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Abstract This study investigated the possible mechanisms of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism. β-Thiol ethanol induced Notch1 mRNA expression, microRNA-124a inhibitor reduced the effects of β-thiol ethanol on Notch1 mRNA expression in BMSCs. Baicalin induced Hes1 mRNA expression, and microRNA-124a inhibitor reduced the effects of baicalin on Hes1 mRNA expression in BMSCs. Si-Notch1 suppressed Hes1 mRNA expression in BMSCs. Baicalin increased the effects of Notch1 on Hes1 mRNA expression in BMSCs. Si-Notch1 increased cell growth of BMSCs. Baicalin reduced the effects of si-Notch1 on cell growth and the differentiation of BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons through Notch/Hes1 signal pathway.

Abstract Background Elevated blood glucose at hospital admission is frequently observed and has been associated with adverse outcomes in various patient populations. This meta-analysis sought to consolidate existing evidence to assess the association between elevated blood glucose at admission and clinical outcomes amongst pneumonia patients. Methods We searched PubMed, Medline, Cochrane library, Web of Science (WoS), and Scopus databases for studies, published up to 31 August 2023, and reporting on the clinical outcomes and the blood glucose levels at admission. Data were extracted by two independent reviewers. Random-effects meta-analyses were used to pool odds ratios (ORs) with 95% confidence intervals (CI) for dichotomous outcomes and weighted mean differences (WMDs) for continuous outcomes. Results A total of 23 studies with 34,000 participants were included. Elevated blood glucose at admission was significantly associated with increased short-term (pooled OR: 2.67; 95%CI: 1.73–4.12) and long-term mortality (pooled OR: 1.70; 95%CI: 1.20–2.42). Patients with raised glucose levels were more likely to require ICU admission (pooled OR: 1.86; 95%CI: 1.31–2.64). Trends also suggested increased risks for hospital readmission and mechanical ventilation, though these were not statistically significant. Elevated blood glucose was linked with approximately 0.72 days longer duration of hospital stay. Conclusion Elevated blood glucose level at the time of hospital admission is associated with several adverse clinical outcomes, especially mortality, in patients with pneumonia. These findings underscore the importance of recognizing hyperglycemia as significant prognostic marker in pneumonia patients. Further research is needed to determine whether targeted interventions to control glucose levels can improve these outcomes.

Abstract Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE); even combining IR with immune checkpoint inhibitors has shown only anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug, disulfiram (DSF), complexed with copper (DSF/Cu) to induce tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anticancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs relative to spontaneous lung metastasis. In addition, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anticancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral (i.t.) injection of DSF/Cu and IR(12Gy) demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8+ and CD4+ cell numbers while decreasing Tregs and myeloid-derived suppressor cells in the 4T1 model, and increased CD8+, dendritic cells (DC), and decreased Treg cell numbers in the MCa-M3C model. Depleting both CD8+ and CD4+ cells abolished the vaccine’s anticancer response. Moreover, vaccinated tumor-bearing mice exhibited increased TNFα levels and reduced levels of immunosuppressive chemokines/cytokines. In conclusion, our novel approach generated an anticancer immune response that results in a lack of or low tumor incidence post-rechallenge and robust AEs, i.e., absence of or decreased spontaneous lung metastasis in tumor-bearing mice. This approach is readily translatable to clinical settings and may increase IR-induced AEs in cancer patients.

Abstract Background S. pyogenes, is a primary pathogen that leads to pharyngitis and can also trigger severe conditions like necrotizing fasciitis and streptococcal toxic shock syndrome (STSS), often resulting in high mortality rates. Therefore, prompt identification and appropriate treatment of S. pyogenes infections are crucial in preventing the worsening of symptoms and alleviating the disease's impact. Results In this study, a newly developed technique called multiple cross displacement amplification (MCDA) was employed to detect S. pyogenes,specifically targeting the speB gene, at a temperature of 63°C within 30 min. Then, an easily portable and user-friendly nanoparticles-based lateral flow biosensor (LFB) assay was introduced for the rapid analysis of MCDA products in just 2 min. The results indicated that the LFB offers greater objectivity compared to Malachite Green and is simpler than electrophoresis. The MCDA-LFB assay boasts a low detection limit of 200 fg and exhibits no cross-reaction with non-S. pyogenes strains. Among 230 clinical swab throat samples, the MCDA-LFB method identified 27 specimens as positive, demonstrating higher sensitivity compared to 23 samples detected positive by qPCR assay and 18 samples by culture. The only equipment needed for this assay is a portable dry block heater. Moreover, each MCDA-LFB test is cost-effective, priced at approximately $US 5.5. Conclusion The MCDA-LFB assay emerges as a straightforward, specific, sensitive, portable, and user-friendly method for the rapid diagnosis of S. pyogenes in clinical samples.

Stroke is a devastating disease with high morbidity, disability, and mortality, among which ischemic stroke is more common. However, there is still a lack of effective methods to improve the prognosis and reduce the incidence of its complications. At present, there is evidence that peripheral organs are involved in the inflammatory response after stroke. Moreover, the interaction between central and peripheral inflammation includes the activation of resident and peripheral immune cells, as well as the activation of inflammation-related signaling pathways, which all play an important role in the pathophysiology of stroke. In this review, we discuss the mechanisms of inflammatory response after ischemic stroke, as well as the interactions through circulatory pathways between peripheral organs (such as the gut, heart, lung and spleen) and the brain to mediate and regulate inflammation after ischemic stroke. We also propose the potential role of meningeal lymphatic vessels (MLVs)-cervical lymph nodes (CLNs) as a brain-peripheral crosstalk lymphatic pathway in ischemic stroke. In addition, we also summarize the mechanisms of anti-inflammatory drugs in the treatment of ischemic stroke.

Abstract Background Rapeseed (Brassica napus L.) is the third largest source of vegetable oil in the world, and Sclerotinia sclerotiorum (Lib.) is a major soil-borne fungal plant pathogen that infects more than 400 plant species, including B. napus. Sclerotinia stem rot caused an annual loss of 10 − 20% in rapeseed yield. Exploring the molecular mechanisms in response to S. sclerotiorum infection in B. napus is beneficial for breeding and cultivation of resistant varieties. To gain a better understanding of the mechanisms regarding B. napus tolerance to Sclerotinia stem rot, we employed a miRNAome sequencing approach and comprehensively investigated global miRNA expression profile among five relatively resistant lines and five susceptible lines of oilseed at 0, 24, and 48 h post-inoculation. Results In this study, a total of 40 known and 1105 novel miRNAs were differentially expressed after S. sclerotiorum infection, including miR156, miR6028, miR394, miR390, miR395, miR166, miR171, miR167, miR164, and miR172. Furthermore, 8,523 genes were predicted as targets for these differentially expressed miRNAs. These target genes were mainly associated with disease resistance (R) genes, signal transduction, transcription factors, and hormones. Constitutively expressing miR156b (OX156b) plants strengthened Arabidopsis resistance against S. sclerotiorum accompanied by smaller necrotic lesions, whereas blocking miR156 expression in Arabidopsis (MIM156) led to greater susceptibility to S. sclerotiorum disease, associated with extensive cell death of necrotic lesions. Conclusions This study reveals the distinct difference in miRNA profiling between the relatively resistant lines and susceptible lines of B. napus in response to S. sclerotiorum. The identified differentially expressed miRNAs related to sclerotinia stem rot resistance are involved in regulating resistance to S. sclerotiorum in rapeseed by targeting genes related to R genes, signal transduction, transcription factors, and hormones. miR156 positively modulates the resistance to S. sclerotiorum infection by restricting colonization of S. sclerotiorum mycelia. This study provides a broad view of miRNA expression changes after S. sclerotiorum infection in oilseed and is the first to elucidate the function and mechanism underlying the miR156 response to S. sclerotiorum infection in oilseed rape.

