Ultrasonic humidifier aerosols: Observed high heavy metal enrichment and a new emission control method.

Ultrasonic humidifiers are commonly used in households to maintain indoor humidity and generate a large number of droplets or spray aerosols. However, there have been various health concerns associated with humidifier use, largely due to aerosols generated during operation. Here, we investigated the size distribution, chemical composition, and charged fraction of aerosol particles emitted from commercial ultrasonic humidifiers. Heavy metals in water used for humidifiers were found to be highly enriched in the ultrasonic humidifier aerosols (UHA), with the enrichment factors ranging from 102 to 107. This enrichment may pose health concerns for the building occupants, as UHA concentrations of up to 106 particles/cm3 or 3 mg/m3 were observed. Furthermore, approximately 90% of UHA were observed to be electrically charged, for the first time according to our knowledge. Based on this discovery, we proposed and tested a new method to remove UHA by using a simple electrical field. The designed electrical field in this work can efficiently remove 81.4% of UHA. Therefore, applying this electrical field could be an effective method to significantly reduce the health risks by UHA.

miR-203-3p promotes senescence of mouse bone marrow mesenchymal stem cells via downregulation of Pbk.

The senescence of bone marrow mesenchymal stem cells (BMSCs) contributes to the development of degenerative skeletal conditions. To date, the molecular mechanism resulting in BMSC senescence has not been fully understood. In this study, we identified a small non-coding RNA, miR-203-3p, the expression of which was elevated in BMSCs from aged mice. On the other hand, overexpression of miR-203-3p in BMSCs from young mice reduced cell growth and enhanced their senescence. Mechanistically, PDZ-linked kinase (PBK) is predicted to be the target of miR-203-3p. The binding of miR-203-3p to Pbk mRNA could decrease its expression, which in turn inhibited the ubiquitination-mediated degradation of p53. Furthermore, the intravitreal injection of miR-203-3p-inhibitor into the bone marrow cavity of aged mice attenuated BMSC senescence and osteoporosis in aged mice. Collectively, these findings suggest that targeting miR-203-3p to delay BMSC senescence could be a potential therapeutic strategy to alleviate age-related osteoporosis.

High-quality chromosome scale genome assemblies of two important Sorghum inbred lines, Tx2783 and RTx436.

Sorghum bicolor (L.) Moench is a significant grass crop globally, known for its genetic diversity. High quality genome sequences are needed to capture the diversity. We constructed high-quality, chromosome-level genome assemblies for two vital sorghum inbred lines, Tx2783 and RTx436. Through advanced single-molecule techniques, long-read sequencing and optical maps, we improved average sequence continuity 19-fold and 11-fold higher compared to existing Btx623 v3.0 reference genome and obtained 19 and 18 scaffolds (N50 of 25.6 and 14.4) for Tx2783 and RTx436, respectively. Our gene annotation efforts resulted in 29 612 protein-coding genes for the Tx2783 genome and 29 265 protein-coding genes for the RTx436 genome. Comparative analyses with 26 plant genomes which included 18 sorghum genomes and 8 outgroup species identified around 31 210 protein-coding gene families, with about 13 956 specific to sorghum. Using representative models from gene trees across the 18 sorghum genomes, a total of 72 579 pan-genes were identified, with 14% core, 60% softcore and 26% shell genes. We identified 99 genes in Tx2783 and 107 genes in RTx436 that showed functional enrichment specifically in binding and metabolic processes, as revealed by the GO enrichment Pearson Chi-Square test. We detected 36 potential large inversions in the comparison between the BTx623 Bionano map and the BTx623 v3.1 reference sequence. Strikingly, these inversions were notably absent when comparing Tx2783 or RTx436 with the BTx623 Bionano map. These inversion were mostly in the pericentromeric region which is known to have low complexity regions and harder to assemble and suggests the presence of potential artifacts in the public BTx623 reference assembly. Furthermore, in comparison to Tx2783, RTx436 exhibited 324 883 additional Single Nucleotide Polymorphisms (SNPs) and 16 506 more Insertions/Deletions (INDELs) when using BTx623 as the reference genome. We also characterized approximately 348 nucleotide-binding leucine-rich repeat (NLR) disease resistance genes in the two genomes. These high-quality genomes serve as valuable resources for discovering agronomic traits and structural variation studies.

Inference for restricted mean survival time as a function of restriction time under length-biased sampling.

