Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus.

During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation. Trim38 also sumoylated Sting during the early phase of viral infection, promoting both Sting activation and protein stability. In the late phase of infection, cGas and Sting were desumoylated by Senp2 and subsequently degraded via proteasomal and chaperone-mediated autophagy pathways, respectively. Our findings reveal an essential role for Trim38 in the innate immune response to DNA virus and provide insight into the mechanisms that ensure optimal activation and deactivation of the cGAS-STING pathway.

Changing spectrum and mortality disparities of etiology of liver cirrhosis in Beijing, China.

Liver cirrhosis remains a major health concern globally, but its epidemiology and etiology evolve with time. However, the changing pattern in etiology and cause of liver-related mortality for patients with cirrhosis are not fully elucidated. Herein, our aim was to characterize the temporal trend of the etiological spectrum and evaluate the impact of etiology on liver-related death among patients with compensated cirrhosis (CC) in Beijing, China. Clinical profiles of patients with CC discharged between January 2008 and December 2015 were retrieved from the Beijing hospital discharge database. The mortalities of different etiologies of cirrhosis were calculated. The risks of readmission and liver-related death associated with etiologies were evaluated by the Cox regression model. A total of 23 978 cirrhotic patients were included. The predominant cause was hepatitis B virus (HBV) (58.93%), followed by alcohol (21.35%), autoimmune (14.85%), miscellaneous etiologies (3.55%), and hepatitis C virus (HCV) (1.32%). From 2008 to 2015, the proportion of HBV-related cirrhosis decreased to 28.11%. Meanwhile, the proportions of autoimmune- and miscellaneous-related cirrhosis increased to 28.54% and 13.11%. The risk of liver-related death ranked the highest in patients with miscellaneous cirrhosis, followed by HBV-related cirrhosis, alcohol-related cirrhosis, autoimmune-related cirrhosis, and HCV-related cirrhosis. The 5-year rates of liver-related death were 22.56%, 18.99%, 18.77%, 16.01%, and 10.76%, respectively. HBV-related cirrhosis caused the highest risk of hepatocellular carcinoma (HCC)-related death, whereas alcohol- and miscellaneous-related cirrhosis caused higher risks of decompensation (DC)-related death than HBV-related cirrhosis, with hazard ratios of 1.35 (95% confidence interval [CI]: 1.24-1.48) and 1.20 (95% CI: 1.03-1.40), respectively. HBV remained a common cause of liver cirrhosis but gradually decreased. Mortality disparities existed in etiologies, with higher risks of HCC-related death in HBV-related cirrhosis, and DC-related death in alcohol- and miscellaneous-related cirrhosis.

YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

Trends in health service needs, utilization, and non-communicable chronic diseases burden of older adults in China: evidence from the 1993 to 2018 National Health Service Survey.

BACKGROUND: Aging is associated with an increased prevalence of non-communicable chronic diseases (NCDs), functional impairments, and diverse demands for health services. This study analyzed the trends in older adults' needs and utilization of health services from 1993 to 2018 in China, as well as chronic disease-related economic burdens. METHODS: The research data were collected from the six cross-sectional National Health Service Survey (NHSS), implemented every 5 years from 1993 to 2018. A multi-stage stratified random cluster sampling method has been adopted in the NHSS. The data on the older population's socio-economic characteristics, health service needs, and utilization were collected from the 6 waves National Health Service Survey (NHSS) 1993-2018. In the 2013 and 2018 NHSSs, EQ-5D-3L and visual analogue scale were used to evaluate the health condition. And the prevalence of NCDs and related Out-of-pocket (OOP) expenditures were collected. Functional dependency and impairment were collected in 2018. The Katz Activities of Daily Living scale was used to evaluate six functions, including self-feeding, dressing, bathing, transferring, toilet hygiene, and controlling bowel movements. RESULTS: The two-week morbidity rate and prevalence of NCDs showed a rapid upward trend in older adults. With the development of health system reform and universal health insurance coverage, older adults' two-week medical consultation rate increased from 25.6% in 1993 to 40.1% in 2018, and the hospitalization rate rose from 6.1% to 24.9%. The difference in health service needs and utilization between urban and rural areas decreased, and the hospitalization rate in rural areas (26.3%) exceeded that in urban areas (23.6%) for the first time in 2018. Functional independence become more severe as aged. The proportion of severe functional impairment was 6.9% and 2% in the group aged 80 or over and group 70-79 years, respectively. Regarding disability status, 32.5% had hearing problems and 31.4% had visual impairment. The highest prevalence rates of NCDs in older adults were found in hypertension (36.9%), followed by diabetes (10.6%), cerebrovascular disease (5.4%), ischemic heart disease (4.5%), and intervertebral disc disease (4.2%). The average annual OOP expenditures attributed to NCDs increased from ¥2481.8 RMB in 2013 to ¥8255.9 RMB in 2018 for older adults. About 90.7% of older adults prefer to live in the residential community, leading to the demands for preventive healthcare (30.4%), medical treatment (14.1%), and elderly education (8.6%). CONCLUSION: The elevated risks of age-related impairments and chronic morbidities, and increased demands for preventive healthcare are critical public health issues. Policymakers should strengthen primary healthcare and move towards integrated delivery to improve access and quality of care for older adults. The integration of healthcare and social security constitutes an adaptive trend in meeting the multi-level demands of an aging society.

