Abstract Tumor necrosis factor (TNF) is a critical cytokine, which contributes to both physiological and pathological processes. This mini-review will briefly touch the history of TNF discovery, its ...family members and its biological and pathological functions. Then, it will focus on new findings on the molecular mechanisms of how TNF triggers activation of the NF-κB and AP-1 pathways, which are critical for expression of pro-inflammatory cytokines, as well as the MLKL cascade, which is critical for the generation of ROS in response to TNF. Finally, this review will briefly summarize recent advances in understanding TNF-induced cell survival, apoptosis and necrosis (also called necroptosis). Understanding new findings and emerging concepts will impact future research on the molecular mechanisms of TNF signaling in immune disorders and cancer-related inflammation.
Abstract
Van der Waals heterobilayers of transition metal dichalcogenides with spin–valley coupling of carriers in different layers have emerged as a new platform for exploring spin/valleytronic ...applications. The interlayer coupling was predicted to exhibit subtle changes with the interlayer atomic registry. Manually stacked heterobilayers, however, are incommensurate with the inevitable interlayer twist and/or lattice mismatch, where the properties associated with atomic registry are difficult to access by optical means. Here, we unveil the distinct polarization properties of valley-specific interlayer excitons using epitaxially grown, commensurate WSe
2
/MoSe
2
heterobilayers with well-defined (AA and AB) atomic registry. We observe circularly polarized photoluminescence from interlayer excitons, but with a helicity opposite to the optical excitation. The negative circular polarization arises from the quantum interference imposed by interlayer atomic registry, giving rise to distinct polarization selection rules for interlayer excitons. Using selective excitation schemes, we demonstrate the optical addressability for interlayer excitons with different valley configurations and polarization helicities.
Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma ...(HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC.
Abstract
Much of the dramatic growth in research on topological materials has focused on topologically protected surface states. While the domain walls of topological materials such as Weyl ...semimetals with broken inversion or time-reversal symmetry can provide a hunting ground for exploring topological interfacial states, such investigations have received little attention to date. Here, utilizing in-situ cryogenic transmission electron microscopy combined with first-principles calculations, we discover intriguing domain-wall structures in MoTe
2
, both between polar variants of the low-temperature(
T
) Weyl phase, and between this and the high-
T
higher-order topological phase. We demonstrate how polar domain walls can be manipulated with electron beams and show that phase domain walls tend to form superlattice-like structures along the
c
axis. Scanning tunneling microscopy indicates a possible signature of a conducting hinge state at phase domain walls. Our results open avenues for investigating topological interfacial states and unveiling multifunctional aspects of domain walls in topological materials.
Non-vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk.
To assess the association between use of ...NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation.
Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016.
NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin.
Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score.
Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years SD, 10.8; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 99% CI, 9.76-18.13); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 99% CI, 80.96-195.97); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 99% CI, 32.18-72.44; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone.
Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs.
To investigate the biologic relevance and clinical implication of genes involved in multiple gene expression signatures for breast cancer prognosis, we identified 16 published gene expression ...signatures, and selected two genes, MAD2L1 and BUB1. These genes appeared in 5 signatures and were involved in cell-cycle regulation. We analyzed the expression of these genes in relation to tumor features and disease outcomes. In vitro experiments were also performed in two breast cancer cell lines, MDA-MB-231 and MDA-MB-468, to assess cell proliferation, migration and invasion after knocking down the expression of these genes. High expression of these genes was found to be associated with aggressive tumors and poor disease-free survival of 203 breast cancer patients in our study, and the association with survival was confirmed in an online database consisting of 914 patients. In vitro experiments demonstrated that lowering the expression of these genes by siRNAs reduced tumor cell growth and inhibited cell migration and invasion. Our investigation suggests that MAD2L1 and BUB1 may play important roles in breast cancer progression, and measuring the expression of these genes may assist the prediction of breast cancer prognosis.
Background and Aims
NASH is an advanced stage of liver disease accompanied by lipid accumulation, inflammation, and liver fibrosis. Guanine nucleotide‐binding protein G(i) subunit alpha‐2 (GNAI2) is ...a member of the “inhibitory” class of α‐subunits, and recent studies showed that Gnai2 deficiency is known to cause reduced weight in mice. However, the role of GNAI2 in hepatocytes, particularly in the context of liver inflammation and lipid metabolism, remains to be elucidated. Herein, we aim to ascertain the function of GNAI2 in hepatocytes and its impact on the development of NASH.
