Analysis of huanglongbing-associated RNA-seq data reveals disturbances in biological processes within Citrus spp. triggered by Candidatus Liberibacter asiaticus infection.

Introduction: Huanglongbing (HLB), a disease that's ubiquitous worldwide, wreaks havoc on the citrus industry. The primary culprit of HLB is the gram-negative bacterium Candidatus Liberibacter asiaticus (CLas) that infects the phloem, but its damaging mechanism is yet to be fully understood. Methods and results: In this study, a multitude of tools including weighted correlation network analysis (WGCNA), protein-protein interaction (PPI) network analysis and gene expression profiling are employed to unravel the intricacies of its pathogenesis. The investigation pinpoints various central genes, such as the ethylene-responsive transcription factor 9 (ERF9) and thioredoxin reductase 1 (TrxR1), that are associated with CLas invasion and resultant disturbances in numerous biological operations. Additionally, the study uncovers a range of responses through the detection of differential expressed genes (DEGs) across different experiments. The discovery of core DEGs leads to the identification of pivotal genes such as the sieve element occlusion (SEO) and the wall-associated receptor kinase-like 15 (WAKL15). PPI network analysis highlights potential vital proteins, while GO and KEGG pathway enrichment analysis illustrate a significant impact on multiple defensive and metabolic pathways. Gene set enrichment analysis (GSEA) indicates significant alterations in biological processes such as leaf senescence and response to biotic stimuli. Discussion: This all-encompassing approach extends valuable understanding into the pathogenesis of CLas, potentially aiding future research and therapeutic strategies for HLB.

Alleviatory Role of Panax Notoginseng Saponins in Modulating Inflammation and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease: mechanisms and Implications.

COPD is an inflammatory lung disease that limits airflow and remodels the pulmonary vascular system. This study delves into the therapeutic potential and mechanistic underpinnings of Panax notoginseng Saponins (PNS) in alleviating inflammation and pulmonary vascular remodeling in a COPD rat model. Symmap and ETCM databases provided Panax notoginseng-related target genes, and the CTD and DisGeNET databases provided COPD-related genes. Intersection genes were subjected to protein-protein interaction analysis and pathway enrichment to identify downstream pathways. A COPD rat model was established, with groups receiving varying doses of PNS and a Roxithromycin control. The pathological changes in lung tissue and vasculature were examined using histological staining, while molecular alterations were explored through ELISA, RT-PCR, and Western blot. Network pharmacology research suggested PNS may affect the TLR4/NF-κB pathway linked to COPD development. The study revealed that, in contrast to the control group, the COPD model exhibited a significant increase in inflammatory markers and pathway components such as TLR4, NF-κB, HIF-1α, VEGF, ICAM-1, SELE mRNA, and serum TNF-α, IL-8, and IL-1ß. Treatment with PNS notably decreased these markers and mitigated inflammation around the bronchi and vessels. Taken together, the study underscores the potential of PNS in reducing lung inflammation and vascular remodeling in COPD rats, primarily via modulation of the TLR4/NF-κB/HIF-1α/VEGF pathway. This research offers valuable insights for developing new therapeutic strategies for managing and preventing COPD.

Operationalizing the Consolidated Framework for Implementation Research to build and support the lived experience workforce in direct health service provision.

BACKGROUND: The involvement of people with lived experience (LEX) workers in the development, design, and delivery of integrated health services seeks to improve service user engagement and health outcomes and reduce healthcare gaps. Yet, LEX workers report feeling undervalued and having limited influence on service delivery. There is a need for systematic improvements in how LEX workforces are engaged and supported to ensure the LEX workforce can fully contribute to integrated systems of care. OBJECTIVE: This study aimed to operationalize the Consolidated Framework for Implementation Research (CFIR) using a rigorous scoping review methodology and co-creation process, so it could be used by health services seeking to build and strengthen their LEX workforce. SEARCH STRATEGY: A systematic literature search of four databases was undertaken to identify peer-reviewed studies published between 2016 and 2022 providing evidence of the inclusion of LEX workers in direct health service provision. DATA EXTRACTION AND SYNTHESIS: A descriptive-analytical method was used to map current evidence of LEX workers onto the CFIR. Then, co-creation sessions with LEX workers (n = 4) and their counterparts-nonpeer workers (n = 2)-further clarified the structural policies and strategies that allow people with LEX to actively participate in the provision and enhancement of integrated health service delivery. MAIN RESULTS: Essential components underpinning the successful integration of LEX roles included: the capacity to engage in a co-creation process with individuals with LEX before the implementation of the role or intervention; and enhanced representation of LEX across organizational structures. DISCUSSION AND CONCLUSION: The adapted CFIR for LEX workers (CFIR-LEX) that was developed as a result of this work clarifies contextual components that support the successful integration of LEX roles into the development, design, and delivery of integrated health services. Further work must be done to operationalize the framework in a local context and to better understand the ongoing application of the framework in a health setting. PATIENT OR PUBLIC CONTRIBUTION: People with LEX were involved in the operationalization of the CFIR, including contributing their expertise to the domain adaptations that were relevant to the LEX workforce.

