Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway.

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1ß⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn's disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn's disease.

The effects of side chain engineering on the morphology and charge transport of the A-DA1D-A type of non-fullerene acceptor: a multiscale study.

The appearance of the A-DA1D-A type of non-fullerene acceptor Y6 and its derivatives significantly improves the power conversion efficiency of organic solar cells. However, the effects of the modulation of the side chains of Y6 on its morphology and charge transport in organic thin films are still not well understood. In this work, we have systematically studied the effects of symmetric modifications of the length of alkyl side chains and the types, such as branched or straight alkyl chains, and the introduction of heteroatoms to side chains on these properties. A multiscale study, including density functional theory and classical molecular dynamics simulations, has been used to answer this open question. We find that face-on configurations are generally dominant for the AA, A1A1, and DD stacking of molecular pairs. With respect to prototype Y6, the introduction of oxygen atoms to outer alkyl side chains could enhance AA stacking but worsen the electrical network and enlarge the reorganization energy during electron transfer, and changing outer side straight alkyl chains to branched chains ruins π-π stacking of all units significantly. Finally, we discover that shortening outer alkyl side chains appropriately or changing inner branched chains to straight chains with the same number of carbon atoms is a good strategy to improve the molecular π-π stacking and electron mobility of Y6 while changing outer straight side chains to branched chains or introducing oxygen atoms to outer straight chains is the opposite. This study provides a new insight into the relationship between morphology and electron mobility and will be helpful for the design of future high-performance non-fullerene acceptors.

Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease.

Farnesoid X receptor (FXR) was considered as a promising drug target in the treatment of cholestasis, drug-induced liver injury, and non-alcoholic steatohepatitis (NASH). However, the existing FXR agonists have shown different degrees of side effects in clinical trials without clear interpretation. MET-409 in clinical phase Ⅲ, has been proven significantly fewer side effects than that of other FXR agonists. This may be due to the completely different structure of FEX and other non-steroidal FXR agonists. Herein, the structure-based drug design was carried out based on FEX, and the more active FXR agonist LH10 (FEX EC50 = 0,3 µM; LH10 EC50 = 0.14 µM)) was screened out by the comprehensive SAR studies. Furthermore, LH10 exhibited robust hepatoprotective activity on the ANIT-induced cholestatic model and APAP-induced acute liver injury model, which was even better than positive control OCA. In the nonalcoholic steatohepatitis (NASH) model, LH10 significantly improved the pathological characteristics of NASH by regulating several major pathways including lipid metabolism, inflammation, oxidative stress, and fibrosis. With the above attractive results, LH10 is worthy of further evaluation as a novel agent for the treatment of liver disorders.

Effect of COVID-19 on Thrombosis Incidence and Patient Prognosis in Kidney Transplant Recipients.

BACKGROUND Thrombosis poses a grave threat to patients undergoing kidney transplants, with a heightened risk of mortality. While previous studies have established a link between COVID-19 and thrombosis, the specific association between COVID-19 and thrombosis in this patient population remains unexplored. MATERIAL AND METHODS We conducted a retrospective analysis utilizing data from 394 individuals who underwent kidney transplantation within the period of September 1, 2015, to April 1, 2023. To evaluate overall survival, we employed Kaplan-Meier analysis and utilized a logistic regression model for risk analysis. Furthermore, we developed a prediction model and assessed its accuracy through calibration curves. RESULTS Out of the 394 patients included in our study, a total of 51 individuals experienced thrombosis, resulting in 2 deaths. Our analysis revealed that COVID-19 infection significantly increased the risk of thrombosis (odds ratio [OR] 8.60, 95% confidence interval 3.13-24.74, P<0.01). Additionally, the use of cyclosporine was found to elevate the risk of death (OR 20.86, 95% CI 7.93-59.24, P<0.01) according to multifactorial analysis. Logistic models were employed to screen variables, and predictive models were constructed based on the presence of COVID-19 infection and the usage of cyclosporine. A nomogram was developed, demonstrating promising accuracy in estimating the risk of thrombosis during internal validation, with a corrected C-index of 0.869. CONCLUSIONS Our study suggests that both COVID-19 infection and the use of cyclosporine can serve as reliable predictors of thrombosis risk in patients undergoing renal transplantation. Furthermore, we developed a mortality risk prediction model based on COVID-19 in assessing thrombosis.

