Genome-wide association study and genomic selection of spike-related traits in bread wheat.

KEY MESSAGE: Identification of 337 stable MTAs for wheat spike-related traits improved model accuracy, and favorable alleles of MTA259 and MTA64 increased grain weight and yield per plant. Wheat (Triticum aestivum L.) is one of the three primary global, staple crops. Improving spike-related traits in wheat is crucial for optimizing spike and plant morphology, ultimately leading to increased grain yield. Here, we performed a genome-wide association study using a dataset of 24,889 high-quality unique single-nucleotide polymorphisms (SNPs) and phenotypic data from 314 wheat accessions across eight diverse environments. In total, 337 stable and significant marker-trait associations (MTAs) related to spike-related traits were identified. MTA259 and MTA64 were consistently detected in seven and six environments, respectively. The presence of favorable alleles associated with MTA259 and MTA64 significantly reduced wheat spike exsertion length and spike length, while enhancing thousand kernel weight and yield per plant. Combined gene expression and network analyses identified TraesCS6D03G0692300 and TraesCS6D03G0692700 as candidate genes for MTA259 and TraesCS2D03G0111700 and TraesCS2D03G0112500 for MTA64. The identified MTAs significantly improved the prediction accuracy of each model compared with using all the SNPs, and the random forest model was optimal for genome selection. Additionally, the eight stable and major MTAs, including MTA259, MTA64, MTA66, MTA94, MTA110, MTA165, MTA180, and MTA164, were converted into cost-effective and efficient detection markers. This study provided valuable genetic resources and reliable molecular markers for wheat breeding programs.

Nrf2 activation by pyrroloquinoline quinone inhibits natural aging-related intervertebral disk degeneration in mice.

Age-related intervertebral disk degeneration (IVDD) involves increased oxidative damage, cellular senescence, and matrix degradation. Pyrroloquinoline quinone (PQQ) is a water-soluble vitamin-like compound with strong anti-oxidant capacity. The goal of this study was to determine whether PQQ can prevent aging-related IVDD, and the underlying mechanism. Here, we found that dietary PQQ supplementation for 12 months alleviated IVDD phenotypes in aged mice, including increased disk height index and reduced histological scores and cell loss, without toxicity. Mechanistically, PQQ inhibited oxidative stress, cellular senescence, and senescence-associated secretory phenotype (SASP) in the nucleus pulposus and annulus fibrosus of aged mice. Similarly, PQQ protected against interleukin-1ß-induced matrix degradation, reactive oxygen species accumulation, and senescence in human nucleus pulposus cells (NPCs) in vitro. Molecular docking predicted and biochemical assays validated that PQQ interacts with specific residues to dissociate the Keap1-Nrf2 complex, thereby increasing nuclear Nrf2 translocation and activation of Nrf2-ARE signaling. RNA sequencing and luciferase assays revealed Nrf2 can transcriptionally upregulate Wnt5a by binding to its promoter, while Wnt5a knockdown prevented PQQ inhibition of matrix metalloproteinase-13 in NPCs. Notably, PQQ supplementation failed to alleviate aging-associated IVDD phenotypes and oxidative stress in aged Nrf2 knockout mice, indicating Nrf2 is indispensable for PQQ bioactivities. Collectively, this study demonstrates Nrf2 activation by PQQ inhibits aging-induced IVDD by attenuating cellular senescence and matrix degradation. This study clarifies Keap1-Nrf2-Wnt5a axis as the novel signaling underlying the protective effects of PQQ against aging-related IVDD, and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging-induced IVDD.

Characterization of a wheat stable QTL for spike length and its genetic effects on yield-related traits.

Spike length (SL) is one of the most important agronomic traits affecting yield potential and stability in wheat. In this study, a major stable quantitative trait locus (QTL) for SL, i.e., qSl-2B, was detected in multiple environments in a recombinant inbred line (RIL) mapping population, KJ-RILs, derived from a cross between Kenong 9204 (KN9204) and Jing 411 (J411). The qSl-2B QTL was mapped to the 60.06-73.06 Mb region on chromosome 2B and could be identified in multiple mapping populations. An InDel molecular marker in the target region was developed based on a sequence analysis of the two parents. To further clarify the breeding use potential of qSl-2B, we analyzed its genetic effects and breeding selection effect using both the KJ-RIL population and a natural mapping population, which consisted of 316 breeding varieties/advanced lines. The results showed that the qSl-2B alleles from KN9204 showed inconsistent genetic effects on SL in the two mapping populations. Moreover, in the KJ-RILs population, the additive effects analysis of qSl-2B showed that additive effect was higher when both qSl-2D and qSl-5A harbor negative alleles under LN and HN. In China, a moderate selection utilization rate for qSl-2B was found in the Huanghuai winter wheat area and the selective utilization rate for qSl-2B continues to increase. The above findings provided a foundation for the genetic improvement of wheat SL in the future via molecular breeding strategies.

