Individualised prediction of progression of solitary sub-solid pulmonary nodules based on CT semantic and clinical features: a 3-year follow-up study.

AIM: To develop and validate a progressive prediction model for estimating the time to progression (TTP) of sub-solid pulmonary nodules (SSNs). MATERIALS AND METHODS: A total of 126 cases who met inclusion and exclusion criteria were included in the study. The primary endpoint of the study was TTP of SSNs. Baseline characteristics were assessed in terms of clinical and CT semantic features. Kaplan-Meier analysis and Cox regression analysis were performed to determine the relationship between SSNs TTP and factors from the entire data set. The nomogram was constructed based on the result of multivariate analysis and internal validation was performed using the bootstrapping. The nomogram's performance was assessed with the C-index, calibration curves, and decision curve analysis. RESULTS: The median follow-up time of the population was 42.5 (21.5) months. On Kaplan-Meier analysis, patients with higher or positive values of the indices had higher cumulative progression rates (p<0.05). Multivariate Cox regression models identified diameter, consolidation tumour ratio (CTR), morphology, and vasodilation sign (VDS) as independent risk factors of TTP. These predictors were included in the final model to estimate individual probabilities of progression in the 3 years, which performed well in the discrimination (the C-index was 0.901 [95%CI: 0.830-0.981] and 0.875 [95%CI: 0.805-0.942] in the training and internally validation sets). CONCLUSION: The radiological semantic features nomogram is a promising and favourable prognostic biomarker for predicting progression and may aid in clinical risk stratification and decision-making for SSNs.

Sudomotor dysfunction is associated with impaired left ventricular diastolic function in persons with type 2 diabetes: a cross-sectional study.

BACKGROUND: The incidence of preserved ejection fraction heart failure has significantly increased in persons with type 2 diabetes mellitus (T2DM). Left ventricular (LV) diastolic dysfunction is an early and important manifestation of preserved ejection fraction heart failure. The onset of heart failure in persons with diabetes is associated with diabetic neuropathy. However, the relationship among sudomotor function, which is an early manifestation of small fiber neuropathy, and LV diastolic function remains unclear. This study aimed to explore the association between sudomotor function and LV diastolic function in persons with T2DM. METHODS: In total, 699 persons with T2DM were enrolled and divided into three groups according to electrochemical skin conductance (ESC) assessed using the SUDOSCAN device: "no dysfunction" group (NSF), "moderate dysfunction" group (MDF), and "severe dysfunction" group (SDF). LV diastolic function was assessed using Doppler echocardiography. To evaluate the relationship between ESC and echocardiographic parameters, Pearson's correlation analysis was performed. Additionally, logistic regression analysis was used to determine the association between LV diastolic function and ESC. A receiver operating characteristic (ROC) curve was constructed to evaluate the performance of sudomotor function indicators in detecting impaired cardiac diastolic function. RESULTS: There were 301 persons (43.06%) in the NSF group, 232 (33.19%) in the MDF group, and 166 (23.75%) in the SDF group. Compared to the NSF group, the MDF and SDF groups had higher A and E/e' and lower e' values (all p < 0.05). Pearson's correlation analysis showed that A and E/e' were negatively associated with foot ESC (FESC) and hand ESC (HESC), whereas e' was positively associated with FESC and HESC (all p < 0.05). After adjusting for confounding factors, binary logistic regression analysis showed that ESC was independently associated with impaired LV diastolic function (p = 0.003). The area under the ROC curve values for FESC and HESC were 0.621 and 0.635, respectively (both p < 0.05). CONCLUSIONS: Deteriorating sudomotor function was associated with reduced diastolic function indicators. ESC can be used as a biomarker for detecting LV diastolic impairment.

Parasitoid-host interaction behaviors in relation to host stages in the Tamarixia triozae (Hymenoptera: Eulophidae)-Bactericera cockerelli (Hemiptera: Triozidae) system.