Vitamin D and CRP are associated in hospitalized inflammatory bowel disease (IBD) patients in Shanghai.

BACKGROUND AND OBJECTIVES: Patients with inflammatory bowel disease (IBD) are more likely to be confirmed with vitamin D deficiency. However, the association between inflammation and vitamin D remains unclear. The purpose of this study was to evaluate the association between inflammation and vitamin D in hospitalized patients with IBD. METHODS AND STUDY DESIGN: All the participants were recruited from one teaching hospital from June 2018 to October 2022. Inflammation was evaluated by serum concentration of C-reactive protein (CRP), using an immunoturbidimetric method at admission. We further divided the participants into five groups based on serum CRP levels: <5, 5-9.9, 10-19.9, 20-39.9, and >40mg/L. Serum 25-hydroxy-vitamin D (25-(OH)-D) was assessed by liquid chromatography tandem mass spectrometry. Addi-tional information, including age, sex, body mass index (BMI), IBD (ulcerative colitis vs. Crohn's disease) subtype, was abstracted from medical records. RESULTS: This study included 1,989 patients with IBD (average age was 39.4 years, 33.8% of them were women, 1,365 CD and 624 UC patients). The median CRP was 5.49 mg/L (range of quartiles: 1.64~19.5 mg/L) and the prevalence of 25-(OH)-D deficiency was 69.8%. CRP was significantly associated with serum level of 25-(OH)-D. The difference in 25-(OH)-D was -4.28 ng/ml (-5.27 ng/ml, -3.31 ng/ml) between two extremist CRP groups after adjustment of potential covariates (age, sex, BMI, type of IBD, dietary type, season, and lymphocyte count). Subgroup analysis in sex, type of IBD, and age, were similar to the main analysis results. CONCLUSIONS: There was a negative association between CRP levels and vitamin D in hospitalized patients with IBD.

Up-regulation of PRKDC was associated with poor renal dysfunction after renal transplantation: A multi-centre analysis.

Renal transplantation is the only efficacious treatment for end-stage kidney disease. However, some people have developed renal insufficiency after transplantation, the mechanisms of which have not been well clarified. Previous studies have focused on patient factors, while the effect of gene expression in the donor kidney on post-transplant renal function has been less studied. Donor kidney clinical data and mRNA expression status were extracted from the GEO database (GSE147451). Weight gene co-expression network analysis (WGCNA) and differential gene enrichment analysis were performed. For external validation, we collected data from 122 patients who accepted renal transplantation at several hospitals and measured the level of target genes by qPCR. This study included 192 patients from the GEO data set, and 13 co-expressed genes were confirmed by WGCNA and differential gene enrichment analysis. Then, the PPI network contained 17 edges as well as 12 nodes, and four central genes (PRKDC, RFC5, RFC3 and RBM14) were identified. We found by collecting data from 122 patients who underwent renal transplantation in several hospitals and by multivariate logistic regression that acute graft-versus-host disease postoperative infection, PRKDC [Hazard Ratio (HR) = 4.44; 95% CI = [1.60, 13.68]; p = 0.006] mRNA level correlated with the renal function after transplantation. The prediction model constructed had good predictive accuracy (C-index = 0.886). Elevated levels of donor kidney PRKDC are associated with renal dysfunction after transplantation. The prediction model of renal function status for post-transplant recipients based on PRKDC has good predictive accuracy and clinical application.

Unlocking the potential of milk whey protein components in colorectal cancer prevention and therapy.

