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Genomic selection (GS) has emerged as an effective technology to accelerate crop hybrid breeding by enabling early selection prior to phenotype collection. Genomic best linear unbiased prediction (GBLUP) is a robust method that has been routinely used in GS breeding programs. However, GBLUP assumes that markers contribute equally to the total genetic variance, which may not be the case. In this study, we developed a novel GS method called GA-GBLUP that leverages the genetic algorithm (GA) to select markers related to the target trait. We defined four fitness functions for optimization, including AIC, BIC, R2, and HAT, to improve the predictability and bin adjacent markers based on the principle of linkage disequilibrium to reduce model dimension. The results demonstrate that the GA-GBLUP model, equipped with R2 and HAT fitness function, produces much higher predictability than GBLUP for most traits in rice and maize datasets, particularly for traits with low heritability. Moreover, we have developed a user-friendly R package, GAGBLUP, for GS, and the package is freely available on CRAN (https://CRAN.R-project.org/package=GAGBLUP).
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Algoritmos , Genômica , Seleção Genética , Zea mays , Genômica/métodos , Zea mays/genética , Oryza/genética , Modelos Genéticos , Melhoramento Vegetal/métodos , Desequilíbrio de Ligação , Fenótipo , Locos de Características Quantitativas , Genoma de Planta , Polimorfismo de Nucleotídeo Único , SoftwareRESUMO
BACKGROUND: The association of a broad spectrum of infectious diseases with cardiovascular outcomes remains unclear. OBJECTIVES: We aim to provide the cardiovascular risk profiles associated with a wide range of infectious diseases and explore the extent to which infections reduce life expectancy. METHODS: We ascertained exposure to 900+ infectious diseases before cardiovascular disease (CVD) onset in 453,102 participants from the UK Biobank study. Time-varying Cox proportional hazard models were used. Life table was used to estimate the life expectancy of individuals aged ≥50 with different levels of infection burden (defined as the number of infection episodes over time and the number of co-occurring infections). RESULTS: Infectious diseases were associated with a greater risk of CVD events (adjusted HR [aHR] 1.79 [95% confidence interval {CI} 1.74-1.83]). For type-specific analysis, bacterial infection with sepsis had the strongest risk of CVD events [aHR 4.76 (4.35-5.20)]. For site-specific analysis, heart and circulation infections posed the greatest risk of CVD events [aHR 4.95 (95% CI 3.77-6.50)], whereas noncardiac infections also showed excess risk [1.77 (1.72-1.81)]. Synergistic interactions were observed between infections and genetic risk score. A dose-response relationship was found between infection burden and CVD risks (p-trend <0.001). Infection burden >1 led to a CVD-related life loss at age 50 by 9.3 years [95% CI 8.6-10.3]) for men and 6.6 years [5.5-7.8] for women. CONCLUSIONS: The magnitude of the infection-CVD association showed specificity in sex, pathogen type, infection burden, and infection site. High genetic risk and infection synergistically increased the CVD risk.
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Doenças Cardiovasculares , Infecção Hospitalar , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Fatores de Risco , Expectativa de Vida , HospitaisRESUMO
Fusarium diseases pose a severe global threat to major cereal crops, particularly wheat. Existing biocontrol strains against Fusarium diseases are believed to primarily rely on antagonistic mechanisms, but not widely used under field conditions. Here, we report an endophytic fungus, Purpureocillium lilacinum YZ1, that shows promise in combating wheat Fusarium diseases. Under glasshouse conditions, YZ1 inoculation increased the survival rate of Fusarium graminearum (Fg)-infected wheat seedlings from 0% to > 60% at the seedling stage, and reduced spikelet infections by 70.8% during anthesis. In field trials, the application of YZ1 resulted in an impressive 89.0% reduction in Fg-susceptible spikelets. While a slight antagonistic effect of YZ1 against Fg was observed on plates, the induction of wheat systemic resistance by YZ1, which is distantly effective, non-specific, and long-lasting, appeared to be a key contributor to YZ1's biocontrol capabilities. Utilizing three imaging methods, we confirmed YZ1 as a potent endophyte capable of rapid colonization of wheat roots, and systematically spreading to the stem and leaves. Integrating dual RNA-Seq, photosynthesis measurements and cell wall visualization supported the link between YZ1's growth-promoting abilities and the activation of wheat systemic resistance. In conclusion, endophytes such as YZ1, which exhibits non-antagonistic mechanisms, hold significant potential for industrial-scale biocontrol applications.