Genome-wide characterization of heavy metal-associated isoprenylated plant protein gene family from Citrus sinensis in response to huanglongbing.

Introduction: Heavy metal-associated isoprenylated plant proteins (HIPPs) play vital roles in maintaining heavy metal balance and responding to both biotic and abiotic stresses in vascular plants. However, the role of HIPPs in the response to Huanglongbing (HLB), a harmful disease of citrus caused by the phloem-colonizing bacterium Candidatus Liberibacter asiaticus (CLas), has not been examined. Methods and results: In this study, a total of 26 HIPP genes were identified in Citrus sinensis, and they were grouped into 5 clades. The CsHIPP genes are distributed on 8 chromosomes and exhibited considerable synteny with HIPPs found in Arabidopsis thaliana. Additionally, we analyzed the gene structure, conserved motifs and domains of the CsHIPPs. Various cis-acting elements related to plant hormones and stress responses were identified in the promoters of CsHIPPs. Public transcriptome data and RT-qPCR analysis showed that the expression level of CsHIPP03 was significantly reduced in samples infected by CLas and Xanthomonas citri ssp. citri (Xcc). Furthermore, silencing the homologous gene of CsHIPP03 in Nicotiana benthamiana increased the disease resistance of plants to bacteria. Discussion: Our results provide a basis for functional studies of HIPP gene family in C. sinensis, highlighting their functions in bacterial resistance, and improve our understanding to the susceptibility mechanism of HLB.

A cost analysis of upscaling access to continuity of midwifery carer: Population-based microsimulation in Queensland, Australia.

OBJECTIVE: To quantify the economic impact of upscaling access to continuity of midwifery carer, compared with current standard maternity care, from the perspective of the public health care system. METHODS: We created a static microsimulation model based on a whole-of-population linked administrative data set containing all public hospital births in one Australian state (Queensland) between July 2017 to June 2018 (n = 37,701). This model was weighted to represent projected State-level births between July 2023 and June 2031. Woman and infant health service costs (inpatient, outpatient and emergency department) during pregnancy and birth were summed. The base model represented current standard maternity care and a counterfactual model represented two hypothetical scenarios where 50 % or 65 % of women giving birth would access continuity of midwifery carer. Costs were reported in 2021/22 AUD. RESULTS: The estimated cost savings to Queensland public hospital funders per pregnancy were $336 in 2023/24 and $546 with 50 % access. With 65 % access, the cost savings were estimated to be $534 per pregnancy in 2023/24 and $839 in 2030/31. A total State-level annual cost saving of $12 million in 2023/24 and $19 million in 2030/31 was estimated with 50 % access. With 65 % access, total State-level annual cost savings were estimated to be $19 million in 2023/24 and $30 million in 2030/31. CONCLUSION: Enabling most childbearing women in Australia to access continuity of midwifery carer would realise significant cost savings for the public health care system by reducing the rate of operative birth.

Economic evaluations performed alongside randomized implementation trials in clinical settings: a systematic review.

