Role and mechanism of NCAPD3 in promoting malignant behaviors in gastric cancer.

Background: Gastric cancer (GC) is one of the major malignancies threatening human lives and health. Non-SMC condensin II complex subunit D3 (NCAPD3) plays a crucial role in the occurrence of many diseases. However, its role in GC remains unexplored. Materials and Methods: The Cancer Genome Atlas (TCGA) database, clinical samples, and cell lines were used to analyze NCAPD3 expression in GC. NCAPD3 was overexpressed and inhibited by lentiviral vectors and the CRISPR/Cas9 system, respectively. The biological functions of NCAPD3 were investigated in vitro and in vivo. Gene microarray, Gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to establish the potential mechanisms. Results: NCAPD3 was highly expressed in GC and was associated with a poor prognosis. NCAPD3 upregulation significantly promoted the malignant biological behaviors of gastric cancer cell, while NCAPD3 inhibition exerted a opposite effect. NCAPD3 loss can directly inhibit CCND1 and ESR1 expression to downregulate the expression of downstream targets CDK6 and IRS1 and inhibit the proliferation of gastric cancer cells. Moreover, NCAPD3 loss activates IRF7 and DDIT3 to regulate apoptosis in gastric cancer cells. Conclusion: Our study revealed that NCAPD3 silencing attenuates malignant phenotypes of GC and that it is a potential target for GC treatment.

CaSTH2 disables CaWRKY40 from activating pepper thermotolerance and immunity against Ralstonia solanacearum via physical interaction.

CaWRKY40 coordinately activates pepper immunity against Ralstonia solanacearum infection (RSI) and high temperature stress (HTS), forms positive feedback loops with other positive regulators and is promoted by CaWRKY27b/CaWRKY28 through physical interactions; however, whether and how it is regulated by negative regulators to function appropriately remain unclear. Herein, we provide evidence that CaWRKY40 is repressed by a SALT TOLERANCE HOMOLOG2 in pepper (CaSTH2). Our data from gene silencing and transient overexpression in pepper and epoptic overexpression in Nicotiana benthamiana plants showed that CaSTH2 acted as negative regulator in immunity against RSI and thermotolerance. Our data from BiFC, CoIP, pull down, and MST indicate that CaSTH2 interacted with CaWRKY40, by which CaWRKY40 was prevented from activating immunity or thermotolerance-related genes. It was also found that CaSTH2 repressed CaWRKY40 at least partially through blocking interaction of CaWRKY40 with CaWRKY27b/CaWRKY28, but not through directly repressing binding of CaWRKY40 to its target genes. The results of study provide new insight into the mechanisms underlying the coordination of pepper immunity and thermotolerance.

Associations of diet with infectious diseases in UK Biobank.

This research aims to utilize multivariate logistic regression to explore associations between the frequency of 13 food groups intake (or four diet groups) and infectious diseases. 487849 participants from the UK Biobank were enrolled, and 75209 participants were diagnosed with infectious diseases. Participants reporting the highest intake frequency of processed meat [odds ratio ( OR) = 1.0964; 95% CI: 1.0622-1.1318] and red meat ( OR = 1.0895; 95% CI: 1.0563-1.1239) had a higher risk of infectious diseases compared to those with the lowest intake frequency. Consuming fish 2.0-2.9 times ( OR = 0.8221; 95% CI: 0.7955-0.8496), cheese ≥5.0 times ( OR = 0.8822; 95% CI: 0.8559-0.9092), fruit 3.0-3.9 servings ( OR = 0.8867; 95% CI: 0.8661-0.9078), and vegetables 2.0-2.9 servings ( OR = 0.9372; 95% CI: 0.9189-0.9559) per week were associated with a lower risk of infection. Low meat-eaters ( OR = 0.9404; 95% CI: 0.9243-0.9567), fish-eaters ( OR = 0.8391; 95% CI: 0.7887-0.8919), and vegetarians ( OR = 0.9154; 95% CI: 0.8561-0.9778) had a lower risk of infectious diseases compared to regular meat-eaters. Mediation analysis was performed, revealing glycosylated hemoglobin, white blood cell counts, and body mass index were mediators in the relationships between diet groups and infectious diseases. This study suggested that intake frequency of food groups is a factor in infectious diseases and fish-eaters have a lower risk of infection.

Revealing Metabolic Dysregulation Induced by Polypropylene Nano- and Microplastics in Nile Tilapia via Noninvasive Probing Epidermal Mucus.

A noninvasive sampling technology was conceived, employing a disposable acupuncture needle in conjunction with high-resolution mass spectrometry (termed as noninvasive direct sampling extractive electrospray ionization mass spectrometry, NIDS-EESI-MS) to scrutinize the epidermal mucus of Nile tilapia for insights into the metabolic dysregulation induced by polypropylene nano- and microplastics. This analytical method initiates with the dispensing of an extraction solvent onto the needles coated with the mucus sample, almost simultaneously applying a high voltage to generate analyte ions. This innovative strategy obliterates the necessitation for laborious sample preparation, thereby simplifying the sampling process. Employing this technique facilitated the delineation of a plethora of metabolites, encompassing, but not confined to, amino acids, peptides, carbohydrates, ketones, fatty acids, and their derivatives. Follow-up pathway enrichment analysis exposed notable alterations within key metabolic pathways, including the biosynthesis of phenylalanine, tyrosine, and tryptophan, lysine degradation, as well as the biosynthesis and metabolism of valine, leucine, and isoleucine pathways in Nile tilapia, consequent to increased concentrations of polypropylene nanoplastics. These metabolic alterations portend potential implications such as immune suppression, among other deleterious outcomes. This trailblazing application of this methodology not only spares aquatic life from sacrifice but also inaugurates an ethical paradigm for conducting longitudinal studies on the same organisms, facilitating detailed investigations into the long-term effects of environmental pollutants. This technique enhances the ability to observe and understand the subtle yet significant impacts of such contaminants over time.

Validating the Baveno Elastography Criteria of Advanced Liver Fibrosis in Two-dimensional Shear Wave Elastography: A Prospective Pathology-based Study.

INTRODUCTION: The Baveno criteria for assessing advanced liver fibrosis were mainly determined by transient elastography (TE), and its pathology-based validation studies in two-dimensional shear-wave elastography (2D-SWE) remain limited. We aimed to validate the Baveno criteria through use of 2D-SWE. METHOD: Consecutive patients who underwent liver biopsies for various benign liver diseases were prospectively recruited. Liver stiffness measurement (LSM) was simultaneously evaluated by TE and 2D-SWE. The optimal cut-off value to predict advanced liver fibrosis was determined by the Youden Index, and the diagnostic performance was estimated using area under the receiver operating characteristic (AUROC) analysis. RESULTS: A total of 101 patients were enrolled having a median age of 55.0 (IQR: 46.0-63.5) years, with 53 (52.48%) of them being male. Using <9 and >14 kPa as the optimal dual cut-offs, the AUROC values in TE and 2D-SWE were 0.92 (95% CI: 0.83-0.97) and 0.93 (95% CI: 0.84-0.98), respectively (P= 0.61). The sensitivity and specificity of LSM by TE/2D-SWE achieved rates of 94.44%/94.44% and 86.00%/88.00%, respectively. However, using the Baveno criteria, the AUROC values in TE and 2D-SWE could remain achieving 0.91 (95% CI: 0.82-0.97) and 0.93 (95% CI: 0.84-0.98), respectively (P= 0.36). The sensitivity and specificity in TE/2D-SWE were 88.24%/88.24% and 86.79%/90.57%, respectively. CONCLUSION: This study establishes the compatibility of the Baveno dual cut-off criteria with 2D-SWE, positioning it as an easily used criteria in clinical practice and research.

Accelerated Activity-Based Sensing by Fluorogenic Reporter Engineering Enables to Rapidly Determine Unstable Analyte.

Accurate detection of labile analytes through activity based fluorogenic sensing is meaningful but remains a challenge because of nonrapid reaction kinetic. Herein, we present a signaling reporter engineering strategy to accelerate azoreduction reaction by positively charged fluorophore promoted unstable anion recognition for rapidly sensing sodium dithionite (Na2S2O4), a kind of widespread used but harmful inorganic reducing agent. Its quick decomposition often impedes application reliability of traditional fluorogenic probes in real samples because of their slow responses. In this work, four azo-based probes with different charged fluorophores (positive, zwitterionic, neutral, and negative) were synthesized and compared. Among of them, with sequestration effect of positively charged anthocyanin fluorophore for dithionite anion via electrostatic attraction, the cationic probe Azo-Pos displayed ultrafast fluorogenic response (∼2 s) with the fastest response kinetic (kpos' = 0.373 s-1) that is better than other charged ones (kzwi' = 0.031 s-1, kneu' = 0.013 s-1, kneg' = 0.003 s-1). Azo-Pos was demonstrated to be capable to directly detect labile Na2S2O4 in food samples and visualize the presence of Na2S2O4 in living systems in a timely fashion. This new probe has potential as a robust tool to fluorescently monitor excessive food additives and biological invasion of harmful Na2S2O4. Moreover, our proposed accelerating strategy would be versatile to develop more activity-based sensing probes for quickly detecting other unstable analytes of interest.

The Impact of Sequential Therapies after First-Line Systemic Therapies in Unresectable Hepatocellular Carcinoma.

Background: The therapeutic options for hepatocellular carcinoma (HCC) have greatly expanded recently, and current first-line therapies include sorafenib, lenvatinib, and atezolizumab-bevacizumab. The aim of this study was to investigate the therapeutic efficacy of sequential systemic treatments after progressing to the first-line agent in patients with unresectable HCC. Methods: Data were collected from subjects with HCC, BCLC stage B or C, who received first-line sorafenib, lenvatinib, or atezolizumab-bevacizumab from September 2020 to December 2022. The patients who progressed after first-line therapy were evaluated according to individual clinical status in order to decide whether or not to accept sequential therapy. The clinical baseline characteristics and overall survival (OS) of enrolled patients were collected and further analyzed. Results: Among the 127 enrolled patients, percentage of sequential therapy was 67.9%, 21.6%, and 37.5% in those with tumor progression after first-line sorafenib, lenvatinib, or atezolizumab-bevacizumab, respectively. Acceptance of sequential therapy (HR 0.46, p = 0.041) and presentation of ALBI grade I (HR 0.36, p = 0.002) had a significantly positive impact on OS. Pre-treatment ALBI grade had a significant impact on the decision to accept sequential therapy in patients with progressed HCC. Conclusions: The patients who were able to undergo sequential therapy had a better survival outcome compared to those who received only one agent, and the pre-treatment ALBI level might be regarded as a cornerstone tool to assess survival outcomes in patients undergoing treatment for HCC.

Fluorescence monitoring of refluxed tyrosinase using endoplasmic reticulum-localized enzymatic activity-based sensing.

A tyrosinase-activatable fluorescent probe with endoplasmic reticulum targetability was developed for the first time. It can ratiometrically fluoresce and hence be used to monitor refluxed tyrosinase into the endoplasmic reticulum.

A 14-3-3 Protein Ca16R Acts Positively in Pepper Immunity against Ralstonia solanacearum by Interacting with CaASR1.

Although 14-3-3 proteins have been implicated in plant growth, development, and stress response, their roles in pepper immunity against R. solanacearum remain poorly understood. In this study, a 14-3-3-encoding gene in pepper, Ca16R, was found to be upregulated by R. solanacearum inoculation (RSI), its silencing significantly reduced the resistance of pepper plants to RSI, and its overexpression significantly enhanced the resistance of Nicotiana benthamiana to RSI. Consistently, its transient overexpression in pepper leaves triggered HR cell death, indicating that it acts positively in pepper immunity against RSI, and it was further found to act positively in pepper immunity against RSI by promoting SA but repressing JA signaling. Ca16R was also found to interact with CaASR1, originally using pull-down combined with a spectrum assay, and then confirmed using bimolecular fluorescence complementation (BiFC) and a pull-down assay. Furthermore, we found that CaASR1 transient overexpression induced HR cell death and SA-dependent immunity while repressing JA signaling, although this induction and repression was blocked by Ca16R silencing. All these data indicate that Ca16R acts positively in pepper immunity against RSI by interacting with CaASR1, thereby promoting SA-mediated immunity while repressing JA signaling. These results provide new insight into mechanisms underlying pepper immunity against RSI.

Photothermal therapy of xenografted tumor by carbon nanoparticles-Fe(II) complex.

Due to the unique structure, carbon nanomaterials could convert near-infrared (NIR) light into heat efficiently in tumor ablation using photothermal therapy (PTT). However, none of them has been applied in clinical treatment, because they have not been approved for clinical evaluations and the precise temperature control facility is scarce. In this study, we designed a temperature-responsive controller for PTT and used carbon nanoparticles-Fe(II) complex (CNSI-Fe) as photothermal conversion agent (PTA) for PTT of tumor in vitro and in vivo. CNSI-Fe was an innovative drug under the evaluations in clinical trials. CNSI-Fe showed excellent photothermal conversion ability in water to increase the water temperature by 40 °C within 5 min under irradiation of 808 nm laser at 0.5 W/cm2. The temperature was precisely controlled at 52 °C for both in vitro and in vivo tumor inhibition. CNSI-Fe with NIR irradiation showed higher tumor cell inhibition than CNSI. In tumor bearing mice, CNSI-Fe with NIR irradiation achieved an inhibition rate of 84.7 % and 71.4 % of them were completely cured. Mechanistically, CNSI-Fe under NIR irradiation induced the radical generation, oxidative damage and ferroptosis to kill tumor. In addition, CNSI-Fe showed good biosafety during PTT according to hematological, serum biological and histopathological examinations. These results indicated that the combination of chemotherapy and PTT provided higher antitumor efficiency using CNSI-Fe as PTA.

