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Exosomes have emerged as a promising noninvasive biomarker for early cancer diagnosis due to their ability to carry specific bioinformation related to cancer cells. However, accurate detection of trace amount of cancer-derived exosomes in complex blood remains a significant challenge. Herein, an ultra-highly sensitive SERS sensor, powered by the branched hybridization chain reaction (bHCR) and tetrahedral DNA-based trivalent aptamer (triApt-TDN), has been proposed for precise detection of cancer-derived exosomes. Taking gastric cancer SGC-7901 cells-derived exosomes as a test model, the triApt-TDNs were constructed by conjugating aptamers specific to mucin 1 (MUC1) protein with tetrahedral DNAs and subsequently immobilized on the surface of silver nanorods (AgNRs) arrays to create SERS-active sensing chips capable of specifically capturing exosomes overexpressing MUC1 proteins. The bHCR was further initiated by the trigger aptamers (tgApts) bound to exosomes, and as a result the SERS tags were assembled into AuNP network structures with abundant SERS hotspots. By optimizing the sensing conditions, the SERS sensor showed good performance in ultra-highly sensitive detection of target exosomes within 60 min detection time, with a broad response ranging of 1.44 to 1.44 × 104 particles·µL-1 and an ultralow limit of detection capable of detecting a single exosome in 2 µL sample. Furthermore, the SERS sensor exhibited good uniformity, repeatability and specificity, and capability to distinguish between gastric cancer (GC) patients and healthy controls (HC) through the detection of exosomes in clinical human serums, indicating its promising clinical potential for early diagnosis of gastric cancer.
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Three previously undescribed pyrrolizidinone alkaloids, penicipyrrolizidinones A and B (1 and 2), possessing an unprecedented 2-methyl-2-(oct-6-enoyl)pyrrolizidin-3-one skeleton, and penicipyrrolizidinone C (3), featuring a rare 1-alkenyl-2-methyl-pyrrolizidin-3,7-dione skeleton, together with four known pyrrolidine derivatives (4-7) were isolated from the mangrove-derived fungus Penicillium sp. DM27. Their structures were elucidated through comprehensive spectroscopic analysis, theoretical calculations of ECD spectra, and the modified Mosher's method. A plausible biosynthetic pathway for penicipyrrolizidinones A-C (1-3) was proposed. Compounds 4 and 5 exhibited moderate cytotoxicity against B16-F10 melanoma cells with IC50 values of 10.5 µM and 15.5 µM, respectively.
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Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.
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STUDY DESIGN: Retrospective cohort study. OBJECTIVES: Investigate the risk factors for delayed extubation after posterior approach orthopedic surgery in patients with congenital scoliosis. METHODS: The clinical data of patients who received surgery for congenital scoliosis at the First Affiliated Hospital of Xinjiang Medical University between January 2021 and July 2023 have been gathered. Patients are categorized into the usual and the delayed extubation groups, depending on the duration of tracheal intubation after surgery. The study employs univariate and multivariate logistic regression models to examine the clinical characteristics of the two cohorts and discover potential risk factors linked to delayed extubation. In addition, a prediction model is created to visually depict the significance of each risk factor in terms of weight according to the nomogram. RESULTS: A total of 119 patients (74.8% females), with a median age of 15 years, are included. A total of 32 patients, accounting for 26.9% of the sample, encountered delayed extubation. Additionally, 13 patients (10.9%) suffered perioperative complications, with pneumonia being the most prevalent. The multivariate regression analysis revealed that the number of osteotomy segments, postoperative hematocrit, postoperative Interleukin-6 levels, and weight are predictive risk factors for delayed extubation. CONCLUSIONS: Postoperative hematocrit and Interleukin-6 level, weight, and number of osteotomy segments can serve as independent risk factors for predicting delayed extubation, with combined value to assist clinicians in evaluating the risk of delayed extubation of postoperative congenital scoliosis patients, improving the success rate of extubation, and reducing postoperative treatment time in the intensive care unit.
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Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 µmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway.
