Long Non-coding RNA Neat1, NLRP3 Inflammasome, and Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients and is associated with high mortality. Inflammation plays a key role in the pathophysiology of AKI. Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of the inflammatory and immune response, but its role in AKI remains unclear. METHODS: We explored the role of lncRNA Neat1 in (1) a cross-sectional and a longitudinal cohort of AKI in human; (2) three murine models of septic and aseptic AKI and (3) cultured C1.1 mouse kidney tubular cells. RESULTS: In human, hospitalized patients with AKI (n=66) demonstrated significantly increased lncRNA Neat1 levels in urinary sediment cells and buffy coat versus control participants (n=152) from a primary care clinic; and among 6 kidney transplant recipients, Neat1 levels were highest immediately after transplant surgery followed by a prompt decline to normal levels in parallel with recovery of kidney function. In mice with AKI induced by sepsis (via LPS injection or cecal ligation and puncture) and renal ischemia-reperfusion, kidney tubular Neat1 was increased versus sham-operated mice. Knockdown of Neat1 in the kidney using short hairpin RNA preserved kidney function, suppressed overexpression of the AKI biomarker NGAL, leukocyte infiltration and both intrarenal and systemic inflammatory cytokines IL-6, CCL-2 and IL-1ß. In LPS-treated C1.1 cells, Neat1 was overexpressed via TLR4/NF-κB signaling, and translocated from the cell nucleus into the cytoplasm where it promoted activation of NLRP3 inflammasomes via binding with the scaffold protein Rack1. Silencing Neat1 ameliorated LPS-induced cell inflammation, whereas its overexpression upregulated IL-6 and CCL-2 expression even without LPS stimulation. CONCLUSIONS: Our findings demonstrate a pathogenic role of Neat1 induction in human and mice during AKI with alleviation of kidney injury in 3 experimental models of septic and aseptic AKI after knockdown of Neat1. LPS/TLR4-induced Neat1 overexpression in tubular epithelial cells increases the inflammatory response by binding with the scaffold protein, Rack1, to activate NLRP3 inflammasomes.

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.

Programmed cell death-1 blockade therapy in melanoma: Resistance mechanisms and combination strategies.

Melanoma is a highly aggressive tumor derived from melanocytes. In recent years, the incidence and mortality of melanoma have gradually increased, seriously threatening human health. Classic treatments like surgery, chemotherapy, and radiotherapy show very limited efficacy. Due to the high immunogenicity of melanoma cells, immune checkpoint inhibitors have received considerable attention as melanoma treatments. One such therapy is blockade of programmed cell death-1 (PD-1), which is one of the most important negative immune regulators and is mainly expressed on activated T cells. Disruption of the interactions between PD-1 and its ligands, programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2) rejuvenates exhausted T cells and enhances antitumor immunity. Although PD-1 blockade therapy is widely used in melanoma, a substantial proportion of patients still show no response or short durations of remission. Recent researches have focused on revealing the underlying mechanisms for resistance to this treatment and improving its efficacy through combination therapy. Here, we will introduce the resistance mechanisms associated with PD-1 blockade therapy in melanoma and review the combination therapies available.

Tubulovascular protection from protease-activated receptor-1 depletion during AKI-to-CKD transition.

BACKGROUND: Thromboembolic events are prevalent in chronic kidney disease (CKD) patients due to increased thrombin generation leading to a hypercoagulable state. We previously demonstrated that inhibition of protease-activated receptor-1 (PAR-1) by vorapaxar reduces kidney fibrosis. METHODS: We used an animal model of unilateral ischemia-reperfusion injury-induced CKD to explore the tubulovascular crosstalk mechanisms of PAR-1 in acute kidney injury (AKI)-to-CKD transition. RESULTS: During the early phase of AKI, PAR-1-deficient mice exhibited reduced kidney inflammation, vascular injury, and preserved endothelial integrity and capillary permeability. During the transition phase to CKD, PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via downregulated transforming growth factor-ß/Smad signaling. Maladaptive repair in the microvasculature after AKI further exacerbated focal hypoxia with capillary rarefaction, which was rescued by stabilization of hypoxia-inducible factor and increased tubular vascular endothelial growth factor A in PAR-1-deficient mice. Chronic inflammation was also prevented with reduced kidney infiltration by both M1- and M2-polarized macrophages. In thrombin-induced human dermal microvascular endothelial cells (HDMECs), PAR-1 mediated vascular injury through activation of NF-κB and ERK MAPK pathways. Gene silencing of PAR-1 exerted microvascular protection via a tubulovascular crosstalk mechanism during hypoxia in HDMECs. Finally, pharmacologic blockade of PAR-1 with vorapaxar improved kidney morphology, promoted vascular regenerative capacity, and reduced inflammation and fibrosis depending on the time of initiation. CONCLUSIONS: Our findings elucidate a detrimental role of PAR-1 in vascular dysfunction and profibrotic responses upon tissue injury during AKI-to-CKD transition and provide an attractive therapeutic strategy for post-injury repair in AKI.

