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Abstract Validating large-scale water quality models is challenging because of the variety of water quality constituents, and scales for which observations are limited. Here, in this perspective, we propose 13 alternative strategies to build trust in large-scale water quality models beyond validation and discuss their strengths and weaknesses regarding their validity, reliability, and applicability. Our alternative strategies aim to evaluate separately model inputs (Strategies 1–4), outputs (Strategies 5–6) and structures (Strategy 7) as well as these aspects together (Strategies 8–13). This is done via methods such as comparisons (Strategies 1–3, 6–8, 12–13), sensitivity analysis (Strategy 5), use of innovations (Strategy 9), expert knowledge (Strategy 11) and local models (Strategy 13). The proposed strategies vary in their validity, reliability, and applicability. Validation is an important starting point but should be used in combination with other strategies. Our proposed list opens the discussion to improve methods to evaluate global water quality models.

Abstract The impact of droughts and heatwaves on agriculture losses has been exacerbated by the occurrence of compound and cascading events. Here we present a study that evaluates the impact of these events both as singly and as compound and cascading on maize yield in Sinaloa Mexico from 1990 to 2022, using the WOFOST crop model. Drought and heatwave events were identified using the Standardized Precipitation Index and threshold method, respectively. Results show that yield reduction (25%) is found during extreme drought events, emphasizing the vulnerability of maize farming to unfavorable drought conditions. While heatwaves alone did not show a significant impact on maize yields, the compound and cascading droughts and heatwaves amplified the loss of maize yields by up to 44% compared to normal conditions. This study highlights the need for adaptive strategies in agriculture to sustain food security during extreme events, especially in the context of multi hazard framework.

Chemoresistance remains a principal culprit for the treatment failure in colorectal cancer (CRC), especially for patients with recurrent or metastatic disease. Deciphering the molecular basis of chemoresistance may lead to novel therapeutic strategies for this fatal disease. Here, UBR5, an E3 ubiquitin ligase frequently overexpressed in human CRC, is demonstrated to mediate chemoresistance principally by inhibiting ferroptosis. Paradoxically, UBR5 shields oxaliplatin-activated Smad3 from proteasome-dependent degradation via Lys 11-linked polyubiquitination. This novel chemical modification of Smad3 facilitates the transcriptional repression of ATF3, induction of SLC7A11 and inhibition of ferroptosis, contributing to chemoresistance. Consequently, targeting UBR5 in combination with a ferroptosis inducer synergistically sensitizes CRC to oxaliplatin-induced cell death and control of tumor growth. This study reveals, for the first time, a major clinically relevant chemoresistance mechanism in CRC mediated by UBR5 in sustaining TGFβ-Smad3 signaling and tuning ferroptosis, unveiling its potential as a viable therapeutic target for chemosensitization.

Abstract Background The COVID-19 pandemic has profoundly affected human social contact patterns, but there is limited understanding regarding the post-pandemic social contact patterns. Our objective is to quantitatively assess social contact patterns in Suzhou post-COVID-19. Methods We employed a diary design and conducted social contact surveys from June to October 2023, utilizing paper questionnaires. A generalized linear model was utilized to analyze the relationship between individual contacts and covariates. We examined the proportions of contact type, location, duration, and frequency. Additionally, age-related mixed matrices were established. Results The participants reported an average of 11.51 (SD 5.96) contact numbers and a total of 19.78 (SD 20.94) contact numbers per day, respectively. The number of contacts was significantly associated with age, household size, and the type of week. Compared to the 0–9 age group, those in the 10–19 age group reported a higher number of contacts (IRR = 1.12, CI: 1.01–1.24), while participants aged 20 and older reported fewer (IRR range: 0.54–0.67). Larger households (5 or more) reported more contacts (IRR = 1.09, CI: 1.01–1.18) and fewer contacts were reported on weekends (IRR = 0.95, CI: 0.90–0.99). School had the highest proportion of contact durations exceeding 4 h (49.5%) and daily frequencies (90.4%), followed by home and workplace. The contact patterns exhibited clear age-assortative mixing, with Q indices of 0.27 and 0.28. Conclusions We assessed the characteristics of social contact patterns in Suzhou, which are essential for parameterizing models of infectious disease transmission. The high frequency and intensity of contacts among school-aged children should be given special attention, making school intervention policies a crucial component in controlling infectious disease transmission.

Abstract Water security is at stake today. While climate changes influence water availability, urbanization and agricultural activities have led to increasing water demand as well as pollution, limiting safe water use. We conducted a global assessment of future clean-water scarcity for 2050s by adding the water pollution aspect to the classical water quantity-induced scarcity assessments. This was done for >10,000 sub-basins focusing on nitrogen pollution in rivers by integrating land-system, hydrological and water quality models. We found that water pollution aggravates water scarcity in >2000 sub-basins worldwide. The number of sub-basins with water scarcity triples due to future nitrogen pollution worldwide. In 2010, 984 sub-basins are classified as water scarce when considering only quantity-induced scarcity, while 2517 sub-basins are affected by quantity & quality-induced scarcity. This number even increases to 3061 sub-basins in the worst case scenario in 2050. This aggravation means an extra 40 million km2 of basin area and 3 billion more people that may potentially face water scarcity in 2050. Our results stress the urgent need to address water quality in future water management policies for the Sustainable Development Goals.

Abstract Interstitial iodides are the most critical type of defects in perovskite solar cells that limits efficiency and stability. They can be generated during solution, film, and device processing, further accelerating degradation. Herein, we find that introducing a small amount of a zinc salt- zinc trifluoromethane sulfonate (Zn(OOSCF3)2) in the perovskite solution can control the iodide defects in resultant perovskites ink and films. CF3SOO̶ vigorously suppresses molecular iodine formation in the perovskites by reducing it to iodide. At the same time, zinc cations can precipitate excess iodide by forming a Zn-Amine complex so that the iodide interstitials in the resultant perovskite films can be suppressed. The perovskite films using these additives show improved photoluminescence quantum efficiency and reduce deep trap density, despite zinc cations reducing the perovskite grain size and iodide interstitials. The zinc additives facilitate the formation of more uniform perovskite films on large-area substrates (78-108 cm2) in the blade-coating process. Fabricated minimodules show power conversion efficiencies of 19.60% and 19.21% with aperture areas of 84 and 108 cm2, respectively, as certified by National Renewable Energy Laboratory (NREL), the highest efficiency certified for minimodules of these sizes.

