Association between thyroid function and nonalcoholic fatty liver disease: a dose-response meta-analysis.

Background: Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research. Methods: The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD. Results: Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels. Conclusions: Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD. Trial registration: Registered number in PROSPERO: CRD42023405052.

Effect of esketamine combined with dexmedetomidine on delirium in sedation for mechanically ventilated ICU patients: protocol for a nested substudy within a randomized controlled trial.

BACKGROUND: Use of sedatives and analgesics is associated with the occurrence of delirium in critically ill patients receiving mechanical ventilation. Dexmedetomidine reduces the occurrence of delirium but may cause hypotension, bradycardia, and insufficient sedation. This substudy aims to determine whether the combination of esketamine with dexmedetomidine can reduce the side effects and risk of delirium than dexmedetomidine alone in mechanically ventilated patients. METHODS: This single-center, randomized, active-controlled, superiority trial will be conducted at The First Affiliated Hospital of Nanjing Medical University. A total of 134 mechanically ventilated patients will be recruited and randomized to receive either dexmedetomidine alone or esketamine combined with dexmedetomidine, until extubation or for a maximum of 14 days. The primary outcome is the occurrence of delirium, while the second outcomes include the number of delirium-free days; subtype, severity, and duration of delirium; time to first onset of delirium; total dose of vasopressors and antipsychotics; duration of mechanical ventilation; ICU and hospital length of stay (LOS); accidental extubation, re-intubation, re-admission; and mortality in the ICU at 14 and 28 days. DISCUSSION: There is an urgent need for a new combination regimen of dexmedetomidine due to its evident side effects. The combination of esketamine and dexmedetomidine has been applied throughout the perioperative period. However, there is still a lack of evidence on the effects of this regimen on delirium in mechanically ventilated ICU patients. This substudy will evaluate the effects of the combination of esketamine and dexmedetomidine in reducing the risk of delirium for mechanically ventilated patients in ICU, thus providing evidence of this combination to improve the short-term prognosis. The study protocol has obtained approval from the Medical Ethics Committee (ID: 2022-SR-450). TRIAL REGISTRATION: ClinicalTrials.gov: NCT05466708, registered on 20 July 2022.

Screening of a Prognostic Gene Signature for Relapsed/Refractory Acute Myeloid Leukemia Based on Altered Circulating CircRNA Profiles.

Background: Relapsed/refractory acute myeloid leukemia (R/R-AML) has dismal prognosis due to chemotherapy resistance. Circular RNAs (circRNAs) have shown emerging roles in chemotherapy resistance in various cancers including hematologic malignancies. However, the potential roles of circRNAs in AML progression and drug resistance remain largely undetermined. Methods: In this study, circulating circRNAs expression profiles were analyzed among R/R-AML, de novo AML and healthy controls (HC) using a human circRNA Array. Bioinformatic analysis was carried out to explore the differentially expressed circRNAs (DE-circRNAs). GO, KEGG pathway analysis, along with circRNA-miRNA-mRNA network analysis, were conducted to identify the potential biological pathways involved in R/R-AML. Finally, the UALCAN database was used to assess the prognosis of different target DE-circRNAs-related mRNAs. Results: Forty-eight DE-circRNAs were upregulated, whereas twenty-seven DE-circRNAs were downregulated in R/R-AML samples. Up-regulated DE-circRNAs in R/R-AML samples were mainly enrichment in the biological processes and pathways of cell migration, microRNAs in cancers, Rap1 and Ras signaling pathways. Six DE-circRNAs were randomly selected to further explore their relationships with R/R-AML. GO and KEGG pathway analyses of the six candidate DE-circRNAs-related target mRNAs were mainly involved in the regulation of signal transduction and Ras signaling pathway. By overlapping our RNA-sequencing results of differentially expressed genes (DEGs) in R/R-AML samples with the candidate DE-circRNAs-predicted target mRNAs, we identified sixty-eight overlapping targeted mRNAs. Using UALCAN database analysis, we identified that AML patients with six upregulated DE-circRNA-related genes (ECE1, PI4K2A, SLC9A6, CCND3, PPP1R16B, and TRIM32) and one downregulated gene DE-circRNA-related genes (ARHGAP10) might have a poor prognosis. Conclusion: This study revealed the overall alterations of circRNAs in R/R-AML. DE-circRNAs and their related genes might be used as potential early, sensitive and stable biomarkers for AML diagnosis, R/R-AML monitoring, and even as novel treatment targets for R/R-AML.