Folate Intake and Risk of Urothelial Carcinoma: A Systematic Review and Meta-Analysis of Epidemiological Studies.

We aimed to investigate the association between folate intake and the risk of urothelial carcinoma (UC). A systematic literature search using Pubmed and EMBASE databases was performed to find prospective cohort studies, population-based case-control study or hospital-based case-control study investigating the association of folate intake and the risk of UC. A total of 19 studies involving 11,175 cases and 656,161 individuals were included. High intake of folate was associated with a decreased risk of UC, with a pooled OR of 0.78 (95% CI: 0.66-0.93, P = 0.006) for the highest category of intake vs. the lowest. The data suggested that folate may contribute to the prevention of urothelial cancer. However, the association was observed only in case-control studies (OR = 0.56, 95% CI: 0.39-0.79, P = 0.001), but not in cohort studies (RR = 0.97, 95% CI: 0.87-1.09, P = 0.638). Dose-response meta-analysis showed that an increment of folate intake (100 µg/day) corresponded to an 8% deceased risk of invasive UC (RR = 0.92, 95% CI: 0.87-0.98, P = 0.004). High folate intake might be inversely associated with risk of UC particularly invasive UC, which needs to be confirmed.

Folate Intake and Risk of Pancreatic Cancer: A Systematic Review and Updated Meta-Analysis of Epidemiological Studies.

INTRODUCTION: Pancreatic cancer is one of the most fatal malignancies and primary prevention strategies are limited. Epidemiological studies focusing on the association between folate intake and pancreatic cancer risk have reported inconsistent findings. METHODS: A systematic search of the literature was conducted using the PubMed and EMBASE databases. A systematic review and meta-analysis of eligible studies was performed to assess the association between folate intake and risk of pancreatic cancer. RESULTS: A total of 16 studies involving 5654 cases and 1,009,374 individuals were included. The result showed a significant association of folate intake with a decreased risk of pancreatic cancer, with a pooled OR of 0.82 (95% CI: 0.69-0.97, P = 0.019) for the highest category of intake vs. the lowest. The data suggested that high intake of folate may contribute to the prevention of pancreatic cancer. However, the association was observed only in case-control studies (OR = 0.78, 95% CI: 0.65-0.93, P = 0.006), but not in cohort studies (RR = 0.85, 95% CI: 0.66-1.09, P = 0.244). Dose-response meta-analysis showed that an increment of folate intake (100 µg/day) was marginally associated with the risk of pancreatic cancer, with a pooled OR of 0.97 (95% CI: 0.93-1.00, P = 0.053). CONCLUSION: High folate intake might be inversely associated with pancreatic cancer risk, which needs to be confirmed.

Theaflavin alleviates oxidative injury and atherosclerosis progress via activating microRNA-24-mediated Nrf2/HO-1 signal.

