A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells. METHODS: We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×109 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored. RESULTS: Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×109 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×109 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56dimCD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased. CONCLUSIONS: In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).

Evolution and post-transcriptional regulation insights of m6A writers, erasers, and readers in plant epitranscriptome.

As a dynamic and reversible post-transcriptional marker, N6-methyladenosine (m6A) plays an important role in the regulation of biological functions, which are mediated by m6A pathway components including writers (MT-A70, FIP37, VIR and HAKAI family), erasers (ALKBH family) and readers (YTH family). There is an urgent need for a comprehensive analysis of m6A pathway components across species at evolutionary levels. In this study, we identified 4062 m6A pathway components from 154 plant species including green algae, utilizing large-scale phylogenetic to explore their origin and evolution. We discovered that the copy number of writers was conserved among different plant lineages, with notable expansions in the ALKBH and YTH families. Synteny network analysis revealed conserved genomic contexts and lineage-specific transpositions. Furthermore, we used Direct RNA Sequencing (DRS) to reveal the Poly(A) length (PAL) and m6A ratio profiles in six angiosperms species, with a particular focus on the m6A pathway components. The ECT1/2-Poeaece4 sub-branches (YTH family) with unique genomic contexts exhibited significantly higher expression level than genes of other ECT1/2 poeaece sub-branches (ECT1/2-Poeaece1-3), accompanied by lower m6A modification and PAL. Besides, conserved m6A sites distributed in CDS and 3'UTR were detected in the ECT1/2-Poaceae4, and the dual-luciferase assay further demonstrated that these conserved m6A sites in the 3'UTR negatively regulated the expression of Firefly luciferase (LUC) gene. Finally, we developed transcription factor regulatory networks for m6A pathway components, using yeast one-hybrid assay demonstrated that PheBPC1 could interact with the PheECT1/2-5 promoter. Overall, this study presents a comprehensive evolutionary and functional analysis of m6A pathway components and their modifications in plants, providing a valuable resource for future functional analysis in this field.

Overexpression of plant chitin receptors in wheat confers broad-spectrum resistance to fungal diseases.

Wheat (Triticum aestivum L.) is a globally staple crop vulnerable to various fungal diseases, significantly impacting its yield. Plant cell surface receptors play a crucial role in recognizing pathogen-associated molecular patterns (PAMPs) and activating PAMP-triggered immunity, boosting resistance against a wide range of plant diseases. Although the role of plant chitin receptor CERK1 in immune recognition and defense has been established in Arabidopsis and rice, its function and potential agricultural applications in enhancing resistance to crop diseases remain largely unexplored. Here, we identify and characterize TaCERK1 in Triticeae crop wheat, uncovering its involvement in chitin recognition, immune regulation, and resistance to fungal diseases. By a comparative analysis of CERK1 homologs in Arabidopsis and monocot crops, we demonstrate that AtCERK1 in Arabidopsis elicits the most robust immune response. Moreover, we show that overexpressing TaCERK1 and AtCERK1 in wheat confers resistance to multiple fungal diseases, including Fusarium head blight, stripe rust, and powdery mildew. Notably, transgenic wheat lines with moderately expressed AtCERK1 display superior disease resistance and heightened immune responses without adversely affecting growth and yield, compared to TaCERK1 overexpression transgenics. Our findings highlight the significance of plant chitin receptors across diverse plant species and suggest potential strategies for bolstering crop resistance against broad-spectrum diseases in agricultural production through the utilization of plant immune receptors.

Plasma metabolomic signature of healthy lifestyle, structural brain reserve and risk of dementia.

