Post intensive care syndrome: A review of clinical symptoms, evaluation, intervention.

Post intensive care syndrome (PICS) is a typical complication of critically ill patients during or after their stay in intensive care unit (ICU), characterized by a high incidence and impairment rate. It significantly impacts the quality of life of patients and their families, as well as consumes a substantial amount of medical resources. Therefore, early intervention and assessment of PICS is crucial. This paper aims to provide clinical professionals with a reference base by focusing on the clinical symptoms, diagnostic assessment, and preventative measures of PICS.

Endoluminal Biopsy for Vein of Galen Malformation.

BACKGROUND AND OBJECTIVES: Vein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. We hypothesized that in situ analysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may advance our understanding of VOGM genetics, pathogenesis, and maintenance. METHODS: We collected germline DNA (cheek swab) from patients and their families for genetic analysis. In situ VOGM "endothelial" cells (ECs), defined as CD31+ and CD45-, were obtained from coils through ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing of both VOGM and peripheral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made with a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations. RESULTS: Our cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ECs (CD31+ and CD45-). There was no discernible correlation between cell yield and coil type or route of access. Single-cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared with peripheral EC controls when annotated using a publicly available cerebrovascular cell atlas. CONCLUSION: ETS may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

Effects of gender-affirming hormone therapy on body fat: a retrospective case‒control study in Chinese transwomen.

BACKGROUND: There is insufficient research on how gender-affirming hormone therapy (GAHT) affects body fat modifications in transwomen from China. It is unclear whether hormone therapy affects the prevalence of obesity and blood lipid levels within this population. The current research aimed to assess how GAHT and treatment duration had an impact on the change in and redistribution of body fat in Chinese transwomen. METHODS: This study included 40 transwomen who had not received GAHT and 59 who had. Body fat, blood lipid, and blood glucose levels were measured. GAHT is mainly a pharmacologic (estrogen and anti-androgen) treatment. The study also stratified participants based on the duration of GAHT to assess its impact on body fat distribution. The duration of GAHT was within one year, one to two years, two to three years, or more than three years. RESULTS: After receiving GAHT, total body fat increased by 19.65%, and the percentage of body fat increased by 17.63%. The arm, corrected leg, and leg regions showed significant increases in fat content (+ 24.02%, + 50.69%, and + 41.47%, respectively) and percentage (+ 25.19%, + 34.90%, and + 30.39%, respectively). The total visceral fat content decreased (-37.49%). Based on the diagnostic standards for a body mass index ≥ 28 or total body fat percentage ≥ 25% or 30%, the chance of developing obesity did not change significantly. Blood glucose levels significantly increased (+ 12.31%). Total cholesterol levels (-10.45%) decreased significantly. Fat changes in those who received GAHT for one to two years were significantly different from those who did not receive GAHT. CONCLUSION: After receiving GAHT, total body fat and regional fat increased in Chinese transwomen, and the body fat distribution changed from masculine to feminine, especially during the first two years. However, neither the increase in total body fat percentage nor the decrease in visceral fat content didn't bring about significant changes in the incidence of obesity, nor did triglycerides or low-density lipoprotein-cholesterol.

Towards inclusive green growth in China: Synergistic roles and mechanisms of new infrastructure construction.

Inclusive green growth (IGG) has been widely discussed for its emphasis on coordinating economic growth quality, social equity, as well as environmentally sustainable development. New infrastructure, representing network and information infrastructure construction, has emerged as a pivotal national strategy to stimulate socioeconomic progress, and its impact on the inclusive green growth deserves careful exploration. Employing the staggered difference-in-difference (staggered DID) approach, this study investigates the influence of new infrastructure on IGG based on Chinese prefecture-level city data from 2011 to 2019, taking advantage of the "Broadband China" strategy (BCS) as a quasi-natural experiment. The results indicate a significant enhancement in IGG due to new infrastructure construction, which remains tenable after rigorous robustness assessments. Further testing with the spatial Durbin DID method reveals that BCS has a significant positive spillover impact on IGG in neighboring areas. For its underlying mechanisms, new infrastructure construction enhances IGG mainly by reinforcing industrial structure supererogation, improving the urban innovation level, and developing digital inclusive finance. There is also evidence that heterogeneity highlights the advancing effects of IGG in the central region, non-aging industrial base cities and non-resource-based cities. This research sheds new light on the understanding of the effect of new infrastructure on promoting IGG through both conceptual and empirical aspects and is conducive to future policymaking for developing countries.

Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Embryo Transfer Strategies for Women with Recurrent Implantation Failure During the Frozen-thawed Embryo Transfer Cycles: Sequential Embryo Transfer or Double-blastocyst Transfer?

OBJECTIVE: Both sequential embryo transfer (SeET) and double-blastocyst transfer (DBT) can serve as embryo transfer strategies for women with recurrent implantation failure (RIF). This study aims to compare the effects of SeET and DBT on pregnancy outcomes. METHODS: Totally, 261 frozen-thawed embryo transfer cycles of 243 RIF women were included in this multicenter retrospective analysis. According to different embryo quality and transfer strategies, they were divided into four groups: group A, good-quality SeET (GQ-SeET, n=38 cycles); group B, poor-quality or mixed-quality SeET (PQ/MQ-SeET, n=31 cycles); group C, good-quality DBT (GQ-DBT, n=121 cycles); and group D, poor-quality or mixed-quality DBT (PQ/MQ-DBT, n=71 cycles). The main outcome, clinical pregnancy rate, was compared, and the generalized estimating equation (GEE) model was used to correct potential confounders that might impact pregnancy outcomes. RESULTS: GQ-DBT achieved a significantly higher clinical pregnancy rate (aOR 2.588, 95% CI 1.267-5.284, P=0.009) and live birth rate (aOR 3.082, 95% CI 1.482-6.412, P=0.003) than PQ/MQ-DBT. Similarly, the clinical pregnancy rate was significantly higher in GQ-SeET than in PQ/MQ-SeET (aOR 4.047, 95% CI 1.218-13.450, P=0.023). The pregnancy outcomes of GQ-SeET were not significantly different from those of GQ-DBT, and the same results were found between PQ/MQ-SeET and PQ/MQ-DBT. CONCLUSION: SeET relative to DBT did not seem to improve pregnancy outcomes for RIF patients if the embryo quality was comparable between the two groups. Better clinical pregnancy outcomes could be obtained by transferring good-quality embryos, no matter whether in SeET or DBT. Embryo quality plays a more important role in pregnancy outcomes for RIF patients.

The impact of environmental regulatory instruments on agribusiness technology innovation-A study of configuration effects based on fsQCA.

This paper investigates the complex causal relationships between various types of environmental regulatory instruments (ERI) and agri-firms' technological innovation employing fuzzy set qualitative comparative analysis (fsQCA). The study finds a well-designed set of ERI can promote technological innovation in agribusiness; control-command ERI cannot promote technological innovation in agribusiness solely, market-incentivized ERI is indispensable in promoting firms' innovation performance, implicit ERI plays an important role in promoting firms' innovation and voluntary ERI does not play a significant role in promoting firms' technological innovation. The government should coordinate among various types of ERI and improve the design of ERI to achieve a win-win situation for both economic and environmental performance in the agriculture sector.

Body Weight Correlates with Molecular Variances in Patients with Cancer.

Overweight and obesity are identified by a high body mass index (BMI) and carry significant health risks due to associated comorbidities. Although epidemiologic data connect overweight/obesity with 13 cancer types, a better understanding of the molecular mechanisms underlying this correlation is needed to improve prevention and treatment strategies. In this study, we conducted a comprehensive analysis of molecular differences between overweight or obese patients and normal weight patients across 14 different cancer types from The Cancer Genome Atlas. Using the propensity score weighting algorithm to control for confounding factors, obesity-specific mutational features were identified, such as higher mutation burden in rectal cancer and biased mutational signatures in other cancers. Differentially expressed genes (DEG) in tumors from patients with overweight/obesity were predominantly upregulated and enriched in inflammatory and hormone-related pathways. These DEGs were significantly associated with survival rates in various cancer types, highlighting the impact of elevated body fat on gene expression profiles and clinical outcomes in patients with cancer. Interestingly, while high BMI seemed to have a negative impact on most cancer types, the normal weight-biased mutational and gene expression patterns indicated overweight/obesity may be beneficial in endometrial cancer, suggesting the presence of an "obesity paradox" in this context. Body fat also significantly impacted the tumor microenvironment by modulating immune cell infiltration, underscoring the importance of understanding the interplay between weight and immune response in cancer progression. Together, this study systematically elucidates the molecular differences corresponding to body weight in multiple cancer types, offering potentially critical insights for developing precision therapy for patients with cancer. SIGNIFICANCE: Elucidation of the complex interplay between body weight and the molecular landscape of cancer could potentially guide tailored therapies and improve patient management amid the global obesity crisis.

