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Abstract Snake venom C-type lectin-like proteins (CLPs) belong to the nonenzymatic proteins. To date, no CLP with both platelet and coagulation factors activating activities has been reported. In this study, a novel CLP, termed protocetin, with molecular weight of 29.986 kDa, was purified from the Protobothrops mucrosquamatus venom (PMV). It consists of α- and β-chains, with 67% similarity in their N-terminal sequence. Protocetin activates glycoprotein Ib (GPIb) by binding to von Willebrand factor (vWF), inducing platelet aggregation. It also activates the intrinsic coagulation pathway by binding to coagulation factor IX. After injection of protocetin into mice at dose of 0.5 µg/g or 1.5 µg/g, it resulted in activation of platelets, a notable reduction in platelet count and prolonged tail bleeding time. Additionally, the plasma activated partial thromboplastin time (APTT) was significantly extended, and the fibrinogen concentration was markedly reduced. Thrombelastogram comfirmed the anticoagulation effect of protocetin. Notably, no microthrombosis was observed in tissues of lung, liver and kidney within 1 h after injection of protocetin into the mice at dose of 0.5 µg/g. This study revealed protocetin as a novel CLP from PMV that has dual functions in activating platelet and coagulation factor IX, thereby modulates coagulation in vivo. This work contributes to a better understanding of the structure and function of snake venom CLP.

Flood frequency in river source regions is significantly affected by rainfall and snowmelt as part of climatic changes. A traditional univariate flood frequency analysis cannot reflect the complexity of floods, and when used in isolation, it can only underestimate flood risk. For effective flood prevention and mitigation, it is essential to consider the combined effects of precipitation and snowmelt. Copula functions can effectively quantify the joint distribution relationship between floods and their associated variables without restrictions on their distribution characteristics. This study uses copula functions to consider a multivariate probability distribution model of flood peak flow (Q) with cumulative snowmelt (CSm) and cumulative precipitation (CPr) for the Hutubi River basin located in northern Xinjiang, China. The joint frequencies of rainfall and snowmelt floods are predicted using copula models based on the Coupled Model Intercomparison Project Phase 6 data. The results show that Q has a significant positive correlation with 24-d CSm (r = 0.559, p = 0.002) and 23-d CPr (r = 0.965, p

Abstract Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Frozen ground (FG) plays an important role in global and regional climates and environments through changes in land freeze‒thaw processes, which have been conducted mainly in different regions. However, the changes in land surface freeze‒thaw processes under climate change on a global scale are still unclear. Based on ERA5-Land hourly land skin temperature data, this study evaluated changes in the global FG area, global land surface first freeze date (FFD), last freeze date (LFD) and frost-free period (FFP) from 1950 to 2020. The results show that the current FG areas (1991–2020 mean) in the Northern Hemisphere (NH), Southern Hemisphere (SH), and globe are 68.50 × 106, 9.03 × 106, and 77.53 × 106 km2, which account for 72.4%, 26.8%, and 60.4% of the exposed land (excluding glaciers, ice sheets, and water bodies) in the NH, SH and the globe, respectively; further, relative to 1951–1980, the FG area decreased by 1.9%, 8.8%, and 2.8%, respectively. Seasonally FG at lower latitudes degrades to intermittently FG, and intermittently FG degrades to non-frozen ground, which caused the global FG boundary to retreat to higher latitudes from 1950 to 2020. The annual FG areas in the NH, SH, and globe all show significant decreasing trends (p

Objective: Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE−/− mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. Approach and results: We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved β-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. Conclusions: Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.

Single Alter shielded T-200BM3 weighing precipitation gauges are widely used in the measurement of all precipitation types (rainfall, snow and mixed precipitation) in unattended boreal or alpine regions, but their original datasets must be adjusted for undercatch errors caused by wind in snowy, windy and harsh environments. Therefore, previous researchers have developed many adjustment methods for all precipitation types on different time scales. However, which adjustment method is suitable for T-200BM3 weighing gauge wind-induced error adjustment in harsh alpine regions is unclear. Therefore, precipitation measurement intercomparison experiments were conducted in the Qilian Mountains from July 2018 to July 2021, and eight adjustment methods; were evaluated for wind-induced errors for daily, individual precipitation event, hourly, and half-hourly time scales. Z2004 outperformed the other adjustment methods in regard to the daily measurements of snow and mixed precipitation. Regarding individual snowfall events, M2007 reduced the absolute value of RMSE (bias) from 1.44 to 1.32 mm (0.77–0.24 mm) and could be recommended for snowfall event adjustment. K2017-1 attained a better performance than K2017-2 in regard to half-hourly snowfall and mixed sample adjustment and was more suitable for half-hourly snowfall sample adjustment. K2017-1 reduced the absolute value of bias from 0.07 to 0.00 mm for snowfall. Finally, Z2004, M2007, and K2017-1 yielded better adjustment results for the daily accumulation precipitation amount (>2 mm d−1), individual snowfall events (>2 mm per event), and half-hourly accumulation snowfall or mixed samples (>1 mm 30 min−1), respectively. However, further intercomparison in different climate regions is needed for trace precipitation samples.

