Thyroid function variations within the reference range and cognitive function: A two-sample Mendelian randomization study.

BACKGROUND: The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach. METHODS: Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy. RESULTS: An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (ß = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (ß = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (ß = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10-5). These findings remained robust in the sensitivity analyses. CONCLUSIONS: Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship. LIMITATIONS: This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups.

Incorporating machine learning and PPI networks to identify mitochondrial fission-related immune markers in abdominal aortic aneurysms.

Purpose: The aim of this study is to investigate abdominal aortic aneurysm (AAA), a disease characterised by inflammation and progressive vasodilatation, for novel gene-targeted therapeutic loci. Methods: To do this, we used weighted co-expression network analysis (WGCNA) and differential gene analysis on samples from the GEO database. Additionally, we carried out enrichment analysis and determined that the blue module was of interest. Additionally, we performed an investigation of immune infiltration and discovered genes linked to immune evasion and mitochondrial fission. In order to screen for feature genes, we used two PPI network gene selection methods and five machine learning methods. This allowed us to identify the most featrue genes (MFGs). The expression of the MFGs in various cell subgroups was then evaluated by analysis of single cell samples from AAA. Additionally, we looked at the expression levels of the MFGs as well as the levels of inflammatory immune-related markers in cellular and animal models of AAA. Finally, we predicted potential drugs that could be targeted for the treatment of AAA. Results: Our research identified 1249 up-regulated differential genes and 3653 down-regulated differential genes. Through WGCNA, we also discovered 44 genes in the blue module. By taking the point where several strategies for gene selection overlap, the MFG (ITGAL and SELL) was produced. We discovered through single cell research that the MFG were specifically expressed in T regulatory cells, NK cells, B lineage, and lymphocytes. In both animal and cellular models of AAA, the MFGs' mRNA levels rose. Conclusion: We searched for the AAA novel targeted gene (ITGAL and SELL), which most likely function through lymphocytes of the B lineage, NK cells, T regulatory cells, and B lineage. This analysis gave AAA a brand-new goal to treat or prevent the disease.

Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.

Impaired Sensitivity to Thyroid Hormones is Associated with Mild Cognitive Impairment in Euthyroid Patients with Type 2 Diabetes.

Purpose: The prevalence of mild cognitive impairment (MCI) in patients with type 2 diabetes (T2D) is rapidly increasing. Thyroid hormones are key regulators of cognitive function in adults. The purpose of this study was to investigate the relationship between thyroid hormone sensitivity and MCI in euthyroid T2D patients. Patients and Methods: A total of 400 euthyroid T2D patients were enrolled in this cross-sectional study, including 218 patients with normal cognition and 182 MCI patients. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function. The free triiodothyronine to free thyroxine (FT3/FT4) ratio was calculated as a measure of peripheral sensitivity to thyroid hormones; the thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI) and thyroid feedback quantile-based index (TFQI) were calculated as measures of central sensitivity to thyroid hormones. Linear regression analysis and logistic regression analysis were performed to explore the relationships between these indices of thyroid hormone sensitivity and the MoCA score and MCI, respectively. Results: Compared with the normal cognitive function group, patients in the MCI group had higher TSHI, TT4RI and TFQI but a lower FT3/FT4 ratio (P<0.05). The MoCA score was positively correlated with the FT3/FT4 ratio but negatively correlated with TSHI, TT4RI and TFQI (P< 0.05). Multivariate logistic regression analysis showed that a low FT3/FT4 ratio and high TSHI, TT4RI and TFQI were independently associated with MCI (P<0.05). After adjustment for confounding factors, the odds ratio (OR) for the association between MCI and the highest tertile of the FT3/FT4 was 0.455 (95% CI: 0.264-0.785), for the highest tertile of TSHI, the OR was 2.380 (95% CI: 1.376-4.119), for the highest tertile of TT4RI, the OR was 2.342 (95% CI:1.353-4.054), and for the highest tertile of TFQI, the OR was 2.536 (95% CI: 1.466-4.387) (P< 0.05). Conclusion: Impaired sensitivity to thyroid hormones is associated with MCI in euthyroid T2D patients.

Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis.