Theaflavin (TF) in black tea has been shown to have significant antioxidant and anti-inflammatory capacity; however, the effects and the underlying mechanism of TF on atherosclerosis (AS) remain unclear. Herein, we investigated the effects and the potential mechanism of TF on AS progression in vivo and in vitro. ApoE-/- mice were administrated with high fat diet (HFD) or HFD + TF (5 or 10 mg, i.g.) for 12 weeks. The results indicated that TF administration effectively decreases the serum lipid levels and the production of MDA in HFD-fed mice. Meanwhile, TF promotes the activities of antioxidant enzymes (SOD, CAT, and GSH-Px) and inhibits the formation of atherosclerotic plaque and the process of histological alterations in the aorta. In vitro, TF pretreatment could protect against cholesterol-induced oxidative injuries in HUVEC cells, decreasing the level of ROS and MDA, maintaining the activities of antioxidant enzymes. Further study revealed that TF upregulates Nrf2/HO-1 signaling pathway in vascular endothelial cells. Moreover, TF increases the level of microRNA-24 (miR-24), and miR-24 inhibition markedly compromises TF-induced Nrf2 activation and protective effects. In conclusion, the present study indicated that theaflavins may achieve the anti-atherosclerotic effect via activating miR-24-mediated Nrf2/HO-1 signaling pathway.

The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis.

Protease-activated receptor (PAR)-1 has emerged as a key profibrotic player in various organs including kidney. PAR-1 activation leads to deposition of extracellular matrix (ECM) proteins in the tubulointerstitium and induction of epithelial-mesenchymal transition (EMT) during renal fibrosis. We tested the anti-fibrotic potential of vorapaxar, a clinically approved PAR-1 antagonist for cardiovascular protection, in an experimental kidney fibrosis model of unilateral ureteral obstruction (UUO) and an AKI-to-chronic kidney disease (CKD) transition model of unilateral ischemia-reperfusion injury (UIRI), and dissected the underlying renoprotective mechanisms using rat tubular epithelial cells. PAR-1 is activated mostly in the renal tubules in both the UUO and UIRI models of renal fibrosis. Vorapaxar significantly reduced kidney injury and ameliorated morphologic changes in both models. Amelioration of kidney fibrosis was evident from down-regulation of fibronectin (Fn), collagen and α-smooth muscle actin (αSMA) in the injured kidney. Mechanistically, inhibition of PAR-1 inhibited MAPK ERK1/2 and transforming growth factor-ß (TGF-ß)-mediated Smad signaling, and suppressed oxidative stress, overexpression of pro-inflammatory cytokines and macrophage infiltration into the kidney. These beneficial effects were recapitulated in cultured tubular epithelial cells in which vorapaxar ameliorated thrombin- and hypoxia-induced TGF-ß expression and ECM accumulation. In addition, vorapaxar mitigated capillary loss and the expression of adhesion molecules on the vascular endothelium during AKI-to-CKD transition. The PAR-1 antagonist vorapaxar protects against kidney fibrosis during UUO and UIRI. Its efficacy in human CKD in addition to CV protection warrants further investigation.

Trace Elements, PPARs, and Metabolic Syndrome.

Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace elements influence the structure of proteins, enzymes, and complex carbohydrates, and thus an imbalance in trace elements is an independent risk factor for MetS. The molecular link between trace elements and metabolic homeostasis has been established, and peroxisome proliferator-activated receptors (PPARs) have appeared as key regulators bridging these two elements. This is because on one hand, PPARs are actively involved in various metabolic processes, such as abdominal adiposity and insulin sensitivity, and on the other hand, PPARs sensitively respond to changes in trace elements. For example, an iron overload attenuates hepatic mRNA expression of Ppar-α; zinc supplementation is considered to recover the DNA-binding activity of PPAR-α, which is impaired in steatotic mouse liver; selenium administration downregulates mRNA expression of Ppar-γ, thereby improving lipid metabolism and oxidative status in the liver of high-fat diet (HFD)-fed mice. More importantly, PPARs' expression and activity are under the control of the circadian clock and show a robust 24 h rhythmicity, which might be the reasons for the side effects and the clinical limitations of trace elements targeting PPARs. Taken together, understanding the casual relationships among trace elements, PPARs' actions, and the pathogenesis of MetS is of great importance. Further studies are required to explore the chronopharmacological effects of trace elements on the diurnal oscillation of PPARs and the consequent development of MetS.

The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal ß2-macroglobulin (ß2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal ß2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.

Detection of Skeletonema costatum based on loop-mediated isothermal amplification combined with lateral flow dipstick.

