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Abstract Relapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo‐HSCT following fludarabine(≥100 mg/m2), busulfan (≥3.2 mg/kg) and melphalan (≥100 mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n = 171, MDS‐IB‐1 or 2 n = 44, CMML n = 6) with median age of 46 were enrolled in this study. The median follow‐up was 507 days for survivors. The 2‐year NRM, CIR, OS and DFS were 10.6% ± 2.2%, 14.8% ± 3.3%, 79.4% ± 3.7% and 74.6% ± 3.7%, respectively. In multivariate analyses, high HCT‐CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p = 0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p = 0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p = 0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR = 7.92, 95%CI 1.05‐60.03, p = 0.045; HR = 3.64, 95%CI 1.40‐9.44, p = 0.008; respectively), while post‐transplantation cyclophosphamide based graft‐versus‐host disease prophylaxis was associated with lower CIR (HR = 0.24 95%CI 0.11‐0.54, p = 0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.

Abstract Background Drug use disorders (DUDs) have emerged as one of the most significant public health crises, exerting a substantial influence on both community health and socio-economic progress. The United States (US) also suffers a heavy burden, it is necessary to figure out the situation from multiple perspectives and take effective measures to deal with it. Therefore, using the data from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2021, we evaluated this topic. Methods Annual data on DUDs-related burden were collected from the GBD study 2021. We calculated the indicator of estimated annual percentage change (EAPC) to evaluate the changing trend of burden. The Bayesian model for age-period-cohort was introduced to forecast the burden. Results In 2021, the number and age-standardized rate of prevalence were particularly prominent, with 12,146.95 thousand and 3821.43 per 100,000, respectively. Higher burden was also observed in males, 15–45 years old populations, and opioid use disorders subtype. From 1990 to 2021, the DUDs-related burden increased in the US and all states, especially in West Virginia; and the national death-related burden with the highest increase (EAPC = 7.96). Other significant inverse associations were seen between EAPC, age-standardized rates, and socio-demographic index (SDI). Moreover, in the next 14 years, the projected DUDs burden remains exigent. Conclusions The burden of DUDs in the US is heavy and has been enlarging. This study proposes that greater attention should be paid to the strategies in males, the younger population, opioid use disorders, and low-SDI states implemented by decision-makers to achieve goals such as reducing burden.

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Abstract Background Rice (Oryza sativa L.) is one of the most widely cultivated grain crops in the world that meets the caloric needs of more than half the world’s population. Salt stress seriously affects rice production and threatens food security. Therefore, mining salt tolerance genes in salt-tolerant germplasm and elucidating their molecular mechanisms in rice are necessary for the breeding of salt tolerant cultivars. Results In this study, a salt stress-responsive jacalin-related lectin (JRL) family gene, OsJRL45, was identified in the salt-tolerant rice variety ‘sea rice 86’ (SR86). OsJRL45 showed high expression level in leaves, and the corresponding protein mainly localized to the endoplasmic reticulum. The knockout mutant and overexpression lines of OsJRL45 revealed that OsJRL45 positively regulates the salt tolerance of rice plants at all growth stages. Compared with the wild type (WT), the OsJRL45 overexpression lines showed greater salt tolerance at the reproductive stage, and significantly higher seed setting rate and 1,000-grain weight. Moreover, OsJRL45 expression significantly improved the salt-resistant ability and yield of a salt-sensitive indica cultivar, L6-23. Furthermore, OsJRL45 enhanced the antioxidant capacity of rice plants and facilitated the maintenance of Na+-K+ homeostasis under salt stress conditions. Five proteins associated with OsJRL45 were screened by transcriptome and interaction network analysis, of which one, the transmembrane transporter Os10g0210500 affects the salt tolerance of rice by regulating ion transport-, salt stress-, and hormone-responsive proteins. Conclusions The OsJRL45 gene isolated from SR86 positively regulated the salt tolerance of rice plants at all growth stages, and significantly increased the yield of salt-sensitive rice cultivar under NaCl treatment. OsJRL45 increased the activity of antioxidant enzyme of rice and regulated Na+/K+ dynamic equilibrium under salinity conditions. Our data suggest that OsJRL45 may improve the salt tolerance of rice by mediating the expression of ion transport-, salt stress response-, and hormone response-related genes.

Neural stem cells (NSCs) play crucial roles in neurological disorders and tissue injury repair through exerting paracrine effects. However, the effects of NSC‐derived factors on glioma progression remain unclear. This study aimed to evaluate the effects of human NSC‐conditioned medium (NSC‐CM) on the behaviour of glioma cells using an in vitro co‐culture system. Cell counting kit‐8 and 5‐ethynyl‐2′‐deoxyuridine assays revealed that NSC‐CM inhibited glioma cell proliferation and growth in a fetal bovine serum (FBS)‐independent manner. In addition, our wound‐healing assay demonstrated that NSC‐CM repressed glioma cell migration, while results from transwell and 3D spheroid invasion assays indicated that NSC‐CM also reduced the invasion capacity of glioma cells. Flow cytometry showed that NSC‐CM prevented cell cycle progression from the G1 to S phase and promoted apoptosis. Western blotting was used to show that the expression of Wnt/β‐catenin pathway‐related proteins, including β‐catenin, c‐Myc, cyclin D1, CD44 and Met, was remarkably decreased in NSC‐CM‐treated glioma cells. Furthermore, the addition of a Wnt/β‐catenin pathway activator, CHIR99021, significantly induced the expression of β‐catenin and Met and increased the proliferative and invasive capabilities of control medium‐treated glioma cells but not those of NSC‐CM‐treated glioma cells. The use of enzyme‐linked immunosorbent assays (ELISA) revealed the secretion of some antitumour factors in human and rat NSCs, including interferon‐α and dickkopf‐1. Our data suggest that NSC‐CM partially inhibits glioma cell progression by downregulating Wnt/β‐catenin signalling. This study may serve as a basis for developing future antiglioma therapies based on NSC derivatives.