White organic light-emitting diodes (WOLEDs) hold vast prospects in the fields of next-generation displays and solid-state lighting. Ultrathin emitting layers (UEMLs) have become a research hotspot because of their unique advantage. On the basis of simplifying the device structure and preparation process, they can achieve electroluminescent performance comparable to that of doped devices. In this review, we first discuss the working principles and advantages of WOLEDs based on UEML architecture, which can achieve low cost and more flexibility by simplifying the device structure and preparation process. Subsequently, the successful applications of doping and non-doping technologies in fluorescent, phosphorescent, and hybrid WOLEDs combined with UEMLs are discussed, and the operation mechanisms of these WOLEDs are emphasized briefly. We firmly believe that this article will bring new hope for the development of UEML-based WOLEDs in the future.

Precipitation data is vital fundamental data for climate change. However, obtaining precise gauge-measured precipitation in high-altitude mountains is challenging, and the precipitation obtained from various gauge types at the same station may vary. To understand the differences in precipitation observations among the three commonly used gauges in China (Chinese Standard Precipitation Gauges (CSPG), Total Rain weighing Sensor (TRwS), and Geonor T-200B (T200B)) in high-altitude mountains and to recommend a stable and cost-effective weighing gauge, a precipitation intercomparison experiment was conducted at Hulu-1 station in the Qilian Mountains. The wind-induced error in measurement was corrected with the ‘universal’ transfer function recommended by the Word Meteorological Organization. The comparison results, adjusted for systematic errors, showed that the rain, snow and mixed precipitation of CSPG and TRwS equipped with the same octagonal vertical double fence shields (CSPGDF and TRwSDF) and single-Alter shields (CSPGs and TRwSs) were close, while the precipitation of Tretyakov-shielded T200B was notably higher than that of CSPGs and TRwSs. The average differences in annual and daily precipitation between CSPGDF and TRwSDF from 2017 to 2021 were 12.9 mm and 0.10 mm, respectively. The daily precipitation difference between CSPGs and TRwSs from April 2019–December 2021 was 0.10 mm, while the differences between T200Bs and CSPGs and TRwSs was 0.28 mm and 0.38 mm, respectively. The wind shield performance of Alter and Tretyakov was not much different at Hulu-1 site with low wind speed, thus the measurement principle of T200Bs was the primary cause of the high observations. Taking the corrected CSPGDF measurement as the standard, the dynamic loss of CSPGs was 17.6%, while that of CSPGUn was 55.6%, indicating that the single-Alter shield could effectively reduce the impact of wind on precipitation measurement. Considering the comparison results and the price difference of the instruments, it was recommended to use a single-Alter shielded TRwS gauge for precipitation observation in high-altitude mountains.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Silencing information regulator 1 (SIRT1) was demonstrated to modulate cholesterol and lipid metabolism in NAFLD. Here, a novel SIRT1 activator, E1231, was studied for its potential improvement effects on NAFLD. C57BL/6J mice were fed a high-fat and high-cholesterol diet (HFHC) for 40 weeks to create a NAFLD mouse model, and E1231 was administered by oral gavage (50 mg/kg body weight, once/day) for 4 weeks. Liver-related plasma biochemistry parameter tests, Oil Red O staining, and hematoxylin-eosin staining results showed that E1231 treatment ameliorated plasma dyslipidemia, plasma marker levels of liver damage (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), liver total cholesterol (TC) and triglycerides (TG) contents, and obviously decreased hepatic steatosis score and NAFLD Activity Score (NAS) in the NAFLD mouse model. Western blot results showed that E1231 treatment significantly regulated lipid-metabolism-related protein expression. In particular, E1231 treatment increased SIRT1, PGC-1α, and p-AMPKα protein expression but decreased ACC and SCD-1 protein expression. Additionally, in vitro studies demonstrated that E1231 inhibited lipid accumulation and improved mitochondrial function in free-fatty-acid-challenged hepatocytes, and required SIRT1 activation. In conclusion, this study illustrated that the SIRT1 activator E1231 alleviated HFHC-induced NAFLD development and improved liver injury by regulating the SIRT1-AMPKα pathway, and might be a promising candidate compound for NAFLD treatment.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

In order to capture the dynamic interaction between users and items during online shopping and improve the accuracy of recommendation systems(RS),a user rating prediction method combining user preference and item attractiveness is proposed.The reviews are divided into user review texts and product review texts,which are fed into two convolutional neural networks(CNN),and combined with an attention mechanism to dynamically capture semantic and contextual information in the texts,and obtain user and item adaptive representations.Subsequently,using the interactive attention network,the dynamic interaction between the item features and the user features is analyzed to calculate the user preference on specific items and the attractiveness of the items to a specific user.Finally,the prediction module is used to provide accurate predictions about user ratings to unseen items.Results on experimental datasets show that the proposed method achieves optimal performance,with at least 15.1% and 13.6% improvement in MAE and RMSE performance compared to other advanced methods.In addition,the statistical metrics based on Top-K further validate the accuracy of the proposed method for product recommendation.

