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BACKGROUND: Due to the high prevalence of multimorbidity and realistic health service demands for fall prevention, there is growing interest in the association between multimorbidity and falls. Our study aimed to identify multimorbidity patterns among Chinese older adults and explore the association between multimorbidity patterns and falls. METHODS: Data from 4,579 Chinese community-dwelling older adults was included in this analysis. Information regarding falls and 10 chronic conditions was collected. An exploratory factor analysis was performed to determine multimorbidity patterns. Regression models were fitted to explore the associations of individual chronic disease or multimorbidity patterns with falls. RESULTS: Among 4,579 participants, 368 (8.0%) were defined as fallers, including 92 (2.0%) frequent fallers, and multimorbidity affected 2,503 (54.7%) participants. Older adults with multimorbidity were more likely to be fallers [odds ratio (OR) = 1.3, P = 0.02] and frequent fallers (OR = 1.7, P = 0.04). Three multimorbidity patterns were identified (i.e., cardiovascular-metabolic diseases, psycho-cognitive diseases and organic diseases), and the associations between psycho-cognitive diseases/organic diseases and prevalent falls or frequent falls were found to be significant. CONCLUSIONS: The psycho-cognitive disease pattern and organic disease pattern are significantly associated with falls. Therefore, more attention should be paid to patients with psycho-cognitive diseases and timely, targeted diagnostic and treatment services should be provided in fall prevention.
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Accidentes por Caídas , Vida Independiente , Multimorbilidad , Humanos , Accidentes por Caídas/prevención & control , Masculino , Anciano , Femenino , Multimorbilidad/tendencias , China/epidemiología , Anciano de 80 o más Años , Vida Independiente/tendencias , Factores de Riesgo , Estudios Transversales , Enfermedad Crónica/epidemiologíaRESUMEN
OBJECTIVE: To compare the changes in the sinonasal mucosa microbiome in patients with nasopharyngeal carcinoma (NPC) before and after radiotherapy (RT), and to explore the pathogenesis of post-irradiation chronic rhinosinusitis (PI-CRS) and its association with dysbiosis. STUDY DESIGN: Prospective cohort study. SETTING: Unicenter, Tertiary referral hospital. METHODS: Included patients newly diagnosed with NPC. Samples of ostiomeatal complex mucosa were collected before and after RT. Microbiome analysis was conducted using 16S rRNA sequencing, and statistical analysis was performed. Subgroup analyses based on RT modality (proton therapy or photon therapy) RESULTS: Total of 18 patients were enrolled in the study, with 62.1% receiving intensity-modulated proton therapy (IMPT). Corynebacterium was the most dominant genus identified in both the pre- and post-RT groups, with a visible increase in Staphylococcus and a decrease in Fusobacterium genus in post-RT group. Alpha-diversity did not significantly differ between groups, although the beta-diversity analysis revealed a dispersed microbiota in the post-RT group. The functional prediction indicated a higher relative abundance of taxonomies associated with biofilm formation in the post-RT group. The subgroup analysis revealed the above changes to be more significant in patients who received photon therapy (Intensity modulated radiation therapy, IMRT). CONCLUSIONS: This is the first study to analyze the microbiome of patients with NPC after IMPT. We identified similarities between the post-RT microenvironment and that reported in patients with CRS, with a more apparent change noted in patients treated with IMRT. Further investigation is required to further elucidate the pathogenesis of PI-CRS and its relationship to post-RT dysbiosis, particularly IMPT.