● Four highlights are identified for agriculture and water from the multi-pollutant perspective.● Large variations in time and space for multiple pollutants in waters and their sources.● Scientific agenda should account for multiple pollutants in agricultural strategies. Agriculture is an important cause of multiple pollutants in water. With population growth and increasing food demand, more nutrients, plastics, pesticides, pathogens and antibiotics are expected to enter water systems in the 21st century. As a result, water science has been shifting from single-pollutant to multi-pollutant perspectives for large-scale water quality assessments. This perspective paper summarizes and discusses four main highlights related to water pollution and agriculture from the multi-pollutant perspective. These highlights reveal the spatial and temporal distribution and main sources of multiple pollutants in waters. Based on the highlights, a scientific agenda is proposed to prioritize solutions for sustainable agriculture (UN Sustainable Development Goal 2) and clean water (UN Sustainable Development Goals 6 and 14). This agenda points out that when formulating solutions for water pollution, it is essential to take into account multiple pollutants and their interactions beyond biogeochemistry.

In this work, magnetic molecularly imprinted polymers (MIPs) for specific recognition of Hydroxytyrosol (HT) were designed by vinyl-modified magnetic particles (Fe3O4@SiO2@VTEOs) as carrier, ternary deep eutectic solvent (DES) as functional monomer, while ethylene glycol dimethacrylate (EGDMA) as crosslinker. The optimum amount of DES was obtained by adsorption experiments (molar ratio, caffeic acid: choline chloride: formic acid = 1:6:3) which were 140 μL in total. Under the optimized amount of DES, the maximum adsorption capacity of the MIPs particles was 42.43 mg g−1, which was superior to non-imprinted polymer (4.64 mg g−1) and the imprinting factor (IF) is 9.10. Syringin and Oleuropicrin were used as two reference molecules to test the selectivity of the DES-MIPs particles. The adsorption capacity of HT was 40.11 mg g−1. Three repeated experiments show that the polymer has high stability and repeatability (RSD = 5.50).

Few work have been performed regarding the quantitative characterization of three-dimensional (3D) pitting corrosion process directly, although the corrosion behaviors and the passivation film stability of metals in various solutions have been studied heavily. The reported work quantitatively characterized the 3D pitting corrosion of the Fe-based amorphous alloy coating (Fe-based AAC) via X-ray micro-computed tomography (X-ray micro-CT) and further elucidated the mechanism of its pitting corrosion. Moreover, the microstructure and electrochemical performance of the Fe-based AAC have also been explored. The results showed that the targeted thermal sprayed Fe43Cr20Mo10W4C15B6Y2 coating was prone to be corroded with the increase of the hydrogen ion concentration, i.e. higher hydrogen ion concentration leads to poorer corrosion performance of the Fe-based AAC. The X-ray micro-CT results revealed that the pits in the Fe-based AAC initially nucleated below the pitting potential, and they also generated in the over-passivation stage. Furthermore, it was found that the corrosive medium does not penetrate into the coating/substrate interface, and the deduced corrosion mechanism from the findings was also discussed.

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that widely exist in eukaryotes. As a new focus in the field of molecular regulation, circRNAs have attracted much attention in recent years. Previous studies have confirmed that circRNAs are associated with many physiological and pathological processes. CircRNAs also participate in the regulation of stem cells. Stem cells have the properties of self-renewal and differentiation, which make stem cell therapy popular. CircRNAs may serve as new targets in stem cell therapy due to their regulation in stem cells. However, the underlying relationships between circRNAs and stem cells are still being explored. In this review, we briefly summarize the effects of circRNAs on stem cells, in the context of biological activities, aging and apoptosis, and aberrant changes. Moreover, we also examine the biological roles of stem cell-derived exosomal circRNAs. We believe our review will provide insights into the effects of circRNAs on stem cells.

Abstract Cardiac myxoma (CM) is the most common benign cardiac tumor, and most CMs are left atrial myxomas (LAMs). Six variations of KIF1C, c.899 A > T, c.772 T > G, c.352 A > T, c.2895 C > T, c.3049 G > A, and c.*442_*443dup in left atrial myxoma tissues are identified by whole-exome sequencing (WES) and Sanger sequencing. RNA-seq and function experiments show the reduction of the expression of KIF1C and PRKAR1A caused by rare variations of KIF1C. KIF1C is observed to be located in the nucleus, bind to the promoter region of PRKAR1A, and regulate its transcription. Reduction of KIF1C decreases PRKAR1A expression and activates the PKA, which causes an increase in ERK1/2 phosphorylation and SRC-mediated STAT3 activation, a reduction of CDH1, TP53, CDKN1A, and BAX, and eventually promotes tumor formation both in vitro and in vivo. The results suggest that inhibition of KIF1C promotes the pathogenesis of LAM through positive feedback formed by the crosstalk between KIF1C and PRKAR1A.