Extensive research from large prospective cohort studies and meta-analytical investigations over recent decades have consistently indicated that dairy foods have protective effects, reducing the risk of colorectal cancer. Most of the literature has explored the potential role of milk minerals and vitamins in managing colorectal cancer. Yet, there is a paucity of a comprehensive summary of the anticancer attributes of milk protein components and their underlying mechanisms of action. Recent advancements have spotlighted the potential of whey proteins, including ß-lactoglobulin, α-lactalbumin, serum albumin, and lactoferrin, as promising candidates for both the prevention and treatment of colorectal cancer. Notably, whey proteins have demonstrated a more pronounced capacity for suppressing carcinogen-induced tumors when compared to casein. Their strong binding affinity enables them to serve as effective carriers for small molecules or drugs targeting colon cancer therapy. Furthermore, numerous studies have underscored the anti-inflammatory and antioxidant prowess of whey proteins in cancer prevention. Additionally, whey proteins have been shown to trigger apoptosis, hinder tumor cell proliferation, and impede metastasis. This comprehensive review, therefore, not only substantiates the significance of incorporating whey protein components into a balanced daily diet but also underscores their potential in safeguarding against the onset and progression of colorectal cancer.

Dairy products have consistently had protective effects in reducing the risk of colorectal cancer.Whey proteins have shown promise as candidates for the prevention and treatment of colorectal cancer.Whey proteins have a strong binding ability, enabling them to act as carriers of small molecules or drugs targeting colon cancer therapy.Their anti-inflammatory and anti-oxidant capacity may play a role in cancer prevention.Whey proteins could induce apoptosis and inhibit the proliferation and metastasis of tumor cells.

Design, synthesis, and biological evaluation studies of novel carboxylesterase 2 inhibitors for the treatment of irinotecan-induced delayed diarrhea.

Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea. Following screening of the in-house library, the lead compound 01 was identified with potent inhibition on hCES2A, which was further optimized to obtain LK-44 with potent inhibitory activity (IC50 = 5.02 ± 0.67 µM) and high selectivity on hCES2A. Molecular docking and molecular dynamics simulations indicated that LK-44 can formed stable hydrogen bonds with amino acids surrounding the active cavity of hCES2A. The results of inhibition kinetics studies unveiled that LK-44 inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a Ki value of 5.28 µM. Notably, LK-44 exhibited low toxicity towards HepG2 cells according to the MTT assay. Importantly, in vivo studies showed that LK-44 significantly reduced the side effects of irinotecan-induced diarrhea. These findings suggested that LK-44 is a potent inhibitor of hCES2A with high selectivity against hCES1A, which has potential as a lead compound for the development of more effective hCES2A inhibitors to mitigate irinotecan-induced delayed diarrhea.

Validation of a methodology for characterization of rumination, lying, standing, and performing non-nutritive oral behaviors and behavioral patterns in Holstein dairy calves.

Calf behavior is closely related to its early growth, production performance, and health performance. Continuous behavior recording is the most accurate but also time-consuming method used for monitoring animal behaviors, so the instantaneous sampling method is often adopted to minimize the time required to quantify behavioral observations in animal studies. Moreover, the optimal sampling intervals required to yield accurate information for estimating Holstein dairy calves' behaviors are still unknown. Our primary objective was to determine the most optimal sampling intervals for monitoring behaviors of Holstein dairy calves during preweaning and weaning periods to improve efficiency while maintaining reliability. The secondary objective was to describe their behavioral patterns. Rumination, lying, standing, and non-nutritive oral behavior (NNOB) data of 18 calves (observation time: 360 h/calf, 6,480 h in total) were continuously recorded for 15 d (3 d at 1, 3, 6, 9, and 12 wk of age). The continuous behavioral data were compared with instantaneous sampling at 5 s, 10 s, 15 s, 30 s,1 min, 3 min, 5 min, 10 min, 15 min, 30 min, and 60 min intervals. Sampling intervals were considered accurate if they met 4 criteria: coefficient of determination ≥0.90 (i.e., strongly related to true values), slope = 1, intercept = 0 (i.e., they did not over- or underestimate true values), and relative error <10%. The most optimal sampling interval was considered the highest sampling interval among the 11 sampling intervals that meet the criteria for accurate monitoring. As expected, the strength of the linear relationship between the continuous recording and instantaneous sampling decreased as the sampling intervals increased. The results varied across the different behaviors, with rumination, lying, standing, and NNOB being reliable at instantaneous recordings of 3 min, 10 min, 10 min, and 1 min for the preweaning period (1, 3, and 6 wk of age) and 10 min, 10 min, 15 min, and 3 min for the postweaning period (9 and 12 wk of age). In terms of behavioral patterns, lying time decreased, whereas rumination, standing, and NNOB time increased with age. After weaning, no significant changes in time spent performing these behaviors. Additionally, the rumination behavioral pattern becomes stable after wk 6 with decreasing after the morning feeding and occurring mainly in the morning. In conclusion, instantaneous sampling is a reliable method for monitoring the behaviors of dairy calves, but the optimal sampling intervals should be selected based on different ages and management conditions.