With global warming and rapid shrinkage of the cryosphere, the decreasing cryosphere water resources (CWR) supply function would weaken its service and then affect local economic development and implement of United Nations Sustainable Development Goals (SDGs) in the world, but how does the CWR supply affect its service and their variations in the past and future are still not clear at present. In this study, the past dynamics (1960–2020), current situation (2010s) and projected changes (2020–2100) of CWR in China were assessed by calculating the meltwater from glacier, snow cover and the ground ice of permafrost under Representative Concentration Pathways scenarios (RCP2.6, RCP4.5, and RCP8.5). Combined with projected data of population and economy, the CWR service potential was also estimated in the 2030s, 2050s and 2090s under scenarios of Shared Socioeconomic Pathways (SSP1, SSP2, and SSP5). The annual CWR in China is about 310.7 × 109 m3 in the 2010s, with glacier runoff, snowmelt, and ground ice meltwater accounting for 24.1%, 72.7% and 3.2%, respectively. Under SSP1-RCP2.6, the quantity of CWR was projected to decline by 14%–18% over the next 80 years, and the service potential would reach the peak in 2100. While under SSP5-RCP8.5, CWR would be reduced by 40% by 2100, and the service would gradually decline from 2050. The study of CWR is of great significance for water security, sustainable development and risk avoidance in the arid endorheic region.

Study of mechanical properties of rock under hydro-mechanical coupling. The MTS815 rock mechanics system is used to perform triaxial compression tests of water-saturated sandstones under different confining pressures and pore water pressures. The results show that the peak deviation stress and its corresponding axial strain, residual deviation stress, initial deviation stress of dilation and deformation modulus of water-saturated sandstone are related to pore water pressure and confining pressure. They decrease with the increase of pore water pressure and increase with the increase of confining pressure. Poisson’s ratio and angle of rupture of water-saturated sandstone increase with pore water pressure. Based on the effective stress principle and Mohr–Coulomb criterion, the effective cohesion and effective residual cohesion of sandstone are 11.49 and 3.13 MPa, respectively, and the effective angle of internal friction and effective residual angle of internal friction are 38.32° and 25.32°, respectively. In addition, according to the variation relationship of sandstone strength, the relative strength criterion of sandstone under hydro-mechanical coupling is established.

The self-rectifying memristor (SRM) is a promising device prototype for high-density three-dimensional (3D) integration and high-efficiency in-memory computing (IMC) by virtue of its ability to effectively suppress sneak current, simple device structure, and low energy consumption. Theoretically understanding the intrinsic mechanisms of SRM is a matter of concern. Here, we fabricated a Ta/TaOx/HfO2/Pt-stacked SRM exhibiting >103 on/off ratio, rectification ratio, and nonlinearity. The SRM can be repeatedly programmed by more than 106 pulses and demonstrates robust retention and high scalability (∼59 Mbit). A reasonable interface model for this SRM is established based on first-principles calculations. Using self-energy corrected density function theory, we calculate the barrier heights at each interface. Detailed I–V curve fitting and energy band analysis are performed and computationally verified to explain the intrinsic reasons for resistive switching, self-rectifying, and nonlinear behaviors. The work may advance the development of SRM prototype to enable energy-efficient 3D IMC. [ABSTRACT FROM AUTHOR]

High harmonics of circular polarization can be directly generated by monochromatic circularly polarized incident light owing to the high density and stable structure of crystal media. If the arrangement of multiple coplanar atoms in the unit structure of the crystal exhibits rotational symmetry, the polarization state of the high harmonics generated from the crystal follows specific selection rules that have been observed in the 2D crystal medium. In addition, the geometric symmetry of the coplanar atom distribution is related to the orientation of cubic crystals. This implies that only the polarization along a specific crystal orientation can achieve a selection of high‐harmonic polarization states. However, this is a very weak process in cubic crystals owing to the attenuation of crystal anisotropy to circularly polarized light and the dependence of the electron transition rate on the crystal orientation. In this study, plasmonic nanoantennas are designed on silicon crystal films to enhance this process. The harmonic emission is more than ten times brighter than that without nanoantennas and conformed to the selection rules for high harmonics. The research results offer a new approach for deep­ultraviolet space filtering, carrier control, and the development of compact extreme­ultraviolet light sources. [ABSTRACT FROM AUTHOR]