Changes of equality of medical service utilization in China between 1993 and 2018: findings from six waves of nationwide household interview survey.

BACKGROUND: Changes in China's health care system in the last three decades was remarkable. The current study aims on examine the change of equality of health care utilization in mainland China based on a nationwide household interview survey. METHODS: We used household interview data extracted from six waves of National Health Service Survey between 1993 and 2018. Changes of health care utilization were descripted. Equality of the utilization were examined with univariate meta-regression across urban and rural areas, socioeconomic development regions and income groups. RESULTS: The proportion of outpatient visits within last two weeks experienced a decrease from 17.0% in 1993 to 13.0% in 2013 and bounced back to 24.0% in 2018. The age-standardized trend remained unchanged. Hospitalization in the last 12 month increased from 2.6% in 1998 to 13.8% in 2018. The perceived unmet need of hospital admission fell from 35.9% in 1998 to 21.5% in 2018. The gaps in health care utilization between urban and rural areas, across regions and by income groups have been narrowed, implying improved equality of using medical services in the last two and a half decades. CONCLUSION: China has experienced significant increases in health care utilization over the past 25 years. Meanwhile, the unmet needs for health care decreased remarkably and the equality of health care utilization improved significantly. These results imply significant achievements in health service accessibility in China.

Poverty alleviation and health services for the poor in China: evidence from national health service surveys in 2013 and 2018.

BACKGROUND: China has made intensive efforts to eliminate extreme poverty by 2020. This paper aims to evaluate the changes in health service needs, utilization, and medical expenses for poor people during the poverty alleviation period. METHODS: The study used data from national health services surveys in 2013 and 2018. The poor people were identified and certified by the local government. Health service needs, utilization, medical expenses, and reimbursement rates were analyzed and compared between 2013 and 2018, between the poor and the non-poor groups. RESULTS: People living in poverty were usually elderly, illiterate, and unemployed. The poor people had a significantly higher two-week morbidity rate and a higher prevalence of chorionic non-communicable diseases than the non-poor group. For both the poor and non-poor, health service needs increased between 2013 and 2018. Accordingly, the poor people had more use of outpatient and inpatient services. The annual inpatient admission rates were 20.8% and 13.1% for the poor and non-poor, respectively, in 2018. The average medical expenses per inpatient admission were much lower for the poor than for the non-poor. Out-of-pocket (OOP) payment share decreased from 41.9% to 2013 to 31.9% in 2018 for the poor, while for the non-poor, the OOP rate was much higher (45.4%) and had no significant changes between the two surveys. The reduction in the OOP share occurred mostly in rural areas. CONCLUSIONS: Poverty alleviation in China may have positive effect in improving poor people's access to health services, and reducing their financial burden due to illness and health service utilization.

Trends in disparities in healthcare utilisation between and within health insurances in China between 2008 and 2018: a repeated cross-sectional study.