Complementary hepatic metabolomics and proteomics reveal the adaptive mechanisms of dairy cows to the transition period.

The transition period from late pregnancy to early lactation is a vital time of the lifecycle of dairy cows due to the marked metabolic challenges. Besides, the liver is the pivot point of metabolism in cattle. Nevertheless, the hepatic physiological molecular adaptation during the transition period has not been elucidated, especially from the metabolomics and proteomics view. Therefore, the present study aims to investigate the hepatic metabolic alterations in transition cows by using integrative metabolomics and proteomics methods. Gas chromatography quadrupole-time-of-flight mass spectrometry-based metabolomics and data-independent acquisition-based quantitative proteomics methods were used to analyze liver tissues collected from 8 healthy multiparous Holstein dairy cows 21 d before and after calving. In total, 44 metabolites and 250 proteins were identified as differentially expressed from 233 metabolites and 3,539 proteins detected from the liver biopsies during the transition period. Complementary functional analysis of different metabolites and proteins indicated the upregulated gluconeogenesis, tricarboxylic acid cycles, AA degradation, fatty acid oxidation, AMP-activated protein kinase signaling pathway, peroxisome proliferator-activated receptor signaling pathway, and ribosome proteins in postpartum dairy cows. In terms of the metabolites and proteins, glucose-6-phosphate, fructose-6-phosphate, carnitine palmitoyltransferase 1A, and phosphoenolpyruvate carboxykinase played a significant role in these pathways. The upregulated oxidative status may be accompanied by the pathways mentioned above. In addition, the upregulated glucagon and insulin signaling pathways also indicated the significant requirement for glucose in postpartum dairy cows. These outcomes, from the view of global metabolites and proteins, may present a better comprehension of the biology of the transition period, which can be helpful in further developing nutritional regulation strategies targeting the liver to help cows overcome this metabolically challenging time.

Growth performance, blood metabolites, ruminal fermentation, and bacterial community in preweaning dairy calves fed corn silage-included starter and total mixed ration.