Comparative genomic profiling of transport inhibitor Response1/Auxin signaling F-box (TIR1/AFB) genes in eight Pyrus genomes revealed the intraspecies diversity and stress responsiveness patterns.

In the genomics of plants and the phytoecosystem, Pyrus (pear) is among the most nutritious fruits and contains fiber that has great health benefits to humans. It is mostly cultivated in temperate regions and is one of the most cultivated pome fruits globally. Pears are highly subjected to biotic and abiotic stresses that affect their yield. TIR1/AFB proteins act as auxin co-receptors during the signaling of nuclear auxins and play a primary role in development-related regulatory processes and responses to biotic and abiotic stresses. However, this gene family and its members have not been explored in Pyrus genomes, and understanding these genes will help obtain useful insights into stress tolerance and ultimately help maintain a high yield of pears. This study reports a pangenome-wide investigation of TIR1/AFB genes from eight Pyrus genomes: Cuiguan (Pyrus pyrifolia), Shanxi Duli (P. betulifolia), Zhongai 1 [(P. ussuriensis × communis) × spp.], Nijisseiki (P. pyrifolia), Yunhong No.1 (P. pyrifolia), d'Anjou (P. communis), Bartlett v2.0 (P. communis), and Dangshansuli v.1.1 (P. bretschneideri). These genes were randomly distributed on 17 chromosomes in each genome. Based on phylogenetics, the identified TIR1/AFB genes were divided into six groups. Their gene structure and motif pattern showed the intraspecific structural conservation as well as evolutionary patterns of Pyrus TIR1/AFBs. The expansion of this gene family in Pyrus is mainly caused by segmental duplication; however, a few genes showed tandem duplication. Moreover, positive and negative selection pressure equally directed the gene's duplication process. The GO and PPI analysis showed that Pyrus TIR1/AFB genes are associated with abiotic stress- and development-related signaling pathways. The promoter regions of Pyrus TIR1/AFB genes were enriched in hormone-, light-, development-, and stress-related cis elements. Furthermore, publicly available RNA-seq data analysis showed that DaTIR1/AFBs have varied levels of expression in various tissues and developmental stages, fruit hardening disease conditions, and drought stress conditions. This indicated that DaTIR1/AFB genes might play critical roles in response to biotic and abiotic stresses. The DaTIR1/AFBs have similar protein structures, which show that they are involved in the same function. Hence, this study will broaden our knowledge of the TIR1/AFB gene family in Pyrus, elucidating their contribution to conferring resistance against various environmental stresses, and will also provide valuable insights for future researchers.

Platinum complexes with aggregation-induced emission.

Transition metal-containing materials with aggregation-induced emission (AIE) have brought new opportunities for the development of biological probes, optoelectronic materials, stimuli-responsive materials, sensors, and detectors. Coordination compounds containing the platinum metal have emerged as a promising option for constructing effective AIE platinum complexes. In this review, we classified AIE platinum complexes based on the number of ligands. We focused on the development and performance of AIE platinum complexes with different numbers of ligands and discussed the impact of platinum ion coordination and ligand structure variation on the optoelectronic properties. Furthermore, this review analyzes and summarizes the influence of molecular geometries, stacking models, and aggregation environments on the optoelectronic performance of these complexes. We provided a comprehensive overview of the AIE mechanisms exhibited by various AIE platinum complexes. Based on the unique properties of AIE platinum complexes with different numbers of ligands, we systematically summarized their applications in electronics, biological fields, etc. Finally, we illustrated the challenges and opportunities for future research on AIE platinum complexes, aiming at giving a comprehensive summary and outlook on the latest developments of functional AIE platinum complexes and also encouraging more researchers to contribute to this promising field.

Orthogonal Radical and Cationic Single-Unit Monomer Insertions for Engineering Polymer Architectures.