BACKGROUND: Fragmentation in China's social health insurance schemes and income gap have been recognised as important factors for the inequitable use of healthcare. This study assessed trends in disparities in healthcare utilisation between and within health insurances in China between 2008 and 2018. METHODS: We used data from the 2008, 2013, and 2018 China National Health Services Survey. Outpatient visit, inpatient admission and foregone inpatient care were chosen to measure healthcare utilisation and underutilisation by health insurances. Absolute differences and rate ratios were generated to examine disparities between and within health insurances, and changes in disparities were analysed descriptively. Pearson χ2 tests were used to test for statistical significance of differences. RESULTS: The outpatient visit rate for respondents covered by the urban resident-based basic medical insurance scheme (URBMI) more than doubled between 2008 and 2018, increasing from 10.5% (9.7-11.2) to 23.5% (23.1-23.8). Inpatient admission rates for respondents covered by URBMI and the new rural cooperative medical scheme (NRCMS) more than doubled between 2008 and 2018, increasing by 7.2 (p < 0.0001) and 7.4 (p < 0.0001) percentage points, respectively. Gaps in outpatient visits and inpatient admissions narrowed across the urban employee-based basic medical insurance scheme (UEBMI), URBMI, and NRCMS through 2008 to 2018, and by 2018 the gaps were small. The rate ratios of foregone inpatient care between NRCMS and UEBMI fell from 0.9 (p > 0.1) in 2008 to 0.8 (p < 0.0001) in 2018. Faster increases in outpatient and inpatient utilisation and greater reductions in foregone inpatient care were observed in poor groups than in wealthy groups within URBMI and NRCMS. However, the poor groups within UEBMI, URBMI, and NRCMS were always more likely to forego inpatient care in comparison with their wealthy counterparts. CONCLUSIONS: Remarkable increases in healthcare utilisation of URBMI and NRCMS, especially among the poorest groups, were accompanied by improvements in inequality in healthcare utilisation across UEBMI, URBMI, and NRCMS, and in income-based inequality in healthcare utilisation within URBMI and NRCMS. However, the poor groups were always more likely to forego admission to hospital, as recommended by doctors. We suggest further focus on the foregoing admission care of the poor groups.

O-GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity.

O-GlcNAcylation is a posttranslational modification that regulates numerous nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes, such as transcription, signal transduction, and cell motility. Although increasing evidence has shown that elevated levels of global O-GlcNAcylation are linked to the metastasis in hepatocellular carcinoma (HCC) cells, the underlying mechanism is still ambiguous. In this study, we demonstrated that forkhead box protein A2 (FOXA2), an essential transcription factor for liver homeostasis and HCC developing, was O-GlcNAcylated by O-GlcNAc transferase (OGT) and regulates HCC cells migration and invasion. Opposite FOXA2 and OGT expression tendency were observed in HCC tissues, and lower FOXA2 levels predicted a poor prognosis in HCC patients. The reduction of FOXA2 in HCC cells was found to be inversely correlated with the cellular O-GlcNAcylation and cell migratory ability. Notably, we found that FOXA2 was modified by O-GlcNAcylation and that O-GlcNAcylation activated the ubiquitination degradation of FOXA2 in highly metastatic HCC cells. Although this modification did not affect FOXA2 nuclear localization capability, O-GlcNAcylation on FOXA2 was key for attenuating FOXA2-mediated transcription. O-GlcNAcylation decreased the transcription of FOXA2 downstream target gene E-cadherin and it ultimately promoted O-GlcNAcylation-mediated HCC cell migration and invasion. The results provide insights into the role of O-GlcNAcylation in regulating FOXA2 activity and suggest its important implications in HCC metastasis.

Reduced expression of ppGalNAc-T4 promotes proliferation of human breast cancer cells.

Breast cancer, one of the most frequently diagnosed and aggressive malignancies, is the major cause of cancer-related death greatly threatening women health. Polypeptide N-acetylgalactosaminyltransferase 4 (ppGalNAc-T4), responsible for the initial step of mucin-type O-glycosylation, has been reported to be implicated in diverse types of human tumors. However, the biological role of ppGalNAc-T4 in breast cancer is still undetermined. In this study, we investigate the effects and mechanism of ppGalNAc-T4 to breast cancer cell proliferation. From analysis of high throughput RNA sequencing datasets of Gene Expression Omnibus and ArrayExpress, a positive correlation between ppGalNAc-T4 and the recurrence-free survival was observed in multigroup of human breast cancer datasets. Moreover, transcriptomes analysis using RNA-sequencing in MCF7 cells revealed that cell cycle-related genes induced the effects of ppGalNAc-T4 on breast cancer cell proliferation. Additionally, investigations showed that ppGalNAc-T4 impaired cell proliferation in MCF-7 and MDA-MB-231 breast cells. Furthermore, our results suggested that the ppGalNAc-T4 knockout activated Notch signaling pathway and enhanced cell proliferation. Collectively, our data indicated that ppGalNAc-T4 affected the proliferation of human breast cancer cells, which appears to be a novel target for understanding the underlying molecular mechanism of breast cancer.

