Comparative efficacy of THR-ß agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis.

AIMS: To compare the efficacy of thyroid hormone receptor beta (THR-ß) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. RESULTS: Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-ß agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-ß agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-ß agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-ß agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-ß agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. CONCLUSION: These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Dietary Clostridium butyricum metabolites mitigated the disturbances in growth, immune response and gut health status of Ctenopharyngodon idella subjected to high cottonseed and rapeseed meal diet.

Cottonseed meal and rapeseed meal exhibit a potential for fishmeal substitute in grass carp feed, while their excessive use contribute to growth decline and weakening immunity of aquatic animals. Clostridium butyricum metabolites (CBM) was recognized as a functional additive due to its antioxidant properties and maintenance of intestinal microbiota balance. CBM was added to a high of cottonseed and rapeseed meal diet to determine its effects on growth, immunity, and intestinal microbiota alterations of grass carp (Ctenopharyngodon idella) over 56 days. Eight hundred grass carp (mean weight, around 50 g) were randomized to five treatments and fed with the basic diet (CON), CBM0 diet (28% cottonseed and 27% rapeseed meal), and CBM diets (CBM0.5, CBM1, and CBM2, namely CBM0 diet supplemented with 500, 1000, and 2000 mg·kg-1 CBM). The results indicated that compared to CBM0, The ingestion of 1000 mg kg-1 CBM diet by grass carp significantly promoted growth as measured by intestinal lipase activity, villus height, and muscle thickness. Moreover, accompanied by a decrease in intestine MDA content, and enhance antioxidant capacity by activating Keap1/Nrf2 signaling pathway to increase enzyme activities (SOD, CAT and T-AOC) and corresponding gene expression (mnsod, cat, gsto and gpx1) in the intestine of grass crap fed CBM1 diet. The dietary CBM1 diet increased serum levels of C3 and IgM, increased ACP activity and expression of the corresponding anti-inflammatory factors (tgf-ß1 and il-15), and suppressed the expression of pro-inflammatory factors (tnf-α and il-12ß), resulting in enhanced immunity. The dietary CBM1 diet up-regulates gene expression of tight junction proteins (zo-1, occludin, occludin7a and occludin-c), coupled with the decreases in DAO and D-lactate contents, implying that the decreased mucosal permeability could be observed in the gut. The dietary CBM1 diet largely altered the intestinal microbial community, especially reducing the relative abundance of intestinal pathogenic bacteria (Streptococcus and Actinomyces). And it significantly increased the content of short-chain fatty acids (acetic acid, butyric acid, isobutyric acid, propionic acid and isovaleric acid). Taken above, dietary CBM supplementation improved growth in grass carp and attenuated the intestinal oxidative stress, inflammation and microflora dysbacteriosis caused by high proportions of cottonseed and rapeseed meal diets.

Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM.

Cross-talk between the microbiome and gut mucosa-resident immune cells plays a pivotal role in modulating immune responses to pathogens, including responses to HIV infection. However, how these interactions may differ between young MSM (YMSM) disproportionately impacted by HIV, as compared to older adult MSM (AMSM), is not well understood. A broad analysis of associations between the microbiome and rectal transcriptome revealed 10 microbial families/genera correlated with immunologic gene pathways. Specifically, the rectal transcriptome of YMSM is characterized by upregulation of T cell activation/differentiation pathways and signaling from multiple cytokine families, compared to AMSM. The microbiome of YMSM is enriched with pathogenic genera including Peptostreptococcus, shown to be positively correlated with type I interferon pathways important for antiviral immunity. These findings demonstrate that YMSM have a unique immune phenotype and rectal microenvironment and support further evaluation of biological factors that influence rectal HIV transmission.

Identifying Key Genes as Progression Indicators of Prostate Cancer with Castration Resistance Based on Dynamic Network Biomarker Algorithm and Weighted Gene Correlation Network Analysis.

Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for prostate cancer, yet dynamic molecular changes from hormone-sensitive to castration-resistant states in patients treated with ADT remain unclear. Methods: In this study, we combined the dynamic network biomarker (DNB) method and the weighted gene co-expression network analysis (WGCNA) to identify key genes associated with the progression to a castration-resistant state in prostate cancer via the integration of single-cell and bulk RNA sequencing data. Based on the gene expression profiles of CRPC in the GEO dataset, the DNB method was used to clarify the condition of epithelial cells and find out the most significant transition signal DNB modules and genes included. Then, we calculated gene modules associated with the clinical phenotype stage based on the WGCNA. IHC was conducted to validate the expression of the key genes in CRPC and primary PCa patients Results:Nomograms, calibration plots, and ROC curves were applied to evaluate the good prognostic accuracy of the risk prediction model. Results: By combining single-cell RNA sequence data and bulk RNA sequence data, we identified a set of DNBs, whose roles involved in androgen-associated activities indicated the signals of a prostate cancer cell transition from an androgen-dependent state to a castration-resistant state. In addition, a risk prediction model including the risk score of four key genes (SCD, NARS2, ALDH1A1, and NFXL1) and other clinical-pathological characteristics was constructed and verified to be able to reasonably predict the prognosis of patients receiving ADT. Conclusions: In summary, four key genes from DNBs were identified as potential diagnostic markers for patients treated with ADT and a risk score-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions of CRPC.

Characterization, Antioxidant Capacity, and Anti-Inflammatory Activity of Polyphenol-Enriched Extracts Obtained from Unripe, Mature, and Overripe Fruits of Red-Fleshed Kiwifruit Cultivars.

Discarded unripe kiwifruits (DUKs) are regarded as the major agro-byproducts in the production of kiwifruits, which have abundantly valuable secondary metabolites. Nevertheless, owing to the limited knowledge about the differences in phytochemicals and bioactivity between DUKs and mature kiwifruits, the utilization of DUKs in the food industry remains scarce. Hence, to promote their food applications, the phenolic compounds and bioactivity of discarded unripe, mature, and overripe fruits from three red-fleshed kiwifruit cultivars were studied and compared. The results revealed that the levels of total phenolics, total flavonoids, and total procyanidins in kiwifruits varied significantly by maturity stage. In addition, our findings demonstrated that DUKs possessed much higher contents of valuable phenolic compounds (e.g., chlorogenic acid (CHA), neochlorogenic acid (NCHA), gallic acid (GA), protocatechuic acid (PA), procyanidin B1 (ProcB1), procyanidin B2 (ProcB2), procyanidin C1 (ProcC1), quercetin 3-O-glucoside (QueG), and quercetin 3-O-rhamnoside (QueR)) than mature and overripe kiwifruits. Furthermore, DUKs exerted much stronger in vitro antioxidant capacity, inhibitory effects on α-glucosidase, and anti-inflammatory activity than mature and overripe kiwifruits, which were mainly attributed to their higher contents of total polyphenols and individual phenolic components, such as GA, CHA, NCHA, PA, ProcB1, ProcB2, ProcC1, and QueR. Overall, these findings provide sufficient evidence for the development and utilization of DUKs in the food/functional food industry.

A Multivariable Mendelian Randomization Study of Systolic and Diastolic Blood Pressure, Lipid Profile, and Heart Failure Subtypes.

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressures and lipids on HF subtypes. Genetic instruments for blood pressures and lipids were derived from genome-wide association studies (GWASs) among the European participants of the UK Biobank. GWAS summaries of HFrEF and HFpEF were obtained from the meta-analysis of the European participants from the Million Veteran Program and the Vanderbilt University DNA Databank. Systolic blood pressure exhibited a supportive MR association primarily with HFpEF (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.04-1.23), while diastolic blood pressure had an independent MR association with HFrEF (OR, 1.43; 95% CI, 1.13-1.77). MR associations also supported the observation that higher levels of low-density lipoprotein cholesterol increase the risk for both subtypes (HFrEF OR, 1.10 and 95% CI, 1.05-1.17; HFpEF OR, 1.05 and 95% CI, 1.02-1.09). These findings underscore differences in HF subtype-specific risk profiles and mechanisms, which may lead to different interventional strategies for different HF subtypes.

Development and Validation of a Predictive Model for Resistance to Platinum-Based Chemotherapy in Patients with Ovarian Cancer through Proteomic Analysis.

