Disrupting circadian control of autophagy induces podocyte injury and proteinuria.

The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by Earth's rotation. The kidney clock plays an important role in maintaining tubular function, but its effect on podocytes remains unclear. Here, we found that podocytes expressed CLOCK proteins, and that 2666 glomerular gene transcripts (13.4%), including autophagy related genes, had 24-hour circadian rhythms. Deletion of Clock in podocytes resulted in 1666 gene transcripts with the loss of circadian rhythm including autophagy genes. Podocyte-specific Clock knockout mice at age three and eight months showed deficient autophagy, loss of podocytes and increased albuminuria. Chromatin immunoprecipitation (ChIP) sequence analysis indicated autophagy related genes were targets of CLOCK in podocytes. ChIP-PCR further confirmed Clock binding to the promoter regions of Becn1 and Atg12, two autophagy related genes. Furthermore, the association of CLOCK regulated autophagy with chronic sleep fragmentation and diabetic kidney disease was analyzed. Chronic sleep fragmentation resulted in the loss of glomerular Clock rhythm, inhibition of podocyte autophagy, and proteinuria. Rhythmic oscillations of Clock also disappeared in high glucose treated podocytes and in glomeruli from diabetic mice. Finally, circadian differences in podocyte autophagy were also abolished in diabetic mice. Deletion Clock in podocytes aggravated podocyte injury and proteinuria in diabetic mice. Thus, our findings demonstrate that clock-dependent regulation of autophagy may be essential for podocyte survival. Hence. loss of circadian controlled autophagy may play an important role in podocyte injury and proteinuria.

Associations of Intracranial Artery Length and Branch Number on Time-of-Flight MRA With Cognitive Impairment in Hypertensive Older Males.

BACKGROUND: Hypertension-induced impairment of the cerebral artery network contributes to cognitive impairment. Characterizing the structure and function of cerebral arteries may facilitate the understanding of hypertension-related pathological mechanisms and lead to the development of new indicators for cognitive impairment. PURPOSE: To investigate the associations between morphological features of the intracranial arteries distal to the circle of Willis on time-of-flight MRA (TOF-MRA) and cognitive performance in a hypertensive cohort. STUDY TYPE: Prospective observational study. POPULATION: 189 hypertensive older males (mean age 64.9 ± 7.2 years). FIELD STRENGTH/SEQUENCE: TOF-MRA sequence with a 3D spoiled gradient echo readout and arterial spin labeling perfusion imaging sequence with a 3D stack-of-spirals fast spin echo readout at 3T. ASSESSMENT: The intracranial arteries were segmented from TOF-MRA and the total length of distal arteries (TLoDA) and number of arterial branches (NoB) were calculated. The mean gray matter cerebral blood flow (GM-CBF) was extracted from arterial spin labeling perfusion imaging. The cognitive level was assessed with short-term and long-term delay-recall auditory verbal learning test (AVLT) scores, and with montreal cognitive assessment. STATISTICAL TESTS: Univariable and multivariable linear regression were used to analyze the associations between TLoDA, NoB, GM-CBF and the cognitive assessment scores, with P < 0.05 indicating significance. RESULTS: TLoDA (r = 0.314) and NoB (r = 0.346) were significantly correlated with GM-CBF. Multivariable linear regression analyses showed that TLoDA and NoB, but not GM-CBF (P = 0.272 and 0.141), were significantly associated with short-term and long-term delay-recall AVLT scores. These associations remained significant after adjusting for GM-CBF. DATA CONCLUSION: The TLoDA and NoB of distal intracranial arteries on TOF-MRA are significantly associated with cognitive impairment in hypertensive subjects. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.

Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.

Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

Structure-activity relationship and biofilm formation-related gene targets of oleanolic acid-type saponins from Pulsatilla chinensis against Candida albicans.

