Data-driven modelling captures dynamics of the circadian clock of Neurospora crassa.

Eukaryotic circadian clocks are based on self-sustaining, cell-autonomous oscillatory feedback loops that can synchronize with the environment via recurrent stimuli (zeitgebers) such as light. The components of biological clocks and their network interactions are becoming increasingly known, calling for a quantitative understanding of their role for clock function. However, the development of data-driven mathematical clock models has remained limited by the lack of sufficiently accurate data. Here we present a comprehensive model of the circadian clock of Neurospora crassa that describe free-running oscillations in constant darkness and entrainment in light-dark cycles. To parameterize the model, we measured high-resolution time courses of luciferase reporters of morning and evening specific clock genes in WT and a mutant strain. Fitting the model to such comprehensive data allowed estimating parameters governing circadian phase, period length and amplitude, and the response of genes to light cues. Our model suggests that functional maturation of the core clock protein Frequency causes a delay in negative feedback that is critical for generating circadian rhythms.

Stem cell homeostasis by integral feedback through the niche.

Hematopoiesis is a paradigm for tissue development and renewal from stem cells. Experiments show that the maintenance of hematopoietic stem cells (HSCs) relies on signals from niche cells. However, it is not known how the size of the HSC compartment is set. Competition by HSCs for niche access has been suggested, yet niche cells in the bone marrow outnumber HSCs. Here we propose a cooperative model of HSC homeostasis in which stem and niche cells mutually interact such that niche cells function as negative feedback regulators of HSC proliferation. This model explains puzzling experimental findings, including homeostatic recovery of the HSC compartment after irradiation versus apparent lack of recovery after HSC ablation. We show that bidirectional niche-stem cell regulation has properties of a proportional-integral feedback controller. Moreover, we predict that the outflux of differentiated cells from HSCs can be regulated by the affinity of HSCs for niche cells. Much effort has been devoted to elucidating niche cell signaling to stem cells; our theoretical insights indicate that studying the effect of stem cells on the niche may be equally important for understanding stem cell homeostasis.

Upregulation of phosphoinositide 3-kinase prevents sunitinib-induced cardiotoxicity in vitro and in vivo.

Sunitinib (SNT) is a multi-targeted receptor tyrosine kinase inhibitor that has been approved by the FDA for cancer therapy. However, its cardiotoxicity has limited the clinical applicability with no effective therapeutic approach available. As a broadband kinase inhibitor, the function of several kinases that are essential to cardiac function might also be affected by SNT, such as calmodulin-dependent protein kinase (CaMKII), cyclic-AMP-dependent protein kinases (PKA), AMP-activated protein kinase (AMPK), and phosphoinositide 3 kinase (PI3K). In this study, we investigated whether SNT-induced cardiotoxicity could be prevented by blocking SNT-induced alteration in the corresponding signaling pathways. In human induced pluripotent stem cell-derived cardiomyocytes, SNT (0.5-20 µmol/L) inhibited contractility of cardiomyocytes in a concentration-dependent manner, and the inhibitory effect was prevented either by PIP3 (1 µmol/L) application or PI3K overexpression. On the contrary, the CaMKII inhibitor KN-93 (50 nmol/L), PKA inhibitor H89 (1 µmol/L), and AMPK activators metformin (2 mmol/L) and 5-aminoimidazole-4-carboxamide 1-b-D-ribofuranoside (2 mmol/L) presented negligible effects. Oral SNT administration (40 mg/kg/day) in mice progressively decreased the PI3K activity and cardiac function in 2 weeks with a significant decrease in the expression and activity of Cav1.2 and SERCA. Cardiac-specific PI3K overexpression through adeno-associated virus 9-mediated gene delivery in mice prevented SNT-induced reduction in cardiac function, calcium transient, calcium current, and Cav1.2 expression. In summary, our data indicate that increased PI3K activity is protective against SNT-induced calcium mishandling and contractile dysfunction. Cardiac-specific PI3K activation could be an effective therapeutic approach to treat SNT cardiotoxicity in patients with cancer.

