Activated factor X delivered by adeno-associated virus significantly inhibited bleeding and alleviated hemophilic synovitis in hemophilic mice.

In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and restore coagulation in hemophilia patients. In this study, the cassettes that expressed FXa, FXaop and FXa-FVII were packaged into an engineered AAV capsid, AAV843, and were delivered into hemophilia A and B mice by intravenous injection. AAV-FXaop could be stably expressed in vivo and showed the best immediate and prolonged hemostatic effects, similar to those of commercial drugs (Xyntha and Benefix). AAV-FXaop also significantly inhibited bleeding in hemophilia A mice with inhibitors. In addition, FXa expression in joints significantly alleviated the occurrence of hemophilic synovitis. AAV-delivered FXa may be a novel target for treating hemophilic and hemophilic synovitis.

Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

Novel insights into biofilm formation and the key differentially expressed genes in Yersinia enterocolitica from meat: Implications for food safety and disease prevention.

Yersinia enterocolitica is an important foodborne pathogen that can cause a zoonotic disease known as yersiniosis, which causes symptoms such as acute diarrhea, mesenteric adenitis, terminal ileum inflammation, pseudo appendicitis, sepsis, and other complications. The mechanism of biofilm formation in Y. enterocolitica remains poorly understood, with limited research available on this topic. This study systematically examined the distribution characteristics and biofilm formation ability of Y. enterocolitica isolated from poultry and livestock related samples. Analysis of food samples collected indicated significant presence of Y. enterocolitica (207/670, 30.9 %), particularly in frozen duck meat (7/11, 63.6 %). Majority of the isolated strains did not demonstrate biofilm-forming ability (52.7 %), while a notable percentage exhibited moderate (6.8 %) to strong (11.6 %) biofilm-forming ability. Additionally, a significant percentage of strains (16/207, 7.7 %) displayed extremely high optical density/cut-off OD (OD/ODC) ratios (the average OD value of each sample divided by the average OD value of the negative controls of each 96-well plate plus 3 standard deviations) (exceeding 10). Time-course analysis of biofilm formation in 10 isolates revealed three distinct patterns: (i) rapid increase from 6 h to 12 h, with gradual peak between 48 and 72 h followed by a slight decline and stabilization; (ii) little biofilm formation at 24 h with a gradual increase up to 96 h, maintaining this level until 120 h; and (iii) complete absence of biofilm formation throughout the experiment. Subsequent examination of differentially expressed genes (DEGs) in planktonic cells and biofilms of two strains with distinct biofilm formation capabilities identified seven metabolic pathways, including ribosome, photosynthesis, fatty acid degradation, valine, leucine, and isoleucine degradation, as well as pinene, camphor, and geraniol degradation. Significantly elevated expression levels of genes associated with flagellar assembly, bacterial chemotaxis, and quorum sensing (partially) were observed exclusively in planktonic cells of the selected strain with stronger biofilm-forming ability, implying that the heightened expression of flagellar assembly and bacterial chemotaxis-related genes is an important but not sole determinant of biofilm formation. The study contributes to the elucidation of the underlying mechanisms governing biofilm formation in Y. enterocolitica and may offer valuable insights for the advancement of novel food safety strategies.

Fulvic acid impact on constructed wetland-microbial electrolysis cell system performance: Metagenomic insights.

This study explores the roles of fulvic acid (FA) in both a conventionally constructed wetland (CCW) and a newly constructed wetland-microbial electrolysis cell (ECW). The results showed that FA increased the average removal efficiency of chemical oxygen demand, total phosphorus, total nitrogen, and ammonia nitrogen in ECW by 8.6, 46.2, 33.0, and 27.9 %, respectively, compared to CCW, and reduced the global warming potential by > 60 %. FA promoted the proliferation of electroactive bacteria (e.g., Chlorobaculum and Candidatus Tenderia) and FA-degrading bacteria (e.g., Anaerolineaceae and Gammaproteobacteria) and reduced methanogens (e.g., Methanothrix) via type-changing. The study's findings suggest that FA influences pollutant removal and microbiome dynamics by altering dissolved oxygen levels and redox potential. In summary, FA and ECW enhanced the efficiency of constructed wetlands by facilitating electron transfer and consumption, and supporting microbial growth and metabolism.

