Regulatory role of the miR-142-3p/CDC25C axis in modulating autophagy in non-small cell lung cancer.

Background: With its diverse genetic foundation and heterogeneous nature, non-small cell lung cancer (NSCLC) needs a better comprehension of prognostic evaluation and efficient treatment targeting. Methods: Bioinformatics analysis was performed of The Cancer Genome Atlas (TCGA)-NSCLC and GSE68571 dataset. Overlapping differentially expressed genes (DEGs) were used for functional enrichment analysis and constructing the protein-protein interaction (PPI) network. In addition, key prognostic genes were identified through prognostic risk models, and their expression levels were verified. The phenotypic effects of cell division cycle 25C (CDC25C) regulation on NSCLC cell lines were assessed by in vitro experiments using various techniques such as flow cytometry, Transwell, and colony formation. Protein levels related to autophagy and apoptosis were assessed, specifically examining the impact of autophagy inhibition [3-methyladenine (3-MA)] and the miR-142-3p/CDC25C axis on this regulatory system. Results: CDC25C was identified as a key prognostic marker in NSCLC, showing high expression in tumor samples. In vitro experiments showed that CDC25C knockdown markedly reduced the capacity of cells to proliferate, migrate, invade, trigger apoptosis, and initiate cell cycle arrest. CDC25C and miR-142-3p displayed a reciprocal regulatory relationship. CDC25C reversed the inhibitory impacts of miR-142-3p on NSCLC cell cycle proliferation and progression. The synergy of miR-142-3p inhibition, CDC25C silencing, and 3-MA treatment was shown to regulate NSCLC cell processes including proliferation, apoptosis, and autophagy. Conclusions: MiR-142-3p emerged as a key player in governing autophagy and apoptosis by directly targeting CDC25C expression. This emphasizes the pivotal role of the miR-142-3p/CDC25C axis as a critical regulatory pathway in NSCLC.

The loss of political connections and the fluctuation of corporate stock prices: Moderating effect based on media attention.

This article examines the impact and mechanism of political connections on stock price fluctuations after the resignation of independent directors with "official" status, based on the exogenous influence of Document No. 18 of the Central Organization Department. Using panel data of A-share listed companies on the Shanghai and Shenzhen stock markets from 2012 to 2020, the experimental group and control group for political affiliation deficiency events were determined through propensity score matching (PSM), and a quasi natural experiment was constructed using differences in differences (DID) for empirical research. By examining the relationship between regional financial development, lack of political connections, and stock price fluctuations, we found that regions with higher levels of financial development are more prone to stock price fluctuations due to the lack of political connections, which is related to higher levels of debt financing in regions with higher levels of financial development. In addition, the increasing level of debt exacerbates conflicts and inconsistencies among stakeholders, which is not conducive to the stability of the company's stock price. Through the above research, relevant suggestions have been provided to enterprises, media, and governments. For example, enterprises should clarify the boundary between government and enterprise, focus on long-term strategic goals, build core competitiveness, and thereby enhance their own value; The media should play a correct role in information transmission and public opinion guidance, and play a positive role in the economic development of the industry; The government should promote market-oriented construction and establish positive government enterprise relationships.

Causal relationships between Sjögren's syndrome and Parkinson's disease: A Mendelian randomization study.

BACKGROUND: Epidemiological and observational studies have indicated an association between Sjögren's syndrome (SS) and Parkinson's disease (PD). However, consistent conclusions have not been reached due to various limitations. In order to determine whether SS and PD are causally related, we conducted a Mendelian randomization study (MR) with two samples. METHODS: Data for SS derived from the FinnGen consortium's R9 release (2495 cases and 365 533 controls). Moreover, data for PD were acquired from the publicly available GWAS of European ancestry, which involved 33 674 cases and 449 056 controls. The inverse variance weighted, along with four other effective methodologies, were employed to comprehensively infer the causal relationships between SS and PD. To assess the estimation's robustness, a number of sensitivity studies were performed. To determine the probability of reverse causality, we performed a reverse MR analysis. RESULTS: There was no evidence of a significant causal effect of SS on PD risks based on the MR [odds ratio (OR) = 1.03; 95% confidence interval (CI) = 0.95-1.11; p = .45]. Similarly, no evidence supported the causal effects of PD on SS (OR = 0.92; 95% CI = 0.81-1.04; p = .20). These findings held up under rigorous sensitivity analysis. CONCLUSIONS: MR bidirectional analysis did not reveal any cause-and-effect relationship between SS and PD, or vice versa. Further study of the mechanisms that may underlie the probable causal association between SS and PD is needed.