Females of host-feeding parasitic wasps often partition hosts of different stages for feeding and parasitization, but the underlying behavioral mechanisms are largely unknown, making it difficult to evaluate parasitoid-host interactions and their effects on biological control success. Tamarixia triozae (Burks) is an ectoparasitoid of tomato-potato psyllid Bactericera cockerelli (Sulc), which utilizes nymphs and kills them both by parasitization and host feeding. In this study, we exposed female wasps to 1st- to 5th-instar psyllid nymphs simultaneously and made 13-h continuous video recording of parasitoid-host interactions. We then quantified host stage-dependent handling time for feeding and oviposition and behaviors of parasitoid attacks and host defenses from encountering to successful feeding and oviposition. Female wasps were more likely to encounter and evaluate older hosts. However, the encounter and evaluation did not necessarily result in the success of feeding and oviposition. Our findings suggest that (i) T. triozae continues to assess the host using its ovipositor after the evaluation phase, (ii) females prefer the mid-aged hosts for feeding piercing and feeding and the later instars for oviposition probing and oviposition, (iii) the combination of stage-specific host nutrition value, integument thickness and defense behavior determines the success of feeding attacks, and (iv) the optimal host resource for parasitoid offspring fitness defines host stage selection for oviposition. This study contributes to our understanding of parasitoid-host interactions and mechanisms behind host stage selections.

Vegetation-fire feedbacks increase subtropical wildfire risk in scrubland and reduce it in forests.

Climate dictates wildfire activity around the world. But East and Southeast Asia are an apparent exception as fire-activity variation there is unrelated to climatic variables. In subtropical China, fire activity decreased by 80% between 2003 and 2020 amid increased fire risks globally. Here, we assessed the fire regime, vegetation structure, fuel flammability and their interactions across subtropical Hubei, China. We show that tree basal area (TBA) and fuel flammability explained 60% of fire-frequency variance. Fire frequency and fuel flammability, in turn, explained 90% of TBA variance. These results reveal a novel system of scrubland-forest stabilized by vegetation-fire feedbacks. Frequent fires promote the persistence of derelict scrubland through positive vegetation-fire feedbacks; in forest, vegetation-fire feedbacks are negative and suppress fire. Thus, we attribute the decrease in wildfire activity to reforestation programs that concurrently increase forest coverage and foster negative vegetation-fire feedbacks that suppress wildfire.

[A prospective birth cohort study on the association between gestational blood pressure and neurodevelopment in 2-year-old children].

Objective: To investigate the association between gestational blood pressure and neurodevelopment in 2-year-old children. Methods: Based on the"Wuhan Healthy Baby Birth Cohort", 3 754 mother-infant pairs were enrolled in this study. Based on multiple blood pressure measurements during pregnancy, the mean, cumulative, and variability of blood pressure throughout the entire pregnancy and each trimester were calculated. Blood pressure variability was evaluated using standard deviation (SD), coefficient of variability (CV), and variability independent of mean (VIM). Follow-up testing of neurodevelopment in infants and young children at the age of two was conducted to obtain the Mental Development Index (MDI) and the Psychomotor Development Index (PDI). The multivariate linear regression and generalized estimation equation were used to analyze the association between gestational blood pressure data and neurodevelopmental index. Results: The age of 3 754 pregnant women was (29.1±3.6) years, with a pre-pregnancy BMI of (20.9±2.7) kg/m² and a gestational age of (39.3±1.2) weeks. The birth weight of 3 754 children was (3 330.9±397.7) grams, and the birth length was (50.3±1.6) centimeters. The results of the multivariate linear regression analysis showed that after adjusting for relevant confounding factors, the mean blood pressure, cumulative blood pressure, standard deviation of blood pressure, coefficient of variation of blood pressure, independent blood pressure variability of systolic blood pressure, diastolic blood pressure, and pulse pressure throughout pregnancy were negatively associated with the MDI and PDI scores of 2-year-old children. The analysis results of the generalized estimation equation showed that after adjusting for relevant confounding factors, the average systolic blood pressure in the first, second, and third trimesters was negatively associated with MDI/PDI. The negative association between cumulative blood pressure and MDI/PDI was only found in the first trimester. The negative association between blood pressure variation during pregnancy and MDI/PDI was mainly concentrated in the second and third trimesters. Conclusion: There is a negative association between gestational blood pressure and the neurodevelopmental index of 2-year-old children.

Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes.

Lipid accumulation in hepatocytes is the distinctive characteristic of nonalcoholic fatty liver disease. Serine/arginine-rich splicing factor 3 (SRSF3) is highly expressed in the liver and expression decreases in high-fat conditions. However, the role of SRSF3 in hepatic lipid metabolism needs to be clarified. Here, we showed that loss of SRSF3 was associated with lipid accumulation. We determined that SRSF3 regulated lipophagy, the process of selective degradation of lipid droplets by autophagy. Mechanistically, loss of SRSF3 impaired the fusion of the autophagosome and lysosome by promoting the proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein. We found that ubiquitination of STX17 was increased and upregulation of seven in absentia homolog 1 was responsible for the increased posttranslational modification of STX17. Taken together, our data primarily demonstrate that loss of SRSF3 weakens the clearance of fatty acids by impairing lipophagy in the progression of nonalcoholic fatty liver disease, indicating a novel potential therapeutic target for fatty liver disease treatment.