Beneficial effects of Lactobacillus plantarum on growth performance, immune status, antioxidant function and intestinal microbiota in broilers.

Lactobacillus plantarum (L. plantarum) has been globally regarded as antibiotic alternative in animal farming in the past few years. However, the potential function of L. plantarum in broilers has not been systemically explored. In this study, a total of 560 one-day-old yellow-feathered broilers were randomly divided into 3 groups, fed with basal diet and drank with L. plantarum HJZW08 (LP) at the concentration of 0 (CON), 1000 × 10^5 (LP1000), and 2000 × 10^5 CFU/L (LP2000) for 70 d. Results showed that the body weight (BW), average daily gain (ADG), average daily feed intake (ADFI), immunoglobulin A (IgA), IgY, and anti-inflammatory interleukin 10 (IL-10) were markedly improved (P < 0.05), while the levels of pro-inflammatory IL-2, IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in serum were decreased (P < 0.05) in the LP2000 group comparing with the CON group. Besides, LP treatment groups prominently increased the levels and activities of antioxidant enzymes and decreased the content of malondialdehyde (MDA). Additionally, the levels of isobutyric acid in the LP1000 and LP2000 groups and isovaleric acid in the LP2000 group were significantly improved. More importantly, the α-diversity and microbial structure of intestinal microbiota were pronounced altered by LP supplementation. The results showed that only the relative abundance of Actinobacteriota was significantly increased in the LP2000 group, while 6 kinds of bacteria on genus level were significantly changed. For further validation, linear discriminant analysis with effect size (LEfSe) plots revealed that 8 amplicon sequence variants (ASVs) were predominant in the CON group, while Bacteroides and other beneficial species such as Lactimicrobium massiliense (ASV4 and ASV36), Intestinimonas butyriciproducens (ASV71), and Barnesiella viscericola (ASV152 and ASV571) were enriched in the LP groups. Taken together, dietary supplementation with LP obviously enhanced the immune status, antioxidant capacity, and stabilized the cecal microbiota and SCFAs, contributing to the improvement of growth performance of broilers. Our study laid good foundation for the application of probiotic Lactobacillus in animal industry in the future.

Gut microbiome pattern impacts treatment response in primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC. METHODS: We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts. FINDINGS: PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridialow microbiomes, Clostridiahigh microbiomes were more similar to healthy controls. Notably, patients in the Clostridialow subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridiahigh subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridialow subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridiahigh group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts. CONCLUSIONS: Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies. FUNDING: This research was mainly supported by the National Natural Science Foundation of China.

Bacterial pneumonia patients with elevated globulin levels did not get infected with SARS-CoV-2: two case reports.

