Dapagliflozin and Apparent Treatment-Resistant Hypertension in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The DELIVER Trial.

BACKGROUND: Apparent treatment-resistant hypertension (aTRH) is prevalent and associated with adverse outcomes in heart failure with mildly reduced or preserved ejection fraction. Less is known about the potential role of sodium-glucose co-transporter 2 inhibition in this high-risk population. In this post hoc analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), we evaluated clinical profiles and treatment effects of dapagliflozin among participants with aTRH. METHODS: DELIVER participants were categorized on the basis of baseline blood pressure (BP), with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with 3 antihypertensive drugs including a diuretic. Nonresistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under threshold. Incidence of the primary outcome (cardiovascular death or worsening heart failure event), key secondary outcomes, and safety events was assessed by baseline BP category. RESULTS: Among 6263 DELIVER participants, 3766 (60.1%) had controlled BP, 1779 (28.4%) had nonresistant hypertension, and 718 (11.5%) had aTRH at baseline. Participants with aTRH had more cardiometabolic comorbidities and tended to have higher left ventricular ejection fraction and worse kidney function. Rates of the primary outcome were 8.7 per 100 patient-years in those with controlled BP, 8.5 per 100 patient-years in the nonresistant hypertension group, and 9.5 per 100 patient-years in the aTRH group. Relative treatment benefits of dapagliflozin versus placebo on the primary outcome were consistent across BP categories (Pinteraction=0.114). Participants with aTRH exhibited the greatest absolute reduction in the rate of primary events with dapagliflozin (4.1 per 100 patient-years) compared with nonresistant hypertension (2.7 per 100 patient-years) and controlled BP (0.8 per 100 patient-years). Irrespective of assigned treatment, participants with aTRH experienced a higher rate of reported vascular events, including myocardial infarction and stroke, over study follow-up. Dapagliflozin modestly reduced systolic BP (by ≈1 to 3 mm Hg) without increasing risk of hypotension, hypovolemia, or other serious adverse events, irrespective of BP category, but did not improve the proportion of participants with aTRH attaining goal BP over time. CONCLUSIONS: aTRH was identified in >1 in 10 patients with heart failure and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin consistently improved clinical outcomes and was well-tolerated, including among those with aTRH. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.

AIMS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. METHODS AND RESULTS: In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001). CONCLUSION: In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.

Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.

AIMS: The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction. METHODS AND RESULTS: Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002). CONCLUSION: In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Influence of atrial fibrillation on efficacy and safety of omecamtiv mecarbil in heart failure: the GALACTIC-HF trial.

AIMS: In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil. METHODS AND RESULTS: GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II-IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P = 0.47) or in digoxin users not in AFF. CONCLUSION: Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin.Clinical Trial Registration: NCT02929329.

Highly efficient blue quantum-dot light-emitting diodes based on a mixed composite of a carbazole donor and a triazine acceptor as the hole transport layer.

Solution-processed thermally activated delayed fluorescence (TADF) exciplexes were employed as the hole transport layer (HTL) of blue quantum dot (QD) light-emitting diodes (QLEDs) by blending polymer donors of poly(N-vinylcarbazole) (PVK) with small molecular acceptors of 2,4,6-tris(biphenyl-3-yl)-1,3,5-triazine (T2T). As a result, the PVK:T2T HTL can harvest holes and electrons leaking from the QD active layer to form exciplex excitons and then this harvested exciton energy can be effectively transferred to the adjacent QD emitters through the Förster resonance energy-transfer process. Furthermore, the TADF exciplexes can enhance the hole mobility of the HTL due to the charge transfer process from the PVK donor to the T2T acceptor under an external electric field. The maximum current efficiency (CE) and external quantum efficiency (EQE) of the fabricated blue ZnCdS/ZnS core/shell QLEDs increase from 4.14 cd A-1 and 7.33% for the PVK HTL to 7.73 cd A-1 and 13.66% for the PVK:(5 wt%)T2T HTL, respectively. Our results demonstrate that the TADF exciplex HTL would be a facile strategy to design high-performance blue QLEDs.

The GHG mitigation opportunity of sludge management in China.