We developed a new assay method, which combines loop-mediated isothermal amplification (LAMP) with a chromatographic lateral flow dipstick (LFD) for the rapid and special detection of the diatom Skeletonema costatum. Four groups of LAMP primers were derived from a conserved DNA sequence unique to S. costatum. The amplifications were carried out at 61, 63, and 65 °C for 60 min in various combinations by the quantitative PCR thermal cycler to confirm optimal primers and reaction temperature. The LAMP-LFD detection limit was 0.94 pg/µL of S. costatum genomic DNA and was 100 times more sensitive than conventional PCR. The LAMP-LFD method had high specificity and accurately identified S. costatum algal isolates, but not other algal isolates. The new LAMP-LFD assay can be used as a reliable and easy method to detect S. costatum.

Integrating single-cell RNA sequencing data to genome-wide association analysis data identifies significant cell types in influenza A virus infection and COVID-19.

With the global pandemic of COVID-19, the research on influenza virus has entered a new stage, but it is difficult to elucidate the pathogenesis of influenza disease. Genome-wide association studies (GWASs) have greatly shed light on the role of host genetic background in influenza pathogenesis and prognosis, whereas single-cell RNA sequencing (scRNA-seq) has enabled unprecedented resolution of cellular diversity and in vivo following influenza disease. Here, we performed a comprehensive analysis of influenza GWAS and scRNA-seq data to reveal cell types associated with influenza disease and provide clues to understanding pathogenesis. We downloaded two GWAS summary data, two scRNA-seq data on influenza disease. After defining cell types for each scRNA-seq data, we used RolyPoly and LDSC-cts to integrate GWAS and scRNA-seq. Furthermore, we analyzed scRNA-seq data from the peripheral blood mononuclear cells (PBMCs) of a healthy population to validate and compare our results. After processing the scRNA-seq data, we obtained approximately 70 000 cells and identified up to 13 cell types. For the European population analysis, we determined an association between neutrophils and influenza disease. For the East Asian population analysis, we identified an association between monocytes and influenza disease. In addition, we also identified monocytes as a significantly related cell type in a dataset of healthy human PBMCs. In this comprehensive analysis, we identified neutrophils and monocytes as influenza disease-associated cell types. More attention and validation should be given in future studies.

Professional development needs and decision-making of new graduate physiotherapists within Australian private practice settings.

INTRODUCTION: Professional development contributes to new graduate health professionals' transition into the workplace. Current literature indicates that new graduate physiotherapists are often underprepared to work within private practice settings, however little is known of their professional development needs to facilitate their transition. OBJECTIVES: This study aimed to understand new graduate physiotherapists' perceived needs and decision-making for professional development within private practice settings. METHODS: This study used a qualitative interpretative phenomenological approach. A sample of new graduate physiotherapists employed within private practice settings (n = 14) participated in semi-structured telephone interviews, after being selected through convenience and randomized sampling. Interview data was subject to thematic analysis. RESULTS: Four key themes emerged from the data: 1) practical and commercial relevance; 2) influence of self and others in decision-making; 3) professional development as a social construct; and 4) access is critical. CONCLUSION: New graduate physiotherapists expressed needs for practically and clinically relevant professional development within formal and informal settings, and this extended to non-clinical skills specific to private practice. Their decision-making was shaped by social influences and perceived barriers to access. This study has identified implications for employers and professional development providers to support and cater to new graduate physiotherapists' perceived needs for professional development, which may facilitate their transition into private practice.

Puerarin alleviates inflammation and pathological damage in colitis mice by regulating metabolism and gut microbiota.

Dysbiosis of gut microbiota and metabolic pathway disorders are closely related to the ulcerative colitis. Through network pharmacology, we found that puerarin is a potential ingredient that can improve the crypt deformation and inflammatory infiltration in mice, and decrease the levels of IL-1ß, IL-6 and TNF-α significantly. Listeria, Alistipes and P. copri gradually became dominant bacteria in UC mice, which were positively correlated with inflammatory factors. Puerarin effectively improved dysbiosis by reducing the abundance of Alistipes, P. copri and Veillonella, and increasing the level of Desulfovibrionacea. Correlation network and metabolic function prediction analysis of the microbiota showed that they formed a tightly connected network and were widely involved in carbohydrate metabolism and amino acid metabolism. Specifically, we observed significant changes in the tryptophan metabolism pathway in DSS mice, with an increase in the abundance of Bacteroidetes and Enterobacteriaceae involved in tryptophan metabolism. However, this metabolic disorder was alleviated after puerarin treatment, including the reversal of 3-HAA levels and an increase in the abundance of Rhodobacteraceae and Halomonadaceae involved in kynurenine metabolism, as well as a significant increase in the purine metabolite guanosine. In conclusion, our study suggests that puerarin has a good therapeutic effect on UC, which is partially achieved by restoring the composition and abundance of gut microbiota and their metabolism.