Pulmonary fibrosis is characterized by stiffening of the extracellular matrix. Fibroblasts migrate in the direction of greater stiffness, a phenomenon termed durotaxis. The mechanically guided fibroblast migration could be a crucial step in the progression of lung fibrosis. In this study, we found primary human lung fibroblasts sense increasing matrix stiffness with a change of mitochondrial dynamics in favor of mitochondrial fission and increased production of ATP. Mitochondria polarize in the direction of a physiologically relevant stiffness gradient, with conspicuous localization to the leading edge, primarily lamellipodia and filopodia, of migrating lung fibroblasts. Matrix stiffness-regulated mitochondrial fission and durotactic lung fibroblast migration are mediated by a dynamin-related protein 1/mitochondrial fission factor-dependent (DRP1/MFF-dependent) pathway. Importantly, we found that the DRP1/MFF pathway is activated in fibrotic lung myofibroblasts in both human IPF and bleomycin-induced mouse lung fibrosis. These findings suggest that energy-producing mitochondria need to be sectioned via fission and repositioned in durotactic lung fibroblasts to meet the higher energy demand. This represents a potentially new mechanism through which mitochondria may contribute to the progression of fibrotic lung diseases. Inhibition of durotactic migration of lung fibroblasts may play an important role in preventing the progression of human idiopathic pulmonary fibrosis.

Suture guided gonioscopy-assisted transluminal trabeculotomy combined with phacoemulsification in the treatment of primary open angle glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the clinical efficacy of suture-guided gonioscopy-assisted transluminal trabeculotomy(GATT)combined with phacoemulsification in the treatment of primary open angle glaucoma(POAG).METHODS: A total of 84 patients(84 eyes)with POAG and cataract who underwent surgery in our hospital from January 2021 to July 2022 were selected and randomly divided into two groups. There were 43 cases(43 eyes)in the combined group who underwent suture-guided GATT combined with phacoemulsification, and 41 cases(41 eyes)in the simple group who underwent suture-guided GATT. The two groups were followed up for 3mo to compare the surgical success rate, intraocular pressure, topical intraocular pressure-lowering drugs, visual acuity and postoperative complications.RESULTS: There was no significant difference in overall success rate between the combination and simple groups at 3 mo after surgery(88% vs. 85%, P&#x003E;0.05). The intraocular pressure levels and topical intraocular pressure-lowering drugs at 1wk, 1 and 3mo after surgery in the two groups were significantly lower than those before surgery(all P&#x003C;0.05), but there was no significant difference between the two groups(all P&#x003E;0.05). The visual acuity at 1wk, 1 and 3mo after surgery of patients in the combined group was significantly better than that in the simple group(P&#x003C;0.01). During the follow-up period, the incidence of anterior chamber hemorrhage and transient hypertension in the combined group was significantly lower than that in the simple group(P&#x003C;0.05).CONCLUSION: Both suture-guided GATT combined with cataract phacoemulsification and suture-guided GATT are effective treatment for POAG, however, suture-guided GATT combined with phacoemulsification has a lower incidence of anterior chamber hemorrhage and transient ocular hypertension.

Value of metagenomic next-generation sequencing in children with hematological malignancies complicated with infections / 中国当代儿科杂志

OBJECTIVES@#To explore the value of metagenomic next-generation sequencing (mNGS) in the pathogen identification in children with hematological malignancies complicated with infections.@*METHODS@#A retrospective analysis was conducted on clinical data and pathogenic test results of 43 children with hematological malignancies who underwent microbial culture and mNGS due to infections in the Third Xiangya Hospital of Central South University between June 2020 and July 2022. Differences in detection rates and characteristics of pathogenic microorganisms detected by mNGS and microbial culture were compared.@*RESULTS@#A total of 54 specimens were examined, and the overall detection rate of pathogen by mNGS (80%, 43/54) was significantly higher than that by microbial culture (30%, 16/54) (P<0.001). The most commonly detected infection type by mNGS was viral infection, followed by fungal infection combined viral infection, while that by microbial culture was bacterial infection, followed by fungal infection. The detection rate of fungi by mNGS (33%, 18/54) was higher than that by microbial culture (6%, 3/54) (P<0.001). The detection rate of two or more pathogenic microorganisms by mNGS was higher at 48% compared to microbial culture at 9% (P<0.05). The detection rate of two or more types of pathogenic microorganisms by mNGS was also significantly higher at 33% compared to microbial culture at 2% (P<0.05). The most commonly detected bacteria and fungi by mNGS were Pseudomonas aeruginosa and Candida tropicalis, respectively, in peripheral blood, while Streptococcus pneumoniae and Pneumocystis jirovecii were most commonly detected in bronchoalveolar lavage fluid. Treatment adjustments based on mNGS results were beneficial for 35% (15/43) of the cases.@*CONCLUSIONS@#mNGS has a higher detection rate than microbial culture and has obvious advantages in diagnosing mixed and fungal infections, making it a useful supplementary diagnostic method to microbial culture.