Research trends and frontiers in lupus nephritis: a bibliometric analysis from 2012 to 2022.

OBJECTIVES: Lupus nephritis is a prevalent renal manifestation of systemic lupus erythematosus (SLE) and represents a significant cause of morbidity and mortality associated with the disease. This study endeavors to undertake a meticulous bibliometric analysis of LN publications to comprehend the research hotspots and future directions. METHODS: The literature on LN was acquired from the Web of Science Core Collection (WoSCC). Co-occurrence and cooperative relationship analysis of authors, institutions, countries, journals, references and keywords in the publication was performed through CiteSpace, VOSviewer and a bibliometric online analysis platform. The knowledge graphs were created, and clustering and emergence analyses were performed. RESULTS: According to the search strategy, a total of 2077 publications related to lupus nephritis (LN) have been identified, with China being the largest contributor globally. The Ohio State University emerged as the most prolific institution. Lupus is the most cited and published journal. Jan J Weening and Brad Rovin were the most prolific and cocited authors. The current research focus revolved around the "nirp3 inflammasome," "biomarker," and "voclosporin". "international society," "thrombotic microangiopathy (TMA)," and "pathway" were identified to be future research hotpots by keyword burst analysis. CONCLUSIONS: This bibliometric analysis summarizes for the first time the progress of LN research (2012-2022), and qualitatively and quantitatively evaluates the bibliometric information of LN research. There has been a steady increase in the scientific literature on LN over the past 11 years, with an average growth rate of 7.27%. In this field, researchers are primarily based in China and the United States. The pathogenic mechanisms, management strategies and prognostic outcomes of LN are acknowledged as prospective research hotspots. Bibliometrically, the research status and trends of LN publications may greatly assist and be a significant reference for future research in the area.

4EBP2-regulated protein translation has a critical role in high-fat diet-induced insulin resistance in hepatocytes.

A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.

Reversible Solid-Solid Conversion of Sulfurized Polyacrylonitrile Cathodes in Lithium-Sulfur Batteries by Weakly Solvating Ether Electrolytes.

Despite carbonate electrolytes exhibiting good stability to sulfurized polyacrylonitrile (SPAN), their chemical incompatibility with lithium (Li) metal anode leads to poor electrochemical performance of Li||SPAN full cells. While the SPAN employs conventional ether electrolytes that suffer from the shuttle effect, leading to rapid capacity fading. Here, we tailor a dilute electrolyte based on a low solvating power ether solvent that is both compatible with SPAN and Li metal. Unlike conventional ether electrolytes, the weakly solvating ether electrolyte enables SPAN to undergo reversibly "solid-solid" conversion. It features an anion-rich solvation structure that allows for the formation of a robust cathode electrolyte interphase on the SPAN, effectively blocking the dissolution of polysulfides into the bulk electrolyte and avoiding the shuttle effect. What's more, the unique electrolyte chemistry endowed Li ions with fast electroplating kinetics and induced high reversibility Li deposition/stripping process from 25 °C to -40 °C. Based on tailored electrolyte, Li||SPAN full cells matched with high loading SPAN cathodes (≈3.6 mAh cm-2 ) and 50 µm Li foil can operate stably over a wide range of temperatures. Additionally, Li||SPAN pouch cell under lean electrolyte and 5 % excess Li conditions can continuously operate stably for over a month.

Enhancers of the PAIR4 regulatory module promote distal VH gene recombination at the Igh locus.

While extended loop extrusion across the entire Igh locus controls VH -DJH recombination, local regulatory sequences, such as the PAIR elements, may also activate VH gene recombination in pro-B-cells. Here, we show that PAIR-associated VH 8 genes contain a conserved putative regulatory element (V8E) in their downstream sequences. To investigate the function of PAIR4 and its V8.7E, we deleted 890 kb containing all 14 PAIRs in the Igh 5' region, which reduced distal VH gene recombination over a 100-kb distance on either side of the deletion. Reconstitution by insertion of PAIR4-V8.7E strongly activated distal VH gene recombination. PAIR4 alone resulted in lower induction of recombination, indicating that PAIR4 and V8.7E function as one regulatory unit. The pro-B-cell-specific activity of PAIR4 depends on CTCF, as mutation of its CTCF-binding site led to sustained PAIR4 activity in pre-B and immature B-cells and to PAIR4 activation in T-cells. Notably, insertion of V8.8E was sufficient to activate VH gene recombination. Hence, enhancers of the PAIR4-V8.7E module and V8.8E element activate distal VH gene recombination and thus contribute to the diversification of the BCR repertoire in the context of loop extrusion.

PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis.

Cytochrome c oxidase, also known as complex IV, facilitates the transfer of electrons from cytochrome c to molecular oxygen, resulting in the production of ATP. The assembly of complex IV is a tightly regulated and intricate process that entails the coordinated synthesis and integration of subunits encoded by the mitochondria and nucleus into a functional complex. Accurate regulation of translation is crucial for maintaining proper mitochondrial function, and defects in this process can lead to a wide range of mitochondrial disorders and diseases. However, the mechanisms governing mRNA translation by mitoribosomes in mammals remain largely unknown. In this study, we elucidate the critical role of PET117, a chaperone protein involved in complex IV assembly, in the regulation of mitochondria-encoded cytochrome c oxidase 1 (COX1) protein synthesis in human cells. Depletion of PET117 reduced mitochondrial oxygen consumption rate and impaired mitochondrial function. PET117 was found to interact with and stabilize translational activator of COX1 (TACO1) and prevent its ubiquitination. TACO1 overexpression rescued the inhibitory effects on mitochondria caused by PET117 deficiency. These findings provide evidence for a novel PET117-TACO1 axis in the regulation of mitochondrial protein expression, and revealed a previously unknown role of PET117 in human cells.

pH-Responsive Selenium Nanoplatform for Highly Efficient Cancer Starvation Therapy by Atorvastatin Delivery.

Recently, starvation-inducing nutrient deprivation has been regarded as a promising strategy for tumor suppression. As a first-line lipid-lowering drug, atorvastatin (ATV) significantly reduces caloric intake, suggesting its potential in starvation therapy for suppressing tumors. Accordingly, we developed a novel starvation therapy agent (HA-Se-ATV) in this study to suppress tumor growth by using hyaluronic acid (HA)-conjugated chitosan polymer-coated nano-selenium (Se) for loading ATV. HA-Se-ATV targets cancer cells, following which it effectively accumulates in the tumor tissue. The HA-Se-ATV nanoplatform was then activated by inducing a weakly acidic tumor microenvironment and subsequently releasing ATV. ATV and Se synergistically downregulate the levels of cellular adenosine triphosphate while inhibiting the expression of thioredoxin reductase 1. Consequently, the starvation-stress reaction of cancer cells is significantly elevated, leading to cancer cell death. Furthermore, the in vivo results indicate that HA-Se-ATV effectively suppresses tumor growth with a low level of toxicity, demonstrating its great potential for clinical translation.

Association between type 1 diabetes mellitus and ankylosing spondylitis: a two-sample Mendelian randomization study.

Objective: The development of ankylosing spondylitis (AS) is closely related to autoimmune system dysfunction. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that is a risk factor for many diseases. This study aimed to investigate the causal relationship between T1DM mellitus and AS genetically. Methods: A genome-wide association study (GWAS) of causal relationships between exposure (T1DM) and outcome (AS) was performed using summary data from the GWAS database. We conducted a two-sample Mendelian randomization (MR) study of these two diseases. Inverse variance weighting (IVW) was used as the primary analysis method, with MR Egger, weighted median, and weighted mode used as supplementary methods. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-Pleiotropy RESidual Sum and outlier methods, leave-one-out analysis, and funnel plots. Results: A total of 11 single nucleotide polymorphisms (SNPs)were identified for instrumental variables(IVs) for MR analysis.IVW found that T1DM was causally associated with AS ((IVW: OR = 1.0006 (95% CI 1.0001, 1.0011), p = 0.0057; MR-Egger: OR = 1.0003 (95% CI 0.9995, 1.0012), p = 0.4147; weighted median: OR = 1.0006 (95% CI 1.0003, 1.0008), p = 0.0001; weighted mode: OR = 1.0007 (95% CI 1.0005, 1.0009), p = 0.0001). No horizontal pleiotropy was found for the MR-Egger intercept, and leave -one-out analysis found that the results remained stable after the removal of individual SNPs. Conclusion: The results of the two-sample MR analysis supported a causal relationship between T1DM and AS risk.

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder.

The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.

The Influence of Language Style and Brand Name on Crowdfunding Performance of Environmental Protection Enterprises.