In the course of our investigations of antifungal natural products, the structure-activity relationship and antifungal activities of oleanolic acid-type saponins (1-28) from Pulsatilla chinensis against human and plant pathogenic fungi were elucidated. The analysis of structure-activity relationship of oleanolic acid-type saponins showed that the free carboxyl at C-28 was essential for their antifungal activities; the free hydroxyl group at the C-23 site of oleanolic acid-type saponins played a crucial role in their antifungal activities; the oligosaccharide chain at C-3 oleanolic acid-type saponins showed significant effects on antifungal efficacy and a disaccharide or trisaccharide moiety at position C-3 displayed optimal antifungal activity. The typical saponin pulchinenoside B3 (16, PB3) displayed satisfactory antifungal activity against human and plant pathogenic fungi, especially, C. albicans with an MIC value of 12.5 µg/mL. Furthermore, PB3 could inhibit the biofilm formation of C. albicans through downregulating the expression of the integrated network of biofilm formation-associated transcription factors (Bcr1 Efg1, Ndt80, Brg1, Rob1 and Tec1) and adhesion-related target genes (HWP1, ALS1, and ALS3). Meanwhile, we found that PB3 could effectively destroy the mature biofilm of C. albicans by the oxidative damage and inducing mitochondria-mediated apoptosis in cells.

The association between monocyte to high-density lipoprotein cholesterol ratio and chronic kidney disease in a Chinese adult population: a cross-sectional study.

BACKGROUND: Monocyte to high-density lipoprotein cholesterol ratio (MHR) was confirmed as a novel inflammatory marker and strongly associated with the risk of several diseases. This study aimed to investigate the relationship between MHR and chronic kidney disease (CKD) in a Chinese adult population. METHODS: In this cross-sectional study, 232,775 community-dwelling adults in Binhai who completed health checkups in 2021 were enrolled. Participants were categorized based on the MHR quartiles. Clinical characteristics of participants across different groups were compared using one-way ANOVA, Kruskal-Wallis h-test, and Chi-squared test as appropriate. Univariate and multivariable logistic regression analyses were taken to assess the relationship between MHR and the presence of CKD, as well as its association with low estimated glomerular filtration rate (eGFR) and proteinuria. Subgroup analyses were further executed to confirm the reliability of this relationship. RESULTS: A total of 21,014 (9.0%) individuals were diagnosed with CKD. Characteristic indicators including waist circumference, body mass index (BMI), blood pressure (BP), serum uric acid (SUA), triglyceride, and fasting blood glucose (FBG) showed a gradual increase with higher MHR quartiles, whereas parameters such as age, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and eGFR decreased (p < .001). In the multivariable logistic regression analysis, we observed independent associations between MHR (per 1 SD increase) and CKD, as well as low eGFR and proteinuria, with odds ratio (ORs) and 95% confidence intervals (95%CIs) of 1.206 (1.186-1.225), 1.289 (1.260-1.319), and 1.150 (1.129-1.171), respectively (p < .001). Similar conclusions were confirmed in subgroup analysis stratified by gender, age, BMI, central obesity, hypertension, and diabetes mellitus, after justification for confounding factors. CONCLUSION: Elevated MHR level was independently associated with the presence of CKD, suggesting that it might serve as a useful clinical tool for risk stratification, offering valuable insights to inform preventive and therapeutic approaches for clinicians in their routine medical practice.

Safety and effectiveness of laparoscopic renal biopsy: a single-center review and meta-analysis.

BACKGROUND: While renal biopsy remains the preferred diagnostic method for assessing proteinuria, hematuria, or renal failure, laparoscopic renal biopsy (LRB) can serve as an alternative for high-risk patients when percutaneous kidney biopsy (PKB) is not recommended. This study was aimed to evaluate the safety of LRB. METHODS: In study 1, Fourteen patients from January 2021 to January 2023 had a LRB taken for various indications, such as morbid obesity, abnormal kidney construction, uncontrolled hypertension, and coagulopathy. We also conducted a Meta-analysis of the success rate and complication rate of previous LRB in study 2. RESULTS: All the patients completed biopsies and adequate renal tissues were obtained. The success rate was 100%. The median number of glomeruli obtained was 22.5 (range:12.0, 45.0). The complication rate was 7.1% (urinary tract infection). There were no significant differences between levels of hemoglobin, serum creatinine, and urinary NAGL before and after surgery. In the meta-analysis, the success rate of operation, satisfactory rate of sample, and complication rate of surgery were 99.9%, 99.1%, and 2.6% respectively. CONCLUSION: LRB can achieve a good success rate and specimen retrieval and does not increase the risk of complications for high-risk patients. It can present as one of the alternative methods for patients with glomerular diseases.

