IFIH1 variants are associated with generalised epilepsy preceded by febrile seizures.

BACKGROUND: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive. METHODS: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations. RESULTS: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients. CONCLUSIONS: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.

Alterations and associations between lung microbiota and metabolite profiles in silica-induced lung injury.

Silicosis, caused by silica exposure, is the most widespread and deadliest occupational disease. However, effective treatments are lacking. Therefore, it is crucial to elucidate the mechanisms and targets involved in the development of silicosis. We investigated the basic processes of silicosis development and onset at different exposure durations (2 or 4 weeks) using various techniques such as histopathology, immunohistochemistry, Enzyme linked immunosorbent assay(ELISA),16 S rRNA, and untargeted metabolomics.These results indicate that exposure to silica leads to progressive damage to lung tissue with significant deterioration observed over time. Time-dependent cytokines such as the IL-4, IL-13, and IL-6 are detected in lung lavage fluid, the model group consistently exhibited elevated levels of these cytokines, indicating a persistent and worsening inflammatory response in the lungs. Meanwhile, HE and Masson results show that 4-week exposure to silica causes more obvious lung injury and pulmonary fibrosis. Besides, the model group consistently exhibited a distinct lung bacterial population, known as the Lachnospiraceae_NK4A136_group, regardless of exposure duration. However, with increasing exposure duration, specific temporal changes were observed in lung bacterial populations, including Haliangium, Allobaculum, and Sandaracinus (at 4 weeks; p < 0.05). Furthermore, our study revealed a strong correlation between the mechanism of silica-induced lung injury and three factors: oxidative stress, impaired lipid metabolism, and imbalanced amino acid metabolism. We observed a close correlation between cytokine levels, changes in lung microbiota, and metabolic disturbances during various exposure periods. These findings propose that a possible mechanism of silica-induced lung injury involves the interplay of cytokines, lung microbiota, and metabolites.

New cembranoid with potent anti-inflammatory effect isolated from Boswellia sacra by inactivating the NF-κB signaling pathway.

Boswellia sacra has the properties of activating blood circulation, fixing pain, subduing swelling and promoting muscle growth. However, the anti-inflammatory active ingredients and molecular mechanisms of Boswellia sacra are still not clearly explored. Boswellia sacra was grounded and extracted using 95% ethanol, the extracts were separated by column chromatography preparation to give compounds. Spectral analysis and quantum calculations confirmed the structures of compounds and identified compound 1 as a new compound. Compounds 1-3 showed potent inhibitory activities and their effects on inflammatory mediator NO and inflammatory cytokines were examined by ELISA assay. Furthermore, their modulatory mechanism on inflammatory signal pathways was explored.

Multiple antibiotic resistance and herbicide catabolic profiles of bacteria isolated from Lake Villarrica surface sediments (Chile).

Antibiotics and herbicides are contaminants of emerging concern in aquatic environments. Lake Villarrica is a relevant freshwater body in Chile and was recently designated a 'saturated nutrient zone'. Here, we investigated the occurrence of multiple antibiotic resistance (MAR) and herbicide catabolic profiles among bacteria present in the surface sediments of Lake Villarrica. The occurrence of antibiotic-resistant genes (ARGs; blaTEM, catA and tetM) and herbicide-catabolic genes (HCGs; phnJ and atzA) was investigated by qPCR. Subsequently, the presence of culturable bacteria with multiple resistance to amoxicillin (AMX), chloramphenicol (CHL) and oxytetracycline (OXT) was studied. Forty-six culturable MAR (AMX + CHL + OXT) strains were isolated and characterized with respect to their resistance to 11 antibiotics by using a disc diffusion assay and testing their ability to use herbicides as a nutrient source. qPCR analyses revealed that ARGs and HCGs were present in all sediment samples (101 to 103 gene copies g-1), with significant (P ≤ 0.05) higher values in sites near Villarrica city and cattle pastures. The plate method was used to recover MAR isolates from sediment (103-106 CFU g-1), and most of the 46 isolates also showed resistance to oxacillin (100%), cefotaxime (83%), erythromycin (96%) and vancomycin (93%). Additionally, 54 and 57% of the MAR isolates were able to grow on agar supplemented (50 mg L-1) with atrazine and glyphosate as nutrient sources, respectively. Most of the MAR isolates were taxonomically close to Pseudomonas (76.1%) and Pantoea (17.4%), particularly those isolated from urbanized sites (Pucón city). This study shows the presence of MAR bacteria with herbicide catabolic activity in sediments, which is valuable for conservation strategies and risk assessments of Lake Villarrica. However, major integrative studies on sediments as reservoirs or on the fate of MAR strains and traces of antibiotics and herbicides as a result of anthropic pressure are still needed.

