Sarcopenia adversely impacts clinical outcomes in patients undergoing pancreaticoduodenectomy: A systematic review and meta-analysis.

BACKGROUND: Sarcopenia is a syndrome marked by a gradual and widespread reduction in skeletal muscle mass and strength, as well as a decline in functional ability, which is associated with malnutrition, hormonal changes, chronic inflammation, disturbance of intestinal flora, and exercise quality. Pancreatoduodenectomy is a commonly employed clinical intervention for conditions such as pancreatic head cancer, ampulla of Vater cancer, and cholangiocarcinoma, among others, with a notably high rate of postoperative complications. Sarcopenia is frequent in patients undergoing pancreatoduodenectomy. However, data regarding the effects of sarcopenia in patients undergoing pancreaticoduodenectomy (PD) are both limited and inconsistent. AIM: To assess the influence of sarcopenia on outcomes in patients undergoing PD. METHODS: The PubMed, Cochrane Library, Web of Science, and Embase databases were screened for studies published from the time of database inception to June 2023 that described the effects of sarcopenia on the outcomes and complications of PD. Two researchers independently assessed the quality of the data extracted from the studies that met the inclusion criteria. Meta-analysis using RevMan 5.3.5 and Stata 14.0 software was conducted. Forest and funnel plots were used, respectively, to demonstrate the outcomes of the sarcopenia group vs the non-sarcopenia group after PD and to evaluate potential publication bias. RESULTS: Sixteen studies encompassing 2381 patients were included in the meta-analysis. The patients in the sarcopenia group (n = 833) had higher overall postoperative complication rates [odds ratio (OR) = 3.42, 95% confidence interval (CI): 1.95-5.99, P < 0.0001], higher Clavien-Dindo class ≥ III major complication rates (OR = 1.41, 95%CI: 1.04-1.90, P = 0.03), higher bacteremia rates (OR = 4.46, 95%CI: 1.42-13.98, P = 0.01), higher pneumonia rates (OR = 2.10, 95%CI: 1.34-3.27, P = 0.001), higher pancreatic fistula rates (OR = 1.42, 95%CI: 1.12-1.79, P = 0.003), longer hospital stays (OR = 2.86, 95%CI: 0.44-5.28, P = 0.02), higher mortality rates (OR = 3.17, 95%CI: 1.55-6.50, P = 0.002), and worse overall survival (hazard ratio = 2.81, 95%CI: 1.45-5.45, P = 0.002) than those in the non-sarcopenia group (n = 1548). However, no significant inter-group differences were observed regarding wound infections, urinary tract infections, biliary fistulas, or postoperative digestive bleeding. CONCLUSION: Sarcopenia is a common comorbidity in patients undergoing PD. Patients with preoperative sarcopenia have increased rates of complications and mortality, in addition to a poorer overall survival rate and longer hospital stays after PD.

Risk assessment of China's Eastern Route of the South-to-north Water Diversion Project from the perspective of Phthalate Esters occurrence in the impounded lakes.

Phthalate esters (PAEs) are widely utilized and can accumulate in lacustrine ecosystems, posing significant ecological and human health hazards. Most studies on PAEs focus on individual lakes, lacking a comprehensive and systematic perspective. In response, we have focused our investigation on characteristic lakes situated along the Eastern Route of the South-to-north Water Diversion Project (SNWDP-ER) in China. We have detected 16 PAE compounds in the impounded lakes of the SNWDP-ER by collecting surface water samples using solid-phase extraction followed by gas chromatography analysis. The concentration of PAEs were found to between 0.80 to 12.92 µg L-1. Among them, Bis (2-ethylhexyl) phthalate (DEHP) was the most prevalent, with mean concentration of 1.56 ±â€¯0.62 µg L-1 (48.44%), followed by Diisobutyl phthalate (DIBP), 0.64 ±â€¯1.40 µg L-1 (19.87%). Spatial distribution showed an increasing trend in the direction of water flow. Retention of DEHP and DIBP has led to increased environmental risks. DEHP, Dimethyl phthalate (DMP) etc. determined by agriculture and human activities. Additionally, Dibutyl phthalate (DBP) and DIBP mainly related to the use of agricultural products. To mitigate the PAEs risk, focusing on integrated management of the lakes, along with the implementation of stringent regulations to control the use of plasticizes in products.

Emission characteristics of condensable particulate matter during the production of solid waste-based sulfoaluminate cement: Compositions, heavy metals, and preparation impacts.