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Resistência à Doença , Endófitos , Fusarium , Doenças das Plantas , Triticum , Fusarium/fisiologia , Fusarium/patogenicidade , Triticum/microbiologia , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Endófitos/fisiologia , Hypocreales/fisiologia , Hypocreales/patogenicidade , Raízes de Plantas/microbiologia , Plântula/microbiologia , Regulação da Expressão Gênica de PlantasRESUMO
BACKGROUND: Large population-based prospective studies are necessary to provide clarification on the associations of panoramic secondhand smoking burden, including prenatal and postnatal secondhand smoke (SHS) exposure, with the risk of developing dementia. METHODS: Our study comprised a sample of 353,756 dementia-free individuals from the UK Biobank who were nonsmokers had data on the exposure of maternal smoking as well as SHS exposure in daily life, which was quantified in terms of hours per week (h/week) and whether they lived with household smokers. Multivariable Cox regression models were utilized to analyze the independent and joint associations of maternal smoking and daily life SHS exposure with dementia risk. RESULTS: During a median follow-up of 11.8 years, 4,113 participants developed dementia. Compared with those who lived in the environment without smokers, multivariable-adjusted hazard ratios (HRs) (95% CIs) were 1.11 (1.02, 1.20) and 1.31 (1.13, 1.52) for those who exposed to SHS for >0 but ≤4 h/week and >4 h/week, respectively, and was 1.25 (1.13, 1.39) for those who lived with smokers in the household. A positive history of maternal smoking was associated with a modestly higher risk of dementia (HR = 1.07; 95% CI: 1.01, 1.15). Furthermore, compared with participants with neither history of maternal smoking nor exposure to SHS, a particularly higher risk of dementia was observed among those with both exposures (HR = 1.48; 95% CI: 1.18, 1.86). Additionally, the HR (95% CI) was 1.32 (1.10, 1.59) when comparing participants with a history of maternal smoking who lived with smokers in their households with those who had neither exposures. CONCLUSIONS: Having a history of maternal smoking, longer exposure to SHS, and living with smokers in the household were each associated with an increased risk of developing dementia. Individuals who were simultaneously exposed to maternal smoking and SHS or lived with household smokers had a particularly higher dementia risk.
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Demência , Poluição por Fumaça de Tabaco , Humanos , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Demência/epidemiologia , Demência/etiologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Estudos de Coortes , Reino Unido/epidemiologia , Adulto , Fatores de Risco , Estudos Prospectivos , não Fumantes/estatística & dados numéricos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologiaRESUMO
BACKGROUND: How physical activity (PA) and different sleep traits and overall sleep pattern interact in the development of Parkinson's disease (PD) remain unknown. OBJECTIVE: To prospectively investigate the joint associations of PA and sleep pattern with risk of PD. METHODS: Included were 339,666 PD-free participants from the UK Biobank. Baseline PA levels were grouped into low (< 600 MET-mins/week), medium (600 to < 3000 MET-mins/week) and high (≥ 3000 MET-mins/week) according to the instructions of the UK Biobank. Healthy sleep traits (chronotype, sleep duration, insomnia, snoring, and daytime sleepiness) were scored from 0 to 5 and were categorized into "ideal sleep pattern" (≥ 3 sleep scores) and "poor sleep pattern" (0-2 sleep scores). Hazard ratios (HRs) and 95% confidence intervals (CIs) of PD were estimated by Cox proportional hazards models. RESULTS: During a median of 11.8 years of follow-up, 1,966 PD events were identified. The PD risk was lower in participants with high PA (HR = 0.73; 95% CI: 0.64, 0.84), compared to those with low PA; and participants with ideal sleep pattern also had a lower risk of PD (HR = 0.78; 95% CI: 0.69, 0.87), compared to those with poor sleep pattern. When jointly investigating the combined effect, participants with both high PA and ideal sleep pattern had the lowest risk of incident PD (HR = 0.55; 95% CI: 0.44, 0.69), compared to those with low PA and poor sleep pattern; notably, participants with high PA but poor sleep pattern also gained benefit on PD risk reduction (HR = 0.74; 95% CI: 0.55, 0.99). CONCLUSIONS: Both high PA and ideal sleep pattern were independently associated with lower risk of developing PD, and those with both high PA level and ideal sleep pattern had the lowest risk. Our results suggest that improving PA levels and sleep quality may be promising intervention targets for the prevention of PD.