Crowdfunding, as an emerging phenomenon of enterprise after entrepreneurship financing, has maintained rapid and sustained growth in recent years. For crowdfunding environmental protection enterprises, one of the main challenges in financing is to reduce the uncertainty of public investors about the quality, management level, and products or services of crowdfunding projects. After reading the text of crowdfunding projects, the public investors have a subjective impression of the crowdfunding environmental protection projects, which determines the public investors' judgment on the risks and prospects of environmental protection projects and the willingness to invest. Therefore, the texts of crowdfunding projects are very important. In this paper, the data of 130 crowdfunding environmental protection projects on the Modian website are selected, and the ordinal logistic regression model is used. This paper explores the influence of language style in the description text and brand name in the title text on crowdfunding performance.

Age-Related Decline of Male Fertility: Mitochondrial Dysfunction and the Antioxidant Interventions.

Mitochondria are structurally and functionally unique organelles in male gametes. Apparently, as the only organelles remaining in mature sperm, mitochondria not only produce adeno-sine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to support sperm mobility, but also play key roles in regulating reactive oxidation species (ROS) signaling, calcium homeostasis, steroid hormone biosynthesis, and apoptosis. Mitochondrial dysfunction is often associated with the aging process. Age-dependent alterations of the epididymis can cause alterations in sperm mitochondrial functioning. The resultant cellular defects in sperm have been implicated in male infertility. Among these, oxidative stress (OS) due to the overproduction of ROS in mitochondria may represent one of the major causes of these disorders. Excessive ROS can trigger DNA damage, disturb calcium homeostasis, impair OXPHOS, disrupt the integrity of the sperm lipid membrane, and induce apoptosis. Given these facts, scavenging ROS by antioxidants hold great potential in terms of finding promising therapeutic strategies to treat male infertility. Here, we summarize the progress made in understanding mitochondrial dysfunction, aging, and male infertility. The clinical potential of antioxidant interventions was also discussed.

Combinatorial nanococktails via self-assembling lipid prodrugs for synergistically overcoming drug resistance and effective cancer therapy.

BACKGROUND: Combinatorial systemic chemotherapy is a powerful treatment paradigm against cancer, but it is fraught with problems due to the emergence of chemoresistance and additive systemic toxicity. In addition, coadministration of individual drugs suffers from uncontrollable pharmacokinetics and biodistribution, resulting in suboptimal combination synergy. METHODS: Toward the goal of addressing these unmet medical issues, we describe a unique strategy to integrate multiple structurally disparate drugs into a self-assembling nanococktail platform. Conjugation of a polyunsaturated fatty acid (e.g., linoleic acid) with two chemotherapies generated prodrug entities that were miscible with tunable drug ratios for aqueous self-assembly. In vitro and in vivo assays were performed to investigate the mechanism of combinatorial nanococktails in mitigating chemoresistance and the efficacy of nanotherapy. RESULTS: The coassembled nanoparticle cocktails were feasibly fabricated and further refined with an amphiphilic matrix to form a systemically injectable and PEGylated nanomedicine with minimal excipients. The drug ratio incorporated into the nanococktails was optimized and carefully examined in lung cancer cells to maximize therapeutic synergy. Mechanistically, subjugated resistance by nanococktail therapy was achieved through the altered cellular uptake pathway and compromised DNA repair via the ATM/Chk2/p53 cascade. In mice harboring cisplatin-resistant lung tumor xenografts, administration of the nanococktail outperformed free drug combinations in terms of antitumor efficacy and drug tolerability. CONCLUSION: Overall, our study provides a facile and cost-effective approach for the generation of cytotoxic nanoparticles to synergistically treat chemoresistant cancers.

Formation mechanism and governance strategies of stigma in public health emergencies: Based on event system theory.

Introduction: With the new coronavirus (COVID-19) pandemic across the world, it is critical to propose effective strategies for stigma governance in public health emergencies in order to reduce negative effects caused by stigma. However, no known research has focused on the essential role of events in understanding stigma phenomenon from the perspective of external dynamic changes. Methods: Based on the event system theory, this paper analyzes the evolution mode and characteristics of specific events in the process of stigmatization from strength, space and time aspects, and taking COVID-19 event as an example, 1202 questionnaires and empirical analysis were conducted. Results and discussion: Our results reveal that event strength directly affects the results of stigmatization, and such impact appears to be more prominent with a novel, disruptive and critical event. In addition, spatial and temporal attributes represent the dynamic development of an event, and they can interact with event strength to regulate the relationship between event strength and outcomes. Finally, stigma governance strategies under public health emergencies from three aspects of event strength, space, and time were put forward.

Kynureninase contributes to the pathogenesis of psoriasis through pro-inflammatory effect.