Forests and grasslands play an important role in carbon cycling. They not only absorb CO2 from the air through vegetation biomass and soil carbon sinks, but also reduce and control the horizontal transport of soil carbon (i.e., reinforcing soil carbon storage via soil conservation), thus avoiding erosion-induced CO2 emissions. In this study, vegetation biomass and soil carbon sinks, soil carbon reinforcement and reduced carbon emissions via soil conservation by forests and grasslands were quantified on the scale of the whole of China. The analysis was based on the distribution of biomass and the soil carbon pool and soil erosion rates derived from national surveys, as well as carbon density values from field surveys and literature. In 2021, forests and grasslands in China generated 394.18 Mt C/year (y) of steady-state carbon sinks through vertical biomass and soil absorption. The biomass carbon sinks of grasslands, and those of leaves, twigs, flowers and fruits of the forests, were not taken into account when quantifying the stable biomass sink, because they can become net producers of CO2 due to seasonal withering and carryover, or they can form soil organic carbon as potential soil carbon sinks. The amount of horizontal soil carbon reinforcement in China’s forests and grasslands in 2021 was 20.31 Mt C/y, which was positively correlated with the reduction in the water erosion area; consequently, vertical emissions of approximately 14.89–29.78 Mt of CO2 into the atmosphere were avoided. Overall, in 2021, China’s forests and grasslands absorbed atmospheric CO2 and reduced emissions by 1.46–1.47 Gt CO2/y, equivalent to approximately 13% of China’s annual fossil CO2 emissions. This study demonstrates the fact that the adoption of forest and grassland measures sequesters carbon in soil and biota and reduces the risks of CO2 emissions by both vertical and horizontal paths, which is important for achieving carbon neutrality and mitigating climate change.

Abstract Background Refractory and relapsed acute myeloid leukemia (r/rAML) is associated with a difficult prognosis; clinical trials are typically suggested despite lack of a recognized standard of care. Combinatorial chemotherapy regimens utilized for r/rAML salvage play a crucial role in battling this invasive phase. Although it is characterized by a low response rate, CLAG is a traditional regimen used in r/rAML. We aimed to compare the efficacy and toxicity of CLAG+PLD to explore whether there was any improvement with the addition of pegylated liposomal doxorubicin (PLD) to CLAG Methods A total of 110 r/rAML patients were retrospectively analyzed from February 2017 to June 2020 at the Medical Center of Hematology, XinQiao Hospital, the 303rd Hospital of the Chinese People's Liberation Army, and Central Hospital of Chang Sha, Hunan Province. The response, overall survival (OS), disease‐free survival (DFS), and side effects in 110 r/rAML patients were evaluated retrospectively. Of these, 55 patients were administered CLAG+PLD, while 55 patients received CLAG alone as salvage therapy. Results In the CLAG+PLD group, there were 27 (49.1%) cases of complete response (CR) with no measurable residual disease (MRD−), 12 (21.8%) cases of CR with positive MRD (MRD+), 5 (9.1%) cases of partial response (PR), 11 (20%) cases of no response (NR), and no cases of death during the cycles. The response rates in the CLAG group were lower: CR was reached in 24 (46.6%) patients with MRD−, 6 (10.9%) patients with MRD+, 10 (18.2%) patients with PR, 13 (23.6%) patients with NR, and 2 (3.6%) patients who passed away, one from infection and the other from cerebral hemorrhage. The median OS and DFS were not attained in the CLAG+PLD group during the 2‐year OS and DFS follow‐up, while both values were 10 months in the CLAG group (p = 0.023 and p = 0.045, respectively). The results of the Cox regression analysis for the CLAG+PLD group were strongly illustrative of the importance of hematopoietic stem cell transplantation (HSCT) following salvage therapy. No increased toxicity was observed in the CLAG+PLD group. Conclusion CLAG+PLD is a potential salvage regimen for r/r AML that has a similar toxicity profile to CLAG and that improves response rates, 2‐year OS, and DFS relative to CLAG.

Abstract Background Exposure to air pollution is an important risk factor for intracerebral hemorrhage (ICH), which is a major cause of death worldwide. However, the relationship between ICH mortality and air quality improvement has been poorly studied. This study aims to evaluate the impact of the air pollution control policies in the Beijing-Tianjin-Hebei region on ICH mortality among Tianjin residents. Methods This study used an interrupted time series analysis. We fitted autoregressive integrated moving average (ARIMA) models to assess the changes in ICH deaths before and after the interventions of air pollution control policies based on the data of ICH deaths in Tianjin collected by the Tianjin Center for Disease Control and Prevention. Results Between 2009 and 2020, there were 63,944 ICH deaths in Tianjin, and there was an overall decreasing trend in ICH mortality. The intervention conducted in June 2014 resulted in a statistically significant (p = 0.03) long-term trend change, reducing the number of deaths from ICH by 0.69 (95% confidence interval [CI]: -1.30 to -0.07) per month. The intervention in October 2017 resulted in a statistically significant (p = 0.04) immediate decrease of 25.74 (95% CI: -50.62 to -0.85) deaths from ICH in that month. The intervention in December 2017 caused a statistically significant (p = 0.04) immediate reduction of 26.58 (95% CI: -52.02 to -1.14) deaths from ICH in that month. The intervention in March 2018 resulted in a statistically significant (p = 0.02) immediate decrease of 30.40 (95% CI: -56.41 to -4.40) deaths from ICH in that month. No significant differences were observed in the changes of male ICH mortality after any of the four interventions. However, female ICH deaths showed statistically significant long-term trend change after the intervention in June 2014 and immediate changes after the interventions in December 2017 and March 2018. Overall, the interventions prevented an estimated 5984.76 deaths due to ICH. Conclusion During the study period, some interventions of air pollution control policies were significantly associated with the reductions in the number of deaths from ICH among residents in Tianjin. ICH survivors and females were more sensitive to the protective effects of the interventions. Interventions for air pollution control can achieve public health gains in cities with high levels of air pollution.

Background: Thalassemia comprises a diverse group of genetic disorders that affects the synthesis of globin chains, with a global distribution. The use of erythrocyte lifespan (ELS) to assess differences among patients with different types of thalassemia and the efficacy of splenectomy has not been implemented.

Abstract The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.

Due to the region’s social economy and historical culture, rough grazing has led to unresolved grassland-based ecological problems in Northern China. Soil microorganisms are essential structural and functional components of underground ecosystems, and the effects of various grazing intensities on the physicochemical properties and bacterial communities of soil are unclear. A stocking density regulation experiment was carried out in the desert steppe of the Inner Mongolia Autonomous Region. In the study area, four grazing intensities were set, namely, the enclosure control group (CK), light grazing, moderate grazing, and heavy grazing. Field investigations and 16S rRNA sequencing were used to compare and analyze the characteristics of soil bacterial community structures and their correlations with soil nutrient factors under different grazing intensities. The experiment showed the following results: (1) The Shannon, Simpson, and Pielou indices of the light grazing group were significantly higher than those of the CK (p < 0.05), and the indices of the moderate and heavy grazing groups were lower than those of the CK, but the difference was not significant, and there were no significant differences in the Chao1 index between each group. (2) Acidobacteria, Actinobacteria, Proteobacteria, and Chloroflexi were the main bacterial phyla. (3) With the exception of soil organic matter and available potassium, which had significant negative correlations with the Shannon index (p < 0.05), other soil factors had no significant correlation with the soil bacterial diversity. (4) The contents of soil organic matter, total phosphorus, alkali-hydrolyzed nitrogen, available phosphorus, and available potassium influenced the differences between soil bacterial communities under different grazing intensities.

Abstract Background Uterine cancer is one of the most common female cancers worldwide, with huge heterogeneity in morbidity and mortality. Although a high body‐mass index (BMI) has been linked to uterine cancer, systematic reports about the influence of high BMI and its temporal trends are scarce. Methods The annual morbidity, mortality, and disability‐adjusted life years (DALYs) of uterine cancer in 204 countries or territories were retrieved from the GBD 2019 study. To reflect trends in disease burden, we also calculated the estimated annual percentage change (EAPC) based on the age‐standardized rates of uterine cancer from 1990 to 2019. Results The global incident cases of uterine cancer increased 2.3 times from 187,190 in 1990 to 435,040 in 2019. Although the age‐standardized incidence rate (ASIR) of uterine cancer increased worldwide from 8.67/100,000 in 1990 to 9.99/100,000 in 2019, the age‐standardized death rate (ASDR) and DALY rate decreased during the same period. High socio‐demographic index (SDI) countries tended to have a higher ASIR than developing regions, and their increasing trend in ASIR was also more pronounced. The disease was rare before 40 years old, but its risk rose sharply among women aged 50–70. A high BMI was linked to more than one‐third of deaths from uterine cancer in 2019. Conclusions The incidence in developed areas was significantly higher than in developing areas and also increased much more rapidly. Elderly females, especially those with a high BMI, have a higher risk of uterine cancer. Therefore, more health resources may be needed to curb the rising burden in specific populations.

BackgroundObservational studies have reported that educational attainment has been related to the risk of esophageal cancer (EC) and its precancerous lesions. However, the causal relationship remains controversial. We aimed to apply the Mendelian randomization (MR) design to determine the causal associations between genetically predicted educational attainment and EC, Barrett's esophagus (BE), and gastroesophageal reflux disease (GERD), and to explore whether modifiable risk factors play a mediating role.MethodsUsing summary statistics from genome-wide association studies (GWASs) based on European ancestry individuals of several years in education (EduYears, primary analysis, n = 293,723), college completion (College, secondary analysis, n = 95,427), EC (n = 420,531), BE (n = 361,194), and GERD (n = 420,531), genetic associations between two education phenotypes and EC, BE, and GERD were tested by two-sample MR analyses. Then, two-step MR mediation analyses were used to assess the proportion of the aforementioned association that might be mediated by body mass index (BMI), major depressive disorder (MDD), smoking, drinking, carbohydrates, fat, and protein intake.ResultsGenetically predicted EduYears was negatively associated with the risk of EC, BE, and GERD {odds ratio (OR), 0.64 [95% confidence interval (CI) 0.44–0.94], 0.86 (95% CI, 0.75–0.99), and 0.62 (95%CI, 0.58–0.67)}. EduYears was negatively associated with BMI, MDD, and smoking (range of OR: 0.76–0.84). There were positive associations between BMI, smoking with EC, BE, and GERD, as well as between MDD with GERD (range of OR: 1.08–1.50). For individual mediating effect, BMI and smoking mediated 15.75 and 14.15% of the EduYears-EC association and 15.46 and 16.85% of the EduYears-BE association. BMI, MDD, and smoking mediated 5.23, 4.98, and 4.49% of the EduYears-GERD association. For combined mediation, the aforementioned mediators explained 26.62, 28.38, and 11.48% of the effect of EduYears on EC, BE, and GERD. The mediating effects of drinking and dietary composition were not significant in the effect of education on EC, BE, and GERD.ConclusionOur study supports that genetically predicted higher educational attainment has a protective effect on EC, BE, and GERD, and is partly mediated by reducing adiposity, smoking, and depression.

Abstract Background To assess the spatiotemporal variation in female breast cancer attributable to low physical activity (LPA) at a global scale from 1990 to 2019, which is essential to promote physical activity, as well as prevent and control breast cancer. Methods The number of deaths and disability-adjusted life years (DALYs), and the corresponding age-standardized rates (ASMR and ASDR) of LPA-related breast cancer in 204 countries and territories from 1990 to 2019 were retrieved from the Global Burden of Disease Study 2019 to measure the related breast cancer burden by age and region. The estimated annual percentage change (EAPC) was calculated to quantify the secular trend in breast cancer burden rates. Results From 1990 to 2019, globally, both breast cancer deaths and DALYs attributable to LPA nearly doubled, although the corresponding ASMR and ASDR decreased slightly, with EAPC of -0.46 (95% confidence interval: -0.52, -0.40) and -0.44 (95% confidence interval: -0.49, -0.39), respectively. The LPA-related breast cancer burden varied considerably across the world, with the highest-burden rates in Oceania, Tropical Latin America and Caribbean, and the fastest growth in North Africa and Middle East. The ASMR and ASDR showed a logarithmic association with the Socio-demographic Index, and a temporally upward trend in most of 204 countries regardless of the Socio-demographic Index or the ASMR in 1990. Conclusions Despite a decline in LPA-related breast cancer burden achieved in many countries during the last 3 decades like Bermuda, Myanmar, USA and China, an increase still occurred in most of 204 countries and territories, such as Solomon Islands, Equatorial Guinea, Japan and India. The findings can bring greater awareness to the importance of promoting physical activity for the local government to control the attributable breast cancer burden.

Constructed wetlands (CWs) widely applied for wastewater treatment release significant greenhouse gases (GHGs), contributing to global warming. It is essential to characterize the comprehensive source-sink effects and affecting factors of GHGs in CWs, offering references and guidance for designing and operating CWs to better control GHG emissions. However, current reviews focus on individual GHG emission mechanisms. With the aid of the Web of Science Core Collection database, the relevant literature on carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) emissions in CWs after 2010 was collected and organized. As highlighted in the review, CWs can produce and transmit these GHGs into the atmosphere, forming sources of GHGs and sequestration CO2 through plants photosynthesis, forming sinks of GHGs. Their overall performance depends on many factors. Hybrid CWs, Cyperus papyrus, Cyperus alternifolius, and Iris pseudacorus, adsorption substrates like Fe-C, low temperatures, and a C/N ratio of five are beneficial for GHG mitigation in CWs. Future studies should focus on in-depth research into the mechanisms and overall source-sink benefits of plants and microorganisms in relation to GHGs. This review provided a comprehensive understanding of the emission mechanisms and affecting factors of the major GHGs in CWs, bridging the research gap in this field, helping researchers to clarify the context, and providing valuable in-sights for further scientific investigations.

This study aimed to estimate the latest magnitudes and temporal trends of melanoma burden at the national, regional, and global levels. The data on melanoma incidence, deaths, and disability-adjusted life-years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease 2019 Study. Estimated annual percentage change (EAPC) was calculated to depict the temporal trends and Spearman rank correlation was used to analyze the influential factors of EAPC. From 1990 to 2019, the incident cases of melanoma increased by 170% to 289,950, death increased by 90% to 62,840, and DALYs increased by 67% to 1,707,800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1.13 [95% confidence interval (CI): 0.93–1.32], while the age-standardized rates of death and DALYs both declined with the EAPC of −0.27 (95% CI: −0.36 to −0.19) and −0.49 (95% CI: −0.57 to −0.41). In 2019, the highest burden of melanoma was observed in Australasia, followed by high-income North America and Europe regions, which all presented an incremental growth in ASIR. The positive association between the EAPC in ASIR and socio-demographic index (SDI) in 2019 (ρ = 0.600, P

BackgroundLead exposure is an important risk factor for stroke. However, the latest global spatiotemporal patterns of lead exposure-related stroke burden were unclear. In this study, we assessed this topic.MethodsThe data were obtained from the Global Burden of Disease Study (2019). The estimated annual percentage change (EAPC) was estimated to evaluate the temporal trends of the age-standardized mortality and disability-adjusted life years (DALYs) rates (ASMR and ASDR) of stroke attributable to lead exposure.ResultsIn 2019, the numbers of global stroke deaths and DALYs attributable to lead exposure were 305.27 and 6738.78 thousand, respectively. The corresponding ASMR and ASDR were highest in males, the elderly population, low and middle-income countries, and the intracerebral hemorrhage subtype. From 1990 to 2019, the ASMR and ASDR of global stroke attributable to lead exposure decreased [ASMR: EAPC = −1.34, 95% confidence interval (CI): (−1.57, −1.10); ASDR: EAPC = −1.74, 95% CI: (−1.95, −1.52)], especially in females, the high-income countries, and the subarachnoid hemorrhage subtype.ConclusionThis study emphasizes the importance of continued implementation of lead exposure prevention strategies and improved high-efficiency treatment and stroke acute health care, especially in low and middle-income countries.

Abstract Background Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. Methods We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. Results Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). Conclusions An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Abstract Background Nearly half of the cases of esophageal cancer in the world were in China, but the corresponding burden in China has not been estimated for the past decades or for the near future. Methods Data on the incidence, mortality, and disability‐adjusted life years (DALYs) rates owing to esophageal cancer in China from 1990 to 2017 were extracted from the Global Burden of Disease Study 2017. To reflect the trend in the disease burden, we calculated the estimated annual percentage change (EAPC) in the age‐standardized rates of these three outcomes in China from 1990 to 2017. Results The age‐standardized incidence rate (ASIR) for esophageal cancer decreased from 19.38/100,000 in 1990 to 12.23/100,000 in 2017, with an EAPC of −2.53 (95%CI: −2.90, −2.16), but the number of cases of esophageal cancer increased from 164,473 to 234,624. The age‐standardized rates of esophageal cancer in females were always lower than they were in males during the study period, and there was a downward trend that was more pronounced among females than males. The most common risk factors for males were smoking and alcohol consumption, while the most common risk factors for females were a diet low in fruits and a high body mass index (BMI). New cases of, and deaths from esophageal cancer are predicted to increase by about 1.5 times in the coming 25 years. Conclusion Although the age‐standardized burden of esophageal cancer has been declining, the number of new cases of, and deaths from esophageal cancer have increased in China over the past 30 years, and they will continue to increase in the near future. Hence, national policies should be adopted to promote the prevention and management of known risk factors for it, especially smoking and excessive caloric intake.

Abstract Background Early diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC. Methods We selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay. Results We found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation. Conclusions Our study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.

High salinity is a major stress factor affecting the quality and productivity of rice (Oryza sativa L.). Although numerous salt tolerance-related genes have been identified in rice, their molecular mechanisms remain unknown. Here, we report that OsJRL40, a jacalin-related lectin gene, confers remarkable salt tolerance in rice. The loss of function of OsJRL40 increased sensitivity to salt stress in rice, whereas its overexpression enhanced salt tolerance at the seedling stage and during reproductive growth. β-glucuronidase (GUS) reporter assays indicated that OsJRL40 is expressed to higher levels in roots and internodes than in other tissues, and subcellular localization analysis revealed that the OsJRL40 protein localizes to the cytoplasm. Further molecular analyses showed that OsJRL40 enhances antioxidant enzyme activities and regulates Na+-K+ homeostasis under salt stress. RNA-seq analysis revealed that OsJRL40 regulates salt tolerance in rice by controlling the expression of genes encoding Na+/K+ transporters, salt-responsive transcription factors, and other salt response-related proteins. Overall, this study provides a scientific basis for an in-depth investigation of the salt tolerance mechanism in rice and could guide the breeding of salt-tolerant rice cultivars.

Salt stress seriously affects plant growth and development and reduces the yield of rice. Therefore, the development of salt-tolerant high-yielding rice cultivars through quantitative trait locus (QTL) identification and bulked segregant analysis (BSA) is the main focus of molecular breeding projects. In this study, sea rice (SR86) showed greater salt tolerance than conventional rice. Under salt stress, the cell membrane and chlorophyll were more stable and the antioxidant enzyme activity was higher in SR86 than in conventional rice. Thirty extremely salt-tolerant plants and thirty extremely salt-sensitive plants were selected from the F2 progenies of SR86 × Nipponbare (Nip) and SR86 × 9311 crosses during the whole vegetative and reproductive growth period and mixed bulks were generated. Eleven salt tolerance related candidate genes were located using QTL-seq together with BSA. Real time quantitative PCR (RT-qPCR) analysis showed that LOC_Os04g03320.1 and BGIOSGA019540 were expressed at higher levels in the SR86 plants than in Nip and 9311 plants, suggesting that these genes are critical for the salt tolerance of SR86. The QTLs identified using this method could be effectively utilized in future salt tolerance breeding programs, providing important theoretical significance and application value for rice salt tolerance breeding.

Background: IVS-II-5 G>C (HBB: c.315+5 G>C) is a rare β-thalassemia mutation. However, there is no clear evidence regarding the effect of this defect or co-inheritance of other β-thalassemia mutations on phenotypes. Methods: The clinical phenotypes associated with compound heterozygosity for the IVS-II-5 G>C mutation with other β-thalassemia mutations, together with the potential effect of the genetic modifiers α-thalassemia were studied in 13 patients. Analyses of red cell indices, hemoglobin component, iron status, and α-globin genes were carried out in 19 heterozygotes. Results: Next-generation sequencing of 24 undiagnosed patients with thalassemia major (TM) or thalassemia intermedia (TI) identified 13 carriers of the IVS-II-5 G>C mutation. There was a wide spectrum of phenotypic severity in compound heterozygotes and 6 (46.2%) of 13 were transfusion dependent. Analysis of 19 heterozygotes indicated that most were hematologically normal without appreciable microcytosis or hypochromia, and approximately half had normal hemoglobin A2 levels at the same time. Conclusion: Compound heterozygotes for IVS-II-5 G>C and other severe β-thalassemia mutations are phenotypically severe enough to necessitate appropriate therapy and counseling. Co-inheritance of this nucleotide substitution with other β-thalassemia mutations may account for a considerable portion of the incidence of undiagnosed patients with TI and TM in Guangxi. The IVS-II-5 G>C mutation can pose serious difficulties in screening and counseling. Keywords: β-thalassemia; IVS-II-5 G>C; genotype; phenotype

Background: Understanding the spatiotemporal trends of colorectal cancer (CRC) deaths caused by low physical activity (LPA) and high body mass index (BMI) is essential for the prevention and control of CRC. We assessed patterns of LPA and high BMI-induced CRC deaths from 1990 to 2019 at global, regional, and national levels.Methods: Data on CRC deaths due to LPA and high BMI was downloaded from the Global Burden of Disease 2019 Study. We calculated estimated annual percentage change (EAPC) to quantify spatiotemporal trends in the CRC age-standardized mortality rate (ASMR) due to LPA and high BMI.Results: In 2019, CRC deaths due to LPA and high BMI were estimated as 58.66 thousand and 85.88 thousand, and the corresponding ASMRs were 0.77/100,000 and 1.07/100,000, with EAPCs of−0.39 [95% confidence interval (CI):−0.49,−0.29] and 0.64[95% CI: 0.57, 0.71] from 1990 to 2019 respectively. Since 1990, the ASMR of CRC attributable to LPA and high BMI has been on the rise in many geographic regions, especially in low middle and middle sociodemographic index (SDI) regions. Thirteen countries had a significant downward trend in CRC ASMR attributed to LPA, with EAPCs < −1. And, only 4 countries had a significant downward trend in CRC ASMR attributable to high BMI, with EAPCs < −1. Countries with a higher baseline burden in 1990 and a higher SDI in 2019 had a faster decline in ASMR due to high BMI and LPA.Conclusions: The burden of CRC caused by LPA and high BMI is on the rise in many countries. Countries should adopt a series of measures to control the local prevalence of obesity and LPA in order to reduce disease burden, including CRC.

Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous and frequently fatal malignancy. The ten-eleven translocation (TET)-mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we find that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, are verified in AML cells in vitro and mouse and human AML models in vivo. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 and thus activates both catalytic-dependent and -independent functions of TET2. Notably, AMLs with TET2 mutations or chemotherapy resistance are sensitive to OPA1 as well. Our results reveal the OPRM1-TET2 regulatory axis in AML and suggest that opioid agonists, particularly OPA1, a US Food and Drug Administration (FDA)-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2-mutated and chemotherapy-resistant AMLs, which have a poor prognosis.

Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank—the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608–0.985, p = 0.037), which was consistent with the results in FinnGen, and the combined OR was 0.764 (95% CI 0.623–0.936, p = 0.010). Likewise, higher absolute retinol levels suggestively reduced the pancreatic cancer risk in FinnGen—the OR per 10% unit increase in ln-transformed retinol was 0.705 (95% CI 0.529–0.940, p = 0.017), which was consistent with the results in UK Biobank and the combined OR was 0.747 (95% CI, 0.584–0.955, p = 0.020). Sensitivity analyses verified the above suggestive evidence. Our findings suggest that higher levels of antioxidants are unlikely to be a causal protective factor for most digestive system cancers, except for the suggestive protective effects of ascorbate on colon cancer and of retinol on pancreatic cancer.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide. Patients with poorly differentiated OSCC often exhibit a poor prognosis. AUNIP (Aurora Kinase A and Ninein Interacting Protein), also known as AIBp, plays a key role in cell cycle and DNA damage repair. However, the function of AUNIP in OSCC remains elusive. Methods: The differentially expressed genes (DEGs) were obtained using R language. Receiver operating characteristic curve analysis was performed to identify diagnostic markers for OSCC. The effectiveness of AUNIP in diagnosing OSCC was evaluated by machine learning. AUNIP expression was analyzed in publicly available databases and clinical specimens. Bioinformatics analysis and in vitro experiments were conducted to explore biological functions and prognostic value of AUNIP in OSCC. Findings: The gene integration analysis revealed 90 upregulated DEGs. One candidate biomarker, AUNIP, for the diagnosis of OSCC was detected, and its expression gradually increased along with malignant differentiation of OSCC. Bioinformatics analysis demonstrated that AUNIP could be associated with tumor microenvironment, human papillomavirus infection, and cell cycle in OSCC. The suppression of AUNIP inhibited OSCC cell proliferation and resulted in G0/G1 phase arrest in OSCC cells. The survival analysis showed that AUNIP overexpression predicted poor prognosis of OSCC patients.Interpretation: AUNIP could serve as a candidate diagnostic and prognostic biomarker for OSCC and suppression of AUNIP may be a potential approach to preventing and treating OSCC. Fund: Taishan Scholars Project in Shandong Province (ts201511106) and the National Natural Science Foundation of China (Nos. 61603218). Keywords: Oral squamous cell carcinoma, Receiver operating characteristic curve, Biomarker, Weighted gene co-expression network analysis, Survival analysis, AUNIP

Abstract The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population‐based case‐control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high‐incidence area in China. Using face‐to‐face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high‐risk areas.

BackgroundChronic myeloid leukemia (CML) is a malignant clonal proliferative disease. Once it progresses into the phase of blast crisis (CML-BP), the curative effect is poor, and the fatality rate is extremely high. Therefore, it is urgent to explore the molecular mechanisms of blast crisis and identify new therapeutic targets.MethodsThe expression levels of miR-181d, RBP2 and NF-κB p65 were assessed in 42 newly diagnosed CML-CP patients and 15 CML-BP patients. Quantitative real-time PCR, Western blots, and cell proliferation assay were used to characterize the changes induced by overexpression or inhibition of miR-181d, RBP2 or p65. Luciferase reporter assay and ChIP assay was conducted to establish functional association between miR-181d, RBP2 and p65. Inhibition of miR-181d expression and its consequences in tumor growth was demonstrated in vivo models.ResultsWe found that miR-181d was overexpressed in CML-BP, which promoted leukemia cell proliferation. Histone demethylase RBP2 was identified as a direct target of miR-181d which downregulated RBP2 expression. Moreover, RBP2 inhibited transcriptional expression of NF-κB subunit, p65 by binding to its promoter and demethylating the tri/dimethylated H3K4 region in the p65 promoter locus. In turn, p65 directly bound to miR-181d promoter and upregulated its expression. Therefore, RBP2 inhibition resulting from miR-181d overexpression led to p65 upregulation which further forwarded miR-181d expression. This miR-181d/RBP2/p65 feedback regulation caused sustained NF-κB activation, which contributed to the development of CML-BP.ConclusionsTaken together, the miR-181d/RBP2/p65 feedback regulation promoted CML-BP and miR-181d may serve as a potential therapeutic target of CML-BP.

Objective: This study focused on the efficacy and safety of thalidomide for patients with thalassemia intermedia (TI) in a multicenter trial. Methods：Clinical and laboratory data of 62 patients subjected to thalidomide therapy in four centers were retrospectively analyzed. We evaluated the efficacy and safety of thalidomide in the short-term (three months) and long-term follow-up (12 and 24 months). Response to thalidomide was defined as follows: Main Responder (MaR) showing an increase in Hb level of >2.0 g/dl or removal from blood transfusion and Minor Responder (MiR) achieving elevated hemoglobin (Hb) level of 1.0-2.0 g/dl or ≥50% reduction in blood transfusion frequency. Results：The overall response rate (ORR) of 62 patients with TI was 93.5% (58/62), with MaR and MiR rates accounting for 62.9% (39/62) and 30.6% (19/62) in short-term follow-up and 66.1% (41/62) and 27.4% (17/62) in long-term follow-up, respectively. The clinical response during long-term follow-up was maintained and the Hb level remained stable during the observation period. The response was still observed in patients with dose reduction despite a slight decrease in Hb level. However, Hb decreased rapidly to the baseline level after drug discontinuation. No effect of thalidomide on spleen size in nonsplenectomized patients was evident. Minimal side-effects were documented throughout, except peripheral neurotoxicity in one patient. Nevertheless, the mean serum ferritin (SF) level was significantly increased after treatment. Conclusion: Thalidomide had significant therapeutic effects on patients with TI, and the response was sustained with acceptable short-term and long-term adverse reactions. While these preliminary results support the potential long-term efficacy and safety of thalidomide as a therapeutic agent for TI, several issues need to be addressed before its application in the clinic.

Background: Acute myeloid leukaemia (AML) is a malignant haematological tumour with high heterogeneity and mortality. A reliable prognostic assessment is critical for treatment strategies. However, the current prognostic evaluation system of AML is insufficient. Methods: Genome-wide univariate Cox regression analysis was performed on three independent AML datasets to screen for the prognostic-related genes. Kaplan–Meier survival analysis was employed to verify the efficacy of FHL1 in evaluating overall survival in 1298 de novo AML patients, 648 non-acute promyelocytic leukaemia AML patients and 407 cytogenetically normal AML patients; the data for some of these patients were also used for EFS and RFS validation. Multivariate Cox regression was performed to validate FHL1 as an independent prognostic indicator. WGCNA, GSEA, and gene correlation analysis were applied to explore the mechanism of FHL1 in AML. The synergistic cytocidal effect of FHL1 knockdown was verified in in vitro experiments. Findings: Comprehensive genome-wide analyses and large-sample validation showed that FHL1 is a powerful prognostic candidate for overall survival, event-free survival, and relapse-free survival in AML and is independent of prognosis-related clinical factors and genetic abnormalities. The molecular mechanism may occur through regulation of FHL1 in leukaemia stem cells, tumour-associated signalling pathways, and transmembrane transport of chemotherapeutic drugs. FHL1-targeted intervention enhances the sensitivity of AML cells to cytarabine. Interpretation: FHL1 may serve as an evaluation factor for clinical strategy selection, and its targeted intervention may be beneficial for chemotherapy in AML patients. Keywords: Acute myeloid leukaemia, Prognosis, FHL1, WGCNA, Cytarabine

Prediction of whole-plant short-term water use efficiency (WUEs,P) is essential to indicate plant performance and facilitate comparison across different temporal and spatial scales. In this study, an isotope model was scaled up from the leaf to the whole-plant level, in order to simulate the variation in WUEs,P in response to different CO2 concentrations (Ca; 400, 600, and 800 μmol·mol−1) and soil water content (SWC; 35–100% of field capacity). For WUEs,P modelling, leaf gas exchange information, plant respiration, and “unproductive” water loss were taken into account. Specifically, in shaping the expression of the WUEs,P, we emphasized the role of both stomatal (gsw) and mesophyll conductance (gm). Simulations were compared with the measured results to check the model’s applicability. The verification showed that estimates of gsw from the coupled photosynthesis (Pn,L)-gsw model accounting for the effect of soil water stress slightly outperformed the model neglecting the soil water status effect. The established coupled Pn,L-gm model also proved more effective in estimating gm than the previously proposed model. Introducing the two diffusion control functions into the whole-plant model, the developed model for WUEs,P effectively captured its response pattern to different Ca and SWC conditions. Overall, this study confirmed that the accurate estimation of WUEs,P requires an improved predictive accuracy of gsw and gm. These results have important implications for predicting how plants respond to climate change.

MicroRNA-mediated posttranscriptional regulation is an important epigenetic regulatory mechanism of gene expression, and its dysregulation is involved in the development and progression of a variety of malignancies, including chronic myeloid leukemia (CML). The BCR-ABL1 fusion gene is not only the initiating factor of CML, but it is also an important driving factor for blastic transformation. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 tyrosine kinase activity, represented by imatinib, are currently the first-line treatment for CML. However, due to primary resistance or secondary resistance caused by mutations in the BCR-ABL1 kinase domain, TKIs cannot completely prevent the progression of CML; thus, the study of BCR-ABL1 gene expression regulation is of great significance. In this study, bioinformatics analysis and our results showed that miR-96 could directly bind to the 3'UTR region of BCR-ABL1 to regulate fusion protein expression, thereby regulating its downstream signaling pathway activity. We also found that miR-96 was downregulated during the progression from the chronic phase (CML-CP) to the blast crisis (CML-BC). Downregulation of miR-96 could promote the proliferation and participate in the cell differentiation of CML-BC cells. Additionally, we found that the novel histone deacetylase drug chidamide and the DNA methyltransferase inhibitor decitabine could restore the low expression of miR-96 in CML cells, and there were two abnormal hypermethylated sites in the promoter region of miR-96 in CML, suggesting that its low expression might be at least partially regulated by epigenetic mechanisms. In addition, re-expression of miR-96 could increase the sensitivity of CML-BC cells to imatinib. Thus, miR-96 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in CML blastic transformation.

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies.

With the increasing and complicated contradiction between the supply and demand of water resources in recent years, a number of inter-basin water diversion projects have been built in various places in China. The water supply objects of the inter-basin water diversion projects are mostly industrial and domestic water, and the water quality is closely related to the success or failure of the water transfer project, which makes it necessary to establish a long-term water quality protection mechanism. On the basis of analyzing major issues in water quality protection in inter-basin water transfer projects, a long-term mechanism framework for water quality protection was established and elaborated from the aspects of institutional system, water quality goals, risk management, guarantee conditions, feedback mechanism, technical evaluation, administrative assessment, public participation, incentive measures, aiming to provides reference for the water quality safety inter-basin water diversion projects.

Aim of study: We studied effects of climatic variability and afforestation on water yield to make a quantitative assessment of the hydrological effects of afforestation on basin water yield in the Rocky Mountain Area of North China. Area of study: Seven typical forest sub-watersheds in Chaobai River watershed, located near Beijing’s Miyun Reservoir, were selected as our study object. Material and methods: Annual water yield model and Separate evaluation method were applied to quantify the respective contributions of changes in climate and different vegetation types on variations in runoff. Main results: Statistical analysis indicated precipitation did not vary significantly whereas the annual runoff decreased significantly in the past decades. Although forest increased significantly in the late 20th century, climatic variations have the strongest contribution to the reductions in runoff, with the average contribution reaching 63.24%, while the remainder caused by human activities. Afforestation has a more positive impact on the reduction in runoff, with a contribution of 65.5%, which was more than the grassland of 17.6% and the farmland of 16.9%. Research highlights: Compared to the impact of climatic change, we believe the large-scale afforestation may not be the main reason for the reductions in basin water yield.

BACKGROUND: Innate immunity of which Toll-like receptor (TLR) 4 and CXCR1 are key elements plays a central role in the development of urinary tract infection (UTI). Although the relation between the genetics of TLR4 and CXCR1 and UTI is investigated partly, the polymorphisms and expression of TLR4 and CXCR1 in different types of UTI in adults are not extremely clear. METHODOLOGY/PRINCIPAL FINDINGS: This study investigates the presence of TLR4 A (896) G and CXCR1 G (2608) C polymorphisms in 129 UTI patients using RFLP-PCR. Gene and allelic prevalence were compared with 248 healthy controls. Flow cytometry was used to detect TLR4 and CXCR1 expression in the monocytes of UTI patients and healthy controls. TLR4 (896) AG genotype and TLR4 (896) G allele had higher prevalence in UTI (especially in acute cystitis and urethritis) patients, whereas CXCR1 (2608) GC genotype and CXCR1 (2608) C allele had lower prevalence in UTI patients than controls. TLR4 expression was significantly lower in chronic UTI patients than in acute pyelonephritis or healthy controls. CXCR1 expression was similar in both controls and patients. TLR4 expression in chronic UTI patients after astragalus treatment was higher than pre-treatment. CONCLUSIONS: The results indicate the relationship between the carrier status of TLR4 (896) G alleles and the development of UTI, especially acute cystitis and urethritis, in adults. TLR4 expression levels are correlated with chronic UTI.