Three‐coil inductive power transfer (IPT) charging system can not only achieve inherent constant current (CC) to constant voltage (CV) transition but also tolerate load open‐circuit. However, due to the cross‐coupling between the auxiliary coil and the receiver coil, the output voltage in CV mode may deviate from the CV voltage significantly, which makes the design freedom of the three‐coil coupler low. By replacing the auxiliary coil with a transformer, an improved auxiliary circuit is proposed in this paper to address the cross‐coupling issue and to increase the design freedom of the loosely coupled transformer (LCT). The improved auxiliary circuit can achieve load short‐circuit and open‐circuit protection. Besides, the optimization design of LCT is easy to achieve by load impedance matching. The operating principle and parameters design of the improved auxiliary circuit are discussed. A 1 kW experimental prototype is built to verify the feasibility of the proposed method. [ABSTRACT FROM AUTHOR]

Background The urinary and sexual outcomes after urethroplasty may be a concern for patients, but there are still some controversies regarding the consequences of buccal mucosal graft urethroplasty (BMG) in terms of erectile dysfunction (ED). Aim This meta-analysis aimed to compare urinary and sexual outcomes of BMG and end-to-end urethroplasty (EE). Methods The PubMed, Web of Science, Cochrane, and Embase databases were searched until February 31, 2023. Data extraction and quality assessment were performed by 2 designated researchers. Dichotomous data were analyzed as odds ratios with 95% confidence intervals (CIs). Heterogeneity across studies was assessed by the I2 quantification, and publication bias using Begg's and Egger's tests. Meta-analysis was performed using RevMan software. Outcomes Outcomes included stricture recurrence, ED, penile complications, and voiding symptoms. Results Eighteen studies, including 1648 participants, were included in our meta-analysis. The meta-analysis revealed that there was no significant difference in stricture recurrence (OR = 0.74; 95% CI, 0.48–1.13; P  = .17) and voiding symptoms (OR = 1.12; 95% CI, 0.32–3.88; P  = .86) between the BMG group and the EE group. BMG was associated with lower risk of penile complications (OR = 0.40; 95% CI, 0.24–0.69; P  = .001) and ED (OR = 0.53, 95% CI, 0.32–0.90, P  = .02). Clinical Implications The study may help clinicians choose procedures that achieve better recovery of the urological and sexual function in the treatment of urethral stricture. Strengths and Limitations This meta-analysis is the first to evaluate the urinary and sexual outcomes of BMG vs EE. A limitation is that most of the included studies were retrospective cohort studies. Conclusion BMG is as effective as EE in the treatment of bulbar urethral stricture, but BMG has fewer complications and ED than EE. [ABSTRACT FROM AUTHOR]

Interfacial exciplex has recently been adopted as an effective host to achieve phosphorescent organic light-emitting diodes (OLEDs) with high efficiencies and low driving voltages. However, a systematic understanding of exciton recombination behavior in either host of interfacial exciplex is still deficient. Herein, the strategic design rule of interfacial exciplex host is proposed to overcome the negative effects of direct trapping recombination by systematically investigating exciton recombination behavior in interfacial exciplex hosts. As a result, blue and orange phosphorescent devices acquire peak external quantum efficiencies of 23.5% and 29.2% with low turn-on voltages. These results provide a simple method to realize highly efficient OLEDs aiming for general lighting and display applications.

Radiotherapy is a valid treatment for nasopharyngeal carcinoma (NPC), and radioresistance is the main cause of local NPC treatment failure. However, the underlying mechanisms and valuable markers of radioresistance for NPC remain have not been established. In this study, we observed that the m6A mRNA demethylase fat mass and obesity-associated protein (FTO) was significantly upregulated in radioresistant NPC tissues and cells relative to parental radiosensitive NPC tissues and cells. FTO enhances radioresistance by repressing radiation-induced ferroptosis in NPC. Mechanistically, FTO acts as an m6A demethylase to erase the m6A modification of the OTUB1 transcript and promote the expression of OTUB1, thereby inhibiting the ferroptosis of cells induced by radiation and finally triggering the radiotherapy resistance of NPC. Furthermore, our in vivo experiment results showed that the FTO inhibitor, FB23-2, and the ferroptosis activator, erastin, altered tumor responsiveness to radiotherapy in NPC cell lines and patient-derived xenografts. Our findings reveal, for the first time, that FTO enhances NPC radiotherapy resistance by withstanding radiation-induced ferroptosis, suggesting that FTO may serve as a potential therapeutic target and valuable prognostic biomarker in patients with NPC.

Abstract Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi‐disciplinary team comprising of experts from all sub‐specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence‐based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow‐up of NPC, which aim to improve the management of NPC.