Although the association between healthy lifestyle and dementia risk has been documented, the relationship between a metabolic signature indicative of healthy lifestyle and dementia risk and the mediating role of structural brain impairment remain unknown. We retrieved 136 628 dementia-free participants from UK Biobank. Elastic net regression was used to obtain a metabolic signature that represented lifestyle behaviours. Cox proportional hazard models were fitted to explore the associations of lifestyle-associated metabolic signature with incident dementia. Causal associations between identified metabolites and dementia were investigated using Mendelian randomization. Mediation analysis was also conducted to uncover the potential mechanisms involving 19 imaging-derived phenotypes (brain volume, grey matter volume, white matter volume and regional grey matter volumes). During a follow-up of 12.55 years, 1783 incident cases of all-cause dementia were identified, including 725 cases of Alzheimer's dementia and 418 cases of vascular dementia. We identified 83 metabolites that could represent healthy lifestyle behaviours using elastic net regression. The metabolic signature was associated with a lower dementia risk, and for each standard deviation increment in metabolic signature, the hazard ratio was 0.89 [95% confidence interval (CI): 0.85, 0.93] for all-cause dementia, 0.95 (95% CI: 0.88, 1.03) for Alzheimer's dementia and 0.84 (95% CI: 0.77, 0.91) for vascular dementia. Mendelian randomization revealed potential causal associations between the identified metabolites and risk of dementia. In addition, the specific structural brain reserve, including the hippocampus, grey matter in the hippocampus, parahippocampal gyrus and middle temporal gyrus, were detected to mediate the effects of metabolic signature on dementia risk (mediated proportion ranging from 6.21% to 11.98%). The metabolic signature associated with a healthy lifestyle is inversely associated with dementia risk, and greater structural brain reserve plays an important role in mediating this relationship. These findings have significant implications for understanding the intricate connections between lifestyle, metabolism and brain health.

Association of metabolic signatures of air pollution with MASLD: Observational and Mendelian randomization study.

BACKGROUND & AIMS: To identify metabolic signatures associated with exposure to ambient air pollution and to explore their associations with risk of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We utilized data from the UK Biobank Cohort. Annual mean concentrations of PM2.5, PM10, NO2 and NOx were assessed for each participant using bilinear interpolation. The Elastic Net regression model was used to identify metabolites associated with four air pollutants and to construct metabolic signatures, respectively. Associations between air pollutants, metabolic signatures and MASLD were analyzed using Cox models. Mendelian randomization (MR) analysis was used to examine potential causality. Mediation analysis was employed to examine the role of metabolic signatures in the association between air pollutants and MASLD. RESULTS: A total of 244,842 participants from the UK Biobank were included in this analysis. We identified 87, 65, 76, and 71 metabolites as metabolic signatures of PM2.5, PM10, NO2, and NOx, respectively. Metabolic signatures were associated with risk of MASLD, with hazard ratios (HRs) and 95% confidence intervals (95% CIs) were 1.10 (1.06, 1.14), 1.06 (1.02, 1.10), 1.24 (1.20, 1.29) and 1.14 (1.10, 1.19). The four pollutants were associated with increased risk of MASLD, with HRs (95% CIs) of 1.03 (1.01, 1.05), 1.02 (1.01, 1.04), 1.01 (1.01, 1.02) and 1.01 (1.00, 1.01). MR analysis indicated an association between PM2.5, NO2 and NOx-related metabolic signatures and MASLD. Metabolic signatures mediated the association of PM2.5, PM10, NO2 and NOx with MASLD. CONCLUSION: There may be association between PM2.5, PM10, NO2 and NOx-related metabolic signatures and MASLD, and metabolic signatures mediate the increase of PM2.5, PM10, NO2 and NOx in the risk of MASLD. IMPACT AND IMPLICATIONS: Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), however, the mechanism by which air pollution affects MASLD remains unclear. Our study used integrated serological metabolic data of 251 metabolites from a large-scale cohort study to demonstrate that metabolic signatures play a crucial role in the elevated risk of MASLD caused by air pollution. These results are relevant to patients and policymakers because they suggest that air pollution-related metabolic signatures are not only potentially associated with MASLD but also involved in mediating the process by which PM2.5, PM10, NO2, and NOx increase the risk of MASLD. Focusing on changes in air pollution-related metabolic signatures may offer a new perspective for preventing air pollution-induced MASLD and serve as protective measures to address this emerging public health challenge.

"Visualization" Gas-Gas Sensors Based on High Performance Novel MXenes Materials.

The detection of toxic, harmful, explosive, and volatile gases cannot be separated from gas sensors, and gas sensors are also used to monitor the greenhouse effect and air pollution. However, existing gas sensors remain with many drawbacks, such as lower sensitivity, lower selectivity, and unstable room temperature detection. Thus, there is an imperative need to find more suitable sensing materials. The emergence of a new 2D layered material MXenes has brought dawn to solve this problem. The multiple advantages of MXenes, namely high specific surface area, enriched terminal functionality groups, hydrophilicity, and good electrical conductivity, make them among the most prolific gas-sensing materials. Therefore, this review paper describes the current main synthesis methods of MXenes materials, and focuses on summarizing and organizing the latest research results of MXenes in gas sensing applications. It also introduces the possible gas sensing mechanisms of MXenes materials on NH3 , NO2 , CH3 , and volatile organic compounds (VOCs). In conclusion, it provides insight into the problems and upcoming challenges of MXenes materials for gas sensing.