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Doença de Parkinson , Humanos , Estudos de Coortes , Doença de Parkinson/epidemiologia , Sono , Exercício Físico , Comportamento de Redução do Risco , Fatores de RiscoRESUMO
Herein, a palladium-catalyzed diastereoselective dearomatization/cross-coupling cyclization reaction between N-arylacyl indoles and (E)-ß-chlorovinyl ketones is reported. Through this cyclization/cycloisomerization cascade, a series of furan-containing indolines were obtained in yields up to 95%. The reaction features readily accessible starting materials, benzyl Pd(II)-catalyzed cycloisomerization of (E)-ß-chlorovinyl ketones, the sequential formation of three bonds and bis-heterocycles, and excellent diastereoselectivity. More importantly, the carbene-secondary benzyl migratory insertion is proven to be a critical process in the sequential cyclizations.
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BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital coronary anomaly with the potential to cause adverse cardiac events. However, there is limited data on the association between AAOCA and coronary artery disease (CAD). Therefore, the aim of this study is to determine the prevalence and symptoms of patients with AAOCA, as well as investigate the correlation between AAOCA and CAD in a population referred for coronary computed tomographic angiography (CTA). METHODS AND RESULTS: All consecutive patients who underwent CTA from 2010 to 2021 were included. Characteristics, symptoms, coronary related adverse events and CTA information were reviewed by medical records. Separate multivariable cumulative logistic regressions were performed, using the stenosis severity in each of the four coronaries as individual responses and as a combined patient clustered response. Finally, we identified 207 adult patients with AAOCA, the prevalence of AAOCA is 0.23% (207/90,501). Moreover, this study found no significant association between AAOCA and CAD. AAOCA did not contribute to higher rates of hospitalization or adverse cardiac events, including calcification. CONCLUSION: AAOCA is a rare congenital disease that is not associated with increased presence of obstructive CAD in adults.
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Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana , Anomalias dos Vasos Coronários , Valor Preditivo dos Testes , Humanos , Anomalias dos Vasos Coronários/diagnóstico por imagem , Anomalias dos Vasos Coronários/epidemiologia , Prevalência , Masculino , Feminino , Pessoa de Meia-Idade , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Idoso , Estudos Retrospectivos , Adulto , Fatores de Risco , Medição de Risco , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: Psoriatic arthritis (PsA) is the most prevalent coexisting condition associated with psoriasis. Early-stage PsA patients always present unspecific and subtle clinical manifestations causing delayed diagnosis and leading to unfavorable health outcomes. The application of ultrasound enables precise identification of inflammatory changes in musculoskeletal structures. Hence, we constructed ultrasound models to aid early diagnosis of PsA. METHODS: This is a cross-sectional study carried out in the Department of Dermatology at West China Hospital (October 2018-April 2021). All participants underwent thorough ultrasound examinations. Participants were classified into the under 45 group (18 ≤ age ≤ 45) and over 45 group (age > 45) and then randomly grouped into derivation and test cohort (7:3). Univariable logistic regression, least absolute shrinkage and selection operator, and multivariable logistic regression visualized by nomogram were conducted in order. Receiver operating characteristic (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA) were performed for model verification. RESULTS: A total of 1256 participants were included, with 767 participants in the under 45 group and 489 in the over 45 group. Eleven and sixteen independent ultrasonic variables were finally selected to construct the under 45 and over 45 model with the area under the ROC of 0.83 (95%CI: 0.78-0.87) and 0.83 (95%CI: 0.78-0.88) in derivation cohort, respectively. The DCA and CICA analyses showed good clinical utility of the two models. CONCLUSION: The implementation of the ultrasound models could streamline the diagnostic process for PsA in psoriasis patients, leading to expedited evaluations while maintaining diagnostic accuracy.
