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Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion. Targeting the abnormal metabolism of tumor endothelial cells (TECs) may provide an opportunity to improve the outcome of immunotherapy. Here, in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer (CRC), TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs. Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor, which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH. Moreover, osimertinib and anti-PD-1 blockade synergistically retarded tumor growth. This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.

Gastrointestinal mucositis is one of the most debilitating side effects of the chemotherapeutic agent irinotecan (CPT-11). Andrographolide, a natural bicyclic diterpenoid lactone, has been reported to possess anti-colitis activity. In this study, andrographolide treatment was found to significantly relieve CPT-11-induced colitis in tumor-bearing mice without decreasing the tumor suppression effect of CPT-11. CPT-11 causes DNA damage and the release of double-stranded DNA (dsDNA) from the intestine, leading to cyclic-GMP-AMP synthase (cGAS)‒stimulator of interferon genes (STING)-mediated colitis, which was significantly decreased by andrographolide both in vivo and in vitro. Mechanistic studies revealed that andrographolide could promote homologous recombination (HR) repair and downregulate dsDNA‒cGAS‒STING signaling and contribute to the improvement of CPT-11-induced gastrointestinal mucositis. These results suggest that andrographolide may be a novel agent to relieve gastrointestinal mucositis caused by CPT-11., Graphical abstract Andrographolide could accelerate HR repair of DNA damage-induced by elevating expression of RAD51 and downregulate cGAS‒STING, thereby improving mucosal damage.Image 1

Purpose: Diabetic retinopathy (DR) has been linked to a range of systemic risk factors, but the evidence supporting these associations is inconsistent. This study aimed to use Mendelian randomization (MR) analysis to establish genetic causal links between different risk factors and DR. Methods: The study analyzed the genetic associations between obesity, overall health status, lifestyle factors, and serum parameters with DR (n=14,584), PDR (n=8,681), and NPDR (n=2,026). Multiple MR models, multivariable MR (MVMR), and meta-analysis were used to identify significant mediators for the relationship between the risk factors and DR. Results: Genetic analysis of the 14,584 cases and 202,082 controls identified two novel genes, rs111953004 and rs9280092 on chromosome 6, with the nearest gene being HLA-DQB1 (p value of 2.146×10-160). Multiple MR models consistently showed genetic associations between obesity and DR. Overall health status, including overall rating (OR: 1.60; 95% confidence interval [CI]: 1.27-2.00), ischemic stroke (OR: 1.16; 95% CI: 1.09-1.24), and hypertension (OR: 1.07; 95% CI: 1.04-1.11) were found to increase the risk of DR. Meanwhile, moderate physical activity frequency (OR: 0.79; 95% CI: 0.68-0.92) and having a college degree (OR: 0.56; 95% CI: 0.48-0.67) were found to protect against DR according to meta-analysis. Serum parameters such as lower LDL cholesterol (OR: 0.94; 95% CI: 0.89-0.98) and higher HDL cholesterol (OR: 0.91; 95% CI: 0.88-0.94) were found to reduce the risk of DR. MVMR revealed that hypertension, coffee intake, and overall health rating were risk factors for DR. Combined meta-analysis results also suggested that alcohol consumption, coffee intake, and daytime napping might increase the risk of DR (all p Conclusions: This study established strong genetic causal links between selected risk factors and DR, which were largely mediated by obesity. Higher education level, physical activity, and better cholesterol control were associated with a decreased risk of DR.

The probabilistic-constrained tracking control issue is investigated for a class of time-varying nonlinear stochastic systems with sensor saturation, deception attacks and limited bandwidth in an unified framework. The saturation of sensors is quantified by a sector-bound-based function satisfying certain conditions, and the random deception attacks are considered and modeled by a random indicator variable. To gain more efficient utilization of communication channels, a Round-Robin (RR) protocol is utilized to orchestrate the transmission order of measurements. The main purposes of this study aim to plan an observer-based tracking controller to achieve the following goals: (1) the related performance indicators of the estimation error is less than given bound at each time step; and (2) the violation probability of the tracking error confined in a predefined scope is supposed to be higher than a prescribed scalar and the area is minimized at each instant. In order to reach these requirements, a group of recursive linear matrix inequalities (RLMIs) are developed to estimate the state and design the tracking controller at the same time. Finally, two simulation examples are exploited to illustrate the availability and flexibility of the proposed scheme.