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Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Envejecimiento de la Piel , Rayos Ultravioleta , Envejecimiento de la Piel/efectos de los fármacos , Animales , Humanos , Rayos Ultravioleta/efectos adversos , Ratones , Estrés Oxidativo/efectos de los fármacos , Metaloproteinasas de la Matriz/metabolismo , Queratinocitos/efectos de los fármacos , Ratones Desnudos , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Piel/efectos de la radiación , Células HaCaT , Masculino , Melaninas/metabolismo , Colágeno/metabolismo , FemeninoRESUMEN
Objective: The causal relationship and mechanisms between lipids and glioblastoma (GBM) remain unclear. This study aims to investigate the independent causal relationship between liposomal phosphatidylcholine 16:0_22:6 (PC16) and GBM, and to identify the potential mediating role of the inflammatory factor-fibroblast growth factor 21(FGF21). Methods: Utilizing summary statistics from genome-wide association studies (GWAS) of lipids (179 types in 7174 Finnish individuals), GBM (243 cases and 287137 controls), and inflammatory factors (91 types in 14824 European individuals), a two-sample Mendelian Randomization (MR) approach was employed to establish the causal link between liposomal PC16 and GBM. Additionally, a two-step MR method was used to quantify the proportion of the causal effect of PC16 on GBM that is mediated by the inflammatory factor FGF21. Results: MR analyses revealed a strong causal relationship between PC16 and GBM (OR=1.72, 95% CI: 1.11-2.68, P=0.016), but no reverse causality was observed from GBM to PC16 (OR=1.01, 95% CI: 0.99-1.02, P=0.38). Mediation analysis showed a strong causal relationship between PC16 and the FGF21 (OR = 0.94, 95% CI: 0.89-0.99, P=0.018) as well as between FGF21 and GBM (OR = 0.42, 95% CI: 0.25-0.71, P=0.001), with the mediation effect accounting for 9.78% of the total effect. This suggests that the causal relationship between PC16 and GBM is likely mediated by the intermediary factor FGF21. No evidence of pleiotropy was found in the sensitivity analysis of these positive results. Conclusion: In summary, the findings of this study suggest that liposomal PC16 may increase the risk of GBM occurrence, and FGF21 may play a significant mediating role in this causal relationship.
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Background: Previous studies indicated that exposure to ambient fine particulate matter (PM2.5) could increase the risk of metabolic syndrome (MetS). However, the specific impact of PM2.5 chemical components remains uncertain. Methods: A national cross-sectional study of 12,846 Chinese middle-aged and older adults was conducted. Satellite-based spatiotemporal models were employed to determine the 3-year average PM2.5 components exposure, including sulfates (SO4 2-), nitrates (NO3 -), ammonia (NH4 +), black carbon (BC), and organic matter (OM). Generalized linear models were used to investigate the associations of PM2.5 components with MetS and the components of MetS, and restricted cubic splines curves were used to establish the exposure-response relationships between PM2.5 components with MetS, as well as the components of MetS. Results: MetS risk increased by 35.1, 33.5, 33.6, 31.2, 32.4, and 31.4% for every inter-quartile range rise in PM2.5, SO4 2-, NO3 -, NH4 +, OM and BC, respectively. For MetS components, PM2.5 chemical components were associated with evaluated risks of central obesity, high blood pressure (high-BP), high fasting glucose (high-FBG), and low high-density lipoprotein cholesterol (low-HDL). Conclusion: This study indicated that exposure to PM2.5 components is related to increased risk of MetS and its components, including central obesity, high-BP, high-FBG, and low-HDL. Moreover, we found that the adverse effect of PM2.5 chemical components on MetS was more sensitive to people who were single, divorced, or widowed than married people.
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Contaminantes Atmosféricos , Exposición a Riesgos Ambientales , Síndrome Metabólico , Material Particulado , Humanos , Síndrome Metabólico/etiología , Material Particulado/efectos adversos , Material Particulado/análisis , Masculino , Persona de Mediana Edad , Femenino , Estudios Transversales , Anciano , China/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Atmosféricos/efectos adversos , Factores de RiesgoRESUMEN
The pathogenesis of myocardial hypertrophy remains incompletely understood, highlighting the critical need for in-depth investigation into its pathogenesis and pathophysiology to develop innovative strategies for preventing and treating heart diseases. In this study, a model of angiotensin II (Ang II)-induced myocardial hypertrophy was established using subcutaneous administration with a micropump. Echocardiography, wheat germ agglutinin staining, and western blot analysis were used to evaluate the myocardial hypertrophy model after 5, 10, and 15â¯days of Ang II treatment. RNA-seq was employed to analyze the differential expression profile of mRNA, followed by bioinformatics analysis. Subsequently, the anti-inflammatory drug meloxicam was utilized to explore its impact on cardiac hypertrophy in mice. The findings demonstrated that mice developed myocardial hypertrophy following subcutaneous administration of Ang II. Transcriptomic analysis revealed significant changes in gene expression in the myocardium induced by Ang II, with the most pronounced differences observed at day 10. Functional analysis and verification of differentially expressed genes indicated that Ang II triggered an inflammatory response in the myocardium, leading to up-regulation of genes associated with fibrosis and apoptosis while decreasing energy metabolism; alterations were also observed in genes related to oxidative stress and calcium ion binding. Treatment with meloxicam improved Ang II-induced myocardial hypertrophy. This study not only elucidated the molecular regulatory mechanism underlying mouse myocardial hypertrophy at a transcriptional level but also provided new insights into clinical prevention and treatment strategies for cardiac diseases such as dilated cardiomyopathy and heart failure.
