research on the antioxidant mechanisms of C. glutamicum and sheds light on its potential applications in industrial production.

Genetic association and functional implications of TLR4 rs1927914 polymorphism on colon cancer risk.

BACKGROUND: Colon cancer remains a major health concern worldwide, with genetic factors playing a crucial role in its development. Toll-like receptors (TLRs) has been implicated in various cancers, but their role in colon cancer is not well understood. This study aims to identify functional polymorphisms in the promoter and 3'UTR regions of TLRs and evaluate their association with colon cancer susceptibility. METHODS: We conducted a case-control study involving 410 colon cancer patients and 410 healthy controls from the Chinese population. Genotyping of polymorphisms in TLR3, TLR4, TLR5 and TLR7 was performed using PCR-RFLP and TaqMan MGB probes. Using logistic regression analysis, we evaluated the association of TLRs polymorphisms and the susceptibility to colon cancer. To understand the biological implications of the TLR4 rs1927914 polymorphism, we conducted functional assays, including luciferase reporter assay and electrophoretic mobility shift assay (EMSA). RESULTS: Our results demonstrated that the G-allele of the TLR4 rs1927914 polymorphism is significantly associated with a decreased risk of colon cancer (OR = 0.68, 95%CI = 0.50-0.91). Stratified analysis showed that TLR4 rs1927914 AG or GG genotype contributed to a decreased risk of colon cancer among younger individuals (OR = 0.52, 95%CI = 0.34-0.81), males (OR = 0.58, 95%CI = 0.38-0.87), non-smokers (OR = 0.58, 95%CI = 0.41-0.83) and non-drinker with OR (95%CI) of 0.66 (0.46-0.93). Functional assays demonstrated that in HCT116 and LOVO colon cancer cells, the luciferase activity driven by the TLR4 promoter with the rs1927914A allele was 5.43 and 2.07 times higher, respectively, compared to that driven by the promoter containing the rs1927914G allele. Electrophoretic mobility shift assay (EMSA) results indicated that the rs1927914G allele enhanced transcription factor binding. Using the transcription factor prediction tool, we found that the G allele facilitates binding of the repressive transcription factor Oct1, while the A allele does not. CONCLUSION: The TLR4 rs1927914 polymorphism influence the susceptibility to colon cancer, with the G allele offering a protective effect through modulation of gene expression. These insights enhance our understanding of the genetic determinants of colon cancer risk and highlight TLR4 as a promising target for cancer prevention strategies.

Immunometabolic alteration of CD4+ T cells in the pathogenesis of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.

Eosin Y Post-Decorated Metal-Organic Framework as a Selectivity Regulator for the Alcohols Oxidation.

The selective oxidation of alcohols into aldehydes is a basic and significant procedure, with great potential for scientific research and industrial applications. However, as an important factor in the C(sp3)-H activation process, high selectivity is generally difficult to achieve due to the fact that the more easily activated properties of aldehydes are compared to alcohols. Herein, by the ingenious decoration of eosin Y into a Zr-based metal-organic framework (MOF-808), EY@MOF-808 was prepared as a selectivity regulator for the aerobic oxidation of the benzyl alcohols into corresponding aldehydes, possessing applicability for the benzylic alcohols with various substituents. By anchoring eosin Y on Zr6O4(OH)4 clusters of MOF-808 and maintaining open metal nodes with selective binding effects, the benzyl alcohol substrates were selectively coordinated to the unsaturated metal clusters adjacent to eosin Y, which ensured that the excited eosin Y rapidly activated substrates to generate carbon radicals by the hydrogen atom transfer (HAT) process. The rapid electron transfer (ET) simultaneously produced reactive oxygen species (O2•-) and then a combination of both to further promote the generation of benzaldehydes. The weak interaction of benzaldehydes with the skeleton allowed it to dissociate rapidly, thus preventing overoxidation. Under the catalysis of EY@MOF-808, the selectivity of various benzaldehydes was more than 99%. In contrast, eosin Y gave only benzoic acid products under the same conditions, which demonstrated the superiority of regulatory selectivity of EY@MOF-808. Taking advantage of the heterogeneity of the MOF, EY@MOF-808 was recycled four times without a decrease in its selectivity and avoided the quenching effect of eosin Y. The organic functional units postdecorated MOF-based photocatalyst strategy exhibits a promising new perspective approach to sustainably regulating the selectivity of inert oxidation.