The objective of this study was to evaluate the effects of the inclusion of whole-plant corn silage (WPCS) in a starter or total mixed ration (TMR) on growth, blood metabolites, ruminal fermentation, and microbial community in preweaning dairy calves. A total of 45 healthy dairy calves were blocked by date of birth and randomly assigned to 1 of 3 treatments: 100% calf starter (CONS), a mix of 85% calf starter and 15% WPCS [dry matter (DM) basis; CSCS], or 100% WPCS-based lactation TMR (CTMR). Pasteurized normal milk was fed to all the animals under the same regimen. The experiment ran from when the calves were 2 d old to weaning at 63 d. Milk and feed intakes were recorded daily. Growth performance data and blood samples were collected on wk 3, 5, 7, and 9 of the experiment. Rumen fluid was sampled at 40 and 60 d. The 3 treatments had different particle size fractions. The CSCS group had greater medium fraction (<19 mm, >8 mm) and particles retained on 8-mm sieves than the other 2 groups, whereas the CTMR group had the greatest long (>19 mm) and fine (<4 mm) fractions and physically effective neutral detergent fiber (NDF) on 8- and 4-mm sieves, but had the smallest short fraction (<8 mm, >4 mm) and particles retained on 4-mm sieves. The 24-h in vitro digestibility of DM, crude protein (CP), NDF, and acid detergent fiber (ADF) were decreased in order by the CONS, CSCS, and CTMR groups. Compared with the CONS group, the digestibility of ether extract (EE) was lower in the CSCS and CTMR groups, whereas the digestibility of starch was similar among treatments. During the experimental period, the DM, CP, and metabolizable energy intakes from milk, solid feed, and total feed were not affected by treatments. The NDF, ADF, and EE intakes and potentially digestible intakes were greater in the CTMR group than in the other 2 groups. With the exception that body barrel was greater for calves fed CSCS, growth parameters and blood metabolites were similar among treatments. Compared with the CSCS group, the CTMR group had greater rumen pH and total volatile fatty acids, propionate, and isovalerate concentrations, but a lower acetate:propionate ratio. The CTMR group had greater relative abundances of some cellulolytic bacteria (Rikenellaceae RC9 gut group, Christensenellaceae R7, Ruminococcaceae NK4A214, Ruminococcaceae UCG, Ruminococcus, and Erysipelotrichaceae UCG) in the rumen, which may be beneficial for the early acquisition of specific adult-associated microorganisms. In summary, a WPCS-based lactation TMR, but not the WPCS-included starter, had the potential to be an alternative starter in preweaning calves without having significant adverse effects. These findings provide theoretical and practical implications for the rational application of TMR in the early life of dairy calves.

Effect of diets enriched in n-6 or n-3 fatty acids on dry matter intake, energy balance, oxidative stress, and milk fat profile of transition cows.

The objective of this study was to determine the effect of dietary supplementation of n-3 polyunsaturated fatty acids (PUFA) and n-6 PUFA on dry matter intake (DMI), energy balance, oxidative stress, and performance of transition cows. Forty-five multiparous Holstein dairy cows with similar parity, body weight (BW), body condition score (BCS), and milk yield were used in a completely randomized design during a 56-d experimental period including 28 d prepartum and 28 d postpartum. At 240 d of pregnancy, cows were randomly assigned to one of the 3 isoenergetic and isoprotein dietary treatments, including a control ration containing 1% hydrogenated fatty acid (CON), a ration with 8% extruded soybean (HN6, high n-6 PUFA source), and a ration with 3.5% extruded flaxseed (HN3; high n-3 PUFA source). The HN6 and HN3 diets had an n-6/n-3 ratio of 3.05:1 and 0.64:1 in prepartum cows and 8.16:1 and 1.59:1 in postpartum cows, respectively. During the prepartum period (3, 2, and 1 wk before calving), DMI, DMI per unit of BW, total net energy intake, and net energy balance were higher in the HN3 than in the CON and NH6 groups. During the postpartum period (2, 3, and 4 wk after calving), cows fed HN3 and HN6 diets both showed increasing DMI, DMI as a percentage of BW, and total net energy intake compared with those fed the CON diet. The BW of calves in the HN3 group was 12.91% higher than those in the CON group. Yield and nutrient composition of colostrum (first milking after calving) were not affected by HN6 or HN3 but milk yield from 1 to 4 wk of milking was significantly improved compared with CON. During the transition period, BW, BCS, and BCS changes were not affected. Cows fed the HN6 diet had a higher plasma NEFA concentration compared with the CON cows during the prepartum period. Feeding HN3 reduced the proportion of de novo fatty acids and increased the proportion of preformed long-chain fatty acids in regular milk. In addition, the n-3 PUFA-enriched diet reduced the n-6/n-3 PUFA ratio in milk. In conclusion, increasing the n-3 fatty acids concentration in the diet increased both DMI during the transition period and milk production after calving, and supplementing n-3 fatty acids was more effective in mitigating the net energy balance after calving.