Platinum resistance in ovarian cancer poses a significant challenge, substantially impacting patient outcomes. Developing an accurate predictive model is crucial for improving clinical decision-making and guiding treatment strategies. Proteomic data from 217 high-grade serous ovarian cancer (HGSOC) biospecimens obtained from JHU, PNNL, and PTRC were used to construct a prediction model for identifying individuals who are resistant to platinum-based chemotherapy. A total of 6437 common proteins were detected across all data sets, with 26 proteins overlapping between the development cohorts JHU and PNNL. Using LASSO and logistic regression analysis, a six-protein model (P31323_PRKAR2B, Q13309_SKP2, Q14997_PSME4, Q6ZRP7_QSOX2, Q7LGA3_HS2ST1, and Q7Z2Z2_EFL1) was developed, which accurately predicted platinum resistance, with an AUC of 0.964 (95% CI, 0.929-0.999). Internal validation by resampling resulted in a C-index of 0.972 (95% CI 0.894-0.988). External validation performed on the PTRC cohort achieved an AUC of 0.855 (95% CI 0.748-0.963). Calibration curves showed good consistency, and DCA indicated superior clinical utility. The model also performed well in predicting PFS and OS at various time points. Based on these proteins, our predictive model can precisely predict platinum response and survival outcomes in HGSOC patients, which can assist clinicians in promptly identifying potentially platinum-resistant individuals.

The clinical efficacy and safety of platelet-rich plasma on frozen shoulder: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To systematically review the clinical efficacy (pain, function, quality of life) and safety of platelet-rich plasma (PRP) in the treatment of frozen shoulder through meta-analysis, and provide evidence-based medical evidence for the effectiveness of PRP in the treatment of frozen shoulder. METHODS: A search was conducted on international databases (Pubmed, Web of science, Embase) and Chinese databases (CNKI, Wanfang, VIP) to search the clinical studies on the efficacy of platelet-rich plasma in treating frozen shoulder (adhesive capsulitis/periarthritis/50 shoulder) and their corresponding references published from inception until January 2024. Thoroughly excluded literature not meeting the predetermined inclusion criteria, extracted relevant data from the literature, and input it into RevMan5.4 for meta-analysis. RESULTS: This study ultimately included 14 RCTs, with a total of 1024 patients. The results showed that PRP has significant advantages compared with control groups in VAS (mean difference (MD) =-0.38, 95% confidence interval(CI)(-0.73, -0.03), P = 0.03), UCLA (MD = 3.31, 95% CI (1.02,5.60),P = 0.005), DASH (MD = -4.94,95% CI (-9.34, -0.53),P = 0.03), SPADI (SPADI Total: MD =-16.87, 95% CI (-22.84, -10.91), P < 0.00001; SPADI Pain: MD =-5.38, 95% CI (-7.80, -2.97), P < 0.0001; SPADI Disability: MD =-11.00, 95% CI (-13.61,-8.39), P < 0.00001), and the active and passive Range of Motion (active flexion: MD = 12.70, 95% CI (7.44, 17.95), P < 0.00001; passive flexion: MD = 9.47, 95% CI(3.80, 15.14), P = 0.001; active extension: MD = 3.45, 95% CI(2.39, 4.50), P < 0.00001; active abduction: MD = 13.54, 95% CI(8.42, 18.67), P < 0.00001; passive abduction: MD = 14.26, 95% CI (5.97, 22.56), P = 0.0008; active internal rotation: MD = 5.16, 95% CI (1.84, 8.48), P = 0.002; passive internal rotation: MD = 3.65, 95% CI(1.15, 6.15), P = 0.004; active external rotation: MD = 10.50, 95% CI(5.47, 15.53), P < 0.0001; passive external rotation: MD = 6.00, 95% CI (1.82, 10.19), P = 0.005) except passive extension (MD = 2.25, 95% CI (-0.77, 5.28), P = 0.14). In terms of safety, most studies reported no adverse effects, and only one study reported common complications of joint puncture such as swelling and pain after treatment in both PRP and control groups. Previous studies have shown a risk of osteonecrosis caused by corticosteroids. Therefore, the safety of PRP treatment is more reliable. CONCLUSION: The results showed that PRP was more durable and safer than corticosteroids and other control groups in the treatment of frozen shoulder. STUDY DESIGN: Systematic review. TRIAL REGISTRATION: PROSPERO CRD42022359444, date of registration: 22-09-2022.

Rapidly progressive malignant glomus tumor of the breast: a case report and review of the literature.