The restricted mean survival time (RMST) is often of direct interest in clinical studies involving censored survival outcomes. It describes the area under the survival curve from time zero to a specified time point. When data are subject to length-biased sampling, as is frequently encountered in observational cohort studies, existing methods cannot estimate the RMST for various restriction times through a single model. In this article, we model the RMST as a continuous function of the restriction time under the setting of length-biased sampling. Two approaches based on estimating equations are proposed to estimate the time-varying effects of covariates. Finally, we establish the asymptotic properties for the proposed estimators. Simulation studies are performed to demonstrate the finite sample performance. Two real-data examples are analyzed by our procedures.

Liposome-based RNAi delivery in honeybee for inhibiting parasite Nosema ceranae.

Nosema ceranae, a parasite that parasitizes and reproduces in the gut of honeybees, has become a serious threat to the global apiculture industry. RNA interference (RNAi) technology can be used to inhibit N. ceranae growth by targeting silencing the thioredoxin reductase (TrxR) in N. ceranae. However, suitable carriers are one of the reasons limiting the application of RNAi due to the easy degradation of dsRNA in honeybees. As a vesicle composed of a lipid bilayer, liposomes are a good carrier for nucleic acid delivery, but studies in honeybees are lacking. In this study, liposomes were used for double-stranded RNA (dsRNA) dsTrxR delivery triggering RNAi to inhibit the N. ceranae growth in honeybees. Compared to naked dsTrxR, liposome-dsTrxR reduced N. ceranae numbers in the midgut and partially restored midgut morphology without affecting bee survival and gut microbial composition. The results of this study confirmed that liposomes could effectively protect dsRNA from entering the honeybee gut and provide a reference for using RNAi technology to suppress honeybee pests and diseases.

Self-polymerization silica nanoparticles based molecularly imprinted polymers for selective recognition of protein.

Molecularly imprinted polymers (MIPs) are promising for precise protein separation and purification. However, challenges persist due to their large size, variable configuration, and instability during preparation. Here, a simple silicon self-assembly program was designed to synthesize MIPs without any organic reagents and acid-base catalysis, avoiding the structural damage of protein under severe conditions. In this method, employing hemoglobin (Hb) as a model protein, with tween-20 in emulsification, and tetraethyl orthosilicate (TEOS) as the cross-linking agent, along with co-functional monomers 3-aminopropyltriethoxysilane (APTES) and benzyl(triethoxy)silane (BnTES), enhanced binding efficacy was achieved. Successful imprinting was evidenced through surface morphology observation and physical/chemical property evaluations of the synthesized MIPs. A series of adsorption experiments were performed to investigate the recognition performance of Hb-MIPs. The Hb-MIPs not only exhibited large adsorption capacity (400 µg/mg) and good imprinting factor (6.09) toward template protein, but also showed satisfactory selectivity for reference proteins. Five cycles of adsorption proved that the Hb-MIPs had good reusability. In addition, the successful isolation of HB from bovine blood indicated that Hb-MIPs were an excellent separation and purification material. The mild preparation conditions and good adsorption capacity demonstrated the potential value of this method in separation and purification research.

Recurrence of Non-Small Cell Lung Cancer With Visceral Pleural Invasion: A Seconday Analysis of a Randomized Clinical Trial.

Importance: The randomized clinical trial Cancer and Leukemia Group B (CALGB) 140503 showed that for patients with clinically staged T1N0 non-small cell lung cancer (NSCLC; ≤2 cm), sublobar resections were associated with similar oncological outcomes to those after lobar resection. The association of the extent of parenchymal resection with recurrence and survival in patients with tumors pathologically upstaged to T2 based on visceral pleural invasion (VPI) is controversial. Objective: To determine survival and recurrence rates in patients with small peripheral pT2 NSCLC (≤2 cm) that was treated by either lobar or sublobar resection in CALGB 140503. Design, Participants, and Setting: CALGB 140503, a randomized multicenter noninferiority trial, included 697 patients with small peripheral NSCLC that was clinically staged as T1N0. Enrollment was from June 2007 through March 2017 at 83 participating institutions, and after a median follow-up of 7 years, the primary outcome of disease-free survival after sublobar resection was noninferior to that after lobar resection. Intervention: Lobar or sublobar resection. Main Outcomes and Measures: Survival end points were estimated by the Kaplan-Meier estimator. Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazard models. Results: Of 679 participants, 390 (57.4%) were female, and the median (range) age was 67.8 (37.8-89.7) years. Among 697 patients randomized, 566 (81.2%) had pT1 tumors (no VPI) and 113 (16.2%) had pT2 tumors (VPI). Five-year disease-free survival was 65.9% (95% CI, 61.9%-70.2%) in patients with pT1 compared with 53.3% (95% CI, 44.3%-64.1%) in patients with pT2 tumors (stratified log-rank: P = .02). Disease recurrence developed in 27.6% of patients with pT1 (locoregional only: 60 [10.8%]; distant only: 81 [14.6%]) and 41.6% of those with pT2 (locoregional only: 17 [15.0%]; distant only: 27 [23.9%]). Five-year recurrence-free survival was 73.1% (95% CI, 69.2%-77.1%) for pT1 tumors and 58.2% (95% CI, 49.2%-68.8%) for pT2 tumors (stratified log-rank: P = .01). There were no intergroup differences in disease-free or recurrence-free survival based on the extent of parenchymal resection. Conclusions and Relevance: The results of this secondary analysis suggest that compared with patients with tumors without VPI, patients who had tumors with VPI had worse disease-free and recurrence-free survival and a higher rate of local and distant disease recurrence. These high rates of recurrence were independent of the extent of parenchymal resection, and these data support the inclusion of these patients in adjuvant therapy trials. Trial Registration: ClinicalTrials.gov Identifier: NCT0049933.