The single-unit monomer insertion (SUMI), derived from living/controlled polymerization, can be directly functionalized at the end or within the chain of polymers prepared by living/controlled polymerization, offering potential applications in the preparation of polymers with complex architectures. Many scenarios demand the simultaneous incorporation of monomers suitable for different polymerization methods into complex polymers. Therefore, it becomes imperative to utilize SUMI technologies with diverse mechanisms, especially those that are compatible with each other. Here, we reported the orthogonal SUMI technique, seamlessly combining radical and cationic SUMI approaches. Through the careful optimization of monomer and chain transfer agent pairs and adjustments to reaction conditions, we can efficiently execute both radical and cationic SUMI processes in one pot without mutual interference. The utilization of orthogonal SUMI pairs facilitates the integration of radical and cationic reversible addition-fragmentation chain transfer (RAFT) polymerization in various configurations. This flexibility enables the synthesis of diblock, triblock, and star polymers that incorporate both cationically and radically polymerizable monomers. Moreover, we have successfully implemented a mixing mechanism of free radicals and cations in RAFT step-growth polymerization, resulting in the creation of a side-chain sequence-controlled polymer brushes.

Prognostic impact of interstitial lung abnormalities in lung cancer: a systematic review and meta-analysis.

Background: Newly identified as a radiological concept, interstitial lung abnormalities (ILA) is emerging as a prognostic factor for lung cancer. Yet, debates persist regarding the prognostic significance of ILA in lung cancer. Our inaugural meta-analysis aimed to investigate the correlation between ILA and lung cancer outcomes, offering additional insights for clinicians in predicting patient prognosis. Methods: Articles meeting the criteria were found through PubMed, the Cochrane Library, EMBASE, and Web of Science by February 29, 2024. The outcomes evaluated were the survival rates such as overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS). Results: A total of 12 articles with 4416 patients were included in this meta-analysis. The pooled results showed that lung cancer patients with interstitial lung abnormalities had an inferior OS (n=11; HR=2.22; 95% CI=1.68-2.95; P<0.001; I2 = 72.0%; Ph<0.001), PFS (n=3; HR=1.59; 95% CI=1.08-2.32; P=0.017; I2 = 0%; Ph=0.772), and CSS (n=2; HR=4.00; 95% CI=1.94-8.25; P<0.001; I2 = 0%; Ph=0.594) than those without, however, the ILA was not significantly associated with the DFS (n=2; HR=2.07; 95% CI=0.94-7.02; P=0.066; I2 = 90.4%; Ph=0.001). Moreover, lung cancer patients with ILA were significantly correlated with male (OR=2.43; 95% CI=1.48-3.98; P<0.001), smoking history (OR=2.11; 95% CI=1.37-3.25; P<0.001), advanced age (OR=2.50; 95% CI=1.56-4.03; P<0.001), squamous carcinoma (OR=0.42; 95% CI=0.24-0.71; P=0.01), and EGFR mutation (OR=0.50; 95% CI=0.32-0.78; P=0.002). The correlation between ILA and race, stage, ALK, however, was not significant. Conclusion: ILA was a availability factors of prognosis in patients with lung cancers. These findings highlight the importance of early pulmonary fibrosis, namely ILA for prognosis in patients with lung cancer, and provide a partial rationale for future clinical work.

Four weeks of off-treatment follow-up is sufficient to determine virologic responses at off-treatment week 12 in patients with hepatitis C virus infection receiving fixed-dose pangenotypic direct-acting antivirals.

Early confirmation of sustained virologic response (SVR) or viral relapse after direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection is essential based on public health perspectives, particularly for patients with high risk of nonadherence to posttreatment follow-ups. A total of 1011 patients who achieved end-of-treatment virologic response, including 526 receiving fixed-dose pangenotypic DAAs, and 485 receiving other types of DAAs, who had available off-treatment weeks 4 and 12 serum HCV RNA data to confirm SVR at off-treatment week 12 (SVR12) or viral relapse were included. The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 to predict patients with SVR12 or viral relapse were reported. Furthermore, we analyzed the proportion of concordance between SVR12 and SVR24 in 943 patients with available SVR24 data. The PPV and NPV of SVR4 to predict SVR12 were 98.5% (95% confidence interval [CI]: 98.0-98.9) and 100% (95% CI: 66.4-100) in the entire population. The PPV of SVR4 to predict SVR12 in patients receiving fixed-dose pangenotypic DAAs was higher than those receiving other types of DAAs (99.8% [95% CI: 98.9-100] vs. 97.1% [95% CI: 96.2-97.8], p < 0.001). The NPVs of SVR4 to predict viral relapse were 100%, regardless of the type of DAAs. Moreover, the concordance between SVR12 and SVR24 was 100%. In conclusion, an off-treatment week 4 serum HCV RNA testing is sufficient to provide an excellent prediction power of SVR or viral relapse at off-treatment week 12 among patients with HCV who are treated with fixed-dose pangenotypic DAAs.