Quantitative trait loci detection for three tiller-related traits and the effects on wheat (Triticum aestivum L.) yields.

KEY MESSAGE: A total of 38 putative additive QTLs and 55 pairwise putative epistatic QTLs for tiller-related traits were reported, and the candidate genes underlying qMtn-KJ-5D, a novel major and stable QTL for maximum tiller number, were characterized. Tiller-related traits play an important role in determining the yield potential of wheat. Therefore, it is important to elucidate the genetic basis for tiller number when attempting to use genetic improvement as a tool for enhancing wheat yields. In this study, a quantitative trait locus (QTL) analysis of three tiller-related traits was performed on the recombinant inbred lines (RILs) of a mapping population, referred to as KJ-RILs, that was derived from a cross between the Kenong 9204 (KN9204) and Jing 411 (J411) lines. A total of 38 putative additive QTLs and 55 pairwise putative epistatic QTLs for spike number per plant (SNPP), maximum tiller number (MTN), and ear-bearing tiller rate (EBTR) were detected in eight different environments. Among these QTLs with additive effects, three major and stable QTLs were first documented herein. Almost all but two pairwise epistatic QTLs showed minor interaction effects accounting for no more than 3.0% of the phenotypic variance. The genetic effects of two colocated major and stable QTLs, i.e., qSnpp-KJ-5D.1 and qMtn-KJ-5D, for yield-related traits were characterized. The breeding selection effect of the beneficial allele for the two QTLs was characterized, and its genetic effects on yield-related traits were evaluated. The candidate genes underlying qMtn-KJ-5D were predicted based on multi-omics data, and TraesKN5D01HG00080 was identified as a likely candidate gene. Overall, our results will help elucidate the genetic architecture of tiller-related traits and can be used to develop novel wheat varieties with high yields.

Fine mapping of a major QTL, qKl-1BL controlling kernel length in common wheat.

KEY MESSAGE: A major stable QTL, qKl-1BL, for kernel length of wheat was narrowed down to a 2.04-Mb interval on chromosome 1BL; the candidate genes were predicated and the genetic effects on yield-related traits were characterized. As a key factor influencing kernel weight, wheat kernel shape is closely related to yield formation, and in turn affects both wheat processing quality and market value. Fine mapping of the major quantitative trait loci (QTL) for kernel shape could provide genetic resources and a theoretical basis for the genetic improvement of wheat yield-related traits. In this study, a major QTL for kernel length (KL) on 1BL, named qKl-1BL, was identified from the recombinant inbred lines (RIL) in multiple environments based on the genetic map and physical map, with 4.76-21.15% of the phenotypic variation explained. To fine map qKl-1BL, the map-based cloning strategy was used. By using developed InDel markers, the near-isogenic line (NIL) pairs and eight key recombinants were identified from a segregating population containing 3621 individuals derived from residual heterozygous lines (RHLs) self-crossing. In combination with phenotype identification, qKl-1BL was finely positioned into a 2.04-Mb interval, KN1B:698.15-700.19 Mb, with eight differentially expressed genes enriched at the key period of kernel elongation. Based on transcriptome analysis and functional annotation information, two candidate genes for qKl-1BL controlling kernel elongation were identified. Additionally, genetic effect analysis showed that the superior allele of qKl-1BL from Jing411 could increase KL, thousand kernel weight (TKW), and yield per plant (YPP) significantly, as well as kernel bulk density and stability time. Taken together, this study identified a QTL interval for controlling kernel length with two possible candidate genes, which provides an important basis for qKl-1BL cloning, functional analysis, and application in molecular breeding programs.

Synthesize magnetic ZnFe2O4@C/Cd0.9Zn0.1S catalysts with S-scheme heterojunction to achieve extraordinary hydrogen production efficiency.