HIF-2α-induced upregulation of CD36 promotes the development of ccRCC.

Clear cell renal cell carcinoma (ccRCC) is characterized by the abundance of lipid droplets and the activation of the hypoxia-inducible factor (HIF) signaling pathway. However, the lipid reprogramming induced by HIF signaling in ccRCC is not fully understood. In this study, we found that the fatty acid receptor CD36 was highly expressed in human ccRCC tissues and ccRCC cell lines. CD36 overexpression increased fatty acid uptake and lipid droplet formation, and enhanced the proliferation and migration of ccRCC cells in a DGAT1-dependent manner. In contrast, the disruption of endogenous CD36 showed the opposite effects. The upregulated expression of CD36 in ccRCC was associated with hypoxia and HIF-2α activation. Furthermore, we identified CD36 as a new target of the transcription factor HIF-2α. The knockdown of CD36 in ccRCC cells reduced lipid accumulation and also blocked the tumor-promoting effects induced by HIF-2α under hypoxia. Our findings suggest that hypoxia-dependent HIF-2α promotes the remodeling of lipid metabolism and the malignant phenotype of ccRCC via CD36, providing a certain theoretical basis for clarifying the mechanism of ccRCC.

[Treatment of intrauterine adhesions in rats with hypoxia-cultured BMSC-derived exosomes].

Objective: To perform intrauterine adhesion modeling, and to investigate the repair effect of hypoxic treated bone marrow mesenchymal stem cells (BMSC) and their derived exosomes (BMSC-exo) on endometrial injury. Methods: BMSC and their exosomes BMSC-exo extracted from rats' femur were cultured under conventional oxygen condition (21%O2) or hypoxia condition (1%O2). Intrauterine adhesion modeling was performed on 40 healthy female SD rats by intrauterine injection of bacterial lipopolysaccharide after curettage. On the 28th day of modeling, 40 rat models were randomly divided into five groups, and interventions were performed: (1) NC group: 0.2 ml phosphate buffered solution was injected into each uterine cavity; (2) BMSC group: 0.2 ml BMSC (1×106/ml) with conventional oxygen culture was injected intrauterine; (3) L-BMSC group: 0.2 ml of hypoxic cultured BMSC (1×106/ml) was injected intrauterine; (4) BMSC-exo group: 0.2 ml of BMSC-exo cultured with conventional oxygen at a concentration of 500 µg/ml was injected into the uterine cavity; (5) L-BMSC-exo group: 0.2 ml hypoxic cultured BMSC-exo (500 µg/ml) was injected intrauterine. On the 14th and 28th day of treatment, four rats in each group were sacrificed by cervical dislocation after anesthesia, and endometrial tissues were collected. Then HE and Masson staining were used to observe and calculate the number of glands and fibrosis area in the endometrium. The expressions of angiogenesis related cytokines [vascular endothelial growth factor A (VEGFA) and CD31], and fibrosis-related proteins [collagen-Ⅰ, collagen-Ⅲ, smooth muscle actin α (α-SMA), and transforming growth factor ß1 (TGF-ß1)] in endometrial tissues were detected by western blot. Results: (1) HE and Masson staining showed that the number of endometrial glands in L-BMSC group, BMSC-exo group and L-BMSC-exo group increased and the fibrosis area decreased compared with NC group on the 14th and 28th day of treatment (all P<0.05). Noteworthily, the changes of L-BMSC-exo group were more significant than those of BMSC-exo group (all P<0.05), and the changes of BMSC-exo group were greater than those of BMSC group (all P<0.05). (2) Western blot analysis showed that, compared with NC group, the expressions of collagen-Ⅲ and TGF-ß1 in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group decreased on the 14th and 28th day of treatment (all P<0.05). As the treatment time went on, the expressions of fibrosis-related proteins were different. Compared with BMSC group, the expressions of collagen-Ⅲ, α-SMA and TGF-ß1 in the BMSC-exo group and L-BMSC group decreased on the 28th day (all P<0.05). Moreover, the expressions of collagen-Ⅲ and TGF-ß1 in L-BMSC-exo group were lower than those in BMSC-exo group on the 28th day (all P<0.05). And the expressions of collagen-Ⅰ, α-SMA and TGF-ß1 in L-BMSC-exo group were lower than those in L-BMSC group on the 28th day (all P<0.05). (3) The results of western blot analysis of VEGFA and CD31 showed that, the expressions of VEGFA and CD31 in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group increased on the 14th and 28th day of treatment compared with NC group (all P<0.05). Treatment for 28 days, the expressions of VEGFA and CD31 in BMSC-exo group and CD31 in L-BMSC group were higher than those in BMSC group (all P<0.05). Moreover, the expressions of VEGFA and CD31 in L-BMSC-exo group were higher than those in BMSC-exo group and L-BMSC group on the 28th day (all P<0.05). Conclusions: Treatment of BMSC and their exosomes BMSC-exo with hypoxia could promote endometrial gland hyperplasia, inhibit tissue fibrosis, and further repair the damaged endometrium in rats with intrauterine adhesion. Importantly, hypoxic treatment of BMSC-exo is the most effective in intrauterine adhesion rats.