Gut microbiota contribution to selenium deficiency-induced gut-liver inflammation.

There is limited knowledge about the factors that drive gut-liver axis changes after selenium (Se) deficiency-induced gut or liver injuries. Thus, we tested Se deficiency in mice to determine its effects on intestinal bacterial balance and whether it induced liver injury. Serum Se concentration, lipopolysaccharide (LPS) level, and liver injury biomarkers were tested using a biochemical method, while pathological changes in the liver and jejunum were observed via hematoxylin and eosin stain, and a fluorescence spectrophotometer was used to evaluate intestinal permeability. Tight junction (TJ)-related and toll-like receptor (TLR) signaling-related pathway genes and proteins were tested using quantitative polymerase chain reaction, western blotting, immunohistochemistry, and 16S ribosomal ribonucleic acid gene-targeted sequencing of jejunum microorganisms. Se deficiency significantly decreased glutathione peroxidase activity and disrupted the intestinal flora, with the most significant effect being a decrease in Lactobacillus reuteri. The expression of TJ-related genes and proteins decreased significantly with increased treatment time, whereas supplementation with Se, fecal microbiota transplantation, or L. reuteri reversed these decreases. Signs of liver injury and LPS content were significantly increased after intestinal flora imbalance or jejunum injury, and the levels of TLR signaling-related genes were significantly increased. The results indicated that Se deficiency disrupted the microbiota balance, decreased the expression of intestinal TJ factors, and increased intestinal permeability. By contrast, LPS increased due to a bacterial imbalance, which may induce inflammatory liver injury via the TLR4 signaling pathway.

Association between Troponin Elevation and Decreased Myocardial Blood Flow Reserve in Patients without Obstructive Coronary Artery Disease.

INTRODUCTION: To study the prognostic factors of patients with chest pain and without obstructive coronary artery disease is of great significance for the management of such patients. We assessed whether a high-sensitivity troponin I (hs-TnI) is associated with prognosis in patients with chest pain and without obstructive coronary artery disease. METHODS: From 2011 to 2017, 489 consecutively hospitalized patients with chest pain and without significant coronary artery stenosis (<50%) were tested for hs-TnI and underwent stress myocardial contrast echocardiography (MCE). Myocardial blood flow reserve (MBFR) was measured by stress MCE. Patients were followed (median, 41 months) for composite endpoints, including cardiovascular death and non-fatal myocardial infarction. Cox proportional hazards models were performed to determine associations between hs-TnI and the composite endpoints. RESULTS: Among 489 patients with chest pain and without significant coronary artery stenosis, 257 patients (52.6%) had elevated hs-TnI. Compared to patients with normal hs-TnI, patients with elevated hs-TnI were older (p = 0.013) and had a higher prevalence of atrial fibrillation (p = 0.003), higher left ventricular mass index (p = 0.002) and E/e' septal (p < 0.001), and a lower MBFR (p < 0.001). After adjustment, there was still a significant association between hs-TnI and MBFR (odds ratio = 1.145; 95% confidence interval [CI], 1.079-1.214; p < 0.001). Compared with patients with normal hs-TnI, patients with elevated hs-TnI had a greater cumulative event rate (log-rank p = 0.002). Males (hazard ratio [HR], 4.770; 95% CI, 1.175-19.363; p = 0.029) and reduced MBFR (HR, 2.496; 95% CI, 1.446-4.311; p = 0.001) were risk factors associated with composite endpoints in patients with elevated hs-TnI. CONCLUSIONS: In patients with chest pain and without obstructive coronary artery disease, elevated hs-TnI is associated with decreased myocardial perfusion by contrast echocardiography as well as a higher incidence of cardiovascular events.

Fabrication of antimicrobial and high-toughness poly (lactic acid) composite films using tung oil derivatives.