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Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement. Conversely, hemophagocytic lymphohistiocytosis (HLH) is an infrequent yet critical condition presenting with fever, hepatosplenomegaly, cytopenias, coagulation abnormalities, and elevated inflammatory markers. The overlapping clinical and laboratory features between DRESS and HLH poses a significant diagnostic challenge. Secondary HLH (sHLH) typically occurs in adults triggered by viral infections, malignancies, rheumatologic diseases, or immune deficiencies. Recently, COVID-19 has also been identified as one of the triggers for sHLH. Herein, we present a case of Sulfasalazine-induced DRESS coinfected with COVID-19 that subsequently progressed into HLH. Our patient exhibited common hepatorenal and splenic involvement along with rare cholecystitis and appendicitis. However, a significant improvement was observed upon the addition of etoposide and azathioprine. We hypothesize that excessive activation of the immune system and cytokine storm due to DRESS combined with COVID-19 infection led to more extensive systemic damage resulting in HLH development. This highlights the potential for severe consequences when DRESS coincides with HLH during a COVID-19 infection.
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COVID-19 , Coinfecção , Síndrome de Hipersensibilidade a Medicamentos , Linfo-Histiocitose Hemofagocítica , SARS-CoV-2 , Sulfassalazina , Humanos , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , COVID-19/complicações , COVID-19/imunologia , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Sulfassalazina/efeitos adversos , Coinfecção/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , FemininoRESUMO
Background: Few studies have analysed oxaliplatin-induced adverse events (ADEs) in the immune system and skin and subcutaneous tissues through pharmacovigilance. We used this approach to analyse the risk of such ADEs when oxaliplatin combined with immune checkpoint inhibitors (ICIs). Methods: We evaluated the association between oxaliplatin and ADEs in the immune system and skin and subcutaneous tissues using the reporting odd ratio (ROR) for mining the ADE report signals in the FDA Adverse Event Reporting System database. Risk factors were analyzed using a binary logistic regression analysis using the sex and age of the patients. Results: There were 40,474 reports of oxaliplatin as primary suspect drug or second suspect drug. The signal intensities of ADEs such as type II hypersensitivity, type I hypersensitivity, type III immune complex-mediated reaction, anaphylactoid shock and cytokine release syndrome were high in PTs classified by SOC as immune system disorders; in the PTs classified as skin and subcutaneous tissue disorders by SOC, the signal intensities of ADEs such as skin toxicity, skin reaction, rash maculo-papular and skin fissures were higher. In the risk assessment between the two groups, rash showed an increased risk in the oxaliplatin-ICI group, with an OR of 1.96. Nivolumab in combination with oxaliplatin had an OR of 2.196 and an adjusted OR of 2.231. Combined with pembrolizumab, OR was 2.762 and the adjusted OR was 2.678. Conclusion: Type II hypersensitivity shows a stronger pharmacovigilance signal. Oxaliplatin in combination with nivolumab or pembrolizumab has been shown to increase the risk of rash.
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Straightforward, sensitive, and specific human immunodeficiency virus (HIV) assays are urgently needed. The creation of a point-of-care (POC) device for decentralized diagnostics has the potential to significantly reduce the time to treatment, especially for infectious diseases. Notably, however, many POC solutions proposed to date fall short of meeting the ASSURED guidelines, which are crucial for effective deployment in the field. Herein, we developed a DNA biosensor platform for the specific and quantitative detection of HIV. The platform contains a rolling circle amplification (RCA)-based DNA biosensor and a portable fluorescence detector, in which HIV-encoded integrase (IN) enzyme activity is used as a biomarker to achieve HIV-specific detection. The cleavage and integration reaction of IN on the sensor surface and RCA are combined in this detection platform to perform detection signal cascade amplification, ultimately achieving a detection limit of 0.125 CFU/µL of HIV particles. Moreover, the DNA sensor system exhibited high sensitivity and accuracy for detecting HIV in clinical samples, suggesting that it has potential for application in clinical settings to detect retroviruses other than HIV. In addition, quantitative detection based on this biosensing platform was significantly correlated with the CD4+ lymphocytes count, which can provide guidance for antiretroviral therapy and which affects long-term death risk assessment in HIV patients. Therefore, this DNA biosensing platform based on IN activity is expected to be useful for rapid HIV testing, diagnosis, and treatment monitoring, enabling the development of new POC diagnostic tests and will thus be highly valuable for developing HIV prevention strategies and effective treatments.