Abstract Aims The aim of this study was to refine the Falling Risk Assessment Tool in Ophthalmology Inpatients (FRAT) and assess its psychometric properties. Design A cross‐sectional design was used. Methods A convenience sample of 730 patients in the ophthalmology department was recruited in a level A tertiary hospital in Guangdong Province from July 2021 to January 2022. Data were analysed using item analysis, interrater reliability, content validation, internal consistency reliability and exploratory factor analysis. Results Five factors were extracted, accounting for 63.039% of the variance. The interrater reliability of the tool was 0.97. Cronbach's α was 0.658. The I‐CVI was 0.75–1.00, the S‐CVI/UA was 0.95 and the adjusted mean values of Kappa for indicators ranged from 0.72 to 1.00, as evaluated by the expert group. The FRAT showed satisfactory reliability and validity, and can be used to measure the fall risk assessment in ophthalmology inpatients. Patient or Public Contribution After explaining the purpose, the patients received our fall risk assessment and answered the corresponding questionnaire questions.

Abstract Chemokines secreted by dendritic cells (DCs) play a key role in the regulation of inflammation and autoimmunity through chemokine receptors. However, the role of chemokine receptor CXCR1 in inflammation-inducing experimental autoimmune encephalomyelitis (EAE) and acute respiratory distress syndrome (ARDS) remains largely enigmatic. Here we reported that compared with healthy controls, the level of CXCR1 was aberrantly increased in multiple sclerosis (MS) patients. Knockout of CXCR1 not only ameliorated disease severity in EAE mice but also suppressed the secretion of inflammatory factors (IL-6/IL-12p70) production. We observed the same results in EAE mice with DCs-specific deletion of CXCR1 and antibody neutralization of the ligand CXCL5. Mechanically, we demonstrated a positive feedback loop composed of CXCL5/CXCR1/HIF-1α direct regulating of IL-6/IL-12p70 production in DCs. Meanwhile, we found CXCR1 deficiency in DCs limited IL-6/IL-12p70 production and lung injury in LPS-induced ARDS, a disease model caused by inflammation. Overall, our study reveals CXCR1 governs DCs-mediated inflammation and autoimmune disorders and its potential as a therapeutic target for related diseases.

Abstract Background Gastric cancer is a common cause of death from cancer and an important global health care issue. Consequently, there is an urgent need to find new drugs and therapeutic targets for the treatment of gastric cancer. Recent studies have shown that tocotrienols (T3) have significant anticancer ability in cancer cell lines. Our previous study found that γ-tocotrienol (γ-T3) induced apoptosis in gastric cancer cells. We further explored the possible mechanisms of γ-T3 therapy for gastric cancer. Methods In this study, we treated gastric cancer cells with γ-T3, collect and deposit the cells. γ-T3-treated gastric cancer cells group and untreated group were subjected to RNA-seq assay, and analysis of sequencing results. Results Consistent with our previous findings, the results suggest that γ-T3 can inhibit mitochondrial complexes and oxidative phosphorylation. Analysis reveals that γ-T3 has altered mRNA and ncRNA in gastric cancer cells. Significantly altered signaling pathways after γ-T3 treatment were enriched for human papillomavirus infection (HPV) pathway and notch signaling pathway. The same significantly down-regulated genes notch1 and notch2 were present in both pathways in γ-T3-treated gastric cancer cells compared to controls. Conclusions It is indicated that γ-T3 may cure gastric cancer by inhibiting the notch signaling pathway. To provide a new and powerful basis for the clinical treatment of gastric cancer.

Understanding the dynamics of ecosystem services (ESs) in arid landscapes and socio-ecological systems is crucial for sustainable development and human well-being. This study uses the Invest model to quantify the spatio-temporal changes in four key ecosystems services in Altay from 1990 to 2020: water yield (water yield), carbon stock (carbon stock), soil retention (soil retention), and habitat quality (habitat quality). The trade-offs/synergies between different ESs were investigated via Spearman’s correlation analysis. Ecosystem service bundles (ESBs) were mapped using self-organizing mapping (SOM), and the key drivers of ES relationships and the spatio-temporal dynamics of ESBs were revealed through redundancy analysis. The results showed that water yield increased by 33.7% and soil retention increased by 1.2%, while carbon stock and habitat quality decreased by 3.5% and 1.24%, respectively. The spatial distribution pattern had a clear zonal pattern, with the northern mountainous areas higher than the southern desert areas. The six pairs of ESs, in general, showed mainly low trade-off and high synergistic relationships, with trade-offs between water yield and carbon stock, soil retention and habitat quality, and a decreasing trend of trade-offs over time. Four types of ESBs were distinguished, and the compositional differences and spatial distribution within each ESB were determined by interactions between ESs and landscape types. There are complex non-linear relationships between the drivers and the four ESBs in different years. Before 2010, ecological factors were the key drivers influencing the spatio-temporal changes in ESBs, whereas social and environmental factors combined to drive changes in ESB allocations after 2010. Additionally, this study found that the implementation of conservation measures, such as reforestation and sustainable land management practices, positively influenced the provision of ecosystem services in the Altay region. These findings underscore the importance of integrating conservation efforts into land use planning and decision-making processes to ensure the sustainable delivery of ecosystem services in arid landscapes.

Incontinentia pigmenti (IP), an X-chromosome dominant genodermatosis caused by mutations in the IKBKG/NEMO gene, is a rare disease affecting the skin, teeth, eyes, and central nervous system. Here, we report two pedigrees of IP and detection of two novel mutations in the IKBKG gene associated with IP via genetic analysis. In addition, different gene mutation types can present with different clinical phenotypes, and the same gene mutation type can show different clinical phenotypes. This study provides clinical cases for further study of the genotype and phenotype of IP and enriches the mutation spectrum of IKBKG gene, which provides a basis for genetic counseling and genetic diagnosis of IP in the future.

Abstract Aim The aim of this study was to examine hope level and its influencing factors in patients with decompensated liver cirrhosis. Design A prospective observational study. Methods We selected 93 patients with decompensated liver cirrhosis from a Chinese university hospital based on the inclusion and exclusion criteria. A general information questionnaire and Herth Hope Index were used, and multiple linear regression identified factors associated with the patients' hope level. Results The participants' average hope level was 32.01 ± 6.14 (moderate). The hope score's highest and lowest dimensions were “interconnectedness” (11.29 ± 2.17) and “temporality and future” (10.12 ± 2.28), respectively. Multiple linear regression showed that education level and monthly per capita income were independent influencing factors (p

Introduction:. Erythropoietic protoporphyria (EPP) is a rare photodermatosis mainly caused by deficiency of the enzyme ferrochelatase (FECH). We herein report a case of EPP associated with 2 novel mutations in FECH. Case presentation:. A 15-year-old boy experienced pain and pruritus after sunlight exposure. He had occasional claret-red urine, hepatomegaly with increased alanine aminotransferase and aspartate aminotransferase levels, and an elevated free erythrocyte protoporphyrin level. He was treated with oral β-carotene and cholestyramine and avoidance of sunlight as much as possible. Discussion:. Genome sequencing revealed 2 novel FECH mutations that had been inherited from his healthy parents. Pathogenicity analysis involving prediction using PolyPhen-2, SIFT, and Mutation Taster revealed that the 2 novel mutations were likely pathogenic. Although the patient’s parents were healthy, they each had one of these 2 mutations. This finding is consistent with previous reports stating that individuals carrying low-expression alleles can be asymptomatic. The pathogenesis of the disease caused by these 2 mutations requires verification by larger and more detailed studies. Conclusion:. Although the precise role of these mutations in EPP is not clear, the findings in the present case expand the genotypic spectrum of the disease.