BACKGROUND: Economic evaluations alongside implementation trials compare the outcomes and costs of competing implementation strategies to identify the most efficient strategies. The aims of this systematic review were to investigate how economic evaluations are performed in randomized implementation trials in clinical settings and to assess the quality of these evaluations. METHODS: A systematic literature review was conducted on 23 March 2023 to identify studies that reported on economic evaluations embedded in randomized implementation trials in clinical settings. A systematic search was applied across seven databases, and references of relevant reviews were screened for additional studies. The Drummond Checklist was used to assess the quality and risk of bias of included economic evaluations. Study characteristics and quality assessments were tabulated and described. RESULTS: Of the 6,550 studies screened for eligibility, 10 met the inclusion criteria. Included studies were published between 1990 and 2022 and from North America, the United Kingdom, Europe, and Africa. Most studies were conducted in the primary and out-patient care setting. Implementation costs included materials, staffing, and training, and the most common approach to collecting implementation costs was obtaining expense and budget reports. Included studies scored medium to high in terms of economic methodological quality. CONCLUSIONS: Economic evidence is particularly useful for healthcare funders and service providers to inform the prioritization of implementation efforts in the context of limited resources and competing demands. The relatively small number of studies identified may be due to lack of guidance on how to conduct economic evaluations alongside implementation trials and the lack of standardized terminology used to describe implementation strategies in clinical research. We discuss these methodological gaps and present recommendations for embedding economic evaluations in implementation trials. First, reporting implementation strategies used in clinical trials and aligning these strategies with implementation outcomes and costs are an important advancement in clinical research. Second, economic evaluations of implementation trials should follow guidelines for standard clinical trial economic evaluations and adopt an appropriate costing and data collection approach. Third, hybrid trial designs are recommended to generate evidence for effective and cost-effective implementation strategies alongside clinical effectiveness and cost-effectiveness. TRIAL REGISTRATION: The review was prospectively registered with PROSPERO (CRD42023410186).

DKK1 activates the PI3K/AKT pathway via CKAP4 to balance the inhibitory effect on Wnt/ß-catenin signaling and regulates Wnt3a-induced MSC migration.

Wnt/ß-catenin signaling plays a crucial role in the migration of mesenchymal stem cells (MSCs). However, our study has revealed an intriguing phenomenon where DKK1, an inhibitor of Wnt/ß-catenin signaling, promotes MSC migration at certain concentrations ranging from 25 ng/ml to 100 ng/ml, while inhibiting Wnt3a-induced MSC migration at a higher concentration (400 ng/ml). Interestingly, DKK1 consistently inhibited Wnt3a-induced phosphorylation of LRP6 at all concentrations. We further identified CKAP4, another DKK1 receptor, to be localized on the cell membrane of MSCs. Overexpressing the CRD2 deletion mutant of DKK1 (ΔCRD2), which selectively binds to CKAP4, promoted the accumulation of active ß-catenin (ABC), the phosphorylation of AKT (Ser473) and the migration of MSCs, suggesting that DKK1 may activate Wnt/ß-catenin signaling via the CKAP4/PI3K/AKT cascade. We also investigated the effect of the CKAP4 intracellular domain mutant (CKAP4-P/A) that failed to activate the PI3K/AKT pathway, and found that CKAP4-P/A suppressed DKK1 (100 ng/ml)-induced AKT activation, ABC accumulation, and MSC migration. Moreover, CKAP4-P/A significantly weakened the inhibitory effects of DKK1 (400 ng/ml) on Wnt3a-induced MSC migration and Wnt/ß-catenin signaling. Based on these findings, we propose that DKK1 may activate the PI3K/AKT pathway via CKAP4 to balance the inhibitory effect on Wnt/ß-catenin signaling and thus regulate Wnt3a-induced migration of MSCs. Our study reveals a previously unrecognized role of DKK1 in regulating MSC migration, highlighting the importance of CKAP4 and PI3K/AKT pathway in this process.

Long-Term Effect of Having a Child at Risk of Developmental Delays on Parental Labor Force Participation.