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The use of Virtual Reality (VR) technology, especially in medical rehabilitation, has expanded to include tactile cues along with visual stimuli. For patients with upper limb hemiplegia, tangible handles with haptic stimuli could improve their ability to perform daily activities. Traditional VR controllers are unsuitable for patient rehabilitation in VR, necessitating the design of specialized tangible handles with integrated tracking devices. Besides, matching tactile stimulation with corresponding virtual visuals could strengthen users' embodiment (i.e., owning and controlling virtual bodies) in VR, which is crucial for patients' training with virtual hands. Haptic stimuli have been shown to amplify the embodiment in VR, whereas the effect of partial tactile stimulation from tangible handles on embodiment remains to be clarified. This research, including three experiments, aims to investigate how partial tactile feedback of tangible handles impacts users' embodiment, and we proposed a design concept called TouchMark for partial tactile stimuli that could help users quickly connect the physical and virtual worlds. To evaluate users' tactile and comfort perceptions when grasping tangible handles in a non-VR setting, various handles with three partial tactile factors were manipulated in Study 1. In Study 2, we explored the effects of partial feedback using three forms of TouchMark on the embodiment of healthy users in VR, with various tangible handles, while Study 3 focused on similar investigations with patients. These handles were utilized to complete virtual food preparation tasks. The tactile and comfort perceptions of tangible handles and users' embodiment were evaluated in this research using questionnaires and interviews. The results indicate that TouchMark with haptic line and ring forms over no stimulation would significantly enhance users' embodiment, especially for patients. The low-cost and innovative TouchMark approach may assist users, particularly those with limited VR experience, in achieving the embodiment and enhancing their virtual interactive experience.
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Ovarian cancer (OC) is the deadliest malignancy of the female reproductive system. The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Despite these treatments, there remains a high rate of tumor recurrence and resistance to platinum. Recent studies have highlighted the potential anti-tumor properties of metformin (met), a traditional diabetes drug. In our study, we investigated the impact of met on the anticancer activities of cisplatin (cDDP) both in vitro and in vivo. Our findings revealed that combining met with cisplatin significantly reduced apoptosis in OC cells, decreased DNA damage, and induced resistance to cDDP. Furthermore, our mechanistic study indicated that the resistance induced by met is primarily driven by the inhibition of the ATM/CHK2 pathway and the upregulation of the Rad51 protein. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP.
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Objective: This study investigates the effect of low-dose dexmedetomidine infusion on perioperative neurocognitive function in elderly patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Patients and Methods: This double-blind trial enrolled 80 elderly ERCP patients randomized to receive dexmedetomidine (Group D) or placebo (Group S). Group D received dexmedetomidine at 0.4 µg·kg-1·h-1 starting 15 minutes before surgery until completion, along with propofol at 1.5 mg/kg for anesthesia. Group S received saline and propofol in a similar manner. Anesthesia was maintained with dexmedetomidine at 0.4 µg·kg-1·h-1 and propofol at 1-2 mg/kg during surgery. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and on postoperative days 1, 3, and 5. Primary outcome was perioperative neurocognitive disorder (PND) incidence on day 5; secondary outcomes included changes in perioperative IL-6, cortisol, S100-ß, hemodynamics, anesthesia parameters, postoperative pain, agitation scores, and adverse events. Results: All 80 patients completed the trial. On postoperative day 5, the cumulative probability of PND incidence was significantly lower in Group D than in Group S (12.5% vs 35%, P=0.018). Group D also had lower levels of IL-6 (F=199.472, P<0.001), S100-ß (F=2681.964, P<0.001), and cortisol (F=137.637, P<0.001). Propofol doses were lower in Group D (706.1 ± 202.4 vs 1003.3 ± 203.7, P<0.001), and bradycardia rates were higher (45% vs 15%, P=0.003), though atropine use did not significantly differ between groups. Group D showed greater stability in mean arterial pressure. Postoperative complications and adverse reactions were similar across groups. Conclusion: Perioperative low-dose dexmedetomidine infusion with propofol in elderly ERCP patients ensures safe and effective monitored anesthesia care (MAC), reducing PND incidence by mitigating peripheral inflammation and stress responses. Long-term follow-up is needed to fully evaluate PND incidence.
