CsRAXs negatively regulate leaf size and fruiting ability through auxin glycosylation in cucumber.

Leaves are the main photosynthesis organ that directly determines crop yield and biomass. Dissecting the regulatory mechanism of leaf development is crucial for food security and ecosystem turn-over. Here, we identified the novel function of R2R3-MYB transcription factors CsRAXs in regulating cucumber leaf size and fruiting ability. Csrax5 single mutant exhibited enlarged leaf size and stem diameter, and Csrax1/2/5 triple mutant displayed further enlargement phenotype. Overexpression of CsRAX1 or CsRAX5 gave rise to smaller leaf and thinner stem. The fruiting ability of Csrax1/2/5 plants was significantly enhanced, while that of CsRAX5 overexpression lines was greatly weakened. Similarly, cell number and free auxin level were elevated in mutant plants while decreased in overexpression lines. Biochemical data indicated that CsRAX1/5 directly promoted the expression of auxin glucosyltransferase gene CsUGT74E2. Therefore, our data suggested that CsRAXs function as repressors for leaf size development by promoting auxin glycosylation to decrease free auxin level and cell division in cucumber. Our findings provide new gene targets for cucumber breeding with increased leaf size and crop yield.

Comparison of the outcome of intentional replantation in teeth with or without periodontal involvement: a retrospective study.

OBJECTIVE: Intentional replantation (IR) is considered as a viable treatment option to preserve the teeth with apical periodontitis. This study aimed to compare the treatment outcomes of IR in teeth with or without periodontal involvement, and to investigate the influence of related factors. METHODS: A total of 157 teeth with a documented history of IR between September 2012 and November 2022 and a follow-up duration of more than 1 year were included. The samples included 100 teeth with simple apical periodontitis and 57 teeth with combined periodontal-endodontic lesions (CPEL). Clinical and radiographic criteria were used to evaluate treatment outcomes including functional retention and extraction. Chi-square analyses and Fisher's exact tests were used to compare bivariate associations between outcomes and clinical or demographic variables. Kaplan-Meier analyses were used to evaluate the cumulative survival rate of the intentionally replanted teeth. RESULTS: The overall cumulative survival rates were 93.0% at 1 year, 76.7% at 5 years, and 56.2% at 10 years. Among the 100 teeth with simple apical periodontitis, the survival rates were 93.0%, 86.7%, and 78.8% at the same time points. In contrast, 57 teeth with CPEL exhibited survival rates of 93.0%, 65.0%, and 36.9%, respectively. The primary postoperative complications that led to extraction were periodontal involvement (51.9%), tooth fracture (18.5%), external root resorption (18.5%), and persistent apical periodontitis (11.1%). The outcomes of teeth with CPEL were significantly affected by the presence of a sinus tract and crown restoration. In contrast, no significant prognostic factors were identified for teeth without periodontal involvement. CONCLUSION: The long-term prognosis of teeth with CPEL is significantly worse than those with simple apical periodontitis. The main reason of extraction was periodontal involvement. Regular periodontal maintenance and appropriate crown restoration may help to improve the prognosis for teeth with CPEL.

MUC16 can Predict the Pregnancy Outcomes in Human and Intraperitoneal Administration of MUC16 can Rescue Pregnancy Losses in Mouse Models.

Mucin 16 (MUC16) participates in the process of embryo implantation, but few studies have examined the association between MUC16 and pregnancy loss. To investigate this association, the expression of MUC16 in serum and decidua was compared between women with pregnancy loss and ongoing pregnancies. In vitro experiments and animal models were used to explore the role and underlying mechanisms of MUC16 in pregnancy loss. In human study, the expression of MUC16 in serum and decidua was both consistently lower in the women with pregnancy loss compared with those in women with ongoing pregnancies. In vitro experiments revealed the interaction of MUC16 with peripheral blood natural killer (pNK) cells. MUC16 changed the phenotype and reduced the pro-inflammation ability of pNK cells. MUC16 also inhibited the cytotoxicity of pNK cells through the Src homology region 2 domain-containing phosphatase-1/extracellular signal-regulated kinase (SHP-ERK) pathway. Furthermore, MUC16 promoted the migration, invasion and tube formation of trophoblast cells by co-culturing together with pNK cells. In vivo experiments, the mouse model of abortion was used to further confirm that intraperitoneal administration of MUC16 could rescue the pregnancy loss. This study reveals the still-unknown connection between MUC16 and pNK cells and indicates that MUC16 provides a novel method for future prediction and treatment of unfavorable pregnancy outcomes.