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Disbiosis , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Masculino , Femenino , Disbiosis/microbiología , Disbiosis/etiología , Persona de Mediana Edad , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/microbiología , Proyectos Piloto , Estudios Prospectivos , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/microbiología , Adulto , Anciano , Microbiota/efectos de la radiación , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodosRESUMEN
Adjuvants for vaccines with characteristics of improving adaptive immunity particularly via leverage of antigen presenting cells (APCs) are currently lacking. In a previous work we obtained a new soluble 300 kDa homogeneous ß-glucan named GFPBW1 from the fruit bodies of Granola frondosa. GFPBW1 could activate macrophages by targeting dendritic cell associated C-type lectin 1 (Dectin-1)/Syk/NF-κB signaling to achieve antitumour effects. In this study the adjuvant effects of GFPBW1 were explored with OVA-antigen and B16-OVA tumor model. We showed that GFPBW1 (5, 50, 500 µg/mL) dose-dependently promoted activation and maturation of APCs in vitro by increasing CD80, CD86 and MHC II expression. We immunized female mice with OVA in combination with GFPBW1 (50 or 300 µg) twice with an interval of two weeks. GFPBW1 markedly and dose-dependently increased OVA-specific antibody titers of different subtypes including IgG1, IgG2a, IgG2b and IgG3, suggesting that it could serve as an adjuvant for both Th1 and Th2 type immune responses. Furthermore, GFPBW1 in combination with aluminum significantly increased the titers of OVA-specific IgG2a and IgG2b, but not those of IgG1, suggesting that GFPBW1 could be used as a co-adjuvant of aluminum to compensate for Th1 deficiency. For mice immunized with OVA plus GFPBW1, no obvious pathological injury was observed in either major organs or injection sites, and no abnormalities were noted for any of the hematological parameters. When GFPBW1 served as an adjuvant in the B16-OVA cancer vaccine models, it could accomplish entire tumor suppression with preventive vaccines, and enhance antitumour efficacy with therapeutic vaccines. Differentially expressed genes were found to be enriched in antigen processing process, specifically increased tumor infiltration of DCs, B1 cells and plasma cells in the OVA plus GFPBW1 group, in accordance with its activation and maturation function of APCs. Collectively, this study systematically describes the properties of GFPBW1 as a novel potent and safe adjuvant and highlights its great potential in vaccine development.
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PURPOSE: TGFß signaling is implicated in the progression of most cancers, including esophageal adenocarcinoma (EAC). Emerging evidence indicates that TGFß signaling is a key factor in the development of resistance toward cancer therapy. EXPERIMENTAL DESIGN: In this study, we developed patient-derived organoids and patient-derived xenograft models of EAC and performed bioinformatics analysis combined with functional genetics to investigate the role of SMAD family member 3 (SMAD3) in EAC resistance to oxaliplatin. RESULTS: Chemotherapy nonresponding patients showed enrichment of SMAD3 gene expression when compared with responders. In a randomized patient-derived xenograft experiment, SMAD3 inhibition in combination with oxaliplatin effectively diminished tumor burden by impeding DNA repair. SMAD3 interacted directly with protein phosphatase 2A (PP2A), a key regulator of the DNA damage repair protein ataxia telangiectasia mutated (ATM). SMAD3 inhibition diminished ATM phosphorylation by enhancing the binding of PP2A to ATM, causing excessive levels of DNA damage. CONCLUSIONS: Our results identify SMAD3 as a promising therapeutic target for future combination strategies for the treatment of patients with EAC.
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Adenocarcinoma , Reparación del ADN , Neoplasias Esofágicas , Oxaliplatino , Proteína smad3 , Animales , Humanos , Ratones , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Organoides/efectos de los fármacos , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Fosforilación/efectos de los fármacos , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/genética , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: HER2-low triple-negative breast cancer (TNBC) accounted for up to 34%-39% of primary TNBC and 22.2%-32% of metastatic TNBC. Our study aims to explore the relationship between HER2 expression and clinicopathological characteristics, analyze the impact of HER2 expression on the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in TNBC. METHODS: This study involved 191 patients with TNBC who underwent operation after NAC from October 2021 to August 2022. Clinicopathological characteristics and the frequency of pCR were compared between HER2-low and HER2-0 TNBC. RESULTS: 42.2% (81/191) patients in our cohort were HER2-low. They exhibited differences in menopausal status, body mass index (BMI), androgen receptor (AR) expression, and histological grade (P < 0.05). Particularly, in HER2-low TNBC, AR was associated with tumor size, lymph node metastase, histological grade, and the incidence of multifocal disease (P < 0.05). The total pCR rate of entire cohor was 39.8%. Tumor size (P = 0.025), AR status (P = 0.033) and histological grade (P = 0.007) were significantly associated with the pCR rate of them, while the HER2 status did not exert a similar association. The multivariate analysis revealed that BMI (P = 0.004) and histological grade (P < 0.001) were associated with pCR of HER2-low TNBC, while tumor size (P = 0.034) and AR (P = 0.034) were associated with pCR of HER2-0 TNBC, respectively. CONCLUSIONS: In our cohort, HER2-low TNBC patients exhibits specific clinical characteristics and response features to NAC.