Greenhouse gas (GHG) mitigation in wastewater treatment sector is indispensable in China's carbon neutral target. As an important component of wastewater system, sludge generation is rapidly increased with the acceleration of urbanization in China. It is crucial to investigate the carbon footprint of various sludge management strategies and quantify the potential optimization of GHG reduction effect at national scale. Therefore, this study conducted a comprehensive analysis of sludge distribution and GHG profiles of various sludge systems. The overall dry sludge generation in China is 12.15 Mt, with spatial resolution at city level. Different sludge treatment options were categorized into four types: energy recovery, nutrient recovery (e.g. phosphorus and nitrogen), material valorisation (e.g. brick, biochar) and conventional disposal. With various sludge treatment options, the GHG profile of annual sludge management in China ranges from -35.86 Mt/year to 57.11 Mt/year. The best GHG mitigation can be achieved through energy recovery by co-incineration system and the greatest reduction opportunity is concentrated in highly urbanized regions, such as Yangtze River Delta, Pearl River Delta, and Beijing-Tianjin-Hebei urban agglomerations.

HOMEOBOX PROTEIN52 Mediates the Crosstalk between Ethylene and Auxin Signaling during Primary Root Elongation by Modulating Auxin Transport-Related Gene Expression.

The gaseous hormone ethylene participates in many physiological processes in plants. Ethylene-inhibited root elongation involves PIN-FORMED2 (PIN2)-mediated basipetal auxin transport, but the molecular mechanisms underlying the regulation of PIN2 function by ethylene (and therefore auxin distribution) are poorly understood. Here, we report that the plant-specific and ethylene-responsive HD-Zip gene HB52 is involved in ethylene-mediated inhibition of primary root elongation in Arabidopsis thaliana Biochemical and genetic analyses demonstrated that HB52 is ethylene responsive and acts downstream of ETHYLENE-INSENSITIVE3 (EIN3). HB52 knockdown mutants displayed an ethylene-insensitive phenotype during primary root elongation, while its overexpression resulted in short roots, as observed in ethylene-treated plants. In addition, root auxin distribution and gravitropism were impaired in HB52 knockdown and overexpression lines. Consistent with these findings, in vitro and in vivo binding experiments showed that HB52 regulates the expression of auxin transport-related genes, including PIN2, WAVY ROOT GROWTH1 (WAG1), and WAG2 by physically binding to their promoter regions. These findings suggest that HB52 functions in the ethylene-mediated inhibition of root elongation by modulating the expression of auxin transport components downstream of EIN3, revealing a mechanism in which HB52 acts as an important node in the crosstalk between ethylene and auxin signaling during plant growth and development.

Shift of Maternal Gut Microbiota of Tibetan Antelope (Pantholops hodgsonii) During the Periparturition Period.

The maternal gut microbiota can influence and be affected by the substantial physiological changes taking place during the periparturition period. However, little information is known about the changes in the maternal gut microbiota and hormonal variations during this period in nonmodel organisms. Tibetan antelope (Pantholops hodgsonii) provide a unique system to address this issue because their summer migration cycle is synchronized with the periparturition period. Here, we used fecal microbiota as a proxy of gut microbiota. We characterized fecal microbial community of female migratory Tibetan antelope in the late pregnancy and postpartum periods using 16S rRNA gene sequencing and quantified fecal glucocorticoids (GCs) and triiodothyronine (T3) metabolite concentrations through enzyme immunoassays to identify the associations between maternal gut microbiota and physiological changes related with reproduction. We found that the fecal microbiota of Tibetan antelope was dominated by Firmicutes and Bacteroidetes. The microbial composition was significantly altered during the transition from late pregnancy to the postpartum period. Fecal T3 concentration was significantly higher in the postpartum period compared to late pregnancy, whereas GC metabolite concentration did not significantly differ between two reproductive states. We identified six genera (Anaerofustis, Bacteroides, Coprococcus_2, Ruminiclostridium_5, Ruminococcaceae_UCG-007, and Tyzzerella) that were significantly associated with reproductive states. We also found two genera (Christensenellaceae_R-7_group and Rikenellaceae_RC9_gut_group) significantly associated with GC metabolite concentration and two genera (Agathobacter and Papillibacter) significantly associated with T3 metabolite concentration, though these correlations were weak with coefficient values ranging from - 0.007 to 0.03. Our results indicate that many members of the gut microbiota are associated with the physiological changes in the transition from late pregnancy to the postpartum period, likely reflecting the metabolic and immune system dynamics during the periparturition period. This study highlights the importance of integrating microbiota, hormones and migration pattern to study the reproductive health of wildlife. By establishing a baseline of the physiological changes during the migration/periparturition period, we can have a better understanding of the impacts of increasing human activities on the Tibetan Plateau on the reproductive health of Tibetan antelope.