The effect of liraglutide combined with metformin on the effect of short-term insulin pump intensive therapy in overweight and obese type 2 diabetes mellitus patients and the effect on pancreatic islets / 中国医师进修杂志

Objective:To investigate the effect of liraglutide combined with metformin on overweight and obese patients with type 2 diabetes mellitus (T2DM) after short-term intensive insulin pump therapy.Methods:A total of 80 overweight and obese patients with T2DM admitted to Ningguo People′s Hospital from November 2018 to December 2020 were selected as the research subjects. After 1 week of intensive insulin pump therapy, they were divided into two groups according to the random number table method. The observation group received liraglutide combined with metformin therapy, the control group received metformin combined with sitagliptin therapy, both for 16 weeks. The blood glucose, blood lipids, body weight and other indicators were compared between the two groups after treatment. The occurrence of adverse drug reactions in the two groups was compared.Results:The levels of fasting plasma glucose (FPG), 2 h postprandial blood glucose (2hPG), and glycosylated hemoglobin (HbA 1c) in the observation group after treatment were lower than those in the control group :(5.14 ± 0.54) mmol/L vs. (5.92 ± 0.71) mmol/L, (5.91 ± 0.83) mmol/L vs. (6.84 ± 0.92) mmol/L, (5.33 ± 0.57)% vs. (6.30 ± 0.82)%, there were statistical differnces ( P<0.05). The triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels had no significant differences ( P>0.05). After treatment, the islet beta cell function index (HOMA-β) and insulin sensitivity index (ISI) in the observation group were higher than those in the control group: 26.84 ± 3.32 vs. 22.15 ± 3.11, -3.84 ± 0.17 vs. -4.09 ± 0.20, and the insulin resistance index (HOMA-IR) was lower than that in the control group: 2.01 ± 0.17 vs. 2.64 ± 0.21, the differences were statistically significant ( P<0.05). After treatment, the waist circumference (WC), body mass index (BMI) and hip-to-waist ratio in the observation group were lower than those in the control group: (95.10 ± 4.08) cm vs. (97.14 ± 4.48) cm, (24.33 ± 1.62) kg/m 2 vs. (26.15 ± 1.40) kg/m 2, 0.89 ± 0.11 vs. 1.11 ± 0.20, the differences were statistically significant ( P<0.05). There was no significant difference in the incidence of adverse drug reactions between the two groups during treatment ( P>0.05). Conclusions:Liraglutide combined with metformin has better clinical effect on overweight and obese T2DM patients after short-term intensive insulin pump therapy, and can better improve their pancreatic islet function.

Development and validation of a risk assessment model for prediabetes in China national diabetes survey.

BACKGROUND: Prediabetes risk assessment models derived from large sample sizes are scarce. AIM: To establish a robust assessment model for prediabetes and to validate the model in different populations. METHODS: The China National Diabetes and Metabolic Disorders Study (CNDMDS) collected information from 47325 participants aged at least 20 years across China from 2007 to 2008. The Thyroid Disorders, Iodine Status and Diabetes Epidemiological Survey (TIDE) study collected data from 66108 participants aged at least 18 years across China from 2015 to 2017. A logistic model with stepwise selection was performed to identify significant risk factors for prediabetes and was internally validated by bootstrapping in the CNDMDS. External validations were performed in diverse populations, including populations of Hispanic (Mexican American, other Hispanic) and non-Hispanic (White, Black and Asian) participants in the National Health and Nutrition Examination Survey (NHANES) in the United States and 66108 participants in the TIDE study in China. C statistics and calibration plots were adopted to evaluate the model's discrimination and calibration performance. RESULTS: A set of easily measured indicators (age, education, family history of diabetes, waist circumference, body mass index, and systolic blood pressure) were selected as significant risk factors. A risk assessment model was established for prediabetes with a C statistic of 0.6998 (95%CI: 0.6933 to 0.7063) and a calibration slope of 1.0002. When externally validated in the NHANES and TIDE studies, the model showed increased C statistics in Mexican American, other Hispanic, Non-Hispanic Black, Asian and Chinese populations but a slightly decreased C statistic in non-Hispanic White individuals. Applying the risk assessment model to the TIDE population, we obtained a C statistic of 0.7308 (95%CI: 0.7260 to 0.7357) and a calibration slope of 1.1137. A risk score was derived to assess prediabetes. Individuals with scores ≥ 7 points were at high risk of prediabetes, with a sensitivity of 60.19% and specificity of 67.59%. CONCLUSION: An easy-to-use assessment model for prediabetes was established and was internally and externally validated in different populations. The model had a satisfactory performance and could screen individuals with a high risk of prediabetes.