The activity of hyaD contributed to the virulence of avian Pasteurella multocida.

Fowl cholera is an infectious disease that affects both poultry and wild birds, characterized by hemorrhagic and septicemic symptoms, caused by Pasteurella multocida (P. multocida), and leading to substantial economic losses in the poultry sector. The development of genetic engineering vaccines against avian P. multocida encountered early-stage challenges due to the limited availability of effective gene editing tools. Presently, NgAgoDM-enhanced homologous recombination stands as a potent technique for achieving efficient gene knockout in avian P. multocida. Hence, this study employed NgAgoDM-enhanced homologous recombination to target and knockout hyaE (239-359aa), hyaD, hexABC, and hexD, denoted as ΔhyaE (239-359aa), ΔhyaD, ΔhexABC, and ΔhexD, respectively. Additionally, we generated a hyaD recovery strain with two point mutations, designated as mhyaD. Thus, this study systematically examined the impact of capsular synthetic gene clusters on the pathogenicity of P. multocida. Moreover, the study demonstrated the critical role of hyaD activity in the virulence of avian P. multocida. This study offers novel insights for enhancing attenuated vaccines further.

Intravenous Golimumab in Children With Polyarticular-Course Juvenile Idiopathic Arthritis: Long-Term Extension of an Open-Label, Phase III Study.

OBJECTIVE: To report pharmacokinetics (PK), immunogenicity, clinical effect, and safety of intravenous (IV) golimumab in children with active polyarticular-course juvenile idiopathic arthritis (pcJIA) who participated in A Study to Evaluate the Pharmacokinetics, Efficacy and Safety of Intravenous Golimumab in Pediatric Participants With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy (GO-VIVA)'s open-label, long-term extension (LTE) through week 252. METHODS: GO-VIVA participants who continued IV golimumab (80 mg/m2 every 8 weeks) after week 52 were included. PK and safety were assessed through week 244 (last dose) and week 252, respectively, and clinical response through week 116. Clinical outcomes included JIA-American College of Rheumatology (ACR) responses and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Binary outcomes used nonresponder imputation, and other descriptive analyses used observed data. RESULTS: Of 112/127 (88.2%) participants entering the LTE, 69 completed the week 252 visit. Median steady-state trough golimumab concentrations were generally maintained from week 52 through week 244 (range 0.3-0.6 µg/mL). Antigolimumab antibody rates were consistent through week 52 (39.2% [49/125]) and week 244 (44.8% [56/125]). Week 52 JIA-ACR 30/50/70/90 response rates (75.6% [96/127], 74% [94/127], 65.4% [83/127], and 48.8% [62/127], respectively) were generally maintained through week 116 (72.4% [92/127], 71.7% [91/127], 63.8% [81/127], and 50.4% [64/127], respectively), when the median cJADAS10 was 1.6 and 56.7% (72/127) of participants achieved cJADAS10 ≤ 5 (minimal disease activity). Rates (per 100 patient-years) of serious adverse events and serious infections through week 252 were 7.7 and 3.9, respectively. CONCLUSION: GO-VIVA LTE participants experienced adequate PK exposure and stable safety and immunogenicity. The majority of participants experienced no more than minimal residual disease activity. Data suggest IV golimumab treatment provided durable clinical response through week 116, with an acceptable risk-benefit profile.

Broadband Yellow-Emitting Oxynitride Phosphor Sr2Si7Al3ON13:Ce3+,Eu2+ for White Light-Emitting Diodes with a High Color Rendering Index.