Physiological and transcriptome analyses reveal tissue-specific responses of Leucaena plants to drought stress.

Leucaena leucocephala (Leucaena) is a leguminous tree widely cultivated in tropical and subtropical regions due to its strong environmental suitability for abiotic stresses, especially drought. However, the molecular mechanisms and key pathways involved in Leucaena's drought response require further elucidation. Here, we comparatively analyzed the physiological and early transcriptional responses of Leucaena leaves and roots under drought stress simulated by polyethylene glycol (PEG) treatments. Drought stress induced physiological changes in Leucaena seedlings, including decreases in relative water content (RWC) and increases in relative electrolyte leakage (REL), malondialdehyde (MDA), proline contents as well as antioxidant enzyme activities. In response to drought stress, 6461 and 8295 differentially expressed genes (DEGs) were identified in the leaves and roots, respectively. In both tissues, the signaling transduction pathway of plant hormones was notably the most enriched. Specifically, abscisic acid (ABA) biosynthesis and signaling related genes (NCED, PP2C, SnRK2 and ABF) were strongly upregulated particularly in leaves. The circadian rhythm, DNA replication, alpha-linolenic acid metabolism, and secondary metabolites biosynthesis related pathways were repressed in leaves, while the glycolysis/gluconeogenesis and alpha-linolenic acid metabolism and amino acid biosynthesis processes were promoted in roots. Furthermore, heterologous overexpression of Leucaena drought-inducible genes (PYL5, PP2CA, bHLH130, HSP70 and AUX22D) individually in yeast increased the tolerance to drought and heat stresses. Overall, these results deepen our understanding of the tissue-specific mechanisms of Leucaena in response to drought and provide target genes for future drought-tolerance breeding engineering in crops.

Silicone oil migrating into the conjunctival space and orbit after surgery for an eye-penetrating injury: A case report.

BACKGROUND: We report a case of eye-penetrating injury in which a massive silicone oil migration into the patient's subconjunctival space and orbit occurred after vitrectomy. CASE SUMMARY: A 30-year-old male patient sought medical attention at Ganzhou People's Hospital after experiencing pain and vision loss in his left eye due to a nail wound on December 9, 2023. Diagnosis of penetrating injury caused by magnetic foreign body retention in the left eye and hospitalization for treatment. On December 9, 2023, pars plana vitrectomy was performed on the left eye for intraocular foreign body removal, abnormal crystal extraction, retinal photocoagulation. Owing to the discovery of retinal detachment at the posterior pole during surgery, silicone oil was injected to fill the vitreous body, following which upper conjunctival bubble-like swelling was observed. Postoperative orbital computed tomography (CT) review indicated migration of silicone oil to the subconjunctival space and orbit through a self-permeable outlet. On December 18, 2023, the patient sought treatment at the First Affiliated Hospital of Nanchang University, China. The patient presented with a pronounced foreign body sensation following left eye surgery. On December 20, 2023, the foreign body was removed from the left eye frame and an intraocular examination was conducted. The posterior scleral tear had closed, leading to termination of the surgical procedure following supplementary laser treatment around the tear. The patient reported a significant reduction in ocular surface symptoms just one day after surgery. Furthermore, a notable decrease in the migration of silicone oil was observed in orbital CT scans. CONCLUSION: The timing of silicone oil injection for an eye-penetrating injury should be carefully evaluated to avoid the possibility of silicone oil migration.

Birth Weight and Risk of Cerebral Aneurysm: A Multivariable Mendelian Randomization Study.