Summary: The enhanced use of protective materials and chemicals during the COVID-19 pandemic has probably increased river pollution, but the effects of country-specific measures on multiple pollutants in rivers worldwide are not well documented. Here, we use an updated, spatially explicit water quality model to estimate the effects of the increased use of hand soap (triclosan), personal protective equipment and packaging materials (plastics), painkillers (diclofenac), and reduced transportation (microplastics from car tires) on river pollution in 10,226 sub-basins worldwide. Model results indicate that, globally, COVID-19 measures increased river pollution with macroplastics by 56%, triclosan by 33%, and diclofenac by 50%. Notably, only microplastics from car tires decreased. We identified priority sub-basins and pollutants across the globe for which water pollution control strategies should consider the impacts of COVID-19 measures. For these sub-basins, our results can inform the development of strategies for ameliorating the impacts of measures taken during the COVID-19 pandemic. Science for society: Globally, river pollution is a growing concern, given its potential impacts on ecosystems. COVID-19 has likely compounded this pollution via an increased use of products such as masks, hand sanitizers, and painkillers. However, we do not have a clear understanding of pollutant types, at which locations pollution might have increased, or the extent of any increase. This hinders the development of pollution control strategies in the worst-affected river basins. Countries encouraged or enforced varying strategies to combat the pandemic; therefore, assessing the impact of these differing COVID-19 measures on river pollution requires models that capture country-specific strategies.

Intonation is the variation in pitch used in speech, which forms the premise of tonal and non-tonal languages. Interrogative words are words that introduce questions. Previous research lacks clarity regarding the specific cues used in the processing of word intonation. To address this gap, this study used the event-related potential electroencephalogram (EEG) research method to explore the intonation processing of tone two (mid-rising) interrogative words in Mandarin. For this, the word “shui,” meaning “who,” was selected as the experimental material. To avoid the influence of the environment, gender, and semantics, the Hum version, corresponding to the stimulus material, was also adopted for the experiment. This study used a passive oddball paradigm to examine the clues of intonation information processing in automatic cognitive processing through amplitude, latency, time window, and evoked location potential mismatch negativity. The standard stimulus was the declarative intonation with a high probability of occurrence (90%), and the deviant stimulus was the interrogative intonation with a low probability of occurrence (10%). In the time window of 370–450 ms, the mismatch negativity was found at the F3, F4, C3, Cz, and C4 channels. The findings show that, in the passive oddball paradigm, lexical semantics are essential for intonation processing at the pre-attentive level, which is dominated by the frontal and central areas of the brain. The results support the functional and comprehensive hypotheses that the processing of intonation is based on the function of language and that bilateral regions are involved in this processing. This study makes an important contribution by providing event-related potential evidence that lexical semantics plays a key role in the pre-attentive processing of intonation, as shown by the significant differences between semantic and non-semantic conditions.

The trade-off of electro-induced shape-changing hydrogels (EISCHs) between mechanical properties and deformation ability limited its further applications. In this work, the double network technique of reinforcing nondeformable hydrogels’ mechanical properties was introduced into EISCHs, and the NIPAAm/CNTs/Fe(phen)3 double network low-voltage-induced shape-changing hydrogel (DN) was synthesized. The experimental results indicated that the DN gained the balance between mechanical properties and deformation ability compared to the NIPAAm-Fe(phen)3 single network and NIPAAm-Fe(phen)3-CNTs nanocomposite single network hydrogels. The DN was found to have the ability to undergo swelling and shrinking as a result of the transition between Fe(phen)3 network iron (Ⅱ) and iron (Ⅲ) states under low-voltage stimulation. The hydrogen bonding and physical entanglement structure between CNTs and polymer chain segments, and physical entanglements between different network, which enable effective energy dissipation. Meanwhile, the special double network structure enabled the hydrogel could decrease the resistance to deformation stress by the slide between two networks.

Guanosine pentaphosphate and guanosine tetraphosphate are collectively called (p)ppGpp (Guanosine tetraphosphate and pentaphosphate). (p)ppGpp content in plants is affected by conditions such as light, salt, pH, UV light, and environmental phytohormones. The synthesis and hydrolysis of (p)ppGpp in plants is accomplished by a class of proteins called RSH (RelA/SpoT homologs). To date, a systematic and comprehensive genome-wide analysis of the RSH gene family in wheat and its closely related species has not been conducted. In this study, 15, 14, 12, and 8 members of RSH were identified in wheat (Triticum aestivum), Triticum dicoccoides, Triticum urartu and Aegilops tauschii respectively. Based on the conserved structural domains of the RSH genes, the TaRSHs have been categorized into TaRSH and TaCRSH. The gene duplications in the TaRSH gene family were all identified as segmental duplications indicating that the TaRSH family plays a significant role in expansion and that segmental duplications maintain a degree of genetic stability. Through the analysis of transcriptome data and RT-qPCR experiments, it was observed that the expression levels of TaRSHs were upregulated in response to abiotic stress. This upregulation suggests that TaRSHs play a crucial role in enhancing the resilience of wheat to adverse environmental conditions during its growth and development. Their increased expression likely contributes to the acquisition of stress tolerance mechanisms in wheat. Especially under NaCl stress, the expression levels increased most significantly. The more detailed systematic analysis provided in this article will help us understand the role of TaRSHs and provide a reference for further research on its molecular biological functions in wheat.

Immune checkpoint blockade (ICB) therapy holds great potentials for the treatment of colorectal peritoneal carcinomatosis (CRPC). However, its efficacy is often suboptimal due to the low immunogenic tumor phenotype, immunosuppressive tumor microenvironment (TME), and low antibody bioavailability at the peritoneal site. Herein, an in situ formed, anti‐cluster of differentiation 47 (aCD47) and anti–programmed cell death 1 ligand 1 (aPDL1) co‐loaded hydrogel (aCD47/aPDL1@PB–TA gel) with excellent peritoneum‐adhesive property and reactive oxygen species (ROS)‐responsive degradation is developed, bridging low‐dose fractionated radiotherapy (LDFRT) and ICB therapy for CRPC. The aCD47/aPDL1@PB‐TA gel is formed instantly upon mixing of the intraperitoneally injected, antibody‐containing solutions of phenylboronic acids‐containing polymer (PB) and tannic acid (TA), which can adhere to the peritoneum over 4 d. LDFRT promotes an immunogenic tumor phenotype by upregulating CD47 and PDL1, and reverses the immunosuppressive TME by fostering M1‐type macrophage polarization, dendritic cell maturation, and T cell infiltration. Moreover, LDFRT generates ROS to degrade the hydrogel and release the antibodies, consequently activating innate and adaptive immune responses. LDFRT and ICB therapy then cooperate to eliminate peritoneally metastasized CT26 colon tumor nodules in mice. Herein, a promising strategy is provided for LDFRT‐reinforced immunotherapy of CRPC, especially for patients with low immunogenic tumor.