The Modulation of Trehalose Metabolism by 20-Hydroxyecdysone in Antheraea pernyi (Lepidoptera: Saturniidae) During its Diapause Termination and Post-Termination Period.

Trehalose plays a crucial role in the diapause process of many insects, serving as an energy source and a stress protectant. Trehalose accumulation has been reported in diapause pupae of Antheraea pernyi; however, trehalose metabolic regulatory mechanisms associated with diapause termination remain unclear. Here, we showed that the enhanced trehalose catabolism was associated with an increase in endogenous 20-hydroxyecdysone (20E) in hemolymph of A. pernyi pupae during their diapause termination and posttermination period. Injection of 20E increased the mRNA level of trehalase 1A (ApTre-1A) and trehalase 2 (ApTre-2) of A. pernyi diapause pupae in a dose-dependent manner but did not affect the mRNA level of trehalase 1B (ApTre-1B). Meanwhile, exogenous 20E increased the enzyme activities of soluble and membrane-bound trehalase, leading to a decline in hemolymph trehalose. Conversely, the expression of ApTre-1A and ApTre-2 were down-regulated after the ecdysone receptor gene (ApEcRB1) was silenced by RNA interference or by injection of an ecdysone receptor antagonist cucurbitacin B (CucB), which inhibits the 20E pathway. Moreover, CucB treatment delayed adult emergence, which suggests that ApEcRB1 might be involved in regulating pupal-adult development of A. pernyi by mediating ApTre-1A and ApTre-2 expressions. This study provides an overview of the changes in the expression and activity of different trehalase enzymes in A. pernyi in response to 20E, confirming the important role of 20E in controlling trehalose catabolism during A. pernyi diapause termination and posttermination period.

Cellular and Molecular State of Myeloid Leukemia Stem Cells.

Leukemia stem cells (LSCs) are leukemia-initiating population with the capacity to self-renew, differentiate, and stay quiescent. Human hematopoietic malignancies such as chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are derived from this cell population. LSCs are also responsible for disease relapse due to its resistance to drug treatment. This rare cell population is phenotypically and functionally heterogeneous. Increasing evidence indicates that this heterogeneous cellular state of LSCs might determine the different drug sensitivity and is the major reason for disease relapse. In here, focusing on myeloid leukemia stem cells, we describe the biological features including cellular and molecular state, heterogeneity of LSCs, and the dynamic cross talk between LSCs and bone marrow microenvironment. These specific features of LSCs highlight the dynamic cellular state of LSCs, and further exploring on it might provide potential therapeutic targets that are important for eliminating LSCs.

Design and optimization of 32-core rod/trench assisted square-lattice structured single-mode multi-core fiber.

We propose and design a kind of heterogeneous rod-assisted and trench-assisted multi-core fiber (Hetero-RA-TA-MCF) with 32 cores arranged in square-lattice structure (SLS), and then we introduce the design method for Hetero-RA-TA-MCF. Simulation results show that the Hetero-RA-TA-32-Core-Fiber achieves average effective area (Aeff) of about 74 µm2, low crosstalk (XT) of about -31 dB/100km, threshold value of bending radius (Rpk) of 7.0 cm, relative core multiplicity factor (RCMF) of 8.74, and cable cutoff wavelength (λcc) of less than 1.53 µm.

TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms.

Tripartite motif (TRIM)38 is an E3 ubiquitin ligase that was reported to regulate signaling in innate immune and inflammatory responses in certain cell lines. In this study, we show that Trim38 deficiency markedly increased TLR3- and TLR4-mediated induction of type I IFNs and proinflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, in immune cells and in vivo. Trim38 deficiency also caused the mice to be more susceptible to death triggered by polyinosinic-polycytidylic acid, LPS, and Salmonella typhimurium. Mechanistically, TRIM38 catalyzed K48-linked polyubiquitination of the TLR3/4 adapter protein TIR domain-containing adapter-inducing IFN-ß at K228 and promoted its proteasomal degradation in immune cells. Moreover, Trim38 was highly induced by type I IFNs, which then negatively regulated TNF-α/IL-1ß signaling in IFN-ß-primed immune cells, but not unprimed immune cells, by mediating degradation of Tab2 in a lysosomal-dependent process. These results suggest that Trim38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. This study increases our understanding of how the innate immune response is initiated during the early phase of infection to defend against microbial invasion and is efficiently terminated during the late phase to prevent excessive and harmful inflammatory responses.