Abstract With the continuous enhancement of human activities, the contradiction between regional development and ecological protection is prominent in the ecologically fragile arid areas. It is of great significance for regional sustainable development to understand the ecological supply and demand problems caused by transformation of land using and formulate ecological compensation scheme scientifically. This study takes Xinjiang in China as the research area. It explores the land use transition characteristics and the changes in carbon supply and demand of Xinjiang using methods such as GIS spatial analysis and modified comparative ecological radiation forcing. Finally, the ecological compensation scheme is studied based on the theory of ecological radiation. The research shows that (I) in the study chronology, most of the areas produced only one change in land use. Land use is gradually developing towards the direction of ecological protection. After 2000, grassland recovered well, and 14,298 km2 of other ecological land was transformed into grassland. (II) The change in the carbon sink of the Xinjiang ecosystem first decreased and then increased, and the ecological deficit area started to appear after 2010. The growth of grassland and cropland areas is essential to enhance the carbon sink capacity of arid zones. (III) The amount of ecological compensation in Xinjiang is 31.47 * 108 yuan, and the proportion of the amount received by ecological compensation areas is related to the distance between the supply and demand areas, the amount of carbon sequestration, and the area of the region. This study provides a reference for achieving the healthy development of sustainable land use ecosystems in arid zones.

Pitaya canker, caused by Neoscytalidium dimidiatum, is one of the most important fungal diseases that cause significant losses in production. To replace chemical pesticides, the use of biocontrol strains to manage plant diseases has been the focus of research. In this study, the bacterial strain AF01, identified as Paenibacillus polymyxa, exhibited significant antifungal effects against N. dimidiatum and four other pitaya fungal pathogens. The strain P. polymyxa AF01 produces 13 fusaricidins, which directly inhibit mycelial growth, spore germination and germ tube elongation by causing the membrane integrity and cell ultrastructure to incur irreversible damage. Pot experiment and yield test confirmed that AF01 provided preservative effects by reducing the disease index. In comparison to the untreated control groups, RNA-seq data showed that P. polymyxa AF01 selectively blocked some transcription and translation processes and inhibited RNA and DNA structural dynamics, energy production and conversion, and signal transduction, particularly cell wall biosynthesis, changes in membrane permeability, and impairment of protein biosynthesis. Thus, P. polymyxa AF01 could be potentially useful as a suitable biocontrol agent for pitaya canker.

Objective: Long non-coding RNAs (lncRNAs) feature prominently in tumors. Reportedly, lncRNA zinc finger E-box-binding homeobox 2 antisense RNA 1 (ZEB2-AS1) is aberrantly expressed in a variety of tumors. The present study was aimed to explore ZEB2-AS1 functions and determine mechanism in hepatocellular carcinoma(HCC) progression.Materials and Methods: In this experimental study, expressions of ZEB2-AS1, microRNA (miR)-582-5p and forkhead box C1 (FOXC1) mRNA in HCC tissues and cell lines were detected via quantitative reveres transcription polymerase chain reaction (qRT-PCR). After establishing gain- and loss-of-functions models, cell counting kit-8, 5-bromo-2’-deoxyuridine (BrdU), Transwell assays and flow cytometry analysis were conducted to examine HCC cell multiplication, migration, invasion and apoptosis, respectively. The targeted relationship between miR-582-5p and ZEB2-AS1 was verified via dual-luciferase reporter gene assay. Western blot was utilized for detecting FOXC1 expression in HCC cells after selectively regulating ZEB2-AS1 and miR-582-5p.Results: In HCC tissues and cells, ZEB2-AS1 expression was increased. High ZEB2-AS1 expression was related to relatively large tumor volume, increased tumor-node-metastasis (TNM) stage and positive lymph node metastasis of the patients. ZEB2-AS1 overexpression facilitated HCC cell multiplication, migration, invasion and suppressed apoptosis, while ZEB2-AS1 knock-down caused the opposite effects. It was also confirmed that ZEB2-AS1 could competitively bind with miR-582-5p to repress its expression, and indirectly up-regulate FOXC1 expression level in HCC cells.Conclusion: The current study revealed that ZEB2-AS1 was over-expressed in HCC tissues and cells. It also upregulated FOXC1, through sponging miR-582-5p, to promote HCC progression. This provides new perspectives for elucidating the pathogenesis of HCC.

Revealing the multidimensional value of cultivated land resources, improving calculation methods, and exploring their spatial distribution characteristics and influencing factors are crucial for the enhancement of natural resource accounting systems and the protection of cultivated land resources. This study takes Guangxi, China, as an example and constructs a comprehensive multidimensional value evaluation system for cultivated land resources at the county scale. The income capitalization method, substitution market method, and value equivalent correction method were applied to calculate the economic, social, and ecological values of cultivated land resources in 111 counties in 2020. Furthermore, spatial autocorrelation analysis was employed to study their distribution characteristics and influencing factors. The results show that: (1) In 2020, the total value of cultivated land resources in Guangxi was USD 2859.3 billion, with the economic, social, and ecological values were USD 1674.2 billion, USD 417.7 billion and USD 767.3 billion USD, respectively. (2) The economic and social value of cultivated land per hectare at the county scale in Guangxi demonstrates similar spatial distribution patterns. High-value counties exhibit a strip-like distribution along the eastern edge, following a north–south orientation, while low-value counties form clusters in the central and western regions. (3) There is a significant spatial clustering effect of all values of cultivated land resources in local space, with “high-high” and “low-low” clustering. (4) The level of economic development in counties has a negative impact on the ecological value of cultivated land resources, while it has a positive impact on their social value. (5) Natural conditions, agricultural infrastructure conditions and agricultural development approaches are the key factors affecting the value of cultivated land resources.

ObjectiveThis study aimed to investigate the correlation between serum laminin (LN) levels and clinical stages of heart failure in patients with chronic heart failure.MethodsA total of 277 patients with chronic heart failure were selected from September 2019 to June 2020 in the Department of Cardiology, Second Affiliated Hospital of Nantong University. Based on stages of heart failure, the patients were divided into four groups: stage A, stage B, stage C, and stage D, with 55, 54, 77, and 91 cases, respectively. At the same time, 70 healthy people in this period were selected as the control group. Baseline data were recorded and serum Laminin (LN) levels were measured. The research compared, the differences in baseline data among the four groups of HF and normal controls, and analyzed the correlation between N-terminal pro-brain natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of LN in the C-D stage of heart failure. Logistic multivariate ordered analysis was applied to screen the independent related factors of clinical stages of heart failure.ResultsSerum LN levels in patients with chronic heart failure were significantly higher than those in healthy people, which were 33.2 (21.38, 101.9) ng/ml and 20.45 (15.53, 23.04) ng/ml, respectively. With the progression of clinical stages of HF, serum LN and NT-proBNP levels increased, while LVEF gradually decreased (P

Oxidative defense or arsenic(As) changes exhibited by Trametes versicolor in response to toxicity under As stress remain unclear. In this study, after internal transcribed spacer identification, a wild T. versicolor HN01 strain was cultivated under 40 and 80 mg/L of As III stress. The antioxidant contents by multifunctional microplate reader and the speciations of As by high performance liquid chromatography in conjunction with inductively coupled plasma mass spectrometry were examined to explore the detoxification mechanisms. The results demonstrated this strain could tolerate As concentration of 80 mg/L with a bio-enrichment coefficients of 11.25. Among the four antioxidants, the activities of catalase, superoxide dismutase, and glutathione in the As-stress group at 80 mg/L improved by 1.10, 1.09, and 20.47 times that of non-stress group, respectively. The speciation results indicated that AsV was the dominant species in the hyphae of T. versicolor regardless of no-stress or As-stress. The detoxification mechanisms of this strain were involved alleviating the toxicity by increasing the activities of antioxidants, especially glutathione, as well as by converting As III into As V and other less toxic As species. T. versicolor could be used as a bio-accumulator to deal with As exposure in contaminated environments based on its extraordinary As tolerance and accumulation capacities.