Epidemiological features and viral shedding in children with SARS-CoV-2 infection.

A pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection broke out all over the world; however, epidemiological data and viral shedding in pediatric patients are limited. We conducted a retrospective, multicenter study, and followed-up with all children from the families with SARS-CoV-2 infected members in Zhejiang Province, China. All infections were confirmed by testing the SARS-CoV-2 RNA with real-time reverse transcription PCR method, and epidemiological data between children and adults in the same families were compared. Effect of antiviral therapy was evaluated observationally and fecal-viral excretion times among groups with different antiviral regiments were compared with Kaplan-Meier plot. By 29 February 2020, 1298 cases from 883 families were confirmed with SARS-CoV-2 infection and 314 of which were families with children. Incidence of infection in child close contacts was significantly lower than that in adult contacts (13.2% vs 21.2%). The mean age of 43 pediatric cases was 8.2 years and mean incubation period was 9.1 days. Forty (93.0%) were family clustering. Thirty-three children had coronavirus disease 2019 (20 pneumonia) with mild symptoms and 10 were asymptomatic. Fecal SARS-CoV-2 RNA detection was positive in 91.4% (32/35) cases and some children had viral excretion time over 70 days. Viral clearance time was not different among the groups treated with different antiviral regiments. No subsequent infection was observed in family contacts of fecal-viral-excreting children. Children have lower susceptibility of SARS-CoV-2 infection, longer incubation, and fecal-viral excretion time. Positive results of fecal SARS-CoV-2 RNA detection were not used as indication for hospitalization or quarantine.

SULTR3s Function in Chloroplast Sulfate Uptake and Affect ABA Biosynthesis and the Stress Response.

Plants are major sulfur reducers in the global sulfur cycle. Sulfate, the major natural sulfur source in soil, is absorbed by plant roots and transported into plastids, where it is reduced and assimilated into Cys for further metabolic processes. Despite its importance, how sulfate is transported into plastids is poorly understood. We previously demonstrated using single Arabidopsis (Arabidopsis thaliana) genetic mutants that each member of the sulfate transporter (SULTR) subfamily 3 was able to transport sulfate across the chloroplast envelope membrane. To resolve the function of SULTR3s, we constructed a sultr3 quintuple mutant completely knocking out all five members of the subfamily. Here we report that all members of the SULTR3 subfamily show chloroplast membrane localization. Sulfate uptake by chloroplasts of the quintuple mutant is reduced by more than 50% compared with the wild type. Consequently, Cys and abscisic acid (ABA) content are reduced to ∼67 and ∼20% of the wild-type level, respectively, and strong positive correlations are found among sulfate, Cys, and ABA content. The sultr3 quintuple mutant shows obvious growth retardation with smaller rosettes and shorter roots. Seed germination of the sultr3 quintuple mutant is hypersensitive to exogenous ABA and salt stress, but is rescued by sulfide supplementation. Furthermore, sulfate-induced stomatal closure is abolished in the quintuple mutant, strongly suggesting that chloroplast sulfate is required for stomatal closure. Our genetic analyses unequivocally demonstrate that sulfate transporter subfamily 3 is responsible for more than half of the chloroplast sulfate uptake and influences downstream sulfate assimilation and ABA biosynthesis.

Arabidopsis MADS-box factor AGL16 negatively regulates drought resistance via stomatal density and stomatal movement.

