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Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.
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Cápsulas , Matriz Extracelular , Imunomodulação , Células-Tronco Mesenquimais , Fibrose Pulmonar , Animais , Matriz Extracelular/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Fibrose Pulmonar/terapia , Fibrose Pulmonar/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos Endogâmicos C57BL , Hidrogéis/química , Camundongos , MasculinoRESUMO
BACKGROUND: Although whole-body vibration (WBV) training is acknowledged for its benefits in enhancing motor functions across several neurological disorders, its precise influence on ankle joint proprioception and balance in stroke patients is still not well understood. This research seeks to assess the impact of WBV training on ankle joint proprioception and balance in stroke patients, thereby filling this important research void. METHODS: In this prospective cohort study, thirty-five stroke patients were randomly assigned to either the WBV group (n = 17) or a control group (n = 18) using a random number table method. The control group received daily general rehabilitation for four weeks, while the WBV group received an additional 30 min of WBV training each day with the Trunsan S110 Vibration Training System. Blinded outcome assessments were conducted at baseline and post-treatment, utilizing the Berg balance scale (BBS), Functional reach test (FRT), Romberg test length (RTL) and area (RTA), and completion rates of ankle joint dorsiflexion-plantar flexion (DP) and inversion-eversion (IE) tests. Follow-up assessments were performed after four weeks of intervention, focusing on RTL, RTA, DP, and IE as primary outcomes. RESULTS: Analysis of intra-group changes from baseline to post-treatment revealed significant improvements across the BBS, FRT, RTL, RTA, and DP and IE assessments (p < 0.001). Notably, the WBV group showed significant enhancements compared to the control group in DP and IE (p < 0.001 and p < 0.05, respectively), with mean values increasing from 13.556 to 16.765 (23.7%) and from 5.944 to 8.118 (36.6%), respectively. However, WBV did not provide additional benefits over the control treatment for balance recovery parameters such as BBS, FRT, RTL, and RTA (p > 0.05). CONCLUSIONS: This study demonstrates that WBV therapy is equally effective as conventional methods in enhancing proprioception and balance in stroke patients, but it does not provide additional benefits for balance recovery. WBV significantly improves proprioceptive functions, particularly in DP and IE parameters. However, it does not surpass traditional rehabilitation methods in terms of balance recovery. These findings indicate that WBV should be incorporated into stroke rehabilitation primarily to enhance proprioception rather than to optimize balance recovery. TRIAL REGISTRATION: This study was retrospectively registered in the ISRCTN Registry on 29/07/2024 ( https://www.isrctn.com/ , ISRCTN64602845).
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Articulação do Tornozelo , Equilíbrio Postural , Propriocepção , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Vibração , Humanos , Propriocepção/fisiologia , Reabilitação do Acidente Vascular Cerebral/métodos , Vibração/uso terapêutico , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Masculino , Equilíbrio Postural/fisiologia , Articulação do Tornozelo/fisiopatologia , Idoso , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Resultado do Tratamento , AdultoRESUMO
BACKGROUND: EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life. METHODS: In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations. RESULTS: We identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family's phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants. CONCLUSIONS: A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss.
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Linhagem , Transativadores , Humanos , Masculino , Feminino , Transativadores/genética , Povo Asiático/genética , Adulto , Sequenciamento do Exoma , Perda Auditiva Neurossensorial/genética , Mutação , China , População do Leste AsiáticoRESUMO
Peptide-drug conjugates (PDCs) have emerged as a promising class of targeted therapeutics with substantial pharmaceutical advantages and market potentials, which is a combination of a peptide (selective to the disease-relevant target), a linker (stable in circulation but cleavable at target site) and a cytotoxic/radioactive drug (efficacious/traceable for disease). Among existing PDCs, those based on radiopharmaceuticals (a.k.a. radioactive drugs) are valued due to their accurate imaging and targeted destruction of disease sites. It's demanded to accumulate the biological activity and pharmaceutical information of PDCs. Herein, a database PDCdb was thus constructed to systematically describe these valuable data. Particularly, biological activities for 2036 PDCs were retrieved from literatures, which resulted in 1684, 613 and 2753 activity data generated based on clinical trial, animal model and cell line, respectively. Furthermore, the pharmaceutical information for all 2036 PDCs was collected, which gave the diverse data of (a) ADME property, plasma half-life and administration approach of a PDC and (b) chemical modification, primary target, mode of action, conjugating feature of the constituent peptide/linker/drug. In sum, PDCdb systematically provided the biological activities and pharmaceutical information for the most comprehensive list of PDCs among the available databases, which was expected to attract broad interest from related communities and could be freely accessible at: https://idrblab.org/PDCdb/.