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This study investigates innovative approaches to improve the quality and aroma characteristics of Muscat Hamburg wine production by substituting the conventional Saccharomyces cerevisiae yeast with an efficient fermentation strain of Schizosaccharomyces pombe. The typical use of S. cerevisiae in Muscat Hamburg wine often leads to uniformity and prolonged processing times, requiring subsequent malolactic fermentation to degrade excessive malic acid. The study advocates for the replacement of S. cerevisiae with a specific S. pombe strain, Sp-410, isolated from the fermented grains of sauce-flavor Baijiu, a Chinese spirit. Muscat Hamburg wine fermented with the S. pombe strain demonstrates decreased malic acid levels, offering a potential alternative to malolactic fermentation. However, exclusive S. pombe fermentation may result in an overproduction of acetic acid metabolites, leading to a monotonous taste. In response, the study proposes a mixed fermentation approach, combining the S. pombe strain with a Saccharomyces uvarum strain and a non-Saccharomyces yeast, Torulaspora delbrueckii. The optimized mixed fermentation strategies (M:SP+TD and M60SP+TD) involve specific proportions and intervals of inoculation, aiming to enhance the quality and aroma complexity of Muscat Hamburg wine. In conclusion, this research contributes to advancing the production of high-quality Muscat Hamburg wines, utilizing S. pombe as the primary yeast strain and implementing mixed fermentation methodologies.
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BACKGROUND: The current understanding of the magnitude and consequences of multimorbidity in Chinese older adults with coronary heart disease (CHD) is insufficient. We aimed to assess the association and population-attributable fractions (PAFs) between multimorbidity and mortality among hospitalized older patients who were diagnosed with CHD in Shenzhen, China. METHODS: We conducted a retrospective cohort study of older Chinese patients (aged ≥ 65 years) who were diagnosed with CHD. Cox proportional hazards models were used to estimate the associations between multimorbidity and all-cause and cardiovascular disease (CVD) mortality. We also calculated the PAFs. RESULTS: The study comprised 76,455 older hospitalized patients who were diagnosed with CHD between January 1, 2016, and August 31, 2022. Among them, 70,217 (91.9%) had multimorbidity, defined as the presence of at least one of the predefined 14 chronic conditions. Those with cancer, hemorrhagic stroke and chronic liver disease had the worst overall death risk, with adjusted HRs (95% CIs) of 4.05 (3.77, 4.38), 2.22 (1.94, 2.53), and 1.85 (1.63, 2.11), respectively. For CVD mortality, the highest risk was observed for hemorrhagic stroke, ischemic stroke, and chronic kidney disease; the corresponding adjusted HRs (95% CIs) were 3.24 (2.77, 3.79), 1.91 (1.79, 2.04), and 1.81 (1.64, 1.99), respectively. All-cause mortality was mostly attributable to cancer, heart failure and ischemic stroke, with PAFs of 11.8, 10.2, and 9.1, respectively. As for CVD mortality, the leading PAFs were heart failure, ischemic stroke and diabetes; the corresponding PAFs were 18.0, 15.7, and 6.1, respectively. CONCLUSIONS: Multimorbidity was common and had a significant impact on mortality among older patients with CHD in Shenzhen, China. Cancer, heart failure, ischemic stroke and diabetes are the primary contributors to PAFs. Therefore, prioritizing improved treatment and management of these comorbidities is essential for the survival prognosis of CHD patients from a holistic public health perspective.