The utilization of blue LED chips in conjunction with the commercial yellow phosphor YAG:Ce3+ currently represents the most straightforward and efficient approach for generating white light, albeit at a slight compromise to the color rendering index. However, by expansion of the spectral coverage of the yellow phosphor, it becomes feasible to achieve a high color rendering index for white light. In this study, we synthesized a broadband yellow oxynitride phosphor through codoping Ce3+ and Eu2+ on highly chemically stable Sr2Si7Al3ON13. We conducted an extensive investigation of the energy transfer process between Ce3+ and Eu2+ within Sr2Si7Al3ON13:Ce3+,Eu2+. By adjusting the doping concentration of Eu2+, we successfully obtained a higher emission intensity and improved thermal stability for Sr2Si7Al3ON13:Ce3+,Eu2+ under 450 nm blue-light excitation. Furthermore, we achieved a full width at half-maximum (fwhm) broadened to 130 nm along with an optimal external quantum efficiency (EQE) of 43.2%. The resulting WLED devices utilizing this yellow phosphor exhibited high color rendering index (CRI, Ra = 86.2) white light emission (0.3488, 0.3407). These exceptional properties highlight the significant potential application of Sr2Si7Al3ON13:Ce3+,Eu2+ in blue light-excited WLED as well as its promising prospects in indoor display lighting.

Unraveling the Ultrasonic-Assisted Synthesis of Green-Emitting CsPbBr3@Cs4PbBr6: Reaction Process, Luminescence Property, and Display Application.

The pursuit of stable and highly emissive perovskite materials has garnered increasing attention in optoelectronic applications. Green-emitting CsPbBr3@Cs4PbBr6, as a green-emissive material in the solid-state form, has great potential as a color conversion material for full-color displays. However, it is a challenge to achieve mass preparation under ambient conditions. Meanwhile, the formation mechanism is ambiguous. This study reports a ligand-free and rapid mass synthesis of nanomicrosized CsPbBr3@Cs4PbBr6 solid via an ultrasonic-assisted method. The synthesized CsPbBr3@Cs4PbBr6 solids exhibit uniform morphology, high stability, and solid-state quantum efficiency of approximately 55%. Moreover, the transformation mechanism from Pb-Br complexes in the synthesis process is fully investigated by monitoring the phase and spectral evolution. By employing it as a green emitter, the obtained white light-emitting diode (LED) device shows high performance with a correlation color temperature of 7635 K and a wide color gamut of 123% NTSC. This study offers a low-cost and simple operation mass production method for solid-state perovskite powders with excellent chemical stability. Additionally, it provides new insights into the formation mechanism of highly efficient perovskite materials and promotes their practical applications.

Health-related quality of life in Chinese SLE patients: evidence from 1568 SLE patients and 2610 healthy controls.

OBJECTIVE: To investigate the effects of systemic lupus erythematosus (SLE) on health-related quality of life (HRQOL), the relationship between disease activity and HRQOL, and potential factors affecting HRQOL in Chinese SLE patients. METHODS: This study recruited 1568 patients and 2610 controls to explore the effects of SLE on HRQOL. The association between disease activity and HRQOL, and the influencing factors of HRQOL were determined in 1568 patients. Then, we prospectively followed 1096 patients to explore the association between reduced disease activity and improved HRQOL, and the influencing factors of improved HRQOL. The Short-Form 36 (SF-36) and SLE disease activity index (SLEDAI) were used to evaluate HRQOL and disease activity. RESULTS: Chinese SLE patients had lower HRQOL than controls in all domains (P < 0.001), especially in role-physical (RP) and role-emotional (RE). Compared with SLE patients from outside China, the HRQOL of Chinese patients appeared to be higher in mental component summary (MCS) but lower in RP and RE. SLEDAI was negatively correlated with HRQOL, which was validated using the results of a follow-up study, where SLEDAI reduction was positively associated with HRQOL improvements (P < 0.05). Furthermore, personality, life nervous and experiences of adverse life events may influence HRQOL and HRQOL improvements. CONCLUSION: SLE significantly affected the HRQOL of Chinese patients, especially in RP and RE. Disease activity was negatively correlated with HRQOL. We also found for the first time some factors affecting HRQOL, which can be regarded as the basis for improving the HRQOL of SLE patients.

The fluoride exporter (CsFEX) regulates fluoride uptake/accumulation in Camellia sinensis under different pH.