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The term metabolic-associated fatty liver disease (MAFLD), with a global prevalence estimated at 38.77%, has gradually replaced the traditional concept of non-alcoholic fatty liver disease (NAFLD). Compared to the general population, the incidence of MAFLD is notably higher among pregnant women, posing potential risks to both maternal and neonatal health. This review summarizes the latest research on MAFLD, focusing on its association with pregnancy complications. Additionally, it provides a comparative analysis with previous studies on NAFLD, presenting a comprehensive perspective for clinical management. Findings suggest that pregnant women with MAFLD face a higher risk of gestational hypertension and cesarean delivery compared to those with NAFLD, while the risk for gestational diabetes mellitus remains similar between the two conditions. Additionally, MAFLD is associated with an increased likelihood of delivering large-for-gestational-age infants and heightened risks of preterm birth and low birth weight. Current treatment strategies for MAFLD focus on lifestyle modifications, such as dietary adjustments and increased physical activity. However, there is an urgent need for the development of safe and effective pharmacological treatments, particularly tailored toward pregnant women. Future research should delve deeper into the causal relationships between MAFLD and pregnancy complications and explore optimal therapeutic approaches to improve outcomes for mothers and their infants.
Metabolic-associated fatty liver disease and pregnancy complications Metabolic-associated fatty liver disease (MAFLD) is a new term for what used to be called non-alcoholic fatty liver disease, affecting nearly two-fifths of people worldwide. It's especially concerning for pregnant women, as it can cause serious problems for both the mother and the baby. This summary looks at the latest studies on how MAFLD affects pregnant women and how it compares to the older diagnosis of NAFLD. The findings show that pregnant women with MAFLD are more likely to have high blood pressure during pregnancy and need a cesarean section. However, the chance of getting gestational diabetes is about the same for both MAFLD and NAFLD. MAFLD also increases the risk of having a baby that is too large for its gestational age, as well as the risks of preterm birth and low birth weight. Right now, the main way to treat MAFLD is through healthy lifestyle changes like diet and exercise. But there's a big need for new medicines that are safe for pregnant women. Future studies should look more into how MAFLD causes complications during pregnancy and find the best ways to treat it to help mothers and their babies.
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Objective: This investigation aimed to explore the potential causal relationship between physical activity, sedentary behavior and the risk of sepsis. Methods: Using a two-sample Mendelian randomization approach, this study evaluated the association between physical activity (including moderate to vigorous physical activity [MVPA], vigorous physical activity [VPA], and accelerometer assessed physical activity) and sedentary behaviors (including television watching, computer use, and driving) with the risk of sepsis. This assessment was based on whole-genome association study data from the UK Biobank and the FinnGen database. Causal inferences were estimated using inverse variance-weighted, weighted median, and MR-Egger methods. Sensitivity analyses were performed using Cochran's Q test, the MR-Egger intercept test, and the leave-one-out method. Results: The risk of sepsis was significantly inversely associated with genetically predicted MVPA (odds ratio [OR] 0.47, 95% confidence interval [CI] 0.24-0.93, P = 0.0296) and VPA alone (OR 0.19, 95% CI 0.04-0.87, P = 0.0324). Conversely, prolonged driving time showed a significant positive association with the risk of sepsis (OR 3.99, 95% CI 1.40-11.40, P = 0.0097). Conclusion: This study provides preliminary evidence of a causal relationship between MVPA and VPA and a reduced risk of sepsis, while prolonged sedentary behaviors such as driving are positively associated with an increased risk of sepsis. These findings provided essential scientific evidence for the development of effective sepsis prevention strategies.