Measurement of the Electric Dipole Moment of

The permanent electric dipole moment (EDM) of the ^{171}Yb (I=1/2) atom is measured with atoms held in an optical dipole trap. By enabling a cycling transition that is simultaneously spin-selective and spin-preserving, a quantum nondemolition measurement with a spin-detection efficiency of 50% is realized. A systematic effect due to parity mixing induced by a static E field is observed, and is suppressed by averaging between measurements with optical dipole traps in opposite directions. The coherent spin precession time is found to be much longer than 300 s. The EDM is determined to be d(^{171}Yb)=(-6.8±5.1_{stat}±1.2_{syst})×10^{-27} e cm, leading to an upper limit of |d(^{171}Yb)|<1.5×10^{-26} e cm (95% C.L.). These measurement techniques can be adapted to search for the EDM of ^{225}Ra.

Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes.

Palmitic acid (PA)-induced hepatocyte apoptosis is critical for the progression of nonalcoholic fatty liver disease (NAFLD). Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is an intracellular Ca2+-release channel and is involved in PA-induced hepatocyte apoptosis. While the expression of IP3R1 is elevated in patients with NAFLD and in hepatocytes treated with PA, it remains unclear how PA promotes the expression of IP3R1. In present study, our results showed that PA induced mitochondrial dysfunction and apoptosis, which is accompanied with the increase of the IP3R1 expression in hepatic cells. The inhibition of IP3R1 expression using siRNA ameliorated the PA-induced mitochondrial dysfunction. Furthermore, PA enhanced the stability of the IP3R1 protein instead of an increase in its mRNA levels. PA also promoted the phosphorylation of IP3R1 at the Tyr353 site and increased the phosphorylation of src in hepatic cells. Moreover, an inhibitor of src kinase (SU6656) significantly reduced the Tyr353 phosphorylation of IP3R1 and decreased its stability. In addition, SU6656 improved mitochondrial function and reduced apoptosis in hepatocytes. Conclusion: PA promotes the Tyr353 phosphorylation of IP3R1 by activating the src pathway and increasing the protein stability of IP3R1, which consequently results in mitochondrial Ca2+ overload and mitochondrial dysfunction in hepatic cells. Our results also suggested that inhibition of the src/IP3R1 pathway, such as by SU6656, may be a novel potential therapeutic approach for the treatment of NAFLD.

A prospective study on vulvovaginal candidiasis: multicentre molecular epidemiology of pathogenic yeasts in China.

BACKGROUND: Vulvovaginal candidiasis (VVC) is frequent in women of reproductive age, but very limited data are available on the epidemiology in cases of VVC in China. OBJECTIVES: The current study has been conducted to reveal the prevalence, species distribution of yeast causing VVC and molecular genetics of Candida albicans in China. METHODS: Vaginal swabs were collected from 543 VVC outpatients recruited in 12 hospitals in China between September 2017 and March 2018. They were preliminarily incubated on Sabouraud dextrose agar and then positive subjects of which were then transmitted to our institute for further identification. CHROMagar™ was used to isolate Candida species, and all isolates were finally identified by DNA sequencing. Multilocus sequence typing (MLST) was used to analyse phylogenetic relationships of the various C. albicans isolates. RESULTS: Eleven different yeast species were identified in 543 isolates, among which C. albicans (84.7%) was the most frequent, followed by C. glabrata (8.7%). We obtained 117 unique diploid sequence types from 451 clinical C. albicans isolates and 92 isolates (20.4%) belonged to a New Clade. All the strains appearing in the New Clade were from northern China and they were isolated from non-recurrent VVC. CONCLUSIONS: Our findings suggest that C. albicans are still the main cause of VVC in China and the majority of C. albicans isolates belongs to Clade 1 with DST 79 and DST 45 being two most common. Moreover, the New Clade revealed in our study seems to be specific to northern China.