Six tert-butyls modified naphthyl derivative (2,6-di-tert-butyl-1,5-bis-(3,5-di-tert-butyl-phenyl)-naphthalene (N(dtb)4) was synthesized and tested for host and guest materials in organic light-emitting diodes (OLEDs). Blue OLED using N(dtb)4 as a host and an emitter DSA-PH as a guest reaches an efficiency of 11.52 cd·A−1 (maximum external quantum efficiency 7.8 % and maximum power efficiency 10.33 lm·W−1). In addition, for the OLED with N(dtb)4 being a guest, we find that the concentrations of N(dtb)4 will also affect the performance of the OLED, among which ADN: 5 wt.% N(dtb)4 has higher efficiency, and the maximum current efficiency, external quantum efficiency (EQE) and power efficiency of the device reach 3.75 cd·A−1, 3.93 % and 3.36 lm·W−1, respectively. We also investigated the pure N(dtb)4 -based ultraviolet OLED (UV-OLED), and achieved the maximum EQE of the device is 1.12 %. These results indicate that N(dtb)4, a novel synthesized fluorescent organic material, has great potential applications in OLEDs and accordingly advancing lightings and displays.

2D transition metal dichalcogenides (TMDs) have been considered as promising non-precious electrocatalysts for the hydrogen evolution reaction (HER). However, their limited active sites and poor electric conductivity pose a significant hurdle to their HER performance, resulting in a large overpotential. Here, we report the defect engineering in ultrathin tungsten telluride (WTe2) nanosheets with semimetal nature to improve hydrogen evolution effectively. We find that the oxygen plasma etching imposes a cutting effect on WTe2 nanosheets, resulting in a large number of tungsten vacancies. Particularly, the sample after plasma treatment for 10 min shows a feather-like structure with an overpotential of 251 mV at 10 mA/cm2 and a Tafel slope of 94 mV/dec, which is 4 times lower than the Tafel slope of pristine nanosheets. Further first-principles calculations shed light on the evolution of defect-rich WTe2 nanosheets and offer rational explanation to their superiority in efficient hydrogen evolution.

Summary Two-dimensional (2D) graphdiyne (GDY) is a promising floating-gate material for flexible optoelectronic flash memory owing to its fascinating electrical and optical properties. However, research in GDY-based flash memory is still in its infancy owing to the huge challenge in the synthesis of large-area and ultrathin GDY films with high quality and uniformity. Here, an electric double-layer-confined strategy is proposed to synthesize a wafer-scale GDY film with thickness of 1 nm. Then, a two-terminal top-floating-gated optoelectronic memory with multibit storage capability is investigated using GDY as a photoresponsive top-floating gate. Benefiting from the excellent charge storage capability and high photoresponse of GDY, this device exhibits over 256 distinct storage levels (8 bits) with signal-to-noise ratios larger than 100. Moreover, the fully 2D material and two-terminal architecture endows the device with robust bending stability for over 1,000 bending circles, paving the way to develop wearable electronics.

The relative efficacy of different sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in reducing cardiorenal events in type 2 diabetic adults is unclear. We searched PubMed and Embase. Three primary endpoints were major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and kidney function progression (KFP). Bayesian network meta-analysis was conducted to synthesize hazard ratio (HR) and 95% confidence interval (CI). We calculated surface under the cumulative ranking curve (SUCRA) to rank drug treatments. Subcutaneous semaglutide (HR 0.73, 95% CI 0.55-0.96) and albiglutide (HR 0.76, 95% CI 0.63-0.93) significantly reduced MACE versus lixisenatide. Canagliflozin (HRs: 0.69, 0.68, 0.67 and 0.58) and empagliflozin (HRs: 0.70, 0.69, 0.68 and 0.59) significantly reduced HHF versus dulaglutide, exenatide, lixisenatide and subcutaneous semaglutide. Dapagliflozin (HRs: 0.62, 0.60, 0.68 and 0.63) and empagliflozin (HRs: 0.64, 0.61, 0.69 and 0.64) significantly reduced KFP versus dulaglutide, exenatide, liraglutide and lixisenatide. Different drug treatments had the maximum SUCRA values as for preventing different cardiorenal endpoints. Different GLP-1 RAs and SGLT2 inhibitors have different efficacy in preventing cardiorenal endpoints in type 2 diabetes, and the most efficacious drugs are different as for preventing different cardiorenal endpoints.