Recycling solid waste for preparing sulfoaluminate cementitious materials (SACM) represents a promising approach for low-carbon development. There are drastic physical-chemical reactions during SACM calcination. However, there is a lack of research on the flue gas pollutants emissions from this process. Condensable particulate matter (CPM) has been found to constitute the majority of the primary PM emitted from various fuel combustion. In this study, the emission characteristics of CPM during the calcination of SACM were determined using tests in both a real-operated kiln and laboratory experiments. The mass concentration of CPM reached 96.6 mg/Nm3 and occupied 87% of total PM emission from the SACM kiln. Additionally, the mass proportion of SO42- in the CPM reached 93.8%, thus indicating that large quantities of sulfuric acid mist or SO3 were emitted. CaSO4 was one key component for the formation of main mineral ye'elimite (3CaO·3Al2O3·CaSO4), and its decomposition probably led to the high SO42- emission. Furthermore, the use of CaSO4 as a calcium source led to SO42- emission factor much higher than conventional calcium sources. Higher calcination temperature and more residence time also increased SO42- emission. The most abundant heavy metal in kiln flue gas and CPM was Zn. However, the total condensation ratio of heavy metals detected was only 40.5%. CPM particles with diameters below 2.5 µm and 4-20 µm were both clearly observed, and components such as Na2SO4 and NaCl were conformed. This work contributes to the understanding of CPM emissions and the establishment of pollutant reduction strategies for waste collaborative disposal in cement industry.

Disclosing the intrinsic nature of efficient removal of antibiotics in N/S dual-doped porous carbon-based materials: The manipulation of internal electric field.

N/S co-doping has emerged as a prevailing strategy for carbon-based adsorbents to facilitate the antibiotic removal efficiency. Nevertheless, the underlying interplay among N, S, and their adjacent vacancy defects remains overlooked. Herein, we present a novel in situ strategy for fabricating pyridinic-N dominated and S dual-doped porous carbon adsorbent with rich vacancy defects (VNSC). The experimental results revealed that N (acting as the electron donor) and S (acting as the electron acceptor) form an internal electric field (IEF), with a stronger IEF generated between pyridinic-N and S, while their adjacent vacancy defects activate carbon π electrons, thus enhancing the charge transfer of the IEF. Density functional theory (DFT) calculations further demonstrated that the rich charge transfer in the IEF facilitated the π-π electron donor-acceptor (EDA) interaction between VNSC and tetracycline (TC) as well as norfloxacin (NOR), and thus is the key to adsorption performance of VNSC. Consequently, VNSC exhibited high adsorption capacities toward TC (573.1 mg g-1) and NOR (517.0 mg g-1), and its potential for environmental applications was demonstrated by interference, environmentally relevant concentrations, fixed-bed column, and regeneration tests. This work discloses the natures of adsorption capacity for N/S dual-doped carbon-based materials for antibiotics.

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn.

BACKGROUND: ß-Propeller protein-associated neurodegeneration (BPAN) is a genetic neurodegenerative disease caused by mutations in WDR45. The impairment of autophagy caused by WDR45 deficiency contributes to the pathogenesis of BPAN; however, the pathomechanism of this disease is largely unknown. Lipid dyshomeostasis is involved in neurogenerative diseases, but whether lipid metabolism is affected by Wdr45 deficiency and whether lipid dyshomeostasis contributes to the progression of BPAN are unclear. METHODS: We generated Wdr45 knockout SN4741 cell lines using CRISPR‒Cas9-mediated genome editing, then lipid droplets (LDs) were stained using BODIPY 493/503. Chaperone-mediated autophagy was determined by RT-qPCR and western blotting. The expression of fatty acid synthase (Fasn) was detected by western blot in the presence or absence of the lysosomal inhibitor NH4Cl and the CMA activator AR7. The interaction between Fasn and HSC70 was analyzed using coimmunoprecipitation (Co-IP) assay. Cell viability was measured by a CCK-8 kit after treatment with the Fasn inhibitor C75 or the CMA activator AR7. RESULTS: Deletion of Wdr45 impaired chaperone-mediated autophagy (CMA), thus leading to lipid droplet (LD) accumulation. Moreover, Fasn can be degraded via CMA, and that defective CMA leads to elevated Fasn, which promotes LD formation. LD accumulation is toxic to cells; however, cell viability was not rescued by Fasn inhibition or CMA activation. Inhibition of Fasn with a low concentration of C75 did not affect cell viability but decreases LD density. CONCLUSIONS: These results suggested that Fasn is essential for cell survival but that excessive Fasn leads to LD accumulation in Wdr45 knockout cells.

Hepatocytic lipocalin-2 controls HDL metabolism and atherosclerosis via Nedd4-1-SR-BI axis in mice.

