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BACKGROUND: Perihematomal edema (PHE) is regarded as a potential intervention indicator of secondary injury following intracerebral hemorrhage (ICH). But it still lacks a comprehensive prediction model for early PHE formation. METHODS: The included ICH patients have received an initial Computed Tomography scan within 6â¯hours of symptom onset. Hematoma volume and PHE volume were computed using semiautomated computer-assisted software. The volume of the hematoma, edema around the hematoma, and surface area of the hematoma were calculated. The platelet-to-lymphocyte ratio (PLR) was calculated by dividing the platelet count by the lymphocyte cell count. All analyses were 2-tailed, and the significance level was determined by P <0.05. RESULTS: A total of 226 patients were included in the final analysis. The optimal cut-off values for PHE volume increase to predict poor outcomes were determined as 5.5â¯mL. For clinical applicability, we identified a value of 5.5â¯mL as the optimal threshold for early PHE growth. In the multivariate logistic regression analyses, we finally found that baseline hematoma surface area (p < 0.001), expansion-prone hematoma (p < 0.001), and PLR (p = 0.033) could independently predict PHE growth. The comprehensive prediction model demonstrated good performance in predicting PHE growth, with an area under the curve of 0.841, sensitivity of 0.807, and specificity of 0.732. CONCLUSION: In this study, we found that baseline hematoma surface area, expansion-prone hematoma, and PLR were independently associated with PHE growth. Additionally, a risk nomogram model was established to predict the PHE growth in patients with ICH.
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Cartilage damage, a common cause of osteoarthritis, requires medical imaging for accurate diagnosis of pathological changes. However, current instruments can acquire limited imaging information due to sensitivity and resolution issues. Therefore, multimodal imaging is considered an alternative strategy to provide valuable images and analyzes from different perspectives. Among all biomaterials, gold nanomaterials not only exhibit outstanding benefits as drug carriers, in vitro diagnostics, and radiosensitizers, but are also widely used as contrast agents, particularly for tumors. However, their potential for imaging cartilage damage is rarely discussed. In this study, we developed a versatile iodinated gadolinium-gold nanomaterial, AuNC@BSA-Gd-I, and its radiolabeled derivative, AuNC@BSA-Gd-131I, for cartilage detection. With its small size, negative charge, and multimodal capacities, the probe can penetrate damaged cartilage and be detected or visualized by computed tomography, MRI, IVIS, and gamma counter. Additionally, the multimodal imaging potential of AuNC@BSA-Gd-I was compared to current multifunctional gold nanomaterials containing similar components, including anionic AuNC@BSA, AuNC@BSA-I, and AuNC@BSA-Gd as well as cationic AuNC@CBSA. Due to their high atomic numbers and fluorescent emission, AuNC@BSA nanomaterials could provide fundamental multifunctionality for imaging. By further modifying AuNC@BSA with additional imaging materials, their application could be extended to various types of medical imaging instruments. Nonetheless, our findings showed that each of the current nanomaterials exhibited excellent abilities for imaging cartilage with their predominant imaging modalities, but their versatility was not comparable to that of AuNC@BSA-Gd-I. Thus, AuNC@BSA-Gd-I could be served as a valuable tool in multimodal imaging strategies for cartilage assessment.
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The protein-induced fluorescence change technique was employed to investigate the interactions between proteins and their DNA substrates modified with the Cy3 fluorophore. It has been reported that the human hepatoma-derived growth factor (HDGF), containing the chromatin-associated N-terminal proline-tryptophan-tryptophan-proline (PWWP) domain (the N-terminal 100 amino acids of HDGF) capable of binding the SMYD1 promoter, participates in various cellular processes and is involved in human cancer. This project investigated the specific binding behavior of HDGF, the PWWP domain, and the C140 domain (the C-terminal 140 amino acids of HDGF) sequentially using protein-induced fluorescence change. We found that the binding of HDGF and its related proteins on Cy3-labeled 15 bp SMYD1 dsDNA will cause a significant decrease in the recorded Cy3 fluorophore intensity, indicating the occurrence of protein-induced fluorescence quenching. The dissociation equilibrium constant was determined by fitting the bound fraction curve to a binding model. An approximate 10-time weaker SMYD1 binding affinity of the PWWP domain was found in comparison to HDGF. Moreover, the PWWP domain is required for DNA binding, and the C140 domain can enhance the DNA binding affinity. Furthermore, we found that the C140 domain can regulate the sequence-specific binding capability of HDGF on SMYD1.