The mixed cohosts of electron transport host (E-host): 4,40-bis(carbazol-9-yl)biphenyl (CBP) have been comparatively investigated for an efficient green fluorescent organic light emitting diode (OLED) doped with a thermally activated delayed fluorescence (TADF) emitter (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN). The E-host:CBP systems significantly enhance the electroluminescent (EL) properties. After doping E-host, the lifetime of the emissive layer decreases and the surface becomes smoother, together with the impedance decreases for one magnitude and the hole-injection depresses. The charge balance and improved interface both contribute to the EL performance enhancement. Here we develop a universal mixed host system suitable to most of emitters.

Maize (Zea mays L.) is one of the most important food crops in the world, and starch is the main component of its endosperm. Transcriptional regulation plays a vital role in starch biosynthesis. However, it is not well understood in maize. We report the identification of the transcription factor ZmNAC126 and its role in regulation of starch synthesis in maize. Transcriptional expression of ZmNAC126 was higher in maize endosperm and kernels than in roots or stems. ZmNAC126 shared a similar expression pattern with starch synthesis genes during seed development, and its expression pattern was also consistent with the accumulation of starch. ZmNAC126 is a typical transcription factor with a transactivation domain between positions 201 and 227 of the amino acid sequence, is located in the nucleus, and binds to CACG repeats in vitro. Yeast one-hybrid assay revealed that ZmNAC126 bound the promoters of ZmGBSSI, ZmSSIIa, ZmSSIV, ZmISA1, and ZmISA2. Transient overexpression of ZmNAC126 in maize endosperm increased the activities of promoters pZmSh2, pZmBt2, pZmGBSSI, pZmSSIIIa, and pZmBT1 but inhibited the activities of pZmISA1 and pZmISA2. ZmNAC126 thus acts in starch synthesis by transcriptionally regulating targeted starch synthesis-related genes in maize kernels.

Combination therapy with cisplatin is the conventional first-line treatment in patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). Ubiquitin-specific protease 9X (USP9X) has been shown to be associated with resistance to chemotherapy drugs in several cancers. The purpose of this study was to explore the predictive effects of USP9X on advanced ESCC patients treated with cisplatin-based regimens.The subjects were 69 advanced ESCC patients who received first-line cisplatin-based chemotherapy or chemoradiotherapy. The quantitative real-time PCR was performed to measure USP9X mRNA expression. The correlation of USP9X expression with clinical parameters and tumor response was analyzed. The Kaplan-Meier method and Cox analysis were employed to analyze differences in overall survival (OS).USP9X mRNA expression was positively associated with the TMN stage at initial diagnosis. Patients with low USP9X mRNA expression had a significantly higher objective response rate (57.1% vs. 17.6%, P=0.001) and longer median OS (25.0 vs. 14.0 months, P0.001) than those with high expression in all patients or in different treatment subgroups (all P0.05). Multivariate analysis showed that low mRNA expression of USP9X emerged as an independent prognostic factor indicating prolonged OS (hazard ratio 0.50, 95% CI 0.34-0.73; P0.001).These findings suggest that high USP9X mRNA expression predicts poor clinical efficacy and survival to cisplatin-based therapy in patients with advanced ESCC.

Purpose Although there have been many population-based studies of age-related macular degeneration (AMD), only limited information is available in Asia on the epidemiology of geographic atrophy (GA). We aimed to determine the prevalence and patterns of GA through an analysis of multiple studies conducted within the Asian Eye Epidemiology Consortium (AEEC). Design Cross-sectional meta-analyses. Participants A total of 97 213 individuals aged 40 years and older. Methods Data from 22 population-based studies from countries belonging to the AEEC were included. In all studies, AMD was defined on the basis of standardized grading systems. Geographic atrophy was defined as an area of pallor in the fundus with visibility of the underlying choroidal blood vessels and sharply defined borders. Random-effects meta-analysis was performed to estimate overall and age-, gender-, and region-specific pooled prevalence of GA. Main Outcome Measures Prevalence of GA per 1000 persons. Results The mean age was 60.8 ± 10.0 years, and 42 673 (43.9%) were male. Overall, a total of 223 individuals (0.2%) had GA. The pooled overall prevalence of GA was 1.57 per 1000 persons (95% confidence interval [CI], 1.04–2.10), which was 3 times less than that of neovascular AMD of 5.20 per 1000 persons (95% CI, 3.97–6.43). Compared with those aged 50 to 59 years, the prevalence of GA increased from 0.34 per 1000 persons (95% CI, 0.07–0.62) to 2.90 per 1000 persons (95% CI, 1.55–4.25) in those aged ≥70 years. The GA prevalence per 1000 persons was similar between urban (2.22; 95% CI, 1.22–3.23) and rural residents (1.33; 95% CI, 0.70–1.96). Geographic atrophy was more prevalent in South Asia (based on studies from India and Nepal, 3.82 per 1000 persons; 95% CI, 1.72–5.93) compared with East Asia (based on studies from China, Korea, Hong Kong, Taiwan, and Japan, and the Singapore Chinese Eye Study, 0.76 per 1000 persons; 95% CI, 0.31–1.22, P = 0.005). Conclusions Geographic atrophy is uncommon in Asian populations compared with those of European ancestry. Even within Asia, geographic differences in GA prevalence were seen. The findings of this meta-analysis suggest that better dissection of risk factors in the Asian population for GA may provide insights into the biological pathways that drive these late-stage manifestations, thus suggesting better targets for prevention.