High-density lipoprotein (HDL) metabolism is regulated by complex interplay between the scavenger receptor group B type 1 (SR-BI) and multiple signaling molecules in the liver. Here, we show that lipocalin-2 (Lcn2) is a key regulator of hepatic SR-BI, HDL metabolism, and atherosclerosis. Overexpression of human Lcn2 in hepatocytes attenuates the development of atherosclerosis via SR-BI in western-diet-fed Ldlr-/- mice, whereas hepatocyte-specific ablation of Lcn2 has the opposite effect. Mechanistically, hepatocyte Lcn2 improves HDL metabolism and alleviates atherogenesis by blocking Nedd4-1-mediated SR-BI ubiquitination at K500 and K508. The Lcn2-improved HDL metabolism is abolished in mice with hepatocyte-specific Nedd4-1 or SR-BI deletion and in SR-BI (K500A/K508A) mutation mice. This study identifies a regulatory axis from Lcn2 to HDL via blocking Nedd4-1-mediated SR-BI ubiquitination and demonstrates that hepatocyte Lcn2 may be a promising target to improve HDL metabolism to treat atherosclerotic cardiovascular diseases.

Depletion of Igfbp7 alleviates zebrafish NAFLD progression through inhibiting hepatic ferroptosis.

AIMS: The global increased expression of Insulin-like growth factor binding protein 7 (IGFBP7) has been detected in non-alcoholic fatty liver disease (NAFLD) patients, however, its roles in NAFLD and the mechanism remain largely unclear. The goal of this study is to investigate the effect and mechanism of Igfbp7 using a zebrafish NAFLD model. MAIN METHODS: The igfbp7-/- null zebrafish mutant and the Igfbp7 liver overexpressed (LOE) transgenic zebrafish based on Gal4/UAS system were generated by CRISPR/Cas9 and Tol2 transgenic technique, respectively. The zebrafish NAFLD models in wildtypes, igfbp7-/- mutants and Igfbp7 LOE fishes have been established by high-fat diet feeding. The Igfbp7 dynamic expression and its effects on NAFLD progression have been detected and analyzed in both human NAFLD patients and zebrafish models. And the potential mechanism has been investigated through transcriptome analysis and subsequent detection and verification. KEY FINDINGS: High Igfbp7 levels in NASH and fibrosis stages have been detected in liver tissues of both human NAFLD patients and zebrafish models. Depletion of Igfbp7 significantly alleviated liver steatosis, inflammation, and fibrosis, whereas liver specific Igfbp7 overexpression dramatically exacerbated liver fibrosis in zebrafish NAFLD model. The hepatic iron deposition, lipid peroxidation products, and ferroptosis-related index were also significantly reduced at the NASH stage in the absence of Igfbp7. Igfbp7 promotes NAFLD progression through regulating ferroptosis, and Ncoa4-mediated ferritinophagy may be the pathway of Igfbp7-regulated ferroptosis. SIGNIFICANCE: Igfbp7 is confirmed as an important regulator in NAFLD progression. Depleting Igfbp7 effectively alleviates zebrafish NAFLD progression by inhibiting hepatic ferroptosis, suggesting a novel potential target for NAFLD treatment.

The influence of embryo stage on obstetric complications and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis.