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Proteínas de Unión al ADN , ADN , Péptidos y Proteínas de Señalización Intercelular , Unión Proteica , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , ADN/química , ADN/metabolismo , Dominios Proteicos , Sitios de Unión , Carbocianinas/química , Proteínas Musculares , Factores de TranscripciónRESUMEN
BACKGROUND: Remdesivir (Veklury, Gilead Sciences, Foster City, CA, USA) and nirmatrelvir-ritonavir (Paxlovid, Pfizer, New York, NY, USA) were reported to improve the outcome of patients with mild-to-moderate COVID-19 symptoms. Preclinical data suggest that nirmatrelvir-ritonavir might be more effective than remdesivir alone or in combination with nirmatrelvir-ritonavir for people at high risk of severe COVID-19. We aimed to assess the safety and effectiveness of combining remdesivir and nirmatrelvir-ritonavir compared with using each drug alone for adults hospitalised with COVID-19. METHODS: In this target trial emulation study, we used electronic health records of patients aged 18 years or older who received either combination treatment of nirmatrelvir-ritonavir and remdesivir or monotherapy of either drug between March 16 and Dec 31, 2022, within 5 days of hospitalisation for COVID-19 in Hong Kong. Inverse probability of treatment weighting was applied to balance baseline patient characteristics across the treatment groups. The primary outcome was all-cause mortality. Cox proportional hazards regression adjusting weighting was used to compare the risk of all-cause mortality, intensive care unit (ICU) admission, or ventilatory support for 90 days of follow-up between groups. FINDINGS: Between March 16 and Dec 31, 2022, 18 196 participants were identified from electronic health records and assigned to receive remdesivir (n=4232), nirmatrelvir-ritonavir (n=13 656), or nirmatrelvir-ritonavir and remdesivir (n=308). By applying an inverse probability of treatment weighting, a weighted sample composed of 18 410 recipients of nirmatrelvir-ritonavir and remdesivir combination treatment, 18 178 recipients of remdesivir monotherapy, and 18 287 recipients of nirmatrelvir-ritonavir monotherapy was obtained. After a median follow-up of 84 days (IQR 45-90), risk of mortality was lower in patients who received nirmatrelvir-ritonavir monotherapy (hazard ratio [HR] 0·18 [95% CI 0·15 to 0·20]; absolute risk reduction [ARR] -16·33% [95% CI -16·98 to -15·68]) or remdesivir and nirmatrelvir-ritonavir combination therapy (HR 0·66 [95% CI 0·49 to 0·89]; ARR -6·52% [95% CI -7·29 to -5·74]) than in patients who received remdesivir monotherapy. Similar results were observed for ICU admission or ventilatory support (nirmatrelvir-ritonavir monotherapy: HR 0·09 [95% CI 0·07 to 0·11]; ARR -10·04% [95% CI -10·53 to -9·56]; combination therapy: HR 0·68 [95% CI 0·42 to 1·12]; ARR -3·24% [95% CI -3·84 to -2·64]). Compared with combination therapy, nirmatrelvir-ritonavir monotherapy was associated with lower risk of mortality (HR 0·27 [95% CI 0·20 to 0·37]; ARR -9·81% [95% CI -10·39 to -9·24]) and ICU admission or ventilatory support (HR 0·13 [95% CI 0·08 to 0·22]; ARR -6·80% [95% CI -7·22 to -6·39]). INTERPRETATION: Our study highlighted the potential for reduced risk of mortality, ICU admission, or the need for ventilatory support in patients hospitalised with COVID-19 treated with nirmatrelvir-ritonavir as a monotherapy compared with treatment regimens based on nirmatrelvir-ritonavir and remdesivir combination therapy or remdesivir monotherapy. Further randomised controlled trials are needed to support the validity of the current results. FUNDING: The Health and Medical Research Fund Commissioned Research on COVID-19. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Assisted reproduction technology (ART) procedures are often impacted by post-ovulatory aging (POA), which can lead to reduced fertilization rates and impaired embryo development. This study used RNA sequencing analysis and experimental validation to study the similarities and differences between in vivo- and vitro-matured porcine oocytes before and after POA. Differentially expressed genes (DEGs) between fresh in vivo-matured oocyte (F_vivo) and aged in vivo-matured oocyte (A_vivo) and DEGs between fresh in vitro-matured oocyte (F_vitro) and aged in vitro-matured oocyte (A_vitro) were intersected to explore the co-effects of POA. It was found that "organelles", especially "mitochondria", were significantly enriched Gene Ontology (GO) terms. The expression of genes related to the "electron transport chain" and "cell redox homeostasis" pathways related to mitochondrial function significantly showed low expression patterns in both A_vivo and A_vitro groups. Weighted correlation network analysis was carried out to explore gene expression modules specific to A_vivo. Trait-module association analysis showed that the red modules were most associated with in vivo aging. There are 959 genes in the red module, mainly enriched in "RNA binding", "mRNA metabolic process", etc., as well as in GO terms, and "spliceosome" and "nucleotide excision repair" pathways. DNAJC7, IK, and DDX18 were at the hub of the gene regulatory network. Subsequently, the functions of DDX18 and DNAJC7 were verified by knocking down their expression at the germinal vesicle (GV) and Metaphase II (MII) stages, respectively. Knockdown at the GV stage caused cell cycle disorders and increase the rate of abnormal spindle. Knockdown at the MII stage resulted in the inefficiency of the antioxidant melatonin, increasing the level of intracellular oxidative stress, and in mitochondrial dysfunction. In summary, POA affects the organelle function of oocytes. A_vivo oocytes have some unique gene expression patterns. These genes may be potential anti-aging targets. This study provides a better understanding of the detailed mechanism of POA and potential strategies for improving the success rates of assisted reproductive technologies in pigs and other mammalian species.