Associations of socioeconomic status with infectious diseases mediated by lifestyle, environmental pollution and chronic comorbidities: a comprehensive evaluation based on UK Biobank.

BACKGROUND: Socioeconomic status (SES) inequity was recognized as a driver of some certain infectious diseases. However, few studies evaluated the association between SES and the burden of overall infections, and even fewer identified preventable mediators. This study aimed to assess the association between SES and overall infectious diseases burden, and the potential roles of factors including lifestyle, environmental pollution, chronic disease history. METHODS: We included 401,009 participants from the UK Biobank (UKB) and defined the infection status for each participant according to their diagnosis records. Latent class analysis (LCA) was used to define SES for each participant. We further defined healthy lifestyle score, environment pollution score (EPS) and four types of chronic comorbidities. We used multivariate logistic regression to test the associations between the four above covariates and infectious diseases. Then, we performed the mediation and interaction analysis to explain the relationships between SES and other variables on infectious diseases. Finally, we employed seven types of sensitivity analyses, including considering the Townsend deprivation index as an area level SES variable, repeating our main analysis for some individual or composite factors and in some subgroups, as well as in an external data from the US National Health and Nutrition Examination Survey, to verify the main results. RESULTS: In UKB, 60,771 (15.2%) participants were diagnosed with infectious diseases during follow-up. Lower SES [odds ratio (OR) = 1.5570] were associated with higher risk of overall infections. Lifestyle score mediated 2.9% of effects from SES, which ranged from 2.9 to 4.0% in different infection subtypes, while cardiovascular disease (CVD) mediated a proportion of 6.2% with a range from 2.1 to 6.8%. In addition, SES showed significant negative interaction with lifestyle score (OR = 0.8650) and a history of cancer (OR = 0.9096), while a significant synergy interaction was observed between SES and EPS (OR = 1.0024). In subgroup analysis, we found that males and African (AFR) with lower SES showed much higher infection risk. Results from sensitivity and validation analyses showed relative consistent with the main analysis. CONCLUSIONS: Low SES is shown to be an important risk factor for infectious disease, part of which may be mediated by poor lifestyle and chronic comorbidities. Efforts to enhance health education and improve the quality of living environment may help reduce burden of infectious disease, especially for people with low SES.

Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases.

Objective: We explore the candidate susceptibility genes for influenza A virus (IAV), measles, rubella, and mumps and their underlying biological mechanisms. Methods: We downloaded the genome-wide association study summary data of four virus-specific immunoglobulin G (IgG) level data sets (anti-IAV IgG, anti-measles IgG, anti-rubella IgG, and anti-mumps virus IgG levels) and integrated them with reference models of three potential tissues from the Genotype-Tissue Expression (GTEx) project, namely, whole blood, lung, and transformed fibroblast cells, to identify genes whose expression is predicted to be associated with IAV, measles, mumps, and rubella. Results: We identified 19 significant genes (ULK4, AC010132.11, SURF1, NIPAL2, TRAP1, TAF1C, AC000078.5, RP4-639F20.1, RMDN2, ATP1B3, SRSF12, RP11-477D19.2, TFB1M, XXyac-YX65C7_A.2, TAF1C, PCGF2, and BNIP1) associated with IAV at a Bonferroni-corrected threshold of p < 0.05; 14 significant genes (SOAT1, COLGALT2, AC021860.1, HCG11, METTL21B, MRPL10, GSTM4, PAQR6, RP11-617D20.1, SNX8, METTL21B, ANKRD27, CBWD2, and TSFM) associated with measles at a Bonferroni-corrected threshold of p < 0.05; 15 significant genes (MTOR, LAMC1, TRIM38, U91328.21, POLR2J, SCRN2, Smpd4, UBN1, CNTROB, SCRN2, HOXB-AS1, SLC14A1, AC007566.10, AC093668.2, and CPD) associated with mumps at a Bonferroni-corrected threshold of p < 0.05; and 13 significant genes (JAGN1, RRP12, RP11-452K12.7, CASP7, AP3S2, IL17RC, FAM86HP, AMACR, RRP12, PPP2R1B, C11orf1, DLAT, and TMEM117) associated with rubella at a Bonferroni-corrected threshold of p < 0.05. Conclusions: We have identified several candidate genes for IAV, measles, mumps, and rubella in multiple tissues. Our research may further our understanding of the pathogenesis of infectious respiratory diseases.