[Changes of hospitalization rates and in-hospital mortality for coronary heart disease in Beijing from 2007-2012].

OBJECTIVE: To observe the changes of hospitalization rates and in-hospital mortality for coronary heart disease (CHD) in Beijing from 2007-2012. METHODS: Patients hospitalized for CHD in Beijing from 1 January 2007 to 31 December 2012 were identified from"The Cardiovascular Disease Surveillance System in Beijing". In total, 421 929 patients aged ≥25 years of permanent Beijing residents were admitted for CHD in Beijing during the 6 years. After excluding duplicate records and validation for the completeness and accuracy of the records, the hospitalization rates for CHD and in-hospital CHD mortality were analyzed. Trends in hospitalization rates and the in-hospital mortality for CHD were analyzed with Poisson regression models. RESULTS: The age-standardized average hospitalization rate of CHD was 515.3 per 100 000 population in patients aged ≥25 years in Beijing. During the six years, an increasing trend was observed in the hospitalization rates for CHD after adjusting the age and gender (P<0.001). The age-standardized hospitalization rates of CHD increased by 43.0% in the past six years. The greatest increases of hospitalization rates were noted in both men and women between 45 to 54 years. The age-standardized in-hospital mortality decreased from 3.3% to 2.2% over the time (P<0.001), with a in-hospital mortality reduction for acute myocardial infarction from 11.3% to 8.5%. CONCLUSIONS: An increasing trend in hospitalization rate was observed during 2007-2012 for Beijing residents aged ≥25 years, indicating an urgent need in CHD prevention in Beijing. The in-hospital mortality reduction during this period might reflect the improvement in the in-hospital treatment modalities of CHD.

Genome sequencing and comparative transcriptomics of the model entomopathogenic fungi Metarhizium anisopliae and M. acridum.

Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ~30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ~16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogeneous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties.

Predicting coronary heart disease in Chinese diabetics using machine learning.

Diabetes, a common chronic disease worldwide, can induce vascular complications, such as coronary heart disease (CHD), which is also one of the main causes of human death. It is of great significance to study the factors of diabetic patients complicated with CHD for understanding the occurrence of diabetes/CHD comorbidity. In this study, by analyzing the risk of CHD in more than 300,000 diabetes patients in southwest China, an artificial intelligence (AI) model was proposed to predict the risk of diabetes/CHD comorbidity. Firstly, we statistically analyzed the distribution of four types of features (basic demographic information, laboratory indicators, medical examination, and questionnaire) in comorbidities, and evaluated the predictive performance of three traditional machine learning methods (eXtreme Gradient Boosting, Random Forest, and Logistic regression). In addition, we have identified nine important features, including age, WHtR, BMI, stroke, smoking, chronic lung disease, drinking and MSP. Finally, the model produced an area under the receiver operating characteristic curve (AUC) of 0.701 on the test samples. These findings can provide personalized guidance for early CHD warning for diabetic populations.

Differentiated functions of Ras1 and Ras2 proteins in regulating the germination, growth, conidiation, multi-stress tolerance and virulence of Beauveria bassiana.

Ras1 and Ras2 are two distinct Ras GTPases in Beauveria bassiana, an entomopathogenic fungus whose biocontrol potential against insect pests depends largely on virulence and multi-stress tolerance. The functions of both proteins were characterized for the first time by constructing dominant-active (GTP-bound) Ras1(G19V) and dominant-negative (GDP-bound) Ras1(D126A) and integrating them and normal Ras1 into wild type and ΔRas2 for a series of phenotypic and transcriptional analyses. The resultant mutants showed gradient changes of multiple phenotypes but little difference in conidial thermotolerance. Expression of Ras1(D126A) caused vigorous hyphal growth, severely defective conidiation, and increased tolerances to oxidation, cell wall disturbance, fungicide and UV-A/UV-B irradiations, but affected slightly germination, osmosensitivity and virulence. These phenotypes were antagonistically altered by mRas1(G19V) expressed in either wild type or ΔRas2, which was severely defective in conidial germination and hyphal growth and displayed intermediate changes in other mentioned phenotypes between paired mutants expressing Ras1(G19V) or Ras1(D126A) in wild type and ΔRas2. Their growth, UV tolerance or virulence was significantly correlated with cellular response to oxidation or cell wall disturbance. Transcriptional changes of 35 downstream effector genes involved in conidiation and multi-stress responses also related to most of the phenotypic changes among the mutants. Our findings highlight that Ras1 and Ras2 regulate differentially or antagonistically the germination, growth, conidiation, multi-stress tolerance and virulence of B. bassiana, thereby exerting profound effects on the fungal biocontrol potential.