BACKGROUND: Birth weight has been linked with various health outcomes. The association between birth weight and cerebral aneurysm remains unknown. METHODS: The two-sample Mendelian randomization (MR) approach was used to evaluate the causal effect of birth weight on cerebral aneurysm based on genome-wide association studies (GWAS), comprising 261,932 UKB participants for birth weight and 204,060 FinnGen participants for cerebral aneurysm. The inverse variance weighted (IVW) method was used as the primary method. Alternative methods were used for comparison. Sensitivity analysis was conducted to evaluate the robustness of the results. Multivariable MR (MVMR) was further conducted to evaluate the direct effect of the birth weight on cerebral aneurysm. RESULTS: The IVW detected a causal association between higher birth weight and increased risk of cerebral aneurysm (OR = 0.521, 95% CI = 0.356 ∼ 0.763, P = 7.88 × 10-4), which was supported by alternative MR models. Sensitivity analysis did not find any evidence of heterogeneity or pleiotropy. MVMR further identified a direct effect of birth weight on cerebral aneurysm, independent of obesity-related traits or smoking. CONCLUSION: This MR study found evidence of the association between birth weight and cerebral aneurysm, providing novel insight into the etiology of cerebral aneurysm, indicating the promising role of birth weight as a marker for screening populations at higher risk of cerebral aneurysm.

Four-Component Radical 1,2-Selenosulfonylation of Allenes.

Selenosulfones, as pivotal pharmaceutical molecule frameworks, have become a research hotspot in modern organic synthesis due to their vital need for efficient preparation. Herein, we have developed an iron-catalyzed four-component controllable radical tandem reaction of allenes involving cycloketone oxime esters, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and diphenyl diselenides for the synthesis of complex selenosulfones. This is the first case of achieving the 1,2-selenosulfonylation of allenes via a radical process, wherein precise control of radical rates and polarity matching enhance high regioselective conversion. The reaction conditions are ecofriendly and mild with step-efficiency by forming two new C-S bonds and one C-Se bond in one pot. Moreover, the 1,2-selenosulfonylation of allenes can be achieved by replacing cycloketone oxime esters with aryldiazonium tetrafluoroborates in this system.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.

Accumulation and ecological risk assessment of diazinon in surface sediments of Baiyangdian lake and its potential impact on probiotics and pathogens.

Diazinon is an organophosphorus pesticide widely used in agriculture and household pest control, and its use also poses several environmental and health hazards. In this study, we investigated the spatial and temporal distribution of diazinon in Baiyangdian, evaluated its potential ecological risk and toxicity to aquatic organisms based on RQ (Risk quotient) and TU (Toxic unit) analysis, and assessed the potential effects of diazinon accumulation on probiotics and pathogens based on statistical analysis of high-throughput sequencing data. The results showed that diazinon in Baiyangdian posed a low to moderate chronic risk to sediment-dwelling organisms and a low toxicity effect on aquatic invertebrates, which was mainly concentrated in October and human-intensive areas. Meanwhile, increases in sediment electrical conductivity (EC), amorphous iron oxides content and phenol oxidase activity favored diazinon accumulation in sediments, whereas the opposite was the case for sediment organic carbon, ß-1,4-glucosidase, phosphatase, catalase and pH, suggesting that environmental indicators play a key role in the behavior and distribution of diazinon. In addition, diazinon in heavily contaminated areas seem to inhibit the rare probiotics (Bifidobacterium adolescentis and Serratia sp.), while promoted dominant pathogens (e.g., Burkholderia cenocepacia), which can lead to increased disease risk to humans and ecosystems, disruption of ecological balance and potential health problems. However, probiotic Streptomyces xiamenensis resist to diazinon would be a potential degrader for diazinon remove. In conclusion, this study unveiled the effects of diazinon pollution on wetland ecosystems, emphasizing ecological impacts and potential health concerns. In addition, the discovery of diazinon resistant probiotics provided new insights into wetland ecological restoration.