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Terapia Neoadyuvante , Receptor ErbB-2 , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Femenino , Terapia Neoadyuvante/métodos , Receptor ErbB-2/metabolismo , Persona de Mediana Edad , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Biomarcadores de Tumor/metabolismo , Pronóstico , Clasificación del Tumor , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genéticaRESUMEN
Eclipta prostrata L. has been used in traditional medicine and known for its liver-protective properties for centuries. Wedelolactone (WEL) and demethylwedelolactone (DWEL) are the major coumarins found in E. prostrata L. However, the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease (NAFLD) still remains to be explored. Utilizing a well-established zebrafish model of thioacetamide (TAA)-induced liver injury, the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis. Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver. The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped, and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized. Based on spatial metabolomics and transcriptomics, we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL. Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD, and presents a "multi-omics" platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.
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PURPOSE: The available data on the treatment strategy of pulsed field ablation (PFA) for patients with atrial fibrillation (AF) is limited. This study aims to provide a comparative analysis of the efficacy, safety, and procedural efficiency between PFA and cryoballoon ablation (CBA) for AF. METHODS: We conducted a comprehensive search of the EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov databases to identify trials comparing PFA with CBA for AF from their inception until December 2023. The odds ratio (OR) and mean difference (MD), along with a 95% confidence interval (CI), were utilized as measures of treatment effect. RESULTS: The analysis included 15 eligible trials with a total enrollment of 1880 patients. No significant differences were found in recurrent atrial arrhythmia (OR 0.83, 95% CI 0.64, 1.07) or periprocedural complications (OR 0.78, 95% CI 0.46, 1.30) between the two ablation techniques examined in this study. However, the PFA technique demonstrated a significantly shorter procedure time (MD -7.17, 95% CI -13.60, -0.73), but a longer fluoroscopy time (MD 2.53, 95% CI 0.87, 4.19). Similarly, PFA was found to be significantly associated with a decreased incidence of phrenic nerve palsy (OR 0.20, 95% CI 0.07, 0.59), but an increased incidence of cardiac tamponade (OR 4.07, 95% CI 1.15, 14.39). Moreover, there was a significantly higher release of troponin with PFA compared to CBA (MD 470.28, 95% CI 18.89, 921.67), while the increase in S100 protein and heart rate was significantly lower with PFA than with CBA (MD -64.41, 95% CI -105.46, -17.36), (MD -8.76, 95% CI -15.12, -2.40). CONCLUSION: The utilization of PFA provides a safer, time-saving, and tissue-specific procedure compared to CBA, while maintaining comparable success rates. This has the potential to enhance procedural efficiency and optimize resource utilization in clinical practice. These findings underscore the feasibility and promise of PFA as an alternative technique for PVI in patients with AF.