A viroid-derived small interfering RNA targets bHLH transcription factor MdPIF1 to regulate anthocyanin biosynthesis in Malus domestica.

Fruit colour is a critical determinant for the appearance quality and commercial value of apple fruits. Viroid-induced dapple symptom severely affects the fruit coloration, however, the underlying mechanism remains unknown. In this study, we identified an apple dimple fruit viroid (ADFVd)-derived small interfering RNA, named vsiR693, which targeted the mRNA coding for a bHLH transcription factor MdPIF1 (PHYTOCHROME-INTERACTING FACTOR 1) to regulate anthocyanin biosynthesis in apple. 5' RLM-RACE and artificial microRNA transient expression system proved that vsiR693 directly targeted the mRNA of MdPIF1 for cleavage. MdPIF1 positively regulated anthocyanin biosynthesis in both apple calli and fruits, and it directly bound to G-box element in the promoter of MdPAL and MdF3H, two anthocyanin biosynthetic genes, to promote their transcription. Expression of vsiR693 negatively regulated anthocyanin biosynthesis in both apple calli and fruits. Furthermore, co-expression of vsiR693 and MdPIF1 suppressed MdPIF1-promoted anthocyanin biosynthesis in apple fruits. Infiltration of ADFVd infectious clone suppressed coloration surrounding the injection sites in apple fruits, while a mutated version of ADFVd, in which the vsiR693 producing region was mutated, failed to repress fruit coloration around the injection sites. These data provide evidence that a viroid-derived small interfering RNA targets host transcription factor to regulate anthocyanin biosynthesis in apple.

Influence of a diet meal plan on pepsinogen I and II, gastrin-17, and nutritional status in gastric ulcer patients.

BACKGROUND: Gastric ulcers (GUs) have a high risk of clinical morbidity and recurrence, and further exploration is needed for the prevention, diagnosis, and treatment of the disease. AIM: To investigated the effects of a diet plan on pepsinogen (PG) I, PG II, gastrin-17 (G-17) levels and nutritional status in patients with GUs. METHODS: A total of 100 patients with GUs treated between May 2022 and May 2023 were enrolled, with 47 patients in the control group receiving routine nursing and 53 patients in the experimental group receiving dietary nursing intervention based on a diet plan. The study compared the two groups in terms of nursing efficacy, adverse events (vomiting, acid reflux, and celialgia), time to symptom improvement (burning sensation, acid reflux, and celialgia), gastric function (PG I, PG II, and G-17 levels), and nutritional status [prealbumin (PA) and albumin (ALB) levels]. RESULTS: The experimental group showed a markedly higher total effective rate of nursing, a significantly lower incidence of adverse events, and a shorter time to symptom improvement than the control group. Additionally, the experimental group's post-intervention PG I, PG II, and G-17 levels were significantly lower than pre-intervention or control group levels, whereas PA and ALB levels were significantly higher. CONCLUSION: The diet plan significantly reduced PG I, PG II, and G-17 levels in patients with GUs and significantly improved their nutritional status.

Abyss Aerosols: Drop Production from Underwater Bubble Collisions.