BackgroundGasdermin (GSDM) B is a member of the GSDM family, which is a protein that may be involved in the cell pyroptosis process and is associated with inflammatory diseases.ObjectiveTo explore the correlation between GSDMB and psoriasis vulgaris.MethodsSkin lesions from 33 patients with psoriasis vulgaris and 69 normal controls were collected. ELISA and Western blot were adopted to detect proteins. The HaCaT cell line was transfected with 3 sets of interfering sequence siRNA, and the mRNA and protein levels before and after the transfection were measured by qPCR and Western blot respectively, so as to establish a cell model with low GSDMB gene expression; the MTT method was used to detect cells viability, flow cytometry to detect cell apoptosis.ResultsThe level of GSDMB protein in the skin lesions of patients with psoriasis vulgaris was lower than that in normal skin tissues (P < 0.05). The mRNA and protein expression levels of the target gene in the siRNA-GSDMB-3 group were lower than those in the control group (P < 0.05). The proliferation of HaCaT cells was decreased by MTT method and flow cytometry, and the apoptosis rate was increased (P < 0.05).ConclusionThe expression level of GSDMB in psoriasis vulgaris lesion tissue is lower than that of normal skin tissue. The down-regulation of GSDMB expression can inhibit cell proliferation and promote cell apoptosis. GSDMB may play a role in the pathogenesis of psoriasis by affecting the differentiation of keratinocytes and the function of T cells.

Ecological protection is the basis for sustainable development of inland river basins in arid areas with fragile ecological environments. The aim of our study is to diagnose the ecological problems and build the ecological security pattern (ESP) of the Aksu River basin (ARB) in Xinjiang which is located in northwest of China. The spatial measurement of ecosystem service value (ESV) was employed to identified ecological problems. Using cold/hot spot detection analysis and the minimum cumulative resistance (MCR) model, the ESP at three security levels were constructed. The results showed that the ESV of ARB showed an upwards trend from 1990 to 2018, the function of water conservation, waste treatment and soil formation and retention grew fastest. The ESV of ARB in 2018 ranged from 5390 yuan/hm2 to 131,080 yuan/hm2. The high-value areas were mainly located in the oasis and the northern mountainous, the low-value areas were widely distributed in desert. The ecological source areas of high, medium and low safety levels were 1806.30 km2, 3416.80 km2 and 4804.32 km2, respectively. Three kinds of ecological protection engineering models were proposed for the four types of ecological protection zones based on the ecological problem identification in ARB. To provide a decision-making basis for ecological environmental management and regional sustainable development in the ARB, the optimization patterns of points (ecological protection projects), lines (ecological corridors) and polygons (ecological source areas) were constructed. The results of this study can also serve as a reference for ecological environmental protection in other arid inland river basins.

The study aims to determine the role of personal factors, consumer social responsibility, and social marketing among meat anti-consumers. The study tests a model of anti-consumption using a sample of 597 (n = 597) participants from a cluster of young consumers through the distribution of the questionnaires in the Pakistani market. SEM employing the AMOS model for path relationships along with the Johnson-Neyman technique for moderation was mainly used. Results prescribe religiosity as the moderating driver of the anti-consumption of meat among young consumers in Pakistan. Consumer social responsibility is a robust antecedent, while social marketing is significantly documented for sustainability motives. Consumers apprise the personal health and environmental domain as an auspicious component for meat anti-consumption. The study reveals social marketing motivations for anti-consumption that eventually steers marketers and policymakers in shaping the concerned strategies. Our study delivers new insights into food anti-consumption behavior that provides guidelines for policymakers who heed consumer eating behaviors. The study is among pioneer work that establishes the moderating role of religious motivations and meat anti-consumption behavior among Muslim consumers to acquire healthy wellbeing.

This article contributes to the limited empirical literature on the impact of decentralization on psychological wellbeing by investigating the hypothesis which signifies that shifts toward more fiscal decentralization in health services would be accompanied by improvements in health outcomes. Formulating a conventional public finance model applied to health care, this hypothesis is tested on a panel data of the Pakistan's provinces during the period 1990 to 2015. The empirical underpinning of the article suggested that the economic reforms of 2001 in Pakistan's healthcare sector, through fiscal decentralization, have imposed a substantial and positive influence on the effectiveness of the public policy in improving the healthcare outcomes over the examined period.

The continuous cropping of cabbage or kidney bean results in a decrease in yield by influencing the soil environment. To decrease the damage caused by continuous cropping, ten treatments of cabbage–maize–cabbage (CMC), kidney bean–maize–cabbage (BMC), cabbage–cabbage–cabbage (CCC), cabbage–maize–kidney bean (CMB), kidney bean–maize–kidney bean (BMB), kidney bean–kidney bean–kidney bean (BBB), cabbage–cabbage–maize (CCM), cabbage–kidney bean–maize (CBM), kidney bean–kidney bean–maize (BBM) and kidney bean–cabbage–maize (BCM) rotation combinations were set up. The changes in soil nutrients, fungal community structure, composition and diversity in topsoil under the ten crop rotation combinations were analyzed using Illumina NovaSeq high-throughput sequencing technology and chemical technology. Fungal species were abundant in the ten treatments. The OTUs (operational taxonomic units) showed no significant differences. The richness index values of each treatment had significant differences. The diversity index value of the CCC treatment was significantly lower than those of the other treatments. The dominant soil fungal phylum was Ascomycota, and the subordinate soil fungal phylum was Basidiomycota. No significant differences were observed in Ascomycota between the treatments. Basidiomycota in the BBM treatment was significantly higher than that in the CCM treatment. Kickxellomycota was not found in the CCM and CCC treatments. The BBM treatment had no Entorrhizomycota. The dominant soil fungal class belonged to Ascomycota. The common distinction between continuous cropping and crop rotation was Diaporthales, which might be the main fungal order causing continuous cropping disorders. As the best choice, the BBM treatment could prevent soil-borne fungal diseases and provide the basis for the rational crop rotation of cabbage, kidney bean, and maize.

Although picornaviruses are conventionally considered 'nonenveloped', members of multiple picornaviral genera are released nonlytically from infected cells in extracellular vesicles. The mechanisms underlying this process are poorly understood. Here, we describe interactions of the hepatitis A virus (HAV) capsid with components of host endosomal sorting complexes required for transport (ESCRT) that play an essential role in release. We show release of quasi-enveloped virus (eHAV) in exosome-like vesicles requires a conserved export signal located within the 8 kDa C-terminal VP1 pX extension that functions in a manner analogous to late domains of canonical enveloped viruses. Fusing pX to a self-assembling engineered protein nanocage (EPN-pX) resulted in its ESCRT-dependent release in extracellular vesicles. Mutational analysis identified a 24 amino acid peptide sequence located within the center of pX that was both necessary and sufficient for nanocage release. Deleting a YxxL motif within this sequence ablated eHAV release, resulting in virus accumulating intracellularly. The pX export signal is conserved in non-human hepatoviruses from a wide range of mammalian species, and functional in pX sequences from bat hepatoviruses when fused to the nanocage protein, suggesting these viruses are released as quasi-enveloped virions. Quantitative proteomics identified multiple ESCRT-related proteins associating with EPN-pX, including ALG2-interacting protein X (ALIX), and its paralog, tyrosine-protein phosphatase non-receptor type 23 (HD-PTP), a second Bro1 domain protein linked to sorting of ubiquitylated cargo into multivesicular endosomes. RNAi-mediated depletion of either Bro1 domain protein impeded eHAV release. Super-resolution fluorescence microscopy demonstrated colocalization of viral capsids with endogenous ALIX and HD-PTP. Co-immunoprecipitation assays using biotin-tagged peptides and recombinant proteins revealed pX interacts directly through the export signal with N-terminal Bro1 domains of both HD-PTP and ALIX. Our study identifies an exceptionally potent viral export signal mediating extracellular release of virus-sized protein assemblies and shows release requires non-redundant activities of both HD-PTP and ALIX.