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Background: Osteoarthritis (OA) can lead to chronic joint pain, and currently there are no methods available for complete cure. Utilizing the Gene Expression Omnibus (GEO) database for bioinformatics analysis combined with Mendelian randomization (MR) has been widely employed for drug repurposing and discovery of novel therapeutic targets. Therefore, our research focus is to identify new diagnostic markers and improved drug target sites. Methods: Gene expression data from different tissues of synovial membrane, cartilage and subchondral bone were collected through GEO data to screen out differential genes. Two-sample MR Analysis was used to estimate the causal effect of expression quantitative trait loci (eQTL) on OA. Through the intersection of the two, core genes were obtained, which were further screened by bioinformatics analysis for in vitro and in vivo molecular experimental verification. Finally, drug prediction and molecular docking further verified the medicinal value of drug targets. Results: In the joint analysis utilizing the GEO database and MR approach, five genes exhibited significance across both analytical methods. These genes were subjected to bioinformatics analysis, revealing their close association with immunological functions. Further refinement identified two core genes (ARL4C and GAPDH), whose expression levels were found to decrease in OA pathology and exhibited a protective effect in the MR analysis, thus demonstrating consistent trends. Support from in vitro and in vivo molecular experiments was also obtained, while molecular docking revealed favorable interactions between the drugs and proteins, in line with existing structural data. Conclusion: This study identified potential diagnostic biomarkers and drug targets for OA through the utilization of the GEO database and MR analysis. The findings suggest that the ARL4C and GAPDH genes may serve as therapeutic targets, offering promise for personalized treatment of OA.
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In recent years, with the advance of research, the role of tumor-associated neutrophils (TANs) in tumors has become a research hotspot. As important effector cells in the innate immune system, neutrophils play a key role in the immune and inflammatory responses of the body. As the first line of defense against bacterial and fungal infections, neutrophils have the ability to kill invading pathogens. In the pathological state of malignant tumors, the phenotype of neutrophils is altered and has an important regulatory function in tumor development. The C-X-C motif chemokine receptor 2(CXCR2) is a key molecule that mediates the migration and aggregation signaling pathway of immune cells, especially neutrophils. This review focuses on the regulation of CXCR2 on TANs in the process of tumorigenesis and development, and emphasizes the application significance of CXCR2 inhibitors in blocking the migration of TANs to tumors.
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The escalating costs and high failure rates have decelerated the pace of drug development, which amplifies the research interests in developing combinatorial/repurposed drugs and understanding off-target adverse drug reaction (ADR). In other words, it is demanded to delineate the molecular atlas and pharma-information for the combinatorial/repurposed drugs and off-target interactions. However, such invaluable data were inadequately covered by existing databases. In this study, a major update was thus conducted to the DrugMAP, which accumulated (a) 20831 combinatorial drugs and their interacting atlas involving 1583 pharmacologically important molecules; (b) 842 repurposed drugs and their interacting atlas with 795 molecules; (c) 3260 off-targets relevant to the ADRs of 2731 drugs and (d) various types of pharmaceutical information, including diverse ADMET properties, versatile diseases, and various ADRs/off-targets. With the growing demands for discovering combinatorial/repurposed therapies and the rapidly emerging interest in AI-based drug discovery, DrugMAP was highly expected to act as an indispensable supplement to existing databases facilitating drug discovery, which was accessible at: https://idrblab.org/drugmap/.