Suppressing the electron-hole recombination rate of catalyst legitimately is one of the effective strategies to improve photocatalytic hydrogen evolution. Herein, carbon-coated metal oxide, ZnFe2O4@C (ZFO@C), nanoparticles were synthesized and employed to couple with quadrupedal Cd0.9Zn0.1S (CZS) via an ordinary ultrasonic self-assembly method combined with calcination to form a novel ZFO@C/CZS catalyst with step-scheme (S-scheme) heterojunction. The photocatalytic hydrogen evolution reaction (HER) was conducted to verify the enhanced photoactivity of ZFO@C/CZS. The optimal ZFO@C/CZS exhibits an extraordinary photocatalytic HER rate of 111.3 ± 0.9 mmol g-1 h-1 under visible-light irradiation, corresponding to an apparent quantum efficiency as high as (76.2 ± 0.9)% at 450 nm. Additionally, the as-synthesized ZFO@C/CZS composite exhibits high stability and recyclability. The excellent photocatalytic hydrogen evolution performance should arise from the formed S-scheme heterojunction and the unique ZFO@C core-shell structure, which inhibit electron hole recombination as well as provide more reactive sites. The pathway of S-scheme charge transfer was validated through density functional theory calculations and electrochemical measurements. This work provides a rational strategy for the synthesis of unique magnetic S-scheme heterojunction photocatalysts for water splitting under visible light irradiation.

Evaluation of the hygiene status of teaching environment in primary and secondary schools in Beijing City from 2016 to 2020 / 中国学校卫生

Objective@#To understand the trend of changes of hygiene status in the teaching environment among primary and secondary schools in Beijing City during 2016-2020, so as to provide basis for further improving the teaching environment and campus hygiene conditions in primary and secondary schools.@*Methods@#A proportional systematic sampling method covered over 50% of schools selected annually in Beijing from 2016 to 2019, and 34% were selected in 2020. Two representative classrooms were selected from each selected school for testing based on their structure and other factors, with 6 196 classrooms supervised, from 2016 to 2020,1 330,1 312,1 384,1 322,848 classrooms were monitored for each year.@*Results@#From 2016 to 2020, the overall lighting qualification rate of classrooms (lighting coefficient 72.8%, window to floor area ratio 41.8%, rear wall reflectance ratio 42.2%, blackboard reflection ratio 37.4%), the overall qualification rate of average blackboard illumination and uniformity (50.6%, 34.9 %), and the overall qualification rate of desk and chair allocation (58.6%) were all below 80%. The overall qualification rate of per capita classroom area (87.5%), blackboard size (83.2%), average desk illumination ( 80.1% ), average desk illumination and uniformity (82.9%), the distance between lamp and desk (99.1%), carbon dioxide ( 86.6% ), temperature (84.9%), and noise (96.6%) were all above 80%. The following indicators, blackboard size, the distance between lamp and desk, average blackboard illumination, lighting coefficient, blackboard reflectance, rear wall reflectance, carbon dioxide, temperature, and noise ( χ 2=78.38, 9.71, 11.76, 320.59, 37.63, 58.45, 236.45, 1 347.56, 101.97), had statistically significance between years. Among those indicators, the qualified rates of blackboard size, blackboard reflectance, lighting coefficient, and noise had been increasing year by year ( χ 2 trend =69.98, 15.82, 240.02, 5.77) ( P <0.05). The qualified rates of per capita classroom area, window to floor area ratio, and blackboard reflection ratio in primary schools (81.6%, 39.8%, 36.3%) were all lower than those in secondary schools (94.9%, 44.5%, 40.3%) ( χ 2=246.32, 12.03, 10.51, P <0.05). The qualified rates of blackboard size, average blackboard illumination, average blackboard illumination and uniformity, and desk and chair allocation (89.3%, 55.6% , 36.0%, and 60.2%) were all higher than those in secondary schools (75.4%, 44.1%, 33.3%, and 56.5%) ( χ 2=209.33, 78.41, 4.44, 8.22) ( P <0.05). The qualified rates of average desk illumination and uniformity, average blackboard illumination, rear wall reflectance ratio, desk and chair allocation, carbon dioxide, temperature, and noise indicators in urban area (82.9%, 84.1% , 51.9%, 45.0%, 60.9%, 91.2%, 89.5%, 97.8%) were all higher than those in suburban area (77.3%, 81.7%, 49.2%, 39.5%, 56.3%, 82.3%, 80.4%, 95.5%) ( χ 2=31.16, 6.28, 4.36, 16.40, 13.39, 105.29, 98.23, 24.66， P <0.05). The qualified rates of the distance between lamp and desk, lighting coefficient, window to floor area ratio, blackboard size, blackboard reflection ratio, average blackboard illumination and uniformity, and per capita classroom area in urban areas (98.8%, 65.2%, 34.3%, 76.7%, 35.9%, 30.1%, 84.6%) were all lower than those in suburban areas (99.4%, 81.4%, 49.8%, 89.7%, 40.2%, 39.6%, 90.3%) ( χ 2=6.80, 171.67, 132.43, 188.46 , 12.45, 60.28, 44.82) ( P <0.05).@*Conclusions@#The main problems in the teaching environment of schools in Beijing are classroom lighting, as well as desk and chair allocation. The findings suggest technical rationality and operability of relevant standard should be considered when under revision, and standard training and supervision management should be strengthened, with the aim of teaching environment improvement.