Background: COVID-19 began in December 2019, rapidly spreading worldwide. China implemented a dynamic zero-COVID strategy and strict control measures after the outbreak. However, Guangzhou city ended closed-off management by the end of November 2022, leading to exposure to SARS-CoV-2. Despite most hospitalized patients being infected or co-infected with SARS-CoV-2, some remained uninfected. We report two cases of bacterial pneumonia with elevated globulin levels not infected with SARS-CoV-2, aiming to identify protection factors of SARS-CoV-2 infection and provide a scientific basis for SARS-CoV-2 prevention. Case presentation: Case 1, a 92-year-old male, admitted on October 21, 2022, developed worsening cough and sputum after aspiration, diagnosed with bacterial pneumonia with Pseudomonas aeruginosa, Escherichia coli (CRE) and carbapenem-resistant Acinetobacter baumannii (CRAB) infections. He was treated with imipenem anti-infective therapy and mechanical ventilation, then switched to a combination of meropenem, voriconazole and amikacin anti-infective therapy due to recurrent infections and septic shock, and died of sepsis on 8 January 2023. Case 2 is an 82-year-old male admitted on 30 September 2022, with recurrent cough, sputum, and shortness of breath, diagnosed with bacterial pneumonia with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Mycobacterium pneumoniae infections. He was treated with ventilator-assisted ventilation, meropenem, amikacin, tigecycline and mucomycin nebulization and discharged with improvement on 26 October. He was readmitted on 21 November 2022 and diagnosed with bacterial pneumonia. He was treated with cefoperazone sulbactam, amikacin, meropenem and fluconazole and discharged on 31 December. Neither patient was infected with SARS-CoV-2 during hospitalization. Notably, their globulin levels were elevated before SARS-CoV-2 exposure, gradually decreasing afterward. Conclusions: Patients with bacterial pneumonia with high globulin levels likely have large amounts of immunoglobulin, and that immunoglobulin cross-reactivity causes this protein to be involved in clearing SARS-CoV-2 and preventing infection. Therefore, bacterial pneumonia patients with high globulin levels included in this study were not infected with SARS-CoV-2. After exposure to SARS-CoV-2, the amount of globulin in the patient's body was reduced because it was used to clear SARS-CoV-2. The results of this study are expected to provide a theoretical basis for the study of the mechanism of prevention and treatment of SARS-CoV-2 infection.

Exploring the molecular and immune landscape of cellular senescence in lung adenocarcinoma.

Introduction: The connection between aging and cancer is complex. Previous research has highlighted the association between the aging process of lung adenocarcinoma (LUAD) cells and the immune response, yet there remains a gap in confirming this through single-cell data validation. Here, we aim to develop a novel aging-related prognostic model for LUAD, and verify the alterations in the genome and immune microenvironment linked to cellular senescence. Methods: We integrated a comprehensive collection of senescence genes from the GenAge and CellAge databases and employed the least absolute shrinkage and selection operator (LASSO) Cox analysis to construct and validate a novel prognostic model for LUAD. This model was then utilized to examine the relationship between aging, tumor somatic mutations, and immune cell infiltration. Additionally, we explored the heterogeneity of senescence and intercellular communication within the LUAD tumor microenvironment (TME) through single-cell transcriptomic data analysis. Results: By exploring the expression profiles of 586 cellular senescence-related genes in 428 LUAD patients, we constructed an aging-related genes (ARGs) risk model included 10 ARGs and validated it as an independent prognostic predictor for LUAD patients. Notably, patients with low aging scores (LAS group) exhibited better survival, lower tumor mutation burden (TMB), lower somatic mutation frequency, lower tumor proliferation rate, and an immune activated phenotype compared to patients with high aging scores (HAS group). While the HAS group was enriched in tumor cells and showed a lower infiltration of CD8-CCR7, CD8- CXCL13, CD8-GNLY, FCGR3A NK cells, XCL1 NK cells, plasma cell (PC) and other immune subsets. Furthermore, the SPP1 and TENASCIN pathways, associated with tumor immune escape and tumor progression, were also enriched in the HAS group. Additionally, our study also indicated that senescence levels were heterogeneous in the LUAD tumor microenvironment (TME), especially with tumor cells in the LAS group showing higher age scores compared to those in the HAS group. Conclusions: Collectively, our findings underscore that ARRS through ARGs serves as a robust biomarker for the prognosis in LUAD.

Hericium erinaceus ß-glucan/tannic acid hydrogels based on physical cross-linking and hydrogen bonding strategies for accelerating wound healing.

The majority of natural fungal ß-glucans exhibit diverse biological functionalities, such as immunomodulation and anti-inflammatory effects, attributed to their distinctive helix or highly branched conformation This study utilized ß-glucan with helix conformation and high-viscosity extracted from Hericium erinaceus, employing freeze-thaw and solvent exchange strategies to induce multiple hydrogen bonding between molecules, thereby initiating the self-assembly process of ß-glucan from random coil to stable helix conformation without chemical modifications. Subsequently, the natural bioactive compound tannic acid was introduced through physical entanglement, imparting exceptional antioxidant properties to the hydrogel. The HEBG/TA hydrogel exhibited injectable properties, appropriate mechanical characteristics, degradability, temperature-responsive tannic acid release, antioxidant activity, and hemostatic potential. In vivo experiments using skin full-thickness defect and deep second-degree burn wound models demonstrated significant therapeutic efficacy, including neovascularization, and tissue regeneration. Moreover, the HEBG/TA hydrogel demonstrated its ability to regulate cytokines by effectively inhibiting the production of inflammatory mediators (TNF-α, IL-6), while simultaneously enhancing the expression of cell proliferation factor KI-67 and markers associated with angiogenesis such as CD31 and α-SMA. This study highlights the potential of combining natural ß-glucan with bioactive molecules for skin repair.

Akkermansia Muciniphila supplementation improves hyperlipidemia, cardiac function, and gut microbiota in high fat fed apolipoprotein E-deficient mice.

Hyperlipidemia, obesity and gut dysbiosis are pivotal risk factors for atherosclerotic cardiovascular disease (ACVD). Supplementation of Akkermansia muciniphila (AKK) has also been proven to be effective in the prevention and treatment of obesity and other metabolic disorders. Here we found that AKK was more abundant in healthy control than ACVD patients via metagenomic sequencing on fecal samples. Subsequently, we investigated the role and underlying mechanism of AKK on obesity-associated atherosclerosis. AKK intervention partially reversed the exacerbation of atherosclerotic lesion formation in ApoE-/- mice by improving dyslipidemia. Interestingly, replenishment with AKK significantly enhanced cardiac function and reduced the body weight. It also reduced pro-inflammatory cytokine IL-6 and increased anti-inflammatory IL-10 in the circulation. Additionally, AKK colonization dramatically regulated gut microbiota and increased the abundance of Lactobacillaceae. Our findings have provided novel insights into the therapeutic potential of AKK as a beneficial microbe for treating atherosclerotic-associated cardiovascular diseases.

Characterization of Food-Additive Titanium Dioxide and Dietary Exposure to Titanium Dioxide Nanoparticles among the Chinese Population.

Titanium dioxide (TiO2) is a prevalent food additive, yet comprehensive data on particle size and dietary exposure are lacking in China. Transmission electron microscopy results revealed that the quantitative proportion of nanoparticles (NPs) in food-additive TiO2 was 37.7%, with a mass fraction of 9.89%. Laboratory test results showed that among the domestic products surveyed, candies excluding gum-based candies contained the highest content of TiO2. Using consumption data from the China Health and Nutrition Survey in 2018, the average dietary exposure for TiO2 and TiO2 NPs in the Chinese population were calculated at 34.84 and 3.44 µg/kg bw/day, respectively. The primary dietary sources were puffed food and powdered drinks. Exposure varied significantly across age and region, with children and Inner Mongolia residents having the highest intake. TiO2 NP exposure showed a negative correlation with age. Despite this, the dietary exposure risk of TiO2 NPs for the Chinese population remains deemed acceptable.

Study of the intensive care unit activity scale in the early rehabilitation of patients after direct cardiac surgery.

BACKGROUND: Direct cardiac surgery often necessitates intensive post-operative care, and the intensive care unit (ICU) activity scale represents a crucial metric in assessing and guiding early rehabilitation efforts to enhance patient recovery. AIM: To clarify the clinical application value of the ICU activity scale in the early recovery of patients after cardiac surgery. METHODS: One hundred and twenty patients who underwent cardiac surgery between September 2020 and October 2021 were selected and divided into two groups using the random number table method. The observation group was rated using the ICU activity scale and the corresponding graded rehabilitation interventions were conducted based on the ICU activity scale. The control group was assessed in accordance with the routine rehabilitation activities, and the postoperative rehabilitation indexes of the patients in both groups were compared (time of tracheal intubation, time of ICU admission, occurrence of complications, and activity scores before ICU transfer). The two groups were compared according to postoperative rehabilitation indicators (time of tracheal intubation, length of ICU stay, and occurrence of complications) and activity scores before ICU transfer. RESULTS: In the observation group, tracheal intubation time lasted for 18.30 ± 3.28 h and ICU admission time was 4.04 ± 0.83 d, which were significantly shorter than the control group (t-values: 2.97 and 2.038, respectively, P < 0.05). The observation group also had a significantly lower number of complications and adverse events compared to the control group (P < 0.05). Before ICU transfer, the observation group (6.7%) had few complications and adverse events than the control group (30.0 %), and this difference was statistically significant (P < 0.05). Additionally, the activity score was significantly higher in the observation (26.89 ± 0.97) compared to the control groups (22.63 ± 1.12 points) (t-value; -17.83, P < 0.05). CONCLUSION: Implementation of early goal-directed activities in patients who underwent cardiac surgery using the ICU activity scale can promote the recovery of cardiac function.

Differential efficacy of modified enriched environment on motor, emotion, and cognition in cortical ischemic mice.

A modified enriched environment (mEE) with 12 h per night was recently proposed and exhibited cognitive improvement. The present study aimed to evaluate the effects of different courses of mEE on different deficits in ischemic mice. Mice were subjected to photothrombotic stroke at the left sensorimotor cortex and then randomly assigned to standard environment or mEE for 7 d (St-PE) or 28 d (Ct-PE) on the third day post-stroke. Neurological deficits and sensorimotor, emotional, and cognitive performances were assessed at the 10th, 17th, and 31st days post-stroke. Our results demonstrated that Ct-PE ameliorated neurological deficits, forelimb using asymmetry, and reduced slip rates of the affected limbs at all time points, while this effect of St-PE was observed only on the 10th day. Similarly, Ct-PE for 28 d promoted spatial learning and working memory, but St-PE did not. Differently, ischemic mice in both St-PE and Ct-PE groups exhibited increased exploration behavior in the open field, light-dark box and elevated plus maze, and less immobile behavior during the tail suspension at all the time points. Our findings indicated that Ct-PE improved sensorimotor and cognitive dysfunctions after cortical ischemia in a time-dependent manner, but St-PE appeared to have greater therapeutic potential on anxiety and depression.

Bacillus licheniformis suppresses Clostridium perfringens infection via modulating inflammatory response, antioxidant status, inflammasome activation and microbial homeostasis in broilers.

Pathogenic bacteria infection, especially Clostridium perfringens (C. perfringens), markedly threatened the health of animals, and further caused huge economic loss. In this study, Bacillus licheniformis HJ0135 (BL) was used. Oxford cup bacteriostatic test and inhibitory rate test were conducted to evaluate the antibacterial ability of BL. Results showed the strongest inhibitory role of BL on C. perfringens (P < 0.05). Afterwards, 540 one-day-old yellow-feather broilers (32.7 ± 0.2 g) were randomly allocated into 3 groups, including CON group (basal diet), CP group (basal diet + 1 × 109 CFU C. perfringens in gavage), and BL + CP group (basal diet containing 7.5 × 106 CFU/g BL + 1 × 109 CFU C. perfringens in gavage). At d 70, broilers in the CP and BL + CP groups were treated with C. perfringens by continuously oral administration for 5 d. The experiment lasted for 75 d. The serum, immune organs, jejunal mucosa, and cecal contents were collected for analysis. In vivo experiment showed that BL supplementation markedly improved (P < 0.05) BW, ADG, thymus index, serum immunoglobins and antioxidases, reduced feed conversion ratio (FCR) and serum pro-inflammatory cytokines of C. perfringens-infected broilers. Furthermore, the increased jejunal injury and levels of pro-inflammatory cytokines, decreased gene expressions of tight junction proteins in the jejunal mucosa were significantly alleviated (P < 0.05) by BL. More importantly, the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome was inhibited (P < 0.05) by BL to further attenuate jejunal damage. Besides, BL supplementation markedly increased (P < 0.05) the cecal isobutyric acid and isovaleric acid. Microbial analysis showed that BL changed the composition and relative abundances of microbiota in the cecal contents (P < 0.05), especially the short chain fatty acids (SCFAs)-producing bacteria including Eubacterium_coprostanoligenes_group, Megamonas, Faecalibacterium, and Lactobacillus, which further protected against C. perfringens-induced jejunal inflammation in broilers. Our study laid a theoretical basis for the application of probiotics in lessening C. perfringens-related diseases in poultry farming.