Analysis of reproductive damage in earthworms (Amynthas corticis) exposed to cypermethrin.

Cypermethrin contamination was a potential threat to soil organisms. In the present work, reproductive damage in earthworms (Amynthas corticis) exposed to cypermethrin was investigated. It was found that earthworms could absorb and accumulate residual cypermethrin in soil, and also earthworm activities helped accelerate the degradation of cypermethrin in soil. The accumulation of cypermethrin in earthworms induced sperm damage, and cypermethrin not only caused the imbalance of calcium homeostasis in earthworm sperm cells by inhibiting earthworm sperm Ca2+-ATP and Ca2+-Mg2+-ATP enzyme activities but also caused barriers in acrosome reaction. It also affected sperm energy supply of earthworms by inhibiting the activity of Na+-K+-ATPase and Mg2+-ATPase of earthworm sperm. Meanwhile, the inhibition of acrosome enzyme activity of earthworm sperm by cypermethrin led to hinder fertilization and reduced cocoon production of earthworms, and the damage of cypermethrin to sperm of earthworm was a significant cause of its reproductive toxicity. The results of the evaluation of IBR index showed that reproductive toxicity of cypermethrin to earthworms reduced with the increasing time. The decreased reproductive toxicity of cypermethrin to earthworms at the later stage of exposure (42-56 d) might be due to a combination of reduced absorption of cypermethrin in soil by earthworms, decreased accumulation of cypermethrin in the body, and improved sperm capacitation.

[Management of the nondisplaced type Herbert D1 scaphoid fracture with robot navigation combined with wrist arthroscopy].

To investigate the feasibility and the clinical efficiency of robot navigation combined with wrist arthroscopy in minimally invasive treatment of nondisplaced type Herbert D1 scaphoid fracture. A retrospective analysis was performed on 9 patients who underwent nondisplaced type Herbert D1 scaphoid fracture in Xuzhou Renci Hospital from December 2019 to January 2021. Before the operation and at the last follow-up, grip strength, pinching force, modified wrist Mayo score and visual analogue scale (VAS) of wrist pain were recorded and compared. The average follow-up time was 14.1 months (7.5-24.0 months). All the fractures achieved primary healing after an average of 13.3 weeks (10-18 weeks). The average flexion and dorsal extension activity of the injured wrist was 51.2°±9.4°, 68.0°±7.3°, and the radial and ulnar deviation was 19.3°±6.2°, 45.7°±7.8°, respectively. At the final follow-up, there were statistically significant differences in grip strength, pinch strength, wrist Mayo score and VAS when compared with those before the operation (all P<0.05). The results demonstrated that robot navigation combined with wrist arthroscopy for nondisplaced type Herbert D1 scaphoid fracture is effective and minimally invasive with a short recovery time and satisfactory healing rate.

[Diagnosis and treatment status of perioperative anemia in patients with gastrointestinal neoplasms: a multi-center study in Hubei Province].

Objective: To investigate the incidence and treatment of perioperative anemia in patients with gastrointestinal neoplasms in Hubei Province. Methods: The clinicopathological data of 7 474 patients with gastrointestinal neoplasms in 62 hospitals in 15 cities (state) of Hubei Province in 2019 were collected in the form of network database. There were 4 749 males and 2 725 females. The median age of the patients was 62 years (range: 17 to 96 years). The hemoglobin value of the first time in hospital and the first day after operation was used as the criterion of preoperative anemia and postoperative anemia. Anemia was defined as male hemoglobin <120 g/L and female hemoglobin <110.0 g/L, mild anemia as 90 to normal, moderate anemia as 60 to <90 g/L, severe anemia as <60 g/L. The t test and χ2 test were used for inter-group comparison. Results: The overall incidence of preoperative anemia was 38.60%(2 885/7 474), and the incidences of mild anemia, moderate anemia and severe anemia were 25.09%(1 875/7 474), 11.37%(850/7 474) and 2.14%(160/7 474), respectively. The overall incidence of postoperative anemia was 61.40%(4 589/7 474). The incidence of mild anemia, moderate anemia and severe anemia were 48.73%(3 642/7 474), 12.20%(912/7 474) and 0.47%(35/7 474), respectively. The proportion of preoperative anemia patients receiving treatment was 26.86% (775/2 885), and the proportion of postoperative anemia patients receiving treatment was 14.93% (685/4 589). The proportions of preoperative anemia patients in grade ⅢA, grade ⅢB, and grade ⅡA hospitals receiving treatment were 26.12% (649/2 485), 32.32% (85/263), and 29.93% (41/137), and the proportions of postoperative anemia patients receiving treatment were 14.61% (592/4 052), 22.05% (73/331), and 9.71% (20/206). The proportion of intraoperative blood transfusion (16.74% (483/2 885) vs. 3.05% (140/4 589), χ²=434.555, P<0.01) and the incidence of postoperative complications (17.78% (513/2 885) vs. 14.08% (646/4 589), χ²=18.553, P<0.01) in the preoperative anemia group were higher than those in the non-anemia group, and the postoperative hospital stay in the preoperative anemia group was longer than that in the non-anemia group ((14.1±7.3) days vs. (13.3±6.2) days, t=5.202, P<0.01). Conclusions: The incidence of perioperative anemia in patients with gastrointestinal neoplasms is high. Preoperative anemia can increase the demand for intraoperative blood transfusion and affect the short-term prognosis of patients. At present, the concept of standardized treatment of perioperative anemia among gastrointestinal surgeons in Hubei Province needs to be improved.