OBJECTIVE: This study aimed to examine the long-term influence of having a child at risk of different developmental delays (communication, mobility, self-care, relating, learning, coping, or behaving) on parental labor force participation as the child grows. METHOD: A retrospective cohort was conducted using data from the Longitudinal Study of Australian Children survey, Waves 1-8 covering birth to 15 years of age of children. Multivariable logistic regressions were used to explore the odds ratio of mothers being out of the labor force at different children's ages. Cox proportional hazards models were utilized to identify the 'risk' of mothers returning to the workforce after leaving. All models were adjusted for the mother's age, education attainment, and employment status at time of birth, as well as marital status at the current wave. RESULTS: There were 5,107 records of children, and 266 of them were at risk of any developmental delays at age 4-5 years. This sample represents 243, 026 children born in Australia in 2003/04. After adjusting for potential confounders, mothers of children at risk of each type of developmental delay (except mobility and self-care) had greater odds of being out of, and not returning to the labor force from children aged 2-3 to 14-15 years, when compared to mothers of children who are not at risk of developmental delays. Similar differences were found for fathers but were distinctly small and with narrower fluctuations, compared to mothers. CONCLUSION: Policies and programs funded by the government are greatly needed to support the mothers of children at risk of developmental delays.

Likelihood of primary cesarean section following induction of labor in singleton cephalic pregnancies at term, compared with expectant management: An Australian population-based, historical cohort study.

INTRODUCTION: There has been increased use of both induction of labor (IOL) and cesarean section for women with term pregnancies in many high-income countries, and a trend toward birth at earlier gestational ages. Existing evidence regarding the association between IOL and cesarean section for term pregnancies is mixed and conflicting, and little evidence is available on the differential effect at each week of gestation, stratified by parity. MATERIAL AND METHODS: To explore the association between IOL and primary cesarean section for singleton cephalic pregnancies at term, compared with two definitions of expectant management (first: at or beyond the week of gestation at birth following IOL; and secondary: only beyond the week of gestation at birth following IOL), we performed analyses of population-based historical cohort data on women who gave birth in one Australian state (Queensland), between July 1, 2012 and June 30, 2018. Women who gave birth before 37+0 or after 41+6 weeks of gestation, had stillbirths, no-labor, multiple births (twins or triplets), non-cephalic presentation at birth, a previous cesarean section, or missing data on included variables were excluded. Four sub-datasets were created for each week at birth (37-40). Unadjusted relative risk, adjusted relative risk using modified Poisson regression, and their 95% confidence intervals were calculated in each sub-dataset. Analyses were stratified by parity (nulliparas vs. parous women with a previous vaginal birth). Sensitivity analyses were conducted by limiting to women with low-risk pregnancies. RESULTS: A total of 239 094 women were included in the analysis, 36.7% of whom gave birth following IOL. The likelihood of primary cesarean section following IOL in a Queensland population-based cohort was significantly higher at 38 and 39 weeks, compared with expectant management up to 41+6 weeks, for both nulliparas and paras with singleton cephalic pregnancies, regardless of risk status of pregnancy and definition of expectant management. No significant difference was found for nulliparas at 37 and 40 weeks; and for paras at 40 weeks. CONCLUSIONS: Future studies are suggested to investigate further the association between IOL and other maternal and neonatal outcomes at each week of gestation in different maternal populations, before making any recommendation.

Bioinformatics reveals diagnostic potential of cuproptosis-related genes in the pathogenesis of sepsis.

Background: Multiple modes of cell death occur during the development of sepsis. Among these patterns, cuproptosis has recently been identified as a regulated form of cell death. However, its impact on the onset and progression of sepsis remains unclear. Method: We screened a dataset of gene expression profiles from patients with sepsis using the GEO database. Survival analysis was performed to analyze the relationship between cuproptosis-related genes (CRGs) and prognosis. Hub genes were identified through univariate Cox regression analysis. The diagnostic value of hub genes in sepsis was tested in both training sets (GSE65682) and validation sets (GSE134347). To examine the association between hub genes and immune cells, single-sample gene set enrichment analysis (ssGSEA) and Pearson correlation analysis were employed. Additionally, the CRGs were validated in a septic mouse model using real-time quantitative PCR (qRT-PCR) and immunohistochemistry (IHC). Results: In sepsis, most CRGs were upregulated, with only DLD and MTF1 downregulated. High expression of three genes (GLE, LIAS, and PDHB) was associated with better prognosis, but only two hub genes (LIAS, PDHB) reached statistical significance. The receiver operating characteristic (ROC) analysis for diagnosing sepsis showed LIAS had a range of 0.793-0.906, while PDHB achieved values of 0.882 and 0.975 in the training and validation sets, respectively. ssGSEA analysis revealed a lower number of immune cells in the sepsis group, and there was a correlation between immune cell population and CRGs (LIAS, PDHB). Analysis in the septic mouse model demonstrated no significant difference in mRNA expression levels and IHC staining between LIAS and PDHB in heart and liver tissues, but up-regulation was observed in lung tissues. Furthermore, the mRNA expression levels and IHC staining of LIAS and PDHB were down-regulated in renal tissues. Conclusions: Cuproptosis is emerging as a significant factor in the development of sepsis. LIAS and PDHB, identified as potential diagnostic biomarkers for cuproptosis-associated sepsis, are believed to play crucial roles in the initiation and progression of cuproptosis-induced sepsis.