This paper is concerned with the long-time dynamical behavior of a piezoelectric system with magnetic effect, which has nonlinear damping terms and external forces with a parameter. At first, we use the nonlinear semigroup theory to prove the well-posedness of solutions. Then, we investigate the properties of global attractors and the existence of exponential attractors. Finally, the upper semicontinuity of global attractors has been investigated.

Abstract Studies have shown that the combination of digital breast tomosynthesis (DBT) and digital mammography (DM) can improve the display of malignant tumors, reduce false positive results, and make up for the major deficiencies of traditional DM. In addition, the recall rate of patients with combined DBT was significantly reduced, especially those under 50 years of age and those with dense breast glands. The objective of this study is to compare the difference of DM and DM+ DBT in the diagnosis of benign and malignant tumors in different subgroups. A retrospective analysis was performed on 578 pathologically confirmed breast diseases in Jiangsu Cancer Hospital from January 2019 to December 2021. All were female, aged 23–85, with an average age of 53. Their DM and DBT images will be reviewed in an independent blind manner by an experienced radiologist. The doctor was unable to obtain the results of previous tests. The sensitivity and specificity of population samples and different subgroups were calculated. Overall sensitivity was 65% for DM, 93% for DM+ DBT. The addition of DBT significantly increased the tumor detection rate (odds ratio, 7.05; 95% confidence interval: 4.78, 10.4; p = .00), the difference was statistically significant. For patients

Nowadays, the requirements of dietary structure are improved with the continuous improvement of people’s living standard, and the food safety problem has become one of the focal point. However, chemical preservatives are no longer sufficient to meet needs of consumers regarding their safety, health, and greenness. Antimicrobial properties of plant-originated essential oils have attracted more and more attention due to their remarkably antimicrobial effects, non-toxic and non-residue characteristics. Therefore, application of essential oils in fruit preservation has become a hot topic. This article first reviews antimicrobial performance of plant-originated essential oils incorporating with their antimicrobial mechanisms. Subsequently, applications of essential oils in the preservation of foods are summarized. Limitations of essential oils were listed and corresponding potential solutions are lastly provided, in order to provide reference for the development of natural food preservatives and the application of plant-originated essential oils in food preservation.

This study aimed to investigate the factors influencing career expectations, determine the influence of college students’ personal ability on personal evaluation in the process of gaining employment, and further explore the impact of personal evaluation and social support on career expectations. This study used a random sampling method to administer questionnaires to final-year undergraduates majoring in the liberal arts, science, art, and sports at two Chinese universities. Career expectations were positively correlated with satisfaction. The preferred employer for graduates is a school. In selecting a career, college students believed that exerting their talents was most important. Personal evaluations had a significant effect on self-development in career expectations. The level of social support had a significant effect on prestige and welfare stability in career expectations.

The UN’s 17 Sustainable Development Goals (SDGs) are highly interrelated. This study finds 319 interactions between SDGs for the case of water pollution in China. Results show that effective pollution control requires accounting for these interactions.

Abstract Background Multiple sclerosis (MS) is one of the most common autoimmune disorders characterized by the infiltration of immune cells into the brain and demyelination. The unwanted immunosuppressive side effect of therapeutically successful natalizumab led us to focus on the choroid plexus (CP), a key site for the first wave of immune cell infiltration in experimental autoimmune encephalomyelitis (EAE), for the control of immune cells trafficking. Adenosine A2A receptor (A2AR) is emerging as a potential pharmacological target to control EAE pathogenesis. However, the cellular basis for the A2AR-mediated protection remains undetermined. Methods In the EAE model, we assessed A2AR expression and leukocyte trafficking determinants in the CP by immunohistochemistry and qPCR analyses. We determined the effect of the A2AR antagonist KW6002 treatment at days 8–12 or 8–14 post-immunization on T cell infiltration across the CP and EAE pathology. We determined the critical role of the CP-A2AR on T cell infiltration and EAE pathology by focal knock-down of CP-A2AR via intracerebroventricular injection of CRE-TAT recombinase into the A2ARflox/flox mice. In the cultured CP epithelium, we also evaluated the effect of overexpression of A2ARs or the A2AR agonist CGS21680 treatment on the CP permeability and lymphocytes migration. Results We found the specific upregulation of A2AR in the CP associated with enhanced CP gateway activity peaked at day 12 post-immunization in EAE mice. Furthermore, the KW6002 treatment at days 8–12 or 8–14 post-immunization reduced T cell trafficking across the CP and attenuated EAE pathology. Importantly, focal CP-A2AR knock-down attenuated the pathogenic infiltration of Th17+ cells across the CP via inhibiting the CCR6–CCL20 axis through NFκB/STAT3 pathway and protected against EAE pathology. Lastly, activation of A2AR in the cultured epithelium by A2AR overexpression or CGS21680 treatment increased the permeability of the CP epithelium and facilitated lymphocytes migration. Conclusion These findings define the CP niche as one of the primary sites of A2AR action, whereby A2AR antagonists confer protection against EAE pathology. Thus, pharmacological targeting of the CP-A2AR represents a novel therapeutic strategy for MS by controlling immune cell trafficking across CP.