Tung oil derivatives are promising alternatives to traditional toxic plasticizers for improving the toughness of poly (lactic acid) (PLA) films. In this study, a tung oil-based quaternary ammonium salt (Q-ETO) was synthesized using a multi-step process involving epoxidation, ring opening, and substitution reactions. PLA based composite films with various amounts of Q-ETO were prepared by solvent casting. The impact of various amount of Q-ETO on PLA/Q-ETO composite films were evaluated with regard to their mechanical properties, hydrophilicity, water vapor permeability, optical properties, thermal stability, antibacterial properties, and leaching properties. The PLA/5%Q-ETO composite film yielded the highest elongation at break (82.52 ± 9.53 %), which was 153.67 % higher than that of pure PLA. All PLA composite films showed an antibacterial efficiency exceeding 90 % against both S. aureus and E. coli. Moreover, the PLA/Q-ETO composite film blocked the transmission of both ultraviolet and visible light while preventing the permeation of water vapor. The addition of Q-ETO only weakly affected the color and thermal stability of the PLA/Q-ETO composite film. Given the numerous advantages of the PLA composite film, it has significant potential for application as a food packaging material.

Melatonin and Its Metabolites Can Serve as Agonists on the Aryl Hydrocarbon Receptor and Peroxisome Proliferator-Activated Receptor Gamma.

Melatonin is widely present in Nature. It has pleiotropic activities, in part mediated by interactions with high-affinity G-protein-coupled melatonin type 1 and 2 (MT1 and MT2) receptors or under extreme conditions, e.g., ischemia/reperfusion. In pharmacological concentrations, it is given to counteract the massive damage caused by MT1- and MT2-independent mechanisms. The aryl hydrocarbon receptor (AhR) is a perfect candidate for mediating the latter effects because melatonin has structural similarity to its natural ligands, including tryptophan metabolites and indolic compounds. Using a cell-based Human AhR Reporter Assay System, we demonstrated that melatonin and its indolic and kynuric metabolites act as agonists on the AhR with EC50's between 10-4 and 10-6 M. This was further validated via the stimulation of the transcriptional activation of the CYP1A1 promoter. Furthermore, melatonin and its metabolites stimulated AhR translocation from the cytoplasm to the nucleus in human keratinocytes, as demonstrated by ImageStream II cytometry and Western blot (WB) analyses of cytoplasmic and nuclear fractions of human keratinocytes. These functional analyses are supported by in silico analyses. We also investigated the peroxisome proliferator-activated receptor (PPAR)γ as a potential target for melatonin and metabolites bioregulation. The binding studies using a TR-TFRET kit to assay the interaction of the ligand with the ligand-binding domain (LBD) of the PPARγ showed agonistic activities of melatonin, 6-hydroxymelatonin and N-acetyl-N-formyl-5-methoxykynuramine with EC50's in the 10-4 M range showing significantly lower affinities that those of rosiglitazone, e.g., a 10-8 M range. These interactions were substantiated by stimulation of the luciferase activity of the construct containing PPARE by melatonin and its metabolites at 10-4 M. As confirmed by the functional assays, binding mode predictions using a homology model of the AhR and a crystal structure of the PPARγ suggest that melatonin and its metabolites, including 6-hydroxymelatonin, 5-methoxytryptamine and N-acetyl-N-formyl-5-methoxykynuramine, are excellent candidates to act on the AhR and PPARγ with docking scores comparable to their corresponding natural ligands. Melatonin and its metabolites were modeled into the same ligand-binding pockets (LBDs) as their natural ligands. Thus, functional assays supported by molecular modeling have shown that melatonin and its indolic and kynuric metabolites can act as agonists on the AhR and they can interact with the PPARγ at high concentrations. This provides a mechanistic explanation for previously reported cytoprotective actions of melatonin and its metabolites that require high local concentrations of the ligands to reduce cellular damage under elevated oxidative stress conditions. It also identifies these compounds as therapeutic agents to be used at pharmacological doses in the prevention or therapy of skin diseases.

Protocol of a multicenter, single-blind, randomized, parallel controlled trial evaluating the effect of microbiological rapid on-site evaluation (M-ROSE) guiding anti-infection treatment in patients with severe hospital-acquired pneumonia.