AimSystemic inflammation plays an important role in the occurrence and development of acute heart failure. The modified Glasgow Prognostic Score (mGPS) and “lymphocyte C-reactive protein score” (LCS) are used to assess the inflammation levels in cancer patients. The purpose of this study was to assess the prognostic value of these two inflammation-related scoring systems in patients with acute heart failure.MethodsTwo hundred and fifty patients with acute heart failure were enrolled in this study. The mGPS and LCS scores were recorded after admission. All patients were divided into 2 groups: the death group and the survival group according to the 3-month follow-up results. The predictive values of mGPS and LCS were assessed using receiver-operating characteristic (ROC) analyses. Univariate and multivariate logistic analyses were used to evaluate the relationships between variables and endpoint.ResultsThe levels of mGPS and LCS in the death group were significantly higher than those in the survival group (P < 0.05). The areas under the ROC curve of the mGPS and LCS for predicting death were 0.695 (95%CI: 0.567~0.823) and 0.736 (95%CI: 0.616~0.856), respectively. Multivariate analysis demonstrated that both LCS, LVEF and serum direct bilirubin were independent predictors of all-cause death, excluding mGPS.ConclusionsCompared with mGPS, LCS is independently associated with short-term outcomes in patients with acute heart failure. LCS was a clinically promising and feasible prognostic scoring system for patients with acute heart failure.

BackgroundAcute myocardial infarction (AMI) is a critical cardiovascular disease (CVD). Laminin (LN) is involved in the process of myocardial fibrosis and ventricular remodeling observed in AMI; however, there are currently no studies on the correlation between LN and AMI prognosis.PurposeTo explore the predictive value of serum LN levels for major adverse cardiovascular events (MACE) in patients, 6 months after an acute myocardial infarction.MethodsA total of 202 AMI patients who were hospitalized in the Department of Cardiology of the Second Affiliated Hospital of Nantong University between December 2019 and December 2020 were included. The observation endpoint was the occurrence of MACE. Univariate and multivariate logistic analyses were used to evaluate the relationships between the variables and endpoint. The predictive value of LN for MACE in AMI patients was assessed using receiver operating characteristic (ROC) analysis.ResultsA total of 47 patients developed MACE. Univariate logistic analysis showed that smoking, emergency percutaneous coronary intervention (EPCI), age, cardiac troponin I (c-TNI) levels, N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels, and LN levels were associated with the occurrence of MACE (p < 0.05). Multivariate logistic analysis showed that LN was an independent predictor of MACE (odds ratio [OR] = 1.021, 95%CI: 1.014–1.032, p < 0.001). According to the ROC curve, LN can be used as an effective predictor of MACE (AUC = 0.856, 95%CI: 0.794–0.918, p < 0.001). According to the cutoff value, LN>58.80 ng/ml (sensitivity = 83.00%, specificity = 76.80%) or LN>74.15 ng/ml (sensitivity = 76.6%, specificity = 83.2%) indicate a poor prognosis for AMI. Different cut-off values are selected according to the need for higher sensitivity or specificity in clinical applications.ConclusionsLN may be a predictor of MACE following AMI in patients and could be utilized as a novel substitute marker for the prevention and treatment of AMI.

Abstract At present, prognostic biomarkers of acute coronary syndrome (ACS) are fewer. The aim of this study was to explore the predictive value of soluble osteoclast-associated receptor (sOSCAR) level for the major adverse cardiovascular events (MACE) occurring within 30 days after ACS. From January to August 2020, a total of 108 patients with ACS who were admitted to our hospital, were enrolled in this study. Of the 108 patients, 79 were men and 29 women. Patient-related data, including age, sex, body mass index, history of type 2 diabetes, history of hyperlipidemia and serum sOSCAR level, were collected. All patients were followed up for 30 days. Based on MACE occurrence, the 108 patients were divided into MACE group (n = 17) and non-MACE group (n = 91). The baseline data were compared between the two groups, MACE-independent risk factors were identified by multivariate regression analysis, and the predictive value of sOSCAR for MACE occurring within 30 days after CAS was analyzed using receiver operating characteristic (ROC) curve. At the same time, according to the type of ACS, the 108 patients with ACS were divided into unstable angina (UA) group (n = 29), non ST-segment elevation myocardial infarction (USTEMI) group (n = 45) and ST-segment elevation myocardial infarction (STEMI) group (n = 34), and then the sOSCAR level and MACE incidence were observed in each group. The serum sOSCAR level was significantly lower in the MACE group [130(100,183)] than in the non-MACE group [301(220,370)] (P = 0.000). The area under ROC curve of sOSCAR level for MACE occurring within 30 days after CAS was 0.860 with 95%CI 0.782–0.919, P

The long-term extensive application of chemical fertilizers wreaks havoc on soil bacterial structure and function. To reduce the damage caused by chemical fertilizers, a six-year experiment was performed to study the effects of replacing 0% (CK), 25% (S25), 50% (S50), 75% (S75), and 100% (S100) of 225 kg ha−1 mineral nitrogen fertilizer with an equivalent amount of nitrogen from maize straw on the soil bacterial community structure, diversity, and function. The results showed that Proteobacteria, Acidobacteria, and Gemmatimonadetes were the dominant soil bacterial phyla after the replacement treatments. Replacing mineral nitrogen fertilizer with an equivalent amount of nitrogen from maize straw significantly reduced the number of Photobacterium and bacterial populations involved in genetic information processing in soil, but significantly increased the number of bacterial populations involved in organismal systems, human diseases, and environmental information processing. Compared with other treatments, the relative abundance of TK10 significantly increased by 33.52–76.36% in S25. The number of subgroup 6, Gram-negative, biofilm-forming, potentially pathogenic, and anaerobic bacteria significantly increased, whereas that of Chloroflexi and Blastocatellia subgroup 4 significantly decreased in S50 and S75 compared with CK. The number of TK10 and Blastocatellia subgroup 4 in S50 and S100, respectively, was significantly lower than that in CK. Bacterial species were significantly more present in S25 than in S75. The diversity of bacterial species in S75 was significantly lower than that in CK. S25 and S100 were more favorable to increasing the number of Gram-positive, aerobic, mobile-element containing, and stress-tolerant bacteria. Rhodobacteraceae, Pyrinomonadaceae, Xanthobacteraceae, Nocardioidaceae, and Vulgatibacteraceae with statistical differences in CK, S25, S50, S75, and S100, respectively, could be used as biomarkers. Chloroflexi, Acidobacteria, and Nitrospirae could be used as the main basis for the bacterial classification of soil samples in the equivalent substitution of nitrogen chemical fertilizer with maize straw. S25 is ideal for increasing soil bacterial species richness and abundance.

Abstract Prolonged type 2 diabetes mellitus (T2DM) produces a common complication, peripheral neuropathy, which is accompanied by nerve fiber disorder, axon atrophy, and demyelination. Growing evidence has characterized the beneficial effects of acidic fibroblast growth factor (aFGF) and shown that it relieves hyperglycemia, increases insulin sensitivity, and ameliorates neuropathic impairment. However, there is scarce evidence on the role of aFGF on remodeling of aberrant myelin under hyperglycemia condition. Presently, we observed that the expression of aFGF was rapidly decreased in a db/db T2DM mouse model. Administration of exogenous aFGF was sufficient to block acute demyelination and nerve fiber disorganization. Furthermore, this strong anti-demyelinating effect was most likely dominated by an aFGF-mediated increase of Schwann cell (SC) proliferation and migration as well as suppression of its apoptosis. Mechanistically, the beneficial biological effects of aFGF on SC behavior and abnormal myelin morphology were likely due to the inhibition of hyperglycemia-induced oxidative stress activation, which was most likely activated by kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-like 2 (Nrf2) signaling. Thus, this evidence indicates that aFGF is a promising protective agent for relieving myelin pathology through countering oxidative stress signaling cascades under diabetic conditions.