Correction: A label-free and immobilization-free approach for constructing photoelectrochemical nucleic acid sensors utilizing DNA-silver nanoparticle affinity interactions.

Correction for 'A label-free and immobilization-free approach for constructing photoelectrochemical nucleic acid sensors utilizing DNA-silver nanoparticle affinity interactions' by Jing Yi et al., Analyst, 2024, https://doi.org/10.1039/D4AN00098F.

14-3-3 binding motif phosphorylation disrupts Hdac4-organized condensates to stimulate cardiac reprogramming.

Cell fate conversion is associated with extensive post-translational modifications (PTMs) and architectural changes of sub-organelles, yet how these events are interconnected remains unknown. We report here the identification of a phosphorylation code in 14-3-3 binding motifs (PC14-3-3) that greatly stimulates induced cardiomyocyte (iCM) formation from fibroblasts. PC14-3-3 is identified in pivotal functional proteins for iCM reprogramming, including transcription factors and chromatin modifiers. Akt1 kinase and protein phosphatase 2A are the key writer and key eraser of the PC14-3-3 code, respectively. PC14-3-3 activation induces iCM formation with the presence of only Tbx5. In contrast, PC14-3-3 inhibition by mutagenesis or inhibitor-mediated code removal abolishes reprogramming. We discover that key PC14-3-3-embedded factors, such as histone deacetylase 4 (Hdac4), Mef2c, and Foxo1, form Hdac4-organized inhibitory nuclear condensates. PC14-3-3 activation disrupts Hdac4 condensates to promote cardiac gene expression. Our study suggests that sub-organelle dynamics regulated by a PTM code could be a general mechanism for stimulating cell reprogramming.

Sharp bend and large FSR ring resonator based on the free-form curves on a thin-film lithium niobate platform.

Sharp bends are crucial for large-scale and high-density photonics integration on thin-film lithium niobate platform. In this study, we demonstrate low-loss (<0.05 dB) and sharp bends (Reff = 30 µm) using free-form curves with a 200-nm-thick slab and a rib height of 200 nm on x-cut lithium niobate. Employing the same design method, we successfully realize a compact fully-etched ring resonator with a remarkably large free spectral range of 10.36 nm experimentally. Notably, the equivalent radius of the ring resonator is a mere 15 µm, with a loaded Q factor reaching 2.2 × 104.

The AGAMOUS-LIKE 16-GENERAL REGULATORY FACTOR 1 module regulates axillary bud outgrowth via catabolism of abscisic acid in cucumber.

Lateral branches are important components of shoot architecture and directly affect crop yield and production cost. Although sporadic studies have implicated abscisic acid (ABA) biosynthesis in axillary bud outgrowth, the function of ABA catabolism and its upstream regulators in shoot branching remain elusive. Here, we showed that the MADS-box transcription factor AGAMOUS-LIKE 16 (CsAGL16) is a positive regulator of axillary bud outgrowth in cucumber (Cucumis sativus). Functional disruption of CsAGL16 led to reduced bud outgrowth, whereas overexpression of CsAGL16 resulted in enhanced branching. CsAGL16 directly binds to the promoter of the ABA 8'-hydroxylase gene CsCYP707A4 and promotes its expression. Loss of CsCYP707A4 function inhibited axillary bud outgrowth and increased ABA levels. Elevated expression of CsCYP707A4 or treatment with an ABA biosynthesis inhibitor largely rescued the Csagl16 mutant phenotype. Moreover, cucumber General Regulatory Factor 1 (CsGRF1) interacts with CsAGL16 and antagonizes CsAGL16-mediated CsCYP707A4 activation. Disruption of CsGRF1 resulted in elongated branches and decreased ABA levels in the axillary buds. The Csagl16 Csgrf1 double mutant exhibited a branching phenotype resembling that of the Csagl16 single mutant. Therefore, our data suggest that the CsAGL16-CsGRF1 module regulates axillary bud outgrowth via CsCYP707A4-mediated ABA catabolism in cucumber. Our findings provide a strategy to manipulate ABA levels in axillary buds during crop breeding to produce desirable branching phenotypes.

Co-expression of immune checkpoints in glioblastoma revealed by single-nucleus RNA sequencing and spatial transcriptomics.

Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system. The pattern of immune checkpoint expression in GBM remains largely unknown. We performed snRNA-Seq and spatial transcriptomic (ST) analyses on untreated GBM samples. 8 major cell types were found in both tumor and adjacent normal tissues, with variations in infiltration grade. Neoplastic cells_6 was identified in malignant cells with high expression of invasion and proliferator-related genes, and analyzed its interactions with microglia, MDM cells and T cells. Significant alterations in ligand-receptor interactions were observed, particularly between Neoplastic cells_6 and microglia, and found prominent expression of VISTA/VSIG3, suggesting a potential mechanism for evading immune system attacks. High expression of TIM-3, VISTA, PSGL-1 and VSIG-3 with similar expression patterns in GBM, may have potential as therapeutic targets. The prognostic value of VISTA expression was cross-validated in 180 glioma patients, and it was observed that patients with high VISTA expression had a poorer prognosis. In addition, multimodal cross analysis integrated SnRNA-seq and ST, revealing complex intracellular communication and mapping the GBM tumor microenvironment. This study reveals novel molecular characteristics of GBM, co-expression of immune checkpoints, and potential therapeutic targets, contributing to improving the understanding and treatment of GBM.

Gelatin/agar pH-indicator film based on cranberry extract loaded with linalool nanoparticle: Survey on physical, antimicrobial, and antioxidant properties.

In this study, linalool-nanoparticles (L-NPs) were prepared (encapsulation efficiency was 68.54 %) and introduced pH-indicator film based on cranberry-extract (CEF) to develop multifunctional smart films. XRD analysis and FTIR spectroscopy indicated that cranberry-extract (CE) and L-NPs were uniformly distributed in the gelatin/agar matrix and could change the intermolecular structure of the film. Color change of smart films showed that CE endowed the film with pH-sensitive property. As CE and L-NPs were added to the film, the water contact angle (WCA) was increased from 57.03° to 117.73°, the elongation at break (EAB) was increased from 12.30 % to 34.60 %. Additionally, the introduction of L-NPs enhanced the antioxidant activity (DPPH free radical scavenging rate increased from 26.80 % to 36.35 %) and antibacterial activity (against S. aureus and E. coli) of the smart film, which were verified by its retarding effect on pork spoilage.

Genetically determined type 1 diabetes mellitus and risk of osteoporosis.

BACKGROUND: Observational evidence suggests that type 1 diabetes mellitus (T1DM) is associated with the risk of osteoporosis (OP). Nevertheless, it is not apparent whether these correlations indicate a causal relationship. To elucidate the causal relationship, a two-sample Mendelian randomization (MR) analysis was performed. METHODS: T1DM data was obtained from the large genome-wide association study (GWAS), in which 6683 cases and 12,173 controls from 12 European cohorts were involved. Bone mineral density (BMD) samples at four sites were extracted from the GEnetic Factors for OSteoporosis (GEFOS) consortium, including forearm (FA) (n = 8,143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). The former three samples were from mixed populations and the last one was from European. Inverse variance weighting, MR-Egger, and weighted median tests were used to test the causal relationship between T1DM and OP. A series of sensitivity analyses were then conducted to verify the robustness of the results. RESULTS: Twenty-three independent SNPs were associated with FN-BMD and LS-BMD, twenty-seven were associated with FA-BMD, and thirty-one were associated with eBMD. Inverse variance-weighted estimates indicated a causal effect of T1DM on FN-BMD (odds ratio (OR) =1.033, 95 % confidence interval (CI): 1.012-1.054, p = 0.002) and LS-BMD (OR = 1.032, 95 % CI: 1.005-1.060, p = 0.022) on OP risk. Other MR methods, including weighted median and MR-Egger, calculated consistent trends. While no significant causation was found between T1DM and the other sites (FA-BMD: OR = 1.008, 95 % CI: 0.975-1.043, p = 0.632; eBMD: OR = 0.993, 95 % CI: 0.985-1.001, p = 0.106). No significant heterogeneity (except for eBMD) or horizontal pleiotropy was found for instrumental variables, suggesting these results were reliable and robust. CONCLUSIONS: This study shows a causal relationship between T1DM and the risk of some sites of OP (FN-BMD, LS-BMD), allowing for continued research to discover the clinical and experimental mechanisms of T1DM and OP. It also contributes to the recommendation if patients with T1DM need targeted care to promote bone health and timely prevention of osteoporosis.

Spatio-temporal variations of methane fluxes in sediments of a deep stratified temperate lake.