ObjectiveWe aimed to investigate the association between the GNRI and the risk of stroke in elderly patients with hypertension.MethodsA total of 5312 elderly hypertensive patients free of history of stroke were included. Multivariate Cox models were used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs) for stroke and its subtypes.ResultsThe average time of follow-up was 3.8 years, and the median time was 3.2 years. We identified 640 individuals with stroke, of whom 526 had an ischemic stroke (IS) and 114 had a hemorrhagic stroke (HS). After adjusting for confounding variables, compared with participants in the lowest quartile of the GNRI, those in the third and fourth quartiles were associated with a decreased risk of stroke (adjusted HR 0.72, 95% CI 0.58–0.90, and adjusted HR 0.58, 95% CI 0.46–0.74, respectively, P for trend < 0.001). Similar results were found for IS and HS. Moreover, there were L-shaped associations of GNRI with new-onset HS (P for non-linearity = 0.034). Multiple sensitivity analyses and stratified analyses did not materially change the results.ConclusionsIn summary, we found that a lower GNRI was associated with a higher risk of incident stroke in elderly hypertensive patients. Additional prospective data collection is required to confirm our findings.

BackgroundThe current status of the dose-response relationship between the metabolic score for insulin resistance (METS-IR) and new-onset stroke in hypertensive patients and its subtypes is unclear. This study aimed to determine the association between METS-IR and incident stroke and its subtypes within a cohort of Chinese hypertensive patients.MethodsA total of 14032 hospitalized patients with hypertension from January 1, 2010, to December 31, 2021, were included in this retrospective cohort study. Cox models and restricted cubic splines were applied to determine the association between METS-IR and the risk of stroke.ResultsDuring a median follow-up of 4.80 years, 1067 incident stroke cases occurred. Patients in the highest quartile group of METS-IR levels exhibited a higher risk of stroke (HR, 1.80; 95% CI, 1.50-2.17) and ischemic stroke (HR, 1.96; 95% CI, 1.60–2.42) than those in the lowest quartile group. However, no significant associations were observed between METS-IR and the risk of hemorrhagic stroke. Restricted cubic spline analysis suggested a nearly J-shaped association between METS-IR and risk of stroke and ischemic stroke (P for nonlinearity < 0.001). METS-IR did produce a significant improvement in the C statistic when added to the basic model (from 0.637 to 0.664, P < 0.001). Notably, the addition of METS-IR to the basic model resulted in a significant improvement in predicting incident total stroke and ischemic stroke.ConclusionsThis cohort study suggests a relationship between METS-IR and the risk of stroke and ischemic stroke. Further studies are required to elucidate the underlying mechanisms.

Optic neuritis (ON), characterized by inflammation of the optic nerve and apoptosis of retinal ganglion cells (RGCs), is one of the leading causes of blindness in patients. Given that RGC, as an energy-intensive cell, is vulnerable to mitochondrial dysfunction, improving mitochondrial function and reducing oxidative stress could protect these cells. Matrine (MAT), an alkaloid derived from Sophoraflavescens, has been shown to regulate immunity and protect neurons in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis and ON. However, the protective mechanism of MAT on RGCs is largely unknown. In this study, we show that MAT treatment significantly reduced the degree of inflammatory infiltration and demyelination of the optic nerve and increased the survival rate of RGCs. The expression of Sirtuin 1 (SIRT1), a member of an evolutionarily conserved gene family (sirtuins), was upregulated, as well as its downstream molecules Nrf2 and PGC-1α. The percentage of TOMM20-positive cells was also increased remarkably in RGCs after MAT treatment. Thus, our results indicate that MAT protects RGCs from apoptosis, at least in part, by activating SIRT1 to regulate PGC-1α and Nrf2, which, together, promote mitochondrial biosynthesis and reduce the oxidative stress of RGCs.

Phenylalanine ammonia-lyase (PAL) is a key enzyme in the phenylalanine metabolism pathway and plays an important role in plant growth and stress response. It has been widely reported in plants, but less studied in wheat. In this study, 54 PAL genes were identified in the wheat genome. Based on phylogenetic analysis, the 54 TaPAL genes were divided into four groups (I, II, III, and IV). Then, the expression levels of TaPALs under biotic stresses were analyzed by transcriptome data analysis. The results showed that 31 genes were up-regulated and one gene was down-regulated after inoculation with Fusarium graminearum, 11 genes were up-regulated and 14 genes were down-regulated after inoculation with Puccinia striiformis, and 32 up-regulated and three down-regulated genes after inoculation with powdery mildew. The expression patterns of the five TaPALs were further analyzed by qRT-PCR. After inoculation with F. graminearum, the expression levels of five TaPALs were up-regulated. However, the TaPALs (expect TaPAL49) were down-regulated when inoculated with P. striiformis. Finally, the functions of TaPAL32 and TaPAL42 in resistance of wheat to the stripe rust were further analyzed by virus induced gene silencing (VIGS) assays. The results showed that the disease severity of TaPAL32 and TaPAL42 silenced plants was higher than that of control plants at 14 days after inoculation. It indicated that these two genes played a positive role in wheat stripe rust resistance. This study provided new evidence support for the functional study of PAL genes in wheat, and provided potential application value for the breeding of wheat resistant varieties.

Ventricular arrhythmia without structural heart disease is an arrhythmic disorder that occurs in structurally normal heart and no transient or reversible arrhythmia factors, such as electrolyte disorders and myocardial ischemia. Ventricular arrhythmias without structural heart disease can be induced by multiple factors, including genetics and environment, which involve different genetic and epigenetic regulation. Familial genetic analysis reveals that cardiac ion-channel disorder and dysfunctional calcium handling are two major causes of this type of heart disease. Genome-wide association studies have identified some genetic susceptibility loci associated with ventricular tachycardia and ventricular fibrillation, yet relatively few loci associated with no structural heart disease. The effects of epigenetics on the ventricular arrhythmias susceptibility genes, involving non-coding RNAs, DNA methylation and other regulatory mechanisms, are gradually being revealed. This article aims to review the knowledge of ventricular arrhythmia without structural heart disease in genetics, and summarizes the current state of epigenetic regulation.

The efficient detection of Fe3+ and MnO4− in a water environment is very important and challenging due to their harmful effects on the health of humanity and environmental systems. Good biocompatibility, sensitivity, selectivity, and superior photophysical properties were important attributes of carbon dot-based CDs sensors for sensing applications. In this work, we synthesized N, P-co-doped carbon dots (N/P CDs) with guanosine 5′-monophosphate (GMP) as a green carbon source, with high fluorescence quantum yield in water (QY, 53.72%). First, the luminescent N/P CDs showed a three-state “on-off-on” fluorescence response upon the sequential addition of Fe3+ and F−, with a low detection limit of 12 nM for Fe3+ and 8.5 nM for F−, respectively. Second, the N/P CDs also exhibited desirable selectivity and sensitivity for toxic MnO4− detection with the limit of detection of 18.2 nM, through a turn-off mechanism. Moreover, the luminescent N/P CDs successfully monitored the aforementioned ions in environmental water samples and in Escherichia coli.

Abstract Inflammatory demyelination and axonal injury of the optic nerve are hallmarks of optic neuritis (ON), which often occurs in multiple sclerosis and is a major cause of visual disturbance in young adults. Although a high dose of corticosteroids can promote visual recovery, it cannot prevent permanent neuronal damage. Novel and effective therapies are thus required. Given the recently defined capacity of matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae flavescens, in immunomodulation and neuroprotection, we tested in this study the effect of matrine on rats with experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. MAT administration, started at disease onset, significantly suppressed optic nerve infiltration and demyelination, with reduced numbers of Iba1+ macrophages/microglia and CD4+ T cells, compared to those from vehicle-treated rats. Increased expression of neurofilaments, an axon marker, reduced numbers of apoptosis in retinal ganglion cells (RGCs). Moreover, MAT treatment promoted Akt phosphorylation and shifted the Bcl-2/Bax ratio back towards an antiapoptotic one, which could be a mechanism for its therapeutic effect in the ON model. Taken as a whole, our results demonstrate that MAT attenuated inflammation, demyelination and axonal loss in the optic nerve, and protected RGCs from inflammation-induced cell death. MAT may therefore have potential as a novel treatment for this disease that may result in blindness.

Acromesomelic dysplasia, Maroteaux type (AMDM) is a rare skeletal dysplasia characterized by severe disproportionate short stature, short hands and feet, normal intelligence, and facial dysmorphism. Homozygous or compound heterozygous mutations in the natriuretic peptide receptor 2 (NPR2) gene produce growth-restricted phenotypes. The current study was designed to identify and characterize NPR2 loss-of-function mutations in patients with AMDM and to explore therapeutic responses to recombinant growth hormone (rhGH). NPR2 was sequenced in two Chinese patients with AMDM via next generation sequencing, and in silico structural analysis or transcript analysis of two novel variants was performed to examine putative protein changes. rhGH treatment was started for patient 1. Three NPR2 mutations were identified in two unrelated cases: two compound heterozygous mutations c.1112G>A p.(Arg371Gln) and c.2887+2T>C in patient 1 and a homozygous mutation c.329G>A p.(Arg110His) in patient 2, yielding distinct phenotypes. RNA extracted from peripheral blood cells of patient 1 showed alternatively spliced transcripts not present in control cells. Homology modeling analyses suggested that the c.1112G>A p.(Arg371Gln) mutation disrupted the binding of NPR-B homodimer to its ligand (C-type natriuretic peptide) in the extracellular domain as a result of global allosteric effects on homodimer formation. Thus, c.2887+2T>C and c.1112G>A p.(Arg371Gln) in NPR2 were loss-of-function mutations. Furthermore, rhGH therapy in patient 1 increased the patient’s height by 0.6SDS over 15 months without adversely affecting the trunk-leg proportion. The short-term growth-promoting effect was equivalent to that reported for idiopathic short stature. Overall, our findings broadened the genotypic spectrum of NPR2 mutations in individuals with AMDM and provided insights into the efficacy of rhGH in these patients.

Abstract Background Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab plus ipilimumab therapy in cancer treatment. Methods We examined data from PubMed, Web of Science, EBSCO, and Cochrane Library. Eleven articles fulfilled our criteria, which we divided into 3 groups: nivolumab plus ipilimumab versus nivolumab (the dose used for monotherapy is 3 mg/kg), nivolumab plus ipilimumab versus ipilimumab (the dose used for monotherapy is 3 mg/kg), and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR), and TRAEs in any grade and grade 3 or higher. Results The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p < 0.001) and PR (RR: 1.50, p < 0.001) than nivolumab alone. Compared with ipilimumab alone, the combined immunotherapy group had better CR (RR: 4.89, p < 0.001), PR (RR: 2.75, p < 0.001), and ORR (RR: 3.31, p < 0.001). Finally, N1I3 showed better PR (RR: 1.35, p = 0.006) and ORR (RR: 1.21, p = 0.03) than N3I1. The incidence of any TRAEs was similar between both groups (RR: 1.05, p = 0.06). However, the incidence of serious adverse events (grade 3 or higher) was lower in group N3I1 than group N1I3 (RR: 1.51, p < 0.001). Conclusion This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of nivolumab or ipilimumab monotherapy. In the combined immunotherapy group, N1I3 was more effective than N3I1. Although the side effects were slightly increased in N1I3 group, overall safety was acceptable.

Abstract To date, the ability of nanoplatforms to achieve excellent therapeutic responses is hindered by short blood circulation and limited tumor accumulation/penetration. Herein, a soft mesoporous organosilica nanoplatform modified with hyaluronic acid and cyanine 5.5 are prepared, denoted SMONs-HA-Cy5.5, and comparative studies between SMONs-HA-Cy5.5 (24.2 MPa) and stiff counterparts (79.2 MPa) are conducted. Results indicate that, apart from exhibiting a twofold increase in tumor cellular uptake, the soft nanoplatforms also display a remarkable pharmacokinetic advantage, resulting in considerably improved tumor accumulation. Moreover, SMONs-HA-Cy5.5 exhibits a significantly higher tumor penetration, achieving 30-μm deeper tissue permeability in multicellular spheroids relative to the stiff counterparts. Results further reveal that the soft nanoplatforms have an easier extravasation from the tumor vessels, diffuse farther in the dense extracellular matrix, and reach deeper tumor tissues compared to the stiff ones. Specifically, the soft nanoplatforms generate a 16-fold improvement (43 vs. 2.72 μm) in diffusion distance in tumor parenchyma. Based on the significantly improved blood circulation and tumor accumulation/penetration, a soft therapeutic nanoplatform is constructed by loading photosensitizer chlorin e6 in SMONs-HA-Cy5.5. The resulting nanoplatform exhibits considerably higher therapeutic efficacy on tumors compared to the stiff ones.

Lake Dianchi is severely polluted with nitrogen (N) and phosphorus (P). The effects of implementing environmental policies and technologies on future lake quality are not well understood. We analyse effects of environmental policies and technologies on future river export of nutrients into Lake Dianchi. We develop scenarios for 2050 and analyse these with the existing MARINA-Lakes model (Model to Assess River Inputs of Nutrient to lAkes). The scenarios differ in assumptions about future nutrient management in agriculture, sewage systems and mining. In the SSP3 (Shared Socio-economic Pathway 3) scenario, river export of nutrients to Lake Dianchi is projected to increase 1.4–4.4 times between 2012 and 2050. In the Current Policies scenario, rivers may export fewer nutrients than in SSP3, but this may not avoid eutrophication. Effects of improved nutrient management on river export of nutrients differ among nutrient forms, sub-basins and sources (e.g., urbanization in the north, agriculture in the middle and south). Pollution levels can be reduced below the 2012 level in an Optimistic scenario assuming advanced wastewater treatment, improved nutrient management in agriculture and no mining. However, even this may not completely prevent eutrophication. Preventing eutrophication requires even more efforts, for example, in implementing circular-oriented management options.

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by miR-190a-5p in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence in situ hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that miR-190a-5p to be downregulated. Luciferase reporter assay, quantitative real-time-PCR, and whole-cell patch-clamp experiments confirmed the downregulation of IL-2 by miR-190a-5p and influence of the latter on the sodium current of SCN3B. Overall, miR-190a-5p suppressed the increase in SCN3B sodium current caused by endogenous IL-2, whereas miR-190a-5p inhibitor significantly reversed this effect. IL-2 was demonstrated to be directly regulated by miR-190a-5p. We, therefore, concluded that the miR-190a-5p/IL-2/SCN3B pathway could be involved in the pathogenesis of CAs and miR-190a-5p might acts as a potential protective factor in pathogenesis of CAs.

Oracle bone inscriptions (OBIs) are ancient Chinese scripts originated in the Shang Dynasty of China, and now less than half of the existing OBIs are well deciphered. To date, interpreting OBIs mainly relies on professional historians using the rules of OBIs evolution, and the remaining part of the oracle's deciphering work is stuck in a bottleneck period. Here, we systematically analyze the evolution process of oracle characters by using the Siamese network in Few-shot learning (FSL). We first establish a dataset containing Chinese characters which have finished a relatively complete evolution, including images in five periods: oracle bone inscriptions, bronze inscriptions, seal inscriptions, official script, and regular script. Then, we compare the performance of three typical algorithms, VGG16, ResNet, and AlexNet respectively, as the backbone feature extraction network of the Siamese network. The results show that the highest F1 value of 83.3% and the highest recognition accuracy of 82.67% are obtained by the combination of VGG16 and Siamese network. Based on the analysis, the typical structural performance of each period is evaluated and we identified that the optimized Siamese network is feasible to study the evolution of the OBIs. Our findings provide a new approach for oracle's deciphering further.

Disruption of cholinergic neurotransmission can affect cognition, but little is known about whether low-to-moderate fluoride exposure affects cholinergic system and its effect on the prevalence of dental fluorosis (DF) and intelligence quotient (IQ). A cross-sectional study was conducted to explore the associations of moderate fluoride exposure and cholinergic system in relation to children's DF and IQ. We recruited 709 resident children in Tianjin, China. Ion selective electrode method was used to detect fluoride concentrations in water and urine. Cholinergic system was assessed by the detection of choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and acetylcholine (ACh) levels in serum. Compared with children in the first quartile, those in fourth quartile the risk of either developing DF or IQ

We previously demonstrated the immunostimulatory efficacy of Pseudomonas aeruginosa flagellar hook protein FlgE on epithelial cells, presumably via ectopic ATP synthases or subunits ATP5B on cell membranes. Here, by using recombinant wild-type FlgE, mutant FlgE (FlgEM; bearing mutations on two postulated critical epitopes B and F), and a FlgE analog in pull-down assay, Western blotting, flow cytometry, and ELISA, actual bindings of FlgE proteins or epitope B/F peptides with ATP5B were all confirmed. Upon treatment with FlgE proteins, human umbilical vein endothelial cells (HUVECs) and SV40-immortalized murine vascular endothelial cells manifested decreased proliferation, migration, tube formation, and surface ATP production and increased apoptosis. FlgE proteins increased the permeability of HUVEC monolayers to soluble large molecules like dextran as well as to neutrophils. Immunofluorescence showed that FlgE induced clustering and conjugation of F-actin in HUVECs. In Balb/c-nude mice bearing transplanted solid tumors, FlgE proteins induced a microvascular hyperpermeability in pinna, lungs, tumor mass, and abdominal cavity. All effects observed in FlgE proteins were partially or completely impaired in FlgEM proteins or blocked by pretreatment with anti-ATP5B antibodies. Upon coculture of bacteria with HUVECs, FlgE was detectable in the membrane and cytosol of HUVECs. It was concluded that FlgE posed a pathogenic ligand of ectopic ATP5B that, upon FlgE–ATP5B coupling on endothelial cells, modulated properties and increased permeability of endothelial layers both in vitro and in vivo. The FlgE-ectopic ATP5B duo might contribute to the pathogenesis of disorders associated with bacterial infection or ectopic ATP5B-positive cells.