Type X collagen knockdown inactivate ITGB1/PI3K/AKT to suppress chronic unpredictable mild stress-stimulated triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, has a poor prognosis and limited access to efficient targeted treatments. Chronic unpredictable mild stress (CUMS) is highly risk factor for TNBC occurrence and development. Type X collagen (COL10A1), a crucial protein component of the extracellular matrix, ranks second among all aberrantly expressed genes in TNBC, and it is significantly up-regulated under CUMS. Nevertheless, the impact of CUMS and COL10A1 on TNBC, along with the underlying mechanisms are still unclear. In this research, we studied the effect of CUMS-induced norepinephrine (NE) elevation on TNBC, and uncovered that it notably enhanced TNBC cell proliferation, migration, and invasion in vitro, and also fostering tumor growth and lung metastasis in vivo. Additionally, our investigation found that COL10A1 directly interacted with integrin subunit beta 1 (ITGB1), then activates the downstream PI3K/AKT signaling pathway, thereby promoting TNBC growth and metastasis, while it was reversed by knocking down of COL10A1 or ITGB1. Our study demonstrated that the TNBC could respond to CUMS, and advocate for COL10A1 as a pivotal therapeutic target in TNBC treatment.

4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.

Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here we show that ferroptosis negative regulation (FNR) signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/4EBP1 signaling promoted SLC7A11 protein synthesis, leading to ferroptosis inhibition in MEK inhibitor resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR-4EBP1 activity to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.

Tracking the impact of perfluoroalkyl acid emissions on antibiotic resistance gene profiles in receiving water by metagenomic analysis.

The ecological risks posed by perfluoroalkyl acids (PFAAs) to the aquatic environment have recently been of great concern. However, little information was available on the impact of PFAAs on antibiotic resistance genes (ARGs) profiles. In this study, the receiving river of the largest fluoropolymer production facility in China was selected to investigate the effects of PFAAs on ARGs profiles. The highest PFAAs concentration for water samples near the industrial effluent discharge point was 310.9 µg/L, which was thousands times of higher than the average concentration collected at upstream sites. Perfluorooctanoic acid accounted for more than 67.2 % of ∑PFAAs concentration in water samples collected at the downstream sites, followed by perfluorohexanoic acid (3.6 %-15.9 %). 145 ARG subtypes including high-risk ARGs were detected by metagenomic technology. The results indicated that the discharge of PFAA-containing effluents had a significant impact on the abundance and diversity of ARGs in receiving waters, and PFAAs and water quality parameters (e.g., pH, NH3N, CODMn, TP) could largely affect ARG profiles. Specifically, short-chain PFAAs had similar impacts on ARG profiles compared to the restricted long-chain PFAAs. This study confirmed the potential effects of PFAAs on ARGs in aquatic environment and provided more insights into the ecological risk raised by PFAAs.

Roles of blood metabolites in mediating the relationship between vitiligo and autoimmune diseases: Evidence from a Mendelian randomization study.

OBJECTIVE: This study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites. METHODS: We performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases. RESULTS: Our findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08-1.27), psoriasis (OR 1.10; 95 % CI 1.04-1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23-1.63), pernicious anemia (OR 1.23; 95 % CI 1.12-1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11-1.26), alopecia areata (OR 1.22; 95 % CI 1.10-1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12-1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated. CONCLUSIONS: We substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities.

Traditional Chinese herbal formulas modulate gut microbiome and improve insomnia in patients with distinct syndrome types: insights from an interventional clinical study.

Background: Traditional Chinese medicine (TCM) comprising herbal formulas has been used for millennia to treat various diseases, such as insomnia, based on distinct syndrome types. Although TCM has been proposed to be effective in insomnia through gut microbiota modulation in animal models, human studies remain limited. Therefore, this study employs machine learning and integrative network techniques to elucidate the role of the gut microbiome in the efficacies of two TCM formulas - center-supplementing and qi-boosting decoction (CSQBD) and spleen-tonifying and yin heat-clearing decoction (STYHCD) - in treating insomnia patients diagnosed with spleen qi deficiency and spleen qi deficiency with stomach heat. Methods: Sixty-three insomnia patients with these two specific TCM syndromes were enrolled and treated with CSQBD or STYHCD for 4 weeks. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) every 2 weeks. In addition, variations in gut microbiota were evaluated through 16S rRNA gene sequencing. Stress and inflammatory markers were measured pre- and post-treatment. Results: At baseline, patients exhibiting only spleen qi deficiency showed slightly lesser severe insomnia, lower IFN-α levels, and higher cortisol levels than those with spleen qi deficiency with stomach heat. Both TCM syndromes displayed distinct gut microbiome profiles despite baseline adjustment of PSQI, ISI, and IFN-α scores. The nested stratified 10-fold cross-validated random forest classifier showed that patients with spleen qi deficiency had a higher abundance of Bifidobacterium longum than those with spleen qi deficiency with stomach heat, negatively associated with plasma IFN-α concentration. Both CSQBD and STYHCD treatments significantly improved sleep quality within 2 weeks, which lasted throughout the study. Moreover, the gut microbiome and inflammatory markers were significantly altered post-treatment. The longitudinal integrative network analysis revealed interconnections between sleep quality, gut microbes, such as Phascolarctobacterium and Ruminococcaceae, and inflammatory markers. Conclusion: This study reveals distinct microbiome profiles associated with different TCM syndrome types and underscores the link between the gut microbiome and efficacies of Chinese herbal formulas in improving insomnia. These findings deepen our understanding of the gut-brain axis in relation to insomnia and pave the way for precision treatment approaches leveraging TCM herbal remedies.