INTRODUCTION: The mortality rate of hospitalized patients with severe hospital-acquired pneumonia (SHAP) remains high. Empirical broad-spectrum antibiotic coverage and the misuse of high-grade antibiotics could lead to the emergence of multi-drug and even pandrug-resistant bacteria. In addition to metagenomic next-generation sequencing (mNGS), microbiological rapid on-site evaluation (M-ROSE) might be a useful technique to identify the pathogens in the early stage; however, the effect of M-ROSE guiding anti-infection treatment on prognostic outcomes of SHAP patients is still unclear. METHODS/DESIGN: This is a multicenter, single-blind, prospective, randomized controlled trial to evaluate the effect of M-ROSE guiding anti-infection treatment in SHAP patients, which will provide new strategies for the prevention and control of clinical multi-drug resistance bacteria. A total of 166 patients with SHAP, aged 18 years and over, will be recruited from seven centers in Beijing and randomly assigned to the intervention group (M-ROSE combined with mNGS) or the control group (mNGS only) in a 1:1 ratio using the central randomization system. Patients in the intervention group will accept M-ROSE and mNGS analysis, and the control group will accept mNGS analysis. Individualized anti-infective treatment and routine treatment will be selected according to the analysis results. The primary outcome is the ICU outcome (mortality). The safety of the intervention measures will be evaluated during the entire trial period. This trial will be the first randomized controlled trial to evaluate the effect of M-ROSE guiding treatment on mortality in patients with SHAP and may change the prevalence of multi-drug resistant bacteria. ETHICS AND DISSEMINATION: This trial adheres to the Declaration of Helsinki and guidelines of Good Clinical Practice. Signed informed consent will be obtained from all participants. The trial has been approved by the Chinese PLA General Hospital (Approval Number: 20220322001). TRIAL REGISTRATION: ClinicalTrials.gov NCT05300776. Registered on 25 March 2022.

RNA-cleaving DNAzymes for accurate biosensing and gene therapy.

RNA-cleaving DNAzymes, which are single-stranded catalytic DNA, have attracted considerable attention in bioanalysis and biomedical applications because of their high stability, high catalytic activity, easy synthesis, easy functionalization, and modification. By incorporating these DNAzymes with amplification systems, the sensing platforms can be used to detect a series of targets with high sensitivity and selectivity. In addition, these DNAyzmes possess therapeutic potential by cutting the mRNA in cells and viruses to regulate the expression of the corresponding proteins. This review systematically summarizes the applications of RNA-cleaving DNAzymes in recent years, explaining the uniqueness and superiority of RNA-cleaving DNAzymes in biosensing and gene therapy. Finally, this review extends the discussion to the challenges and perspectives of applying RNA-cleaving DNAzyme as a diagnostic and therapeutic agent. This review provides the researchers with valuable suggestions and promotes the development of DNAzymes for accurate analysis, early diagnosis, and effective therapy in medicine and their broader applications beyond biomedicine.

The role of hormones in the pathogenesis and treatment mechanisms of delirium in ICU: The past, the present, and the future.

Delirium is an acute brain dysfunction. As one of the common psychiatric disorders in ICU, it can seriously affect the prognosis of patients. Hormones are important messenger substances found in the human body that help to regulate and maintain the function and metabolism of various tissues and organs. They are also one of the most commonly used drugs in clinical practice. Recent evidences suggest that aberrant swings in cortisol and non-cortisol hormones might induce severe cognitive impairment, eventually leading to delirium. However, the role of hormones in the pathogenesis of delirium still remains controversial. This article reviews the recent research on risk factors of delirium and the association between several types of hormones and cognitive dysfunction. These mechanisms are expected to offer novel ideas and clinical relevance for the treatment and prevention of delirium.

Adaptive Changes in Detoxification Metabolism and Transmembrane Transport of Bombyx mori Malpighian Tubules to Artificial Diet.

The high adaptability of insects to food sources has contributed to their ranking among the most abundant and diverse species on Earth. However, the molecular mechanisms underlying the rapid adaptation of insects to different foods remain unclear. We explored the changes in gene expression and metabolic composition of the Malpighian tubules as an important metabolic excretion and detoxification organ in silkworms (Bombyx mori) fed mulberry leaf and artificial diets. A total of 2436 differentially expressed genes (DEGs) and 245 differential metabolites were identified between groups, with the majority of DEGs associated with metabolic detoxification, transmembrane transport, and mitochondrial function. Detoxification enzymes, such as cytochrome P450 (CYP), glutathione-S-transferase (GST), and UDP-glycosyltransferase, and ABC and SLC transporters of endogenous and exogenous solutes were more abundant in the artificial diet group. Enzyme activity assays confirmed increased CYP and GST activity in the Malpighian tubules of the artificial diet-fed group. Metabolome analysis showed increased contents of secondary metabolites, terpenoids, flavonoids, alkaloids, organic acids, lipids, and food additives in the artificial diet group. Our findings highlight the important role of the Malpighian tubules in adaptation to different foods and provide guidance for further optimization of artificial diets to improve silkworm breeding.