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Fibrilación Atrial , Criocirugía , Fibrilación Atrial/cirugía , Humanos , Criocirugía/métodos , Ablación por Catéter/métodosRESUMEN
PURPOSE: The high prevalence of multimorbidity in aging societies has posed tremendous challenges to the healthcare system. The aim of our study was to comprehensively assess the association of multimorbidity patterns and health-related quality of life (HRQOL) among rural Chinese older adults. METHODS: This was a cross-sectional study. Data from 4,579 community-dwelling older adults aged 60 years and above was collected by the clinical examination and questionnaire survey. Information on 10 chronic conditions was collected and the 3-Level EQ-5D (EQ-5D-3L) was adopted to measure the HRQOL of older adults. An exploratory factor analysis was performed to determine multimorbidity patterns. Regression models were fitted to explore the associations of multimorbidity patterns with specific health dimensions and overall HRQOL. RESULTS: A total of 2,503 (54.7%) participants suffered from multimorbidity, and they reported lower HRQOL compared to those without multimorbidity. Three kinds of multimorbidity patterns were identified including cardiovascular-metabolic diseases, psycho-cognitive diseases and organic diseases. The associations between psycho-cognitive diseases/organic diseases and overall HRQOL assessed by EQ-5D-3L index score were found to be significant (ß = - 0.097, 95% CI - 0.110, - 0.084; ß = - 0.030, 95% CI - 0.038, - 0.021, respectively), and psycho-cognitive diseases affected more health dimensions. The impact of cardiovascular-metabolic diseases on HRQOL was largely non-significant. CONCLUSION: Multimorbidity was negatively associated with HRQOL among older adults from rural China. The presence of the psycho-cognitive diseases pattern or the organic diseases pattern contributed to worse HRQOL. The remarkable negative impact of psycho-cognitive diseases on HRQOL necessiates more attention and relevant medical assistance to older rural adults.
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Vida Independiente , Multimorbilidad , Calidad de Vida , Población Rural , Humanos , Calidad de Vida/psicología , Anciano , Masculino , China/epidemiología , Femenino , Estudios Transversales , Población Rural/estadística & datos numéricos , Persona de Mediana Edad , Vida Independiente/psicología , Encuestas y Cuestionarios , Anciano de 80 o más Años , Enfermedad Crónica/psicología , Enfermedad Crónica/epidemiología , Estado de SaludRESUMEN
Pancreatic ß cell damage is the primary contributor to type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains nebulous. This study explored the role of ferroptosis in pancreatic ß cell damage and the protective effects of grape seed proanthocyanidin extract (GSPE). In T2DM model rats, the blood glucose, water intake, urine volume, HbA1c, and homeostasis model assessment-insulin resistance were significantly increased, while the body weight and the insulin level were significantly decreased, indicating the successful establishment of the T2DM model. MIN6 mouse insulinoma ß cells were cultured in high glucose and sodium palmitate conditions to obtain a glycolipid damage model, which was administered with GSPE, ferrostatin-1 (Fer-1), or nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering (si) RNA. GSPE and Fer-1 treatment significantly improved pancreatic ß-cell dysfunction and protected against cell death. Both treatments increased the superoxide dismutase and glutathione activity, reduced the malondialdehyde and reactive oxygen species levels, and improved iron metabolism. Furthermore, the treatments reversed the expression of ferroptosis markers cysteine/glutamate transporter (XCT) and glutathione peroxidase 4 (GPX4) caused by glycolipid toxicity. GSPE treatments activated the expression of Nrf2 and related proteins. These effects were reversed when co-transfected with si-Nrf2. GSPE inhibits ferroptosis by activating the Nrf2 signaling pathway, thus reducing ß-cell damage and dysfunction in T2DM. Therefore, GSPE is a potential treatment strategy against T2DM.