Enhanced Photovoltaic Properties of Y6 Derivatives with Asymmetric Terminal Groups: A Theoretical Insight.

Y6 derivatives with asymmetric terminal groups have attracted considerable attention in recent years. However, the effects of the asymmetric modification of terminal groups on the photovoltaic performance of Y6 derivatives are not well understood yet. Therefore, we designed a series of Y6-based acceptors with asymmetric terminal groups by endowing them with various electron-withdrawing abilities and different conjugated rings to conduct systematic research. The electron-withdrawing ability of the Y6-D1 terminal group (substituted by IC-2F and IC-2NO2 terminals) is strongest, followed by Y6 (substituted by two same IC-2F terminals), Y6-D2 (substituted by IC-2F and 2-(4-oxo-4,5-dihydro-6H-cyclopenta[b]thiophen-6-ylidene)malononitrile terminals), Y6-D4 (substituted by IC-2F and indene ring), and Y6-D3 (substituted by IC-2F and thiazole ring). Computed results show that A-A stacking is the main molecular packing mode of Y6 and four other asymmetric Y6 derivatives. The ratios of A-A stacking face-on configuration of Y6-D1, Y6-D2, Y6-D3, Y6-D4, and Y6 are 51.6%, 55.0%, 43.5%, 59.3%, and 62.4%, respectively. Except for Y6-D1 substituted by the IC-2F and IC-2NO2 (the strongest electron-withdrawing capacity) terminal groups, the other three asymmetric molecules are mainly electron-transporting and can therefore act as acceptors. The open-circuit voltages of organic solar cells (OSCs) based on Y6-D2, Y6-D3, and Y6-D4, except for Y6-D1, may be higher than those of OSCs based on the Y6 acceptor because of their higher energy levels of lowest unoccupied molecular orbital (LUMO). PM6/Y6-D3 and PM6/Y6-D4 have better light absorption properties than PM6/Y6 due to their higher total oscillator strength. These results indicate that Y6-D3 and Y6-D4 can be employed as good acceptors.

Design, synthesis, and biological studies of dual URAT1 inhibitor and FXR agonist based on benzbromarone.

With increased unhealthy dietary patterns and a sedentary lifestyle, the prevalence of hyperuricemia is growing rapidly, placing a tremendous burden on the public health system. Persistent hyperuricemia in extreme cases induces gout, gouty arthritis, and other metabolic diseases. Benzbromarone is a potent human urate transporter 1 (URAT1) inhibitor that is widely used as a uric acid-lowering drug. Recent studies indicated that benzbromarone can also activate farnesoid X receptor (FXR), whereas its agonistic activity on FXR is rather poor. Mounting evidence suggested that the etiology of gout is directly related to NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes, and FXR suppresses the expression of NLRP3 in various ways. Therefore, the dual URAT1 inhibitor and FXR agonist may exert synergistic effects on decreasing uric acid (UA) levels and inhibiting inflammation. To obtain a better dual URAT1 inhibitor and FXR agonist, we performed the structure-based drug design (SBDD) strategy to improve the FXR activation of benzbromarone by forming strong interactions with ARG331 in FXR binding pocket. All of these efforts lead to the identification of compound 4, which exerts better activity on FXR and uric acid-lowering effect than benzbromarone.

Design, synthesis and biological evaluation studies of novel anti-fibrosis agents bearing sulfoxide moiety.