Navigating therapeutic challenges in VEXAS syndrome: exploring IL-6 and JAK inhibitors at the forefront.

VEXAS syndrome, an uncommon yet severe autoimmune disorder stemming from a mutation in the UBA1 gene, is the focus of this paper. The overview encompasses its discovery, epidemiological traits, genetic underpinnings, and clinical presentations. Delving into whether distinct genotypes yield varied clinical phenotypes in VEXAS patients, and the consequent adjustment of treatment strategies based on genotypic and clinical profiles necessitates thorough exploration within the clinical realm. Additionally, the current therapeutic landscape and future outlook are examined, with particular attention to the potential therapeutic roles of IL-6 inhibitors and JAK inhibitors, alongside an elucidation of prevailing limitations and avenues for further research. This study contributes essential theoretical groundwork and clinical insights for both diagnosing and managing VEXAS syndrome.

Hypermethylation and downregulation of microRNA219a-2 activates the ALDH1L2/GSH/PAI-1 pathway for fibronectin degradation in renal fibrosis.

Epigenetic regulations, such as DNA methylation and microRNAs, play an important role in renal fibrosis. Here, we report the regulation of microRNA-219a-2 by DNA methylation in fibrotic kidneys, unveiling the crosstalk between these epigenetic mechanisms. Through genome-wide DNA methylation analysis and pyro-sequencing, we detected the hypermethylation of microRNA219a-2 in renal fibrosis induced by unilateral ureter obstruction (UUO) or renal ischemia/reperfusion, which was accompanied by a significant decrease in microRNA-219a-5p expression. Functionally, overexpression of microRNA219a-2 enhanced fibronectin induction during hypoxia or TGF-ß1 treatment of cultured renal cells. In mice, inhibition of microRNA-219a-5p suppressed fibronectin accumulation in UUO and ischemic/reperfused kidneys. Aldehyde dehydrogenase 1 family member L2 (ALDH1L2) was identified to be the direct target gene of microRNA-219a-5p in renal fibrotic models. MicroRNA-219a-5p suppressed ALDH1L2 expression in cultured renal cells, while inhibition of microRNA-219a-5p prevented the decrease of ALDH1L2 in injured kidneys. Knockdown of ALDH1L2 enhanced plasminogen activator inhibitor-1(PAI-1) induction during TGF-ß1 treatment of renal cells, which was associated with fibronectin expression. In conclusion, the hypermethylation of microRNA219a-2 in response to fibrotic stress may attenuate microRNA-219a-5p expression and induce the up-regulation of its target gene ALDH1L2, which reduces fibronectin deposition by suppressing PAI-1.

Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Distinguishing surface and bulk electromagnetism via their dynamics in an intrinsic magnetic topological insulator.

The indirect exchange interaction between local magnetic moments via surface electrons has been long predicted to bolster the surface ferromagnetism in magnetic topological insulators (MTIs), which facilitates the quantum anomalous Hall effect. This unconventional effect is critical to determining the operating temperatures of future topotronic devices. However, the experimental confirmation of this mechanism remains elusive, especially in intrinsic MTIs. Here, we combine time-resolved photoemission spectroscopy with time-resolved magneto-optical Kerr effect measurements to elucidate the unique electromagnetism at the surface of an intrinsic MTI MnBi2Te4. Theoretical modeling based on 2D Ruderman-Kittel-Kasuya-Yosida interactions captures the initial quenching of a surface-rooted exchange gap within a factor of two but overestimates the bulk demagnetization by one order of magnitude. This mechanism directly explains the sizable gap in the quasi-2D electronic state and the nonzero residual magnetization in even-layer MnBi2Te4. Furthermore, it leads to efficient light-induced demagnetization comparable to state-of-the-art magnetophotonic crystals, promising an effective manipulation of magnetism and topological orders for future topotronics.