Serial Thyroglobulin Variation Trend Shortly after Radioiodine Therapy in Poorly to Moderately Differentiated Recurrent Thyroid Cancer.

Objective To dynamically observe the early change of thyroglobulin(Tg) levels after (131)I therapy in differentiated thyroid cancer(DTC) patients. Methods The study enrolled 22 post-total-thyroidectomy DTC patients and they were stratified as low to intermediate recurrence according to the 2009 American Thyroid Association Guidelines. The clinical data including pre-ablation stimulated Tg (ps-Tg),corresponding thyroid stimulating hormone(TSH),anti-thyroglobulin (TgAb) values,and the afterwards parameters were dynamically measured each week in the first month after (131)I therapy. Values collected at the first time were defined as Tg 0 and TSH0,while Tg1 and TSH1 were collected at the first week after (131)I therapy respectively. Then the variation trend curves of Tg were drawn,and factors influencing the variation of Tg were analyzed. Two groups were divided according to Tg levels:G1 (Tg≤0.1 ng/ml,n=9) and G2(Tg>0.1 ng/ml,n=13). Results The rates of negative Tg were 4.5%,18.0%,27.0%,36.0%,and 41.0%,respectively,exactly before (131)I therapy and the 1(st),2(nd),3(rd),and 4(th) week after the therapy. One-way analysis of variance showed that the two groups statistically differed in age (F=3.182,P=0.04) and remnant thyroid (U=4.849,P=0.026). Multivariate logistic regression analysis showed that early negative Tg was related to remnant thyroid tissue (OR:2.132;95%Cl:1.418- 6.532,P=0.009). Conclusions Negative Tg can be achieved in nearly half of DTC patients by the end of first month after (131)I therapy. The negative conversion is closely related with the volume of remnant thyroid tissue.

Relationship between Variation of Pre-ablation Stimulated Thyroglobulin and Distant Metastasis in Patients with Differentiated Thyroid Cancer.

OBJECTIVE: To investigate the relationship between the dynamic variation of pre-ablation stimulated thyroglobulin(sTg)and distant metastasis in patietns with differentiated thyroid cancer(DTC). METHODS: DTC patients after total or near total thyroidectomy were divided into two groups as M1 group(n=38)and M0 group(n=130)according to the presence of distant metastases or not. Clinical data including pre-ablation sTg and the corresponding thyrotropin(TSH)values were dynamically measured. The pre-ablation sTg and corresponding TSH collected at the first time were defined as Tg1 and TSH1,while as Tg2 and TSH2 at the last time. χ(2) test was used to compare the variation tendency of sTg between these two groups. Tg1,Tg2,pre-ablation sTg variation(∆Tg),and ∆Tg/∆TSH ratio between M0 and M1 were compared by Mann-Whitney rank-sum test. The receiver operating characteristic(ROC)curves and diagnostic critical point(DCP)were employed to evaluate the predictive values of the above indicators. RESULTS: Both Tg1 and Tg2 of M1 were significantly higher than those of M0(the Mann-Whitney rank-sum test:Tg1 P<0.001,Tg2 P<0.001). The corresponding areas under the ROC curve(AUC)to differentiate the two groups were 0.921 and 0.942,respectively. The cut-off value of Tg2,which was more accurate in predicting distant metastasis,was 24.3 ng/ml with a sensitivity of 92.11% and a specificity of 83.85%. Both ∆Tg and ∆Tg/∆TSH between these two groups were significantly different(the Mann-Whitney rank-sum test:∆Tg P=0.002,∆Tg/∆TSH P<0.001). ∆Tg/∆TSH worked better than Tg2 in predicting distant metastasis with both higher accuracy(87.50%)and higher specificity(86.92%). CONCLUSIONS: Dynamically tracing pre-ablation sTg may improve the accuracy and specificity of distant metastases prediction in DTC patients. ∆Tg/∆TSH,which means the ratio of sTg variation to TSH variation,may be a useful diagnostic marker for predicting distant metastases in DTC.

[Effects of miRNA-21 on paclitaxel-resistance in human breast cancer cells].

