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The riverine nutrient inputs to the ocean reflects land-use changes and can affect the health of coastal environments over time, especially for a highly-anthropogenically influenced river-estuary-shelf system. To investigate the impact of riverine inputs on the Changjiang Estuary ecosystem at a multi-decadal time scale where long-term observations are limited, we built a three-dimensional physics-biogeochemistry-coupled model system based on the Finite-Volume Community Ocean Model (FVCOM) and the European Regional Shelf Ecosystem Model (ERSEM). Our model successfully simulated the temporal and spatial nutrient variabilities in the river-estuary-shelf con7tinuum from 1960 to 2018. The results showed increasing trends of nitrate and phosphate and fluctuating silicate variability, thereby leading to rising nitrogen (N) to phosphorus (P) ratios and decreasing silicon (Si) to N and P ratios. Such changes in the stoichiometric relationship of nutrient species also alter the community structure of the primary producers in estuaries. Our model showed a general increase of diatoms over the 59 years, corresponding to decreased proportions of micro-phytoplankton and pico- phytoplankton. With different backgrounds of light and nutrient limitations in the river and inner shelf, our model suggests that the trend of the diatom proportion in the light-limited river mouth is more associated with silicate variability, with decreased diatom proportions occurring in the 2000s. Our model relates the hydroclimate, nutrient load, and biogeochemical cycling, reproducing estuarine ecosystem variability and clarifying issues such as the causality of the ecosystem interactions.

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML., (© 2022. The Author(s).)

Background: In the TWILIGHT trial, ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) was shown to be a safe bleeding avoidance strategy in high-risk patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES)., Aims: The aim of this study was to evaluate the effects of ticagrelor monotherapy after three-month DAPT in patients undergoing PCI, according to DES type., Methods: In the current sub-analysis from TWILIGHT, patients were stratified into three groups based on DES type: durable polymer everolimus-eluting stents (DP-EES), durable polymer zotarolimus-eluting stents (DP-ZES), and biodegradable polymer DES (BP-DES). Bleeding and ischaemic outcomes were assessed at one year after randomisation., Results: Out of 5,769 patients, 3,014 (52.2%) had DP-EES, 1,350 (23.4%) had DP-ZES and 1,405 (24.4%) had BP-DES. Compared with ticagrelor plus aspirin, ticagrelor monotherapy had significantly lower BARC type 2, 3 or 5 bleeding compared with DAPT; DP-EES (3.8% vs 6.7%; HR 0.56, 95% CI: 0.41-0.78), DP-ZES (4.6% vs 6.9%; HR 0.66, 95% CI: 0.42-1.04) and BP-DES (4.2% vs 7.9%; HR 0.52, 95% CI: 0.33-0.81; p interaction =0.76). Ticagrelor monotherapy resulted in similar rates of death, MI, or stroke: DP-EES (4.2% vs 4.3%; HR 0.97; 95% CI: 0.68-1.37); DP-ZES (4.1% vs 3.1%; HR 1.32; 95% CI: 0.75-2.33); BP-DES (3.9% vs 4.2%; HR 0.92; 95% CI: 0.54-1.55; p interaction =0.60). In both unadjusted and covariate-adjusted analyses, DES type was not associated with any differences in ischaemic or bleeding complications., Conclusions: As compared with ticagrelor plus aspirin, ticagrelor monotherapy after a short DAPT duration lowered bleeding complications without increasing the ischaemic risk, irrespective of DES type. We observed no significant differences among DES types.