A fluorene-bridged double carbonyl/amine multiresonant thermally activated delayed fluorescence emitter for efficient green OLEDs.

Herein, we report a fluorene-bridged double carbonyl/amine-based MR TADF emitter DDiKTa-F, formed by locking the conformation of the previously reported compound DDiKTa. Using this strategy, DDiKTa-F exhibited narrower, brighter, and red-shifted emission. The OLEDs with DDiKTa-F emitted at 493 nm and showed an EQEmax of 15.3% with an efficiency roll-off of 35% at 100 cd m-2.

Complement components regulates ferroptosis in CVB3 viral myocarditis by interatction with TFRC.

BACKGROUND: Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response. Complement C4 and C3 are considered the central components of the classical activation pathway and often participate in the response process in the early stages of virus infection. METHODS: In our study, we constructed a mouse model of CVB3-related viral myocarditis via intraperitoneal injection of Fer-1 and detected myocarditis and ferroptosis markers in the mouse myocardium. Then, we performed co-IP and protein mass spectrometry analyses to explore which components interact with the ferroptosis gene transferrin receptor (TFRC). Finally, functional experiments were conducted to verify the role of complement components in regulating ferroptosis in CVB3 infection. RESULTS: It showed that the ferroptosis inhibitor Fer-1 could alleviate the inflammation in viral myocarditis as well as ferroptosis. Mechanistically, during CVB3 infection, the key factor TFRC was activated and inhibited by Fer-1. Fer-1 effectively prevented the consumption of complement C3 and overload of the complement product C4b. Interestingly, we found that TFRC directly interacts with complement C4, leading to an increase in the product of C4b and a decrease in the downstream complement C3. Functional experiments have also confirmed that regulating the complement C4/C3 pathway can effectively rescue cell ferroptosis caused by CVB3 infection. CONCLUSIONS: In this study, we found that ferroptosis occurs through crosstalk with complement C4 in viral myocarditis through interaction with TFRC and that regulating the complement C4/C3 pathway may rescue ferroptosis in CVB3-infected cardiomyocytes.

The financial impact of offering publicly funded homebirths: A population-based microsimulation in Queensland, Australia.

BACKGROUND: Despite strong evidence of benefits and increasing consumer demand for homebirth, Australia has failed to effectively upscale it. To promote the adoption and expansion of homebirth in the public health care system, policymakers require quantifiable results to evaluate its economic value. To date, there has been limited evaluation of the financial impact of birth settings for women at low risk of pregnancy complications. OBJECTIVE: This study aimed to examine the difference in inpatient costs around birth between offering homebirth in the public maternity system versus not offering public homebirth to selected women who meet low-risk pregnancy criteria. METHODS: We used a whole-of-population linked administrative dataset containing all women who gave birth in Queensland (one Australian State) between 01/07/2012 and 30/06/2018 where publicly funded homebirth is not currently offered. We created a static microsimulation model to compare the inpatient cost difference for mother and baby around birth based on the women who gave birth between 01/07/2017 and 30/06/2018 (n = 36,314). The model comprised of a base model - representing standard public hospital care, and a counterfactual model - representing a hypothetical scenario where 5 % of women who gave birth in public hospitals planned to give birth at home prior to the onset of labour (n = 1816). Costs were reported in 2021/22 AUD. RESULTS: In our hypothetical scenario, after considering the effect of assumptive place and mode of birth for these planned homebirths, the estimated State-level inpatient cost saving around birth (summed for mother and babies) per pregnancy were: AU$303.13 (to Queensland public hospitals) and AU$186.94 (to Queensland public hospital funders). This calculates to a total cost saving per annum of AU$11 million (to Queensland public hospitals) and AU$6.8 million (to Queensland public hospital funders). CONCLUSION: A considerable amount of inpatient health care costs around birth could be saved if 5 % of women booked at their local public hospitals, planned to give birth at home through a public-funded homebirth program. This finding supports the establishment and expansion of the homebirth option in the public health care system.