Over the past century, drops production mechanisms from bubble bursting have been extensively studied. They include the centrifugal fragmentation of liquid ligaments from the bubble cap during film rupture, the flapping of the cap film, and the disintegration of Worthington jets after cavity collapse. We show here that a dominant fraction of previously identified as "surface bubble bursting" submicron drops are, in fact, generated underwater, in the abyss, inside the bubbles themselves before they have reached the surface. Several experimental evidences demonstrate that these drops originate from the flapping instability of the film squeezed between underwater colliding bubbles. This finding, emphasizing the eminent role of bubble-bubble collisions, alters fundamentally our understanding of fine aerosol production and opens a novel perspective for transfers across water-air interfaces.

Effects of Acute Mental Stress on Choroidal Thickness.

Purpose: Previous studies have indicated an association between education and myopia, suggesting that numerous stress events during the educational process may influence eye health. This study aimed to investigate the impact of mental stress induced by mental arithmetic (MA) on choroidal thickness (CT). Methods: This study included 33 participants aged between 19 and 29 years. Swept-source optical coherence tomography (SS-OCT) was used to capture images of the posterior segment of the left eye during baseline and MA to assess changes in the CT. After denoising and compensation, the baseline images and MA images that had been rigidly registered and resampled to the baseline images were segmented using a deep learning-based method. Based on the segmentation results, the CT within the regions of 1 mm and 3 mm diameter centered at the lowest point of the fovea was calculated. Results: Significant increases were observed in both CT1mm and CT3mm during MA, with mean changes of 2.742 ± 7.098 µm (p = 0.034) and 3.326 ± 6.143 µm (p < 0.001), respectively. Conclusions: Thickening of the choroid has been observed during acute mental stress. We speculate that long-term or chronic mental stress could have a potential adverse impact on myopia progression.

Matrine reduces traumatic heterotopic ossification in mice by inhibiting M2 macrophage polarization through the MAPK pathway.

In this study, the role of matrine, a component derived from traditional Chinese medicine, in modulating macrophage polarization and its effects on traumatic heterotopic ossification (HO) in mice was investigated. Traumatic HO is a pathological condition characterized by abnormal bone formation in nonskeletal tissues, often following severe trauma or surgery. The mechanisms underlying HO involve an enhanced inflammatory response and abnormal bone formation, with macrophages playing a crucial role. Our study demonstrated that matrine effectively inhibits the polarization of bone marrow-derived macrophages (BMDMs) toward the M2 phenotype, a subtype associated with anti-inflammatory processes and implicated in the progression of HO. Using in vitro assays, we showed that matrine suppresses key M2 markers and inhibits the MAPK signaling pathway in BMDMs. Furthermore, in vivo experiments revealed that matrine treatment significantly reduced HO formation in the Achilles tendons of mice and downregulated the expression of markers associated with M2 macrophages and the MAPK pathway. Our findings suggest that the ability of matrine to modulate macrophage polarization and inhibit the MAPK pathway has therapeutic potential for treating traumatic HO, providing a novel approach to managing this complex condition.

Lamina Cribrosa Configurations in Highly Myopic and Non-Highly Myopic Eyes: The Beijing Eye Study.

Purpose: The purpose of this study was to examine characteristics of lamina cribrosa (LC) configuration in highly myopic (HM) eyes. Methods: Participants from the Beijing Eye Study 2011, free of optic nerve or retinal diseases, were randomly selected to examine LC depth (LCD) and LC tilt (LCT) using three-dimensional optical coherent tomography images of the optic nerve head (ONH). LCD and LCT were measured as the distance and angle between the LC plane with two reference planes, including the Bruch's membrane opening (BMO) plane and the peripapillary sclera (PPS) plane, respectively. Each parameter was measured in both horizontal and vertical B-scans. Results: The study included 685 individuals (685 eyes) aged 59.6 ± 7.7 years, including 72 HM eyes and 613 non-HM eyes. LCD measurements showed no significant differences between HM eyes and non-HM eyes in both horizontal (LCD-BMO = 421.83 ± 107.86 µm for HM eyes vs. 447.24 ± 104.94 µm for non-HM eyes, P = 0.18; and LCD-PPS = 406.39 ± 127.69 µm vs. 394.00 ± 101.64 µm, P = 1.00) and vertical directions (LCD-BMO = 435.78 ± 101.29 µm vs. 450.97 ± 106.54 µm, P = 0.70; and LCD-PPS = 401.62 ± 109.9 µm vs. 379.85 ± 110.35 µm, P = 0.35). However, the LCT was significantly more negative (tilted) in HM eyes than in non-HM eyes horizontally (LCT-BMO = -4.38 ± 5.94 degrees vs. -0.04 ± 5.86 degrees, P < 0.001; and LCT-PPS = -3.16 ± 5.23 degrees vs. -0.94 ± 4.71 degrees, P = 0.003), but not vertically (P = 1.00). Conclusions: Although LCD did not differ significantly between HM and non-HM eyes, LCT was more negative in HM eyes, suggesting that the temporal or inferior side of the LC was closer to the reference plane. These findings provide insights into morphological and structural changes in the LC and ONH between HM and non-HM eyes.

PTBP1-mediated biogenesis of circATIC promotes progression and cisplatin resistance of bladder cancer.

Background: Cisplatin (DDP) based combination chemotherapy is a vital method for the treatment of bladder cancer (BLca). Chemoresistance easily occurs in the course of cisplatin chemotherapy, which is one of the important reasons for the unfavorable prognosis of BLca patients. Circular RNAs (circRNAs) are widely recognized for their role in the development and advancement of BLca. Nevertheless, the precise role of circRNAs in DDP resistance for BLca remains unclear. Methods: To study the properties of circATIC, sanger sequencing, agarose gel electrophoresis and treatment with RNase R/Actinomycin D were utilized. RT-qPCR assay was utilized to assess the expression levels of circRNA, miRNA and mRNA in BLca tissues and cells. Functional experiments were conducted to assess the function of circATIC in BLca progression and chemosensitivity in vitro. Various techniques such as FISH, Dual-luciferase reporter assay, TRAP, RNA digestion assay, RIP and ChIRP assay were used to investigate the relationships between PTBP1, circATIC, miR-1247-5p and RCC2. Orthotopic bladder cancer model, xenograft subcutaneous tumor model and xenograft lung metastasis tumor model were performed to indicate the function and mechanism of circATIC in BLca progression and chemosensitivity in vivo. Results: In our study, we observed that circATIC expression was significantly enhanced in BLca tissues and cells and DDP resistant cells. Patients with higher circATIC expression have larger tumor diameter, higher incidence of postoperative metastasis and lower overall survival rate. Further experiments showed that circATIC accelerated BLca cell growth and metastasis and induced DDP resistance. Mechanistically, alternative splicing enzyme PTBP1 mediated the synthesis of circATIC. circATIC could enhance RCC2 mRNA stability via sponging miR-1247-5p or constructing a circATIC/LIN28A/RCC2 RNA-protein ternary complex. Finally, circATIC promotes RCC2 expression to enhance Epithelial-Mesenchymal Transition (EMT) progression and activate JNK signal pathway, thus strengthening DDP resistance in BLca cells. Conclusion: Our study demonstrated that circATIC promoted BLca progression and DDP resistance, and could serve as a potential target for BLca treatment.

Effect of Eye Globe and Optic Nerve Morphologies on Gaze-Induced Optic Nerve Head Deformations.

Purpose: The purpose of this study was to investigate the effect of globe and optic nerve (ON) morphologies and tissue stiffnesses on gaze-induced optic nerve head deformations using parametric finite element modeling and a design of experiment (DOE) approach. Methods: A custom software was developed to generate finite element models of the eye using 10 morphological parameters: dural radius, scleral, choroidal, retinal, pial and peripapillary border tissue thicknesses, prelaminar tissue depth, lamina cribrosa (LC) depth, ON radius, and ON tortuosity. A central composite face-centered design (1045 models) was used to predict the effects of each morphological factor and their interactions on LC strains induced by 13 degrees of adduction. Subsequently, a further DOE analysis (1045 models) was conducted to study the effects and potential interactions between the top five morphological parameters identified from the initial DOE study and five critical tissue stiffnesses. Results: In the DOE analysis of 10 morphological parameters, the 5 most significant factors were ON tortuosity, dural radius, ON radius, scleral thickness, and LC depth. Further DOE analysis incorporating biomechanical parameters highlighted the importance of dural and LC stiffness. A larger dural radius and stiffer dura increased LC strains but the other main factors had the opposite effects. Notably, the significant interactions were found between dural radius with dural stiffness, ON radius, and ON tortuosity. Conclusions: This study highlights the significant impact of morphological factors on LC deformations during eye movements, with key morphological effects being more pronounced than tissue stiffnesses.

Pan-cancer analysis and the oncogenic role of Glypican 1 in hepatocellular carcinoma.