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BACKGROUND: To assess the roles of diabetic microvascular disease and modifiable risk factors and their combination in the development of arrhythmias. METHODS: We included participants with type 2 diabetes (T2D) who were free of arrhythmias during recruitment in the UK Biobank study. The associations of microvascular disease states (defined by the presence of retinopathy, peripheral neuropathy or chronic kidney disease), four modifiable arrhythmic risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin) and their joint associations with incident arrhythmias were examined. RESULTS: Among the 25 632 participants with T2D, 1705 (20.1%) of the 8482 with microvascular disease and 2017 (11.8%) of the 17 150 without microvascular disease developed arrhythmias during a median follow-up of 12.3 years. Having any of the three microvascular diseases was associated with a 48% increase in the hazard of developing arrhythmias. Incorporating microvascular disease states into a model alongside 11 traditional risk factors significantly enhanced arrhythmia prediction. Furthermore, individuals with microvascular disease who had optimal levels of zero to one, two, three or four arrhythmic risk factors showed an HR of 2.05 (95% CI 1.85, 2.27), 1.67 (95% CI 1.53, 1.83), 1.35 (95% CI 1.22, 1.50) and 0.91 (95% CI 0.73, 1.13), respectively, compared with those without microvascular disease. CONCLUSIONS: Although microvascular disease, a non-traditional risk factor, was associated with incident arrhythmias in individuals with T2D, having optimal levels of risk factors may mitigate this risk.
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Arritmias Cardíacas , Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/etiologia , Incidência , Reino Unido/epidemiologia , Fatores de Risco , Idoso , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/diagnóstico , Medição de Risco/métodos , Índice de Massa Corporal , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
Background: Refractory diabetic wounds are a common occurrence in patients with diabetes and epidermis-specific macroautophagy/autophagy impairment has been implicated in their pathogenesis. Therefore, identifying and developing treatment strategies capable of normalizing epidermis-specific macroautophagy/autophagy could facilitate diabetic wound healing. The study aims to investigate the potential of bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) from hypoxic conditions as a treatment to normalize epidermis-specific autophagy for diabetic wound healing. Methods: We compared the effects of bone marrow mesenchymal stem cell (BMSC)-sourced exosomes (BMSC-Exos) from hypoxic conditions to those of BMSC in normoxic conditions (noBMSC-Exos). Our studies involved morphometric assessment of the exosomes, identification of the microRNA (miRNA) responsible for the effects, evaluation of keratinocyte functions and examination of effects of the exosomes on several molecules involved in the autophagy pathway such as microtubule-associated protein 1 light chain 3 beta, beclin 1, sequestosome 1, autophagy-related 5 and autophagy-related 5. The experiments used human BMSCs from the American Type Culture Collection, an in vivo mouse model of diabetes (db/db) to assess wound healing, as well as the human keratinocyte HaCaT cell line. In the methodology, the authors utilized an array of approaches that included electron microscopy, small interfering RNA (siRNA) studies, RNA in situ hybridization, quantitative real-time reverse transcription PCR (qRT-PCR), the isolation, sequencing and differential expression of miRNAs, as well as the use of miR-4645-5p-specific knockdown with an inhibitor. Results: Hypoxia affected the release of exosomes from hypoxic BMSCs (hy-BMSCs) and influenced the size and morphology of the exosomes. Moreover, hyBMSC-Exo treatment markedly improved keratinocyte function, including keratinocyte autophagy, proliferation and migration. miRNA microarray and bioinformatics analysis showed that the target genes of the differentially expressed miRNAs were mainly enriched in 'autophagy' and 'process utilizing autophagic mechanism' in the 'biological process' category and miR-4645-5p as a major contributor to the pro-autophagy effect of hyBMSC-Exos. Moreover, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) was identified as a potential target of exosomal miR-4645-5p; this was confirmed using a dual luciferase assay. Exosomal miR-4645-5p mediates the inactivation of the MAPKAPK2-induced AKT kinase group (comprising AKT1, AKT2, and AKT3), which in turn suppresses AKT-mTORC1 signaling, thereby facilitating miR-4645-5p-mediated autophagy. Conclusions: Overall, the results of this study showed that hyBMSC-Exo-mediated transfer of miR-4645-5p inactivated MAPKAPK2-induced AKT-mTORC1 signaling in keratinocytes, which activated keratinocyte autophagy, proliferation and migration, resulting in diabetic wound healing in mice. Collectively, the findings could aid in the development of a novel therapeutic strategy for diabetic wounds.