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Colangiopancreatografia Retrógrada Endoscópica , Dexmedetomidina , Humanos , Dexmedetomidina/administración & dosificación , Dexmedetomidina/farmacología , Método Doble Ciego , Anciano , Masculino , Femenino , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Relación Dosis-Respuesta a Droga , Anciano de 80 o más Años , Trastornos Neurocognitivos/prevención & control , Propofol/administración & dosificación , Propofol/efectos adversos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacologíaRESUMEN
This study aimed to investigate the relationships among growth mindset, cognitive fusion, bias towards negative information, and bias towards positive information. The Growth Mindset Scale, the Attention to Positive and Negative Information Scale, and the Cognitive Fusion Questionnaire were employed. A total of 470 college students in China participated in the study. The findings showed a negative correlation between a growth mindset and cognitive fusion. In addition, a parallel mediation analysis demonstrated that bias towards negative information mediated the relationship between a growth mindset and cognitive fusion and that the indirect effect was significant. However, the mediation of bias towards positive information in this model was not significant. These results suggest that possessing a growth mindset is advantageous for mental health.
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We have determined the crystal structure of a pseudoknot (PK)-containing hammerhead ribozyme that closely resembles the pistol ribozyme, with essentially identical secondary structure and connectivity. The activity is more sensitive to deletion of the G8 2'OH than to the absence of magnesium ions, indicating that the catalytic mechanism is the same as the extended hammerhead, and distinct from the pistol ribozyme. Here we show that nucleophilic attack is almost perfectly in-line, and the G8 2'OH is well positioned to act as general acid, being directed towards the O5' leaving group, and 2.9 Å away from it. Despite the similarity in overall structure to the pistol ribozyme, the local structure close to the cleavage site differs, and the PK hammerhead retains its unique mechanistic identity and demonstrates enhanced activity over other hammerhead ribozymes under standard conditions.
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Conformación de Ácido Nucleico , ARN Catalítico , ARN Catalítico/química , ARN Catalítico/metabolismo , ARN Catalítico/genética , Catálisis , Cristalografía por Rayos X , Modelos Moleculares , Magnesio/metabolismo , Magnesio/químicaRESUMEN
Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies toward clinical trials for treating SCD and other blood disorders.
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The metastasis-associated protein (MTA) family plays a crucial role in the development of breast cancer, a common malignancy with a high incidence rate among women. However, the mechanism by which each member of the MTA family contributes to breast cancer progression is poorly understood. In this study, we aimed to investigate the roles of MTA1, MTA3, and tripartite motif-containing 21 (TRIM21) in the proliferation, invasion, epithelial-mesenchymal transition (EMT), and stem cell-like properties of breast cancer cells in vivo and in vitro. The molecular mechanisms of the feedback loop between MTA1 and MTA3/TRIM21 regulated by estrogen were explored using Chromatin immunoprecipitation (ChIP), luciferase reporter, immunoprecipitation (IP), and ubiquitination assays. These findings demonstrated that MTA1 acts as a driver to promote the progression of breast cancer by repressing the transcription of tumor suppressor genes, including TRIM21 and MTA3. Conversely, MTA3 inhibited MTA1 transcription and TRIM21 regulated MTA1 protein stability in breast cancer. Estrogen disrupted the balance between MTA1 and MTA3, as well as between MTA1 and TRIM21, thereby affecting stemness and the EMT processes in breast cancer. These findings suggest that MTA1 plays a vital role in stem cell fate and the hierarchical regulatory network of EMT through negative feedback loops with MTA3 or TRIM21 in response to estrogen, supporting MTA1, MTA3, and TRIM21 as potential prognostic biomarkers and MTA1 as a treatment target for future breast cancer therapies.