OBJECTIVE: To investigate the effects of miR-21 on paclitaxel-resistance in human breast cancer MCF-7/PR and SKBR-3/PR cells. METHODS: Paclitaxel-resistant human breast cancer cell lines MCF-7/PR and SKBR-3/PR were established by stepwise selection in increasing concentration of paclitaxel. Cellular morphology, mRNA and protein level of MDR1, BCRP and MRP1 in MCF-7/PR and SKBR-3/PR cells were determined. The expression of Bax, Bcl-2 and miR-21 in parental and paclitaxel-resistant cells was detected by RT-PCR and Western blotting. The synthetic miR-21 inhibitor or miR-21 mimic were transfected into MCF-7/PR, SKBR-3/PR and MCF-7, SKBR-3 cells with Lipofectamine 2000. The miR-21 levels were determined by RT-PCR, and P-gp, Bcl-2 and Bax protein levels were examined by Western blotting. MTT assay was used to measure the cell viability, and flow cytometry was performed to analyze the cell cycle and apoptosis. RESULTS: The levels of MDR1, BCRP, MRP1, Bcl-2/Bax and miR-21 in MCF-7/PR and SKBR-3/PR cells were significantly higher than those in MCF-7 and SKBR-3 cells. The protein levels of P-gp, Bcl-2 were up-regulated, and Bax was down-regulated compared with parental cells. MiR-21 was significantly down-regulated after miR-21 inhibitor was transfected; and the levels of MDR1, BCRP, MRP1 and Bcl-2/Bax (P <0.05) were also down-regulated. MiR-21 inhibitors significantly suppressed G0/G1 transition of the cell cycle, and induced cell apoptosis in MCF-7/PR and SKBR-3/PR cells. MTT results showed that miR-21 inhibitors induced sensitivity of MCF-7/PR and SKBR-3/PR cells to paclitaxel. And miR-21 mimic can increase the expression of MDR1, Bcl-2/Bax and change cell morphology from parental cells to resistant cells. RESULTS: The established MCF-7/PR and SKBR-3/PR breast cancer cells show typical multidrug resistance characteristics, which can be used as the model for drug resistance study. Down-regulated miR-21 expression in MCF-7/PR and SKBR-3/PR breast cancer cells can enhance cell sensitivity to paclitaxel.

The safety and efficacy of NOACs versus LMWH for thromboprophylaxis after THA or TKA: A systemic review and meta-analysis.

The differences in the safety and efficacy of anticoagulation between different types of new oral anticoagulants(NOACs) and low molecular weight heparin(LMWH) are still controversial. The main purposes of this study were to analyze safety and efficacy of NOACs versus LMWH for thromboprophylaxis, and perform subgroup analyses stratified by individual NOACs and different populations after total hip arthroplasty (THA) or total knee arthroplasty (TKA). Literature search was performed in PubMed, EMBASE, Cochrane Library, CNKI and Wanfang databases until June 31, 2022. This systematic review and meta-analysis included 46 randomized controlled trials (RCT) with 39, 924 patients. We evaluated the safety and efficacy of thromboprophylaxis between LMWH and NOACs. NOACs were more effective in reducing deep vein thrombosis (DVT) (RR0.59; 95%CI 0.49-0.71) and adverse events (RR: 0.96; 95%CI: 0.93-0.99) than LMWH. The subgroup analyses for different anticoagulants revealed that rivaroxaban (RR:0.49; 95%CI:0.36-0.66), apixaban (RR: 0.54; 95%CI: 0.36-0.81) and edoxaban (RR:0.49; 95%CI: 0.32-0.75) have the lower risk of DVT than LMWH. Apixaban (RR:0.89; 95%CI: 0.80-1.00) had superior prevention of bleeding to LMWH. Edoxaban exhibited a lower risk of VTE (RR: 0.46; 95%CI: 0.33-0.65), advantage events (RR: 0.87; 95%CI: 0.82-0.93), and drug-related adverse events (DRAEs) (RR: 0.64; 95%CI: 0.53-0.76) than LMWH. East Asian population was superior to western population for preventing DVT, advantage events, and DRAE using NOACs. In conclusion, NOACs are more effective than LMWH at preventing DVT and adverse events after arthroplasty. Apixaban has lower bleeding than LMWH, and East Asian populations may benefit more than western population from NOACs.

The Different Therapeutic Effects of Traditional Chinese Medicine Shensong Yangxin Capsule and Salubrinal in High-intensity Exercise-induced Heart Failure in Rats with Acute Myocardial Infarction.

BACKGROUND: Currently, endoplasmic reticulum stress is studied utilizing a dephosphorylation inhibitor (Sal). The traditional Chinese patent medicine and simple formulation Shensong Yangxin Capsule is a commonly used medication for the treatment of arrhythmia. However, the efficacy and underlying mechanism of the capsule in treating post-ischemic heart failure in myocardial tissue have not yet been investigated. OBJECTIVE: The therapeutic effects and the underlying mechanism of the Shensong Yangxin Capsule (SSYX) and the dephosphorylation inhibitor Salubrinal (Sal) on heart failure (HF) induced by high-intensity exercise in rats with acute myocardial infarction (AMI) were investigated. METHODS: Male infants of 8 weeks Spragge-Dawley (SD) rats were randomly assigned to one of four groups: sham surgery group, AMI+placebo group, AMI+Shensong Yangxin Capsule group (AMI+SSYX), and AMI+Sal administration group. Rats' myocardial infarction was induced by left coronary artery ligation. Rats were subjected to a 3-week high-intensity exercise program to simulate heart failure after 7 days of postoperative rest. After the fourth postoperative week, echocardiography was applied to determine the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular systolic volume (LVESV) in each group. HE and TUNEL labeling were employed to examine the morphology of cardiac cells and measure the percentage of apoptosis in each group; Western blotting was applied to detect the cardiomyocyte apoptosis-related proteins p-JNK, p-P38, and NOX2, while ELISA was used to detect glutathione(GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum. RESULTS: Following a 4-week drug intervention:(1)LVFS and LVEF in the AMI+placebo group were statistically significantly reduced, while LVESV were significantly higher, compared to those in the sham surgery group (P<0.05); The AMI+SSYX group performed statistically significantly better than the AMI+placebo group(P<0.05). (2) The myocardial cells in the AMI+placebo group exhibited significant swelling and inflammatory cell infiltration; the myocardial cells in the AMI+SSYX group and AMI+Sal group displayed mild swelling and minimal inflammatory cell infiltration; the AMI+SSYX group's myocardial cell morphology was superior to that of the AMI+Sal group; (3) The apoptosis rate of the AMI+placebo group was around 95%, greater than that of the sham surgery group (2.55%). The apoptosis rate of the AMI+SSYX group is approximately 21%, while the apoptosis rate of the AMI+Sal group is about 43%. (4) In the AMI+placebo group, p-JNK, p-P38, and NOX2 protein expression dramatically increased compared to the sham surgery group. The expression of p-P38, NOX2, and p-JNK/t-JNK was considerably reduced in the AMI+Shensong group and AMI+Sal group, compared to the AMI+placebo group. (P<0.01)The AMI+SSYX group's result is superior to that of the AMI+Sal group. (5) Compared to the sham surgery group, the serum levels of SOD and GSH were significantly lower, and MDA was significantly higher in the AMI+placebo group. Compared to the AMI+placebo group, the serum levels of SOD and GSH were significantly higher, and MDA was significantly lower in the AMI+SSYX group and the AMI+Sal group. (P<0.05) Conclusion: In rats with acute myocardial infarction in high-intensity exercise-induced heart failure, Shensong Yangxin Capsule dramatically reduces myocardial cell death and cardiac dysfunction. SSYX has a shorter course of treatment and a better therapeutic effect than Sal.

iGlarLixi for type 2 diabetes: a systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy and tolerability of iGlarLixi-a novel, fixed-ratio, soluble combination of insulin glargine and lixisenatide-for the treatment of type 2 diabetes (T2D). METHODS: The PubMed, Embase, Cochrane Library and ClinicalTrials.gov databases were searched from inception to November 15, 2023 to identify randomized controlled trials (RCTs) comparing iGlarLixi with a placebo or any other antidiabetic agent in adults with T2D. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated to evaluate the outcomes. RESULTS: A total of 10 trials enrolling 6071 T2D patients were included. Compared with placebos or other antidiabetic agents, iGlarLixi exerted beneficial effects on changes in HbA1c, the percentage of patients who achieved an HbA1c < 7%, the percentage of patients who achieved an HbA1c < 6.5%, the percentage of patients who achieved an HbA1c < 7.0% without weight gain and/or without severe or blood glucose-confirmed hypoglycemic episodes, changes in fasting plasma glucose, and changes in self-measured plasma glucose. Regarding safety, iGlarLixi did not increase the incidence of severe hypoglycemia or serious adverse events but did increase the incidence of gastrointestinal adverse events, symptomatic hypoglycemia, and adverse events (e.g., nausea, vomiting, diarrhea). CONCLUSIONS: iGlarLixi showed improved efficacy and safety in patients with T2D. Additional large, multicenter RCTs are warranted to obtain deeper insights into the efficacy and safety of iGlarLixi, thereby providing guidance for clinical treatment decisions.

Phosphoproteomics reveals a novel mechanism underlying the proarrhythmic effects of nilotinib, vandetanib, and mobocertinib.

The use of tyrosine kinase inhibitors (TKIs) has resulted in significant occurrence of arrhythmias. However, the precise mechanism of the proarrhythmic effect is not fully understood. In this study, we found that nilotinib (NIL), vandetanib (VAN), and mobocertinib (MOB) induced the development of "cellrhythmia" (arrhythmia-like events) in a concentration-dependent manner in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Continuous administration of NIL, VAN, or MOB in animals significantly prolonged the action potential durations (APD) and increased susceptibility to arrhythmias. Using phosphoproteomic analysis, we identified proteins with altered phosphorylation levels after treatment with 3 µM NIL, VAN, and MOB for 1.5 h. Using these identified proteins as substrates, we performed kinase-substrate enrichment analysis to identify the kinases driving the changes in phosphorylation levels of these proteins. MAPK and WNK were both inhibited by NIL, VAN, and MOB. A selective inhibitor of WNK1, WNK-IN-11, induced concentration- and time-dependent cellrhythmias and prolonged field potential duration (FPD) in hiPSC-CMs in vitro; furthermore, administration in guinea pigs confirmed that WNK-IN-11 prolonged ventricular repolarization and increased susceptibility to arrhythmias. Fingding indicated that WNK1 inhibition had an in vivo and in vitro arrhythmogenic phenotype similar to TKIs. Additionally,three of TKIs reduced hERG and KCNQ1 expression at protein level, not at transcription level. Similarly, the knockdown of WNK1 decreased hERG and KCNQ1 protein expression in hiPSC-CMs. Collectively, our data suggest that the proarrhythmic effects of NIL, VAN, and MOB occur through a kinase inhibition mechanism. NIL, VAN, and MOB inhibit WNK1 kinase, leading to a decrease in hERG and KCNQ1 protein expression, thereby prolonging action potential repolarization and consequently cause arrhythmias.

Position-dependent effects of RNA-binding proteins in the context of co-transcriptional splicing.

Alternative splicing is an important step in eukaryotic mRNA pre-processing which increases the complexity of gene expression programs, but is frequently altered in disease. Previous work on the regulation of alternative splicing has demonstrated that splicing is controlled by RNA-binding proteins (RBPs) and by epigenetic DNA/histone modifications which affect splicing by changing the speed of polymerase-mediated pre-mRNA transcription. The interplay of these different layers of splicing regulation is poorly understood. In this paper, we derived mathematical models describing how splicing decisions in a three-exon gene are made by combinatorial spliceosome binding to splice sites during ongoing transcription. We additionally take into account the effect of a regulatory RBP and find that the RBP binding position within the sequence is a key determinant of how RNA polymerase velocity affects splicing. Based on these results, we explain paradoxical observations in the experimental literature and further derive rules explaining why the same RBP can act as inhibitor or activator of cassette exon inclusion depending on its binding position. Finally, we derive a stochastic description of co-transcriptional splicing regulation at the single-cell level and show that splicing outcomes show little noise and follow a binomial distribution despite complex regulation by a multitude of factors. Taken together, our simulations demonstrate the robustness of splicing outcomes and reveal that quantitative insights into kinetic competition of co-transcriptional events are required to fully understand this important mechanism of gene expression diversity.

The role of sphingosine-1-phosphate in autophagy and related disorders.

S1P, also referred to as sphingosine-1-phosphate, is a lipid molecule with bioactive properties involved in numerous cellular processes such as cell growth, movement, programmed cell death, self-degradation, cell specialization, aging, and immune system reactions. Autophagy is a meticulously controlled mechanism in which cells repurpose their elements to maintain cellular balance. There are five stages in autophagy: initiation, nucleation, elongation and maturation, fusion, and degradation. New research has provided insight into the complex connection between S1P and autophagy, uncovering their interaction in both normal and abnormal circumstances. Gaining knowledge about the regulatory mechanism of S1P signaling on autophagy can offer a valuable understanding of its function in well-being and illness, potentially leading to innovative therapeutic concepts for diverse ailments. Hence, this review analyzes the essential stages in mammalian autophagy, with a specific emphasis on recent research exploring the control of each stage by S1P. Additionally, it sheds light on the roles of S1P-induced autophagy in various disorders.

The role of Lactobacillus in inflammatory bowel disease: from actualities to prospects.

Inflammatory Bowel Disease (IBD), a chronic nonspecific intestinal inflammatory disease, is comprised of Ulcerative Colitis (UC) and Crohn's Disease (CD). IBD is closely related to a systemic inflammatory reaction and affects the progression of many intestinal and extraintestinal diseases. As one of the representative bacteria for probiotic-assisted therapy in IBD, multiple strains of Lactobacillus have been proven to alleviate intestinal damage and strengthen the intestinal immunological barrier, epithelial cell barrier, and mucus barrier. Lactobacillus also spares no effort in the alleviation of IBD-related diseases such as Colitis-associated Colorectal cancer (CAC), Alzheimer's Disease (AD), Depression, Anxiety, Autoimmune Hepatitis (AIH), and so on via gut-brain axis and gut-liver axis. This article aims to discuss the role of Lactobacillus in IBD and IBD-related diseases, including its underlying mechanisms and related curative strategies from the present to the future.

Berberine attenuates sunitinib-induced cardiac dysfunction by normalizing calcium regulation disorder via SGK1 activation.

Sunitinib (SNT)-induced cardiotoxicity is associated with abnormal calcium regulation caused by phosphoinositide 3 kinase inhibition in the heart. Berberine (BBR) is a natural compound that exhibits cardioprotective effects and regulates calcium homeostasis. We hypothesized that BBR ameliorates SNT-induced cardiotoxicity by normalizing the calcium regulation disorder via serum and glucocorticoid-regulated kinase 1 (SGK1) activation. Mice, neonatal rat cardiomyocytes (NRVMs), and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study the effects of BBR-mediated SGK1 activity on the calcium regulation disorder caused by SNT as well as the underlying mechanism. BBR offered prevention against SNT-induced cardiac systolic dysfunction, QT interval prolongation, and histopathological changes in mice. After the oral administration of SNT, the Ca2+ transient and contraction of cardiomyocytes was significantly inhibited, whereas BBR exhibited an antagonistic effect. In NRVMs, BBR was significantly preventive against the SNT-induced reduction of calcium transient amplitude, prolongation of calcium transient recovery, and decrease in SERCA2a protein expression; however, SGK1 inhibitors resisted the preventive effects of BBR. In hiPSC-CMs, BBR pretreatment significantly prevented SNT from inhibiting the contraction, whereas coincubation with SGK1 inhibitors antagonized the effects of BBR. These findings indicate that BBR attenuates SNT-induced cardiac dysfunction by normalizing the calcium regulation disorder via SGK1 activation.

How industrial upgrading can improve China's air quality: empirical analysis based on multilevel growth model.

With the rapid development of industrialization and urbanization in China, the ecological environment has been damaged, especially the air quality, which has negatively impacted the productivity and lives of residents. China has taken various measures to improve air quality, and industrial upgrading is one of these measures. This article uses urban and provincial data from 2015 to 2018 and a multilevel growth model to study how industrial upgrading can improve air quality. The following conclusions are drawn through empirical analysis. If industrial upgrading is not considered, with time, air quality will gradually deteriorate. However, once the country adopts strategic measures for industrial upgrading, the combined effect of industrial upgrading and time will improve air quality. Industrial upgrading and industrial restructuring jointly reduce air pollution and have a significant impact on the improvement of air quality. Company goals for economic profit and survival will eventually lead to overall industrial upgrades that have little effect on air improvement. According to the empirical results, this paper puts forward some suggestions to improve the air quality.

Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis.

Cardiotoxicity by tyrosine kinase inhibitors remains an important concern. Nilotinib and vandetanib clinically carry high proarrhythmic risk and the exact mechanism underlying arrhythmogenesis is not fully understood. In this study, we investigated the effects of nilotinib and vandetanib on the abundance of human ether-á-go-go-related gene (hERG) K+ channel and assessed the potential role of acute hERG blockage versus chronic effects in arrhythmogenesis. We found that both nilotinib and vandetanib prolonged the field potential duration reflecting the repolarisation process and induced cellrythmias of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in a time-and concentration-dependent manner after, after chronic exposure. Patch-clamp recordings revealed significant reductions of hERG current densities by nilotinib or vandetanib after chronic incubation with hERG-HEK293 cells in addition to the acute inhibition. Western blot analysis showed that nilotinib and vandetanib decreased mature hERG protein (155-kDa) expression, in a greater extent than that of the immature form (135-kDa). A serum and glucocorticoid kinase 1 (SGK1) activator, C4-ceramide, prevented the nilotinib-and vandetanib-induced hERG protein downregulation and thus the incidence of cellrrhythmias. Taken together, our data demonstrated that the downregulation of hERG channel abundance on the cellular membrane predominantly contributed to the proarrhythmic effect of nilotinib and vandetanib.

Toll-like receptor 4-mediated endoplasmic reticulum stress induces intestinal paneth cell damage in mice following CLP-induced sepsis.

A marked elevation of TLR4 was observed in various organs of septic mice. The mechanism of TLR4 in intestinal epithelial cell damage in sepsis remains unclear. CLP mice models were used to assess the role of TLR4 in intestinal Paneth cell damage by histological, polymerase chain reaction, western-blot analyses. The ileal expression of TLR4 was increased by more than five-fold after CLP. CLP significantly increased 7-day mortality and was associated with a higher murine sepsis score (MSS), closely related with increased TLR4 expression. Histological staining revealed that a reduced number of Paneth cells, accompanied by reduced lysozyme and defensin alpha 5(DEF-5) expression as detected by PCR. Of note, the expression levels of ATF6, XBP1 and CHOP increased in the ileal of the sepsis group. Meanwhile, the uncleaved p90 ATF6 was markedly reduced and cleaved p50 ATF6 was increased in the sepsis group. Intriguingly, The TAK-242 had improved intestinal mucosal injury, reduced the expression of ATF6, XBP1 and CHOP and relieved the cleavage of ATF6. We found that increased the expression level of TLR4 in the ileal of CLP mice promoted the depletion of Paneth cell and reduced LYZ and DEF-5 expression. Furthermore, our findings suggested that TLR4-mediated the hyperactivation of ER stress, via activating the ATF6/CHOP pathway, might be one of the mechanisms associated with Paneth cells loss and dysfunction during intestinal barrier impairment of sepsis.

T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1.