Fibrosis, a chronic disease with high morbidity and mortality, is mainly characterized by excessive accumulation of extracellular matrix (ECM). At present, pathogenesis of fibrosis is incompletely understood, and there is an urgent need to develop safe and effective drugs. In this study, we designed and synthesized a series of novel small-molecule compounds through structural modification and fragment hybridization. Among them, a potential anti-fibrosis drug compd.1 was founded to be able to dose-dependently down-regulate ACTA2 and CTGF mRNA levels in human hepatic stellate cells (LX-2) treated with TGF-ß. In addition, compd.1 significantly improved the bridging fibrosis and collagen content in the CCl4-induced liver fibrosis mice model. Moreover, compd.1 reduced lung inflammation and fibrotic area in bleomycin-induced pulmonary fibrosis mice model. These findings suggested that compd.1 is a promising candidate for further anti-fibrosis researches, and extended chemical space might help us to explore better anti-fibrosis drug.

Involvement of the neddylation modification system in Bombyx mori nucleopolyhedrovirus replication.

Neddylation is a posttranslational modification that is similar to ubiquitination, and involved in some critical biological processes, such as DNA repair, transcription regulation, and ubiquitin-proteasome pathway. Recently, it was found that neddylation inhibitor MLN4924 has potent antiviral activity against human viruses including herpes simplex virus (HSV)-1, HSV-2, and influenza viruses. Here, we report that MLN4924 could dramatically and dose-dependently inhibits the propagation, formation of budding virus (BV) and occlusion body (OB) of a lepidopteran virus-Bombyx mori nucleopolyhedrovirus (BmNPV), impaired OB assembly. In addition, the neddylation modification protein NEDD8 is colocalized with aggresome and autophagosome. Our findings suggest that inhibiting neddylation could be an antibaculovirus strategy and MLN4924 may be used as candidate drug for that purpose.

The Emerging Portrait of Glial Cell Line-derived Neurotrophic Factor Family Receptor Alpha (GFRα) in Cancers.

Glial cell line-derived neurotrophic factor family receptor alpha (GFRα) members have been widely connected to the mechanisms contributing to cell growth, differentiation, cell migration and tissue maturation. Here we review GFRα biological functions and discussed the evidence indicating whether GFRα signaling complex present novel opportunities for oncogenic intervention and treatment resistance. Thus, our work systematically reviewed the emerging role of GFRα family members in cancers, and provided novel insights for further researches.

Down-regulation of miR-219-5p increase the risk of cancer-related mortality in patients with prostate cancer.

INTRODUCTION: Prostate cancer is a common malignancy in men that is difficult to treat and carries a high risk of death. miR-219-5p is expressed in reduced amounts in many malignancies. However, the prognostic value of miR-219-5p for patients with prostate cancer remains unclear. METHODS: We retrospectively analysed data from 213 prostate cancer patients from 10 June 2012 to 9 May 2015. Overall survival was assessed by Kaplan-Meier analysis and Cox regression models. Besides, a prediction model was constructed, and calibration curves evaluated the model's accuracy. RESULTS: Of the 213 patients, a total of 72 (33.8%) died and the median survival time was 60.0 months. We found by multifactorial analysis that miR-219-5p deficiency increased the risk of death by nearly fourfold (HR: 3.86, 95% CI): 2.01 to 7.44, p<0.001) and the risk of progression by twofold (HR: 2.79, 95% CI: 1.68 to 4.64, p<0.001). To quantify each covariate's weight on prognosis, we screened variables by cox model to construct a predictive model. The Nomogram showed excellent accuracy in estimating death's risk, with a corrected C-index of 0.778. CONCLUSIONS: miR-219-5p can be used as a biomarker to predict death risk in prostate cancer patients. The mortality risk prediction model constructed based on miR-219-5p has good consistency and validity in assessing patient prognosis.

Virulence profiles of Klebsiella pneumoniae isolated from 2 large dairy farms in China.