Drought is one of the most important environmental factors limiting plant growth and productivity. The molecular mechanisms underlying plant drought resistance are complex and not yet fully understood. Here, we show that the Arabidopsis MADS-box transcription factor AGL16 acts as a negative regulator in drought resistance by regulating stomatal density and movement. Loss-of-AGL16 mutants were more resistant to drought stress and had higher relative water content, which was attributed to lower leaf stomatal density and more sensitive stomatal closure due to higher leaf ABA levels compared with the wild type. AGL16-overexpressing lines displayed the opposite phenotypes. AGL16 is preferentially expressed in guard cells and down-regulated in response to drought stress. The expression of CYP707A3 and AAO3 in ABA metabolism and SDD1 in stomatal development was altered in agl16 and overexpression lines, making them potential targets of AGL16. Using chromatin immunoprecipitation, transient transactivation, yeast one-hybrid, and electrophoretic mobility shift assays, we demonstrated that AGL16 was able to bind the CArG motifs in the promoters of the CYP707A3, AAO3, and SDD1 and regulate their transcription, leading to altered leaf stomatal density and ABA levels. Taking our findings together, AGL16 acts as a negative regulator of drought resistance by modulating leaf stomatal density and ABA accumulation.

Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small-cell lung cancer cell survival in brain.

Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for early brain metastases. Despite efforts and advances in new therapeutics for SCLC, the prognosis of patients with SCLC with brain metastases is consistently poor. Therefore, a better understanding of the mechanisms of SCLC brain metastasis is important in improving current treatments. In this study, elevated S100A16 levels were associated with SCLC brain metastases, which was a possible secondary event arising from the brain metastatic microenvironment. Using an in vitro cell coculture system, we found that the coculturing of SCLC cells with human brain microvascular endothelial cells (HBMECs) led to an increased expression of S100A16 in SCLC cells. Conversely, treatment of HBMECs with GW4869, an inhibitor of exosome release, significantly blocked this effect in the cocultured SCLC cells. Alternatively, the results from Western blot analyses and immunofluorescence indicated that the HBMEC exosomes purified by ultracentrifugation also induced the elevation and translocation from the cytoplasm to the nucleus of S100A16 in the recipient SCLC cells. The inhibition experiments demonstrated that elevated S100A16 contributed a benefit of HBMEC exosomes for the survival of the recipient SCLC cells under stress. Moreover, the elevation of S100A16 in SCLC cells prevented the loss of mitochondrial membrane potential (Δψm) and enhanced resistance to apoptosis under stressful conditions, which were determined by Annexin V/propidium iodide and JC-1 assay. Further results showed that the S100A16-mediated protective effect was caused by the presence of an important element in Δψm, prohibitin (PHB)-1, a protein in the mitochondrial inner membrane. Conversely, the delivery of PHB-1 siRNAs into S100A16 overexpressing SCLC cells weakened these protective effects. Our findings suggest that elevated S100A16 plays an active role in facilitating the survival of SCLC cells through modulating the mitochondrial function, identifying S100A16 as an important potential target in SCLC brain metastasis.-Xu, Z.-H., Miao, Z.-W., Jiang, Q.-Z., Gan, D.-X., Wei, X.-G., Xue, X.-Z., Li, J.-Q., Zheng, F., Qin, X.-X., Fang, W.-G., Chen, Y.-H., Li. B. Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small cell lung cancer cell survival in brain.

Chemical Constituents and Bioactivities of Starfishes: An Update.

Starfishes produce various structurally unique secondary metabolites with diverse biological activities. This review is an update summary of the new compounds and their bioactivities from starfish (the Asteroidea Class) with 71 references covering from January 2007 to December 2018. During this period, 216 new compounds were obtained from 36 species. The chemical constituents are mostly steroids, steroidal glycosides, and gangliosides. These components have been found to possess various bioactivities, including anticancer, anti-inflammation, etc.

Activation of brain endothelium by Escherichia coli K1 virulence factor cglD promotes polymorphonuclear leukocyte transendothelial migration.