Objective: To investigate the effect of embryo stage at the time of transfer on obstetric and perinatal outcomes in programmed frozen-thawed embryo transfer (FET) versus natural FET cycles. Design: Systematic review and meta-analysis. Setting: Not applicable. Patients: Women with programmed frozen-thawed embryo transfer (FET) and natural FET. Interventions: The PubMed, MEDLINE, and EMBASE databases and the Cochrane Central Register of Controlled Trials (CCRT) were searched from 1983 to October 2022. Twenty-three observational studies were included. Primary outcome measure: The primary outcomes were hypertensive disorders of pregnancy (HDPs), gestational hypertension and preeclampsia (PE). The secondary outcomes were gestational diabetes mellitus (GDM), placenta previa, postpartum haemorrhage (PPH), placental abruption, preterm premature rupture of membranes (PPROM), large for gestational age (LGA), small for gestational age (SGA), macrosomia, and preterm delivery (PTD). Results: The risk of HDP (14 studies, odds ratio (OR) 2.17; 95% confidence interval (CI) 1.95-2.41; P<0.00001; I2 = 43%), gestational hypertension (11 studies, OR 1.38; 95% CI 1.15-1.66; P=0.0006; I2 = 19%), PE (12 studies, OR 2.09; 95% CI 1.88-2.32; P<0.00001; I2 = 0%), GDM (20 studies, OR 1.09; 95% CI 1.02-1.17; P=0.02; I2 = 8%), LGA (18 studies, OR 1.11; 95% CI 1.07-1.15; P<0.00001; I2 = 46%), macrosomia (12 studies, OR 1.15; 95% CI 1.07-1.24; P=0.0002; I2 = 31%), PTD (22 studies, OR 1.21; 95% CI 1.15-1.27; P<0.00001; I2 = 49%), placenta previa (17 studies, OR 1.2; 95% CI 1.02-1.41; P=0.03; I2 = 11%), PPROM (9 studies, OR 1.19; 95% CI 1.02-1.39; P=0.02; I2 = 40%), and PPH (12 studies, OR 2.27; 95% CI 2.02-2.55; P <0.00001; I2 = 55%) were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer. Blastocyst transfer had a higher risk of HDP (6 studies, OR 2.48; 95% CI 2.12-2.91; P<0.00001; I2 = 39%), gestational hypertension (5 studies, OR 1.87; 95% CI 1.27-2.75; P=0.002; I2 = 25%), PE (6 studies, OR 2.23; 95% CI 1.93-2.56; P<0.00001; I2 = 0%), GDM (10 studies, OR 1.13; 95% CI 1.04-1.23; P=0.005; I2 = 39%), LGA (6 studies, OR 1.14; 95% CI 1.07-1.21; P<0.0001; I2 = 9%), macrosomia (4 studies, OR 1.15; 95% CI 1.05-1.26; P<0.002; I2 = 68%), PTD (9 studies, OR 1.43; 95% CI 1.31-1.57; P<0.00001; I2 = 22%), PPH (6 studies, OR 1.92; 95% CI 1.46-2.51; P<0.00001; I2 = 55%), and PPROM (4 studies, OR 1.45; 95% CI 1.14-1.83; P=0.002; I2 = 46%) in programmed FET cycles than in natural FET cycles. Cleavage-stage embryo transfers revealed no difference in HDPs (1 study, OR 0.81; 95% CI 0.32-2.02; P=0.65; I2 not applicable), gestational hypertension (2 studies, OR 0.85; 95% CI 0.48-1.51; P=0.59; I2 = 0%), PE (1 study, OR 1.19; 95% CI 0.58-2.42; P=0.64; I2not applicable), GDM (3 study, OR 0.79; 95% CI 0.52-1.20; P=0.27; I2 = 21%), LGA (1 study, OR 1.15; 95% CI 0.62-2.11; P=0.66; I2not applicable), macrosomia (1 study, OR 1.22; 95% CI 0.54-2.77; P=0.64; I2 not applicable), PTD (2 studies, OR 1.05; 95% CI 0.74-1.49; P=0.79; I2 = 0%), PPH (1 study, OR 1.49; 95% CI 0.85-2.62; P=0.17; I2not applicable), or PPROM (2 studies, OR 0.74; 95% CI 0.46-1.21; P=0.23; I2 = 0%) between programmed FET cycles and natural FET cycles. Conclusions: The risks of HDPs, gestational hypertension, PE, GDM, LGA, macrosomia, SGA, PTD, placenta previa, PPROM, and PPH were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer and blastocyst transfer, but the risks were not clear for cleavage-stage embryo transfer.

Cepharanthine Exerts Antioxidant and Anti-Inflammatory Effects in Lipopolysaccharide (LPS)-Induced Macrophages and DSS-Induced Colitis Mice.

Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, has been widely used for the treatment of various acute and chronic diseases, including leukopenia, and snake bites. Here, our objective was to investigate the anti-oxidative stress and anti-inflammatory response effects of CEP in lipopolysaccharide (LPS)-induced macrophages as well as dextran sulfate sodium (DSS)-induced colitis mice. Our findings demonstrated that supplementation with CEP effectively mitigates body weight loss and elevation of disease activity index (DAI), reduces the malondialdehyde (MDA) content to 2.45 nM/mL while increasing the reduced glutathione (GSH) content to 35.53 µg/mL, inhibits inflammatory response, and maintains proper intestinal epithelium tight junctions in DSS-induced wild type (WT) mice. However, it failed to provide protective effects in DSS-induced transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) knockout (NRF2-/-) mice. GSH content decreased to 10.85 µg/106 cells following LPS treatment, whereas supplementation with CEP increased the GSH content to 12.26 µg/106 cells. Moreover, CEP effectively attenuated ROS production in LPS-induced macrophages. Additionally, CEP exhibited inhibitory effects on pro-inflammatory cytokines and mediators in LPS-induced macrophages. Furthermore, we observed that supplementation with CEP promoted the expression of NRF2/heme oxygenase 1 (HO-1)/NADPH quinone oxidoreductase-1 (NQO-1) as well as the phosphorylation of the adenosine monophosphate-activated protein kinase alpha 1 (AMPK-α1)/protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK-3ß) signaling pathway in macrophages while inhibiting the phosphorylation of the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B p65 (NF-κB p65) signaling pathway in LPS-induced macrophages. Although CEP did not demonstrate inhibitory effects on oxidative stress or promote the expression of HO-1/NQO-1, it effectively activated the phosphorylation of the AMPK-α1/AKT/GSK-3ß signaling pathway which is an upstream regulator of NRF2 in LPS-induced primary peritoneal macrophages from NRF2-/- mice. In summary, our findings suggest that CEP exerts protective effects against oxidative stress and inflammatory response by activating the AMPK-α1/AKT/GSK-3ß/NRF2 signaling pathway while concurrently inhibiting the activation of mitogen activated protein kinases (MAPKs) and the NF-κB p65 signaling pathway. These results not only elucidate the mechanisms underlying CEP's protective effects on colon oxidative stress and inflammation but also provide evidence supporting NRF2 as a potential therapeutic target for IBD treatment.

CRISPR/Cas9-induced asap1a and asap1b co-knockout mutant zebrafish displayed abnormal embryonic development and impaired neutrophil migration.

ASAP1 (Arf-GAP with SH3 domain, the ankyrin repeat and the PH domain) is the GTPase activating protein of the small G protein Arf. To understand more about the physiological functions of ASAP1 in vivo, we chose to use the zebrafish as an animal model, and analyzed the characterization of asap1 using loss-of-function studies. Here, two isoforms in zebrafish, asap1a and asap1b, were found to be homologous to human ASAP1, and the gene knockout zebrafish lines for asap1a and asap1b were established using the CRISPR/Cas9 technique with different insertions and deletions of bases. Zebrafish with asap1a and asap1b co-knockout showed a significant reduction in survival and hatching rates, as well as an increase in malformation rates during the early stages of development, while the asap1a or asap1b single knockout mutants did not affect the growth and development of individual zebrafish. Exploring the gene expression compensation between asap1a and asap1b using qRT-PCR, we found that asap1b had increased expression when asap1a was knocked out, showing a clear compensatory effect against asap1a knockout; In turn, asap1a did not have detectable compensating expression after asap1b knockout. Furthermore, the co-knockout homozygous mutants displayed impaired neutrophil migration to Mycobacterium marinum infection, and showed an increased bacterial load. Together, these are the first inherited asap1a and/or asap1b mutant zebrafish lines by the CRISPR/Cas9 gene editing approach, and by serving as useful models, they can significantly contribute to better annotation and follow-up physiological studies of human ASAP1.

Effects of different colors of film mulch on soil temperature and rice growth in a non-flooded condition.

BACKGROUND: Rice cultivation under film mulching with no flooding is widely used as an effective water-saving technology. Different colors of film mulch have different effects on the soil hydrothermal environment and crop growth because of their different optical properties. However, the effects of different colors of film mulch on soil temperature and rice physiological growth are not clearly understood. RESULTS: Field experiments were conducted in 2019 and 2020 to investigate the effects of different color mulches on soil temperature and rice growth in a non-flooded condition. Transparent film (TM), black film (BM), two-color film (BWM, silver on the front and black on the back), and no film (NM) in a non-flooded condition were designed. Soil temperature variation at different soil depths of 0-0.25 m and rice plant height, stem thickness, dry matter, yield and quality were monitored. The results showed that compared to no mulching, the mulching treatment effectively increased the average soil temperature during the whole rice growth stage with the soil temperature ranked TM > BM > BWM. Compared with NM, the BM and BWM treatments increased rice yield by 12.1-17.7% and 6.4-14.4% in 2019 and 2020, respectively. The BWM had 18.2% and 6.8% greater gel consistency than NM in 2019 and 2020, respectively. CONCLUSION: Transparent film should be applied with care because of the high soil temperature stress. Black film and two-color film (silver on the front and black on the back) could be better option for rice yield, increasing and quality improving in a non-flooded condition. © 2023 Society of Chemical Industry.

WDR45 mutation dysregulates iron homeostasis by promoting the chaperone-mediated autophagic degradation of ferritin heavy chain in an ER stress/p38 dependent mechanism.