We recently reported on the diversity of Klebsiella pneumoniae isolated from dairy herds in China. In our previous work, isolates from subclinical mastitis (SCM) had lower indices of diversity when compared with bacteria from other sources, possibly due to a contagious-like spread of udder adapted strains. Here we explored the virulence profile and capsular types of K. pneumoniae isolated from different sources on 2 dairy farms in China. Our overarching goal was to gain insights on the role of virulence genes toward the severity of mastitis caused by K. pneumoniae. A total of 1,484 samples were collected from clinical mastitis (CM; n = 355), SCM (n = 561), bulk tank milk (BTM; n = 130), and environmental and extramammary (EE) sites (n = 438). From those, 431 K. pneumoniae isolates were obtained, including 129, 77, 66, and 159 isolates from CM, SCM, BTM, and EE samples, respectively. Polymerase chain reactions were used to determine the capsular types and to detect potential virulence genes in all isolates. No significant farm effects were observed when comparing the distribution of most virulence genes in K. pneumoniae isolated from each source. K57 was the most prevalent capsular type in K. pneumoniae from all sources, but with increased detection rate in isolates from CM. entB, kfu, fimH1, mrkD, and ß-d-lacZ were frequently detected in K. pneumoniae from all sources. ß-d-lacZ, entB, and ituA were more prevalent in isolates from CM, whereas kfu, allS, and nif were more frequently detected in isolates from SCM. ybtS, aerobactin, and rpmA had increased prevalence in K. pneumoniae from BTM when compared with bacteria from other sources. No association was detected between virulence genes and the severity of CM. K57 and the nif gene had the highest discriminatory power to classify isolates from CM and SCM, respectively. Based on our findings, it is likely that K57 is the dominant capsular type in K. pneumoniae causing CM in large Chinese dairy herds. Likewise, we demonstrated that ß-d-lacZ is disseminated in K. pneumoniae isolated from large Chinese dairy farms, irrespectively of the source of bacteria. Our results also suggest a low contribution of the virulence profile of K. pneumoniae toward CM severity. Finally, the role of nif in increasing the adaptability to the udder and promoting a contagious-like spread of K. pneumoniae warrants further investigation.

Different feed presentations affect subsequent feed sorting and rumen pH for a short period in weaned calves.

The objective of this study was to investigate the short- and long-term effects of different feed presentations on feed sorting and rumen pH in weaned calves. Thirty-six weaned female calves at the age of 12 wk (78 d) were raised in pairs (18 pens; n = 6/treatment) and randomly exposed to 1 of 3 feed presentation treatments: (1) concentrate ration (CON, only exposed to concentrate); (2) separate ration (CH, exposed to concentrate and hay as separate components); and (3) mixed ration (Mix, exposed to a mixed diet containing 75% concentrate and 25% hay). After 4 wk (from d 78 to 105) on different feed presentations, all weaned calves were introduced to a novel total mixed ration (TMR) for another 12 wk (from d 106 to 189). Fresh feed and orts were sampled daily before (wk 12 to 15) and after (wk 16, 17, and 28) transitioning to a TMR diet for analysis of feed sorting. Rumen fluid was sampled in wk 12, 13, 15, 16, 17, and 28 to determine rumen pH. The performance of weaned calves was affected by the different feed presentations during the pre-changing period, such that calves fed CON had a lower dry matter intake (DMI) and average daily gain than calves fed CH and Mix diets. When calves were introduced to the Mix diet, they immediately developed a higher degree of sorting behavior against the long particle fractions. Upon transition to TMR, we did not observe any differences in the performance of calves. However, the sorting behavior established in Mix calves persisted and was similar to calves previously fed the CON diet, whereas the extent of feed sorting in calves initially fed CH was less compared with that in the other 2 treatments in wk 16 and 17. Before changing the diet was transitioned to a TMR, calves fed CON had a lower rumen pH than calves fed CH and Mix. Although rumen pH in all treatments increased to the same level after the diet changed, we observed a tendency toward lower rumen pH in calves fed Mix compared with calves fed CH at wk 17, which might have resulted from the higher degree of feed sorting in these calves. However, by the end of the experiment (wk 28), feed sorting and rumen pH were similar across all treatments. These results indicated a short-term effect of previous feed presentations on subsequent feed sorting and rumen pH, but in the long term disappeared.