Hyperphosphatemia in chronic kidney disease exacerbates atherosclerosis via a mannosidases-mediated complex-type conversion of SCAP N-glycans.

Blood phosphate levels are linked to atherosclerotic cardiovascular disease in patients with chronic kidney disease (CKD), but the molecular mechanisms remain unclear. Emerging studies indicate an involvement of hyperphosphatemia in CKD accelerated atherogenesis through disturbed cholesterol homeostasis. Here, we investigated a potential atherogenic role of high phosphate concentrations acting through aberrant activation of sterol regulatory element-binding protein (SREBP) and cleavage-activating protein (SCAP)-SREBP2 signaling in patients with CKD, hyperphosphatemic apolipoprotein E (ApoE) knockout mice, and cultured vascular smooth muscle cells. Hyperphosphatemia correlated positively with increased atherosclerotic cardiovascular disease risk in Chinese patients with CKD and severe atheromatous lesions in the aortas of ApoE knockout mice. Mice arteries had elevated SCAP levels with aberrantly activated SCAP-SREBP2 signaling. Excess phosphate in vitro raised the activity of α-mannosidase, resulting in delayed SCAP degradation through promoting complex-type conversion of SCAP N-glycans. The retention of SCAP enhanced transactivation of SREBP2 and expression of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, boosting intracellular cholesterol synthesis. Elevated α-mannosidase II activity was also observed in the aortas of ApoE knockout mice and the radial arteries of patients with uremia and hyperphosphatemia. High phosphate concentration in vitro elevated α-mannosidase II activity in the Golgi, enhanced complex-type conversion of SCAP N-glycans, thereby upregulating intracellular cholesterol synthesis. Thus, our studies explain how hyperphosphatemia independently accelerates atherosclerosis in CKD.

Loss of CD36 impairs hepatic insulin signaling by enhancing the interaction of PTP1B with IR.

A contradictory role of CD36 in insulin resistance was found to be related to the nutrient state. Here, we examined that the physiological functions of CD36 in insulin signal transduction in mice fed a low-fat diet. CD36 deficiency led to hepatic insulin resistance and decreased insulin-stimulated tyrosine phosphorylation of insulin receptor ß (IRß) in mice fed a low-fat diet. The ability of insulin to bind with IR did not differ between WT and CD36-deficient hepatocytes. CD36 formed a complex with IRß and dissociation of CD36/Fyn complex or inhibition of Fyn only partially reversed the effects of CD36 on hepatic insulin signaling. Furthermore, we found that CD36 deficiency led to abnormally increased hepatic protein-tyrosine phosphatase 1B (PTP1B) expression and enhanced PTP1B and IR interactions, which contributed to the decreased insulin signaling and disordered glucose metabolism. In addition, increased endoplasmic reticulum (ER) stress was found in the livers of the CD36-deficient mice, while inhibited ER stress normalized the PTP1B expression and restored insulin signaling in the CD36-deficient mice. Our findings suggest that the loss of CD36 impairs hepatic insulin signaling by enhancing the PTP1B/IR interaction that is induced by ER stress, indicating a possible critical step in the progression of hepatic insulin resistance.

[The clinical application of blood routine and liver and kidney function test in COVID-19 disease prediction].