X-ray focusing below 3 nm with aberration-corrected multilayer Laue lenses.

Multilayer Laue lenses are volume diffractive optical elements for hard X-rays with the potential to focus beams to sizes as small as 1 nm. This ability is limited by the precision of the manufacturing process, whereby systematic errors that arise during fabrication contribute to wavefront aberrations even after calibration of the deposition process based on wavefront metrology. Such aberrations can be compensated by using a phase plate. However, current high numerical aperture lenses for nanometer resolution exhibit errors that exceed those that can be corrected by a single phase plate. To address this, we accumulate a large wavefront correction by propagation through a linear array of 3D-printed phase correcting elements. With such a compound refractive corrector, we report on a point spread function with a full-width at half maximum area of 2.9 × 2.8 nm2 at a photon energy of 17.5 keV.

Conformational disorder in the crystal structure of methyl 2-acetamido-2-deoxy-ß-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-ß-D-glucopyranoside (methyl ß-chitobioside) methanol monosolvate.

Methyl 2-acetamido-2-deoxy-ß-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-ß-D-glucopyranoside (methyl ß-chitobioside), (IV), crystallizes from aqueous methanol at room temperature to give a structure (C17H30N2O22·CH3OH) containing conformational disorder in the exocyclic hydroxymethyl group of one of its ßGlcNAc residues. As observed in other X-ray structures of disaccharides containing ß-(1→4) O-glycosidic linkages, inter-residue hydrogen bonding between O3H of the ßGlcNAc bearing the OCH3 aglycone and O5 of the adjacent ßGlcNAc is observed based on the 2.79 Šinternuclear distance between the O atoms. The structure of (IV) was compared to that determined previously for 2-acetamido-2-deoxy-ß-D-glucopyranosyl-(1→4)-2-acetamido-2-deoxy-ß-D-glucopyranose (ß-chitobiose), (III). The O-glycosidic linkage torsion angles, phi (φ) and psi (ψ), in (III) and (IV) differ by 6-8°. The N-acetyl side chain conformation in (III) and (IV) shows some context dependence, with the C1-C2-N-Ccar torsion angle 10-15° smaller for the ßGlcNAc residue involved in the internal O-glycosidic linkage. In (IV), conformational disorder is observed in the exocyclic hydroxymethyl (-CH2OH) group in the ßGlcNAc residue bearing the OCH3 aglycone, and a fitting of the electron density indicates an approximate 50:50 distribution of the gauche-gauche (gg) and gauche-trans (gt) conformers in the lattice. Similar behavior is not observed in (III), presumably due to the different packing structure in the vicinity of the -CH2OH substituent that affects its ability to hydrogen bond to proximal donors/acceptors. Unlike (IV), a re-examination of the previously reported electron density of (III) revealed conformational disorder in the N-acetyl side chain attached to the reducing-end ßGlcNAc residue caused by rotation about the C2-N bond.

Separation of Palladium by an Imine-Linked Cu(I)-Organic Framework.

Selective capture of palladium (Pd) is one of the important works in science due to its high application and low content in the Earth's crust. To this end, we present herein a new Cu(I)-organic framework (ECUT-MOF-1) by introducing pyridine N active sites to chelate Pd(II). ECUT-MOF-1 demonstrated that the maximal adsorption capacity of Pd(II) was 350 mg/g in pH = 3 solution. In addition, kinetic analysis, cycle performance, selectivity, and adsorption mechanisms were also investigated. All of the results suggested its superior application in the recovery of Pd(II).

RNA Coating Promotes Peri-Implant Osseointegration.