The autophagy gene BbATG5, involved in the formation of the autophagosome, contributes to cell differentiation and growth but is dispensable for pathogenesis in the entomopathogenic fungus Beauveria bassiana.

Autophagy is a highly conserved process, representing the major eukaryotic degradative pathway of cellular components. Autophagy-mediated recycling of cellular materials contributes to cell differentiation, tissue remodelling and proper development. In fungi, autophagy is required for normal growth and cell differentiation. The entomopathogenic fungus Beauveria bassiana and its invertebrate targets represent a unique model system with which to examine host-pathogen interactions. The ATG5 gene is one of 17 involved in autophagosome formation, and the B. bassiana homologue (BbATG5) was identified. The role of autophagy in B. bassiana growth and virulence was investigated via construction of a targeted gene knockout of BbATG5. The mutant strain displayed increased sensitivity to nutrient limitation, with decreased germination and growth as compared with the wild-type parent. Conidiation was severely compromised and conidia derived from the ΔBbATG5 strain were altered in morphology. Cell differentiation into blastospores was also greatly reduced. Despite the significant growth and developmental defects, insect bioassays using the oriental leafworm moth, Spodoptera litura, indicated a modest (~40 %) decrease in virulence in the ΔBbATG5 strain. The phenotypic defects of the ΔBbATG5 strain could be restored by introduction of an intact copy of BbATG5. These data suggest that unlike several plant and animal pathogenic fungi, where ATG5 is required for infection, in B. bassiana it is dispensable for pathogenesis.

Integrated bioinformatics analysis of microarray data from the GEO database to identify the candidate genes linked to poor prognosis in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common cancers with high morbidity and mortality and remains a crucial factor endangering human health. OBJECTIVE: This study aimed to elucidate the potential treatment target and prognostic biomarker in patients with LUAD through a comprehensive bioinformatics analysis. METHODS: The three public microarray datasets of GSE118370, GSE116959, and GSE43767 were obtained from the GEO data resource. The DEGs were explored between LUAD and non-malignant samples using GEO2R online tool in GEO data resource. GO along with KEGG analysis of DEGs were examined using WebGestalt tool. The STRING web resource was employed to develop the PPI network of DEGs, whereas Cytoscape software was employed to perform module analysis. Finally, the mRNA, protein expression along with survival analysis of hub genes were explored via GEPIA, HPA along with Kaplan-Meier plotter web resource, respectively. RESULTS: Only 82 upregulated and 105 downregulated DEGs were found among the three datasets. Further, GO analysis illustrated that 187 DEGs were primary enriched in extracellular structure organization, tube development along with cell adhesion. The KEGG enrichments showed that these DEGs were primary linked to leukocyte transendothelial migration, vascular smooth muscle contraction along with ECM-receptor interaction. Among the 187 DEGs, the 10 hub genes (P4HB, SPP1, CP, GOLM1, COL1A1, MMP9, COL10A1, APOA1, COL4A6, and TIMP1) were identified. The mRNA along with protein levels of hub genes in LUAD tissues were further verified by Oncomine, UCSC Xena, GEPIA and HPA databases. Additionally, overall survival curves illustrated that LUAD patients with the higher levels of P4HB, SPP1, COL1A1, and MMP9 were dramatically linked to shorter overall survival. CONCLUSIONS: The current study identified DEGs candidate genes (P4HB, SPP1, COL1A1, and MMP9) and pathways in LUAD using bioinformatics analysis, which could enhance our understanding of pathogenesis along with underlying molecular events in LUAD, and these hub genes and pathways may help provide candidate treatment targets for LUAD.

Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review.

Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.