The glomus tumor is a rare neoplasm that is typically found subungually in the extremities and functions as a specialized neurovascular organ. An extremely rare site for glomus tumors is the breast, with only a few reported cases. Breast glomus tumors present with three typical clinical signs: dull pain, focal tenderness, and cold sensitivity. Less than 10% of all glomus tumors are malignant. We herein present a case of a malignant glomus tumor originating in the breast. Distant metastasis was ruled out, and the tumor was completely resected. However, the patient unexpectedly developed rapid systemic metastasis, detected 5 weeks after tumor removal. Despite the administration of analgesics and targeted therapy, the patient died 1 month later. When treating patients with undiagnosed breast tumors, clinicians should pay attention to unexplained and repeatedly reported symptoms and consider the possibility of a rare disease. Our literature search revealed no cases of malignant glomus tumors originating in the breast, making this case the first of its kind.

VSTM2A reverses immunosuppression in colorectal cancer by antagonizing the PD-L1/PD-1 interaction.

Immunoglobulin (Ig) VSTM2A (V-set and transmembrane domain containing 2A) is a top-ranked secretory protein frequently silenced during colorectal carcinogenesis; however, its role in immune modulation remains largely unknown. Bioinformatic and immunohistochemistry analysis of human colorectal specimens and Vstm2a+/- knockout mice indicated that VSTM2A positively correlated with CD8a and immune infiltration in both physiological and pathological conditions. We then utilized liquid chromatography-mass spectrometry to pinpoint programmed death ligand 1 (PD-L1) as a membrane receptor of VSTM2A. A series of in vitro biochemistry assays further revealed the binding pattern and kinetics between VSTM2A and PD-L1 proteins through their IgV domains at a dissociation constant of 0.7-2.5 nM. Recombinant VSTM2A protein inhibited the PD-1/PD-L1 interaction and induced NFAT response element (RE) luciferase activity dose dependently. Furthermore, interleukin (IL)-2 production from DO11.10 T cells upon co-culture with mouse non-T splenocytes was upregulated in the presence of VSTM2A conditioned medium. Finally, tumor killing assay and ex vivo data from human peripheral blood mononuclear cells and autologous dendritic cell-T cell co-culture demonstrated that VSTM2A significantly enhanced immune activation via the release of granzyme B and interferon (IFN)-γ cytokines. In conclusion, our study demonstrates the tumor-extrinsic role of VSTM2A in sterically blocking the PD-L1/PD-1 interaction at a picomole to nanomole affinity, which leads to the enhanced anti-tumor effect of cytotoxic T cells.

Macrophages regulate plaque progression in diabetic Apoe-/- mice dependent on Pi4p/Nlrp3 signaling pathway.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. METHODS: The expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe-/-) and Apoe-/- DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe-/- mice to explore the effects on atherosclerosis. RESULTS: DM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe-/- mice. CONCLUSIONS: Our data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.

Naringenin ameliorates MASH fibrosis via regulating TAK1/MAPK/FoxO3a-mediated apoptosis in the activated hepatic stellate cells.

This study aims to explore the regulating effect and mechanism of naringenin (NGN) on the hepatic stellate cells (HSCs) apoptosis and its preventive effects on MASH fibrosis. C57BL/6 mice were subjected to either high-fat diet (HFD) plus carbon tetrachloride (CCl4) injection (HFD + CCl4) for 8 weeks to induce a MASH fibrosis model or bile duct ligation (BDL) to establish a liver fibrosis model, NGN was administered by gavage. LX2 cells were stimulated by oleic acid (OA) and lipopolysaccharide (LPS) (OA + LPS) to study the effects of NGN on activated hepatic stellate cell (HSC). Additionally, LO2 cells stimulated with OA + LPS were used to assess the protective effects of NGN on lipotoxicity of hepatocytes. Our in vivo results showed that NGN administration effectively inhibited mouse liver fibrosis in both of the MASH model and BDL model. The in vitro results indicate that NGN directly inhibited HSCs activation and promoted apoptosis of the activated HSCs, while it suppressed the apoptosis of LO2 cells induced by OA + LPS. The underlying mechanisms were mainly elucidated through the reduction of TAK1 phosphorylation, leading to the downregulation of p-JNK and p-ERK expression. This in turn, inhibited the phosphorylation of FoxO3a and promoted the nuclear localization of FoxO3a. Consequently, this may enhance the transcription of apoptosis-related genes, resulting in the apoptosis of activated HSCs. In conclusion, NGN ameliorates MASH fibrosis by enhancing apoptosis of the activated HSCs. The inhibitory effects of NGN on the TAK1/MAPK/FoxO3a pathway were demonstrated as its preventive mechanisms against MASH fibrosis.

Simultaneous Oxidation of Bromide and Dissolution of Manganese Oxide Induced by Freezing.

This study demonstrates that the oxidation of bromide by birnessite (δ-MnO2) results in the concurrent production of soluble manganese (Mn(II)) and reactive bromine (RBr) species in frozen solutions, a process not observed in aqueous solutions. This enhanced oxidation in ice is attributed to the concentration of protons, birnessite, or bromide in the ice grain boundary region. Furthermore, different types of commercial manganese oxides can also oxidize bromide to RBr and release Mn(II) in ice. The presence of fulvic acid (FA) further increases the simultaneous production of RBr and Mn(II) in ice, accompanying the formation of organobromine compounds (OBCs). In frozen δ-MnO2/Br-/FA system, a significant increase in OBCs, mainly highly unsaturated and phenolic compounds, was detected using Fourier transform ion cyclotron resonance mass spectrometry. A marked contrast was observed in the number of OBCs formed in frozen solutions (853 and 415 OBCs at initial pH 3.0 and 5.8, respectively) compared to their aqueous counterparts (11 and 23 OBCs). These findings introduce a new pathway for the formation of RBr, Mn(II), and OBCs in ice, highlighting the need for further research on the environmental fate of bromide and manganese.

Comparative analysis of phenolic compounds in different thinned unripe kiwifruits and their biological functions.

Thinned unripe kiwifruits (TUK) are considered the major agro by-products in kiwifruit production. To promote their potential applications, polyphenols and biological effects of unripe fruits from nine commercial kiwifruit cultivars were compared. Our findings showed that TUK were rich in bioactive polyphenols, which varied greatly by different cultivars. Indeed, catechin, epicatechin, procyanidin PB1, procyanidin B2, protocatechuic acid, neochlorogenic acid, and gallic acid were measured as the major phenolic components in most TUK, with the highest levels observed in 'Hongao' and 'Cuiyu' cultivars. Furthermore, TUK exerted strong in vitro antioxidant capacities, inhibitory effects on digestive enzymes, and anti-inflammatory activities. Particularly, their stronger antioxidant effects and inhibitory effects on digestive enzymes were probably attributed to their higher contents of phenolic compounds, especially procyanidin B2. Collectively, our findings reveal that TUK are potential resources of valuable polyphenols, which can be exploited as natural antioxidants and natural inhibitors of α-glucosidase and α-amylase.

B cells enhance EphA2 chimeric antigen receptor T cells cytotoxicity against glioblastoma via improving persistence.

Chimeric antigen receptor (CAR) T cell therapy is a powerful adoptive immunotherapy against blood cancers, but the therapeutic effect was not efficient enough on solid tumors. B cells have been reported to play a critical role in regulating memory T differentiation and cytotoxic T development. However, as of yet the influence of such B cells on CAR T cells has not been discussed. In this study, using ephrin type-A receptor 2 (EphA2) specific CAR T cells, we cultured B cells successfully to stimulate CAR T cells in vitro, and investigated the cell differentiation and anti-tumor efficiency. We observed that EphA2-CAR T cells stimulated by B cells performed increased interferon γ (IFN γ) production and upregulated OX40 expression, as well as the enhanced anti-tumor activity and reduced PD-1 expression. The persistence of CAR T cells was enhanced after B cells stimulation for more than 7 days with the increased subset of central memory T cells (TCM). In addition, next generation sequencing was performed to explore the underlying mechanisms. The up-regulated genes clustered in, immune response activation, chemokine signaling pathway, calcium signaling pathway, cGMP-PKG signaling pathway and et al. which contributed to the upregulated anti-glioblastoma (GBM) activity of CAR T cells stimulated by B cell. Furthermore, MEF2C, CD40, SYK and TNFRSF13B were upregulated in CAR T cells after co-culturing with B cells. These genes functionally enriched in promoting lymphocytes proliferation and may contribute to the enhanced persistence of CAR T cells. In conclusion, these results indicated the critical role of B cells in prolonging CAR T cells longevity and enhancing anti-tumor activity, which paves the way for the therapeutic exploitation of EphA2-CAR T cells against GBM in the future.

ZCCHC8 p.P410A disrupts nucleocytoplasmic localization, promoting idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients. METHODS: Here, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients. RESULTS: Among these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders. CONCLUSIONS: We may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.

Carrier-free cryptotanshinone-peptide conjugates self-assembled nanoparticles: An efficient and low-risk strategy for acne vulgaris.

Acne vulgaris ranks as the second most prevalent dermatological condition worldwide, and there are still insufficient safe and reliable drugs to treat it. Cryptotanshinone (CTS), a bioactive compound derived from traditional Chinese medicine Salvia miltiorrhiza, has shown promise for treating acne vulgaris due to its broad-spectrum antimicrobial and significant anti-inflammatory properties. Nevertheless, its local application is hindered by its low solubility and poor skin permeability. To overcome these challenges, a carrier-free pure drug self-assembled nanosystem is employed, which can specifically modify drug molecules based on the disease type and microenvironment, offering a potential for more effective treatment. We designed and synthesized three distinct structures of cationic CTS-peptide conjugates, creating self-assembled nanoparticles. This study has explored their self-assembly behavior, skin permeation, cellular uptake, and both in vitro and in vivo anti-acne effects. Molecular dynamics simulations revealed these nanoparticles form through intermolecular hydrogen bonding and π-π stacking interactions. Notably, self-assembled nanoparticles demonstrated enhanced bioavailability with higher skin permeation and cellular uptake rates. Furthermore, the nanoparticles exhibited superior anti-acne effects compared to the parent drug, attributed to heightened antimicrobial activity and significant downregulation of the MAPK/NF-κB pathway, leading to reduced expression of pro-inflammatory factors including TNF-α, IL-1ß and IL-8. In summary, the carrier-free self-assembled nanoparticles based on CTS-peptide conjugate effectively address the issue of poor skin bioavailability, offering a promising new approach for acne treatment.

Precision mapping of snail habitat in lake and marshland areas: Integrating environmental and textural indicators using Random Forest modeling.

Schistosomiasis japonica continues to pose a significant public health challenge in China, primarily due to the widespread distribution of Oncomelania hupensis, the sole intermediate host of Schistosoma. This study aims to address the constraints of existing remote sensing analyses for identifying snail habitats, which frequently neglect spatial scale and seasonal variations. To this end, we adopt a multi-source data-driven Random Forest approach that integrates bottomland and ground-surface texture data with traditional environmental variables, enhancing the accuracy of snail habitat assessments. We developed four distinct models for the lake and marshland areas of Guichi, China: a baseline model incorporating ground-surface texture, bottomland variables, and environmental variables; Model 1 with only environmental variables; Model 2 adding ground-surface texture and environmental variables; and Model 3 integrating bottomland with environmental variables. The baseline model outperformed the others, achieving a true skill statistic of 0.93, an accuracy of 0.97, a kappa statistic of 0.94, and an area under the curve of 0.99. Our analysis pinpointed critical high-risk snail habitats distributed in a belt-like pattern along major water bodies, near the Yangtze River, QiuPu River, and around Shengjin Lake, Jiuhua River, and Qingtong River. These insights can aid local health authorities in more efficiently allocating limited resources, developing effective snail surveillance and control strategies to combat schistosomiasis. Additionally, this approach can be adapted to localize other endemic hosts with similar ecological characteristics.

Structural Diversity of 2D Molecular Self-Assemblies Arising from Carboxyl Groups Attached to a Molecule: An STM Study at the Liquid-Solid Interface.

Understanding the molecular self-assembly behavior, especially at the microscopic level, sheds light on the rational design of artificial supramolecular systems at surfaces. In this work, scanning tunneling microscopy (STM) and force field simulations were utilized to explore two molecular systems where two and four carboxyl groups are symmetrically modified onto a skeleton. The two target molecules are 4,4'-(ethyne-1,2-diyl) dibenzoic acid (EBA) and 1,1'-ethynebenzene-3,3',5,5,'-tetracarboxylic acid (TCA). The former molecular assembly led to robust close packing, whereas the latter resulted in low-density arrangements that present significant adaption, namely, undergoing phase transformations upon external stimulations, e.g., sensitive to STM-polarity switching and guest molecule incorporations.