In addition to transmitting and carrying genetic information, RNA plays an important abiotic role in the world of nanomaterials. RNA is a natural polyanionic biomacromolecule, and its ability to promote osteogenesis by binding with other inorganic materials as an osteogenic induction agent was discovered only recently. However, whether it can promote osseointegration on implants has not been reported. Here, we investigated the effect of the RNA-containing coating materials on peri-implant osseointegration. Total RNA extracted from rat muscle tissue was used as an osteogenic induction agent, and hyaluronic acid (HA) was used to maintain its negative charge. In simulated body fluids (SBF), in vitro studies demonstrated that the resulting material encouraged calcium salt deposition. Cytological experiments showed that the RNA-containing coating induced greater cell adhesion and osteogenic differentiation in comparison to the control. The results of animal experiments showed that the RNA-containing coating had osteoinductive and bone conduction activities, which are beneficial for bone formation and osseointegration. Therefore, the RNA-containing coatings are useful for the surface modification of titanium implants to promote osseointegration.

Integrated bioinformatics investigation of adenylyl cyclase family co-expression network in bladder cancer followed by preliminary validation of member 2 (ADCY2) in tumorigenesis and prognosis.

Background: The adenylyl cyclase (ADCY) gene family encodes enzymes responsible for the synthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), which comprises nine transmembrane isoforms (ADCYs 1-9). Although ADCYs correlate with intracellular signalling and tumorigenesis in different malignancies, their roles in bladder cancer remain unclear. Methods: Utilizing the bladder urothelial carcinoma (BLCA) dataset from The Cancer Genome Atlas (TCGA), we employed the R package 'limma' to identify differential genes. Subsequent correlation analysis with corresponding clinical data was conducted. Prognostic significance of ADCY family genes was assessed through survival analysis. Univariate and multivariate Cox regression determined ADCY2 as a potential independent risk factor for BLCA. Validation was performed using immunohistochemistry results from independent cohorts. Additionally, we delved into the mechanism of genetic variations, methylation modifications, and signalling pathways of ADCY family genes. Evaluation of their role in the immune microenvironment was achieved through R packages single-sample gene set enrichment analysis (ssGSEA), CIBERPORT, and ESTIMATE. Results: Cases of bladder cancer were retrieved from TCGA, and the transcriptionally differentially expressed members of ADCY were identified (members 2, 4, and 5). Genomic alteration, epigenomic modification, clinicopathological characteristics and clinical survival were systematically investigated. A co-expression network was established based on the intersection of correlated genes, which was centred around ADCY2, ADCY4, and ADCY5. Enrichment analysis revealed that correlated genes were involved in epithelial-mesenchymal transition (EMT). The ADCY2 was selected as the most representative biomarker for prognosis in bladder cancer. Bladder tumour with higher ADCY2 expression had higher prognostic risk and worse survival outcomes. Moreover, ADCY2 was correlated with classic immune checkpoints, and a better responsiveness to immunotherapy was exhibited in high-expression subsets. To ameliorate universality of the conclusion, our study also included several real-world cohorts into the preliminary validation, using datasets from the Gene Expression Omnibus (GEO; GSE13507), tissue microarray (TMA) with 80 bladder cancer inclusion and clinical trial IMvigor210, which were associated with immunotherapy sensitivity, prognosis, and common biomarker presentation. Conclusions: Our study reveals that ADCY family has prognostic value in patients with bladder cancer; the ADCY2 is a prominent prognostic biomarker. The bioinformatics analyses and validation provide direction for further functional and mechanistic studies on the screened members of ADCY family.

The circular RNA hsa_circ_0045800 serves as a favorable biomarker in pathogenesis of sjögren's syndrome.