Analysis of associated factors of attempting e-cigarettes use among senior high school students in Beijing City between 2019 and 2023 / 中国学校卫生

Objective@#To analyze prevalence and associated factors of attempting e cigarettes use among senior high school students in Beijing City between 2019 and 2023, in order to providing references for the construction of smoke free senior high schools environments.@*Methods@#In 2019, 9 137 students from 44 senior high schools in Beijing City were monitored, including 27 general senior high schools and 17 vocational senior high schools. In 2023, the study included 6 709 students from 30 senior high schools comprising 21 general senior high schools and 9 vocational senior high schools. On site investigations using anonymous questionnaires were conducted. The monitoring content included demographic information, second hand smoke exposure, tobacco product use and tobacco awareness. Chi square test was used to compare the differences of various indicators in different groups, and multivariate Logistic regression analysis was adopted to analysis the influencing factors among senior high school students attempting to use e cigarettes between 2019 and 2023.@*Results@#In 2019, the rates of vocational senior high school and general senior high school students attempting to use e-cigarettes were 22.57% and 9.78%, respectively. In 2023, it decreased to 14.39% and 6.43%, respectively. In 2019 ( OR =1.59,95% CI =1.35-1.88) and 2023 ( OR =1.71,95% CI =1.38-2.11), vocational senior high school students both hold higher risk of attempting to use e-cigarettes,compared with general senior high school students. In 2019, non-indigenous senior high school students attempting to use e cigarettes were more than indigenous senior high school students ( OR = 1.28 , 95% CI =1.05-1.56). In 2019 ( OR =1.62, 95% CI =1.34-1.95) and 2023 ( OR =1.77, 95% CI =1.35-2.31), smoking anywhere in households increased the risk of attempting to use e-cigarettes among senior high school students. In both 2019 and 2023, not attempting to smoke cigarettes ( OR =0.24,95% CI =0.21-0.29; OR =0.15,95% CI =0.11-0.19), not currently smoking cigarettes ( OR =0.29,95% CI =0.22-0.40; OR =0.30,95% CI =0.17-0.53), not being exposed to secondhand smoke in school ( OR =0.62, 95% CI = 0.53 -0.72; OR =0.51, 95% CI =0.41-0.64) or in outdoor public places ( OR =0.74, 95% CI =0.63-0.86; OR = 0.62 , 95% CI =0.50-0.78) all reduced the risk of attempting to use e-cigarettes among senior hgih school students( P <0.05).@*Conclusion@#The influencing factors of attempts by senior high school students in Beijing City to use e-cigarettes are generally consistent between 2023 and 2019, with a focus on vocational senior high schools to ensure the continuity of intervention measures and promote the construction of smoke free senior high schools.

Characterization and fine mapping analysis of a major stable QTL qKnps-4A for kernel number per spike in wheat.

KEY MESSAGE: A major stable QTL for kernel number per spike was narrowed down to a 2.19-Mb region containing two potential candidate genes, and its effects on yield-related traits were characterized. Kernel number per spike (KNPS) in wheat is a key yield component. Dissection and characterization of major stable quantitative trait loci (QTLs) for KNPS would be of considerable value for the genetic improvement of yield potential using molecular breeding technology. We had previously reported a major stable QTL controlling KNPS, qKnps-4A. In the current study, primary fine-mapping analysis, based on the primary mapping population, located qKnps-4A to an interval of approximately 6.8-Mb from 649.0 to 655.8 Mb on chromosome 4A refering to 'Kenong 9204' genome. Further fine-mapping analysis based on a secondary mapping population narrowed qKnps-4A to an approximately 2.19-Mb interval from 653.72 to 655.91 Mb. Transcriptome sequencing, gene function annotation analysis and homologous gene related reports showed that TraesKN4A01HG38570 and TraesKN4A01HG38590 were most likely to be candidate genes of qKnps-4A. Phenotypic analysis based on paired near-isogenic lines in the target region showed that qKnps-4A increased KNPS mainly by increasing the number of central florets per spike. We also evaluated the effects of qKnps-4A on other yield-related traits. Moreover, we dissected the QTL cluster of qKnps-4A and qTkw-4A and proved that the phenotypic effects were probably due to close linkage of two or more genes rather than pleiotropic effects of a single gene. This study provides molecular marker resource for wheat molecular breeding designed to improve yield potential, and lay the foundation for gene functional analysis of qKnps-4A.