Introduction: At L5-S1, anterior access can be performed with a supine anterior lumbar interbody fusion (ALIF) or lateral position oblique lumbar interbody fusion (LOLIF). We compared clinical and radiographic features of both approaches., Methods: A retrospective study of L5-S1 ALIF and LOLIF patients (2013-2018) by 3 spine surgeons and a vascular surgeon at our hospital was performed. Inclusion criteria were patients undergoing L5-S1 anterior surgery only without other anterior or lateral fusion levels, and data collected were patient demographics, cage parameters, perioperative variables, and radiographic parameters. 58 patients were included (33 ALIF and 25 LOLIF)., Results: The average surgical time was 211.94 min for ALIF and 154.86 min for LOLIF (p < 0.001). The average blood loss was 214 ml for ALIF and 74 ml for LOLIF (p < 0.001). The average number of days to solid food was 2.55 for ALIF and 0.8 for LOLIF (p < 0.001). The average anterior L5-S1 disc height increase was 8.52 mm for ALIF and 5.02 mm LOLIF (p = 0.018), and the average posterior L5-S1 disc height increase was 3.34 mm for ALIF and 1.30 mm for LOLIF (p = 0.034). The average L5-S1 segmental lordosis increase was 6.82 degrees for ALIF and 7.63 degrees for LOLIF (p = 0.638)., Conclusion: The LOLIF is a feasible option for L5-S1 anterior access compared to ALIF. However, supine ALIF afforded larger cages to be placed, resulting in greater postoperative disc height. There did not appear to be a significant difference in postoperative L5-S1 segmental lordosis between the two approaches., Competing Interests: Declaration of Competing Interest Zhuo Xi, MD, Chih-Chang Chang, MD and Huibing Ruan, MD: None. Shane Burch, MD, Consultant for Medtronic, Zimmer-Biomet. Praveen V. Mummaneni, MD, consultant: Depuy Synthes, Stryker, Globus. Royalties: Thieme Publishing, Springer Publishing, and DePuy Synthes.Research Support: NREF, ISSG, AO spine. Purchased stock in Spinicity/ ISD.Charles Eichler, MD: consultant: Medtronic Spine & Nuvasive Spine. Dean Chou, MD, consultant: Globus, royalty: Globus., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syndromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES)., Methods and Results: We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus aspirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary outcome. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by 53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36-0.61; P < 0.001) and in stable patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54-1.06; P = 0.11; nominal Pint = 0.03). Rates of all-cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74-1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61-1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation (Pint = 0.96)., Conclusion: Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS., Trial Registration: Clinicaltrials.gov identifier: NCT02270242., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Surfactants possess the ability to reduce surface tension at low concentrations, resulting in emulsification, foaming, wetting, and solubilizing. As a versatile industrial material, surfactants can be widely used as additives in the industrial field as different as textile, metal processing, mineral processing, new materials, industrial cleaning, construction, and pharmaceuticals. The most extensive application of surfactants perhaps is in the household and cosmetic industries, such as laundry detergents, dishwashing detergents, facial and body cleansers, and preparation of emulsions and creams. However, the extensive use of detergents, cleaners, and cleansers on skin may cause itching, redness, and dryness termed as surfactant-induced irritation, which is at least, partially due to surfactant penetration into skin. To understand how surfactants penetrate into skin, this review summarizes the penetration models proposed by researchers in the past two decades, including the surfactant monomer penetration model, the surfactant micelle and submicelle penetration model, and the recently proposed surfactant charge density and penetration correlation model that demonstrates the correlation between the surfactant charge density and skin penetration.

In addition to genomic mutations, RNA editing is another major mechanism creating sequence variations in proteins by introducing nucleotide changes in mRNA sequences. Deregulated RNA editing contributes to different types of human diseases, including cancers. Here we report that peptides generated as a consequence of RNA editing are indeed naturally presented by human leukocyte antigen (HLA) molecules. We provide evidence that effector CD8 + T cells specific for edited peptides derived from cyclin I are present in human tumours and attack tumour cells that are presenting these epitopes. We show that subpopulations of cancer patients have increased peptide levels and that levels of edited RNA correlate with peptide copy numbers. These findings demonstrate that RNA editing extends the classes of HLA presented self-antigens and that these antigens can be recognised by the immune system.

Moxibustion () is a traditional Chinese medicine therapy performed using Artemisia argyii. Zusanli (, ST36) is an acupoint in the stomach meridian, long associated in ancient Chinese medical practices with the extension of life span when moxibustion is applied to it. The aim of this study was to investigate changes in insulin-like growth factor 1 (IGF-1) levels after application of moxibustion to ST36. Four healthy men and women participated in this 28-day trial and were randomly divided into 2 groups. Group A received moxibustion treatment from days 1 to 14, while group B received moxibustion treatment from days 15 to 28. Blood samples were taken 5 times during this study to measure serum IGF-1 (s-IGF-1) levels. The s-IGF-1 levels increased in both groups after 7 and 14 d of moxibustion therapy (group A: 11.02% [7 d] and 29.65% [14 d]; group B: 169.12% [7 d] and 274.85% [14 d]). After moxibustion therapy had been completed (day 14), s-IGF-1 levels continued to increase in group A (increases on day 21 and day 28 were 53.19% and 61.45%, respectively). There were no adverse events in either group. The s-IGF-1 levels were significantly raised in both groups after 7 and 14 d of moxibustion therapy. Moreover, once therapy had been completed, s-IGF-1 levels continued to increase in group A up to 14 d after the treatment.

Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Previous studies show inconsistent associations between α-linolenic acid (ALA) and risk of CHD. We aimed to examine an aggregate association between ALA intake and risk of CHD, and assess for any dose-response relationship. We searched the PubMed, EMBASE and Web of Science databases for prospective cohort studies examining associations between ALA intake and CHD, including composite CHD and fatal CHD. Data were pooled using random-effects meta-analysis models, comparing the highest category of ALA intake with the lowest across studies. Subgroup analysis was conducted based on study design, geographic region, age and sex. For dose-response analyses, we used two-stage random-effects dose-response models. In all, fourteen studies of thirteen cohorts were identified and included in the meta-analysis. The pooled results showed that higher ALA intake was associated with modest reduced risk of composite CHD (risk ratios (RR)=0·91; 95 % CI 0·85, 0·97) and fatal CHD (RR=0·85; 95 % CI 0·75, 0·96). The analysis showed a J-shaped relationship between ALA intake and relative risk of composite CHD (χ 2=21·95, P<0·001). Compared with people without ALA intake, only people with ALA intake <1·4 g/d showed reduced risk of composite CHD. ALA intake was linearly associated with fatal CHD - every 1 g/d increase in ALA intake was associated with a 12 % decrease in fatal CHD risk (95 % CI -0·21, -0·04). Though a higher dietary ALA intake was associated with reduced risk of composite and fatal CHD, the excess composite CHD risk at higher ALA intakes warrants further investigation, especially through randomised controlled trials.