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Objectives: Lung adenocarcinomas have different prognoses depending on their histological growth patterns. Micropapillary growth within lung adenocarcinoma, particularly metastasis, is related to dismal prognostic outcome. Metastasis accounts for a major factor leading to mortality among lung cancer patients. Understanding the mechanisms underlying early stage metastasis can help develop novel treatments for improving patient survival. Methods: Here, quantitative mass spectrometry was conducted for comparing protein expression profiles among various histological subtypes, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma (including acinar and micropapillary [MIP] types). To determine the mechanism of MIP-associated metastasis, we identified a protein that was highly expressed in MIP. The expression of the selected highly expressed MIP protein was verified via immunohistochemical (IHC) analysis and its function was validated by an in vitro migration assay. Results: Proteomic data revealed that low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) was highly expressed in MIP group, which was confirmed by IHC. The co-expressed proteins in this study, PSMD1 and HSP90AB1, have been reported to be highly expressed in different cancers and play an essential role in metastasis. We observed that LRPAP1 promoted lung cancer progression, including metastasis, invasion and proliferation in vitro and in vivo. Conclusion: LRPAP1 is necessary for MIP-associated metastasis and is the candidate novel anti-metastasis therapeutic target.
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BACKGROUND: The prevalence and outcomes of coronavirus 2019 (COVID-19) among patients using glucocorticoids and immunosuppressants remain controversial. AIM: The study aims to investigate the impact of immunosuppressants especially glucocorticoids on patients in the Autoimmune Bullous Diseases Cohort of West China Hospital (AIBDWCH) during COVID-19. METHODS: We conducted a cross-sectional survey from December 7, 2022, to February 8, 2023, using questionnaires administered either face-to-face or by phone. COVID-19 cases were classified as confirmed, probable, or suspected according to World Health Organization criteria. Patients were divided into Group A (confirmed and probable cases) and Group B (suspected and other cases). The impact of glucocorticoids and immunosuppressive agents on COVID-19 disease and progression was evaluated with logistic regression models. RESULTS: This study included 111 patients with pemphigus. Overweight patients had a reduced risk of confirmed COVID-19 (odds ratio [OR] 0.35 [95 % CI 0.13-0.97], p = 0.045). Patients treated with a medium dose of prednisone during the pandemic had a lower incidence of COVID-19 compared to those on low doses, though the difference was not statistically significant. No independent effects of age, sex, comorbidities, and therapies were observed. No significant differences were found in COVID-19 symptoms among different therapy groups. CONCLUSIONS: Treatment with immunosuppressants, particularly glucocorticoids at low-to-medium doses, did not elevate COVID-19 risk in pemphigus patients. Consistent outcomes across treatments confirm the safety of these therapies during the pandemic.
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COVID-19 , Glucocorticoides , Imunossupressores , Pênfigo , Humanos , Pênfigo/tratamento farmacológico , Pênfigo/epidemiologia , COVID-19/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Estudos Transversais , Adulto , Idoso , Glucocorticoides/uso terapêutico , Glucocorticoides/efeitos adversos , China/epidemiologia , SARS-CoV-2 , Inquéritos e Questionários , Fatores de RiscoRESUMO
CONTEXT: The interplay between cardiovascular health metrics (CVHMs) and microvascular disease (MVD) in relation to the risk of incident coronary heart disease (CHD) among individuals with type 2 diabetes mellitus (T2DM) remains to be evaluated. OBJECTIVE: To investigate the role of MVD and CVHMs in the development of CHD among T2DM. DESIGN: We included 19 664 participants with T2DM from the UK Biobank who had CVHM data and were free of CHD during recruitment. CVHMs were defined based on 5 behavioral (body mass index, diet, sleep duration, smoking, and regular exercise) and 3 biological (glycemic control, hyperlipidemia, and hypertension) factors. MVD was defined as the presence of retinopathy, peripheral neuropathy, or chronic kidney disease. Hazard ratio (HR) and 95% CI of CHD were estimated by multivariable Cox regression models. RESULTS: There were 3252 incident cases of CHD recorded after a median follow-up of 12.3 years. After multivariable adjustment, each MVD was separately associated with risk of CHD, and those who had 1 or ≥â¯2 MVD had a 27% and an 87% increased risk of developing CHD, respectively. Each unfavorable CVHM was associated with a higher risk of CHD. As compared with MVD-free participants who had ideal CVHMs, those who had ≥â¯2 MVD and had poor CVHMs were at particularly high risk of incident CHD (HR = 4.58; 95% CI: 3.58, 5.86), similarly when considering behavioral CVH or biological CVH separately. On an additive scale, there was a positive statistically significant interaction between number of MVD and CVHMs. CONCLUSION: Coexistence of multiple MVDs was associated with a substantially higher risk of CHD among individuals with T2DM. Such association may be amplified by unfavorable CVHMs.