BACKGROUND: Circular RNAs (circRNAs) play various roles in the development of many autoimmune diseases. However, their expression profiles and specific function in Sjögren's Syndrome remains largely unknown. OBJECTIVES: We aimed to investigate circRNAs potential diagnostic value in primary Sjögren's syndrome (pSS) and contribution to the pathogenesis of pSS. METHODS: This study included 102 subjects, 51 pSS patients and 51 healthy controls. The concentration of hsa_circ_0045800 was analyzed in peripheral blood mononuclear cells obtained from 51 pSS patients and 51 healthy controls by qRT-PCR. We established a receiver operating characteristic curve (ROC) to assess the biological diagnostic value of hsa_circ_0045800 for pSS. In addition, we analyzed the correlation between hsa_circ_0045800 and disease activity in Sjogren's syndrome. A differential analysis was also conducted on the concentration of hsa_circ_0045800 in patients in pSS patients before and after treatment. We studied the downstream mechanism of hsa_circ_0045800 through bioinformatics analysis and confirmed it using luciferase reporter gene assay. RESULTS: We confirmed that the concentration of hsa_circ_0045800 was elevated 10.4-fold in peripheral blood mononuclear cells of pSS patients than in healthy controls (p = 0.00). In the pSS active disease group, the concentration of hsa_circ_0045800 is 2.5-fold higher compared to the pSS non-active disease group (p = 0.04). The concentration of hsa_circ_0045800 after treatment was decreased by 80% compared with that before treatment (p = 0.037), suggesting its utility as a potential marker for monitoring treatment efficacy. ROC curve analysis showed that the diagnostic value of hsa_circ_0045800 in pSS patients was significantly higher than that in healthy controls, with an area under the curve of 0.865, a sensitivity of 74%, and a specificity of 92%. The concentration of hsa_circ_0045800 is correlated with various clinical factors: the concentration of hsa_circ_0045800 is positively associated with age (r = 0.328, P = 0.019), oral dryness (r = 0.331, P = 0.017), while it is negatively correlated with HGB (r = -0.435, P = 0.001) and and hypothyroidism (r = -0.318, P = 0.023). Bioinformatics predictions and luciferase assays indicated that hsa_circ_0045800 acts as a molecular sponge for miR-1247-5p, with SMAD2 being a target gene of miR-1247-5p. CONCLUSION: Our study results show that hsa_circ_0045800 potentially contributes to the development and progression of pSS via the miR-1247-5p/SMAD2 pathway. Peripheral blood mononuclear cells are directly involved in the pathogenesis of pSS, and the discovery of hsa_circ_0045800 in peripheral blood mononuclear cells highlights its potential as a novel biomarker for disease activity and diagnosis in patients with pSS. Key Points • The concentration of hsa_circ_0045800 was higher in peripheral blood mononuclear cells of pSS patients. • Hsa_circ_0045800 promoted pSS progression through miR-1247-5p-SMAD2 axis. • Hsa_circ_0045800 is a potential biomarker for pSS.

METTL3-mediated N6-methyladenosine modification of STAT5A promotes gastric cancer progression by regulating KLF4.

N6-methyladenosine (m6A) is the predominant post-transcriptional RNA modification in eukaryotes and plays a pivotal regulatory role in various aspects of RNA fate determination, such as mRNA stability, alternative splicing, and translation. Dysregulation of the critical m6A methyltransferase METTL3 is implicated in tumorigenesis and development. Here, this work showed that METTL3 is upregulated in gastric cancer tissues and is associated with poor prognosis. METTL3 methylates the A2318 site within the coding sequence (CDS) region of STAT5A. IGF2BP2 recognizes and binds METTL3-mediated m6A modification of STAT5A through its GXXG motif in the KH3 and KH4 domains, leading to increased stability of STAT5A mRNA. In addition, both METTL3 and IGF2BP2 are positively correlated with STAT5A in human gastric cancer tissue samples. Helicobacter pylori infection increased the expression level of METTL3 in gastric cancer cells, thereby leading to the upregulation of STAT5A. Functional studies indicated that STAT5A overexpression markedly enhances the proliferation and migration of GC cells, whereas STAT5A knockdown has inhibitory effects. Further nude mouse experiments showed that STAT5A knockdown effectively inhibits the growth and metastasis of gastric cancer in vivo. Moreover, as a transcription factor, STAT5A represses KLF4 transcription by binding to its promoter region. The overexpression of KLF4 can counteract the oncogenic impact of STAT5A. Overall, this study highlights the crucial role of m6A in gastric cancer and provides potential therapeutic targets for gastric cancer.

Association between autoimmune liver diseases and chronic hepatitis B: A multivariable Mendelian randomization study in European population.