A natural promoter variation of SlBBX31 confers enhanced cold tolerance during tomato domestication.

Cold stress affects crop growth and productivity worldwide. Understanding the genetic basis of cold tolerance in germplasms is critical for crop improvement. Plants can coordinate environmental stimuli of light and temperature to regulate cold tolerance. However, it remains unknown which gene in germplasms could have such function. Here, we utilized genome-wide association study (GWAS) to investigate the cold tolerance of wild and cultivated tomato accessions and discovered that increased cold tolerance is accompanied with tomato domestication. We further identified a 27-bp InDel in the promoter of the CONSTANS-like transcription factor (TF) SlBBX31 is significantly linked with cold tolerance. Coincidentally, a key regulator of light signalling, SlHY5, can directly bind to the SlBBX31 promoter to activate SlBBX31 transcription while the 27-bp InDel can prevent S1HY5 from transactivating SlBBX31. Parallel to these findings, we observed that the loss of function of SlBBX31 results in impaired tomato cold tolerance. SlBBX31 can also modulate the cold-induced expression of several ERF TFs including CBF2 and DREBs. Therefore, our study has uncovered that SlBBX31 is possibly selected during tomato domestication for cold tolerance regulation, providing valuable insights for the development of hardy tomato varieties.

Solid-liquid-gas reaction accelerated by gas molecule tunnelling-like effect.

Solid-liquid-gas reactions are ubiquitous and are encountered in both nature and industrial processes1-4. A comprehensive description of gas transport in liquid and following reactions at the solid-liquid-gas interface, which is substantial in regard to achieving enhanced triple-phase reactions, remains unavailable. Here, we report a real-time observation of the accelerated etching of gold nanorods with oxygen nanobubbles in aqueous hydrobromic acid using liquid-cell transmission electron microscopy. Our observations reveal that when an oxygen nanobubble is close to a nanorod below the critical distance (~1 nm), the local etching rate is significantly enhanced by over one order of magnitude. Molecular dynamics simulation results show that the strong attractive van der Waals interaction between the gold nanorod and oxygen molecules facilitates the transport of oxygen through the thin liquid layer to the gold surface and thus plays a crucial role in increasing the etching rate. This result sheds light on the rational design of solid-liquid-gas reactions for enhanced activities.

Alkaline α-galactosidase 2 (CsAGA2) plays a pivotal role in mediating source-sink communication in cucumber.

Sugars are necessary for plant growth and fruit development. Cucumber (Cucumis sativus L.) transports sugars, mainly raffinose family oligosaccharides (RFOs), in the vascular bundle. As the dominant sugars in cucumber fruit, glucose and fructose are derived from sucrose, which is the product of RFO hydrolysis by α-galactosidase (α-Gal). Here, we characterized the cucumber alkaline α-galactosidase 2 (CsAGA2) gene and found that CsAGA2 has undergone human selection during cucumber domestication. Further experiments showed that the expression of CsAGA2 increases gradually during fruit development, especially in fruit vasculature. In CsAGA2-RNA interference (RNAi) lines, fruit growth was delayed because of lower hexose production in the peduncle and fruit main vascular bundle (MVB). In contrast, CsAGA2-overexpressing (OE) plants displayed bigger fruits. Functional enrichment analysis of transcriptional data indicated that genes related to sugar metabolism, cell wall metabolism, and hormone signaling were significantly downregulated in the peduncle and fruit MVBs of CsAGA2-RNAi plants. Moreover, downregulation of CsAGA2 also caused negative feedback regulation on source leaves, which was shown by reduced photosynthetic efficiency, fewer plasmodesmata at the surface between mesophyll cell and intermediary cell (IC) or between IC and sieve element, and downregulated gene expression and enzyme activities related to phloem loading, as well as decreased sugar production and exportation from leaves and petioles. The opposite trend was observed in CsAGA2-OE lines. Overall, we conclude that CsAGA2 is essential for cucumber fruit set and development through mediation of sugar communication between sink strength and source activity.

SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney.

Large clinical trials and real-world studies have demonstrated that the beneficial effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal outcomes regardless of the presence of diabetes. However, the mechanism remains obscure. Here, we analyze the anti-fibrotic and anti-inflammatory effects of dapagliflozin, a SGLT2 inhibitor, on renal alternations using the ischemia/reperfusion-induced fibrosis model. Transcriptome and metabolome analysis showed that the accumulation of tricarboxylic acid (TCA) cycle metabolites and upregulation of inflammation in fibrosis renal cortical tissue were mitigated by dapagliflozin treatment. Moreover, dapagliflozin markedly relieved the activation of mammalian target of rapamycin and hypoxia inducible factor-1α signaling and restored tubular cell-preferred fatty acid oxidation. Notably, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation was strikingly blocked by dapagliflozin. We further demonstrated that the immunomodulatory metabolite itaconate derived from the TCA cycle was significantly boosted as a result of decreased isocitrate dehydrogenase 2 and increased immune-responsive gene 1 and mitochondrial citrate carrier in dapagliflozin-treated mice, which contributed to the inhibitory effect of dapagliflozin on NLRP3 inflammasome activation. Furthermore, administration of cell-permeable itaconate surrogate prevented activation of NLRP3 inflammasome and protected kidney against fibrosis development. Our results identify a novel mechanism coupling metabolism and inflammation for kidney benefits of SGLT2 inhibition in progressive chronic kidney disease.

A hydrochemical and isotopic approach for source identification and health risk assessment of groundwater arsenic pollution in the central Yinchuan basin.

Arsenic contamination of groundwater is becoming a major global issue as it can severely affect the safety of drinking water and human health. In this paper, 448 water samples were investigated to study the spatiotemporal distribution, source identification and human health risk of groundwater arsenic pollution in the central Yinchuan basin by applying a hydrochemical and isotopic approach. The results showed that arsenic concentrations in groundwater ranged from 0.7 µg/L to 26 µg/L with a mean of 2.19 µg/L, and 5.9% of samples were above 5 µg/L, indicating the arsenic pollution of groundwater in the study area. High arsenic groundwater was mainly distributed in the northern and eastern areas along the Yellow river. The main hydrochemistry type of high arsenic groundwater was HCO3·SO4-Na·Mg, and the dissolution of arsenic-bearing minerals in sediment, irrigation water infiltration and aquifer recharge from the Yellow river were the main sources of arsenic in groundwater. The arsenic enrichment was dominantly controlled by the TMn redox reaction and the competitive adsorption of HCO3-, and the influence of anthropogenic activities was limited. The health risk assessment suggested that the carcinogenic risk of As for children and adults greatly exceeded the acceptable risk threshold of 1E-6, displaying a high carcer risk, while the non-carcinogenic risks of As, F-, TFe, TMn and NO3- in 2019 were largely higher than the acceptable risk threshold (HQ > 1). The present study provides insight into the occurrence, hydrochemical processes and potential health risk of arsenic pollution in groundwater.

Development and properties evaluation of multi-strain probiotic with cholesterol-lowering potential in vitro.