Ferritin is the main iron storage protein that plays a pivotal role in the regulation of iron homeostasis. Mutations in the autophagy protein WD repeat domain 45 (WDR45) that lead to iron overload is associated with the human ß-propeller protein-associated neurodegeneration (BPAN). Previous studies have demonstrated that ferritin was decreased in WDR45 deficient cells, but the mechanism remains unclear. In this study, we have demonstrated that the ferritin heavy chain (FTH) could be degraded via chaperone-mediated autophagy (CMA) in ER stress/p38-dependent pathway. In HeLa cells, inducing the ER stress activated CMA, therefore facilitated the degradation of FTH, and increased the content of Fe2+. However, the increased CMA activity and Fe2+ as well as the decreased FTH by ER stress inducer were restored by pre-treatment with p38 inhibitor. Overexpression of a mutant WDR45 activated CMA thus promoted the degradation of FTH. Furthermore, inhibition of ER stress/p38 pathway resulted in reduced activity of CMA, which consequently elevated the protein level of FTH but reduced the Fe2+ level. Our results revealed that WDR45 mutation dysregulates iron homeostasis by activating CMA, and promotes FTH degradation through ER stress/p38 signaling pathway.

Podocyte-specific deletion of ubiquitin carboxyl-terminal hydrolase L1 causes podocyte injury by inducing endoplasmic reticulum stress.

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a unique component of the ubiquitin-proteasome system (UPS), which has multiple activities in maintaining intracellular ubiquitin levels. We previously reported the aberrant low expression of UCHL1 in podocytes of non-immune complex-mediated glomerulonephritis, and recent studies indicate that anti-UCHL1 antibody was responsible for the refractory minimal change disease (MCD), but the specific effect of UCHL1 to the podocytopathy has not been determined. Therefore, we generated podocyte-specific UCHL1 gene knockout (UCHL1cre/cre) rats model. Podocyte-specific UCHL1 knockout rats exhibited severe kidney damage, including segmental/global glomerulosclerosis, kidney function damage and severe proteinuria, compared with littermate control. Subsequently, by carrying out mass spectrometry analysis of isolated glomeruli of rats, abnormal protein accumulation of ECM-receptor Interaction was found in UCHL1cre/cre rats. Mechanistic studies in vivo and in vitro revealed that aberrant protein accumulation after UCHL1 deficiency induced endoplasmic reticulum (ER) stress, unfolded protein reaction (UPR) to reduce the protein level of podocyte skeleton proteins, and CHOP mediated apoptosis as well, which related to the dysfunction of the ubiquitin-proteasome system with decreased free monomeric ubiquitin level, thereby affecting protein ubiquitination and degradation. In addition, inhibition of ER stress by 4-PBA could attenuate the degree of ER stress and podocyte dysfunction. Our study indicates that UCHL1 is a potential target for preventing podocytes injury in some non-immune complex-mediated glomerulopathy.

Quantifying Podocyte Number in a Small Sample Size of Glomeruli with CUBIC to Evaluate Podocyte Depletion of db/db Mice.

The loss of podocyte is crucial for diagnosis and prognosis of diabetic kidney disease, whereas commonly two-dimensional methods for quantifying podocyte number existed with issues of low fidelity and accuracy. In this study, clear, unobstructed brain imaging cocktails and computational analysis (CUBIC), one of three-dimensional optical clearing approaches, was used which combines tissue clearing, immunolabeling, and a light-sheet microscope to image and evaluate podocytes in C57BL/6 (C57) and db/db mice. We discovered that 77 podocytes per glomerulus were in C57 mice. On the subject of db/db mice, there were 74 podocytes by the age of 8 w, 72 podocytes by the age of 12 w, and 66 podocytes by the age of 16 w, compared with 76 podocytes in the control group, suggesting that there was a significant decrease in podocyte number in db/db mice with the age of 16 w, showing a trend which positively correlated to the deterioration of kidney function. Sample size estimation using the PASS software revealed that taking 5%, 7.5%, and 10% of the mean podocyte number per glomerulus as the statistical allowable error and 95% as total confidence interval, 33, 15, and 9 glomeruli were independently needed to be sampled in C57 mice to represent the overall glomeruli to calculate podocyte number. Furthermore, in the control group of db/db mice, 36, 18, and 11 glomeruli were needed, compared with 46, 24, and 14 glomeruli in db/db mice by the age of 8 w, 43, 21, and 12 glomeruli by the age of 12 w, and 52, 27, and 16 by the age of 16 w. These findings indicated that precise quantification of podocyte number could judge the progression of diabetic kidney disease. In addition, a small number of glomeruli could be actually representative of the whole sample size, which indicated apparent practicability of CUBIC for clinical use.