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Bancos de Espécimes Biológicos , Doença das Coronárias , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Reino Unido/epidemiologia , Pessoa de Meia-Idade , Doença das Coronárias/epidemiologia , Doença das Coronárias/etiologia , Idoso , Fatores de Risco , Incidência , Adulto , Seguimentos , Microvasos/patologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Biobanco do Reino UnidoRESUMO
BACKGROUND: Sex differences exist in the prevalence of microvascular disease (MVD) and healthy-lifestyle adherence. Whether MVD and healthy lifestyles are associated with mortality risk similarly for women and men who have type 2 diabetes mellitus (T2DM) remains unknown. METHODS: The present study included 9992 women and 15,860 men with T2DM from the UK Biobank. MVDs included retinopathy, peripheral neuropathy, and chronic kidney disease. Healthy lifestyle factors consisted of ideal BMI, nonsmoking, healthy diet, regular exercise, and appropriate sleep duration. Sex-specific hazard ratios (HRs) of mortality associated with the MVDs or healthy lifestyles were calculated and women-to-men ratio of HRs (RHR) were further estimated, after multivariable adjustment for potential confounders. RESULTS: During a median of 12.7 years of follow-up, 4346 (1202 in women) all-cause and 1207 (254 in women) CVD deaths were recorded. The adjusted HRs (95% CI) of all-cause mortality for 1 additional increment of the MVDs were 1.71 (1.55, 1.88) for women and 1.48 (1.39, 1.57) for men, with an RHR of 1.16 (1.03, 1.30). The corresponding RHR was 1.36 (1.09, 1.69) for cardiovascular mortality. Adhering to a healthy lifestyle (≥4 vs. ≤1 lifestyle factor) was associated with an approximately 60%-70% lower risk of all-cause and cardiovascular mortality without sex differences (P-interaction >0.70). Furthermore, as compared with having no MVD and an unfavorable lifestyle, having ≥2 MVDs but a favorable lifestyle was not associated with a higher risk of all-cause mortality either in women (HR = 0.88; 95% CI: 0.49, 1.60) or in men (HR = 0.95; 95% CI: 0.64, 1.40), similarly when considering cardiovascular mortality. CONCLUSIONS: In T2DM, while MVDs are more strongly associated with mortality risk in women than in men, adhering to a favorable lifestyle is associated with a substantially lower risk of mortality and may eliminate the detrimental impact of MVDs in both sexes.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Feminino , Masculino , Fatores de Risco , Estilo de Vida Saudável , Estilo de VidaRESUMO
Diabetic wounds remain a global challenge due to disordered wound healing led by inflammation, infection, oxidative stress, and delayed proliferation. Therefore, an ideal wound dressing for diabetic wounds not only needs tissue adhesiveness, injectability, and self-healing properties but also needs a full regulation of the microenvironment. In this work, adhesive wound dressings (HA-DA/PRP) with injectability were fabricated by combining platelet rich plasma (PRP) and dopamine-modified-hyaluronic acid (HA-DA). The engineered wound dressings exhibited tissue adhesiveness, rapid self-healing, and shape adaptability, thereby enhancing stability and adaptability to irregular wounds. The in vitro experiments demonstrated that HA-DA/PRP adhesives significantly promoted fibroblast proliferation and migration, attributed to the loaded PRP. The adhesives showed antibacterial properties against both gram-positive and negative bacteria. Moreover, in vitro experiments confirmed that HA-DA/PRP adhesives effectively mitigated oxidative stress and inflammation. Finally, HA-DA/PRP accelerated the healing of diabetic wounds by inhibiting bacterial growth, promoting granulation tissue regeneration, accelerating neovascularization, facilitating collagen deposition, and modulating inflammation through inducing M1 to M2 polarization, in an in vivo model of infected diabetic wounds. Overall, HA-DA/PRP adhesives with the ability to comprehensively regulate the microenvironment in diabetic wounds may provide a novel approach to expedite the diabetic wounds healing in clinic.