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Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Estrógenos , Histona Desacetilasas , Células Madre Neoplásicas , Proteínas Represoras , Transactivadores , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Transactivadores/metabolismo , Transactivadores/genética , Estrógenos/farmacología , Estrógenos/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Retroalimentación Fisiológica/efectos de los fármacos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Ratones Desnudos , Células MCF-7 , Ratones Endogámicos BALB C , Proteínas de NeoplasiasRESUMEN
Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132-/- mice to obtain mechanistic insights. In vivo experiments established an immune-competent tumour-bearing mouse model, and CD8 T cell, Treg, and macrophage infiltration post-Myc overexpression were evaluated via flow cytometry. Additionally, adoptive transfer of OTI CD8 T cells was conducted to investigate antigen-specific immune response variations after Myc overexpression. The findings revealed a noteworthy delay in HIF1a degradation, enhancing its functionality and promoting the classical Warburg effect upon Myc overexpression. Lactic acid secretion by Myc-overexpressing tumour cells promoted Gpr132-dependent M2 macrophage polarization, leading to the induction of macrophages capable of significantly suppressing CD8 T cell function. Remarkably, heightened macrophage infiltration in tumour microenvironments post-Myc overexpression was observed alongside impaired CD8 T cell infiltration and function. Interestingly, CD4 T-cell infiltration remained unaltered, and immune-suppressive effects were alleviated when Myc-overexpressing tumour cells were administered to Gpr132-/- mice, shedding light on potential therapeutic avenues for ovarian cancer management.
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Linfocitos T CD8-positivos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ácido Láctico , Macrófagos , Neoplasias Ováricas , Proteínas Proto-Oncogénicas c-myc , Animales , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Linfocitos T CD8-positivos/inmunología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Línea Celular Tumoral , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ácido Láctico/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Humanos , Microambiente Tumoral/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Pressure ulcer dressings with different functions can enhance wound healing ability to varying degrees; however, pressure ulcer dressings that integrate various functions and break the resistance of bacteria to traditional antibiotics have not been widely studied. We proposed a self-pumping/super-absorbent/transportable drug dressing (PLD-SLD), polycaprolactone (PCL)/sodium alginate (SA) was used to load platelet-derived growth factor (PDGF) and lidocaine hydrochloride (LID) by Janus electrospinning and self-assembly technology, and Æ-polylysine was used as a biological bacteriostatic agent to prepare a multi-layer dressing. SEM showed that the dressing had a fluffy structure. The dressing can pump the exudate to the SA layer away from the skin. The swelling ratio reached 1378.667 ± 44.752 %. Coagulate blood in 5 min. On the 8th day, the unclosed area rate of the PLD-SLD dressing group was 16.112 ± 0.088 % lower than that of the model group. Importantly, the dressing can induce the expression of CD31, VEGF, α-SMA, and reduce the expression of CD68, thereby giving priority to wound healing. There was no scar formation after healing. In this study, a new dressing preparation method was proposed for the problems of exudate management, infection control, pain relief and healing promotion of stage 3-4 pressure ulcer healing.
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Alginatos , Vendajes , Poliésteres , Úlcera por Presión , Cicatrización de Heridas , Alginatos/química , Úlcera por Presión/tratamiento farmacológico , Úlcera por Presión/terapia , Poliésteres/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Ratas , Masculino , Lidocaína/farmacología , Lidocaína/químicaRESUMEN
BACKGROUND: Recently pilot published city-level air quality health index (AQHI) provides a useful tool for communicating short-term health risks of ambient air pollution, but fails to account for intracity spatial heterogeneity in exposure and associated population health impacts. This study aims to develop the intracity spatiotemporal AQHI (ST-AQHI) via refined air pollution-related health risk assessments. METHODS: A three-stage analysis was conducted through integrating province-wide death surveillance data and high-resolution gridded estimates of air pollution and climate factors spanning 2016-2019 in Jiangsu Province, eastern China. First, an individual-level case-crossover design was employed to quantify the short-term risk of nonaccidental mortality associated with residential exposure to individual pollutant (i.e., PM2.5, NO2, O3, and SO2). Second, we accumulated and scaled the excess risks arising from multiple pollutants to formulate daily gridded ST-AQHI estimates at 0.1° × 0.1°, dividing exposure-related risks into low (0-3), moderate (4-6), high (7-9), and extreme high (10+) levels. Finally, the effectiveness of ST-AQHI as composite risk communication was validated through checking the dose-response associations