Public perceptions of digital fashion: An analysis of sentiment and Latent Dirichlet Allocation topic modeling.

Since digital technology has had a significant impact on the fashion industry, digital fashion has become a hot topic in today's society. Currently, research on digital fashion is focused on the transformation of enterprise marketing strategies and the discussion of digital technology. Despite this, the current study does not include an analysis of the audience's emotional and cognitive responses to digital fashion on social networking platforms. A comprehensive analysis and discussion of 52,891 posts about digital fashion and virtual fashion published on social networking sites was conducted using k-means clustering analysis, Latent Dirichlet Allocation (LDA) topic modeling, and sentiment analysis in this study. The study examines the public's perception and hot topics about digital fashion, as well as the industry's development situation and trends. According to the findings, both positive and neutral emotions accompany the public's attitude toward digital fashion. There is a wide range of topics covered in the discussion. Innovations in digital technology have impacted the creation of jobs, talent demand, marketing strategies, profit forms, and industrial chain innovation of fashion-related businesses. Researchers in related fields will find this study useful not only as a reference for research methods and directions, but also as a source of references for research methodology. A case study and data reference will also be provided to industry practitioners.

Identifying and Exploring the Candidate Susceptibility Genes of Cirrhosis Using the Multi-Tissue Transcriptome-Wide Association Study.

Objective: We identify and explore the candidate susceptibility genes for cirrhosis and their underlying biological mechanism. Methods: We downloaded the genome-wide association studies summary data of 901 cirrhosis cases and 451,363 controls and integrated them with reference models of five potential tissues from the Genotype-Tissue Expression (GTEx) Project, including whole blood, liver, pancreas, spleen, and thyroid, to identify genes whose expression is predicted to be associated with cirrhosis. Then, we downloaded gene expression data of individuals with hepatocellular carcinoma from TCGA database to conduct differential expression analysis to validate these identified genes and explored their possible role in driving cirrhosis via functional enrichment and gene set enrichment analysis (GSEA). Results: We identified 10 significant genes (SKIV2L, JPH4, UQCC2, RP11-91I8.3, MAU2, ERAP1, PUS3, ZNF677, ARHGAP40, and SHANK3) associated with cirrhosis at a Bonferroni-corrected threshold of p < 0.01, among which two (SKIV2L and JPH4) were identified in the liver and five (SKIV2L, JPH4, MAU2, SHANK3, and UQCC2) were validated by differential expression analysis at an FDR-corrected threshold of p < 0.01. The enrichment analysis showed that the degradation process of RNA, which is enriched by 58 genes, is significantly under-enriched in liver cancer tissues (p = 0.0268). Conclusion: We have identified several candidate genes for cirrhosis in multiple tissues and performed differential genetic analysis using the liver cancer database to verify the significant genes. We found that the genes SKIV2L and JPH4 identified in the liver are of particular concern. Finally, through enrichment analysis, we speculate that the process of mRNA transcription and RNA degradation may play a role in cirrhosis.

Overexpression of c-Myc-dependent heterogeneous nuclear ribonucleoprotein A1 promotes proliferation and inhibits apoptosis in NOTCH1-mutated chronic lymphocytic leukemia cells.