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BACKGROUND: This study compared the survival outcomes after thermal ablation versus wedge resection in patients with stage I non-small cell lung cancer (NSCLC) ≤ 2 cm. METHODS: Data from the United States (US) National Cancer Institute Surveillance Epidemiology and End Results (SEER) database from 2004 to 2019 were retrospectively analyzed. Patients with stage I NSCLC and lesions ≤ 2 cm who received thermal ablation or wedge resection were included. Patients who received chemotherapy or radiotherapy were excluded. Propensity-score matching (PSM) was applied to balance the baseline characteristics between patients who underwent the two procedures. RESULTS: Univariate and Cox regression analyses were performed to determine the associations between study variables, overall survival (OS), and cancer-specific survival (CSS). After PSM, 328 patients remained for analysis. Multivariable Cox regression analysis revealed, compared to wedge resection, thermal ablation was significantly associated with a greater risk of poor OS (adjusted HR [aHR]: 1.34, 95% CI: 1.09-1.63, p = 0.004) but not CSS (aHR: 1.28, 95% CI: 0.96-1.71, p = 0.094). In stratified analyses, no significant differences were observed with respect to OS and CSS between the two procedures regardless of histology and grade. In patients with tumor size 1 to 2 cm, compared to wedge resection, thermal ablation was significantly associated with a higher risk of poor OS (aHR: 1.35, 95% CI: 1.10-1.66, p = 0.004). In contrast, no significant difference was found on OS and CSS between thermal ablation and wedge resection among those with tumor size < 1 cm. CONCLUSIONS: In patients with stage I NSCLC and tumor size < 1 cm, thermal ablation has similar OS and CSS with wedge resection.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Estadificación de Neoplasias , Programa de VERF , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Masculino , Femenino , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Estados Unidos/epidemiología , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Neumonectomía/métodos , Neumonectomía/mortalidad , Tasa de SupervivenciaRESUMEN
Seven undescribed abietane diterpenoids [abietamethinols A-G (1-7)] were isolated from the twigs and leaves of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic methods including 2D NMR, and they were further confirmed by X-ray crystallographic data. Lophanic acid was considered as the precursor of 1-7 in the biosynthesis pathway hypothesis. These compounds were evaluated for their cytotoxic, anti-bacterial and anti-AIV (avian influenza virus) activities. Compound 5 showed 42.9% inhibitory activity against the cancer cell line SMMC-7721 at the concentration of 40 µM, 3 and 4 could inhibit the bacterial growth of Streptococcus sobrinus by 55.3% and 63.2% at the concentrations of 148.6 and 141.9 µM, respectively, and 4 was demonstrated with antiviral activity against AIV with the inhibitory effect of 68.4% at 25 µM.