of individual ST-AQHI exposure with deaths from nonaccidental and major cardiopulmonary causes via repeating case-crossover analyses. RESULTS: We analyzed a total of 1,905,209 nonaccidental death cases, comprising 785,567 from circulatory diseases and 247,336 from respiratory diseases. In the first-stage analysis, for each 10-µg/m3 rise in PM2.5, NO2, O3, and SO2 exposure at lag-01 day, population risk of nonaccidental death was increased by 0.8% (95% confidence interval: 0.7%, 0.9%), 1.9% (1.7%, 2.0%), 0.4% (0.3%, 0.5%), and 4.1% (3.7%, 4.5%), respectively. Spatiotemporal distribution of ST-AQHI exhibited a consistent declining trend throughout the study period (2016-2019), with annual average ST-AQHI decreasing from 5.2 ± 1.3 to 4.0 ± 1.0 and high-risk days dropping from 15.8% (58 days) to 1.6% (6 days). Exposure associated health risks showed great intracity- and between-city heterogeneities. In the validation analysis, ST-AQHI demonstrated approximately linear, threshold-free associations with multiple death events from nonaccidental and major cardiopulmonary causes, suggesting excellent performance in predicting exposure-related health risks. Specifically, each 1-unit rise in ST-AQHI was significantly associated with an excess risk of 2.0% (1.8%, 2.1%) for nonaccidental mortality, 2.3% (2.1%, 2.6%) for overall circulatory mortality, and 2.7% (2.3%, 3.1%) for overall respiratory mortality, as well as 1.7%-3.0% for major cardiopulmonary sub-causes. CONCLUSIONS: ST-AQHI developed in this study performed well in predicting intracity spatiotemporal heterogeneity of death risks related to multiple air pollutants, and may hold significant practical importance in communicating air pollution-related health risks to the public at the community scales.
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Contaminantes Atmosféricos , Contaminación del Aire , Exposición a Riesgos Ambientales , China , Contaminación del Aire/estadística & datos numéricos , Contaminantes Atmosféricos/análisis , Humanos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Medición de Riesgo , Material Particulado/análisis , Monitoreo del Ambiente , Análisis Espacio-TemporalRESUMEN
Disentangling microbial community diversity patterns and assembly mechanisms is critical for understanding ecological processes and evaluating biogeochemical cycling in ecosystems. However, the diversity patterns and assembly mechanism of the microbial communities in the epipelagic waters in the northeastern Indian Ocean (NEIO) on the spatial scale are still unclear. In this study, we investigated the spatial dynamics, geographic distribution pattern, and assembly process of the bacterial community using 532 samples collected from the epipelagic waters in the NEIO during the northeast monsoon. The results indicate that the bacterial richness and Bray-Curtis dissimilarity exhibited the strongest correlations with depth compared to the latitudinal and longitudinal scales. The dissolved oxygen was identified as the most important environmental factor affecting the bacterial richness and Bray-Curtis dissimilarity compared to temperature and salinity. The distance-decay relationship (DDR) of the bacterial community strengthened with increasing water depth. Turnover was the predominant ß-diversity component influencing the spatial changes in the whole bacterial community. The dispersal limitation of the stochastic process and homogeneous selection of the deterministic process governed the bacterial ecological assembly process of the whole bacterial community. Abundant and rare subcommunities differed in terms of the niche breath, composition changes. The abundant subcommunities exhibited a much wider niche breath than the rare subcommunities. Regarding the abundant subcommunity species changes, the contributions of the turnover and nestedness varied with the water depth and oceanic region. In contrast, turnover was the major ß-diversity component regarding the changes in the rare species. These data improve our understanding of the ecological processes of bacterial community assemblages in the NEIO.
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Bacterias , Biodiversidad , Microbiota , Agua de Mar , Océano Índico , Agua de Mar/microbiología , Bacterias/clasificación , Salinidad , Monitoreo del Ambiente , Microbiología del Agua , EcosistemaRESUMEN
DNA double-strand break repair by homologous recombination has a specialised role in meiosis by generating crossovers that enable the formation of haploid germ cells. This requires meiosis-specific MEILB2-BRME1, which interacts with BRCA2 to facilitate loading of recombinases onto resected DNA ends. Here, we report the crystal structure of the MEILB2-BRME1 2:2 core complex, revealing a parallel four-helical assembly that recruits BRME1 to meiotic double-strand breaks in vivo. It forms an N-terminal ß-cap that binds to DNA, and a MEILB2 coiled-coil that bridges to C-terminal ARM domains. Upon BRCA2-binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex, with rod-like MEILB2-BRME1 components arranged at right-angles. The ß-caps located at the tips of the MEILB2-BRME1 limbs are separated by 25 nm, allowing them to bridge between DNA molecules. Thus, we propose that BRCA2 induces MEILB2-BRME1 to function as a DNA clamp, connecting resected DNA ends or homologous chromosomes to facilitate meiotic recombination.