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BACKGROUND: Dried blood spot (DBS) testing provides an alternative to phlebotomy and addresses barriers to accessing healthcare experienced by some key populations. Large-scale evaluations of DBS testing programs are needed to understand their feasibility. This study evaluated the implementation of a state-wide DBS HIV and hepatitis C virus (HCV) testing pilot. METHODS: The New South Wales (NSW) DBS Pilot is an interventional cohort study of people testing for HIV antibody and/or HCV RNA from DBS samples in NSW, Australia. Participants at risk of HIV/HCV participated in testing via: 1) self-registration online with a DBS collection kit delivered and returned by conventional postal service; or 2) assisted DBS sample collection at 36 community health sites (including drug treatment and harm-minimisation services) and prisons. Participants received results by text (HIV antibody/ HCV RNA not detected) or a healthcare provider (HIV antibody/ HCV RNA detected). The RE-AIM framework was used to evaluate reach, effectiveness, adoption, and implementation. RESULTS: Reach: Between November 2016 and December 2020, 7,392 individuals were tested for HIV and/or HCV (21% self-registration, 34% assisted in community, and 45% assisted in prison). EFFECTIVENESS: Of 6,922 people tested for HIV (19% men who have sex with men, 13% living outside major cities, 21% born outside Australia), 51% (3,521/6,922) had no HIV test in the past two years, 0.1% (10/6,922) were newly diagnosed with HIV, and 80% (8/10) initiated HIV treatment within six months. Of 5,960 people tested for HCV (24% women, 35% Aboriginal and/or Torres Strait Islander, 55% recently injected drugs), 15% had detectable HCV RNA (878/5,960), and 45% (393/878) initiated treatment within six months. Adoption: By the end of 2020, DBS via assisted registration was available at 36 community sites and 21 prisons. IMPLEMENTATION: 90% of DBS cards arriving at the laboratory had the three full spots required for testing; the proportion was higher in assisted (94%) compared to online (76%) registration. CONCLUSIONS: This study demonstrated the feasibility of DBS testing for HIV and HCV in key populations including Aboriginal and Torres Strait Islander peoples, men who have sex with men, people who inject drugs, and demonstrated the utility of DBS in the prison setting.
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Infecciones por VIH , VIH-1 , Hepatitis C , Minorías Sexuales y de Género , Masculino , Humanos , Femenino , Nueva Gales del Sur , Estudios de Cohortes , Pruebas con Sangre Seca/métodos , Homosexualidad Masculina , Sensibilidad y Especificidad , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepacivirus/genética , ARN Viral , Anticuerpos Anti-VIH , VIH-1/genética , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológicoRESUMEN
To address the challenge of increasing nitrogen retention in compost, this study investigated the effects of microbial communities on denitrification and ammonia assimilation during sludge composting by inoculating microbial inoculants. The results showed that the retention rates of total Kjeldahl nitrogen (TKN) and humic acid (HA) in MIs group (with microbial inoculants) were 4.94 % and 18.52 % higher than those in the control group (CK), respectively. Metagenomic analysis showed that Actinobacteria and Proteobacteria were identified as main microorganisms contributing to denitrification and ammonia assimilation. The addition of microbial agents altered the structure of the microbial community, which in turn stimulated the expression of functional genes. During cooling period, the ammonia assimilation genes glnA, gltB and gltD in MIs were 15.98 %, 24.84 % and 32.88 % higher than those in CK, respectively. Canonical correspondence analysis revealed a positive correlation between the dominant bacterial genera from the cooling stage to the maturity stage and the levels of NO3--N, NH4+-N, HA, and TKN contents. NH4+-N was positively correlated with HA, indicating NH4+-N might be incorporated into HA. Heat map and network analyses revealed NH4+-N as a key factor affecting functional genes of denitrification and ammonia assimilation, with Nitrospira identified as the core bacteria in the microbial network. Therefore, the addition of microbial agents could increase nitrogen retention and improve compost product quality.
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Inoculantes Agrícolas , Compostaje , Aguas del Alcantarillado/microbiología , Inoculantes Agrícolas/metabolismo , Desnitrificación , Amoníaco/metabolismo , Nitrógeno/metabolismo , Bacterias/metabolismo , SueloRESUMEN
PURPOSE: The conventional surgical treatment for postinfarction left ventricular aneurysm (LVA) is open-heart repair with cardiopulmonary bypass. However, the risk of the open-heart surgery under cardiopulmonary bypass may result in an unacceptable risk for many patients with multiple comorbidities. Here, we reported a new off-pump repair technique for postinfarction apical LVA. METHODS: A new off-pump repair technique, circular banding and occlusion technique, was applied to repair the postinfarction apical LVA in 12 patients. Clinical data of all those 12 patients were retrospectively reviewed. Patients were followed up prospectively by direct interviews and echocardiographic examination. RESULTS: The new repair technique was successfully performed in all these 12 patients. Acute reduction of the LVA mouth diameter, the left ventricular (LV) end-diastolic volume and end-systolic volume, and an increase in the LV ejection fraction (EF) were immediately obtained after the repair. Patients had an uneventful postoperative course. They were in New York Heart Association class 1-2, and the LV volume and EF detected by echocardiography remained unchanged during an average 28.4 ± 9.9 months (range 13 to 45 months) follow-up. CONCLUSIONS: Circular banding and occlusion is a simple, safe, and effective off-pump repair technique for postinfarction apical LVA. It can allow effective LV remodeling and improve heart function.