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Abietanos , Antibacterianos , Antineoplásicos Fitogénicos , Antivirales , Isodon , Pruebas de Sensibilidad Microbiana , Abietanos/farmacología , Abietanos/química , Abietanos/aislamiento & purificación , Humanos , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Isodon/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Relación Estructura-Actividad , Hojas de la Planta/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conformación Molecular , Virus de la Influenza A/efectos de los fármacosRESUMEN
BACKGROUND: Whole plant senescence represents the final stage in the life cycle of annual plants, characterized by the decomposition of aging organs and transfer of nutrients to seeds, thereby ensuring the survival of next generation. However, the transcriptomic profile of vegetative organs during this death process remains to be fully elucidated, especially regarding the distinctions between natural programmed death and artificial sudden death induced by herbicide. RESULTS: Differential genes expression analysis using RNA-seq in leaves and roots of Arabidopsis thaliana revealed that natural senescence commenced in leaves at 45-52 days after planting, followed by roots initiated at 52-60 days. Additionally, both organs exhibited similarities with artificially induced senescence by glyphosate. Transcription factors Rap2.6L and WKRY75 appeared to serve as central mediators of regulatory changes during natural senescence, as indicated by co-expression networks. Furthermore, the upregulation of RRTF1, exclusively observed during natural death, suggested its role as a regulator of jasmonic acid and reactive oxygen species (ROS) responses, potentially triggering nitrogen recycling in leaves, such as the glutamate dehydrogenase (GDH) shunt. Root senescence was characterized by the activation of AMT2;1 and GLN1;3, facilitating ammonium availability for root-to-shoot translocation, likely under the regulation of PDF2.1. CONCLUSIONS: Our study offers valuable insights into the transcriptomic interplay between phytohormones and ROS during whole plant senescence. We observed distinct regulatory networks governing nitrogen utilization in leaf and root senescence processes. Furthermore, the efficient allocation of energy from vegetative organs to seeds emerges as a critical determinant of population sustainability of annual Arabidopsis.
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Arabidopsis , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Herbicidas , Senescencia de la Planta , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Arabidopsis/efectos de los fármacos , Arabidopsis/metabolismo , Herbicidas/farmacología , Herbicidas/toxicidad , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Senescencia de la Planta/genética , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Hojas de la Planta/crecimiento & desarrollo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/metabolismo , Raíces de Plantas/genética , Transcriptoma , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
During mammalian oocyte meiosis, spindle migration and asymmetric cytokinesis are unique steps for the successful polar body extrusion. The asymmetry defects of oocytes will lead to the failure of fertilization and embryo implantation. In present study, we reported that an actin nucleating factor Formin-like 2 (FMNL2) played critical roles in the regulation of spindle migration and organelle distribution in mouse and porcine oocytes. Our results showed that FMNL2 mainly localized at the oocyte cortex and periphery of spindle. Depletion of FMNL2 led to the failure of polar body extrusion and large polar bodies in oocytes. Live-cell imaging revealed that the spindle failed to migrate to the oocyte cortex, which caused polar body formation defects, and this might be due to the decreased polymerization of cytoplasmic actin by FMNL2 depletion in the oocytes of both mice and pigs. Furthermore, mass spectrometry analysis indicated that FMNL2 was associated with mitochondria and endoplasmic reticulum (ER)-related proteins, and FMNL2 depletion disrupted the function and distribution of mitochondria and ER, showing with decreased mitochondrial membrane potential and the occurrence of ER stress. Microinjecting Fmnl2-EGFP mRNA into FMNL2-depleted oocytes significantly rescued these defects. Thus, our results indicate that FMNL2 is essential for the actin assembly, which further involves into meiotic spindle migration and ER/mitochondria functions in mammalian oocytes.
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Actinas , Retículo Endoplásmico , Forminas , Meiosis , Mitocondrias , Oocitos , Animales , Femenino , Ratones , Actinas/metabolismo , Retículo Endoplásmico/metabolismo , Forminas/metabolismo , Forminas/genética , Mitocondrias/metabolismo , Oocitos/metabolismo , Huso Acromático/metabolismo , PorcinosRESUMEN
A novel Gram-staining-positive actinobacterium with antimicrobial activity, designated CFH 90308T, was isolated from the sediment of a salt lake in Yuncheng, Shanxi, south-western China. The isolate exhibited the highest 16S rRNA gene sequence similarities to Microbacterium yannicii G72T, Microbacterium hominis NBRC 15708T and Microbacterium xylanilyticum S3-ET (98.5, 98.4 and 98.2â%, respectively), and formed a separate clade with M. xylanilyticum S3-ET in phylogenetic trees. The strain grew at 15-40âºC, pH 6.0-8.0 and could tolerate NaCl up to a concentration of 15â% (w/v). The whole genome of strain CFH 90308T consisted of 4.33 Mbp and the DNA G+C content was 69.6 mol%. The acyl type of the peptidoglycan was glycolyl and the whole-cell sugars were galactose and mannose. The cell-wall peptidoglycan mainly contained alanine, glycine and lysine. The menaquinones of strain CFH 90308T were MK-12, MK-13 and MK-11. Strain CFH 90308T contained anteiso-C15:0, anteiso-C17:0, iso-C16:0 and iso-C15:0 as the predominant fatty acids. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between CFH 90308T and the other species of the genus Microbacterium were found to be low (ANIb <81.3â%, dDDH <25.6â%). The secondary metabolite produced by strain CFH 90308T showed antibacterial activities against Bacillus subtilis, Pseudomonas syringae, Aeromonas hydrophila and methicillin-resistant Staphylococcus aureus. Based on genotypic, phenotypic and chemotaxonomic results, the isolate is considered to represent a novel species of the genus Microbacterium, for which the name Microbacterium salsuginis sp. nov. is proposed. The type strain is CFH 90308T (=DSM 105964T=KCTC 49052T).