Surprising Hydrophobic Polymer Surface with a High Content of Hydrophilic Polar Groups.

The wetting property of a solid surface has been a hotspot for centuries, and many studies suggest that the hydrophobicity is highly related to the polar components. However, the underlying mechanism of polar moieties on the hydrophobicity remains unclear. Here, we tailor the surface polar moieties of epoxy resin (EP) by ozone modification and assess their wetting properties. Our results show that, for the modified EP with more (60.54%) polar moieties, the polar effect on hydrophobicity cannot be empirically observed. To reveal the underlying mechanism, the absorption parameters, including equilibrium distance, adsorption radius, and effective adsorption sites for water on EP before and after ozone treatment, are calculated on the basis of molecular simulations. After ozone modification, the equilibrium distance (from 1.95 to 1.70 Å), adsorption radius (from 3.80 to 4.50 Å), and effective adsorption sites (from 1 to 2) change slightly and the EP surface remains hydrophobic, although the polar groups significantly increase. Therefore, it is concluded that the wetting properties of solid surfaces are dominated by the equilibrium distance, adsorption radius, and effective adsorption sites for water on solids, and the nonlinear relationship between polar groups and hydrophilicity is clarified.

Verteporfin inhibits the dedifferentiation of tubular epithelial cells via TGF-ß1/Smad pathway but induces podocyte loss in diabetic nephropathy.

AIMS: The dedifferentiation of tubular epithelial cells has been identified as an important trigger of renal fibrosis. The Hippo pathway is a crucial regulator of cell proliferation and differentiation. In this study, we determined the role of Hippo proteins in tubular dedifferentiation in diabetic nephropathy (DN). MAIN METHODS: In this study, we measured dedifferentiation markers and Hippo proteins in db/db mice and high glucose treated tubular epithelial cells. Then, verteporfin and knockdown of large tumor suppressor kinase (LATS) 1 and 2 were performed to uncover therapeutic targets for DN. KEY FINDINGS: Here, we found dedifferentiation and upregulated Hippo proteins in tubular epithelial cells in DN model both in vivo and in vitro. Both verteporfin and LATS knockdown could inhibit the tubular mesenchymal transition, but verteporfin showed broad inhibitory effect on Hippo proteins, especially nuclear YAP, and exacerbated podocyte loss of DN. LATS2 knockdown did not reverse the tubular E-Cadherin loss while it also induced podocyte apoptosis. Overall, intervention of LATS1 inhibited tubular dedifferentiation efficiently without affecting YAP and bringing podocyte apoptosis. Further mechanistic investigations revealed that the TGF-ß1/Smad, instead of the YAP-TEAD-CTGF signaling, might be the underlying pathway through which verteporfin and LATS1 engaged in the tubular dedifferentiation. SIGNIFICANCE: In conclusion, verteporfin is not a suitable treatment for DN owing to evitable podocyte loss and apoptosis. Targeting LATS1 is a better choice worthy of further investigation for DN therapy.

Prophylactic cranial irradiation (PCI) versus active surveillance in patients with limited-stage small cell lung cancer: a retrospective, multicentre study.

BACKGROUND: The recommendation of PCI for limited-stage small cell lung cancer (LS-SCLC) is primarily based on evidence from the pre-magnetic resonance imaging (MRI) era. However, as MRI accuracy improves and stereotactic radiosurgery advances, the role of PCI for LS-SCLC has become uncertain. This study aims to compare the contemporary survival outcomes of patients with LS-SCLC treated with PCI versus active surveillance. METHODS: We conducted a retrospective cohort study in which 1068 patients with LS-SCLC who achieved a good response to first-line chemoradiotherapy were consecutively enrolled from 5 tertiary medical centres between June 2009 and June 2019. Of these patients, 440 received PCI, while 628 received surveillance without PCI. Propensity score matching with a 1:1 ratio was performed to balance the baseline characteristics of the two cohorts. The endpoints were overall survival (OS) and the incidence of brain metastasis (BM). RESULTS: In total, 648 patients were matched. The baseline characteristics were generally well balanced. At a median follow-up of 64.5 months (range 2-190), patients who underwent PCI had a significantly lower risk for BM than those who underwent surveillance. The 3-year cumulative incidence rate of BM was 28.2% (95% CI 22.5-33.8%) in the PCI cohort and 38.5% (32.6-44.5%) in the surveillance cohort (Gray's p = 0.002). However, the lower incidence of BM in the PCI cohort did not translate into a significant extension of OS. The median OS was 35.8 months (95% CI 27.6-44.0 months) in the PCI cohort versus 32 months (26.4-37.6 months) in the surveillance cohort (HR 0.90, 95% CI 0.74-1.10, p = 0.29). Multivariable analysis showed that disease stage, chemoradiotherapy sequence, and response to chemoradiotherapy were independent prognostic factors for BM or OS. CONCLUSIONS: Overall, PCI reduces the risk for BM but does not substantially prolong OS compared with active surveillance. A phase 3, prospective clinical trial (NCT04829708) we initiated is currently underway, which is expected to corroborate our results.