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Procedimientos Quirúrgicos Cardíacos , Aneurisma Cardíaco , Humanos , Estudios Retrospectivos , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/cirugía , Resultado del Tratamiento , Aneurisma Cardíaco/diagnóstico por imagen , Aneurisma Cardíaco/etiología , Aneurisma Cardíaco/cirugía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/métodos , Función Ventricular Izquierda , Volumen SistólicoRESUMEN
Sustained autocatalysis coupled to compartment growth and division is a key step in the origin of life, but an experimental demonstration of this phenomenon in an artificial system has previously proven elusive. We show that autocatalytic reactions within compartments-when autocatalysis, and reactant and solvent exchange outpace product exchange-drive osmosis and diffusion, resulting in compartment growth. We demonstrate, using the formose reaction compartmentalized in aqueous droplets in an emulsion, that compartment volume can more than double. Competition for a common reactant (formaldehyde) causes variation in droplet growth rate based on the composition of the surrounding droplets. These growth rate variations are partially transmitted after selective division of the largest droplets by shearing, which converts growth-rate differences into differences in droplet frequency. This shows how a combination of properties of living systems (growth, division, variation, competition, rudimentary heredity and selection) can arise from simple physical-chemical processes and may have paved the way for the emergence of evolution by natural selection.
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Origen de la Vida , Reproducción , Catálisis , Difusión , AguaRESUMEN
Vegetation is an essential component of terrestrial ecosystems, influenced by climate change and human activities. Quantifying the relative contributions of climate change and human activities to vegetation dynamics is crucial for addressing global climate change. Sichuan Province is one of the essential ecological functional areas in the upper reaches of the Yangtze River, and its vegetation change is of great significance to the environmental function and ecological security of the Yangtze River Basin and southwest China. In this paper, the modified Carnegie-Ames-Stanford Approach(CASA) model was used to estimate the monthly NPP (Net Primary Productivity) of vegetation in Sichuan Province from 2000 to 2018, and the univariate linear regression analysis was used to analyze the temporal and spatial variation of vegetation NPP in Sichuan Province from 2000 to 2018. In addition, taking vegetation NPP as an index, Pearson correlation analysis, partial correlation analysis, and second-order partial correlation analysis were carried out to quantitatively analyze the contribution of climate change and human activities to vegetation NPP. Finally, the Hurst index and nonparametric Man-Kendall significance test were used to predict the future change trend of vegetation NPP in Sichuan Province. The results show that (1) from 2000 to 2018, the NPP of vegetation in Sichuan Province has a significant increasing trend (Slope = 6.09gC·m-2·a-1), with a multi-year average of 438.72 gC·m-2·a-1, showing a trend of low in the east and high in the middle. The response of vegetation NPP to altitude is different at different elevations; (2) the contribution rates of climate change and human activities to vegetation NPP change are 4.12gC·m-2·a-1 and 1.97gC·m-2·a-1, respectively. In contrast, the impact of human activities on NPP is more significant than climate change. Human activities are the main factors affecting vegetation restoration and degradation in Sichuan Province. However, the positive contribution to NPP change is less than climate change; (3) the future vegetation NPP change trend in Sichuan Province is mainly rising, and the same direction change trend is much larger than the reverse change trend. The areas with an increasing trend in the future account for 89.187% of the total area. This research helps understand the impact of climate change and human activities on vegetation change in Sichuan Province. It offers scientific bases for vegetation restoration and ecosystem management in Sichuan and the surrounding areas.