Objective: Interleukin (IL)-33 promotes T helper (Th2) immune response and may be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Using murine and human specimens, we evaluated the role of IL-33 in CRSwNP., Materials and Methods: To establish CRSwNP, Balb/c mice were sensitized with house dust mite, followed up by intranasal exposure to Staphylococcus aureus to stimulate the inflammatory response of nasal mucosa. The hematoxylin-eosin staining and total serum IgE were used to the successful construction of CRSwNP model. For mechanistic studies, we blocked mice with IL-33 and the Th2 cells counts in tissue were detected. Th2 cytokine expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 in control group, CRSwNP group and IL-33 blockade group at 12 weeks after CRSwNP model establishment, were analyzed by qRT-PCR. Meanwhile, the relative mRNA and protein expression levels of NF-κB, MyD88 and TLR7 were detected after IL-33 blockade. To document the inflammatory response in patients with CRSwNP, The relative mRNA expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 in control individuals and patients with CRSwNP (chronic rhinosinusitis with nasal polyps) were analyzed by qRT-PCR., Results: The CRSwNP model was successfully constructed. After IL-33 blocked, the relative expression of IL-33 and Th2 cells counts were reduced significantly. CRSwNP mice showed overproduction of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24 and IL-33 blockade inhibited the expression of IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24. Furthermore, IL-33 blockade decreased the mRNA levels of NF-κB, MyD88 and TLR7, and also restrained the protein expression of them. On the other hand, patients' specimens with CRSwNP showed high levels of Th2 cytokines including IL-33, IL-4, IL-5, IL-13, IL-22, CCL-11, and CCL-24., Conclusions: CRSwNP is associated with overexpression of IL-33, with subsequent activation of Th2 immune response by NF-κB signaling pathway.

Objectives: Apomorphine is used to symptomatically treat Parkinson's disease (PD). Oral delivery of apomorphine is generally limited by its short plasma half-life and a hepatic first-pass metabolism. This study was aimed at evaluating the behavioural response of apomorphine and its prodrug administered in oral lipid-based formulations., Methods: The behavioural response of apomorphine and its prodrug administered in oral lipid-based formulations was evaluated using a 6-hydroxydopamine-lesioned rat model simulating PD symptomatology. Apomorphine or dipalmitoyl apomorphine (DPA) was incorporated into different lipid-based formulations and orally administered (0.24 mmol/kg) to the PD rat model. The rotations by the rats were counted., Key Findings: The duration of response lasted to about 2.5 h with oral apomorphine- and DPA-loaded o/w emulsion, while it was increased to 6 h when DPA was incorporated in self-emulsifying drug delivery systems compared to s.c. apomorphine (1 h). This suggests that the lipid-based formulations provide a sustained drug release allowing for a steady exposure to the brain., Conclusions: Oral lipid-based apomorphine delivery has a potential in achieving a steady response, though at a higher dose possibly eliminating the need for frequent s.c. apomorphine administration., (© 2017 Royal Pharmaceutical Society.)

This multicenter clinical trial was conducted to examine current practice of benign epilepsy with centrotemporal spikes and especially address the question that in what circumstances 1 antiepileptic drug (AED) should be preferred.Twenty-five medical centers participate in this clinical trial. The general information, clinical information, and treatment status were collected under the guidance of clinicians and then analyzed. Difference between different treatment groups was compared, and usefulness of the most commonly used AEDs was evaluated.A total of 1817 subjects were collected. The average age of the subject was 8.81 years. The average age of onset is 6.85 years (1-14 years). Male-to-female ratio is 1.13:1. A total of 62.9% of the patients are receiving monotherapies, and 10.6% are receiving multidrug therapy. Both age and course of disease of treated rolandic epilepsy (RE) patients are significantly different from those of untreated patients. Bilateral findings on electroencephalography (EEG) are less seen in patients with monotherapy compared with patients with multidrug therapy. Except for 25.4% patients not taking any AEDs, oxcarbazepine (OXC), sodium valproate (VPA), and levetiracetam (LEV) are the most commonly used 3 AEDs. VPA and LEV are commonly used in add-on therapy. OXC and LEV are more effective as monotherapy than VPA.Age of onset of Chinese RE patients is 6.85 years. Bilateral findings on EEG could be a risk factor to require multidrug therapy. In Chinese patients, OXC, VPA, and LEV are most commonly used AEDs as monotherapy and OXC and LEV are more effective than VPA., Competing Interests: The authors report no conflicts of interest.