A transgenic zebrafish for in vivo visualization of cilia.

Cilia are organelles for cellular signalling and motility. Mutations affecting ciliary function are also associated with cilia-related disorders (ciliopathies). The identification of cilia markers is critical for studying their function at the cellular level. Due to the lack of a conserved, short ciliary localization motif, the full-length ARL13b or 5HT6 proteins are normally used for cilia labelling. Overexpression of these genes, however, can affect the function of cilia, leading to artefacts in cilia studies. Here, we show that Nephrocystin-3 (Nphp3) is highly conserved among vertebrates and demonstrate that the N-terminal truncated peptide of zebrafish Nphp3 can be used as a gratuitous cilia-specific marker. To visualize the dynamics of cilia in vivo, we generated a stable transgenic zebrafish Tg (ß-actin: nphp3N-mCherry)sx1001. The cilia in multiple cell types are efficiently labelled by the encoded fusion protein from embryonic stages to adulthood, without any developmental and physiological defects. We show that the line allows live imaging of ciliary dynamics and trafficking of cilia proteins, such as Kif7 and Smo, key regulators of the Hedgehog signalling pathway. Thus, we have generated an effective new tool for in vivo cilia studies that will help shed further light on the roles of these important organelles.

Molecular characterization of a novel virga-like virus associated with wheat.

In this work, we report the detection of a novel single-strand RNA virus from wheat, tentatively named "Triticum aestivum-associated virga-like virus 1" (TaAVLV1). Further characterization revealed that the complete genome of TaAVLV1 is divided into two segments, RNA1 and RNA2, which are 3530 and 3466 nt in length, excluding their respective polyA tails, and each contains only one open reading frame (ORF). The ORF of RNA1 encodes an RNA-dependent RNA polymerase (RdRp), while the ORF of RNA2 encodes a putative protein with methyltransferase and helicase domains. Phylogenetic analysis showed that the RdRp of TaAVLV1 is closely related to those of members of the unclassified virga-like virus group in the family Virgaviridae. Thus, we have identified TaAVLV1 as a putative novel virga-like virus belonging to the family Virgaviridae.

Sediment organic matter properties facilitate understanding nitrogen transformation potentials in East African lakes.

East African lakes include the most productive and alkaline lake group in the world. Yet, they generally receive fewer nutrient inputs than the densely populated subtropical and temperate lakes in the northern hemisphere. In these lakes with insufficient supplies of inorganic nitrogen, the mineralization of benthic organic matter can play an important role in driving the nutrient cycle and nitrogen loss. Using a suite of stable 15N isotope dilution and tracer techniques, we examined five main processes of the sediment nitrogen cycle in 16 lakes and reservoirs of Tanzania and Kenya, East Africa: gross nitrogen mineralization, ammonium immobilization, dissimilatory nitrate reduction to ammonium (DNRA), and the dinitrogen (N2) production via denitrification and anaerobic ammonium oxidation (anammox). Gross nitrogen mineralization and ammonium immobilization showed the maximum values of 9.84 and 12.39 µmol N kg-1 h-1, respectively. Potential DNRA rates ranged from 0.22 to 8.15 µmol N kg-1 h-1 and accounted for 10 %-74 % (average 25 %) of the total dissimilatory nitrate reduction. Potential nitrate reduction rates in most lakes were dominated by denitrification with a contribution of 26 %-85 % and a mean of 65 %. We further found that the sediment nitrogen transformations were driven mainly by benthic organic matter properties and water column phosphate concentrations, reflecting microbial metabolic responses to the changing carbon and nutrients availability. For instance, autochthonous production of protein-like organic matter attributed to active sediment nitrogen mineralization, DNRA, and denitrification. In contrast, the high degree of humification caused by the inputs of terrestrial humic-like substances slowed down the sediment nitrogen transformations. The contribution of DNRA to total dissimilatory nitrate reduction was significantly positively correlated to sediment C: N ratios. These results indicate that predictions of sediment N supply and loss in East African lakes can be improved by incorporating sediment organic matter properties.