CD34+ cell-derived fibroblast-macrophage cross-talk drives limb ischemia recovery through the OSM-ANGPTL signaling axis.

CD34+ cells improve the perfusion and function of ischemic limbs in humans and mice. However, there is no direct evidence of the differentiation potential and functional role of these cells in the ischemic muscle microenvironment. Here, we combined the single-cell RNA sequencing and genetic lineage tracing technology, then provided exact single-cell atlases of normal and ischemic limb tissues in human and mouse, and consequently found that bone marrow (BM)-derived macrophages with antigen-presenting function migrated to the ischemic site, while resident macrophages underwent apoptosis. The macrophage oncostatin M (OSM) regulatory pathway was specifically turned on by ischemia. Simultaneously, BM CD34+-derived proregenerative fibroblasts were recruited to the ischemia niche, where they received macrophage-released OSM and promoted angiopoietin-like protein-associated angiogenesis. These findings provided mechanisms on the cellular events and cell-cell communications during tissue ischemia and regeneration and provided evidence that CD34+ cells serve as fibroblast progenitors promoting tissue regeneration.

B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis.

Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (ß2GPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-ß2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.

Selenium Deficiency via the ROS/NLRP3/IL-1ß Signaling Pathway Leads to Pyroptosis Injury in Pig Spleen.

The aim of the present study was to investigate the effect of selenium (Se) deficiency on the relationship between the pyroptosis and MAPK signaling pathway in spleen injury. A total of 10 two-month-old Sus scrofa domesticus specimens were allocated to two groups. The control group was fed a basal diet (0.15-mg/kg Se), and the experimental group was fed a 0.03-mg/kg Se-deficient diet for 2 months. The pig-spleen histopathological changes were observed with hematoxylin-eosin staining. Frozen sections were prepared to detect the content of ROS in pig-spleen cells. The oxidation stress related indexes were determined using a spectrophotometer. The levels of pyroptosis- and MAPK signaling pathway-related factors were detected via quantitative real-time polymerase chain reaction (qPCR) and western blotting (WB). The results of sections showed that the lymphocytes decreased in number, the spacing of cells widened, and some cells were necrotic in the spleen tissue of pigs fed a low-selenium diet. The content of ROS, malondialdehyde, nitric oxide, H2O2, and catalase activity in the low-selenium group was significantly higher than that in the control group, and SOD activity was decreased. The protein-ratio-levels of p-Nrf2 to Nrf2 were decreased. The expression levels of nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3), IL-1ß, IL-18, ASC, gasdermin D, and caspase-1, the protein-ratio-levels of p-AKT serine/threonine kinase (p-AKT) to AKT, p-extracellular regulated protein kinases (ERK) to ERK, p-P38 MAPK to p-P38, and p-c-Jun N-terminal kinase (p-JNK) to JNK were significantly increased in the Se-deficient group compared with the control group. These results suggested that Se deficiency can induce oxidant stress, which increases pyroptosis- and inflammation-related factors of pig-spleen injury.

Gene Fusion Detection and Characterization in Long-Read Cancer Transcriptome Sequencing Data with FusionSeeker.

Gene fusions are prevalent in a wide array of cancer types with different frequencies. Long-read transcriptome sequencing technologies, such as PacBio, Iso-Seq, and Nanopore direct RNA sequencing, provide full-length transcript sequencing reads, which could facilitate detection of gene fusions. In this work, we developed a method, FusionSeeker, to comprehensively characterize gene fusions in long-read cancer transcriptome data and reconstruct accurate fused transcripts from raw reads. FusionSeeker identified gene fusions in both exonic and intronic regions, allowing comprehensive characterization of gene fusions in cancer transcriptomes. Fused transcript sequences were reconstructed with FusionSeeker by correcting sequencing errors in the raw reads through partial order alignment algorithm. Using these accurate transcript sequences, FusionSeeker refined gene fusion breakpoint positions and predicted breakpoints at single bp resolution. Overall, FusionSeeker will enable users to discover gene fusions accurately using long-read data, which can facilitate downstream functional analysis as well as improved cancer diagnosis and treatment. SIGNIFICANCE: FusionSeeker is a new method to discover gene fusions and reconstruct fused transcript sequences in long-read cancer transcriptome sequencing data to help identify novel gene fusions important for tumorigenesis and progression.