Spatio-temporal variability of sediment-mediated methane (CH4) production in freshwater lakes causes large uncertainties in predicting global lake CH4 emissions under different climate change and eutrophication scenarios. We conducted extensive sediment incubation experiments to investigate CH4 fluxes in Lake Stechlin, a deep, stratified temperate lake. Our results show contrasting spatial patterns in CH4 fluxes between littoral and profundal sites. The littoral sediments, ∼33% of the total sediment surface area, contributed ∼86.9% of the annual CH4 flux at the sediment-water interface. Together with sediment organic carbon quality, seasonal stratification is responsible for the striking spatial difference in sediment CH4 production between littoral and profundal zones owing to more sensitive CH4 production than oxidation to warming. While profundal sediments produce a relatively small amount of CH4, its production increases markedly as anoxia spreads in late summer. Our measurements indicate that future lake CH4 emissions will increase due to climate warming and concomitant hypoxia/anoxia.

Betamethasone transdermal administration combined with fractional Er:YAG lasers or microplasma radiofrequency technology improved hypertrophic scars: A retrospective study.

OBJECTIVE: This retrospective study aims to compare the efficacy rates in treating hypertrophic scars among four distinct groups of patients who either underwent fractional Erbium: yttrium-aluminum-garnet (Er:YAG) laser or microplasma radiofrequency technology as standalone treatments or in combination with compound betamethasone transdermal administration. METHOD: The study retrospectively examined 208 patients treated at our institution from April 2011 to December 2022 for hypertrophic scars, receiving no less than three treatments (with an interval of 8 weeks between each). The patients were categorized into four groups: the F group (treated with fractional Er:YAG laser), the F + B group (treated with fractional Er:YAG laser combined with compound betamethasone transdermal administration), the P group (treated with microplasma radiofrequency technology), and the P + B group (treated with microplasma radiofrequency technology combined with compound betamethasone transdermal administration). The therapeutic effects were evaluated based on the changes in the Vancouver Scar Scale (VSS) scores before and after treatment in these groups. RESULTS: There was no statistically significant difference in the VSS scores among the four groups before treatment. After undergoing three sessions of the aforementioned four types of treatment, all groups showed a decrease in VSS scores, with average posttreatment VSS scores for the F group scored 5.15 ± 2.084, F + B group scored 3.7 ± 1.781, P group scored 4.41 ± 1.933, and P + B group scored 3.16 ± 1.775, respectively. With an increasing number of treatments, the total effective rate gradually increased in all four groups, and the combination treatment using compound betamethasone transdermal administration proved more effective than the standalone treatment. CONCLUSION: All four treatments yielded favorable outcomes, with the combined therapy involving compound betamethasone transdermal administration proving more effective than the standalone treatments, meriting further clinical attention.

Innovative applications of artificial intelligence during the COVID-19 pandemic.

The COVID-19 pandemic has created unprecedented challenges worldwide. Artificial intelligence (AI) technologies hold tremendous potential for tackling key aspects of pandemic management and response. In the present review, we discuss the tremendous possibilities of AI technology in addressing the global challenges posed by the COVID-19 pandemic. First, we outline the multiple impacts of the current pandemic on public health, the economy, and society. Next, we focus on the innovative applications of advanced AI technologies in key areas such as COVID-19 prediction, detection, control, and drug discovery for treatment. Specifically, AI-based predictive analytics models can use clinical, epidemiological, and omics data to forecast disease spread and patient outcomes. Additionally, deep neural networks enable rapid diagnosis through medical imaging. Intelligent systems can support risk assessment, decision-making, and social sensing, thereby improving epidemic control and public health policies. Furthermore, high-throughput virtual screening enables AI to accelerate the identification of therapeutic drug candidates and opportunities for drug repurposing. Finally, we discuss future research directions for AI technology in combating COVID-19, emphasizing the importance of interdisciplinary collaboration. Though promising, barriers related to model generalization, data quality, infrastructure readiness, and ethical risks must be addressed to fully translate these innovations into real-world impacts. Multidisciplinary collaboration engaging diverse expertise and stakeholders is imperative for developing robust, responsible, and human-centered AI solutions against COVID-19 and future public health emergencies.

DHEA down-regulates mitochondrial dynamics and promotes apoptosis of lung adenocarcinoma cells through FASTKD2.