Patterns in the provision of government-subsidised hormonal postpartum contraception in Queensland, Australia between 2012 and 2018: a population-based cohort study.

BACKGROUND: Short birth intervals and unintended pregnancy are associated with poorer maternal and infant outcomes. There is a risk of pregnancy during the immediate postpartum period unless contraception is initiated. This retrospective cohort study aimed to capture the current patterns of hormonal contraceptive provision within 12 months postpartum in a high-income country. METHODS: We used a linked administrative dataset comprising all women who gave birth in Queensland, Australia between 1 July 2012 and 30 June 2018 (n=339 265 pregnancies). We described our cohort by whether they were provided with government-subsidised hormonal contraception within 12 months postpartum. The associations between hormonal postpartum contraceptive provision and demographic and clinical characteristics were examined using univariate and multivariate logistic regression and presented in terms of crude and adjusted odds ratios with 95% confidence intervals. RESULTS: A majority of women (60.2%) were not provided with government-subsidised hormonal postpartum contraception within 12 months postpartum. Women who were younger (<25 years), were overweight or obese, smoked, were born in Australia, were non-Indigenous, gave birth in a public hospital, or were in the lowest socioeconomic status group were more likely to be provided with postpartum contraception after adjusting for other covariates, compared with their counterparts. CONCLUSIONS: Strategies to increase the provision and uptake of contraception in the immediate postpartum period are needed to prevent short birth intervals and unintended pregnancy and ensure women's fertility intentions are enacted. Ongoing research is needed to examine the factors influencing women's access to contraceptive services and, further, the types of contraception provided.

Pan-Cancer Analysis of the Cuproptosis-Related Gene DLD.

Background: Cancer affects millions of people each year and imposes a huge economic and social burden worldwide. Cuproptosis is a recently discovered novel mode of cell death. The exact function of the cuproptosis-related gene dihydrolipoamide dehydrogenase (DLD) and its role in pan-cancer is unknown. Methods: Data were retrieved from the GTEx, TCGA, and multiple online websites. These data were used to assess the expression, prognosis, and diagnostic value of DLD in various tumors. The relationship of DLD with immune microenvironment immunomodulators, immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI), and oncology drug sensitivity was explored by correlation analysis. Results: The mRNA and protein expression of DLD differs in most cancers. Survival analysis showed that DLD was associated with prognosis with KIRC, KIRP, KICH, and UCS. DLD had a strong diagnostic value in KIRC, GBM, PAAD, and LGG (AUC > 0.9). DLD promoter methylation affects the aberrant expression of LIHC, LUSC, PAAD, READ, and THCA. DLD was negatively correlated with stromal score, immune score, and ESTIMATE score in UCEC, TGCT, LUSC, and SARC. In UCS, resting memory CD4 T cells and activated NK cells were significantly correlated with DLD expression. Significant correlations were also observed between DLD expression and immunomodulators, immune checkpoints, TMB, and MSI in various cancers. Importantly, we also identified a number of potential drugs that may target DLD. Conclusion: DLD expression is associated with a variety of tumor prognoses and plays an integral role in tumorigenesis, tumor metabolism, and immunity.

Acetylation of FOXO1 activates Bim expression involved in CVB3 induced cardiomyocyte apoptosis.