The ecosystem of inland river basin is of great significance to the socio-economic stability in arid area. Therefore, to evaluate the ecosystem service values (ESVs) is necessary for monitor ecosystem changes. In this paper, the response of land use/land cover (LULC) during 1990 to 2020 in Aksu River Basin (ARB) to ESV was explored. The advanced equivalent factor which modified by biomass factor and socio-economic was used to evaluate the ESVs of the ARB. A patch-generating land use simulation (PLUS) was used to simulate the ESV spatial distribution considering the influences of temperature (TEM), precipitation (PRE), NDVI, DEM, Soil organic matter content (SOMC) and Human Activity Intensity of Land Surface (HAILS) of the ARB in 2030. The results show that the total ESV in the study area showed an increasing trend (1.63 × 1010 yuan to 5.64 × 1010 yuan) from 1990 to 2020. The grassland had the highest ESV, accounting for nearly 50% of the total ESV for the ARB. The factor detection results showed that q value had the following explanatory power to ESV: HAILS (0.332) > NDVI (0.126) > TEM (0.125) > PRE (0.108) > DEM(0.096) > SOMC(0.089)and the interaction between HAILS and PRE had an effect of 0.493 on ESV. The shape index (SI) was negatively correlated with the ESV, and the correlation coefficient was −0.794. The aggregation index (AI) and Shannon's Diversity Index (SHDI) were positively correlated with the ESV, and the correlation coefficients were 0.872 and 0.878, respectively. The simulation results showed a rapid increase in ESVs in 2030, the ESV of grassland would still be the largest, and the per unit ESV of plowland, forestland, unused land and water area would be 20131.07 yuan/km2, 64743.29 yuan/km2, 3054.21 yuan/km2, 41398.54 yuan/km2, respectively. This paper can help decision-makers achieve sustainable ecosystem service management and develop land-use strategies in inland river basins in arid oases.

ABSTRACT: Background: Many cases of Class II deformities have been reported to be treated with prefabricated appliances. The aim of this study was to distinguish the clinical effect of traditional custom-made appliances and prefabricated appliances in the treatment of Class II division 1 malocclusion. Therefore, soft and hard tissue changes following treatment of Class II division 1 malocclusion using the twin-block (TB) appliance was compared to that using the Myofunctional Research Company (MRC) appliance (K1 + K2) combined with oral myofunctional treatment (OMT) (MRC + OMT). Methods: The study included 22 children (6 boys and 16 girls aged 9–11 years) with Class II division 1 malocclusion along with mandibular retrognathism with a 5–12 mm overjet, basic normal maxillary status, and stage 2 or 3 cervical vertebral maturation (CVM). Participants were randomly assigned into two groups, the TB group and the MRC + OMT group for 12 months. Standardized lateral cephalograms were used to assess skeletal, dental, and soft tissue changes from pre- to post-treatment. Independent t-tests were used to compare the initial and final cephalometric status and tissue changes between the groups. Results: The TB and MRC + OMT groups resulted in different degrees of lateral changes; however, improvements of skeletal and soft tissue indices were significantly greater in the TB group than in the MRC + OMT group. Conclusion: TB was more effective than MRC + OMT in treating children aged 9–11 years with Class II division 1 malocclusion. However, further research using custom-made appliances with OMT is recommended, and further investigations are needed to confirm these findings.

Abstract Background Brassica napus is one of the most important oilseed crops, and also an important biofuel plant due to its low air pollution and renewability. Growth period are important traits that affect yield and are crucial for its adaptation to different environments in B. napus. Results To elucidate the genetic basis of growth period traits, genome-wide association analysis (GWAS) and linkage mapping were employed to detect the quantitative trait loci (QTL) for days to initial flowering (DIF), days to final flowering (DFF), flowering period (FP), maturity time (MT), and whole growth period (GP). A total of 146 SNPs were identified by association mapping, and 83 QTLs were identified by linkage mapping using the RIL population. Among these QTLs, 19 were pleiotropic SNPs related to multiple traits, and six (q18DFF.A03-2, q18MT.A03-2, q17DFF.A05-1, q18FP.C04, q17DIF.C05 and q17GP.C09) were consistently detected using both mapping methods. Additionally, we performed RNA sequencing to analyze the differential expression of gene (DEG) transcripts between early- and late-flowering lines selected from the RIL population, and the DEGs were integrated with association mapping and linkage analysis to confirm their roles in the growth period. Consequently, 12 candidate genes associated with growth period traits were identified in B. napus. Among these genes, seven have polymorphic sites in the coding sequence and the upstream 2-kb sequence based on the resequencing data. The haplotype BnaSOC1.A05-Haplb and BnaLNK2.C06-Hapla showed more favorable phenotypic traits. Conclusions The candidate genes identified in this study will contribute to our genetic understanding of growth period traits and can be used as targets for target mutations or marker-assisted breeding for rapeseed adapted to different environments.

Promoting blood–spinal cord barrier (BSCB) repair at the early stage plays a crucial role in treatment of spinal cord injury (SCI). Excessive activation of autophagy can prevent recovery of BSCB after SCI. Basic fibroblast growth factor (bFGF) has been shown to promote BSCB repair and locomotor function recovery in SCI. However, the therapeutic effect of bFGF via direct administration on SCI is limited because of its rapid degradation and dilution at injury site. Based on these considerations, controlled release of bFGF in the lesion area is becoming an attractive strategy for SCI repair. At present, we have designed a sustained-release system of bFGF (called ALG-bFGF) using sodium alginate hydrogel, which is able to load large amounts of bFGF and suitable for in situ administration of bFGF in vivo. Here, traumatic SCI mice models and oxygen glucose deprivation (OGD)–stimulated human brain microvascular endothelial cells were performed to explore the effects and the underlying mechanisms of ALG-bFGF in promoting SCI repair. After a single in situ injection of ALG-bFGF hydrogel into the injured spinal cord, sustained release of bFGF from ALG hydrogel distinctly prevented BSCB destruction and improved motor functional recovery in mice after SCI, which showed better therapeutic effect than those in mice treated with bFGF solution or ALG. Evidences have demonstrated that autophagy is involved in maintaining BSCB integrity and functional restoration in animals after SCI. In this study, SCI/OGD exposure–induced significant upregulations of autophagy activation-related proteins (Beclin1, ATG5, LC3II/I) were distinctly decreased by ALG-bFGF hydrogel near the baseline and not less than it both in vivo and in vitro, and this inhibitory effect contributed to prevent BSCB destruction. Finally, PI3K inhibitor LY294002 and KLF4 inhibitor NSC-664704 were applied to further explore the underlying mechanism by which ALG-bFGF attenuated autophagy activation to alleviate BSCB destruction after SCI. The results further indicated that ALG-bFGF hydrogel maintaining BSCB integrity by inhibiting autophagy activation was regulated by PI3K/Akt/FOXO1/KLF4 pathway. In summary, our current study revealed a novel mechanism by which ALG-bFGF hydrogel improves BSCB and motor function recovery after SCI, providing an effective therapeutic strategy for SCI repair.

Rural settlements in oasis are primary habitations, and their changes are related to natural environment and anthropogenic activities. The spatiotemporal variations of rural settlements in an oasis are significant in arid regions. In this study, Qipan Township (QPT) and Yamansu Township (YMST) were chosen as a case study and validation case, respectively. Datasets, including Landsat images in 2002, 2010, and 2018, were collected. The cellular automata (CA)-agent-based model (ABM) and patch-generating land use simulation (PLUS) model were used to simulate the spatiotemporal dynamic variations of rural settlement and other land use types in the oasis in this study. Natural environmental, socioeconomic conditions, and human decision-making are the three driving factors that were used in the model. Human decision-making involves the actions of two types of agents: authority agent and resident agent. On the basis of land use data of 2002 and 2010, the rural settlement and other land use in 2018 were predicted using the CA-MAS and PLUS models. The following results were obtained: First, human decision-making behaviors were the leading factor in the changes of rural settlements in the CA-ABM model. Second, CA based on multiple random seed (CARS) of PLUS could better simulate the spatiotemporal variations of QPT rural settlements than CA-ABM and linear regression of PLUS. Similarly, CARS of PLUS also simulated the spatiotemporal evolution of rural settlements in YMST with high accuracy. Third, the areas of croplands, roads, and residential lands in QPT will expand to 20.7, 5.7, and 4.6 km2, respectively, in 2026, but the unused land will shrink, as predicted by CARS of PLUS. This study provides a scientific basis for the environmental protection of rural settlements in the oasis and sustainable settlement planning in arid regions.