Background: DHEA is a steroid hormone produced by the gonads, adrenal cortex, brain, and gastrointestinal tract. While the anti-obesity, anti-atherosclerosis, anti-cancer, and memory-enhancing effects of DHEA have been substantiated through cell experiments, animal studies, and human trials, the precise mechanisms underlying these effects remain unclear. Altered mitochondrial dynamics can lead to mitochondrial dysfunction, which is closely related to many human diseases, especially cancer and aging. This study was to investigate whether DHEA inhibits lung adenocarcinoma through the mitochondrial pathway and its molecular mechanism. Methods: Through animal experiments and cell experiments, the effect of DHEA on tumor inhibition was determined. The correlation between FASTKD2 expression and DHEA was analyzed by Western blot, Reverse transcription-quantitative PCR, Immunohistochemistry, and TCGA database. Results: In this study, DHEA supplementation in the diet can inhibit the tumor size of mice, and the effect of adding DHEA one week before the experiment is the best. DHEA limits the glycolysis process by inhibiting G6PDH activity, increases the accumulation of reactive oxygen species, and initiates apoptosis in the mitochondrial pathway of cancer cells. Conclusion: DHEA suppresses mitochondrial fission and promotes mitochondrial fusion by downregulating the expression of FASTKD2, thereby inhibiting tumor growth and prolonging the overall survival of lung adenocarcinoma patients, which also provides a new target for the prevention and treatment of lung adenocarcinoma.

Discovery of Novel PD-L1 Small-Molecular Inhibitors with Potent In Vivo Anti-tumor Immune Activity.

Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8+ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.

Evidence linking COVID-19 and the health/well-being of children and adolescents: an umbrella review.

BACKGROUND: Experiences during childhood and adolescence have enduring impacts on physical and mental well-being, overall quality of life, and socioeconomic status throughout one's lifetime. This underscores the importance of prioritizing the health of children and adolescents to establish an impactful healthcare system that benefits both individuals and society. It is crucial for healthcare providers and policymakers to examine the relationship between COVID-19 and the health of children and adolescents, as this understanding will guide the creation of interventions and policies for the long-term management of the virus. METHODS: In this umbrella review (PROSPERO ID: CRD42023401106), systematic reviews were identified from the Cochrane Database of Systematic Reviews; EMBASE (OvidSP); and MEDLINE (OvidSP) from December 2019 to February 2023. Pairwise and single-arm meta-analyses were extracted from the included systematic reviews. The methodological quality appraisal was completed using the AMSTAR-2 tool. Single-arm meta-analyses were re-presented under six domains associated with COVID-19 condition. Pairwise meta-analyses were classified into five domains according to the evidence classification criteria. Rosenberg's FSN was calculated for both binary and continuous measures. RESULTS: We identified 1551 single-arm and 301 pairwise meta-analyses from 124 systematic reviews that met our predefined criteria for inclusion. The focus of the meta-analytical evidence was predominantly on the physical outcomes of COVID-19, encompassing both single-arm and pairwise study designs. However, the quality of evidence and methodological rigor were suboptimal. Based on the evidence gathered from single-arm meta-analyses, we constructed an illustrative representation of the disease severity, clinical manifestations, laboratory and radiological findings, treatments, and outcomes from 2020 to 2022. Additionally, we discovered 17 instances of strong or highly suggestive pairwise meta-analytical evidence concerning long-COVID, pediatric comorbidity, COVID-19 vaccines, mental health, and depression. CONCLUSIONS: The findings of our study advocate for the implementation of surveillance systems to track health consequences associated with COVID-19 and the establishment of multidisciplinary collaborative rehabilitation programs for affected younger populations. In future research endeavors, it is important to prioritize the investigation of non-physical outcomes to bridge the gap between research findings and clinical application in this field.

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression.

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-ß1 promotes abnormal glycosylation of SEMA7A via induction of epithelial-mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

A label-free and immobilization-free approach for constructing photoelectrochemical nucleic acid sensors utilizing DNA-silver nanoparticle affinity interactions.

Efficient and affordable nucleic acid detection methods play a pivotal role in various applications. Herein, we developed an immobilization-free and label-free strategy to construct a photoelectrochemical nucleic acid biosensing platform based on interactions between silver nanoparticles and DNA. First, CRISPR-Cas12a exhibited a trans-cleavage effect on adenine nucleotide sequences upon recognizing the target DNA. The resulting adenine nucleotide sequences of varying lengths then engaged in interactions with silver nanoparticles, leading to a solution characterized by distinct light transmittance. Subsequently, the solution was positioned between the light source and the photoelectrode, strategically impacting the photon absorption step within the photoelectrochemical process. Consequently, the detection of nucleic acid was accomplished through the analysis of the resultant photocurrent signal. The developed platform exhibits a detection limit of 0.06 nM (S/N = 3) with commendable selectivity. The innovative use of adenine nucleotide sequences as cost-effective probes interacting with silver nanoparticles eliminates the need for complex interfacial immobilization processes, significantly simplifying the fabrication of DNA sensors. The outcomes of our research present a promising pathway for advancing the development of economically feasible miniature DNA sensors.