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The recognition of RNA N4-acetylcytidine (ac4C) modification as a significant type of gene regulation is growing; nevertheless, whether ac4C modification or the N-acetyltransferase 10 protein (NAT10, the only ac4C "writer" that is presently known) participates in thalamus hemorrhage (TH)-induced central poststroke pain (CPSP) is unknown. Here, we observed NAT10 was primarily located in the neuronal nuclei of the thalamus of mice, with Fn14 and p65. An increase of NAT10 mRNA and protein expression levels in the ipsilateral thalamus was observed from days 1 to 14 after TH. Inhibition of NAT10 by several different approaches attenuated Fn14 and p65 upregulation of TH mice, as well as tissue injury in the thalamus on the ipsilateral side, and the development and maintenance of contralateral nociceptive hypersensitivities. NAT10 overexpression increased Fn14 and p65 expression and elicited nociceptive hypersensitivities in naïve mice. Our findings suggest that ac4C modification and NAT10 participate in TH-induced CPSP by activating the NF-κB pathway through upregulating Fn14 in thalamic neurons. NAT10 could serve as a promising new target for CPSP treatment.
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Recently, great efforts have been made to advance the pilot-scale and engineering-scale applications of Fenton-like processes using various nano-metal catalysts (including nanosized metal-based catalysts, smaller nanocluster catalysts, and single-atom catalysts, etc.). This step is essential to facilitate the practical applications of advanced oxidation processes (AOPs) for these highly active nano-metal catalysts. Before large-scale implementation, these nano-metal catalysts must be converted into the effective catalyst modules (such as catalytic membranes, fluidized beds, or polypropylene sphere suspension systems), as it is not feasible to use suspended powder catalysts for large-scale treatment. Therefore, the pilot-scale and engineering applications of nano-metal catalysts in Fenton-like systems in recent years is exciting. In addition, the combination of life cycle assessment (LCA) and techno-economic analysis (TEA) can provide a useful support tool for engineering scale Fenton-like applications. This paper summarizes the designs and fabrications of various advanced modules based on nano-metal catalysts, analyzes the advantages and disadvantages of these catalytic modules, and further discusses their Fenton-like pilot scale or engineering applications. Concepts of future Fenton-like engineering applications of nano-metal catalysts were also discussed. In addition, current challenges and future expectations in pilot-scale or engineering applications are assessed in conjunction with LCA and TEA. These challenges require further technological advances to enable larger scale engineering applications in the future. The aim of these efforts is to increase the potential of nanoscale AOPs for practical wastewater treatment.
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BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.
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Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/genética , Adulto , PrognósticoRESUMO
Fluoride-ion batteries have several potential advantages over lithium-ion batteries. Materials development is still needed, however, to realize electrolytes with sufficiently high anion conductivity and compatibility with anode and cathode layers. Fluoride compounds are difficult to synthesize directly as single crystals but can be realized from oxide film precursors via topotactic chemistry techniques. Here, we create crystalline alkaline earth bismuth fluoride films BaBiF5 and SrBiF5 through oxide molecular beam epitaxy and topotactic fluorination. We characterize their ionic conductivities and demonstrate their potential as electrolytes. Finally, we realize epitaxial synthesis of BaBiF5 on BaF2 substrates, providing a route to thin film fluoride-ion battery devices.
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OBJECTIVES: The ALINA trial introduced anaplastic lymphoma kinase (ALK) inhibitors in an early-stage context, generating notable interest. This study aims to investigate the characteristics and prognostic implications of ALK rearrangement in patients with resected lung adenocarcinoma (LUAD). METHODS: We retrospectively evaluated resected LUAD cases with documented ALK status from 2008 to 2020. The association between ALK positivity and clinicopathological characteristics, molecular profiles, and outcomes was explored. RESULTS: Among 4944 cases, 238 (4.8%) were ALK-positive, correlating with younger age and non-smokers. ALK positivity was also significantly associated with pure-solid nodules, spread through air spaces, and solid-predominant adenocarcinoma. ALK-positive tumors exhibited an overall low frequency of co-mutations (e.g., TP53, STK11). ALK positivity was associated with inferior recurrence-free survival (RFS) in stage I patients who did not receive adjuvant chemotherapy while with prolonged RFS in stage II and III patients who received adjuvant chemotherapy. Notably, six patients treated with adjuvant ALK inhibitors experienced no recurrence or metastasis during the follow-up period. Additionally, the administration of ALK inhibitors significantly improved post-recurrence survival in ALK-positive patients. CONCLUSIONS: ALK positivity was associated with specific aggressive pathological features and inferior RFS in stage I LUAD. ALK-positive patients seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.