BackgroundBreast cancer is one of the most common cancers and the leading cause of death from cancer among women worldwide. The genetic predisposition to breast cancer may be associated with a mutation in particular genes such as gene BRCA1/2. Patients who carry a germline pathogenic mutation in BRCA1/2 genes have a significantly increased risk of developing breast cancer and might benefit from targeted therapy. However, genetic testing is time consuming and costly. This study aims to predict the risk of gBRCA mutation by using the whole-slide pathology features of breast cancer H&E stains and the patients’ gBRCA mutation status.MethodsIn this study, we trained a deep convolutional neural network (CNN) of ResNet on whole-slide images (WSIs) to predict the gBRCA mutation in breast cancer. Since the dimensions are too large for slide-based training, we divided WSI into smaller tiles with the original resolution. The tile-based classification was then combined by adding the positive classification result to generate the combined slide-based accuracy. Models were trained based on the annotated tumor location and gBRCA mutation status labeled by a designated breast cancer pathologist. Four models were trained on tiles cropped at 5×, 10×, 20×, and 40× magnification, assuming that low magnification and high magnification may provide different levels of information for classification.ResultsA trained model was validated through an external dataset that contains 17 mutants and 47 wilds. In the external validation dataset, AUCs (95% CI) of DL models that used 40×, 20×, 10×, and 5× magnification tiles among all cases were 0.766 (0.763–0.769), 0.763 (0.758–0.769), 0.750 (0.738–0.761), and 0.551 (0.526–0.575), respectively, while the corresponding magnification slides among all cases were 0.774 (0.642–0.905), 0.804 (0.676–0.931), 0.828 (0.691–0.966), and 0.635 (0.471–0.798), respectively. The study also identified the influence of histological grade to the accuracy of the prediction.ConclusionIn this paper, the combination of pathology and molecular omics was used to establish the gBRCA mutation risk prediction model, revealing the correlation between the whole-slide histopathological images and gRCA mutation risk. The results indicated that the prediction accuracy is likely to improve as the training data expand. The findings demonstrated that deep CNNs could be used to assist pathologists in the detection of gene mutation in breast cancer.

The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from Ldlr–/– rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.

The hydroxylase EgIN2 contributes to triple negative breast cancers. Here, using an enzyme-substrate trapping strategy, the authors identify ASDL as a bona fide substrate of EgIN2 promoting aggressive properties of TNBC via the activation of cMYC signaling.

The microphthalmia (MiT) subfamily of transcription factors includes TFE3, TFEB, TFEC, and MITF. In the 2016 World Health Organization classification, MiT family translocation renal cell carcinoma (tRCC) including Xp11 tRCC and t(6;11) RCC, was newly defined as an RCC subtype. Xp11 and t(6;11) RCC are characterized by the rearrangement of the MiT transcription factors TFE3 and TFEB, respectively. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with TFEB amplification, melanotic MiT family translocation neoplasms, was identified may as a unique subtype of MiT family associated renal neoplasms, along with MITF associated RCC. In this review, we will collect available literature of these newly-described RCCs, analyze their clinicopathological and immunohistochemical features, and summarize their molecular and genetic evidences. We expect this review would be beneficial for the understanding of these rare subtypes of RCCs, and eventually promote clinical management strategies. Keywords: Microphthalmia, TFE3, TFEB, MITF, Kidney, Renal cell carcinoma, Translocation

Summary: Proliferative and invasive breast tumors evolve heterogeneously in individual patients, posing significant challenges in identifying new druggable targets for precision, effective therapy. Here we present a functional multi-omics method, interaction-Correlated Multi-omic Aberration Patterning (iC-MAP), which dissects intra-tumor heterogeneity and identifies in situ the oncogenic consequences of multi-omics aberrations that drive proliferative and invasive tumors. First, we perform chromatin activity-based chemoproteomics (ChaC) experiments on breast cancer (BC) patient tissues to identify genetic/transcriptomic alterations that manifest as oncogenically active proteins. ChaC employs a biotinylated small molecule probe that specifically binds to the oncogenically active histone methyltransferase G9a, enabling sorting/enrichment of a G9a-interacting protein complex that represents the predominant BC subtype in a tissue. Second, using patient transcriptomic/genomic data, we retrospectively identified some G9a interactor-encoding genes that showed individualized iC-MAP. Our iC-MAP findings represent both new diagnostic/prognostic markers to identify patient subsets with incurable metastatic disease and targets to create individualized therapeutic strategies. : Biological Sciences; Cancer Systems Biology; Cancer Subject Areas: Biological Sciences, Cancer Systems Biology, Cancer

Three new species isolated from sugarcane rhizosphere in China, namely Conlarium baiseense sp. nov., C. nanningense sp. nov., and C. sacchari sp. nov., are described and illustrated. Molecular evidence (phylogenetic analysis of combined LSU, SSU, ITS and RPB2 sequence data) and phenotypical characters support their independent status from related and similar species. The new species, as dark spetate endophytes, inhabit sugarcane rhizosphere and can form a symbiosis with sugarcane.

Abstract Background Presently, a 50-gene expression model (PAM50) serves as a breast cancer (BC) subtype classifier that is insufficient to distinguish, within each single PAM50-classified subtype, patient subpopulations having different prognosis. There is a pressing need for inexpensive and minimally invasive biomarker tests to easily and accurately predict individuals’ clinical outcomes and response to treatments. Although quantitative proteomic approaches have been developed to identify/profile proteins secreted (secretome) from various cancer cell lines in vitro, missing are the clinicopathological relevance and the associated prognostic value of these secretomic identifications. Methods To discover biomarkers to predict individualized prognosis we introduce a new multi-omics (secreto-transcriptomics) method that identifies, in their oncogenically secreted states, candidate markers of BC subtypes whose genes bear patient-specific mRNA expression alterations of prognostic significance. First, we used label-free quantitative (LFQ) proteomics to identify the proteins showing BC-subtypic secretion from a series of BC cell lines representing major BC-subtypes. To determine and externally validate the prognostic value of these secreted proteins, we developed a secreto-transcriptomic approach that discovered a PAM50-subtypic Secretion-Correlated mRNA Expression Pattern (SeCEP) wherein the PAM50-subtypic secretion of select proteins statistically correlated with cis-mRNA expression of their encoding genes in patients of the corresponding PAM50-subtypes. Kaplan-Meier analysis of SeCEP genes was used to identify new liquid biopsy biomarkers for predicting individualized prognosis. Results The mRNA expression-to-secretion correlation (SeCEP) pinpointed multiple genes that are fully translated into the oncogenically active secretome in a PAM50-subtypic manner. Further, multiple SeCEP genes in distinct combinations or panels of multiple SeCEP genes were identified as ‘systems prognostic markers’ that showed mRNA co-overexpression patterns in the distinct subpopulations of PAM50-subtypic patients with poor prognosis or high-risk of relapse. Thus, our secreto-transcriptomic approach statistically linked BC subtypic secretome genes with patient-specific information about their mRNA expression alterations and significantly improved the sensitivity and specificity in patient stratification in the context of clinical outcomes or prognosis. Conclusions By combining LFQ secretome screening with proteo-transcriptomic retrospective analysis of patient data our integrated multi-omics approach bypasses costly, tedious, genome-wide fishing and predictive modeling that are commonly required to distinguish a few prognostically altered genes from thousands of other non-BC related genes in a genome.