Objective: To explore the clinical application value of routine indicators such as blood routine and liver and kidney function in auxiliary diagnosis and prognosis of COVID-19 patients. Methods: SNK-q and other methods were used to retrospectively analyzed the differences of blood routine test, liver and kidney function and other inflammatory indexes of 30 patients with covid-19, 29 patients with other viral pneumonia, 35 patients with influenza A/B and 25 healthy persons from January 28 to February 14, 2020 in Xiangya Hospital of Central South University. Results: The neutrophils count increased gradually in COVID-19 group, influenza A/B group and other types of viral pneumonia group, and the difference between COVID-19 group and other viral pneumonia groups was statistically significant(H=-19.064,P<0.05); The lymphocyte count decreased gradually in the control group, influenza A/B group, other viral pneumonia group and COVID-19 group. In addition, DB, UA and GLU were also different among groups. Subgroup analysis showed that there were statistically significant differences in N(F=9.581,t=-0.152,P<0.05), N%(F=5.723,t=-0.600, P<0.05), NLR(F=4.773, t=-1.161, P<0.05), PCT(F=17.464, t=-1.477, P<0.05)and CRP(F=7.656, t=-1.973, P<0.05) between patients with lung involvement +-++ and patients with lung involvement +++-++++. There were statistically significant differences in NLR(F=63.931, t=-2.815, P<0.01), AST(F=15.704, t=-1.930, P<0.01), ALT(F=35.551, t=-2.199, P<0.01), LDH(F=7.715, t=-2.703, P<0.05) and GLU(F=6.306, t=-5.116, P<0.05) between the light+common subgroup and the heavy+critical subgroup of COVID-19 clinical classification. Correlation analysis showed that clinical stage and imaging credit period were significantly correlated with NLR (r=0.406, P=0.026; r=0.397, P=0.030), ALT (r=0.403, P=0.049; r=0.418, P=0.047), LDH (r=0.543, P<0.01; r=0.643, P<0.01) and GLU(r=0.750, P<0.01; r=0.471, P=0.042). A total of 5 principal components were extracted from all the included indicators, and the comprehensive information extraction rate was 82.86%. Indicators of a large load included Ur, PCT and CRP in PC1; ALT, AST and GLU in PC2; N%, L%, L and NLR in PC3. It indicated that the indicators of acute infection, liver function and blood routine had certein warning effect on disease surveillance. The results of ROC curve analysis showed that the combined detection of N+TB+Urea was the best practice to distinguish COVID-19 and other viral pneumonia, while the combined detection of N+L+UA was the most effective solution to make a distinction between COVID-19 and influenza A/B patients. In the aspect of disease evaluation, NL+LDH+GLU+ALT combined detection represent the best diagnostic performance to distinguish the clinical stage of light+common type and heavy+critical type, achieving the AUC (ROC) to 0.904, with the sensitivity 75% and the specificity 100% at the cut-off value of 0.477. Conclusion: In addition to etiology and imaging examination, doctors can also improve the routine laboratory tests such as blood routine test, liver and kidney function to assist diagnosis and disease prediction of patients with respiratory tract infection.

Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release.

In proteinuric renal diseases, excessive plasma nonesterified free fatty acids bound to albumin can leak across damaged glomeruli to be reabsorbed by renal proximal tubular cells and cause inflammatory tubular cells damage by as yet unknown mechanisms. The present study was designed to investigate these mechanisms induced by palmitic acid (PA; one of the nonesterified free fatty acids) overload. Our results show that excess PA stimulates ATP release through the pannexin 1 channel in human renal tubule epithelial cells (HK-2), increasing extracellular ATP concentration approximately threefold compared with control. The ATP release is dependent on caspase-3/7 activation induced by mitochondrial reactive oxygen species. Furthermore, extracellular ATP aggravates PA-induced monocyte chemoattractant protein-1 secretion and monocyte infiltration of tubular cells, enlarging the inflammatory response in both macrophages and HK-2 cells via the purinergic P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3 inflammasome pathway. Hence, PA increases mitochondrial reactive oxygen species-induced ATP release and inflammatory stress, which cause a "first hit," while ATP itself is a "second hit" in amplifying the renal tubular inflammatory response. Thus, inhibition of ATP release or the purinergic P2X7 receptor may be an approach to reduce renal inflammation and improve renal function.

SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE-/- mice.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that plays a critical role in regulating intracellular cholesterol levels, but the association between SCAP and foam cell formation in vascular smooth muscle cells (VSMCs) is poorly understood. Using tissue-specific SCAP knockdown in apolipoprotein E (ApoE)-/- mice, we sought to search the mechanism through which SCAP signaling affects VSMC foam cell development. VSMC-specific SCAP knockdown mice were generated by Cre/LoxP-mediated gene targeting in ApoE-/- mice. Breeding SCAPflox/flox mice with SM22α-Cre mice resulted in no viable offspring with the homozygote SM22-Cre: SCAPflox/flox genotype due to embryonic lethality. We found that the heterozygote SM22α-Cre:SCAPflox/+:ApoE-/- mice fed a Western diet for 12 wk had significantly fewer atherosclerotic plaques in their aortas than the control mice due to reduced cholesterol uptake and synthesis. Furthermore, we found that autophagy in VSMCs was increased in SM22α-Cre:SCAPflox/+:ApoE-/- mice. Similarly, in vitro, SCAP knockdown in human coronary artery VSMCs by RNA interference reduced lipid accumulation and increased autophagy under LDL cholesterol loading. SCAP knockdown in VSMCs reduced oxidative stress and increased AMPK phosphorylation, which contributed to the up-regulation of autophagy in vivo and in vitro. VSMC-specific SCAP knockdown decreased the lipid accumulation and intracellular oxidative stress, increased excessive lipid clearance by enhancing lipid autophagy mediated by the reactive oxygen species/AMPK pathway in VSMCs, and consequently alleviated atherosclerosis plaque formation.-Li, D., Chen, A., Lan, T., Zou, Y., Zhao, L., Yang, P., Qu, H., Wei, L., Varghese, Z., Moorhead, J. F., Chen, Y., Ruan, X. Z. SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE-/- mice.

[Construction and evaluation of a novel diagnosis pathway for 2019-Corona Virus Disease].

Objective: To construct and evaluate a diagnosis pathway (Xiangya pathway) for Corona Virus Disease 2019 (COVID-19). Methods: Consecutive subjects aged ≥12 years old who were screened for COVID-19 were included in Xiangya Hospital of Central South University from January 23 to February 3, 2020, and the subjects were further divided into the inception cohort and the validation cohort. The gender, age, onset time of disease of the subjects were recorded. The information of epidemiological history, fever, and the declined blood lymphocytes were collected as clinical indicators, CT scan was used to evaluate the possibility of COVID-19 and range of lung involvement. According to the current Chinese national standards, throat swabs of suspected cases were collected and the nucleic acid of COVID-19 was detected by reverse transcription-polymerase chain reaction (RT-PCR). The Xiangya pathway was constructed with multi-indexes, compared with clinical indicators, CT results and Chinese national standards, their effectiveness of detecting confirmed cases were verified in the inception and validation cohort. Results: A total of 382 consecutive adults who was screened for COVID-19 were included, and 261 cases were in the inception cohort and 121 cases were in the validation cohort. Among the 382 cases, 192 were males (50.3%) and 190 were females (49.7%), with a median age of 35 years (range: 15-92 years). There were 183 cases (47.9%) with epidemiological history, 275 cases (72.0%) with fever, 212 cases (55.5%) with decreased peripheral blood lymphocytes, 114 cases (29.8%) with positive CT findings, 43 cases (11.3%) with positive CT-COVID-19, and 30 cases (7.9%) with positive virus nucleic acid by throat swab. Compared with clinical indicators, the sensitivity and specificity of CT were 0.950 and 0.704, respectively. The accuracy of CT to make a definite diagnosis was higher than that of epidemiological history, fever, and declined blood lymphocyte count (0.809 vs 0.660, 0.532, 0.596, P=0.001, 0.002, 0.003, respectively). The sensitivity of this pathway and the pathway recommended by the Health Commission of China were both high (all were 1.000), while the specificity and accuracy of the Xiangya pathway were higher than the one recommended by the Health Commission (0.872 vs 0.765, 0.778 vs 0.592, both P<0.001). The CT-COVID-19 reduced the missed diagnosis rate caused by false negative of nucleic acid test (31 vs 64), with difference rate of 51.6%, and the positive rate of nucleic acid test was 64.5% (20/31). In validation cohort, the specificity and accuracy of the Xiangya pathway was 0.967, the positive rate of nucleic acid test was 76.9%(10/13). Conclusions: The Xiangya pathway can predict the nucleic acid test results of COVID-19, and can be applied as a reliable strategy to screen patients with suspected COVID-19 among people aged ≥12 years in areas other than Hubei during the epidemic period of COVID-19. The cohort size needs to be increased for further validation.