Fluoride (F) can be absorbed from the environment and hyperaccumulate in leaves of Camellia sinensis without exhibiting any toxic symptoms. Fluoride exporter in C. sinensis (CsFEX) could transport F to extracellular environment to alleviate F accumulation and F toxicity, but its functional mechanism remains unclear. Here, combining with pH condition of C. sinensis growth, the characteristics of CsFEX and mechanism of F detoxification were further explored. The results showed that F accumulation was influenced by various pH, and pH 4.5 and 6.5 had a greater impact on the F accumulation of C. sinensis. Through Non-invasive Micro-test Technology (NMT) detection, it was found that F uptake/accumulation of C. sinensis and Arabidopsis thaliana might be affected by pH through changing the transmembrane electrochemical proton gradient of roots. Furthermore, diverse expression patterns of CsFEX were induced by F treatment under different pH, which was basically up-regulated in response to high F accumulation, indicating that CsFEX was likely to participate in the process of F accumulation in C. sinensis and this process might be regulated by pH. Additionally, CsFEX functioned in the mitigation of F sensitivity and accumulation strengthened by lower pH in Escherichia coli and A. thaliana. Moreover, the changes of H+ flux and potential gradient caused by F were relieved as well in transgenic lines, also suggesting that CsFEX might play an important role in the process of F accumulation. Above all, F uptake/accumulation were alleviated in E. coli and A. thaliana by CsFEX through exporting F-, especially at lower pH, implying that CsFEX might regulate F accumulation in C. sinensis.

High-Precision Inertial Sensor Charge Ground Measurement Method Based on Phase-Sensitive Demodulation.

Inertial sensors are the key payloads in space gravitational wave detection missions, and they need to ensure that the test mass (TM), which serves as the inertial reference, freely floats in the spacecraft without contact, so that the TM is not disturbed by the satellite platform and the cosmic environment. Space gravitational wave detection missions require that the residual acceleration of the TM should be less than 3×10-15ms-2Hz-1/2. However, the TM with charges will interact with surrounding conductors and magnetic fields, introducing acceleration noise such as electrostatic force and Lorentz force. Therefore, it is necessary to carry out charge management on the TM, in which the high-precision measurement of charge is crucial. Space gravitational wave detection missions require a residual charge measurement accuracy of 3×10-13C for the TM. In this paper, we design a high-precision inertial sensor charge measurement method based on phase-sensitive demodulation (PSD). By establishing a torsion pendulum rotation model based on the force modulation method, the characteristics of the TM torsion angle signal are analyzed. The PSD is used to extract the amplitude of the specific frequency signal component containing the charge information, and then to calculate the value of the accumulated charges. The method is compared with the Butterworth band-pass filtering method, and the simulation results show that the method has a higher measurement accuracy, shorter settling time, and stronger anti-interference ability, meeting the TM residual charge measurement accuracy index requirement.

Aesthetic impact of resin infiltration and its mechanical effect on ceramic bonding for white spot lesions.

BACKGROUND: Treating white spot lesions (WSLs) with resin infiltration alone may not be sufficient, raising questions about its compatibility with other treatments amid controversial or incomplete data. Therefore, this study aimed to assess the aesthetic feasibility of resin infiltration combined with bleaching, as well as its potential mechanical effect on ceramic bonding to WSLs. METHODS: One hundred and fifty flat enamel surfaces of bovine incisors were prepared. Ninety specimens were deminerailized and randomly assigned to three groups(n = 30): post-bleaching resin infiltration (Bl-R), pre-bleaching resin infiltration (R-Bl), and only resin infiltration (R). Color, surface roughness and microhardness were assessed in immediate, thermocycling and pigmentation tests. The remaining sixty samples were randomly assigned to three groups (n = 20): control (Ctrl), bonding (Bo), pre-bonding resin infiltration (R-Bo). Shear bonding strength, failure mode, micro-leakage depth and interface morphology were evaluated after ceramic bonding. The Tukey test and analysis of variance (ANOVA) were used for statistical analysis. RESULTS: For the effect of resin infiltration and bleaching on WSLs, the R-Bl group showed the worst chromic masking ability, with the highest |ΔL|, |Δa|, |Δb|, and ΔE values after treatment. Compared with those in the Bl-R group, the R-Bl and R groups showed significant time-dependent staining, which is possibly attributed to their surface roughness. For the effect of resin infiltration on the adhesive properties of WSLs, resin infiltration reduced the staining penetration depth of WSLs from 2393.54 ± 1118.86 µm to 188.46 ± 89.96 µm (P < 0.05) while reducing WSLs porosity in SEM observation. CONCLUSIONS: Post-bleaching resin infiltration proved to be advantageous in the aesthetic treatment of WSLs. Resin infiltration did not compromise bonding strength but it did reduce microleakage and enhance marginal sealing. Overall, resin infiltration can effectively enhance the chromatic results of treated WSLs and prevent long-term bonding failure between ceramics and enamel. Based on these findings, the use of post-bleaching resin infiltration is recommended, and resin infiltration before ceramic bonding is deemed viable in clinical practice.

Baricitinib for the treatment of refractory vascular Behçet's disease.

OBJECTIVE: The pilot study aims to evaluate the effectiveness and safety of baricitinib in Behcet's Disease (BD) patients with refractory vascular involvement. METHODS: We consecutively enrolled vascular/cardiac BD patients who received baricitinib (2 mg/day) along with glucocorticoids (GCs) and immunosuppressants in our center. Efficacy assessment mainly depends on the proportion of clinical remission and side effects were recorded. RESULTS: 17 patients (12 males) were included with a mean follow-up of 10.7 ± 5.3 months. At 3 months of follow-up, 76.5% of patients achieved a complete response and the proportion increased to 88.2% at the last visit. During follow-up, ESR (p < 0.01) and hsCRP (p < 0.0001) decreased significantly, as well as Behçet's Disease Current Activity Form score (p < 0.01). In addition, baricitinib showed a GCs-sparing effect. No serious adverse events were noted. CONCLUSIONS: Our study suggests that baricitinib is well-tolerated and effective in treating refractory vascular/cardiac BD patients.

Nrf2 regulates iron-dependent hippocampal synapses and functional connectivity damage in depression.

Neuronal iron overload contributes to synaptic damage and neuropsychiatric disorders. However, the molecular mechanisms underlying iron deposition in depression remain largely unexplored. Our study aims to investigate how nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) ameliorates hippocampal synaptic dysfunction and reduces brain functional connectivity (FC) associated with excessive iron in depression. We treated mice with chronic unpredictable mild stress (CUMS) with the iron chelator deferoxamine mesylate (DFOM) and a high-iron diet (2.5% carbonyl iron) to examine the role of iron overload in synaptic plasticity. The involvement of Nrf2 in iron metabolism and brain function was assessed using molecular biological techniques and in vivo resting-state functional magnetic resonance imaging (rs-fMRI) through genetic deletion or pharmacologic activation of Nrf2. The results demonstrated a significant correlation between elevated serum iron levels and impaired hippocampal functional connectivity (FC), which contributed to the development of depression-induced CUMS. Iron overload plays a crucial role in CUMS-induced depression and synaptic dysfunction, as evidenced by the therapeutic effects of a high-iron diet and DFOM. The observed iron overload in this study was associated with decreased Nrf2 levels and increased expression of transferrin receptors (TfR). Notably, inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Nrf2-/- mice exhibited compromised FC within the limbic system and the basal ganglia, particularly in the hippocampus, and inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Activation of Nrf2 restored iron homeostasis and reversed vulnerability to depression. Mechanistically, we further identified that Nrf2 deletion promoted iron overload via upregulation of TfR and downregulation of ferritin light chain (FtL), leading to BDNF-mediated synapse damage in the hippocampus. Therefore, our findings unveil a novel role for Nrf2 in regulating iron homeostasis while providing mechanistic insights into poststress susceptibility to depression. Targeting Nrf2-mediated iron metabolism may offer promising strategies for developing more effective antidepressant therapies.

Constructing Spatially Separated Cage-Like Z-scheme Heterojunction Photocatalyst for Enhancing Photocatalytic H2 Evolution.

Heterojunctions coupled into micro-mesoscopic structures is an attractive strategy to optimize the light harvesting and carrier separation of semiconductor photocatalysts. A self-templating method of ion exchange is reported to synthesize an exquisite hollow cage-structured Ag2 S@CdS/ZnS that direct Z-scheme heterojunction photocatalyst. On the ultrathin shell of the cage, Ag2 S, CdS, and ZnS with Zn-vacancies (VZn ) are arranged sequentially from outside to inside. Among them, the photogenerated electrons are excited by ZnS to the VZn energy level and then recombine with the photogenerated holes that are generated by CdS, while the electrons remained in the CdS conduction band are further transferred to Ag2 S. The ingenious cooperation of the Z-scheme heterojunction with the hollow structure optimizes the photogenerated charges transport channel, spatially separated the oxidation and reduction half-reactions, decreases the charge recombination probability, and simultaneously improves the light harvesting efficiency. As a result, the photocatalytic hydrogen evolution activity of the optimal sample is 136.6 and 17.3 times higher than that of cage-like ZnS with VZn and CdS by, respectively. This unique strategy demonstrates the tremendous potential of the incorporation of heterojunction construction to morphology design of photocatalytic materials, and also provided a reasonable route for designing other efficient synergistic photocatalytic reactions.

Dual Recognition of H3K4me3 and DNA by the ISWI Component ARID5 Regulates the Floral Transition in Arabidopsis.

Chromatin remodeling and histone modifications are important for development and floral transition in plants. However, it is largely unknown whether and how these two epigenetic regulators coordinately regulate the important biological processes. Here, we identified three types of Imitation Switch (ISWI) chromatin-remodeling complexes in Arabidopsis (Arabidopsis thaliana). We found that AT-RICH INTERACTING DOMAIN5 (ARID5), a subunit of a plant-specific ISWI complex, can regulate development and floral transition. The ARID-PHD dual domain cassette of ARID5 recognizes both the H3K4me3 histone mark and AT-rich DNA. We determined the ternary complex structure of the ARID5 ARID-PHD cassette with an H3K4me3 peptide and an AT-containing DNA. The H3K4me3 peptide is combinatorially recognized by the PHD and ARID domains, while the DNA is specifically recognized by the ARID domain. Both PHD and ARID domains are necessary for the association of ARID5 with chromatin. The results suggest that the dual recognition of AT-rich DNA and H3K4me3 by the ARID5 ARID-PHD cassette may facilitate the association of the ISWI complex with specific chromatin regions to regulate development and floral transition.

Pax transactivation domain-interacting protein is required for preserving hematopoietic stem cell quiescence via regulating lysosomal activity.

Hematopoietic stem cells (HSC) maintain lifetime whole blood hematopoiesis through self-renewal and differentiation. In order to sustain HSC stemness, most HSC reside in a quiescence state, which is affected by diverse cellular stress and intracellular signal transduction. How HSC accommodate those challenges to preserve lifetime capacity remains elusive. Here we show that Pax transactivation domain-interacting protein (PTIP) is required for preserving HSC quiescence via regulating lysosomal activity. Using a genetic knockout mouse model to specifically delete Ptip in HSC, we find that loss of Ptip promotes HSC exiting quiescence, and results in functional exhaustion of HSC. Mechanistically, Ptip loss increases lysosomal degradative activity of HSC. Restraining lysosomal activity restores the quiescence and repopulation potency of Ptip-/- HSC. Additionally, PTIP interacts with SMAD2/3 and mediates transforming growth factor-ß signaling-induced HSC quiescence. Overall, our work uncovers a key role of PTIP in sustaining HSC quiescence via regulating lysosomal activity.

Global disease burden attributed to high sugar-sweetened beverages in 204 countries and territories from 1990 to 2019.

High sugar-sweetened beverages (SSBs) are a controllable risk factor for chronic non-communicable diseases (NCDs), but their effect on the global disease burden is uncertain. The study aims to assess the global burden of high SSBs from 1990 to 2019. Global Burden of Disease (GBD) 2019 provides data on deaths, disability-adjusted life years (DALYs), years of life with disabilities (YLDs) and years of life lost (YLLs) ascribe to high SSBs by ages, genders, regions and countries. For the past 30 years, overall exposure to high SSBs decreased for males and increased for females. The number of deaths from chronic NCDs ascribed to high SSBs increased from 149,988 (110,278-182,947) to 242,218 (172,045-302,250), DALYs increased from 3,698,578 (2,693,476-4,559,740) to 6,307,562 (4,300,765-8,079,556), especially the males. Age-standardized YLDs rate (ASYLDs) increased from 11.58 to 17.03. The number of ischemic heart disease (IHD) and diabetes mellitus (DM) deaths and DALYs ascribed to high SSBs has been increasing. Age-standardized death rate (ASDR) for DM risen from 0.56 to 0.62, age-standardized DALYs rate (ASDALYs) risen from 21.41 to 28.21. The burden of disease ascribed to high SSBs was in the elderly significantly higher than in the young and middle-aged, mainly concentrated in Central Asia and Oceania. The disease burden was highest in regions with moderate sociodemographic index (SDI). More extraordinary efforts should be made to raise awareness among the general public about interventions aimed at limiting the use of high SSBs, to reduce disease burden ascribed to high SSBs.