Relation extraction aims to predict the relation triple between the tail entity and head entity in a given text. A large body of works adopt meta-learning to address the few-shot issue faced by relation extraction, where each relation category only contains few labeled data for demonstration. Despite promising results achieved by existing meta-learning methods, these methods still struggle to distinguish the subtle differences between different relations with similar expressions. We argue this is largely owing to that these methods cannot capture unbiased and discriminative features in the very few-shot scenario. For alleviating the above problems, we propose a taxonomy-aware prototype network, which consists of a category-aware calibration module and a task-aware training strategy module. The former implicitly and explicitly calibrates the representation of prototype to become sufficiently unbiased and discriminative. The latter balances the weight between easy and hard instances, which enables our proposal to focus on data with more information during the training stage. Finally, comprehensive experiments are conducted on four typical meta tasks. Furthermore, our proposal presents superiority over the competitive baselines with an improvement of 3.30% in terms of average accuracy.

Atmospheric nitrogen (N) deposition is a vital component of the global N cycle. Excessive N deposition on the Earth’s surface has adverse impacts on ecosystems and humans. Quantification of atmospheric N deposition is indispensable for assessing and addressing N deposition-induced environmental issues. In the present review, we firstly summarized the current methods applied to quantify N deposition (wet, dry, and total N deposition), their advantages and major limitations. Secondly, we illustrated the long-term N deposition monitoring networks worldwide and the results attained via such long-term monitoring. Results show that China faces heavier N deposition than the United States, European countries, and other countries in East Asia. Next, we proposed a framework for estimating the atmospheric wet and dry N deposition using a combined method of surface monitoring, modeling, and satellite remote sensing. Finally, we put forth the critical research challenges and future directions of the atmospheric N deposition. Capsule: A review of quantification methods and the global data on nitrogen deposition and a systematic framework was proposed for quantifying nitrogen deposition.

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.

Abstract Fast socio‐economic development in agriculture and urbanization resulted in increasing nutrient export by rivers, causing coastal eutrophication in China. In addition, climate change may affect hydrology, and as a result, nutrient flows from land to sea. This study aims at a better understanding of how future socio‐economic and climatic changes may affect coastal eutrophication in China. We modeled river export of total dissolved nitrogen (TDN) and phosphorus (TDP) in 2050 for six scenarios combining socio‐economic pathways (SSPs) and Representative Concentration Pathways (RCPs). We used the newly developed MARINA 2.0 (Model to Assess River Inputs of Nutrients to seAs) model. We found that global change can make coastal eutrophication control in China more difficult. In 2050 coastal waters may be considerably more polluted or considerably cleaner than today depending on the SSP‐RCP scenarios. By 2050, river export of TDN and TDP is 52% and 56% higher than in 2012, respectively, in SSP3‐RCP8.5 (assuming large challenges for sustainable socio‐economic development, and severe climate change). In contrast, river export of nutrients could be 56% (TDN) and 85% (TDP) lower in 2050 than in 2012 in SSP1‐RCP2.6 (assuming sustainable socio‐economic development, and low climate change). Climate change alone may increase river export of nutrients considerably through hydrology: We calculate 24% higher river export of TDN and 16% higher TDP for the SSP2 scenario assuming severe climate change compared to the same scenario with low climate change (SSP2‐RCP8.5 vs. SSP2‐RCP2.6). Policies and relevant technologies combining improved nutrient management and climate mitigation may help to improve water quality in rivers and coastal waters of China.

Photocatalytic inactivation has been proved to be an effective strategy to eliminate pathogenic bacteria in water. Herein, a novel 0D/2D p-n heterojunction of Ag _2 S-anchored P-doped g-C _3 N _4 (Ag _2 S/PCN) were constructed by a simple two-step process coupling one-pot calcination and ultrasonic-assisted synthesis. The photocatalytic performance of as-prepared Ag _2 S/PCN composites was investigated by inactivating multidrug-resistant E. coli under visible light irradiation. The results indicated that Ag _2 S/PCN-5 possessed outstanding photocatalytic inactivation activity and superior stability, which could completely inactivate 7.0 log E. coli cells within 60 min. The enhanced photocatalytic activity of Ag _2 S/PCN-5 was mainly attributed to the elevated visible-light response and improved production and transfer of photoexcited charges. In addition, the free radicals trapping experiments results revealed that h ^+ and •O _2 ^− were predominantly responsible for the efficient inactivation activity. Finally, according to the 0D/2D structure and energy band configuration analysis, the enhanced p-n type heterojunction photocatalytic inactivation mechanism of Ag _2 S/PCN was discussed in detail.

Background/Aims: Diabetes mellitus (DM) has been demonstrated to have a strong association with heart failure. Conventional echocardiographic analysis cannot sensitively monitor cardiac dysfunction in type I diabetic Akita hearts, but the phenotype of heart failure is observed in molecular levels during the early stages. Methods: Male Akita (Ins2WT/C96Y) mice were monitored with echocardiographic imaging at various ages, and then with conventional echocardiographic analysis and speckle-tracking based strain analyses. Results: With speckle-tracking based strain analyses, diabetic Akita mice showed changes in average global radial strain at the age of 12 weeks, as well as decreased longitudinal strain. These changes occurred in the early stage and remained throughout the progression of diabetic cardiomyopathy in Akita mice. Speckle-tracking showed that the detailed and precise changes of cardiac deformation in the progression of diabetic cardiomyopathy in the genetic type I diabetic Akita mice were uncoupled. Conclusions: We monitored early-stage changes in the heart of diabetic Akita mice. We utilize this technique to elucidate the underlying mechanism for heart failure in Akita genetic type I diabetic mice. It will further advance the assessment of cardiac abnormalities, as well as the discovery of new drug treatments using Akita genetic type I diabetic mice.