Rhein ameliorates transverse aortic constriction-induced cardiac hypertrophy via regulating STAT3 and p38 MAPK signaling pathways.

The progression from compensatory hypertrophy to heart failure is difficult to reverse, in part due to extracellular matrix fibrosis and continuous activation of abnormal signaling pathways. Although the anthraquinone rhein has been examined for its many biological properties, it is not clear whether it has therapeutic value in the treatment of cardiac hypertrophy and heart failure. In this study, we report for the first time that rhein can ameliorate transverse aortic constriction (TAC)-induced cardiac hypertrophy and other cardiac damage in vivo and in vitro. In addition, rhein can reduce cardiac hypertrophy by attenuating atrial natriuretic peptide, brain natriuretic peptide, and ß-MHC expression; cardiac fibrosis; and ERK phosphorylation and transport into the nucleus. Furthermore, the inhibitory effect of rhein on myocardial hypertrophy was similar to that of specific inhibitors of STAT3 and ERK signaling. In addition, rhein at therapeutic doses had no significant adverse effects or toxicity on liver and kidney function. We conclude that rhein reduces TAC-induced cardiac hypertrophy via targeted inhibition of the molecular function of ERK and downregulates STAT3 and p38 MAPK signaling. Therefore, rhein might be a novel and effective agent for treating cardiac hypertrophy and other cardiovascular diseases.

Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury.

The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.

Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: A prospective multicenter, randomized, controlled, crossover pilot trial.

OBJECTIVES: Muscle cramps occur in 33% to 78% of patients with dialysis. The etiology of muscle cramps is poorly understood, and no clear evidence-based prevention or treatment strategies exist. Improved interventions are urgently needed. The aim of this study was to investigate the effect of vitamin K2 in reducing the frequency and severity of muscle cramps in hemodialysis (HD) patients. METHODS: This multicenter, randomized, placebo-controlled, crossover clinical trial was conducted from June 2019 to May 2020. Each participant received vitamin K2 (360 µg/d) or placebo for two 4-wk phases, and then crossed to the alternative arm for two 4-wk phases after a 2-wk washout. The primary endpoint was the frequency of muscle cramps during HD. The secondary endpoints were severity and duration of muscle cramps during HD. RESULTS: A total of 523 patients with maintenance HD were screened for muscle cramps, including 41 patients with muscle cramps refractory to conventional interventions, were enrolled. Nineteen patients in the vitamin K2-initial group and 20 in the placebo-initial group completed the protocol, and were included in the final analysis. Vitamin K2 reduced the frequency, duration, and severity of muscle cramps in HD patients (all P < 0.05). The frequency, duration, and severity of muscle cramps in HD patients increased again after crossing over to the placebo. There were no serious adverse events. One patient experienced gastrointestinal discomfort when taking vitamin K2. CONCLUSIONS: This pilot trial demonstrated that vitamin K2 supplementation could decrease the frequency, duration, and severity of muscle cramps in HD patients.

Epidemiological characteristics of tuberculosis in Haikou in 2016-2020 / 公共卫生与预防医学

Objective To analyze the epidemiological characteristics of tuberculosis in Haikou from 2016 to 2020, and to provide theoretical support for the implementation of TB prevention and control measures in this region . Methods Collect data of active tuberculosis patients registered and managed in Haikou for 2016-2020 years, analyze the registration rate of tuberculosis in Haikou in 5 years. Comparison of tuberculosis registration rates among different gender, age groups, nationalities and occupation. Results In 2016-2020 years, 3 256 cases of tuberculosis were registered in Haikou. The average annual TB registration rate was 27.09/100 000, showing a gradual decrease. The incidence rate was the highest in 2016 (34.99/100 000) and the lowest in 2020 (17.99/100 000). The registration rate of tuberculosis in men was significantly higher than that of women (P<0.05). Compared with the registration rate of tuberculosis in different age groups, the incidence rate of the 0-14 year old group was the lowest, and the registration rate of people aged 60 or above was the highest, with a statistically significant difference (P<0.05). From 2016 to 2020, the highest tuberculosis registration rate among different ethnic groups was Han nationality (92.63%), followed by Li nationality (3.53%), Miao nationality (2.09%), Hui nationality (1.14%) and others (0.61%).The three highest occupation rates of tuberculosis were farmers, unemployed workers and workers, 55.80%, 14.74% and 8.88% respectively. Conclusion The registration rate of pulmonary tuberculosis in Haikou has a downward trend overall, and prevention and control work needs to focus on the male and the elderly in order to better prevent and control the epidemic of tuberculosis in this area.