Viral myocarditis (VMC) is the major reason for sudden cardiac death among both children and young adults. Of these, coxsackievirus B3 (CVB3) is the most common causative agent of myocarditis. Recently, the role of signaling pathways in the pathogenesis of VMC has been evaluated in several studies, which has provided a new perspective on identifying potential therapeutic targets for this hitherto incurable disease. In the present study, in vivo and in vitro experiments showed that CVB3 infection leads to increased Bim expression and triggers apoptosis. In addition, by knocking down Bim using RNAi, we further confirmed the biological function of Bim in apoptosis induced by CVB3 infection. We additionally found that Bim and forkhead box O1 class (FOXO1) inhibition significantly increased the viability of CVB3-infected cells while blocking viral replication and viral release. Moreover, CVB3-induced Bim expression was directly dependent on FOXO1 acetylation, which is catalyzed by the co-regulation of CBP and SirTs. Furthermore, the acetylation of FOXO1 was an important step in Bim activation and apoptosis induced by CVB3 infection. The findings of this study suggest that CVB3 infection induces apoptosis through the FOXO1 acetylation-Bim pathway, thus providing new insights for developing potential therapeutic targets for enteroviral myocarditis.

Tuftelin1 drives experimental pulmonary fibrosis progression by facilitating stress fiber assembly.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive. METHODS: To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis. RESULTS: Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pY256N-WASP). Furthermore, TUFT1 promoted transforming growth factor-ß1 (TGF-ß1) induced fibroblast activation by increasing nuclear translocation of pY256N-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes. CONCLUSIONS: Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.

Prophylactic supplement with melatonin prevented the brain injury after cardiac arrest in rats.

Prophylactic pharmacotherapy for health care in patients with high risk of cardiac arrest (CA) is an elusive and less explored strategy. Melatonin has possibilities used as a daily nutraceutical to trigger the cellular adaptation. We sought to find the effects of long-term daily prophylactic supplement with melatonin on the victim of CA. Rats were divided into sham, CA, and melatonin + CA (Mel + CA) groups. The rats in the Mel + CA group received daily IP injection of melatonin 100 mg/kg for 14 days. CA was induced by 8 min asphyxia and followed by manual cardiopulmonary resuscitation. The endpoint was 24 h after resuscitation. Survival, neurological outcome, and hippocampal mitochondrial integrity, dynamics and function were assessed. Survival was significantly higher in the Mel + CA group than the CA group (81 vs. 42%, P = 0.04). Compared to the CA group, neurological damage in the CA1 region and the level of cytochrome c, cleaved caspase-3 and caspase-9 in the Mel + CA group were decreased (P < 0.05). Mitochondrial function and integrity were protected in the Mel + CA group compared to the CA group, according to the results of mitochondrial swelling, ΔΨm, ROS production, oxygen consumption rate, and respiratory control rate (P < 0.05). Melatonin increased SIRT3 and downregulated acetylated CypD. The mitochondrial dynamics and autophagy were improved in the Mel + CA group (P < 0.05). Long-term daily prophylactic supplement with melatonin buy the time from brain injury after CA.

FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1.

Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.

Hospital length of stay prediction tools for all hospital admissions and general medicine populations: systematic review and meta-analysis.

Background: Unwarranted extended length of stay (LOS) increases the risk of hospital-acquired complications, morbidity, and all-cause mortality and needs to be recognized and addressed proactively. Objective: This systematic review aimed to identify validated prediction variables and methods used in tools that predict the risk of prolonged LOS in all hospital admissions and specifically General Medicine (GenMed) admissions. Method: LOS prediction tools published since 2010 were identified in five major research databases. The main outcomes were model performance metrics, prediction variables, and level of validation. Meta-analysis was completed for validated models. The risk of bias was assessed using the PROBAST checklist. Results: Overall, 25 all admission studies and 14 GenMed studies were identified. Statistical and machine learning methods were used almost equally in both groups. Calibration metrics were reported infrequently, with only 2 of 39 studies performing external validation. Meta-analysis of all admissions validation studies revealed a 95% prediction interval for theta of 0.596 to 0.798 for the area under the curve. Important predictor categories were co-morbidity diagnoses and illness severity risk scores, demographics, and admission characteristics. Overall study quality was deemed low due to poor data processing and analysis reporting. Conclusion: To the best of our knowledge, this is the first systematic review assessing the quality of risk prediction models for hospital LOS in GenMed and all admissions groups. Notably, both machine learning and statistical modeling demonstrated good predictive performance, but models were infrequently externally validated and had poor overall study quality. Moving forward, a focus on quality methods by the adoption of existing guidelines and external validation is needed before clinical application. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021272198.