Kynureninase (KYNU) is a key enzyme in the tryptophan metabolism pathway with elevated expression in psoriatic lesions relative to normal skin. However, whether KYNU contributes to the pathogenesis of psoriasis remains unknown. We sought to investigate the role of KYNU in psoriasis and its possible regulation mechanism. In the results, KYNU is upregulated in psoriatic skin samples from patients or animal models compared with normal skin control which was assayed in psoriatic patient samples, IMQ-induced psoriasis-like skin inflammation in BABL/c mice and M5-stimulated keratinocyte cell lines by immunohistochemistry (IHC). KYNU knockdown had a trivial impact on keratinocyte proliferation, but significantly inhibited the production of inflammatory cytokines in HaCaT, HEKα, and HEKn cells by quantitative reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and western blot analysis. The 3'-untranslated region of KYNU contains a conserved target site of a skin-specific microRNA (miRNA), miR-203a, as predicted by TargetScan software. Furthermore, miR-203a exhibited an inversed expression kinetics to KYNU during the development of IMQ-induced psoriasis-like skin inflammation in BABL/c mice. Overexpression of miR-203 subsequently leading to the inhibition of KYNU, could significantly reduce the production of M5-induced, psoriasis-related inflammatory factors in keratinocytes. Finally, KYNU inhibitors could alleviate the pathological phenotypes in IMQ-mice. Our study supported the contributive role of KYNU in the development of psoriasis and provided preliminary evidence for KYNU as a potential therapeutic target in psoriasis.

Driver gene alterations profiling of Chinese non-small cell lung cancer and the effects of co-occurring alterations on immunotherapy.

BACKGROUND: Molecular testing for alterations in oncogenic driver genes and targeted therapies have become standard procedures for non-small cell lung cancer (NSCLC) patients. However, little evidence has shed light on the pattern of co-existence of driver genes in NSCLC, and whether they may have different tumor features affecting immunotherapy is still unclarified. METHODS: Genomic alterations in 14 lung cancer-related genes were conducted in 3440 Chinese NSCLC patients using next-generation sequencing. Meanwhile, tumor mutational burden and immunotherapy dataset from the Memorial sloan kettering cancer center (MSKCC) and lung adenocarcinoma dataset from The Cancer Genome Atlas (TCGA) were utilized for analyzing the impact of the co-occurring alterations on patients' survival following immunotherapy. RESULTS: In this cohort, 90.17% of patients had at least one somatic alteration in the 14 genes, including 51% of co-occurring alterations. TP53 and epidermal growth factor receptor (EGFR) were the most prevalent genes (54.74% and 53.55%, respectively), followed by KRAS, ERBB2, ALK, PIK3CA, ROS1, RET, MET, BRAF, KIT, FGFR1, PDGFRA, and NRAS. The prevalence of TP53, EGFR, and ERBB2 in our cohort were significantly higher than that from the TCGA database, whereas KRAS, BRAF, and PDGFRA were significantly lower than the latter. Furthermore, the patients who harbored multiple alterations (8.86%, 31/350) in eight driver genes survived longer and have a higher tumor mutation burden compared to the patients with a single alteration. Similar result was found between the patients with co-occurring alteration of EGFR and other driver genes and the patients with single EGFR alteration. Meanwhile, we found a distinct immune cell infiltration feature between patients with single and multiple driver gene alterations, as well as between patients with only EGFR alteration and co-occurring groups. CONCLUSION: This study identified a unique driver gene feature and found patients harboring co-occurring alterations of EGFR and other driver genes may benefit from immunotherapy, which may provide more therapeutic selections for EGFR-mutated NSCLC patients and merit additional investigation.

Pax5 regulates B cell immunity by promoting PI3K signaling via PTEN down-regulation.

The transcription factor Pax5 controls B cell development, but its role in mature B cells is largely enigmatic. Here, we demonstrated that the loss of Pax5 by conditional mutagenesis in peripheral B lymphocytes led to the strong reduction of B-1a, marginal zone (MZ), and germinal center (GC) B cells as well as plasma cells. Follicular (FO) B cells tolerated the loss of Pax5 but had a shortened half-life. The Pax5-deficient FO B cells failed to proliferate upon B cell receptor or Toll-like receptor stimulation due to impaired PI3K-AKT signaling, which was caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrained PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescued FO B cell numbers and the development of MZ B cells but did not restore GC B cell formation. Hence, the posttranscriptional down-regulation of PTEN expression is an important function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity.