Interference-induced generation of a chirp-free short isolated attosecond pulse in the water window region with multicolor laser fields.

Compensating for the intrinsic attosecond chirp (atto-chirp) of wideband high-order harmonics in the water window region is a significant challenge, in order to obtain isolated attosecond pulses (IAPs) with a width of tens of attoseconds (as). Here, we propose to realize the generation of IAP with duration as short as 20 as, central energy of 365 eV, and bandwidth exceeding 150 eV from chirp-free high harmonics generated by a four-color driving laser, without the necessity for atto-chirp compensation with natural materials. Unlike any other gating methods that an IAP arises from only one electron ionization event, we take advantage of the interference between harmonic radiation produced by multiple ionizing events. We further demonstrate that such chirp-free short IAP survives after taking account of macroscopic propagation effects. Given that the synthesized multicolor laser field can also effectively increase the harmonic flux, this work provides a practical way for experiments to generate the broad bandwidth chirp-free IAPs in the water window region.

Controllable waveform terahertz generation using rippled plasma driven by an inhomogeneous electrostatic field.

We theoretically present the waveform controls of terahertz (THz) radiations generated from homogeneous and rippled plasma within inhomogeneous external electrostatic field. The Particle-in-cell (PIC) simulations is implemented to demonstrate generation and controllability of three types of THz pulses: single frequency THz pulse in homogeneous plasma, broadband THz pulse and dual frequency THz pulse in rippled plasma. The single frequency THz pulse can be tuned via shifting the knob of electron density of homogeneous plasma. Waveform of broadband THz pulse can be regulated into an envelope-like shape by varying amplitude of electron density of rippled plasma. The two center frequencies' interval of dual frequency THz pulse can be controlled by wave numbers of density distribution of rippled plasma. This work provides a potential means to generate the dual frequency THz pulses with two harmonic frequencies (ω+Ωω, Ω=2) or incommensurate frequencies (ω+Ωω, Ω=1.7,1.8, 2.2…).

Follicle stimulating hormone promotes production of renin through its receptor in juxtaglomerular cells of kidney.

BACKGROUND: Post-menopausal hypertension has been attributed solely to declining estrogen levels. The purpose of the research is to elucidate the mechanism by which follicle stimulating hormone(FSH) increases renin production involved in the regulation of blood pressure. METHODS: The expression of follicle stimulating hormone receptors (FSHRs) in renal juxtaglomerular cells and a As4.1 juxtaglomerular mouse cell line was evaluated. We established a mouse model by ovariectomy (OVX). Ovariectomized mice were treated with gonadotropin-releasing hormone agonist (GnRHa) (OVX + GnRHa). Ovariectomized mice initially received physiological doses of estrogen and were then injected with recombinant FSH (OVX + E + FSH). RESULTS: We found that FSHR was expressed in mouse renal juxtaglomerular cells labeled by renin antibody and in As4.1 cells. FSH promoted renin synthesis via Gsα-coupled FSHRs that activated protein kinase A, cyclic adenosine monophosphate(cAMP) response element-binding protein, extracellular signal-regulated kinase (Erk1/2), Protein kinase B(AKT), and c-Jun N-terminal kinase signaling pathways in As4.1 cells. We found increased serum FSH levels in the ovariectomized mouse with concurrent increases in renin, angiotensin II, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP). Additionally, increases in serum renin, angiotensin II, HR, SBP, DBP, and MAP were reduced by the additional injection of GnRHa. Exogenous FSH administration completely reversed decreases in renin, angiotensin II, HR, SBP, DBP, and MAP even in mice that received physiological doses of estrogen to maintain normal estradiol levels. CONCLUSIONS: Elevated FSH stimulates renin production involving a mechanism that may be relevant to the expression of FSH receptors in renal juxtaglomerular cells.

Lymphocytes ≥ 2.9 (109/L) in Newly Diagnosed Diabetes Are A Predictor of Future CVD Events.

OBJECTIVE: Atherosclerosis is considered a chronic inflammatory condition. The immune system is a key mediator in the initiation and progression of atherosclerosis. In a previous study, we found that the immune system was activated in diabetes and that total white blood cell (WBC) counts were elevated significantly in diabetic patients. To investigate whether WBC subtype counts in newly diagnosed diabetes are risk factors for future cardiovascular disease (CVD) events, we conducted a prospective population-based cohort study. METHODS: A total of 1498 newly diagnosed diabetic patients aged 40 to 70 years old were followed up for three years. Participants with previous CVD history and abnormal WBC counts were excluded. CVD events were recorded during follow-up. RESULTS: We found that the baseline lymphocyte counts were independently associated with cardiovascular events during follow-up, with the Exp (ß) (95% CI) at 1.749 (1.084-2.821). Lymphocyte count ≥2.9 (109/L) was significantly associated with the development of CVD (HR, 2.29; 95% CI, 1.12-4.67). The corresponding incidence of CVD per 1000 person-year for the lymphocyte count ≤2.8 (109/L) and lymphocyte count ≥2.9 (109/L) groups were 11.26 and 26.38, respectively. CONCLUSION: We concluded that even in a normal range, higher lymphocyte levels may result in a significantly higher CVD risk among diabetic patients. Lymphocyte count ≥2.9 (109/L) is an independent predictor of developing future CVD events.

Advanced Glycation End Products (AGEs) Inhibit Macrophage Efferocytosis of Apoptotic ß Cells through Binding to the Receptor for AGEs.

Pancreatic ß cell apoptosis is important in the pathogenesis of type 2 diabetes mellitus (T2DM). Generally, apoptotic ß cells are phagocytosed by macrophages in a process known as "efferocytosis." Efferocytosis is critical to the resolution of inflammation and is impaired in T2DM. Advanced glycation end products (AGEs), which are increased in T2DM, are known to suppress phagocytosis function in macrophages. In this study, we found that AGEs inhibited efferocytosis of apoptotic ß cells by primary peritoneal macrophages in C57BL/6J mice or mouse macrophage cell line Raw264.7. Mechanistically, AGEs inhibit efferocytosis by blocking Ras-related C3 botulinum toxin substrate 1 activity and cytoskeletal rearrangement through receptor for advanced glycation end products/ras homolog family member A/Rho kinase signaling in macrophages. Furthermore, it was observed that AGEs decreased the secretion of anti-inflammatory factors and promoted the proinflammatory ones to modulate the inflammation function of efferocytosis. Taken together, our results indicate that AGEs inhibit efferocytosis through binding to receptor for advanced glycation end products and activating ras homolog family member A/Rho kinase signaling, thereby inhibiting the anti-inflammatory function of efferocytosis.

Irreversible Electroporation Treatment With Intraoperative Biliary Stenting for Unresectable Perihilar Cholangiocarcinoma: A Pilot Study.

BACKGROUND: Treating perihilar cholangiocarcinoma (PHCC) is particularly difficult due to the fact that it is usually in an advanced stage at the time of diagnosis. Irreversible electroporation treatment (IRE) involves the local administration of a high-voltage electric current to target lesions without causing damage to surrounding structures. This study investigated the safety and efficacy of using IRE in conjunction with intraoperative biliary stent placement in cases of unresectable PHCC. METHODS: This study enrolled 17 patients with unresectable Bismuth type III/IV PHCC who underwent IRE in conjunction with intraoperative biliary stent placement (laparotomic) in two medical centers in Asia between June 2015 and July 2018. Analysis focused on the perioperative clinical course, the efficacy of biliary decompression, and outcomes (survival). RESULTS: Mean total serum bilirubin levels (mg/dL) on postoperative day (POD) 7, POD30, and POD90 were significantly lower than before IRE (respectively 3.46 vs 4.54, p=0.007; 1.21 vs 4.54, p<0.001; 1.99 vs 4.54, p<0.001). Mean serum carbohydrate antigen 19-9 (CA19-9, U/ml) levels were significantly higher on POD3 than before the operation (518.8 vs 372.4, p=0.001) and significantly lower on POD30 and POD90 (respectively 113.7 vs 372.4, p<0.001; 63.9 vs 372.4, p<0.001). No cases of Clavien-Dindo grade III/IV adverse events or mortality occurred within 90 days post-op. The median progression-free survival was 21.5 months, and the median overall survival was 27.9 months. All individuals who survived for at least one year did so without the need to carry percutaneous biliary drainage (PTBD) tubes. CONCLUSIONS: It appears that IRE treatment in conjunction with intraoperative biliary stent placement is a safe and effective approach to treating unresectable PHCC. The decompression of biliary obstruction without the need for PTBD tubes is also expected to improve the quality of life of patients.

miR-484 targeting of Yap1-induced LPS-inhibited proliferation, and promoted apoptosis and inflammation in cardiomyocyte.

Apoptosis and inflammation were the main hallmarks of sepsis-induced cardiomyopathy (SIC). Yes-associated protein isoform 1 (Yap1) and miR-484 were involved in mitochondrial fission and apoptosis, especially proapoptotic roles in SIC. Here, we investigated the role of Yap1 and miR-484 in lipopolysaccharide (LPS)-treated H9c2 cells. Yap1 was downregulated, while miR-484 was elevated by LPS treatment. Cell counting kit-8, flow cytometry, western blotting, and ELISA showed that miR-484 inhibitor significantly improved cell viability, decreased apoptosis, suppressed NLRP3 inflammasome formation, and reduced secretion of inflammatory cytokines TNF-α, IL-1ß, and IL-6. Yap1, directly targeted by miR-484 shown in the luciferase assay, was more like a compensatory regulator of LPS stimulation. Knockdown of Yap1 inverted the effects of miR-484 inhibitor, including decreased cell viability, and promoted apoptosis and inflammation. These revealed miR-484 directly targeted mRNA of Yap1 to inhibit cell viability, and promote apoptosis and inflammation in LPS-treated H9c2 cells.

Blood tests for prediction of deep endometriosis: A case-control study.

BACKGROUND: Deep endometriosis (DE) is the most aggressive subtype of endometriosis. The diagnosis may be challenging, and no biomarkers that can discriminate women with DE from those without DE have been developed. AIM: To evaluate the role of blood hemostatic parameters and inflammatory indices in the prediction of DE. METHODS: This case-control study was performed at the Women's Hospital, Zhejiang University School of Medicine between January 2015 and December 2016. Women with DE and women with benign gynecologic disease (control group) eligible for gynecological surgery were enrolled. Routine plasma hemostatic parameters and inflammatory indices were obtained before surgery. Univariate and multivariate analysis were performed. Receiver operating characteristic (ROC) curves were generated, and areas under the curve (AUC) were calculated to assess the predictive values of the selected parameters. RESULTS: A total of 126 women were enrolled, including 31 with DE and 95 controls. Plasma fibrinogen (Fg, P < 0.01), international normalized ratio (P < 0.05), and C-reactive protein levels (P < 0.01) were significantly higher in women with DE compared with controls. Plasma hemoglobin (HB) levels (P < 0.05) and shortened thrombin time (P < 0.05) were significantly lower in women with DE than in controls. Plasma Fg levels [adjusted OR (aOR) 2.12, 95%confidence interval (CI): 1.31-3.75] and plasma HB levels (aOR 0.48, 95%CI: 0.29-0.78) were significantly associated with DE (both P < 0.05). ROC analysis showed that the diagnostic value of Fg or HB alone for DE was limited. The AUC of the combination of both markers as a dual marker index was 0.773 with improved sensitivity (67.7%) and specificity (78.9%) at cutoffs of 3.09 g/L and 126 g/L, respectively. CONCLUSION: The combination of Fg and HB was a reliable predictor of DE. A larger study is needed to confirm the findings.

Prognostic factor analysis of irreversible electroporation for locally advanced pancreatic cancer - A multi-institutional clinical study in Asia.

INTRODUCTION: Irreversible electroporation (IRE) is a modality that utilizes high electric voltage to cause cell apoptosis. IRE has been used to treat locally advanced pancreatic cancer (LAPC). However, studies of IRE via surgical approaches for LAPC are limited. This study aims to analyse the outcomes and related prognostic factors of IRE for Asian patients with LAPC. MATERIALS AND METHODS: From 2012 to 2017, this prospective trial for using IRE through surgical approaches for LAPC was conducted in 11 medical centres in Asia. All related and treatment outcomes were analysed from a prospective database. RESULTS: Seventy-four patients were enrolled. Thirty complications occurred in thirteen (17.6%) patients without mortality. The electrode placement direction (anteroposterior vs. craniocaudal, HR = 14.2, p < 0.01) and gastrointestinal invasion (HR = 15.7, p < 0.01) were significant factors for complications. The progression-free survival (PFS) rate in one year, three years, and five years were 69.1%, 48.7%, and 28.8%, and the overall survival (OS) rate in one year, three years, and five years were 97.2%, 53%, and 31.2%. In univariate analysis, the chemotherapy regimen, local tumour recurrence, axial tumour length, tumour volume, and serum carbohydrate antigen 19-9 levels were all significantly associated with PFS and OS. In multivariate analysis, the chemotherapy regimen was the only significant factor associated with PFS and OS. TS-1 (Tegafur, gimeracil, and oteracil) group has superior survival outcome than gemcitabine group. CONCLUSION: This study showed that combined induction chemotherapy and surgical IRE for LAPC is safe. For well-selected patients, IRE can achieve encouraging survival outcomes.

LncRNA LEGLTBC Functions as a ceRNA to Antagonize the Effects of miR-34a on the Downregulation of SIRT1 in Glucolipotoxicity-Induced INS-1 Beta Cell Oxidative Stress and Apoptosis.

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.

Babao Dan attenuates acute ethanol-induced liver injury via Nrf2 activation and autophagy.

BACKGROUND: Babao Dan (BBD), a traditional Chinese medicine, has been used as a complementary and alternative medicine to treat multifarious liver diseases. In this study, we aimed to observe its protective effect on ethanol-induced liver injury and explore potential mechanisms. METHODS: Mice pretreated with BBD (0.125, 0.25 and 0.5 g/kg BW) were administrated by ethanol gavage (5 g/kg BW). Liver injury biomarkers and hepatic redox parameters were evaluated by histopathology as well as serum and hepatic content analysis. AML-12 cell was also utilized to determine the efficacy of BBD against ethanol-induced hepatotoxicity. RESULTS: Drunkenness experiment showed that the latency was significantly increased and the drunken sleep time was decreased in mice pretreated with BBD. We then found that BBD could reduce hepatic lipid peroxidation and steatosis induced by ethanol exposure. BBD could also suppress ethanol-induced depletion of hepatic antioxidant enzyme. Besides that, BBD treatment lessened the induction of hepatic cytochrome P450 2E1, a major contributor to ethanol-mediated oxidative stress, and up-regulated the expression of nuclear factor erythroid 2-related factor 2 and its two transcriptional targets hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. Furthermore, autophagy induced by BBD contributed to hepatoprotection activity. CONCLUSIONS: Our results suggest that BBD can markedly dispel acute ethanol-induced hepatotoxicity through multiple pathways including attenuation of ethanol-mediated oxidative stress, enhancement of the oxidative defense systems and activation of autophagy.

Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation.

Metastasis and recurrence severely impact the treatment effect of hepatocellular carcinoma (HCC). HCC complicated with cholestasis is more prone to recurrence and metastasis. Previous studies have implicated pathogenesis of HCC by bile acid; however, the underlying mechanism is unknown yet. Glycochenodeoxycholate (GCDC) is one of most important component of bile acid (BA). In the present study, the role of GCDC in HCC cells invasion was detected by in vitro and in vivo assays. GCDC was found to significantly enhance the invasive potential of HCC cells; Further studies showed that GCDC could induce autophagy activation and higher invasive capability in HCC cells. Interestingly, inhibition of autophagy by chloroquine (CQ) reversed this phenomenon. Subsequently, the correlation between TBA expression level and clinicopathological characteristics was analyzed in HCC patients. Clinically, high TBA level in HCC tissue was found to be associated with more invasive and poor survival in HCC patients. Mechanistic study showed that bile acid induced autophagy by targeting the AMPK/mTOR pathway in HCC cells. Therefore, our results suggest that bile acid may promote HCC invasion via activation of autophagy and the level of bile acid may serve as a potential useful indicator for prognosis of HCC patients.

Cultivation of Chlorella pyrenoidosa in anaerobic wastewater: The coupled effects of ammonium, temperature and pH conditions on lipids compositions.

Anaerobic wastewater potentially was an ideal medium for cultivating microalgae. The coupled effect of ammonium, temperature and pH on lipids accumulation was a core issue during algal culture using anaerobic wastewater. Therefore, their combined effects on Chlorella pyrenoidosa culture and lipids accumulation in anaerobic effluent were investigated. Free ammonia induced from the rising pH and temperature inhibited algal growth, but significantly promoted lipid accumulation. The highest lipids content reached 30.2% when pH rose to 8.3-8.5 (25 °C, ammonium 280 mg/L), which was 1.6-fold higher than that under neutral condition. Moreover, the percentage of unsaturated fatty acids (un-SFAs) increased to 74.8-77.9% at pH 8.3-8.5, whereas it was only 56.1-58.9% under neutral condition. The C18:2 and C18:3 dominated the un-SFAs increase at high pH, typically the percentage of C18:3 increased by 74.5-153.1%. This study provides a potential way for lipid accumulation in algal culture using anaerobic wastewater.

[Arthroscopic cyst removal and wire-guided suture for the treatment of lateral meniscal cyst of knee joint].

OBJECTIVE: To explore clinical effect of arthroscopic cyst removal and wire-guided suture for the treatment of lateral meniscal cyst of knee joint. METHODS: From July 2014 to December 2017, 33 patients with lateral meniscal cyst of knee joint were treated by arthroscopic cysts removal and wire-guided suture, including 13 males and 20 females, aged from 20 to 55 years old with an average age of(36.23 ±2.30) years old, the courses of disease ranged from 3 to 14 months with an average of(4.60±0.83) months; Preoperative MRI examination was clear diagnosed. There were 14 cysts on anterior horn, 18 cysts on meniscal body and 1 cyst on posterior horn;all cysts were solitary, and 3 of them were multilocular. Lysholm score and GLASOW score of knee joint function and clinical efficacy were observed before and after operation at 6 months. RESULTS: All patients were followed up form 6 to 24 months with an average of (7.5±1.2) months. Preoperative symptoms disappeared or significantly alleviated, and all incisions were healed by intention without complication and neurovascular injury. MRI showed meniscal tear areas and cystic defective areas healed, cyst was not recurrenced, healing time ranged form 8 to 12 weeks with an average of (9.6±1.6) weeks, and patients recovered their daily life and exercise. There was significant difference in Lysholm score before operation (61.12±4.35) and after operation at 6 momths(91.32±3.36)(t=46.11, P<0.01);according to GLASOW assessment, 31 patients with excellent recovery, and 2 good. CONCLUSIONS: Arthroscopic cyst removal and wire-guided suture for the treatment of lateral meniscal cyst of knee joint could reserve meniscus, repair injury of meniscus, recover knee joint function after operation, and is worth popularizing.

25-Hydroxyvitamin D Status and Its Association with Sleep Duration in Chinese Schoolchildren.

OBJECTIVE: To examine the association between 25-Hydroxyvitamin D (25(OH)D) levels and sleep duration among Chinese adolescents. SUBJECTS AND METHODS: A school-based cross-sectional study was conducted among Chinese adolescents in 2017. Data on a total of 800 adolescents aged 8⁻14 years was used for this study. Anthropometric measurements such as height and weight were measured by trained research staff. Serum 25(OH)D and lipids were measured in the laboratory. Sleep habits and other health-related behaviors were tested by questionnaire. RESULTS: 25(OH)D levels were significantly positively correlated with sleep duration (r = 0.11, p < 0.05). In multivariate logistic regression analyses, insufficiency/deficiency of vitamin D (25(OH)D ≤ 20 ng/mL) was significantly associated with increased probability of short sleep (AOR = 1.67, 95% CI = 1.14⁻2.43). CONCLUSIONS: Low 25(OH)D levels were independently associated with the risk of insufficient sleep in Chinese adolescents.

Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis.

Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are well-known leading causes of HCC. However, the mechanism of the induction of HCC by these virus is still being debated. This review will focus on the current knowledge of the pathogenesis of HBV- and HCV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC. It is well established that the recruitment of certain number and type of immune cells to liver is essential for the resolution of HBV and HCV infection and the prevention of subsequent chronic persistent infection. However, in case that the immune response do not completely clear virus, persistent chronic infection occurs, and the perpetual immune response may contribute to chronic damages of the liver. Such chronic inflammatory damages further harm hepatocytes, but not hepatic progenitor cells (HPCs). Thus, following chronic damages, HPCs are activated and their dysregulated proliferation ensures survival in the hostile environment, contributing to the tumorigenesis of HCC. Furthermore, accumulating evidence also provides a strong link between HPCs and human hepatocellular carcinoma. Collectively, these findings support a notion that immune response is involved in liver damage during hepatitis virus infection, and the activation and dysregulated differentiation of hepatic progenitor cells promote the tumorigenesis of human hepatocellular carcinoma.