Recent studies indicate that Glypican 1 (GPC-1) is aberrantly expressed and plays a key role in certain cancers, but little is known in the hepatocellular carcinoma. Raw data from TCGA, GTEx and TIMER databases were utilized to comprehensively analyze GPC-1 expression landscape in pan-cancer, and the biological function of GPC-1 was investigated in liver cancer cells. The results revealed that GPC-1 is highly expressed in HCC, negatively correlated with survival, and also positively correlated with immune infiltration and clinical stage. Furthermore, GPC-1 promoted cell proliferation and inhibited apoptosis in the HCC cell lines. WGCNA analysis and HCCDB database revealed that Akt acted as a key molecule related to GPC-1, influencing biological functions and regulating cell malignant behaviors via the AKT signaling pathway. In conclusion, our findings provide a relatively comprehensive understanding of the oncogenic role of GPC-1 in HCC, implying that GPC-1 could serve as an innovative therapeutic target.

Lignin-assisted electronic modulation on NiSe/FeOx heterointerface for boosting electrocatalytic oxygen evolution reaction.

The development of productive and durable non-precious metal catalysts for the sluggish oxygen evolution reaction (OER) is critical for water splitting. Herein, a novel NiSe-FeOx heterojunction encapsulated in lignin-derived carbon layer (NiSe-FeOx@LC) was synthesized via hydrothermal self-assembly and in-situ pyrolysis. NiSe-FeOx@LC exhibited excellent OER performance with an overpotential of 265 mV at 50 mA·cm-2, a Tafel slope of 83 mV·dec-1, as well as long-term stability. Both experimental and DFT calculation results indicated that the doping of FeOx into NiSe@LC successfully optimized the dual interface structure between NiSe and FeOx, thereby promoted the d-bands orbital hybridization, that facilitated electron transfer. Besides, the carbon coating effectively protected the NiSe-FeOx components from leaching and agglomerating during the reaction. This study provides insight into the significance of lignin-derived carbon-encapsulated metallic catalyst for electrocatalytic OER process.

Integrating genetic and proteomic data to elucidate the association between immune system and blood-brain barrier dysfunction with multiple sclerosis risk and severity.

BACKGROUND: Immune system dysfunction and blood-brain barrier (BBB) impairment are implicated in multiple sclerosis (MS) risk and severity. However, the causal relationships and potential therapeutic targets remain unclear. METHODS: Leveraging the MRC IEU OpenGWAS data infrastructure, we extracted 1254 peripheral immune systems and 792 BBB biomarkers as genetic instruments for exposure. MS risk data from the International Multiple Sclerosis Genetics Consortium (IMSGC) (47,429 MS cases, 68,374 controls) served as one outcome, replicated in FinnGen (1048 cases, 217,141 controls) and the UK Biobank (1679 cases, 461,254 controls). Genetic associations with MS severity derived from IMSGC and MultipleMS Consortium GWAS data (12,584 cases). Two-sample, bidirectional, and protein drug-target MR analyses were conducted, along with interaction analysis of identified proteins and druggability assessment. RESULTS: Causal relationships between 45 immunological markers, 15 BBB markers, and MS risk were strongly supported. In peripheral immunity, the causal associations with MS are predominantly concentrated in CD4+ T cells and CD8+ T cells. Notably, anti-Epstein-Barr virus nuclear antigen (EBNA) IgG levels exhibited the most significant causal effect on MS risk (OR = 225.62, P = 5.63E-208), replicated in the MS severity (OR = 1.11, P = 0.04). Weak causal evidence was found between 62 immunological markers, 35 BBB markers, and MS severity. Reverse MR analysis suggested potential causal effects of MS risk on 8 markers. Drug-targeted MR analysis indicated potential therapeutic benefits in reducing MS risk for CD40 (OR = 0.71, P = 7.24E-13, PPH4 = 97.6 %), AHSG (OR = 0.88, P = 2.91E-05, PPH4 = 94.4 %), and FCRL3 (Sun BB et al.: OR = 0.83, P = 8.93E-09, PPH4 = 94.2 %, Suhre K et al.: OR = 0.88, P = 5.20E-08, PPH4 = 99.2 %). CONCLUSIONS: This study provides evidence supporting the causal effects of immune system and BBB dysfunction on MS risk and severity. It emphasizes the significant role of anti-EBNA IgG levels, CD4+ T cells, and CD8+ T cells in MS, and delineates the potential therapeutic benefits of targeting three proteins associated with MS risk: CD40, AHSG, and FCRL3.

Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells.

Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism-rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis-related genes following FOXK1 protein activation contributes to the energy-related metabolic shift. Nuclear-translocated FOXK1 forms condensate through liquid-liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, the mechanism of a FOXK1-mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated.