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Abstract Protein Disulfide-Isomerase A2 (PDIA2) is a gene that encodes proteins, responsible for protein folding and modification within cells. The development and course of many disorders are intimately linked to the aberrant expression of PDIA2. Nevertheless, more research is necessary to fully understand PDIA2’s biological significance in pan-cancer, notably in prostate cancer (PCa). PDIA2 expression is elevated in various tumors and closely related to patient prognosis. Patients with prostate cancer who express PDIA2 high in particular have a bad prognosis in terms of progression-free survival. In addition, the upregulation of PDIA2 expression in prostate cancer patients is accompanied by higher Gleason scores, advanced tumor staging, lymph node metastasis, and elevated PSA levels. Detailed experiments further demonstrate that PDIA2 is a carcinogenic gene affecting prostate cancer cells’ response to dasatinib therapy. For patients with prostate cancer, there is a clear positive connection between the expression level of PDIA2 and a bad prognosis. The prostate cancer treatment efficacy of dasatinib is hampered by PDIA2, which is intimately linked to the growth, invasion, and metastasis of PCa cells. In summary, our research highlights the potential of PDIA2 as a biomarker for the diagnosis and management of PCa.

This manuscript investigates the multifaceted concept of urban resilience amidst escalating urbanization and environmental challenges. The study identifies and examines key problems across environmental, infrastructural, economic, human, social, and institutional dimensions of urban resilience through a systematic review of literature and consultations with experts in the field. Emphasizing the significance of interdisciplinary collaboration and community involvement, the research underscores the necessity for innovative approaches to bolster urban resilience. By shedding light on the intricate dynamics of urban challenges, the study advocates for sustainable urban development strategies that prioritize resilience-building. Insights from the study pave the way for future research endeavors aimed at addressing urban complexities and fostering resilient urban environments that can withstand and adapt to external and internal disturbances effectively.

Air pollution exposure, especially particulate matter (PM) and ozone (O3), poses significant health risks, but the systemic metabolic consequences of combined exposures to PM and O3, remain poorly understood. This study investigated systemic metabolic changes in male spontaneously hypertensive (SH) rats following inhalation exposure to concentrated ambient particles (CAPs) (PM2.5, 150 μg/m3), ozone (O3) (0.2 ppm), and their combination. Rats were exposed for 4 h, and serum samples were collected 1-hour post-exposure. Using targeted metabolomics, we identified significant alterations in metabolites involved in lipid metabolism (phosphatidylcholines), energy metabolism (acylcarnitine C3), and oxidative stress (glutamine). Notably, the combination exposure induced distinct metabolic changes, including increased acylcarnitine C3 levels, suggesting heightened mitochondrial dysfunction. Principal component analysis revealed overlapping profiles between CAPs and controls, indicating a subtler impact of CAPs compared to ozone or combined exposure. These systemic metabolic alterations are aligned with our previously published proteomics findings in cardiac tissues from the same rats, which showed elevated inflammatory markers (e.g., IL-6, TNF-α) and mitochondrial dysfunction. In conclusion, this study provides new insights into the systemic metabolic effects of air pollutant exposure, identifies novel metabolic targets of pollutant-induced toxicity, highlights the complex interactions resulting from combined exposure to multiple pollutants, and underscores the importance of assessing the combined effects of multiple pollutants in air pollution risk assessments.

Background & Aims: Hepatic immune imbalance is crucial for driving metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the role of hepatic regulatory T cells (Tregs) in MASLD initiation and the mechanisms responsible for their change are not completely understood. Methods: A mouse model subjected to a short-term high-fat diet (HFD) to mimic early steatosis, along with liver biopsy samples from patients with simple steatosis, and macrophage-specific Notch1-knockout mice (Notch1M-KO), were used to investigate the role of Tregs in early MASLD and the effect of hepatic macrophage Notch1 signaling on Treg frequency. The miRNAs correlated with Treg differentiation were analyzed using exosomal miRNA sequencing. Results: A decrease in Tregs contributed to HFD-induced hepatic steatosis and insulin resistance (five/group/time point, p

Abstract. Background:. Although some well-established oncogenes are involved in cancer initiation and progression such as prostate cancer (PCa), the long tail of cancer genes remains to be defined. Goosecoid (GSC) has been implicated in cancer development. However, the comprehensive biological role of GSC in pan-cancer, specifically in PCa, remains unexplored. The aim of this study was to investigate the role of GSC in PCa development. Methods:. We performed a systematic bioinformatics exploration of GSC using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, German Cancer Research Center, and our in-house cohorts. First, we evaluated the expression of GSC and its association with patient prognosis, and identified GSC-relevant genetic alterations in cancers. Further, we focused on the clinical characterization and prognostic analysis of GSC in PCa. To understand the transcriptional regulation of GSC by E2F transcription factor 1 (E2F1), we performed chromatin immunoprecipitation quantitative polymerase chain reaction (qPCR). Functional experiments were conducted to validate the effect of GSC on the tumor cellular phenotype and sensitivity to trametinib. Results:. GSC expression was elevated in various tumors and significantly correlated with patient prognosis. The alterations of GSC contribute to the progression of various tumors especially in PCa. Patients with PCa and high GSC expression exhibited worse progression-free survival and biochemical recurrence outcomes. Further, GSC upregulation in patients with PCa was mostly accompanied with higher Gleason score, advanced tumor stage, lymph node metastasis, and elevated prostate-specific antigen (PSA) levels. Mechanistically, the transcription factor, E2F1, stimulates GSC by binding to its promoter region. Detailed experiments further demonstrated that GSC acted as an oncogene and influenced the response of PCa cells to trametinib treatment. Conclusions:. GSC was highly overexpressed and strongly correlated with patient prognosis in PCa. We found that GSC, regulated by E2F1, acted as an oncogene and impeded the therapeutic efficacy of trametinib in PCa.

Advancing our understanding of pancreatic toxicity and metabolic disorders caused by environmental exposures requires innovative approaches. The pancreas, a vital organ for glucose regulation, is increasingly recognized as a target of harm from environmental chemicals and dietary factors. Traditional toxicological methods, while foundational, often fail to address the mechanistic complexities of pancreatic dysfunction, particularly under real-world conditions involving multiple exposures. New Approach Methodologies (NAMs)—including high-throughput screening (HTS), OMICS technologies, computational modeling, and advanced in vitro systems—offer transformative tools to tackle these challenges. NAMs enable the identification of mechanistic pathways, improve testing efficiency, and reduce reliance on animal testing. This commentary explores the integration of NAMs into pancreatic toxicity screening, addresses critical gaps in evaluating the cumulative risks of chemical and dietary exposures, and proposes solutions for integrating the pancreas into toxicity screening through NAMs. By highlighting recent advancements and emphasizing their adoption in environmental toxicity assessment frameworks, this work demonstrates the potential of NAMs to revolutionize environmental health research, inspire interdisciplinary collaboration, and protect public health.

Abstract Background Epithelial–mesenchymal transition (EMT) is associated with early recurrence and a poor prognosis in clear cell renal cell carcinoma (ccRCC). Studies have shown that EMT‐related genes play an important regulatory role in tumor invasion, metastasis, and drug resistance, but the biological functions of EMT‐related genes in ccRCC have not been specifically described. Methods The mRNA and clinicopathological data of 532 ccRCC and 72 normal samples were downloaded from The Cancer Genome Atlas as a training set. The gene expression matrix and survival data of 91 and 101 ccRCC samples were obtained from the International Cancer Genome Consortium and the ArrayExpress databases as validation sets, respectively. Univariate Cox analysis was used to identify and cluster prognostic genes, and multivariate Cox was performed to construct a prognostic signature. Moreover, CIBERSORT and CellMiner were used to assess immune cell infiltration and prognostic gene‐drug sensitivity of the signature, respectively. Most importantly, we performed detailed experiments to verify the oncogenic function of a significant gene, OLFML2B, in vitro and in vivo. Results We constructed a prognostic signature including seven genes and divided patients into high‐risk and low‐risk groups. The prognosis of the high‐risk group was significantly worse than that of the low‐risk group through Kaplan–Meier survival analysis. Interestingly, significant differences were observed in clinical characteristics and immune cell infiltration between the two groups. In addition, a significant correlation was found between the expression of prognostic genes and the sensitivity of tumor cells to chemotherapeutics. Most importantly, OLFML2B was proved to contribute to the proliferation and metastasis of ccRCC through detailed functional experiments in vitro and in vivo, and its prognostic efficacy for ccRCC patients was affirmed. Conclusion We identified the prognostic signature of seven genes based on EMT‐related genes as prognostic biomarkers for ccRCC. Besides, OLFML2B was validated as a potential diagnostic and therapeutic target for ccRCC by our detailed experiments.

Abstract Terpenoids are pervasive in nature and display an immense structural diversity. As the largest category of plant secondary metabolites, terpenoids have important socioeconomic value in the fields of pharmaceuticals, spices, and food manufacturing. The biosynthesis of terpenoid skeletons has made great progress, but the subsequent modifications of the terpenoid framework are poorly understood, especially for the functionalization of inert carbon skeleton usually catalyzed by hydroxylases. Hydroxylase is a class of enzymes that plays an important role in the modification of terpenoid backbone. This review article outlines the research progress in the identification, molecular modification, and functional expression of this class of enzymes in the past decade, which are profitable for the discovery, engineering, and application of more hydroxylases involved in the plant secondary metabolism. Graphical Abstract

Background: Per- and poly-fluoroalkyl substances (PFAS) are ubiquitous chemicals in the environment and our daily lives. Several epidemiological studies have revealed that PFAS exposure is linked to male sex hormone levels; however, the conclusions are inconsistent across studies. Consequently, we performed a meta-analysis to systematically evaluate the association between PFAS exposure and male sex hormones. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standards were followed during the meta-analysis. PubMed, Wed of Science, Embase, Cochrane Library, and Ovid databases were used to identify suitable articles before June 2023. The 95% CI and β values were calculated to assess the association between male sex hormone levels and PFAS exposure. Heterogeneity among the included studies was tested using inconsistency statistics (I2). Results: The literature search identified 12 published articles that met our search criteria, involving 7506 participants. Our results revealed that perfluorononanoic acid (PFNA) and perfluorooctanoic acid (PFOA) exposures were negatively correlated with testosterone (β = –0.05; 95% CI: –0.09, –0.02, P = 0.003) and (β = –0.04; 95% CI: –0.08, 0.00, P = 0.049), respectively. Conclusion: Exposure to PFNA and PFOA is negatively correlated with changes in male testosterone levels. This correlation suggests that we need to pay attention in the future to whether they are potential risk factors for male reproductive health.

Abstract Background Prompt and appropriate clinical management of malaria is critical for reducing the continued high burden of malaria among children under five years in sub-Saharan countries. However, more remains to be known about how a patient’s socioeconomic status (SES) would affect the access to diagnosis of malaria. Methods In this cross-sectional study using the Demographic and Health Survey and Malaria Indicators Survey, we pooled the data of 38,567 febrile under-five children in 2016–2018 from 19 sub-Saharan countries. Multivariable logistic regression was used to assess the associations between SES and two binary outcomes: the visit to a health facility and a blood test for fever. Stratified analyses were further conducted by the type of health facilities (public hospitals/public primary healthcare facilities/private hospitals/private primary healthcare facilities) for the latter outcome. Results Fifty-eight percent of the febrile children were taken to health facilities, among whom only 55% took blood tests. Compared to children from households in the highest wealth quintile, children in the lowest quintile were less likely to be taken to medical facilities [adjusted odds ratio (aOR) = 0.775, 95% confidence interval (CI): 0.675–0.889]. Parents with more than secondary education were more likely to seek care (aOR = 1.830, 95% CI: 1.561–2.145) and to have blood tests (aOR = 1.729, 95% CI: 1.436–2.082) for their febrile children than parents without formal education. The probabilities of receiving blood tests at public hospitals and public primary healthcare facilities stayed relatively high across parental education levels and wealth quintiles, while these probabilities remained the lowest at private primary healthcare facilities, ranging from 0.100 (95% CI: 0.074–0.127) to 0.139 (95% CI: 0.083–0.194) across parental education levels and from 0.104 (95% CI: 0.078–0.130) to 0.125 (95% CI: 0.090–0.160) across wealth quintiles. Conclusions Significant socioeconomic disparities existed both in the access to health facilities and laboratory diagnosis of malaria in children in sub-Saharan African countries. These disparities were particularly evident in the private sector. Universal health coverage needs to be further strengthened to make formal healthcare in general and the laboratory diagnosis of malaria more accessible and affordable. Graphical abstract

Abstract Background Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative. Methods Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity. Results Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8+ T cells. Conclusions Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations.

Abstract The serological diagnostic criteria for the immune-tolerant (IT) phase have not been strictly defined and it is hard to determine an accurate rate for significant histologic changes among IT patients. The aim of this study was to establish a baseline rate of significant histologic changes and to determine the main characteristics of IT patients. We systematically searched PubMed, Embase, and Web of Science. Studies reporting liver biopsy results (inflammation grade or fibrosis stage) for adults with chronic hepatitis B virus (HBV) infection in the IT phase diagnosed by serological criterion were included to pool the rate of significant histologic changes. Studies that enrolled subjects with confirmed chronic HBV infection in the IT phase diagnosed by serological and liver biopsy criteria (dual criteria) were included to pool the mean values of main characteristics among IT patients. Of 319 studies screened, 15 were eventually included in the meta-analysis. The pooled rates of significant liver fibrosis and inflammatory activity for 10 studies were 10% (95% confidence interval [CI] 0.06–0.18) and 16% (95% CI 0.07–0.31), respectively. The pooled mean values of age, alanine aminotransferase level, HBV DNA level, and HBsAg level for another 5 studies with IT patients diagnosed by dual criteria were 30.7 years (95% CI 27.31–34.09), 26.64 IU/mL (95% CI 24.45–28.83), 8.41 log10 cp/mL (95% CI 7.59–9.23), and 4.24 log10 IU/mL (95% CI 3.67–4.82), respectively. Significant histologic changes were not rare events among IT patients. Strictly defined serological diagnostic criteria for the IT phase are warranted.

The identification and control of safety risks in the loading state of goods wagon is one of the important tasks to ensure the safety of goods in transit. In view of the problem that the current risk assessment of transportation schemes is mainly based on manual experience and cannot be quantified, which makes it difficult to accurately determine the safety risk of transportation on the way, a risk assessment method for loading status of goods wagon based on scenario classification was proposed. Firstly, based on a detailed analysis of the safety risk points in various stages of railway freight operations, a SHEL influencing factor model based on scenario classification was constructed. Then, considering the characteristics of railway freight transportation, a fuzzy accident tree model (FTA) of goods wagon loading state risk was constructed, and the fault tree was transformed into a Bayesian network structure according to the mapping algorithm of fuzzy fault tree and Bayesian. Furthermore, a triangular fuzzy membership function was introduced to describe the fault probability of nodes, and a BN based fuzzy fault tree inference algorithm was proposed. Finally, taking a railway station and route transporting coil steel goods in China as an example, this paper explained how to integrate expert knowledge through fault tree and Bayesian network to support railway freight scheme designers in conducting risk quantification assessment of freight wagon loading status.

Abstract The Warburg effect‐related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation‐induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha‐ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex‐I (MHC‐I) antigen processing and presentation, as well as the expression of β2‐microglobulin (B2M). While αKG modulates broad‐spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD‐1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti‐tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

In order to investigate the influence of various factors on working performance, mechanical properties and durability of sustainable Reactive Powder Concrete (RPC), and make it convenient for choose more cost-effective RPC incorporating industrial byproducts. The effective parameters (water-binder ratio, contents of water reducer, replacement ratios of fly ash (FA), silica fume (SF) and slag powder (SL)) of RPCs were examined by the tests of paste fluidity, compressive and flexural strength as well as water absorption. Besides, the effect of the active mineral admixtures on pore size distribution and surface morphology of RPCs was studied by Mercury Injection Porosimeter (MIP) and Scanning electron microscope (SEM). Results indicate that an obvious reduction in the workability of RPC, enhancement of strength, and reduction in water absorption can be achieved by substituting part of the cement with silica fume. Fly ash and slag powder can be used to substitute some cement in producing RPC, and the workability is improved, meanwhile the effect of fly ash is higher than that of slag powder. However, excessive replacement of cement with slag powder or fly ash leads to a reduction of the strength in the early stage and a greater absorption of water. Increment of curing age is associated with an enhancement of strength and a decrease in water absorption. The porosity is reduced by 5.2 % when cement is partially replaced with silica fume, and the microstructure is dominated by harmless pores. When replacement of silica fume is kept at 25 %, using slag powder or fly ash substitute part of cement also reduces the number of less harmful pores. It is beneficial to add slag powder to increase the number of gel pores, whereas fly ash reduces the number of gel pores. RPC can achieve a high strength, low water absorption, and improved economy and environmental protection when silica fume replaces up to 25 % cement, slag powder or fly ash replaces up to 30 % cement. This investigation is expected to provide a practical method in the mix design and engineering application of economical and sustainable RPC.

Influenza virus, with a global distribution, diverse animal host range and multiple virus subtypes, has caused several pandemics. To better prepare for the emergence of new subtypes and the possible threat of the next pandemic, the global status of animal influenza must be defined and documented. We created a global database of animal influenza events by searching scientific databases and the primary literature on animal influenza-related events up to and including 2016. The temporal, spatial and host distribution of animal influenza and the diversity of influenza subtypes in different regions were analyzed. A total of 70,472 records and 4712 events of animal influenza throughout the world were identified. Events involving subtypes H5N2, H7N7 and H7N9 were relatively constant, with a slow upward trend during the past decade. Asia was the region with the most clusters of events. Poultry was the main host reported in Asia and Africa, and wild birds in Europe and North America. We found that wild birds carried a very rich array of virus subtypes, a warning for the possible generation of reassortment viruses with pandemic potential. Influenza virus subtype diversity - a risk for virus reassortment - was greatest in Asia, North America and Europe. Our database provides a comprehensive overview of the historical and current status of animal influenza events throughout the world. Influenza surveillance needs to be strengthened in some countries and regions to prevent the emergence of new subtypes. Importantly, improvement of the global influenza surveillance system and structures to enable sharing of surveillance data is very much needed to prepare for the next pandemic.

Abstract Background (−)-Limonene, one of cyclic monoterpenes, is an important renewable compound used widely as a key building block for the synthesis of new biologically active molecules and fine chemicals. (−)-Perillamine, as derived from (−)-limonene, is a highly useful synthon for constructing more complicated and functionally relevant chemicals. Aim We aimed to report a more sustainable and more efficient method for the regiospecific C–H amination of (−)-limonene into (−)-perillamine. Results Here, we report an artificial penta-enzymatic cascade system for the transformation of the cheap and easily available (−)-limonene into (−)-perillamine for the first time. This system is composed of cytochrome P450 monooxygenase, alcohol dehydrogenase and w-transaminase for the main reactions, as well as formate dehydrogenase and NADH oxidase for cofactor recycling. After optimization of the multi-enzymatic cascade system, 10 mM (−)-limonene was smoothly converted into 5.4 mM (−)-perillamine in a one-pot two-step biotransformation, indicating the feasibility of multi-enzymatic C7-regiospecific amination of the inert C–H bond of (−)-limonene. This method represents a concise and efficient route for the biocatalytic synthesis of derivatives from similar natural products.

To study the effect of rigor state on physicochemical characteristics of Funiu white goat and Oula sheep meat batters. In this study, the effect of rigor state of Funiu white goat and Oula sheep silverside muscle on meat batter quality and physicochemical properties was determined. Results indicated that meat batters obtained from post-rigor meat had less water holding capacity and lower immobilized water than that obtained from pre-rigor meat. The gel network of meat batters produced with Funiu white goat muscle appeared denser and smoother compared with Oula sheep meat batters. Furthermore, meat batters produced with pre-rigor meat had higher hardness compared to that produced with post-rigor meat. Differences in response values were found for CPS (sensitivity to sweet taste) of meat batters made with meat in the three rigor states. Collectively, both Funiu white goat and Oula sheep meat in pre-rigor state were more suitable to minced meat product production compared to post-rigor meat based on gel properties.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage–CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Clear cell renal cell carcinoma (ccRCC) is considered to be related to the worse prognosis, which might in part be attributed to the early recurrence and metastasis, compared with other type of kidney cancer. Oxidative stress refers to an imbalance between production of oxidants and antioxidant defense. Accumulative studies have indicated that oxidative stress genes contribute to the tumor invasion, metastasis and drug sensitivity. However, the biological functions of oxidative stress genes in ccRCC remain largely unknown. In this study, we identified 1,399 oxidative stress genes from GeneCards with a relevance score ≥7. Data for analysis were accessed from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database, and were utilized as training set and validation set respectively. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox were employed to construct a prognostic signature in ccRCC. Finally, a prognostic signature including four different oxidative stress genes was constructed from 1,399 genes, and its predictive performance was verified through Kaplan-Meier survival analysis and the receiver operating characteristic (ROC) curve. Interestingly, we found that there was significant correlation between the expression of oxidative stress genes and the immune infiltration and the sensitivity of tumor cells to chemotherapeutics. Moreover, the highest hazard ratio gene urocortin (UCN) was chosen for further study; some necessary vitro experiments proved that the UCN could promote the ability of ccRCC proliferation and migration and contribute to the degree of oxidative stress. In conclusion, it was promising to predict the prognosis of ccRCC through the four oxidative stress genes signature. UCN played oncogenic roles in ccRCC by influencing proliferation and oxidative stress pathway, which was expected to be the novel therapeutic target for ccRCC.

Abstract Background Anemia in pregnancy is behind a significant burden of maternal mortality and poor birth outcomes globally. Efforts to address it need evidence on trends and its pertinent factors as they vary from one area to another. Methods We pooled data of 23,203 women of reproductive age whose hemoglobin levels were measured from two Tanzania Demographic and Health Surveys (TDHS). Of them, 2,194 women were pregnant. Analyses employed descriptive analyses to determine the burden of anemia, its characteristics, and severity; GIS mapping to determine the regional changes of anemia between 2005 and 2015; and logistic regression to determine the remaining determinants of anemia among pregnant women using Stata 15. Results The burden of anemia among pregnant women in Tanzania has remained unprecedently high, and varies between regions. There was no significant decline of anemia in general between the two periods after adjusting for individual, households, reproductive, and child characteristics [AOR = 0.964, 95% CI = 0.774–1.202, p = 0.747). Anemia is currently prevalent in 57% of pregnant women in Tanzania. The prevalence is more likely to be higher among women aged 15–19 years than those aged between 20–34 years. It is more likely to be prevalent among those within large families, with no formal education, food insecurity, lack of health insurance, had no antimalaria during pregnancy, and had low frequency of ANC attendance. On the other hand, delivery in a health facility may be potentially protective against anemia. Conclusions Anemia in pregnancy remained persistently high and prevalent among 57% of pregnant women in Tanzania. Efforts to address anemia are crucial and need to be focused in regions with increasing burden of anemia among pregnant women. It is imperative to address important risk factors such as food insecurity, strengthening universal health coverage, empowering women of reproductive age with education and especially nutritional knowledge and advocating for early antenatal booking, attendance, and facility delivery.

Micro-expressions are fleeting and subtle emotional expressions. As they are spontaneous and uncontrollable by one’s mind, micro-expressions are considered an indicator of genuine emotions. Their accurate recognition and interpretation promote interpersonal interaction and social communication. Therefore, enhancing the ability to recognize micro-expressions has captured much attention. In the current study, we investigated the effects of training on micro-expression recognition with a Chinese version of the Micro-Expression Training Tool (METT). Our goal was to confirm whether the recognition accuracy of spontaneous micro-expressions could be improved through training and brain stimulation. Since the right temporal parietal junction (rTPJ) has been shown to be involved in the explicit process of facial emotion recognition, we hypothesized that the rTPJ would play a role in facilitating the recognition of micro-expressions. The results showed that anodal transcranial direct-current stimulation (tDCS) of the rTPJ indeed improved the recognition of spontaneous micro-expressions, especially for those associated with fear. The improved accuracy of recognizing fear spontaneous micro-expressions was positively correlated with personal distress in the anodal group but not in the sham group. Our study supports that the combined use of tDCS and METT can be a viable way to train and enhance micro-expression recognition.

Abstract As part of the Hudson Bay drainage system in North America, the Red River of the North Basin (RRB) has been subject to Spring River flooding in the past century. Previously, forecast errors had led to inadequate flood preparations that resulted in tremendous losses and overspending of taxpayer's dollars in flood response. National Aeronautics and Space Administration’s satellite microwave remote sensing technology offers improved snow water equivalent measurement information needed for spring flood forecasting in this region. This study evaluates the economic benefits of the technology use to the farm sector in the RRB. We found that farm support for the technology use for river flood forecast is overwhelming, and higher farm support yields higher willingness to pay for the product use. However, respondents who are content with the existing spring flood forecasts tend to have a lower valuation of the new product. Tellingly, landowners who lease to farm operators have noticeably zero perceived economic valuation of the product even though river flooding on their land could depress future land value.

This paper numerically investigates flexural performance of Ultra-High Performance Concrete (UHPC) beam reinforced with Steel-Fibre-Reinforced Polymer (FRP) Composite Bars (SFCBs) in terms of flexural stiffness, moment capacity, deflection, ductility and energy dissipation. The effect of various parameters, include the inner steel core area ratio of SFCB, yield strength of inner steel core, elastic modulus and ultimate strength of outer-wrapped FRP, reinforcement ratio, type and strength of concrete were studied. The results demonstrate that the inner steel core area ratio of SFCB, reinforcement ratio and the elastic modulus of SFCB's outer FRP have significant effect on the overall flexural performance of SFCB reinforced UHPC beam. The overall flexural performance of SFCB reinforced UHPC beam is slightly improved by increasing the yield strength of inner steel core of SFCB, but not affected by the ultimate strength of SFCB's outer FRP when specimen occurred compression failure. The results also exhibit that the flexural performance of UHPC beam reinforced with SFCBs is significantly improved when compared to those of reinforced high strength concrete (HSC) beam and normal strength concrete (NSC) beam. The flexural stiffness and the moment capacity of SFCB reinforced UHPC beam at the ultimate point were 2.0 and 2.4 times, respectively, of those of reinforced NSC counterpart.

Pancreatic β-cell dysfunction is a key link during the progression of type 2 diabetes (T2DM), and SIRT1 participates in the regulation of various physiological activities of islet β-cells. However, as a key link in signal transduction, it is not clear how SIRT1 is regulated. By TargetScan prediction, we found that miR-204, which is enriched in islets, has highly complementary binding sites with SIRT1. Therefore, we speculate that miR-204 may be the upstream regulatory target of SIRT1 in islets and thus participate in the occurrence of β-cell dysfunction. In this study, we explored the association between miR-204 and β-cell dysfunction, the therapeutic effects of berberine (BBR) on β-cell function and the possible mechanisms. We found that miR-204 increased and SIRT1 mRNA and protein levels decreased significantly in islets both in vivo and in vitro. MIN6 cells induced by palmitic acid exhibited increased apoptosis, and the accumulation of insulin and ATP in the supernatant decreased. Importantly, palmitic acid treatment combined with miR-204 silencing showed opposite changes. MiR-204 overexpression in MIN6 cells increased apoptosis and decreased insulin and ATP production and SIRT1 expression. SIRT1 overexpression reversed the damage to β-cells caused by miR-204. The BBR treatment effectively improved insulin synthesis, reduced miR-204 levels, and increased SIRT1 expression in islet tissue in diabetic mice. Overexpression of miR-204 reversed the protective effect of BBR on apoptosis and insulin secretion in MIN6 cells. Our study identifies a novel correlation between miR-204 and β-cell dysfunction in T2DM and shows that administration of BBR leads to remission of β-cell dysfunction by regulating the miR-204/SIRT1 pathway.

Searchable encryption (SE) allows users to search over encrypted data without decrypting. In most existing SE schemes, server returns all matched files without relevance ranking, and the update mechanism are suffering with high communication and computation cost, which are not efficient enough to satisfy the real-life dynamic scenario. Addressing the above issues, we proposed TS-RDSE-a Two-Server Ranked Dynamic Searchable Encryption scheme. We integrate orthogonal vector and efficient homomorphic encryption cryptosystems to build a vector-level dynamic secure index, which simultaneously supports efficient dynamic update operations like deletion and insertion of files flexibly. Moreover, in order to rank the search results by relevance without decryption, we build a secure sorting protocol based on the widely-used tf-idf weighting formula and addition property of partial homomorphic encryption, which achieves accurate sorting for the search results while protecting the privacy of relevance scores. We give a comprehensive analysis of the correctness of TS-RDSE in the aspect of searching and sorting with mathematical proofs. The security analysis shows that TS-RDSE is secure against adaptive dynamic chosen-keyword attacks (CKA2) by honest-but-curious adversaries in random oracle model. The performance analysis shows that TS-RDSE has both a very light user workload and a moderate server workload, and it is superior to the existing approaches in terms of functionalities and expansibility. Extensive experiments on the real-world dataset validate our analysis and show that TS-RDSE is suitable for the real world cloud storage environment.

Dysregulation of transcription factors contributes to the carcinogenesis and progression of cancers. However, their roles in clear cell renal cell carcinoma remain largely unknown. This study aimed to evaluate the clinical significance of TFs and investigate their potential molecular mechanisms in ccRCC. Data were accessed from the cancer genome atlas kidney clear cell carcinoma cohort. Bioinformatics algorithm was used in copy number alterations mutations, and differentially expressed TFs’ analysis. Univariate and multivariate Cox regression analyses were performed to identify clinically significant TFs and construct a six-TF prognostic panel. TFs’ expression was validated in human tissues. Gene set enrichment analysis (GSEA) was utilized to find enriched cancer hallmark pathways. Functional experiments were conducted to verify the cancer-promoting effect of BARX homeobox 1 (BARX1) and distal-less homeobox 4 (DLX4) in ccRCC, and Western blot was performed to explore their downstream pathways. As for results, many CNAs and mutations were identified in transcription factor genes. TFs were differentially expressed in ccRCC. An applicable predictive panel of six-TF genes was constructed to predict the overall survival for ccRCC patients, and its diagnostic efficiency was evaluated by the area under the curve (AUC). BARX1 and DLX4 were associated with poor prognosis, and they could promote the proliferation and migration of ccRCC. In conclusion, the six-TF panel can be used as a prognostic biomarker for ccRCC patients. BARX1 and DLX4 play oncogenic roles in ccRCC via promoting proliferation and epithelial–mesenchymal transition. They have the potential to be novel therapeutic targets for ccRCC.

Obesity is an important cause of diseases such as type 2 diabetes, non-alcoholic fatty liver and atherosclerosis. The use of ingredients extracted from traditional Chinese medicine for weight loss is now receiving more and more attention. Ginseng has been recorded since ancient times for the treatment of diabetes. The (20R)-Panaxadiol (PD) belongs to the ginseng diol type compounds, which are moderately bioavailable and may remain in the intestinal tract for a longer period of time. This study investigated the potential positive effect of PD in ob/ob mice and evaluated its effect against obesity. The ob/ob mice were administered PD for ten weeks. Our study showed that PD could improve obesity, glucose tolerance disorder, as well as gut dysbiosis. Panaxadiol decreased ob/ob mice’s Firmicutes/Bacteroidetes (F/B). Furthermore, 16S rRNA gene sequencing of the fecal microbiota suggested that PD changed the composition of the gut microbiota in ob/ob mice and modulated specific bacteria such as lactobacillus, prevotellace and so on. Moreover, PD improved the intestinal wall integrity. In conclusion, our results suggest that (20R)-Panaxadiol, as an active ingredient of the traditional Chinese medicinal herb ginseng, may improve obesity to some extent via improving gut microbiota

Focusing on the diversified demands of location privacy in mobile social networks (MSNs), we propose a privacy-enhancing k-nearest neighbors search scheme over MSNs. First, we construct a dual-server architecture that incorporates location privacy and fine-grained access control. Under the above architecture, we design a lightweight location encryption algorithm to achieve a minimal cost to the user. We also propose a location re-encryption protocol and an encrypted location search protocol based on secure multi-party computation and homomorphic encryption mechanism, which achieve accurate and secure k-nearest friends retrieval. Moreover, to satisfy fine-grained access control requirements, we propose a dynamic friends management mechanism based on public-key broadcast encryption. It enables users to grant/revoke others’ search right without updating their friends’ keys, realizing constant-time authentication. Security analysis shows that the proposed scheme satisfies adaptive L-semantic security and revocation security under a random oracle model. In terms of performance, compared with the related works with single server architecture, the proposed scheme reduces the leakage of the location information, search pattern and the user–server communication cost. Our results show that a decentralized and end-to-end encrypted k-nearest neighbors search over MSNs is not only possible in theory, but also feasible in real-world MSNs collaboration deployment with resource-constrained mobile devices and highly iterative location update demands.

The study of migrations and mobility has historically been severely limited by the absence of reliable data or the temporal sparsity of available data. Using geospatial digital trace data, the study of population movements can be much more precisely and dynamically measured. Our research seeks to develop a near real-time (one-day lag) Twitter census that gives a more temporally granular picture of local and non-local population at the county level. Internal validation reveals over 80% accuracy when compared with users’ self-reported home location. External validation results suggest these stocks correlate with available statistics of residents/non-residents at the county level and can accurately reflect regular (seasonal tourism) and non-regular events such as the Great American Solar Eclipse of 2017. The findings demonstrate that Twitter holds the potential to introduce the dynamic component often lacking in population estimates. This study could potentially benefit various fields such as demography, tourism, emergency management, and public health and create new opportunities for large-scale mobility analyses.

Understanding the mechanisms underlying toxicity initiated by nickel, a ubiquitous environmental contaminant and known human carcinogen is necessary for proper assessment of its risks to human and environment. Among a variety of toxic mechanisms, disruption of protein responses and protein response-based biochemical pathways represents a key mechanism through which nickel induces cytotoxicity and carcinogenesis. To identify protein responses and biochemical pathways that are critical to nickel-induced toxicity responses, we measured cytotoxicity and changes in expression and phosphorylation status of 14 critical biochemical pathway regulators in human BEAS-2B cells exposed to four concentrations of nickel using an integrated proteomic approach. A subset of the pathway regulators, including interleukin-6, and JNK, were found to be linearly correlated with cell viability, and may function as molecular determinants of cytotoxic responses of BEAS-2B cells to nickel exposures. In addition, 128 differentially expressed proteins were identified by two dimensional electrophoresis (2-DE) and mass spectrometry. Principal component analysis, hierarchical cluster analyses, and ingenuity signaling pathway analysis (IPA) identified putative nickel toxicity pathways. Some of the proteins and pathways identified have not previously been linked to nickel toxicity. Based on the consistent results obtained from both ELISA and 2-DE proteomic analysis, we propose a core signaling pathway regulating cytotoxic responses of human BEAS-2B cells to nickel exposures, which integrates a small set of proteins involved in glycolysis and gluconeogenesis pathways, apoptosis, protein degradation, and stress responses including inflammation and oxidative stress.

Although the generation of BCR-ABL is the molecular hallmark of chronic myeloid leukemia (CML), the comprehensive molecular mechanisms of the disease remain unclear yet. Growth arrest specific 2 (GAS2) regulates multiple cellular functions including cell cycle, apoptosis and calpain activities. In the present study, we found GAS2 was up-regulated in CML cells including CD34+ progenitor cells compared to their normal counterparts. We utilized RNAi and the expression of dominant negative form of GAS2 (GAS2DN) to target GAS2, which resulted in calpain activity enhancement and growth inhibition of both K562 and MEG-01 cells. Targeting GAS2 also sensitized K562 cells to Imatinib mesylate (IM). GAS2DN suppressed the tumorigenic ability of MEG-01 cells and impaired the tumour growth as well. Moreover, the CD34+ cells from CML patients and healthy donors were transduced with control and GAS2DN lentiviral vectors, and the CD34+ transduced (YFP+) progeny cells (CD34+YFP+) were plated for colony-forming cell (CFC) assay. The results showed that GAS2DN inhibited the CFC production of CML cells by 57±3% (n = 3), while affected those of normal hematopoietic cells by 31±1% (n = 2). Next, we found the inhibition of CML cells by GAS2DN was dependent on calpain activity but not the degradation of beta-catenin. Lastly, we generated microarray data to identify the differentially expressed genes upon GAS2DN and validated that the expression of HNRPDL, PTK7 and UCHL5 was suppressed by GAS2DN. These 3 genes were up-regulated in CML cells compared to normal control cells and the growth of K562 cells was inhibited upon HNRPDL silence. Taken together, we have demonstrated that GAS2 is up-regulated in CML cells and the inhibition of GAS2 impairs the growth of CML cells, which indicates GAS2 is a novel regulator of CML cells and a potential therapeutic target of this disease.

How do people interpret the meaning of a smile? Previous studies with Westerners have found that both the eyes and the mouth are crucial in identifying and interpreting smiles, yet less is known about Easterners. Here we reported that when asking the Chinese to judge the Duchenne and non-Duchenne smiles as either real or fake, their accuracy and sensitivity were negatively correlated with their individualism scores but positively correlated with their collectivism scores. However, such correlations were found only for participants who stated the eyes to be the most useful references, but not for those who favored the mouth. Moreover, participants who favored the eyes were more accurate and sensitive than those who favored the mouth. Our results thus indicate that Chinese who follow the typical Eastern decoding process of using the eyes as diagnostic cues to identify and interpret others' facial expressions and social intentions, are particularly accurate and sensitive, the more they self-report greater collectivistic and lower individualistic values.

A future possibility for treatment of genetic diseases may be gene therapy using autologous cord blood (CB) stem/progenitor cells. This might require cryopreservation of CB stem/progenitor cells prior to purification, gene transduction, and ex vivo expansion of cells. To address this possibility, nonadherent low density T-lymphocyte depleted (NALT-) cells from fresh or cryopreserved cord blood were sorted for CD34+++ phenotype, transduced with a recombinant retroviral vector encoding Fanconi anemia complementation C (FACC) gene, and cells expanded ex vivo in suspension culture for 7 days with growth factors. The results demonstrate: 1) high recovery of viable cells after thawing; 2) high efficiency purification of CD34+++ cells from NALT- cells prior to and after cryopreservation; 3) high degree of expansion of nucleated cells and immature progenitors from CD34+++ cells before and after cryopreservation; 4) efficient transduction with stable integration and expression of newly introduced genes in cryopreserved and then sorted stem/progenitor cells, as detected prior to and after ex vivo expansion; and 5) high efficiency transduction of single isolated CD34+++ cells obtained from cryopreserved NALT- CB. This information should be of value for future studies evaluating the use of cryopreserved cord blood for gene transfer/gene therapy.

Objective: To optimize the best process for the extraction of pine needle essential oil from Pinus tabuliformis, and to conduct its compositional analysis and antioxidant capacity. Methods: Response surface methodology was used to optimize the process of extracting the pine needle essential oil from Pinus tabuliformis by microwave-assisted extraction (MAE), the components of essential oil were identified by gas chromatography-mass spectrometry (GC-MS) and the antioxidant activity was verified by DPPH and ABTS+ free radicals scavenging ability as indicators. Results: The optimal extraction processes were as follows: extraction time 55 min, microwave power 550 W, liquid-to-solid ratio 10:1 mL/g, the predicted yield was 0.245%, and the validation result of the optimized process was 0.238%. A total of 104 candidate components were obtained from the essential oil, with major components including thunbergol (3.938%), and verticillol (3.597%), and so on. In the antioxidant experiment, L-ascorbic acid was used as a control to determine the DPPH and ABTS+ free radicals scavenging ability, and the half maximal inhibitory concentration (IC50) was 101.74 and 12.39 mg/mL, respectively. Meanwhile, at the concentration of essential oil of 128.00 mg/mL, the DPPH free radical scavenging rate could reach 64.92% and the ABTS+ free radical scavenging rate could reach 84.11%. Conclusion: By optimizing the microwave-assisted extraction process of pine needle essential oil from Pinus tabuliformis, and measuring the main volatile components of pine needle essential oil obtained by this method, its antioxidant activity was confirmed, which would provide theoretical support for the development of green and efficient extraction methods of pine needle essential oil and further utilization of pine needle essential oil resources.