The effect of targeted therapy for metastatic hepatocellular carcinoma (HCC) is still unsatisfactory. Exploring the underlying mechanism of HCC metastasis is favorable to provide new therapeutic strategies. T-box (TBX) transcription factor family genes, which are crucial regulators in embryo and organ development, are vital for regulating tumor initiation, growth and metastasis. Here we explored the role of TBX19 in HCC metastasis, which is one of the most upregulated TBX family genes in human HCC tissues. TBX19 expression was markedly upregulated in HCC tissues and elevated TBX19 expression predicted poor prognosis. Overexpression of TBX19 enhanced HCC metastasis through upregulating epidermal growth factor receptor (EGFR) and Rac family small GTPase 1 (RAC1) expression. Downregulation of EGFR and RAC1 inhibited TBX19-mediated HCC metastasis, while upregulation of EGFR and RAC1 restored inhibition of HCC metastasis mediated by TBX19 knockdown. Furthermore, epidermal growth factor (EGF)/EGFR signaling upregulated TBX19 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor (NF)-kB axis. Besides, the combined application of EGFR inhibitor Erlotinib and RAC1 inhibitor NSC23766 markedly inhibited TBX19-mediated HCC metastasis. In HCC cohorts, TBX19 expression was positively associated with EGFR and RAC1 expression. Patients with positive coexpression of TBX19/EGFR or TBX19/RAC1 displayed the poorest prognosis. In conclusion, EGF/EGFR signaling upregulated TBX19 expression via ERK/NF-kB pathway and TBX19 fostered HCC metastasis by enhancing EGFR and RAC1 expression, which formed an EGF-TBX19-EGFR positive feedback loop. Targeting this signaling pathway may offer a potential therapeutic strategy to efficiently restrain TBX19-mediated HCC metastasis.

Fate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis.

Hematopoietic stem cells (HSCs) produce highly diverse cell lineages. Here, we chart native lineage pathways emanating from HSCs and define their physiological regulation by computationally integrating experimental approaches for fate mapping, mitotic tracking, and single-cell RNA sequencing. We find that lineages begin to split when cells leave the tip HSC population, marked by high Sca-1 and CD201 expression. Downstream, HSCs either retain high Sca-1 expression and the ability to generate lymphocytes, or irreversibly reduce Sca-1 level and enter into erythro-myelopoiesis or thrombopoiesis. Thrombopoiesis is the sum of two pathways that make comparable contributions in steady state, a long route via multipotent progenitors and CD48hi megakaryocyte progenitors (MkPs), and a short route from HSCs to developmentally distinct CD48-/lo MkPs. Enhanced thrombopoietin signaling differentially accelerates the short pathway, enabling a rapid response to increasing demand. In sum, we provide a blueprint for mapping physiological differentiation fluxes from HSCs and decipher two functionally distinct pathways of native thrombopoiesis.

Impact of China's water pollution on agricultural economic growth: an empirical analysis based on a dynamic spatial panel lag model.

The average annual growth rate of China's waste emissions from 2007 to 2017 was 2.3%. The main pollutants in the wastewater are chemical oxygen demand, ammonia nitrogen, total ammonia, total phosphorus, and so on which pollute groundwater and destroy ecosystems. Poor water quality reduces the edible value of agricultural products and has an impact on human health. Based on the panel data of 31 provinces in China from 2007 to 2017, this paper uses a dynamic spatial panel lag model to study the impact of China's water pollution on agricultural economic growth. The results show that the impact of China's water pollution on agricultural economic growth is significant. If the intensity of wastewater discharge is taken as an input factor in the process of agricultural production, the growth of agricultural economy tends to decline with the increase of water pollution. In the effect analysis, the short-term and long-term effects are significant. The absolute value of the long-term total effect is far greater than the short-term total effect, indicating that the inhibitory effect of water pollution on agricultural economic growth is more obvious. The cumulative effect of water pollution on agricultural economic growth continues to expand, resulting in more and more economic losses. The central and local governments should take various measures to reduce water pollution, guide the green development of agriculture, and increase farmers' income to realize the rural revitalization plan.