Introduction: Lung cancer is the leading cause of cancer-related morbidity and mortality in the People’s Republic of China. Targeted therapies for patients with lung cancer, which depend on accurate identification of actionable genomic alteration, have improved survival compared with previously available treatments. However, data on the types of molecular testing often used in the People’s Republic of China, and how they have changed over time, are scarce. We explored the overall landscape of molecular testing of lung cancer in mainland People’s Republic of China in the past decade. Methods: We distributed a stratified random sampling survey of molecular testing to 49 hospitals from members of the Molecular Pathology Collaboration Group of Chinese Anti-Cancer Association which was weighted by the numbers of lung cancer cases in seven different geographic regions in mainland People’s Republic of China from 2010 to 2019. The questionnaire contained four parts for all respondents. The questionnaire ascertained the use of approved in vitro diagnostic (IVD) devices published by the Center for Medical Device Evaluation, National Medical Products Administration of the People’s Republic of China. Results: A total of 226,227 NSCLC specimens were tested from 2010 to 2019 in the selected hospitals. The annual number of initiated molecular tests increased over time (p < 0.0001), with an average annual growth rate of 31.8%. A notable increase in the number of molecular tests occurred during 2014 and 2016, which coincided with the approval of the National Medical Products Administration to IVD devices. For the diagnosis of molecular subtypes, EGFR mutation testing was first conducted in year 2007, followed by ALK translocation testing in 2010 and ROS1 in 2011. For other rare genetic variations in NSCLC, BRAF mutation testing was first launched in 2012, MET exon 14 skipping mutation in 2014, HER2 exon 20 mutations in 2017, and RET translocation in 2015. A markedly uneven distribution was also observed in the geography of leading units with the largest number of leading units located in east People’s Republic of China (34.7%, 17 of 49) and the smallest number located in northwest People’s Republic of China (6.1%, 3 of 49). The growth trends we observed illustrate the progress and increasing capability of molecular testing of lung cancer achieved in mainland People’s Republic of China in the decade from 2010. Conclusions: In the decade 2010 to 2019, progress and increased capability of molecular testing of lung cancer were achieved in mainland People’s Republic of China. Further efforts should address the clinical application of next-generation sequencing technology, rare genomic aberrations, and the balance between novel genomic testing techniques and the approval of IVD products.

Astragaloside II (AS II), a novel saponin purified from Astragalus membranes, has been reported to modulate the immune response, repair tissue injury, and prevent inflammatory response. However, the protective effects of AS II on podocyte injury in diabetic nephropathy (DN) have not been investigated yet. In this study, we aimed to investigate the beneficial effects of AS II on podocyte injury and mitochondrial dysfunction in DN. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection at 55 mg/kg in rats. Diabetic rats were randomly divided into four groups, namely, diabetic rats and diabetic rats treated with losartan (10 mg·kg−1·d−1) or AS II (3.2 and 6.4 mg·kg−1·d−1) for 9 weeks. Normal Sprague-Dawley rats were chosen as nondiabetic control group. Urinary albumin/creatinine ratio (ACR), biochemical parameters, renal histopathology and podocyte apoptosis, and morphological changes were evaluated. Expressions of mitochondrial dynamics-related and autophagy-related proteins, such as Mfn2, Fis1, P62, and LC3, as well as Nrf2, Keap1, PINK1, and Parkin, were examined by immunohistochemistry, western blot, and real-time PCR, respectively. Our results indicated that AS II ameliorated albuminuria, renal histopathology, and podocyte foot process effacement and podocyte apoptosis in diabetic rats. AS II also partially restored the renal expression of mitochondrial dynamics-related and autophagy-related proteins, including Mfn2, Fis1, P62, and LC3. AS II also increased the expression of PINK1 and Parkin associated with mitophagy in diabetic rats. Moreover, AS II facilitated antioxidative stress ability via increasing Nrf2 expression and decreasing Keap1 protein level. These results suggested that AS II ameliorated podocyte injury and mitochondrial dysfunction in diabetic rats partly through regulation of Nrf2 and PINK1 pathway. These important findings might provide an innovative therapeutic strategy for the treatment of DN.

BackgroundTo evaluate the value of pretreatment inflammatory-nutritional biomarkers in predicting responses to neoadjuvant chemoradiotherapy (nCRT) and survival in patients with locally advanced rectal cancer (LARC).MethodsPatients with LARC who underwent nCRT and subsequent surgery between October 2012 and December 2019 were considered for inclusion. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prognostic nutritional index (PNI) were calculated from according to routine laboratory data within 1 week prior to nCRT. The correlations between baseline inflammatory-nutritional biomarkers and responses were analyzed using Chi-square test or Fisher’s exact test, and multivariate logistic regression analysis was performed to identify the independent predictors of pathological responses to nCRT. Univariate and multivariate Cox proportional hazard models were used to assess the correlations of predictors with disease-free survival (DFS) and overall survival (OS).ResultsA total of 273 patients with LARC were enrolled in this study. Higher LMR and PNI were observed in the good-response group, meanwhile higher NLR and PLR were observed in the poor-response group. Multivariate logistic regression analysis results revealed that PLR and PNI independently predicted responses to nCRT. Multivariable Cox regression analysis determined that PNI was an independent predictor of DFS and OS in patients with LARC. The value of pretreatment PNI in predicting responses and survival was continuously superior to those of NLR, PLR, and LMR. The optimal cutoff value of the PNI was approximate 45. Subgroup analyses indicated that the pathological responses and survival in the high PNI group (≥ 45) were significantly better than those in the low PNI group (< 45), especially in patients with clinical stage III rectal cancer.ConclusionThe pretreatment PNI can serve as a promising predictor of response to nCRT and survival in patients with LACR, which is superior to NLR, PLR, and LMR, and the patients with clinical stage III rectal cancer who have a higher PNI are more likely to benefit from nCRT.

Summary: Inter- or intra-patient tumor heterogeneity hinders the discovery of biomarkers for predicting individualized prognosis. Here, we present a protocol for an alternative splicing activity-based proteogenomic approach for identification of candidate prognostic markers in cancer cell lines and human breast cancer specimens. The pull-down of protein complexes with intronic splicing enhancer (ISE) probes is followed by tandem mass spectrometry (MS/MS) peptide sequencing. The proteogenomic analysis of data from these ISE-MS/MS assays identifies new prognostic markers that can be utilized to stratify patients with poor prognosis.For complete details on the use and execution of this protocol, please refer to Wang et al. (2018).

The study aims to depict the temporal and spatial distributions of hand-foot-and-mouth disease (HFMD) in Xinjiang, China and reveal the relationships between the incidence of HFMD and meteorological factors in Xinjiang. With the national surveillance data of HFMD in Xinjiang and meteorological parameters in the study area from 2008 to 2016, in GeoDetector Model, we examined the effects of meteorological factors on the incidence of HFMD in Xinjiang, China, tested the spatial-temporal heterogeneity of HFMD risk, and explored the temporal-spatial patterns of HFMD through the spatial autocorrelation analysis. From 2008 to 2016, the HFMD distribution showed a distinct seasonal pattern and HFMD cases typically occurred from May to July and peaked in June in Xinjiang. Relative humidity, precipitation, barometric pressure and temperature had the more significant influences on the incidence of HFMD than other meteorological factors with the explanatory power of 0.30, 0.29, 0.29 and 0.21 (P

Streptococccus agalactiae (S. agalactiae) is an important neonatal pathogen that is associated with mortality and morbidity. Therefore, we developed a rapid, accurate, and sensitive method based on multiple cross displacement amplification (MCDA) for the detection of the target pathogen. Four sets of MCDA primers were designed for targeting the S. agalactiae-specific groEL gene, and one set of MCDA primers with the optimum amplification efficiency was screened for establishing the S. agalactiae-MCDA assay. As a result, the newly-developed assay could be conducted at a fixed temperature (61°C) for only 30 min, eliminating the use of complex instruments. A portable and user-friendly nanoparticle-based lateral flow biosensor (LFB) assay was employed for reporting MCDA results within 2 min. Our results suggested that the detection limit of the S. agalactiae-MCDA-LFB assay is 300 fg per reaction, and no cross-reaction occurred with non-S. agalactiae strains. For 260 vaginal and rectal swabs, the detection rate of the MCDA-LFB assay was 7.7%, which was in accordance with the reference method of enrichment/qPCR, and higher by 4.6% than the CHROMagar culture. Moreover, the total procedure time of the MCDA-LFB assay was around 50 min, including sample collection, template preparation, MCDA reaction, and result reporting. Therefore, the MCDA-LFB assay is superior to enrichment/qPCR and CHROMagar culture and has great promise for point-of-care testing of S. agalactiae from vaginal and rectal swabs of pregnant women in resource-limited settings.