Reduced graphene oxide promotes the biodegradation of sulfamethoxazole by white-rot fungus Phanerochaete chrysosporium under cadmium stress.

The biodegradation of antibiotics in aquatic environment is consistently impeded by the widespread presence of heavy metals, necessitating urgent measures to mitigate or eliminate this environmental stress. This work investigated the degradation of sulfamethoxazole (SMX) by the white-rot fungus Phanerochaete chrysosporium (WRF) under heavy metal cadmium ion (Cd2+) stress, with a focus on the protective effects of reduced graphene oxide (RGO). The pseudo-first-order rate constant and removal efficiency of 5 mg/L SMX in 48 h by WRF decrease from 0.208 h-1 and 55.6% to 0.08 h-1 and 28.6% at 16 mg/L of Cd2+, while these values recover to 0.297 h-1 and 72.8% by supplementing RGO. The results demonstrate that RGO, possessing excellent biocompatibility, effectively safeguard the mycelial structure of WRF against Cd2+ stress and provide protection against oxidative damage to WRF. Simultaneously, the production of manganese peroxidase (MnP) by WRF decreases to 38.285 U/L in the presence of 24 mg/L Cd2+, whereas it recovers to 328.51 U/L upon the supplement of RGO. RGO can induce oxidative stress in WRF, thereby stimulating the secretion of laccase (Lac) and MnP to enhance the SMX degradation. The mechanism discovered in this study provides a new strategy to mitigate heavy metal stress encountered by WRF during antibiotic degradation.

Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy.

Smoking disrupts bone homeostasis and serves as an independent risk factor for the development and progression of osteoporosis. Tobacco toxins inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), promote BMSCs aging and exhaustion, but the specific mechanisms are not yet fully understood. Herein, we successfully established a smoking-related osteoporosis (SROP) model in rats and mice through intraperitoneal injection of cigarette smoke extract (CSE), which significantly reduced bone density and induced aging and inhibited osteogenic differentiation of BMSCs both in vivo and in vitro. Bioinformatics analysis and in vitro experiments confirmed that CSE disrupts mitochondrial homeostasis through oxidative stress and inhibition of mitophagy. Furthermore, we discovered that CSE induced BMSCs aging by upregulating phosphorylated AKT, which in turn inhibited the expression of FOXO3a and the Pink1/Parkin pathway, leading to the suppression of mitophagy and the accumulation of damaged mitochondria. MitoQ, a mitochondrial-targeted antioxidant and mitophagy agonist, was effective in reducing CSE-induced mitochondrial oxidative stress, promoting mitophagy, significantly downregulating the expression of aging markers in BMSCs, restoring osteogenic differentiation, and alleviating bone loss and autophagy levels in CSE-exposed mice. In summary, our results suggest that BMSCs aging caused by the inhibition of mitophagy through the AKT/FOXO3a/Pink1/Parkin axis is a key mechanism in smoking-related osteoporosis.

Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.

Gut microbial features may influence antiviral IgG levels after vaccination against viral respiratory infectious diseases: the evidence from two-sample bidirectional mendelian randomization.

BACKGROUND: Vaccination is effective in preventing viral respiratory infectious diseases through protective antibodies and the gut microbiome has been proven to regulate human immunity. This study explores the causal correlations between gut microbial features and serum-specific antiviral immunoglobulin G (IgG) levels. METHODS: We conduct a two-sample bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to explore the causal relationships between 412 gut microbial features and four antiviral IgG (for influenza A, measles, rubella, and mumps) levels. To make the results more reliable, we used four robust methods and performed comprehensive sensitivity analyses. RESULTS: The MR analyses revealed 26, 13, 20, and 18 causal associations of the gut microbial features influencing four IgG levels separately. ​Interestingly, ten microbial features, like genus Collinsella, species Bifidobacterium longum, and the biosynthesis of L-alanine have shown the capacity to regulate multiple IgG levels with consistent direction (rise or fall). The ​reverse MR analysis suggested several potential causal associations of IgG levels affecting microbial features. CONCLUSIONS: The human immune response against viral respiratory infectious diseases could be modulated by changing the abundance of gut microbes, which provided new approaches for the intervention of viral respiratory infections.