BACKGROUND: Observational studies have indicated a link between autoimmune liver diseases (AILD) and chronic hepatitis B (CHB) through observational studies. The association between AILD and CHB remains indeterminate. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to scrutinize the causal nexus between AILD and CHB utilizing summary statistics derived from extensive genome-wide association studies (GWASs) in European populations. The primary statistical methodology employed was the inverse variance-weighted (IVW) method to deduce the causal connection of AILD on CHB. This study incorporated primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) as subtypes of AILD. Additionally, we conducted a multivariable MR (MVMR) analysis to account for the potential confounding effects of smoking, alcohol consumption, body mass index (BMI), and some autoimmune diseases. RESULTS: Our MR investigation encompassed a cohort of 725,816 individuals. The MR analysis revealed that genetically predicted PSC significantly correlated with a reduced risk of CHB (IVW OR = 0.857; 95%CI: 0.770-0.953, P = 0.005). Conversely, the reverse MR analysis suggested that genetic susceptibility to PSC might not modify the risk of CHB (IVW OR = 1.004; 95% CI: 0.958-1.053, P = 0.866). Genetically proxied PBC and AIH exhibited no discernible causal association with CHB in the MR analysis using the IVW method (P = 0.583; P = 0.425). The MVMR analysis still indicated a decreased risk of CHB associated with PSC (OR = 0.853, P = 0.003). CONCLUSION: Our study elucidates a causal relationship between PSC and a diminished risk of CHB.

Discovery of novel cholesteryl ester transfer protein (CETP) inhibitors by a multi-stage virtual screening.

Cholesteryl ester transfer protein (CETP) is a promising therapeutic target for cardiovascular diseases. It effectively lowers the low-density lipoprotein cholesterol levels and increases the high-density lipoprotein cholesterol levels in the human plasma. This study identified novel and highly potent CETP inhibitors using virtual screening techniques. Molecular docking and molecular dynamics (MD) simulations revealed the binding patterns of these inhibitors, with the top 50 compounds selected according to their predicted binding affinity. Protein-ligand interaction analyses were performed, leading to the selection of 26 compounds for further evaluation. A CETP inhibition assay confirmed the inhibitory activities of the selected compounds. The results of the MD simulations revealed the structural stability of the protein-ligand complexes, with the binding site remaining significantly unchanged, indicating that the five compounds (AK-968/40709303, AG-690/11820117, AO-081/41378586, AK-968/12713193, and AN-465/14952302) identified have the potential as active CETP inhibitors and are promising leads for drug development.

Rehabilitation Applications Based on Behavioral Therapy for People With Knee Osteoarthritis: Systematic Review.

BACKGROUND: The development of digital applications based on behavioral therapies to support patients with knee osteoarthritis (KOA) has attracted increasing attention in the field of rehabilitation. This paper presents a systematic review of research on digital applications based on behavioral therapies for people with KOA. OBJECTIVE: This review aims to describe the characteristics of relevant digital applications, with a special focus on the current state of behavioral therapies, digital interaction technologies, and user participation in design. The secondary aim is to summarize intervention outcomes and user evaluations of digital applications. METHODS: A systematic literature search was conducted using the keywords "Knee Osteoarthritis," "Behavior Therapy," and "Digitization" in the following databases (from January 2013 to July 2023): Web of Science, Embase, Science Direct, Ovid, and PubMed. The Mixed Methods Assessment Tool (MMAT) was used to assess the quality of evidence. Two researchers independently screened and extracted the data. RESULTS: A total of 36 studies met the inclusion criteria and were further analyzed. Behavioral change techniques (BCTs) and cognitive behavioral therapy (CBT) were frequently combined when developing digital applications. The most prevalent areas were goals and planning (n=31) and repetition and substitution (n=27), which were frequently used to develop physical activity (PA) goals and adherence. The most prevalent combination strategy was app/website plus SMS text message/telephone/email (n=12), which has tremendous potential. This area of application design offers notable advantages, primarily manifesting in pain mitigation (n=24), reduction of physical dysfunction (n=21), and augmentation of PA levels (n=12). Additionally, when formulating design strategies, it is imperative to consider the perspectives of stakeholders, especially in response to the identified shortcomings in application design elucidated within the study. CONCLUSIONS: The results demonstrate that "goals and planning" and "repetition and substitution" are frequently used to develop PA goals and PA behavior adherence. The most prevalent combination strategy was app/website plus SMS text message/telephone/email, which has tremendous potential. Moreover, incorporating several stakeholders in the design and development stages might enhance user experience, considering the distinct variations in their requirements. To improve the efficacy and availability of digital applications, we have several proposals. First, comprehensive care for patients should be ensured by integrating multiple behavioral therapies that encompass various aspects of the rehabilitation process, such as rehabilitation exercises and status monitoring. Second, therapists could benefit from more precise recommendations by incorporating additional intelligent algorithms to analyze patient data. Third, the implementation scope should be expanded from the home environment to a broader social community rehabilitation setting.