Feasibility of measuring pulmonary venous blood flow spectrum by transesophageal ultrasound in evaluating intraoperative left atrial pressure in pediatric patients with complex congenital heart disease / 中华麻醉学杂志

Objective:To evaluate the feasibility of measuring pulmonary venous blood flow spectrum by transesophageal ultrasound in assessing intraoperative left atrial pressure (LAP) in pediatric patients with complex congenital heart disease.Methods:Twenty-five pediatric patients with complex congenital heart disease of either sex, aged < 3 yr, of American Society of Anesthesiologists physical status Ⅲ or Ⅳ, with New York Heart Association class Ⅲ or Ⅳ, undergoing surgery with general anesthesia and requiring LAP monitoring during surgery, were selected.Transesophageal echocardiography was used to record the left pulmonary venous blood flow spectrum during surgery.S wave velocity (PV S), D wave velocity (PV D), AR wave velocity (PV AR), and deceleration time of pulmonary venous diastolic flow (DT D) were measured at 15 min after termination of CPB.The ratio of S wave peak velocity to D wave peak velocity (S/D ratio) was calculated.Measurement was carried out for 3 consecutive cardiac cycles, and the average value was calculated.The LAP was simultaneously measured through the left atrial piezometer.Pearson correlation analysis was performed between PV S, PV D, PV AR, DT D, S/D ratio and LAP. Results:PV S, PV D, PV AR and S/D ratio had no correlation with LAP ( r=-0.06, 0.21, 0.19, -0.38, respectively, P>0.05), while DT D was negatively correlated with LAP ( r=-0.84, P<0.05). Conclusions:DT D measured by transesophageal ultrasound can be used to evaluate intraoperative LAP in pediatric patients with complex congenital heart disease.

Clinical efficacy of atezolizumab plus bevacizumab in the first-line treatment of advanced huge hepatocellular carcinoma / 中华消化外科杂志

The incidence and mortality of hepatocellular carcinoma (HCC) is very high in China, which seriously threatens human life and health. There were limited treatment options for advanced HCC in the past, and the overall survival of HCC patients was poor. In recent years, immuno-therapy and targeted therapy have been recommended as effective means for the treatment of advan-ced HCC. The authors report a case of advanced huge HCC which has achieved a maintained partial response for 6 months after the treatment of atezolizumab combined with bevacizumab. The tumor shrunk by 32.4% and 47.5% after 3 and 6 months of treatment. Besides, the alpha-fetoprotein and abnormal tumor protein value of the patient continued to decrease without any adverse reactions. The treatment is evaluated as partial response and patients has a good short-term effect.

Sodium starch octenyl succinate facilitated the production of water-soluble yellow pigments in Monascus ruber fermentation.

Natural water-soluble Monascus pigments (WSMPs) have been in increasing demand but have not been able to achieve industrial production due to the low production rate. This study aimed to improve the biosynthesis and secretion of extracellular yellow pigments (EYPs) through submerged fermentation with Monascus ruber CGMCC 10,910 supplemented with sodium starch octenyl succinate (OSA-SNa). The results demonstrated that the yield was 69.68% and 48.89% higher than that without OSA-SNa in conventional fermentation (CF) and extractive fermentation (EF), respectively. The mainly increased EYP components were Y3 and Y4 in CF, but they were mainly Y1 and Y2 as well as secreted intracellular pigments, including Y5, Y6, O1, and O2, in EF. Scanning electron microscopy analysis revealed that the mycelium presented an uneven surface profile with obvious wrinkles and small fragments with OSA-SNa. It was found that a higher unsaturated/saturated fatty acids ratio in the cell membrane resulted in increased permeability and facilitated the export of intracellular yellow pigments into the broth with OSA-SNa treatment. In addition, a higher NAD+/NADH ratio and glucose-6-phosphate dehydrogenase activity provided a reducing condition for yellow pigment biosynthesis. Gene expression analysis showed that the expression levels of the key genes for yellow pigment biosynthesis were significantly upregulated by OSA-SNa. This study provides an effective strategy to promote the production of WSMPs by microparticle-enhanced cultivation using OSA-SNa. KEY POINTS: • OSA-SNa addition facilitated the production of Monascus yellow pigments. • Mycelial morphology and membrane permeability were affected by OSA-SNa. • The key gene expression of yellow pigments was upregulated.

Targeting mechanosensitive MDM4 promotes lung fibrosis resolution in aged mice.

Aging is a strong risk factor and an independent prognostic factor for progressive human idiopathic pulmonary fibrosis (IPF). Aged mice develop nonresolving pulmonary fibrosis following lung injury. In this study, we found that mouse double minute 4 homolog (MDM4) is highly expressed in the fibrotic lesions of human IPF and experimental pulmonary fibrosis in aged mice. We identified MDM4 as a matrix stiffness-regulated endogenous inhibitor of p53. Reducing matrix stiffness down-regulates MDM4 expression, resulting in p53 activation in primary lung myofibroblasts isolated from IPF patients. Gain of p53 function activates a gene program that sensitizes lung myofibroblasts to apoptosis and promotes the clearance of apoptotic myofibroblasts by macrophages. Destiffening of the fibrotic lung matrix by targeting nonenzymatic cross-linking or genetic ablation of Mdm4 in lung (myo)fibroblasts activates the Mdm4-p53 pathway and promotes lung fibrosis resolution in aged mice. These findings suggest that mechanosensitive MDM4 is a molecular target with promising therapeutic potential against persistent lung fibrosis associated with aging.

Inducing red pigment and inhibiting citrinin production by adding lanthanum(III) ion in Monascus purpureus fermentation.

Monascus pigments (MPs) are widely used natural colorants in Asian countries. The problems of low extracellular red pigment (ERP) and high citrinin remain to be solved in Monascus pigment production. The effect of lanthanum(III) ion (LaCl3) on Monascus purpureus fermentation was investigated in this study. The yields of ERP and biomass respectively reached maxima of 124.10 U/mL and 33.10 g/L by adding 0.4 g/L La3+ on the second day in the total 8-day fermentation; simultaneously, citrinin was decreased by 59.93% and 38.14% in the extracellular and intracellular fractions, respectively. Reactive oxygen species (ROS) levels were obviously improved by La3+ treatment, while the activities of catalase (CAT) and superoxide dismutase (SOD) were increased compared with the control. The ratio of unsaturated/saturated fatty acids in mycelia was increased from 2.94 to 3.49, indicating that the permeability and fluidity of the cell membrane were enhanced under La3+ treatment. Gene expression analysis showed that the relative expression levels of Monascus pigment synthesis genes (pksPT, mppB, mppD, MpFasB2, and MpPKS5) were significantly upregulated by La3+ treatment, and in contrast, the relative expression levels of citrinin synthesis genes (ctnA, pksCT and mppC) were markedly downregulated. This work confirmed that LaCl3 possesses the potential to induce red pigment biosynthesis and inhibit citrinin production in M. purpureus fermentation. KEY POINTS: • La3+ induced red pigment and inhibited citrinin production in Monascus fermentation. • La3+ regulated genes expression up for Monascus pigment and down for citrinin. • La3+ increased the UFAs in cell membrane to enhance the permeability and fluidity.

Natural variation in the promoter of GsERD15B affects salt tolerance in soybean.

Salt stress has detrimental effects on crop growth and yield, and the area of salt-affected land is increasing. Soybean is a major source of vegetable protein, oil and feed, but considered as a salt-sensitive crop. Cultivated soybean (Glycine max) is domesticated from wild soybean (G. soja) but lost considerable amount of genetic diversity during the artificial selection. Therefore, it is important to exploit the gene pool of wild soybean. In this study, we identified 34 salt-tolerant accessions from wild soybean germplasm and found that a 7-bp insertion/deletion (InDel) in the promoter of GsERD15B (early responsive to dehydration 15B) significantly affects the salt tolerance of soybean. GsERD15B encodes a protein with transcriptional activation function and contains a PAM2 domain to mediate its interaction with poly(A)-binding (PAB) proteins. The 7-bp deletion in GsERD15B promoter enhanced the salt tolerance of soybean, with increased up-regulation of GsERD15B, two GmPAB genes, the known stress-related genes including GmABI1, GmABI2, GmbZIP1, GmP5CS, GmCAT4, GmPIP1:6, GmMYB84 and GmSOS1 in response to salt stress. We propose that natural variation in GsERD15B promoter affects soybean salt tolerance, and overexpression of GsERD15B enhanced salt tolerance probably by increasing the expression levels of genes related to ABA-signalling, proline content, catalase peroxidase, dehydration response and cation transport.