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Cambio Climático , Ecosistema , Humanos , Modelos Teóricos , Actividades Humanas , ChinaRESUMEN
Helicobacter pylori (H. pylori) is the leading risk factor for gastric carcinogenesis. Fibroblast growth factor receptor 4 (FGFR4) is a member of transmembrane tyrosine kinase receptors that are activated in cancer. We investigated the role of FGFR4 in regulating the cellular response to H. pylori infection in gastric cancer. High levels of oxidative stress signature and FGFR4 expression were detected in gastric cancer samples. Gene set enrichment analysis (GSEA) demonstrated enrichment of NRF2 signature in samples with high FGFR4 levels. H. pylori infection induced reactive oxygen species (ROS) with a cellular response manifested by an increase in FGFR4 with accumulation and nuclear localization NRF2. Knocking down FGFR4 significantly reduced NRF2 protein and transcription activity levels, leading to higher levels of ROS and DNA damage following H. pylori infection. We confirmed the induction of FGFR4 and NRF2 levels using mouse models following infection with a mouse-adapted H. pyloristrain. Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, remarkably reduced the level of NRF2 with a reduction in the size and number of gastric cancer spheroids. Mechanistically, we detected binding between FGFR4 and P62 proteins, competing with NRF2-KEAP1 interaction, allowing NRF2 to escape KEAP1-dependent degradation with subsequent accumulation and translocation to the nucleus. These findings demonstrate a novel functional role of FGFR4 in cellular homeostasis via regulating the NRF2 levels in response to H. pylori infection in gastric carcinogenesis, calling for testing the therapeutic efficacy of FGFR4 inhibitors in gastric cancer models.
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Neoplasias Gástricas , Animales , Ratones , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine characterized by a compromised intestinal epithelial barrier. Mucin glycans are crucial in preserving barrier function during bacterial infections, although the underlying mechanisms remain largely unexplored. METHODS: A cohort comprising 15 patients diagnosed with UC and 15 healthy individuals was recruited. Stool samples were collected to perform 16S rRNA gene sequencing, while biopsy samples were subjected to nanocapillary liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) to assess O-glycosylation. Gene expression was evaluated through qPCR analysis and Western blotting. Furthermore, animal experiments were conducted to investigate the effects of Escherichia coli and/or O-glycan inhibitor benzyl-α-GalNAc on the development of colitis in mice. RESULTS: Our findings revealed that the mucus barrier was disrupted during the early stages of UC, while the MUC2 protein content remained unaltered. Additionally, a noteworthy reduction in the O-glycosylation of MUC2 was observed, along with significant changes in the intestinal microbiota during the early stages of UC. These changes included a decrease in intestinal species richness and an increase in the abundance of Escherichia coli (E. coli). Moreover, subsequent to the administration of galactose or O-glycan inhibitor to intestinal epithelial cells, it was observed that the cell culture supernatant had the ability to modify the proliferation and adhesive capacity of E. coli. Furthermore, when pathogenic E. coli or commensal E. coli were cocultured with intestinal epithelium, both strains elicited activation of the NF-KB signaling pathway in epithelial cells and facilitated the expression of serine protease in comparison to the untreated control. Consistently, the inhibition of O-glycans has been observed to enhance the pathogenicity of E. coli in vivo. Furthermore, a correlation has been established between the level of O-glycans and the development of ulcerative colitis. Specifically, a reduction in the O-glycan content of MUC2 cells has been found to increase the virulence of E. coli, thereby compromising the integrity of the intestinal epithelial barrier. CONCLUSIONS: Together, there exist complex interactions between the intestinal epithelium, O-glycans, and the intestinal microbiota, which may inform the development of novel therapeutic strategies for the treatment of ulcerative colitis.