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BACKGROUND: Information about the distribution characteristics and prognostic significance of lateral lymph nodes (LLNs) on primary computed tomography (CT) scan in rectal cancer patients is lacking. METHODS: Between January 2013 and December 2016, patients with pathologically proved rectal cancer and pretreatment abdominal enhanced CT in our department were screened. We firstly redivided LLNs into seven categories based on their locations. Then, the number and distribution of all measurable LLNs and the characteristics of the largest LLN in each lateral compartment were recorded. Furthermore, we investigated the long-term outcomes in patients with different LLN characteristics and LLN risk scoring. RESULTS: A total of 572 patients were enrolled in this study. About 80% of patients had measurable LLNs, and most patients developed measurable LLNs in the obturator cranial compartment. Lateral local recurrence (LLR) was observed in 20 patients, which accounted for 83.3% of the local recurrence (LR). Patients with the largest LLN short-axis diameter >10 mm had a poor prognosis, which was similar to that in patients with simultaneous distant metastasis (SDM). Patients with LLN risk scoring ≥2 had a worse prognosis than those with LLN risk scoring <2, while better than those with SDM. CONCLUSION: This study suggests that LLR is the main locoregional recurrence pattern. Most rectal cancer patients have measurable LLNs on primary CT scan. However, patients with enlarged LLNs <10 mm or LLN risk scoring <2 still have a significantly better prognosis than patients with SDM, which indicated the potential value of locoregional treatment for these LLNs.
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Linfonodos , Metástase Linfática , Recidiva Local de Neoplasia , Neoplasias Retais , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Retais/patologia , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Neoplasias Retais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Linfonodos/patologia , Linfonodos/diagnóstico por imagem , Prognóstico , Idoso , Recidiva Local de Neoplasia/patologia , Estudos Transversais , Adulto , Idoso de 80 Anos ou mais , Estudos RetrospectivosRESUMO
OBJECTIVES: Functional training mimics the coordinated motions of multiple muscle groups and joints performed during exercise. The purpose of this study was to compare the effects of a 12-week functional training and traditional resistance training on the performance in junior tennis players. METHODS: Trained tennis players (mean age: 16.6 years) were assigned to a traditional training group (n = 20) or functional training group (n = 20). The traditional training group received a resistance training program by their coach, while the functional training group was given Santana's Racket Sport Program. At baseline, after six weeks, and after 12 weeks (T12), the participants' tennis-specific physical fitness and functional movement screen (FMS) were evaluated. RESULTS: At T12, both training improved the values for multistage fitness test, hexagon test, planned agility test, sit and reach, and 20 metre sprint (p < 0.05); except the flexibility, functional training provided no additional advantages. At T12, functional training enhanced (p < 0.01) all seven components of the FMS, and there is a 100% probability that the total score of the FMS would be enhanced. In contrast, for the traditional training group, shoulder mobility of the FMS decreased (p = 0.03), and there was no changes in other FMS components at T12. CONCLUSIONS: Functional training is not only effective in improving tennis-specific physical fitness, but it also provides greater functional movement advantages for junior tennis players compared to traditional resistance training.