Fabrication of Nanocatalytic Medicine from Self-Assembling Peptides Containing an ATCUN-Like Copper-Binding Motif for Anticancer Therapy.

Development of nanomaterials with multiple enzymatic activities via a facile approach receives growing interests in recent years. Although peptide self-assembling provides an effective approach for the construction of biomimetic materials in recent years, fabrication of artificial enzymes from self-assembling peptides with multiple catalytic activities for anticancer therapy is still a challenge. Here, we report a simple method to prepare nanocatalysts with multienzyme-like activities from self-assembling peptides containing ATCUN copper-binding motifs. With the aid of the coordination interactions between the ATCUN motif and Cu(II) ions, these peptides could perform supramolecular self-assembly to form nanomaterials with biomimetic peroxidase, ascorbate oxidase and glutathione peroxidase activities. Moreover, these trienzyme-like effects can elevate oxidative stress levels and suppress the antioxidative capability of cancer cells, which synergistically induce the apoptosis of cancer cells. Because of the high biocompatibility, catalytic activities and drug encapsulation properties, this self-assembled peptide provides a biomimetic platform for the development of new nanocatalytic medicines for multimodal synergistic cancer therapies.

CSF3 aggravates acute exacerbation of pulmonary fibrosis by disrupting alveolar epithelial barrier integrity.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive respiratory disorder characterized by poor prognosis, often presenting with acute exacerbation. The primary cause of death associated with IPF is acute exacerbation of IPF (AE-IPF). However, the pathophysiology of acute exacerbation has not been clearly elucidated yet. This study aims to investigate the underlying pathophysiological molecular mechanism in a mouse AE-PF model. C57BL/6J mice were intratracheally administered bleomycin (BLM, 5 mg/kg) to induce pulmonary fibrosis. After 14 days, lipopolysaccharide (LPS, 2 mg/kg) was injected via the trachea route. Histological assessments, including H&E and Masson staining, as well as inflammatory indicators, were included to evaluate the induction of AE-PF by BLM and LPS in mice. Transcriptomic profiling of pulmonary tissues identified CSF3 as one of the top 10 upregulated DEGs in AE-PF mice. Indeed, administration of exogenous CSF3 protein exacerbated AE-PF in mice. Mechanistically, CSF3 disrupted alveolar epithelial barrier integrity and permeability by regulating specialized cell adhesion complexes such as tight junctions (TJs) and adherens junctions (AJs) via PI3K/p-Akt/Snail pathway, contributing to the aggravation of AE-PF in mice. Moreover, the discovery of elevated sera CSF3 indicated a notable increase in IPF patients during the exacerbation of the disease. Pearson correlation analysis in IPF patients revealed significant positive associations between CSF3 levels and KL-6 levels, LDH levels, CRP levels, respectively. These results provide mechanistic insights into the role of CSF3 in exacerbating of lung fibrotic disease and indicate monitoring CSF3 levels may aid in early clinical decisions for alternative therapy in the management of rapidly progressing IPF.

High expression of SRSF1 facilitates osteosarcoma progression and unveils its potential mechanisms.

BACKGROUND: SRSF1, a member of Serine/Arginine-Rich Splicing Factors (SRSFs), has been observed to significantly influence cancer progression. However, the precise role of SRSF1 in osteosarcoma (OS) remains unclear. This study aims to investigate the functions of SRSF1 and its underlying mechanism in OS. METHODS: SRSF1 expression level in OS was evaluated on the TCGA dataset, TAGET-OS database. qRT-PCR and Western blotting were employed to assess SRSF1 expression in human OS cell lines as well as the interfered ectopic expression states. The effect of SRSF1 on cell migration, invasion, proliferation, and apoptosis of OS cells were measured by transwell assay and flow cytometry. RNA sequence and bioinformatic analyses were conducted to elucidate the targeted genes, relevant biological pathways, and alternative splicing (AS) events regulated by SRSF1. RESULTS: SRSF1 expression was consistently upregulated in both OS samples and OS cell lines. Diminishing SRSF1 resulted in reduced proliferation, migration, and invasion and increased apoptosis in OS cells while overexpressing SRSF1 led to enhanced growth, migration, invasion, and decreased apoptosis. Mechanistically, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA) revealed that the biological functions of SRSF1 were closely associated with the dysregulation of the protein targeting processes, location of the cytosolic ribosome, extracellular matrix (ECM), and proteinaceous extracellular matrix, along with the PI3K-AKT pathway, Wnt pathway, and HIPPO pathway. Transcriptome analysis identified AS events modulated by SRSF1, especially (Skipped Exon) SE events and (Mutually exclusive Exons) MXE events, revealing potential roles of targeted molecules in mRNA surveillance, RNA degradation, and RNA transport during OS development. qRT-PCR confirmed that SRSF1 knockdown resulted in the occurrence of alternative splicing of SRRM2, DMKN, and SCAT1 in OS. CONCLUSIONS: Our results highlight the oncogenic role of high SRSF1 expression in promoting OS progression, and further explore the potential mechanisms of action. The significant involvement of SRSF1 in OS development suggests its potential utility as a therapeutic target in OS.

Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis.

With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic ß-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.

Microstructure and Mechanical Properties of a New TWIP Steel under Different Heat Treatments.

The effects of solution treatment and annealing temperature on the microstructure and mechanical properties of a new TWIP steel that was alloyed from aluminum (Al), silicon (Si), vanadium (V), and molybdenum (Mo) elements were investigated by a variety of techniques such as microstructural characterization and room tensile testing. The austenite grain size grew slowly with the increase in annealing temperature. The relatively weak effect of the solution treatment and annealing temperature on the austenite grain size was attributed to the precipitation of MC and M2C, which hindered the growth of the austenite grain. The plasticity of the TWIP steel in cold rolling and annealing after solution treatment was obviously higher than that in cold rolling and annealing without solution treatment. This was because the large-size precipitates redissolved in the matrix after solution treatment, which were not retained in the subsequently annealed structure. Through cold rolling and annealing at 800 °C after solution treatment, the prepared steel exhibited excellent strength and plasticity simultaneously, with a yield strength of 877 MPa, a tensile strength of 1457 MPa, and an elongation of 46.1%. The strength improvement of the designed TWIP steel was mainly attributed to the grain refinement and precipitation strengthening.

Genome-wide analysis of long noncoding RNAs as cis-acting regulators of transcription factor-encoding genes in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world, but the disease pathogenesis noncoding is yet to be elucidated. Previous studies have revealed regulatory functions for long noncoding RNA (lncRNA) in various diseases; however, the roles of lncRNA in IgAN and regulation of transcription factors (TFs) have been scarcely investigated. METHODS: Renal tissue samples (n = 5) from patients with IgAN and control samples (n = 4) were collected and RNA sequencing (RNA-seq) was performed. Four software programs were employed for lncRNA prediction. GO (Gene Ontology)/KEGG (Kyoto Encyclopedia of Genes and Genomes) were employed for analysis of the identified differentially expressed genes (DEGs). A regulatory network model of DE lncRNA-TF-DEG was developed, and the levels of expression of key lncRNAs, TFs, and corresponding target genes were assessed using qRT-PCR and immunofluorescence. RESULTS: The current study identified 674 upregulated and 1,011 downregulated DE mRNAs and 260 upregulated and 232 downregulated DE lncRNAs in IgAN samples compared with control samples. The upregulated DE mRNAs showed enrichment in cell adhesion and collagen glial fiber organization pathways. The DE lncRNAs-DE mRNAs showing co-expression are associated with transmembrane transport. A novel regulatory network model of lncRNA-TF-DEG has been developed. This study identified seven TFs that are cis-regulated by 6 DE lncRNAs, and show co-expression with 132 DEGs (correlation coefficient ≥ 0.8, P ≤ 0.01), generating 158 pairs that showed co-expression. The lncRNAs NQO1-DT and RP5-1057120.6 were found to be highly expressed in IgAN samples. The TFs vitamin D Receptor (VDR) and NFAT5, along with their target genes were also aberrantly expressed. CONCLUSION: Key lncRNAs and TFs centrally associated with IgAN have been identified in this study. A regulatory network model of lncRNA-TF-mRNA was constructed. Further studies on the genes identified herewith could provide insight into the pathogenesis of IgAN.