Diagnostic Efficacy of 18F-FDG PET/CT in Detecting Bone Marrow Infiltration in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma.

Objective: Diffuse large B-cell lymphoma (DLBCL) is often associated with bone marrow infiltration, and 2-deoxy-2-(18F) fluorodeoxyglucose positron emission tomography/computed tomography ( 18F-FDG PET/CT) has potential diagnostic significance for bone marrow infiltration in DLBCL. Methods: A total of 102 patients diagnosed with DLBCL between September 2019 and August 2022 were included. Bone marrow biopsy and 18F-FDG PET/CT examinations were performed at the time of initial diagnosis. Kappa tests were used to evaluate the agreement of 18F-FDG PET/CT with the gold standard, and the imaging features of DLBCL bone marrow infiltration on PET/CT were described. Results: The total detection rate of bone marrow infiltration was not significantly different between PET/CT and primary bone marrow biopsy ( P = 0.302) or between the two bone marrow biopsies ( P = 0.826). The sensitivity, specificity, and Youden index of PET/CT for the diagnosis of DLBCL bone marrow infiltration were 0.923 (95% CI, 0.759-0.979), 0.934 (95% CI, 0.855-0.972), and 0.857, respectively. Conclusion: 18F-FDG PET/CT has a comparable efficiency in the diagnosis of DLBCL bone marrow infiltration. PET/CT-guided bone marrow biopsy can reduce the misdiagnosis of DLBCL bone marrow infiltration.

Safety and Clinical Response to Combined Immunotherapy with Autologous iNKT Cells and PD-1+CD8+ T Cells in Patients Failing First-line Chemotherapy in Stage IV Pancreatic Cancer.

Purpose: A phase I clinical trial was conducted to assess the safety and feasibility of invariant natural killer T (iNKT) cells combined with PD-1+CD8+ T cells in patients with advanced pancreatic cancer and failing the first-line chemotherapy. Patients and Methods: Fifteen eligible patients were enrolled, of whom 9 received at least three cycles of treatment each. In total, 59 courses were administered. Results: Fever was the most common adverse event, peaking at about 2-4 hours after cell infusion and reverting within 24 hours without treatment in all patients. Influenza-like reactions such as headache, myalgia, and arthralgia were also observed in 4, 4, and 3 of the patients, respectively. In addition, vomiting and dizziness were prevalent, while abdominal pain, chest pain, rash, and stuffy nose were rare adverse events, each reported in 1 patient. Side effects above grade 2 were not observed. Two patients achieved partial regression, while 1 patient experienced disease progression assessed 4 weeks after the third course. Three patients are still alive at the time of writing and have progression-free survival longer than 12 months. The overall survival time has been extended to over 12 months in 6 of the 9 patients. No constant changes of CD4+ T, B, and NK cells were recorded except for elevated CD8+ T cells after the first course. Conclusions: The combination of autologous iNKT cells and PD-1+CD8+ T cells was a safe therapeutic strategy against advanced pancreatic cancer. The patients exhibited a potentially promising prolonged survival time. Further study appears warranted to evaluate the efficacy of these combined cell infusions in pancreatic cancer. Trial registration: This trial was included in the clinical trial which was registered in ClinicalTrials.gov (ID:NCT03093688) on March 15, 2017. Significance: There is an unmet need for novel, more effective, and tolerable therapies for pancreatic cancer. Here we present a phase I clinical trial employing iNKT cells combined with PD-1+CD8+ T cells in 9 patients with advanced pancreatic cancer and failing the first-line chemotherapy. The combined immunotherapy was shown to be feasible in the enrolled patients with limited side effects and optimistic clinical responses, which could bring opportunity of therapeutic advancement.

Pyrroloquinoline quinone alleviates natural aging-related osteoporosis via a novel MCM3-Keap1-Nrf2 axis-mediated stress response and Fbn1 upregulation.

Age-related osteoporosis is associated with increased oxidative stress and cellular senescence. Pyrroloquinoline quinone (PQQ) is a water-soluble vitamin-like compound that has strong antioxidant capacity; however, the effect and underlying mechanism of PQQ on aging-related osteoporosis remain unclear. The purpose of this study was to investigate whether dietary PQQ supplementation can prevent osteoporosis caused by natural aging, and the potential mechanism underlying PQQ antioxidant activity. Here, we found that when 6-month-old or 12-month-old wild-type mice were supplemented with PQQ for 12 months or 6 months, respectively, PQQ could prevent age-related osteoporosis in mice by inhibiting osteoclastic bone resorption and stimulating osteoblastic bone formation. Mechanistically, pharmmapper screening and molecular docking studies revealed that PQQ appears to bind to MCM3 and reduces its ubiquitination-mediated degradation; stabilized MCM3 then competes with Nrf2 for binding to Keap1, thus activating Nrf2-antioxidant response element (ARE) signaling. PQQ-induced Nrf2 activation inhibited bone resorption through increasing stress response capacity and transcriptionally upregulating fibrillin-1 (Fbn1), thus reducing Rankl production in osteoblast-lineage cells and decreasing osteoclast activation; as well, bone formation was stimulated by inhibiting osteoblastic DNA damage and osteocyte senescence. Furthermore, Nrf2 knockout significantly blunted the inhibitory effects of PQQ on oxidative stress, on increased osteoclast activity and on the development of aging-related osteoporosis. This study reveals the underlying mechanism of PQQ's strong antioxidant capacity and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging-induced osteoporosis.

1,25-Dihydroxyvitamin D Deficiency Accelerates Aging-related Osteoarthritis via Downregulation of Sirt1 in Mice.

Emerging observational data suggest that vitamin D deficiency is associated with the onset and progression of knee osteoarthritis (OA). However, the relationship between vitamin D level and OA and the role of vitamin D supplementation in the prevention of knee OA are controversial. To address these issues, we analyzed the articular cartilage phenotype of 6- and 12-month-old wild-type and 1α(OH)ase-/- mice and found that 1,25(OH)2D deficiency accelerated the development of age-related spontaneous knee OA, including cartilage surface destruction, cartilage erosion, proteoglycan loss and cytopenia, increased OARSI score, collagen X and Mmp13 positive chondrocytes, and increased chondrocyte senescence with senescence-associated secretory phenotype (SASP). 1,25(OH)2D3 supplementation rescued all knee OA phenotypes of 1α(OH)ase-/- mice in vivo, and 1,25(OH)2D3 rescued IL-1ß-induced chondrocyte OA phenotypes in vitro, including decreased chondrocyte proliferation and cartilage matrix protein synthesis, and increased oxidative stress and cell senescence. We also demonstrated that VDR was expressed in mouse articular chondrocytes, and that VDR knockout mice exhibited knee OA phenotypes. Furthermore, we demonstrated that the down-regulation of Sirt1 in articular chondrocytes of 1α(OH)ase-/- mice was corrected by supplementing 1,25(OH)2D3 or overexpression of Sirt1 in mesenchymal stem cells (MSCs) and 1,25(OH)2D3 up-regulated Sirt1 through VDR mediated transcription. Finally, we demonstrated that overexpression of Sirt1 in MSCs rescued knee OA phenotypes in 1α(OH)ase-/- mice. Thus, we conclude that 1,25(OH)2D3, via VDR-mediated gene transcription, plays a key role in preventing the onset of aging-related knee OA in mouse models by up-regulating Sirt1, an aging-related gene that promotes articular chondrocyte proliferation and extracellular matrix protein synthesis, and inhibits senescence and SASP.

17ß-estradiol plays the anti-osteoporosis role via a novel ESR1-Keap1-Nrf2 axis-mediated stress response activation and Tmem119 upregulation.

Increased oxidative stress and decreased osteoblastic bone formation contribute to estrogen deficiency-induced osteoporosis. However, the role and mechanism of estrogen-deficiency in regulating oxidative stress and osteoblastic activity remain unclear. Here, we showed that estrogen-deficient bone marrow stromal/stem cells (BMSCs) exhibited impaired capacity to combat stress, characterized by increased oxidative stress, shortened cell survival and reduced osteogenic differentiation and bone formation, which were due to a decrease of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 re-activation induced by the pyrazinyl dithiolethione oltipraz significantly rescued the cell phenotype of estrogen-deficient BMSCs in vitro and ex vivo. Mechanistically, we found that 17ß-estradiol/ESR1 (Estrogen Receptor 1) facilitated Nrf2 accumulation, and activated its target genes by competing with Nrf2 for binding to Kelch-like ECH-associated protein 1 (Keap1) via ESR1 containing a highly conserved DLL motif. Of note, oltipraz, an Nrf2 activator, rescued ovariectomy-induced osteoporosis partly by inhibiting oxidative stress and promoting osteoblastic bone formation via Nrf2-induced antioxidant signaling activation and Tmem119 (transmembrane protein 119) upregulation. Conversely, Nrf2 knockout largely blocked the bone anabolic effect of 17ß-estradiol in vivo and ex vivo. This study provides insight into the mechanisms whereby estrogen prevents osteoporosis through promoting osteoblastic bone formation via Nrf2-mediated activation of antioxidant signaling and upregulation of Tmem119, and thus provides evidence for Nrf2 as a potential target for clinical prevention and treatment of menopause-related osteoporosis.

Biomarkers predicting the efficacy of immune checkpoint inhibitors in hepatocellular carcinoma.

In recent years, immune checkpoint inhibitors (ICIs) have emerged as a transformative approach in treating advanced hepatocellular carcinoma (HCC). Despite their success, challenges persist, including concerns about their effectiveness, treatment costs, frequent occurrence of treatment-related adverse events, and tumor hyperprogression. Therefore, it is imperative to identify indicators capable of predicting the efficacy of ICIs treatment, enabling optimal patient selection to maximize clinical benefits while minimizing unnecessary toxic side effects and economic losses. This review paper categorizes prognostic biomarkers of ICIs treatment into the following categories: biochemical and cytological indicators, tumor-related markers, imaging and personal features, etiology, gut microbiome, and immune-related adverse events (irAEs). By organizing these indicators systematically, we aim to guide biomarker exploration and inform clinical treatment decisions.

A multilevel model analysis of the association between reading and writing posture with myopia in primary and secondary school students / 中国学校卫生

Objective@#To explore the association between reading and writing posture with the occurrence of myopia in Chinese children and adolescents, so as to provide a reference for reducing its prevalence among primary and secondary school students.@*Methods@#Using data from the 2020 survey on the current status of hyperopia reserve in primary and secondary school students from six provinces/cities, namely Beijing, Zhejiang, Chongqing, Shaanxi, Liaoning, and Henan selected by multi stage stratified cluster probability sampling method during November 2020 to June 2022. A total 16 782 students who completed the optometry examination of cycloplegia according to the Children and Adolescents Myopia Screening Standard and questionnaire survey were included for analyzing analyze the association between reading and writing posture with myopia.@*Results@#The overall detection rate of myopia among primary and secondary school students was 45.7%, of which 35.0% were primary school students, 84.1% junior high school students, and 90.4% senior high school students. Poor reading and writing posture was found in 73.6% of primary and secondary school students. Adjusting for confounding factors such as gender, school period, region, outdoor time every day, and whether parents were myopic, the results of the multilevel Logistic regression showed that the following factors were positively correlated with myopia:poor reading and writing posture ( OR=1.17, 95%CI =1.07-1.28), never/occasionally reading and writing with a reading distance which was more than one foot away between the eyes and book ( OR=1.28, 95%CI=1.08-1.53, OR=1.23, 95%CI = 1.08- 1.40), teachers occasionally reminding the child of their reading and writing posture ( OR=1.13, 95%CI =1.01-1.25), and often/always reading and writing while lying down or with the face on the arm ( OR=1.15, 95%CI=1.01-1.32, OR=1.46, 95% CI = 1.17-1.82), always reading and writing with the head in the hand ( OR=1.56, 95%CI =1.20-2.01). Further, a negative correlation was detected between myopia and parents occasionally reminding their children of their reading and writing posture ( OR= 0.85 , 95%CI =0.76-0.96) ( P <0.05).@*Conclusion@#Poor reading and writing posture is a risk factor for the development of myopia in primary and secondary school students, and interventions for reading and writing posture need to be strengthened to reduce the occurrence of myopia among primary and secondary school students.

Prevalence of myopia of primary and middle school students in Beijing from 2018 to 2021 / 中国学校卫生

Objective@#To understand the vision status of primary and secondary school students in Beijing, in order to provide scientific reference for myopia prevention and control.@*Methods@#From 2018 to 2021, a stratified cluster sampling method was used to monitor myopia among 191 293 primary and secondary school students selected from 6 urban areas and 10 suburban areas in Beijing. Myopic screening was in accordance with the "standards for children and adolescents myopic screening", and was measured by an automatic desktop computer optometer under non-cycloplegic conditions. Statistical analysis was used by Chi-square test.@*Results@#The total myopia rate of primary and middle school students in Beijing from 2018 to 2021 were 60.7%, 57.6%, 59.2% and 59.7%, respectively. In 2018, the myopia rates of primary school students, middle school students, regular high school students and vocational high school students were 38.3%, 77.3%, 88.3% and 73.2% respectively. In 2019, they were 34.7%, 76.4%, 87.7% and 72.0%, respectively; in 2020, they were 37.5%, 76.8%, 86.8%, 74.9%; in 2021, they were 38.7%, 77.4%, 86.5% and 74.9 % respectively. Significant differences in educational stage were observed ( χ 2=7 386.07, 11 104.28, 9 850.08, 9 714.59, P <0.01). From 2018 to 2021, the overall myopia rate of girls (62.1%) was higher than that of boys (56.5%)( χ 2=613.75, P <0.01). The myopia rate of girls were higher than that of boys in each year, and significant differences in educational stage were observed, respectively( χ 2=120.47, 163.47, 168.01, 162.24, P <0.01). The overall myopia rate of urban students(63.0%) was higher than that of suburban students (56.0%)( χ 2=978.82, P <0.01). The myopia rate of urban students were higher than that of suburban students every year, and significant differences in educational stage were observed, respectively ( χ 2=86.71, 240.96, 302.56, 409.30 , P < 0.01 ).@*Conclusion@#The detection rate of myopia rate of primary and middle school students in Beijing is still high. It is necessary to strengthen the publicity and intervention of poor visual acuity in primary and middle school students, especially among urban area students, with the aim of effectively control and reduction in the myopia rate, and the improvement of student visual health.

Improving the ex vivo expansion of human tumor-reactive CD8 + T cells by targeting toll-like receptors.

Toll-like receptors (TLRs) are important pattern recognition receptor(s) known to mediate the sensing of invading pathogens and subsequent immune responses. In this study, we investigate whether TLRs could be explored for the preparation of human CD8+ T cell products used in adoptive cell therapy (ACT). Following characterization of TLRs expression on human CD8+ T cells, we screened TLR-specific agonists for their ability to act in concert with anti-CD3 to stimulate the proliferation of these cells and corroborated the observed co-stimulatory effect by transcriptional profiling analyses. Consequently, we developed an optimal formulation for human CD8+ T cell amplification by combining CD3/CD28 antibody, interleukin 7 (IL-7), interleukin 15 (IL-15), and three agonists respectively targeting TLR1/2, TLR2/6, and TLR5. This new formulation performed better in amplifying PD-1+CD8+ T cells, a potential repertoire of tumor-reactive CD8+ T cells, from tumor patients than the conventional formulation. Importantly, the expanded CD8+ T cells showed restored functionality and consequently a robust anti-tumor activity in an in vitro co-culturing system. Together, our study established the utility of TLR agonists in ex vivo expansion of tumor-targeting CD8+ T cells, thus providing a new avenue toward a more effective ACT.

Calcareous Materials Effectively Reduce the Accumulation of Cd in Potatoes in Acidic Cadmium-Contaminated Farmland Soils in Mining Areas.

The in situ chemical immobilization method reduces the activity of heavy metals in soil by adding chemical amendments. It is widely used in farmland soil with moderate and mild heavy metal pollution due to its high efficiency and economy. However, the effects of different materials depend heavily on environmental factors such as soil texture, properties, and pollution levels. Under the influence of lead-zinc ore smelting and soil acidification, Cd is enriched and highly activated in the soils of northwestern Guizhou, China. Potato is an important economic crop in this region, and its absorption of Cd depends on the availability of Cd in the soil and the distribution of Cd within the plant. In this study, pot experiments were used to compare the effects of lime (LM), apatite (AP), calcite (CA), sepiolite (SP), bentonite (BN), and biochar (BC) on Cd accumulation in potatoes. The results showed that the application of LM (0.4%), AP (1.4%), and CA (0.4%) had a positive effect on soil pH and cations, and that they effectively reduced the availability of Cd in the soil. In contrast, the application of SP, BN, and BC had no significant effect on the soil properties and Cd availability. LM, AP, and CA treatment strongly reduced Cd accumulation in the potato tubers by controlling the total 'flux' of Cd into the potato plants. In contrast, the application of SP and BN promoted the migration of Cd from the root to the shoot, while the effect of BC varied by potato genotype. Overall, calcareous materials (LM, CA, and AP) were more applicable in the remediation of Cd-contaminated soils in the study area.

MicroRNA-125b Accelerates and Promotes PML-RARa-driven Murine Acute Promyelocytic Leukemia.

Objective: Most acute promyelocytic leukemia cases are characterized by the PML-RARa fusion oncogene and low white cell counts in peripheral blood. Methods: Based on the frequent overexpression of miR-125-family miRNAs in acute promyelocytic leukemia, we examined the consequence of this phenomenon by using an inducible mouse model overexpressing human miR-125b. Results: MiR-125b expression significantly accelerates PML-RARa-induced leukemogenesis, with the resultant induced leukemia being partially dependent on continued miR-125b overexpression. Interestingly, miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio, confirming the clinical observation in acute promyelocytic leukemia patients. Conclusion: This study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia, indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.