Silica's silent threat: Contributing to skin fibrosis in systemic sclerosis by targeting the HDAC4/Smad2/3 pathway.

Nowadays, silica products are widely used in daily life, especially in skin applications, which inevitably increases the risk of silica exposure in general population. However, inadequate awareness of silica's potential hazards and lack of self-protection are of concern. Systemic sclerosis (SSc) is characterized by progressive tissue fibrosis under environmental and genetic interactions. Silica exposure is considered an important causative factor for SSc, but its pathogenesis remains unclear. Within this study, we showed that lower doses of silica significantly promoted the proliferation, migration, and activation of human skin fibroblasts (HSFs) within 24 h. Silica injected subcutaneously into mice induced and exacerbated skin fibrosis. Notably, silica increased histone deacetylase-4 (HDAC4) expression by inducing its DNA hypomethylation in normal HSFs. The elevated HDAC4 expression was also confirmed in SSc HSFs. Furthermore, HDAC4 was positively correlated with Smad2/3 phosphorylation and COL1, α-SMA, and CTGF expression. The HDAC4 inhibitor LMK235 mitigated silica-induced upregulation of these factors and alleviated skin fibrosis in SSc mice. Taken together, silica induces and exacerbates skin fibrosis in SSc patients by targeting the HDAC4/Smad2/3 pathway. Our findings provide new insights for evaluating the health hazards of silica exposure and identify HDAC4 as a potential interventional target for silica-induced SSc skin fibrosis.

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression.

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

Neutrophil-to-lymphocyte ratio associated with renal function in type 2 diabetic patients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a leading risk factor for the development and progression of chronic kidney disease (CKD). However, an accurate and convenient marker for early detection and appropriate management of CKD in individuals with T2DM is limited. Recent studies have demonstrated a strong correlation between the neutrophil-to-lymphocyte ratio (NLR) and CKD. Nonetheless, the predictive value of NLR for renal damage in type 2 diabetic patients remains understudied. AIM: To investigate the relationship between NLR and renal function in T2DM patients. METHODS: This study included 1040 adults aged 65 or older with T2DM from Shanghai's Community Health Service Center. The total number of neutrophils and lymphocytes was detected, and NLR levels were calculated. CKD was defined as an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m². Participants were divided into four groups based on NLR levels. The clinical data and biochemical characteristics were compared among groups. A multivariate logistic regression model was used to analyze the association between NLR levels and CKD. RESULTS: Significant differences were found in terms of sex, serum creatinine, blood urea nitrogen, total cholesterol, and low-density lipoprotein cholesterol among patients with T2DM in different NLR groups (P < 0.0007). T2DM patients in the highest NLR quartile had a higher prevalence of CKD (P for trend = 0.0011). Multivariate logistic regression analysis indicated that a high NLR was an independent risk factor for CKD in T2DM patients even after adjustment for important clinical and pathological parameters (P = 0.0001, odds ratio = 1.41, 95% confidence intervals: 1.18-1.68). CONCLUSION: An elevated NLR in patients with T2DM is associated with higher prevalence of CKD, suggesting that it could be a marker for the detection and evaluation of diabetic kidney disease.