Escherichia coli K1 is the most common Gram-negative bacteria causing neonatal meningitis. Polymorphonuclear leukocyte (PMN) transmigration across the blood-brain barrier (BBB) is the hallmark of bacterial meningitis. Reportedly, the deletion of virulence factor cglD (E44:ΔcglD) from E44 is responsible for a less efficient PMN transendothelial migration ability. In the present study, we found that complementation of the cglD gene into E44:ΔcglD mutant strain might restore the PMN count and myeloperoxidase level in a neonatal mouse meningitis. Using human brain microvascular endothelial cells (HBMECs), the main model of the BBB in vitro, we found that E44:ΔcglD mutant strain induced a less efficient PMN adhesion to HBMECs and down-regulated chemokines CXCL1, CXCL6 and CXCL8 and adhesion molecule E-selectin, compared with the E44 strain. Complementation of cglD restored the PMN adhesion to HBMECs and the level of these proteins. E44:ΔcglD mutant strain also induced a less efficient NF-κB pathway activation in HBMECs and reduced the soluble p65 (sp65) level in the cerebral spinal fluid of newborn mice, compared with the E44 strain. Complementation of cglD restored the NF-κB pathway activation and increased the sp65 levels. This suggests that cglD in E44 contributes to NF-κB pathway activation in the brain endothelium to promote PMN adhesion to HBMECs and transendothelial migration. Our identified novel requirement of cglD for immune activation and subsequent PMN entry into the central nervous system suggests that therapies directed at neutralising this molecule will be beneficial in preventing bacterial meningitis progression.

Correction: Arabidopsis ERF1 Mediates Cross-Talk between Ethylene and Auxin Biosynthesis during Primary Root Elongation by Regulating ASA1 Expression.

[This corrects the article DOI: 10.1371/journal.pgen.1005760.].

Arabidopsis ERF1 Mediates Cross-Talk between Ethylene and Auxin Biosynthesis during Primary Root Elongation by Regulating ASA1 Expression.

The gaseous phytohormone ethylene participates in the regulation of root growth and development in Arabidopsis. It is known that root growth inhibition by ethylene involves auxin, which is partially mediated by the action of the WEAK ETHYLENE INSENSITIVE2/ANTHRANILATE SYNTHASE α1 (WEI2/ASA1), encoding a rate-limiting enzyme in tryptophan (Trp) biosynthesis, from which auxin is derived. However, the molecular mechanism by which ethylene decreases root growth via ASA1 is not understood. Here we report that the ethylene-responsive AP2 transcription factor, ETHYLENE RESPONSE FACTOR1 (ERF1), plays an important role in primary root elongation of Arabidopsis. Using loss- and gain-of-function transgenic lines as well as biochemical analysis, we demonstrate that ERF1 can directly up-regulate ASA1 by binding to its promoter, leading to auxin accumulation and ethylene-induced inhibition of root growth. This discloses one mechanism linking ethylene signaling and auxin biosynthesis in Arabidopsis roots.

Identifying Potential Norovirus Epidemics in China via Internet Surveillance.

BACKGROUND: Norovirus is a common virus that causes acute gastroenteritis worldwide, but a monitoring system for norovirus is unavailable in China. OBJECTIVE: We aimed to identify norovirus epidemics through Internet surveillance and construct an appropriate model to predict potential norovirus infections. METHODS: The norovirus-related data of a selected outbreak in Jiaxing Municipality, Zhejiang Province of China, in 2014 were collected from immediate epidemiological investigation, and the Internet search volume, as indicated by the Baidu Index, was acquired from the Baidu search engine. All correlated search keywords in relation to norovirus were captured, screened, and composited to establish the composite Baidu Index at different time lags by Spearman rank correlation. The optimal model was chosen and possibly predicted maps in Zhejiang Province were presented by ArcGIS software. RESULTS: The combination of two vital keywords at a time lag of 1 day was ultimately identified as optimal (ρ=.924, P<.001). The exponential curve model was constructed to fit the trend of this epidemic, suggesting that a one-unit increase in the mean composite Baidu Index contributed to an increase of norovirus infections by 2.15 times during the outbreak. In addition to Jiaxing Municipality, Hangzhou Municipality might have had some potential epidemics in the study time from the predicted model. CONCLUSIONS: Although there are limitations with early warning and unavoidable biases, Internet surveillance may be still useful for the monitoring of norovirus epidemics when a monitoring system is unavailable.