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Complex-oxide materials exhibit physical properties that involve the interplay of charge and spin degrees of freedom. However, an ambipolar oxide that is able to exhibit both electron-doped and hole-doped ferromagnetism in the same material has proved elusive. Here we report ambipolar ferromagnetism in LaMnO 3 , with electron–hole asymmetry of the ferromagnetic order. Starting from an undoped atomically thin LaMnO 3 film, we electrostatically dope the material with electrons or holes according to the polarity of a voltage applied across an ionic liquid gate. Magnetotransport characterization reveals that an increase of either electron-doping or hole-doping induced ferromagnetic order in this antiferromagnetic compound, and leads to an insulator-to-metal transition with colossal magnetoresistance showing electron–hole asymmetry. These findings are supported by density functional theory calculations, showing that strengthening of the inter-plane ferromagnetic exchange interaction is the origin of the ambipolar ferromagnetism. The result raises the prospect of exploiting ambipolar magnetic functionality in strongly correlated electron systems. An ambipolar ferromagnet with both electron- and hole-doped ferromagnetism in a single material would facilitate understanding of ferromagnetic semiconductors for spintronic applications. Here the authors demonstrate ambipolar ferromagnetism in LaMnO 3 , using ionic liquid gating enabled electrostatic doping to produce electron–hole asymmetry.

Key Points Drug combinations are highly useful for enhanced therapeutics. Understanding of their mechanisms facilitates the discovery of new multicomponent and multi-target therapeutics. This article describes the extensive investigation of the published literature on a large number of drug combinations from interaction and network perspectives, which reveals general and specific modes of action. Understanding the molecular mechanisms underlying the effects of efficacious drug combinations could aid the discovery of novel combinations and multi-targeted drugs. This article presents an extensive investigation of drug combinations for which rigorous analytical information is available in published literature, which illustrates several general types of combination mechanisms and highlights the potential value of molecular interaction profiles for studying such mechanisms. Understanding the molecular mechanisms underlying synergistic, potentiative and antagonistic effects of drug combinations could facilitate the discovery of novel efficacious combinations and multi-targeted agents. In this article, we describe an extensive investigation of the published literature on drug combinations for which the combination effect has been evaluated by rigorous analysis methods and for which relevant molecular interaction profiles of the drugs involved are available. Analysis of the 117 drug combinations identified reveals general and specific modes of action, and highlights the potential value of molecular interaction profiles in the discovery of novel multicomponent therapies.

Multiple sclerosis (MS) is a chronic and debilitating autoimmune disease, characterized by chronic inflammatory demyelination in the nervous tissue and subsequent neurological dysfunction. Spermidine, a natural polyamine, has been shown to affect inflammation in some experimental models. We show here that spermidine could alleviate experimental autoimmune encephalomyelitis (EAE), a model for MS, through regulating the infiltration of CD4 + T cells and macrophages in central nervous system. Unexpectedly, we found that spermidine treatment of MOG-specific T cells did not affect their pathogenic potency upon adaptive transfer; however, spermidine diminished the ability of macrophages in activating MOG-specific T cells ex vivo . Depletion of macrophages in diseased mice completely abolished the therapeutic effect of spermidine, indicating a critical role of spermidine-activated macrophages. Mechanistically, spermidine was found to specifically suppress the expression of interleukin-1beta (IL-1 β ), IL-12 and CD80 while enhance the expression of arginase 1 in macrophages. Interestingly, macrophages from spermidine-treated mice could also reverse EAE progression, while pretreatment of those macrophages with the arginase 1 inhibitor abrogated the therapeutic effect. Therefore, our studies revealed a critical role of macrophages in spermidine-mediated treatment on EAE and provided novel information for better management of MS.

The breach of landslide dam often causes significant disaster in the inundated area; the prediction of breach hydrograph is in high demand for the dam breach risk evaluation. In this study, according to the model tests and Tangjiashan landslide dam breach case, the surface erosion accompanied by intermittent mass failure is known as the key breaching mechanism for landslide dam due to overtopping failure. The downstream slope angle would gradually decrease during the dam-breaching process, whereas a planar wedge failure occurs when the breach slopes at the dam crest and downstream breach channel fail. Based on the breach mechanism, a numerical model for landslide dam breach due to overtopping is developed to simulate the coupling process of water and soil. The model focuses on the breach morphology evolution during the breaching for the sake of the improvement of breach hydrograph prediction. Furthermore, the model can handle one- and two-sided breach, as well as incomplete and base erosion at the vertical direction. The case study of Tangjiashan landslide dam-breaching feedback analysis testifies the rationality of the present model with the relative errors less than 10% for peak discharge, final breach widths, and time to peak. The sensitivity analysis indicates that the final breach depth and soil erodibility affect the breach flow prediction of the landslide dam significantly, whereas the one- or two-sided breach mode is less sensitive.

The clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein 1/PD-1 ligand (PD-1/PD-L1) has initiated a new era in the treatment of metastatic cancer. PD-L1 expression is upregulated in many solid tumors including lung cancer and functions predominantly in lactate-enriched tumor microenvironments. Here, we provided evidence for PD-L1 induction in response to lactate stimulation in lung cancer cells. Lactate-induced PD-L1 induction was mediated by its receptor GPR81. The silencing of GPR81 signaling in lung cancer cells resulted in a decrease in PD-L1 protein levels and functional inactivation of PD-L1 promoter activity. In addition, GPR81-mediated upregulation of PD-L1 in glucose-stimulated lung cancer cells that recapitulates the enhanced glycolysis in vivo was dependent on lactate dehydrogenase A (LDHA). We also demonstrated that activation of GPR81 decreases intracellular cAMP levels and inhibits protein kinase A (PKA) activity, leading to activation of the transcriptional coactivator TAZ. Interaction of TAZ with the transcription factor TEAD was essential for TAZ activation of PD-L1 and induction of its expression. Furthermore, we found that lactate-induced activation of PD-L1 in tumor cells led to reduced production of interferon-γ and induction of apoptosis of cocultured Jurkat T-cell leukemia cells. Our findings reveal an unexpected role of lactate in contributing to tumor cell protection from cytotoxic T-cell targeting and establishes a direct connection between tumor cell metabolic reprograming and tumor evasion from the immune response.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by a novel bunyavirus, SFTSV. The study aimed to disclose the epidemiological and clinical characteristics of SFTSV infection in China so far. An integrated clinical database comprising 1920 SFTS patients was constructed by combining first-hand clinical information collected from SFTS sentinel hospitals (n = 1159) and extracted data (n = 761) from published literature. The considered variables comprised clinical manifestations, routine laboratory tests of acute infection, hospitalization duration and disease outcome. SFTSV-IgG data from 19 119 healthy subjects were extracted from the published papers. The key clinical variables, case-fatality rate (CFR) and seroprevalence were estimated by meta-analysis. The most commonly seen clinical manifestations of SFTSV infection were fever, anorexia, myalgia, chill and lymphadenopathy. The major laboratory findings were elevated lactate dehydrogenase, aminotransferase, followed by thrombocytopenia, lymphocytopenia, elevated alanine transaminase and creatine kinase. A CFR of 12·2% was estimated, significantly higher than that obtained from national reporting data, but showing no geographical difference. In our paper, the mortality rate was about 1·9 parts per million. Older age and longer delay to hospitalization were significantly associated with fatal outcome. A pooled seroprevalence of 3·0% was obtained, which increased with age, while comparable for gender. This study represents a clinical characterization on the largest group of SFTS patients up to now. A higher than expected CFR was obtained. A wider spectrum of clinical index was suggested to be used to identify SFTSV infection, while the useful predictor for fatal outcome was found to be restricted.

Summary This cross-sectional study has been performed to investigate the relationship between serum carotenoids and bone mineral density (BMD) in Chinese population. We found that women with higher serum β-cryptoxanthin, lycopene, or α-carotene exhibited higher BMD at various bone sites. Similar association was observed between α-carotene and BMD in men. Introduction Carotenoids may positively regulate bone metabolism through their antioxidant properties; however, few studies have examined the relation between serum carotenoids and bone health. We aimed to determine the associations between the serum concentration of several carotenoid subclasses and BMD in a Chinese population. Methods This study was a community-based cross-sectional study. We measured 1898 women and 933 men aged 59.6 years who completed serum β-cryptoxanthin, zeaxanthin + lutein, lycopene, and α-carotene concentration analyses and BMD assessments. Serum individual carotenoids were assessed by the methods of reverse-phase high-performance liquid chromatography. Dual-energy X-ray absorptiometry was applied to determine BMD at whole body, lumbar spine, total hip, femur neck, and trochanter. ANCOVA was used to examine the correlations between categorized individual carotenoids and BMD at measured sites. Results After adjusting for potential covariates, a monotonic dose–response positive correlation between circulating levels of β-cryptoxanthin, lycopene, and α-carotene and BMD at various skeletal sites was observed in women. Women in the top (vs. bottom) quartiles of serum β-cryptoxanthin, lycopene, or α-carotene exhibited 1.8–2.3, 1.5–2.0, or 1.3–2.7 % higher BMD at the bone sites with significant results ( P -trend <0.05), respectively. For men, the corresponding values were 2.6–4.0 % for α-carotene at the whole body and hip regions ( P -trend <0.001–0.023). Conclusion These results suggest that serum carotenoids have a favorable association with bone health in the study population, especially in women.

IL-17 is one of the most potent and most actively investigated proinflammatory cytokines. In this study, we examined the effect of IL-17 on mesenchymal stem cells (MSCs) under the influence of inflammatory cytokines. Ironically, IL-17 dramatically enhanced the immunosuppressive effect of MSCs induced by IFN γ and TNF α , revealing a novel role of IL-17 in immunosuppression. Interestingly, we found that this action of IL-17 was dependent on the promoted expression of a key immune suppressive molecule, inducible nitric oxide synthase (iNOS), in MSCs. In a concanavalin A (ConA)-induced hepatitis mouse model, we found that IL-17 also enhanced the in vivo immunosuppressive effect of MSCs in an iNOS-dependent manner. Moreover, this promoting effect of IL-17 was found to be exerted through enhancing mRNA stability by modulating the protein level of ARE/poly(U)-binding/degradation factor 1 (AUF1), a well-known factor that promotes mRNA decay. In auf1 −/− MSCs, IFN γ and TNF α could induce maximal immunosuppressive effect, both in vitro and in vivo , without the need for IL-17. Thus, our studies demonstrated that in the presence of MSCs, IL-17 promotes immunosuppression.

There is a lack of research on how vegetable and fruit consumption patterns affect cognitive function in older adults with varying BMIs. Therefore, this study aims to explore their relationship, with a special focus on gender differences. A cross-sectional survey was conducted in Anhui Province, China, between July and September 2019, and information was collected from 6211 participants regarding socio-demographics, the frequency of vegetable and fruit consumption per week, and cognitive function. The study utilized descriptive analysis and binary logistic regression to determine the association between cognitive function and consumption patterns of vegetable and fruit. There were no statistically significant associations between vegetable and fruit consumption patterns and cognitive function in underweight and obese older adults. Among normal weight men, older adults in the V+/F- (AOR=1.65; 95% CI: 1.16-2.35) and V-/F- (AOR=3.95; 95% CI: 1.86-8.42) groups were more likely to have cognitive impairment compared with the V+/F+ group. However, no associations were observed between the two in women of normal weight. For the overweight women, a higher risk of cognitive impairment was found in the V+/F- group (AOR=1.54; 95% CI: 1.12-2.11), while older men did not. The correlation between vegetable and fruit consumption patterns and cognitive function varies among older adults with different BMIs. Findings suggest the need for targeted nutritional interventions for these communities to maintain cognitive function in older adults.

There is a high demand and expectation for subseasonal to seasonal (S2S) prediction, which provides forecasts beyond 2 weeks, but less than 3 months ahead. To assess the potential benefit of artificial intelligence (AI) methods for S2S prediction through better postprocessing of ensemble prediction system outputs, the World Meteorological Organization (WMO) coordinated a prize challenge in 2021 to improve subseasonal prediction. The goal of this competition was to produce the most skillful forecasts of precipitation and 2-m temperature globally averaged over forecast weeks 3 and 4 and over weeks 5 and 6 for the year 2020 using artificial intelligence techniques. The top three submissions, described in this article, succeeded in producing S2S forecasts significantly more skillful than the bias-corrected ECMWF operational reference forecasts, particularly for precipitation, through improved calibration of the ECMWF raw forecast outputs or multimodel combination. These forecast improvements should benefit the use of S2S forecasts in applications.