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Colitis Ulcerosa , Colitis , Escherichia coli Enteropatógena , Humanos , Ratones , Animales , Colitis Ulcerosa/patología , Mucinas/metabolismo , FN-kappa B/metabolismo , Escherichia coli Enteropatógena/metabolismo , Glicosilación , ARN Ribosómico 16S/metabolismo , Espectrometría de Masas en Tándem , Colitis/patología , Mucosa Intestinal/patología , Polisacáridos/metabolismo , Transducción de Señal , Sulfato de Dextran/metabolismo , Modelos Animales de Enfermedad , Colon/patologíaRESUMEN
Short-chain fatty acids (SCFAs), as the main metabolites of gut microbiota, are recognized as crucial players in the host's inflammatory response and metabolic disease. Imaging the spatial distributions and calculating the accurate contents of SCFAs in the heterogeneous intestinal tissue are critical to reveal their biological functions. Here, we develop an isotope-coded on-tissue derivatization method combined with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to map the spatial expressions of SCFAs in the colon tissue based on pair-labeled N,N,N-trimethyl-2-(piperazin-1-yl)ethan-1-aminium iodide (TMPA) and D3-TMPA. A noticeable increase in the MALDI-MSI sensitivity of SCFAs was achieved after on-tissue derivatization, which enables the visualization of acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, hydroxy acetic acid, and hydroxy propionic acid in the colon tissue. Moreover, the introduction of D3-TMPA-tagged SCFAs as internal standards can significantly reduce quantitation deviation from the matrix effects, ensuring the quantitative MALDI-MSI of SCFAs. We further used this method to characterize the spatial alterations of SCFAs in the colon tissues of mice with enterocolitis. The development of this strategy provides a reliable approach to image the spatial expressions of SCFAs in tissues and paves an insight way to study the roles of SCFAs in the gut microbiota and disease.
Asunto(s)
Ácidos Grasos Volátiles , Propionatos , Ratones , Animales , Ácidos Grasos Volátiles/análisis , Ácido Acético , Isótopos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Ácido ButíricoRESUMEN
Background: Dried blood spot (DBS) testing for hepatitis C virus (HCV) RNA provides a sampling option that avoids venepuncture and can be carried out in a nonclinical setting. Large-scale evaluations are needed to understand how DBS testing can reduce HCV burden. This study estimated prevalence of, and factors associated with, HCV RNA and treatment initiation among people enrolled in a state-wide pilot of people testing in the NSW DBS Pilot in New South Wales, Australia. Methods: People at risk of HIV/HCV could participate via (1) self-registration online with a DBS collection kit delivered and returned by conventional postal service; or (2) assisted DBS sample collection at a community site or prison. Logistic regression was used to identify factors associated with detectable HCV RNA and treatment initiation within 6 months of testing. Results: Between September 2017 and December 2020, 5960 people were tested for HCV (76% men, 35% Aboriginal and/or Torres Strait Islander, 55% recently injected drugs): 21% online self-registration, 34% assisted registration in the community, 45% assisted registration in prison. Fifteen percent had detectable HCV RNA (878/5960). Overall, 44% (n = 386/878) of people with current HCV initiated treatment within 6 months (13% online self-registration, 27% assisted registration in the community, 61% assisted registration in prison). Testing in prison compared with the community (adjusted odds ratio [aOR], 4.28; 95% CI, 3.04-6.03) was associated with increased odds of treatment initiation. Being a woman compared with a man (aOR, 0.68; 95% CI, 0.47-0.97) was associated with reduced treatment initiation. Conclusions: The NSW DBS Pilot demonstrates the feasibility of using DBS to promote HCV testing and treatment in community and prison settings.
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The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in EAC and its precancerous condition (Barrett's esophagus, BE) has not been investigated. In the present study, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which 8 contain EAC and 6 contain BE) using bioinformatic approaches for NEKs expression in EAC and BE. We identified that several NEK members, such as NEK2 (7/8), NEK3 (6/8), and NEK6 (6/8), were significantly upregulated in EAC as compared to normal esophagus samples. Alternatively, NEK1 was downregulated in EAC as compared to the normal esophagus. On the contrary, genomic alterations of these NEKs are not frequent in EAC. We validated the above findings using qRT-PCR and the protein expression of NEKs in EAC cell lines using Western blotting and in primary EAC tissues using immunohistochemistry and immunofluorescence. Our data suggest that frequent upregulation of NEK2, NEK3, and NEK7 may be important in EAC.
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Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.