Summary With rapid progress in perovskite light-emitting diodes (PeLEDs), the electroluminescence performance of large-area is of increasing interest. We investigated why large-area performance lags behind that achieved in laboratory-scale devices and found that defects in perovskite films—emerging from thermal convection during solvent evaporation, as well as electronic traps formed during perovskite crystallization—are chief causes. Here, we report a molecular modification strategy that simultaneously eliminates pinholes in perovskite layers by controlling the dynamics of film formation and that passivates defects in perovskites by incorporating Br species, thereby preventing shorts and non-radiative recombination. The molecular modifier 1,3,5-tris (bromomethyl) benzene (TBB) also modulates the electronic structure of injection or transport materials to achieve improved charge injection and balanced charge transport. As a result, we demonstrate 20 mm × 20 mm green perovskite nanocrystal LEDs that achieve an external quantum efficiency (EQE) of over 16%, a record for large-area PeLEDs.

‘Lvbao-701’ is a cultivar of Chinese flowering cabbage (Brassica parachinensis) that exhibits low cadmium (Cd) accumulation and high Cd tolerance. In this study, this cultivar was compared with a high-Cd accumulating cultivar, ‘Chixin-4’, to characterize the mechanisms influencing Cd accumulation in B. parachinensis. Root cell walls were isolated by dissolving the cytoplasm with an organic solvent, and root Cd and phytochelatin (PC) contents were analyzed. In addition, a PC synthase gene fragment was cloned and expressed under Cd stress conditions. The proportions of Cd bound to root cell walls were higher in the ‘Lvbao-701’ plants (68.32%–76.80%) than in the ‘Chixin-4’ plants (35.36%–54.18%) after exposure to Cd stress. The proportions of Cd bound to root cell walls measured using cell walls isolated with a non-destructive method were higher than those obtained using a conventional method that required grinding and centrifugation. Exposure to Cd stress induced the PC production and resulted in higher PC contents in the ‘Lvbao-701’ plants than in the ‘Chixin-4’ plants. Cloning and expression analysis of a B. parachinensis PC synthase cDNA fragment indicated that PC synthase gene expression was induced by Cd and occurred mainly in the roots of both ‘Lvbao-701’ and ‘Chixin-4’ plants. However, the PC synthase gene expression level was higher in the ‘Lvbao-701’ roots than in the ‘Chixin-4’ roots. Therefore, a higher abundance of Cd in the root cell walls of ‘Lvbao-701’ and up-regulated PC production in the roots are probably the main reasons why ‘Lvbao-701’ exhibits lower Cd translocation to the shoots and higher tolerance to Cd than ‘Chixin-4’.

Two-dimensional (2D) CuInP2X6 (X = S or Se) materials have emerged as promising candidates for various technological applications due to their lamellar structures and ferroelectric properties. However, 2D CuInP2Se6 material has not been well explored yet for the difficulty in acquiring ultrathin flakes. Here, we prepare, for the first time, CuInP2Se6 crystals by the chemical vapor deposition method and its 2D flakes, and demonstrate that the thinnest CuInP2Se6 flakes of 4 nm are achieved. X-ray diffraction and atomic-resolution scanning transmission electron microscopy analyses reveal their single crystal phase and the corresponding atomic structure of bulk CuInP2Se6 with good crystallization. Raman results further exhibit obvious thickness dependence of Raman peak position and intensity for the CuInP2Se6 flake. First-principles calculations validate the ferroelectric property of CuInP2Se6 monolayer. Importantly, we find that the antiferroelectric (AFE) state is slightly stable than the ferroelectric (FE) state in bulk form, yet these two states are far more stable than the paraelectric (PE) state, resulting in the coexistence of AFE and FE states in this material.