Probiotics have a cholesterol-lowering effect. Multi-strain probiotics (MSPs) outperformed single-strain probiotics due to the interaction of strains. Hence, we expect to develop a high-efficiency MSP for lowering cholesterol. Three strains, including Lactobacillus caseiS1, Enterococcus faeciumS4, and L. harbinensisS6, were used to develop the MSPs. To evaluate their effect, gastrointestinal tolerance, bile salt hydrolase (BSH) activity, cholesterol-lowering rate, antioxidant ability, gamma-aminobutyric acid (GABA) production, and antibiotic sensitivity were determined. The triple lactic acid bacteria probiotic (TLP) was the most efficient one. After 24 h treatment with artificial gastric fluid, 47.88% of TLP survived. TLP exhibited the highest BSH activity (149.40 U·ml-1) and cholesterol-lowering rate (75.05%) in vitro, with co-precipitation reducing the majority of cholesterol. The reducing power and superoxide radical scavenging rate of the cell-free supernatant and the hydroxyl radical scavenging rate in viable cells were 1.52, 85.03%, and 89.66%, respectively, and the GABA production was 0.67 mg·ml-1, which enhanced the health benefit effects. By fuzzy mathematical analysis, TLP was the optimal probiotic and was competitive with commercial probiotics. The three strains were susceptible to 13 antibiotics. Therefore, TLP has the potential to develop into a cholesterol-lowering probiotic preparation.

Genome-wide association study of eigenvectors provides genetic insights into selective breeding for tomato metabolites.

BACKGROUND: Long-term domestication and intensive breeding of crop plants aim to establish traits desirable for human needs, and characteristics related to yield, disease resistance, and postharvest storage have traditionally received considerable attention. These processes have led also to negative consequences, as is the case of loss of variants controlling fruit quality, for instance in tomato. Tomato fruit quality is directly associated to metabolite content profiles; however, a full understanding of the genetics affecting metabolite content during tomato domestication and improvement has not been reached due to limitations of the single detection methods previously employed. Here, we aim to reach a broad understanding of changes in metabolite content using a genome-wide association study (GWAS) with eigenvector decomposition (EigenGWAS) on tomato accessions. RESULTS: An EigenGWAS was performed on 331 tomato accessions using the first eigenvector generated from the genomic data as a "phenotype" to understand the changes in fruit metabolite content during breeding. Two independent gene sets were identified that affected fruit metabolites during domestication and improvement in consumer-preferred tomatoes. Furthermore, 57 candidate genes related to polyphenol and polyamine biosynthesis were discovered, and a major candidate gene chlorogenate: glucarate caffeoyltransferase (SlCGT) was identified, which affected the quality and diseases resistance of tomato fruit, revealing the domestication mechanism of polyphenols. CONCLUSIONS: We identified gene sets that contributed to consumer liking during domestication and improvement of tomato. Our study reports novel evidence of selective sweeps and key metabolites controlled by multiple genes, increasing our understanding of the mechanisms of metabolites variation during those processes. It also supports a polygenic selection model for the application of tomato breeding.

Increased thoracic fluid content is associated with higher risk for pneumonia in patients undergoing maintenance hemodialysis.

BACKGROUND: Pneumonia is the most common infectious disease in patients undergoing maintenance hemodialysis (MHD). The aim of this study is to determine the possible predictive value of thoracic fluid content (TFC) for pneumonia in this population. METHOD: Clinical data were recorded for 1412 MHD patients who were hospitalized for certain comorbidities or complications. Each patient underwent an impedance cardiography (ICG) examination before next dialysis session after admission. Patients were divided into Having-, Will-have-, and Non-pneumonia groups based on whether they had pneumonia at the time of ICG examination after the admission and within five months after the examination. Hemodynamic parameters and other clinical data were compared and analyzed. RESULTS: Patients who were going to develop pneumonia were older, and had a higher proportion of diabetes, poorer nutritional status, a higher level of inflammatory, poorer cardiac function, and more fluid volume load than those who did not develop pneumonia. Multivariate binary logistic analysis revealed that for each 1/KΩ increase in TFC and 1 increase in neutrophil-to-lymphocyte ratio (NLR), the risk of the development of pneumonia increased by 3.1% (p ˂ 0.01) and 7.2% (p = 0.035), respectively, whereas for each 1 g/L increase in hemoglobin and 1 g/L increase in serum albumin, the risk of the development of pneumonia decreased by 1.3% (p = 0.034) and 5% (p = 0.048), respectively. CONCLUSIONS: TFC, NLR, hemoglobin, and serum albumin were independent risk factors for the development of pneumonia in MHD patients. Given the advantages of ICG, TFC can be used clinically as a helpful predictor of pneumonia in MHD patients.

Association between sleep quality and cardiovascular disease in maintenance hemodialysis patients: a prospective cohort study.

OBJECTIVE: This study aimed to analyze the association between sleep quality and cardiovascular disease in patients on maintenance hemodialysis (MHD). METHODS: A total of 601 patients with MHD in the second affiliated hospital of Nanjing Medical University, were prospectively enrolled in this cohort study from January 2019 to December2019. The global Pittsburgh sleep quality index (PSQI) score > 7 indicates that a person with poor sleep quality. Patients were divided into two groups according to the PSQI score. Follow-up was conducted about 3 years with all-cause death and major adverse cardiovascular events (MACEs) as the endpoint events. RESULTS: Of the 601 patients, 595 patients completed the PSQI assessment, with 278 patients having poor sleep quality. Patients in the PSQI > 7 group were older and had a higher proportion of cardiovascular disease or diabetes. Years of education, diastolic blood pressure, and heart rate were lower in the PSQI > 7 group. At a mean follow-up period of 3 years, 116 patients died, 64 patients were lost to follow-up, and 115 patients experienced MACEs. After adjusting for confounding factors such as age, gender, dialysis age, and previous cardiovascular disease, the risk of MACE in patients with poor sleep quality was twice that of patients with good sleep quality (HR = 2.037 (1.339, 3.097), p = 0.001). There was no significant difference in the risk of all-cause death between the two groups. CONCLUSION: The prevalence of poor sleep quality was 46.7% in patients with MHD. Poor sleep quality was an independent risk factor for MACEs in patients with MHD.

Transcriptome Mechanisms of Tomato Seedlings Induced by Low-Red to Far-Red Light Ratio under Calcium Nitrate Stress.

In recent times, the excessive accumulation of nitrate has been one of the main reasons for the secondary salinization of greenhouse soils. Light plays a key role in a plant's growth, development, and response to stress. A low-red to far-red (R:FR) light ratio could enhance plant salinity tolerance, but the mechanism at a molecular level is unclear. Thus, we analyzed the transcriptome responses of tomato seedlings to calcium nitrate stress under either a low R:FR ratio (0.7) or normal light conditions. Under calcium nitrate stress, a low R:FR ratio enhanced both the antioxidant defense system and the rapid physiological accumulation of proline in tomato leaves, which promoted plant adaptability. Using weighted gene co-expression network analysis (WGCNA), three modules including 368 differentially expressed genes (DEGs) were determined to be significantly associated with these plant traits. Functional annotations showed that the responses of these DEGs to a low R:FR ratio under excessive nitrate stress were enriched in the areas of hormone signal transduction, amino acid biosynthesis, sulfide metabolism, and oxidoreductase activity. Furthermore, we identified important novel hub genes encoding certain proteins, including FBNs, SULTRs, and GATA-like transcription factor, which may play a vital role in low R:FR light-induced salt responses. These findings offer a new perspective on the mechanisms and environmental implications behind low R:FR ratio light-modulated tomato saline tolerance.

Novel lanthanum-iron oxide nanoparticles alleviate the inhibition of anaerobic digestion by carbamazepine through adsorption and bioaugmentation.

Several reports have shown that pharmaceuticals and personal care products (PPCPs) have some negative effects on anaerobic digestion (AD), yet there are no convenient and efficient strategies for mitigating the adverse influences. The typical PPCPs of carbamazepine have a strong negative effect on lactic acid AD process. Therefore, in this work, novel lanthanum-iron oxide (LaFeO3) nanoparticles (NPs) were used for adsorption and bioaugmentation to weak the negative effects of carbamazepine. The adsorption removal of carbamazepine increased from 0 to 44.30% as the dosage of LaFeO3 NPs was increased from 0 to 200 mg/L, providing the necessary prerequisites for bioaugmentation. Adsorption reduced the probability of direct contact between carbamazepine and anaerobes, partly alleviating the inhibition of carbamazepine on microbes. The highest methane (CH4) yield induced by LaFeO3 NPs (25 mg/L) was 226.09 mL/g lactic acid, increasing by 30.06% compared to the control yield with a recovery to 89.09% of the normal CH4 yield. Despite the ability of LaFeO3 NPs to restore normal AD performance, the biodegradation rate of carbamazepine remained below 10% due to its anti-biodegradability. Bioaugmentation was primarily reflected in the enhanced bioavailability of dissolved organic matter, while the intracellular LaFeO3 NPs promoted coenzyme F420 activity through binding to humic substances. Under the mediation of LaFeO3, a direct interspecies electron transfer system with Longilinea and Methanosaeta as functional bacteria was successfully constructed and the corresponding electron transfer rate was accelerated from 0.021 s-1 to 0.033 s-1. LaFeO3 NPs eventually recovered AD performance under carbamazepine stress in an adsorption and bioaugmentation manner.

Molecular basis of high temperature-induced bolting in lettuce revealed by multi-omics analysis.

BACKGROUND: High temperature induces early bolting in lettuce (Lactuca sativa L.), which affects both quality and production. However, the molecular mechanism underlying high temperature-induced bolting is still limited. RESULTS: We performed systematical analysis of morphology, transcriptome, miRNAs and methylome in lettuce under high temperature treatment. Through a comparison of RNA-Seq data between the control and the high temperature treated lettuces at different time points totally identified 2944 up-regulated genes and 2203 down-regulated genes, which cover three floral pathways including photoperiod, age and gibberellin (GA) pathways. Genome wide analysis of miRNAs and methylome during high temperature treatment indicated miRNAs and DNA methylation might play a role controlling gene expression during high temperature-induced bolting. miRNA targets included some protein kinase family proteins, which potentially play crucial roles in this process. CONCLUSIONS: Together, our results propose a possible regulation network involved in high temperature-induced bolting.

Pyruvate kinase M2 mediates fibroblast proliferation to promote tubular epithelial cell survival in acute kidney injury.

Acute kidney injury (AKI) is a devastating condition with high morbidity and mortality rates. The pathological features of AKI are tubular injury, infiltration of inflammatory cells, and impaired vascular integrity. Pyruvate kinase is the final rate-limiting enzyme in the glycolysis pathway. We previously showed that pyruvate kinase M2 (PKM2) plays an important role in regulating the glycolytic reprogramming of fibroblasts in renal interstitial fibrosis. The present study aimed to determine the role of PKM2 in fibroblast activation during the pathogenesis of AKI. We found increased numbers of S100A4 positive cells expressing PKM2 in renal tissues from mice with AKI induced via folic acid or ischemia/reperfusion (I/R). The loss of PKM2 in fibroblasts impaired fibroblast proliferation and promoted tubular epithelial cell death including apoptosis, necroptosis, and ferroptosis. Mechanistically, fibroblasts produced less hepatocyte growth factor (HGF) in response to a loss of PKM2. Moreover, in two AKI mouse models, fibroblast-specific deletion of PKM2 blocked HGF signal activation and aggravated AKI after it was induced in mice via ischemia or folic acid. Fibroblast proliferation mediated by PKM2 elicits pro-survival signals that repress tubular cell death and may help to prevent AKI progression. Fibroblast activation mediated by PKM2 in AKI suggests that targeting PKM2 expression could be a novel strategy for treating AKI.