BACKGROUND: NOTCH1 mutation is an essential molecular biologic aberration in chronic lymphocytic leukemia (CLL). CLL patients with NOTCH1 mutation have shown an unfavorable survival and a poor response to chemoimmunotherapy. This study aims to present the mechanisms of adverse prognosis caused by NOTCH1 mutation from the perspective of the splicing factor heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). METHODS: The microarray data in Gene Expression Omnibus datasets were analyzed by bioinformatics and the function of hnRNPA1 was checked by testing the proliferation and apoptosis of CLL-like cell lines. Afterward, quantitative reverse transcription-polymerase chain reaction and Western blotting were applied to explore the relationship among NOTCH1, c-Myc, and hnRNPA1. RESULTS: RNA splicing was found to play a vital part in NOTCH1-mutated CLL cells; hence, hnRNPA1 was selected as the focus of this study. Higher expression of hnRNPA1 validated in primary NOTCH1-mutated CLL samples could promote proliferation and inhibit apoptosis in CLL. The expression of hnRNPA1 increased when NOTCH1 signaling was activated by transfection with NOTCH1 intracellular domain (NICD)-overexpressed adenovirus vector and declined after NOTCH1 signaling was inhibited by NOTCH1-shRNA. Higher expression of c-Myc was observed in NICD-overexpressed cells and hnRNPA1 expression was downregulated after applying c-Myc inhibitor 10058-F4. Moreover, in NICD-overexpressed cells, hnRNPA1 expression decreased through c-Myc inhibition. CONCLUSION: Overexpression of c-Myc-dependent hnRNPA1 could promote proliferation and inhibit apoptosis in NOTCH1-mutated CLL cells, which might partly account for the poor prognosis of patients with NOTCH1 mutation.

Potential Therapeutic Targets of Rehmannia Formulations on Diabetic Nephropathy: A Comparative Network Pharmacology Analysis.

Background: Previous retrospective cohorts showed that Rehmannia-6 (R-6, Liu-wei-di-huang-wan) formulations were associated with significant kidney function preservation and mortality reduction among chronic kidney disease patients with diabetes. This study aimed to investigate the potential mechanism of action of common R-6 variations in a clinical protocol for diabetic nephropathy (DN) from a system pharmacology approach. Study Design and Methods: Disease-related genes were retrieved from GeneCards and OMIM by searching "Diabetic Nephropathy" and "Macroalbuminuria". Variations of R-6 were identified from a published existing clinical practice guideline developed from expert consensus and pilot clinical service program. The chemical compound IDs of each herb were retrieved from TCM-Mesh and PubChem. Drug targets were subsequently revealed via PharmaMapper and UniProtKB. The disease gene interactions were assessed through STRING, and disease-drug protein-protein interaction network was integrated and visualized by Cytoscape. Clusters of disease-drug protein-protein interaction were constructed by Molecular Complex Detection (MCODE) extension. Functional annotation of clusters was analyzed by DAVID and KEGG pathway enrichment. Differences among variations of R-6 were compared. Binding was verified by molecular docking with AutoDock. Results: Three hundred fifty-eight genes related to DN were identified, forming 11 clusters which corresponded to complement and coagulation cascades and signaling pathways of adipocytokine, TNF, HIF-1, and AMPK. Five variations of R-6 were analyzed. Common putative targets of the R-6 variations on DN included ACE, APOE, CCL2, CRP, EDN1, FN1, HGF, ICAM1, IL10, IL1B, IL6, INS, LEP, MMP9, PTGS2, SERPINE1, and TNF, which are related to regulation of nitric oxide biosynthesis, lipid storage, cellular response to lipopolysaccharide, inflammatory response, NF-kappa B transcription factor activity, smooth muscle cell proliferation, blood pressure, cellular response to interleukin-1, angiogenesis, cell proliferation, peptidyl-tyrosine phosphorylation, and protein kinase B signaling. TNF was identified as the seed for the most significant cluster of all R-6 variations. Targets specific to each formulation were identified. The key chemical compounds of R-6 have good binding ability to the putative protein targets. Conclusion: The mechanism of action of R-6 on DN is mostly related to the TNF signaling pathway as a core mechanism, involving amelioration of angiogenesis, fibrosis, inflammation, disease susceptibility, and oxidative stress. The putative targets identified could be validated through clinical trials.