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Aptidão Física , Tênis , Humanos , Tênis/fisiologia , Adolescente , Aptidão Física/fisiologia , Masculino , Feminino , Treinamento Resistido/métodos , Movimento/fisiologia , Desempenho Atlético/fisiologiaRESUMO
Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Mutação , Análise de Célula Única , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Sequenciamento do Exoma , Feminino , Genômica , Masculino , Linfócitos T CD8-Positivos/imunologia , Pessoa de Meia-Idade , Heterogeneidade Genética , Idoso , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Primárias Múltiplas/patologiaRESUMO
Genome differential positioning within interphase nuclei remains poorly explored. We extended and validated Tyramide Signal Amplification (TSA)-seq to map genomic regions near nucleoli and pericentric heterochromatin in four human cell lines. Our study confirmed that smaller chromosomes localize closer to nucleoli but further deconvolved this by revealing a preference for chromosome arms below 36-46 Mbp in length. We identified two lamina associated domain subsets through their differential nuclear lamina versus nucleolar positioning in different cell lines which showed distinctive patterns of DNA replication timing and gene expression across all cell lines. Unexpectedly, active, nuclear speckle-associated genomic regions were found near typically repressive nuclear compartments, which is attributable to the close proximity of nuclear speckles and nucleoli in some cell types, and association of centromeres with nuclear speckles in human embryonic stem cells (hESCs). Our study points to a more complex and variable nuclear genome organization than suggested by current models, as revealed by our TSA-seq methodology.
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Nucléolo Celular , Centrômero , Heterocromatina , Humanos , Heterocromatina/metabolismo , Heterocromatina/genética , Nucléolo Celular/metabolismo , Nucléolo Celular/genética , Centrômero/metabolismo , Centrômero/genética , Linhagem CelularRESUMO
Solution chemistry of actinide ions is critical to understanding the solvation behaviors and hydrolysis process. Using tetravalent thorium ion Th4+ as a representative example, we investigate the local structures and dynamic behaviors of hydrated Th4+ ions by ab initio molecular dynamics (AIMD) simulations using the recently developed norm-conserving pseudopotentials and basis sets optimized for actinides (J.-B. Lu et al., J. Chem. Theory Comput. 2021, 17, 3360-3371). AIMD simulations reveal two distinct solvation shells, with the first shell comprising 9 water molecules at approximately rTh-O = 2.50 Å and exhibiting a tricapped trigonal prism geometry. These conclusions are confirmed through metadynamics simulations and further structural analysis. AIMD simulations also show the slight effect of temperature and counterions on the structure of the solution. The structured solvation shells of the highly charged Th4+ ion with the specific geometry, distinct from the structure of liquid water, lead to corresponding structural changes in the hydrogen bond network in water. Additionally, beyond the solvent-shared ion pair (SIP) state observed in the unbiased AIMD simulations, the metadynamics simulations reconstruct a two-dimensional free energy surface that clearly indicates the potential stability of the contact ion pair (CIP) state in the system with Cl- as a counterion. The findings in this work provide insights into the solution chemistry of actinides and serve as a reference for studying other actinide solution systems.
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Cyclo (Phe-Pro) (cFP), a cyclic dipeptide with notable antifungal, antibacterial, and antiviral properties, shows great promise for biological control of plant diseases. Produced as a byproduct by non-ribosomal peptide synthetases (NRPS), the regulatory mechanism of cFP biosynthesis remains unclear. In a screening test of 997 Tn5 mutants of Burkholderia seminalis strain R456, we identified eight mutants with enhanced antagonistic effects against Fusarium graminearum (Fg). Among these, mutant 88's culture filtrate contained cFP, confirmed through HPLC and LC-MS, which actively inhibited Fg. The gene disrupted in mutant 88 is part of the Dct transport system (Dct-A, -B, -D), responsible for C4-dicarboxylate transport. Knockout mutants of Dct genes exhibited higher cFP levels than the wild type, whereas complementary strains showed no significant difference. Additionally, the presence of exogenous C4-dicarboxylates reduced cFP production in wild type R456, indicating that these substrates negatively regulate cFP synthesis. Given that cFP synthesis is related to NRPS, we previously identified an NRPS cluster in R456, horizontally transferred from algae. Specifically, knocking out gene 2061 within this NRPS cluster significantly reduced cFP production. A Fur box binding site was predicted upstream of gene 2061, and yeast one-hybrid assays confirmed Fur protein binding, which increased with additional C4-dicarboxylates. Knockout of the Fur gene led to up-regulation of gene 2061 and increased cFP production, suggesting that C4-dicarboxylates suppress cFP synthesis by enhancing Fur-mediated repression of gene 2061.