Approach and Results
Human liver tissues were obtained from NASH patients and healthy persons to evaluate the expression and clinical relevance of GNAI2. In addition, hepatocyte‐specific Gnai2‐deficient mice (Gnai2hep−/−) were fed either a Western diet supplemented with fructose in drinking water (WDF) for 16 weeks or a methionine/choline–deficient diet (MCD) for 6 weeks to investigate the regulatory role and underlying mechanism of Gnai2 in NASH. GNAI2 was significantly up‐regulated in liver tissues of patients with NASH. Following feeding with WDF or MCD diets, livers from Gnai2hep−/− mice had reduced steatohepatitis with suppression of markers of inflammation and an increase in lipophagy compared to Gnai2flox/flox mice. Toll‐like receptor 4 signals through nuclear factor kappa B to trigger p65‐dependent transcription of Gnai2. Intriguingly, immunoprecipitation, immunofluorescence, and mass spectrometry identified peroxiredoxin 1 (PRDX1) as a binding partner of GNAI2. Moreover, the function of PRDX1 in the suppression of TNF receptor‐associated factor 6 ubiquitin‐ligase activity and glycerophosphodiester phosphodiesterase domain‐containing 5–related phosphatidylcholine metabolism was inhibited by GNAI2. Suppression of GNAI2 combined with overexpression of PRDX1 reversed the development of steatosis and fibrosis in vivo.
Conclusions
GNAI2 is a major regulator that leads to the development of NASH. Thus, inhibition of GNAI2 could be an effective therapeutic target for the treatment of NASH.
Wellbores are destabilized by the immersion of a formation in drilling fluid during deep well drilling. To address this issue, in the present study, trimethylolethane triallyl ether (TMETE), ...2‐acrylamide‐2‐methylpropanesulfonic acid (AMPS), acrylamide, and N‐vinylpyrrolidone undergo free radical copolymerization to produce a PTAAN filter loss reducer. The Box–Behnken response surface method is used to optimize the synthesis of PTAAN; the optimal conditions are 1 wt% TMETE and 0.1111 wt% initiator at 60°C. Fourier transform infrared spectroscopy, transmission electron microscopy, and thermogravimetric analysis are used to characterize the composition, micromorphology, and thermal stability of the PTAAN product, respectively. The synthesized product is resistant to high temperatures and salt under the optimal synthesis conditions. It has an API filtration loss of 8.2 mL for freshwater‐based mud, an API filtration loss of 13.8 mL for 20% by weight brine mud after aging at 220°C, and an API filtration loss of 29.5 mL at 150°C under high temperatures and pressures. Incorporating PTAAN into the base slurry prevents clay particle agglomeration at elevated temperatures and high mineralization, resulting in a broader clay particle size distribution and ultimately leading to the formation of a thin and compact filter cake.
A filter loss reducer of PTAAN has been synthesized from trimethylolethane triallyl ether, 2‐acrylamide‐2‐methylpropanesulfonic acid, N‐vinylpyrrolidone, and acrylamide by free radical copolymerization. The Box–Behnken response surface method was used to optimize the synthesis process. The PTAAN has excellent tolerance in 20% NaCl aqueous solution and 1% CaCl2 aqueous solution after aging at 220°C.
2D ternary semiconductor single crystals, an emerging class of new materials, have attracted significant interest recently owing to their great potential for academic interest and practical ...application. In addition to other types of metal dichalcogenides, 2D tin dichalcogenides are also important layered compounds with similar capabilities. Yet, multi‐elemental single crystals enable to assist multiple degrees of freedom for dominant physical properties via ratio alteration. This study reports the growth of single crystals Se‐doped SnS2 or SnSSe alloys, and demonstrates their capability for the fabrication of phototransistors with high performance. Based on exfoliation from bulk high quality single crystals, this study establishes the characteristics of few‐layered SnSSe in structural, optical, and electrical properties. Moreover, few‐layered SnSSe phototransistors are fabricated on both rigid (SiO2/Si) and versatile polyethylene terephthalate substrates and their optoelectronic properties are examined. SnSSe as a phototransistor is demonstrated to exhibit a high photoresponsivity of about 6000 A W−1 with ultra‐high photogain (η) ≈8.8 × 105, fast response time ≈9 ms, and specific detectivity (D*) ≈8.2 × 1012 J. These unique features are much higher than those of recently published phototransistors configured with other few‐layered 2D single crystals, making ultrathin SnSSe a highly qualified candidate for next‐generation optoelectronic applications.
Ultra‐thin layered ternary single crystals of Sn(SxSe1−x)2 with bandgap engineering are proposed to serve as phototransistors, capable of conducting photodetection with high photoresponsivities up to 6000 A W−1. The flexibility and excellent performance of the phototransistor on polyethylene terephthalate substrates make it a promising candidate for next‐generation opto‐electronic applications.
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