Acupuncture for the treatment of painful diabetic peripheral neuropathy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: A growing number of studies have investigated the efficacy of acupuncture in the treatment of painful diabetic peripheral neuropathy (PDPN), but the findings of these studies have generated conflicting results. This study therefore aimed to assess the efficacy of acupuncture for treating PDPN so as to offer more conclusive results. METHODS: Seven databases were systematically searched for studies published up until December 1, 2023. All randomized controlled trials (RCTs) of acupuncture for PDPN with visual analog scale (VAS) for pain score were included. Study selection, data extraction, and evaluation were conducted independently by researchers. The Risk of Bias 2 (RoB2) tool was employed to assess the risk of bias. From this sample, the mean difference (MD), 95 % confidence intervals (CI), publication bias, and heterogeneity were then computed. RESULTS: The manual acupuncture group exhibited a significant decrease in the VAS for pain score compared with the routine care group (p < 0.0001; MD = -1.45 [95 % CI, -1.97 to -0.93], I2 = 84 %). The real acupuncture group demonstrated a greater reduction in VAS scores than the sham acupuncture group (p = 0.004; MD = -0.97 [95 % CI, -1.63 to -0.31], I2 = 65 %). Additionally, the acupuncture group showed improvements in sensory nerve conduction velocity (SNCV, p < 0.0001; MD = 2.29 [95 % CI, 1.79 to 2.78], I2 = 14 %) as well as motor nerve conduction velocity (MNCV, p < 0.0001; MD = 2.87 [95 % CI, 2.46 to 3.27], I2 = 0). Different durations of acupuncture treatment, including 6-10 weeks and 3-4 weeks, demonstrated a significant reduction in VAS scores compared with the routine care group. CONCLUSION: This meta-analysis provides preliminary evidence for the claim that acupuncture has the potential to alleviate PDPN symptoms and improve SNCV and MNCV. However, high-quality RCTs are needed to offer further evidence and thus better substantiate such a contention.

Utilizing machine learning and bioinformatics analysis to identify drought-responsive genes affecting yield in foxtail millet.

Drought stress is a major constraint on crop development, potentially causing huge yield losses and threatening global food security. Improving Crop's stress tolerance is usually associated with a yield penalty. One way to balance yield and stress tolerance is modification specific gene by emerging precision genome editing technology. However, our knowledge of yield-related drought-tolerant genes is still limited. Foxtail millet (Setaria italica) has a remarkable tolerance to drought and is considered to be a model C4 crop that is easy to engineer. Here, we have identified 46 drought-responsive candidate genes by performing a machine learning-based transcriptome study on two drought-tolerant and two drought-sensitive foxtail millet cultivars. A total of 12 important drought-responsive genes were screened out by principal component analysis and confirmed experimentally by qPCR. Significantly, by investigating the haplotype of these genes based on 1844 germplasm resources, we found two genes (Seita.5G251300 and Seita.8G036300) exhibiting drought-tolerant haplotypes that possess an apparent advantage in 1000 grain weight and main panicle grain weight without penalty in grain weight per plant. These results demonstrate the potential of Seita.5G251300 and Seita.8G036300 for breeding drought-tolerant high-yielding foxtail millet. It provides important insights for the breeding of drought-tolerant high-yielding crop cultivars through genetic manipulation technology.

Interfacial engineering of Ag/C catalysts for practical electrochemical CO2 reduction to CO.

Electrochemical CO2 reduction to value-added chemicals by renewable energy sources is a promising way to implement the artificial carbon cycle. During the reaction, especially at high current densities for practical applications, the complex interaction between the key intermediates and the active sites would affect the selectivity, while the reconfiguration of electrocatalysts could restrict the stability. This paper describes the fabrication of Ag/C catalysts with a well-engineered interfacial structure, in which Ag nanoparticles are partially encapsulated by C supports. The obtained electrocatalyst exhibits CO Faradaic efficiencies (FEs) of over 90% at current densities even as high as 1.1 A/cm2. The strong interfacial interaction between Ag and C leads to highly localized electron density that promotes the rate-determining electron transfer step by enhancing the adsorption and the stabilization of the key *COO‒ intermediate. In addition, the partially encapsulated structure prevents the reconfiguration of Ag during the reaction. Stable performance for over 600 h at 500 mA/cm2 is achieved with CO FE maintaining over 95%, which is among the best stability with such a high selectivity and current density. This work provides a novel catalyst design showing the potential for the practical application of electrochemical reduction of CO2.