Gsk3ß aggravates the depression symptoms in chronic stress mouse model.

Depression caused by genetic and environmental factors is acomplicated disease. Here, it is demonstrated that glycogen synthase kinase-3ß is highly expressed and phosphorylated in the brain of a chronic stress mouse. Inhibition of glycogen synthase kinase-3ßleads to decreased depression-like symptoms which manifest in open-field test, tail-suspension test, forced swim test, and a novelty suppressed feeding test. It was also found that ß-catenin is attenuated, and its target genes Cyclin D1 and c-Myc are down-regulated. Glycogen synthase kinase-3ß was also found to inhibit Erk-Creb-BDNF signaling. These results show that glycogen synthase kinase-3ß may promote the progression of depression. Therefore, targeting glycogen synthase kinase-3ß may be an effective therapeutic strategy.

Activation of NLRP3 Inflammasome by Advanced Glycation End Products Promotes Pancreatic Islet Damage.

Accumulation of advanced glycation end products (AGEs) contributes to ageing and age-related diseases, especially type 2 diabetes. The NLRP3 inflammasome, as a vital component of the innate immune system, is implicated in the pathogenesis of type 2 diabetes. However, the role of the NLRP3 inflammasome in AGE-induced pancreatic islet damage remains largely unclear. Results showed that administration of AGEs (120 mg/kg for 6 weeks) in C57BL/6J mice induced an abnormal response to glucose (as measured by glucose tolerance and insulin release), pancreatic ß-cell ultrastructural lesion, and cell death. These effects were associated with an excessive superoxide anion level, significant increased protein expression levels for NADPH oxidase 2 (NOX2), thioredoxin-interacting protein (TXNIP), NLRP3, and cleaved IL-1ß, enhanced caspase-1 activity, and a significant increase in the levels of TXNIP-NLRP3 protein interaction. Ablation of the NLRP3 inflammasome or treatment with antioxidant N-acetyl-cysteine (NAC) clearly ameliorated these effects. In conclusion, our results reveal a possible mechanism for AGE-induced pancreatic islet damage upon NLRP3 inflammasome activation.

Dense Bicoid hubs accentuate binding along the morphogen gradient.

Morphogen gradients direct the spatial patterning of developing embryos; however, the mechanisms by which these gradients are interpreted remain elusive. Here we used lattice light-sheet microscopy to perform in vivo single-molecule imaging in early Drosophila melanogaster embryos of the transcription factor Bicoid that forms a gradient and initiates patterning along the anteroposterior axis. In contrast to canonical models, we observed that Bicoid binds to DNA with a rapid off rate throughout the embryo such that its average occupancy at target loci is on-rate-dependent. We further observed Bicoid forming transient "hubs" of locally high density that facilitate binding as factor levels drop, including in the posterior, where we observed Bicoid binding despite vanishingly low protein levels. We propose that localized modulation of transcription factor on rates via clustering provides a general mechanism to facilitate binding to low-affinity targets and that this may be a prevalent feature of other developmental transcription factors.

Hepatocyte nuclear factor-1beta enhances the stemness of hepatocellular carcinoma cells through activation of the Notch pathway.

Hepatocyte nuclear factor-1beta plays an important role in the development and progression of liver cancer. In recent years, the expression of HNF-1ß has been reported to be associated with risk for a variety of cancers. The purpose of this study is to investigate whether the expression of HNF-1ß promotes the malignancy of HCC and its mechanism. We retrospectively investigated the expression of HNF-1ß in 90 patients with hepatocellular carcinoma and found that the high expression of HNF-1ß indicated poor prognosis. We overexpressed HNF-1ß in liver cancer cell lines and found the expression of liver progenitor cell markers and stemness were upregulated. The invasion ability and epithelial-mesenchymal transition (EMT)-associated genes were also significantly higher in liver cancer cells overexpressing HNF-1ß than in the control group. A mechanistic study suggested the activation of the Notch signalling pathway probably plays a key role downstream of HNF-1ß. More importantly, HNF-1ß promoted tumourigenesis of HCC cells in vivo. In conclusion, high expression of HNF-1ß not only promoted the de-differentiation of HCC cells into liver cancer stem cells through activating the Notch pathway but also enhanced the invasive potential of HCC cells and EMT occurrence, which would contribute to the enhancement of cell migration and invasion.