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Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano , Ácidos Grasos , Sedimentos Geológicos , Microbacterium , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Vitamina K 2 , ARN Ribosómico 16S/genética , ADN Bacteriano/genética , China , Vitamina K 2/análogos & derivados , Sedimentos Geológicos/microbiología , Peptidoglicano , Lagos/microbiología , Hibridación de Ácido Nucleico , Cloruro de Sodio/metabolismo , Genoma BacterianoRESUMEN
Background: We explore the effect of suboptimal glycemic control on the incidence of diabetic peripheral neuropathy (DPN) in both non-elderly and elderly patients with type 2 diabetes mellitus (T2DM). Methods: A 6-year follow-up study (2013-2019) enrolled T2DM patients aged >20 without DPN. Participants were classified into two groups: those below 65 years (non-elderly) and those 65 years or older (elderly). Biochemical measurements, including glycated hemoglobin (HbA1C), were recorded regularly. DPN was diagnosed using the Michigan Neuropathy Screening Instrument examination. The outcome was DPN occurrence in 2019. Results: In 552 enrollments (69% non-elderly), DPN occurred in 8.4% non-elderly and 24.0% elderly patients. A higher initial HbA1C level was significantly linked with a higher risk of future DPN in the non-elderly group (adjusted odds ratio [AOR] 1.46, 95% CI 1.13-1.89, p=0.004). In comparison, HbA1c at the end of the study period was not associated with DPN in the non-elderly group (AOR 1.17, 95% CI 0.72-1.90, p=0.526). In the elderly group, no statistical relationship was found between HbA1C levels and DPN, either in 2013 or in 2019. Conclusion: Suboptimal glycemic control at baseline, rather than at the end of the study period, predicts an increased risk of future DPN in individuals with T2DM under age 65. This correlation is not seen in elderly patients. Therefore, we recommend implementing enhanced glycemic control early in middle-aged T2DM patients and propose individualized therapeutic strategies for diabetes in different age groups.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Hemoglobina Glucada , Control Glucémico , Humanos , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/etiología , Masculino , Femenino , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Persona de Mediana Edad , Anciano , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Estudios de Seguimiento , Factores de Edad , Glucemia/análisis , Glucemia/metabolismo , Adulto , Incidencia , Factores de RiesgoRESUMEN
Background: Limited research has explored the relationship between the valence of olfactory dysfunction and PD clinical symptoms. This study aimed to investigate correlations between the emotional valence of olfactory impairment and different domains of PD symptoms. Methods: PD patients who fulfilled the clinically probable PD diagnostic criteria of the International Parkinson and Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's Disease were recruited from the Center for Parkinson and Movement Disorders at Taichung Veterans General Hospital between October 2016 and April 2022. Demographic data and serial clinical assessments were collected, including the traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC) and Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Thirty-five odors from the UPSIT-TC were classified into neutral, pleasant or unpleasant groups. Group comparisons, correlation analyses, and linear regression analyses were conducted to examine the relationship between olfactory impairment of UPSIT-TC odors, considering emotional valence, and MDS-UPDRS subscores across various domains. Results: A total of 176 PD patients were recruited for analysis. Patients in the predominantly neutral/unpleasant odor impairment groups had higher MDS-UPDRS part III scores compared to those in the predominantly pleasant odor impairment group (pleasant vs. neutral vs. unpleasant odor impairment groups: 26.79 ± 13.59 vs. 35.33 ± 16.36 vs. 31.57 ± 12.37, p = 0.009). This trend was also noted in MDS-UPDRS rigidity, bradykinesia, and akinetic-rigid subscores (p = 0.003, p = 0.012, and p = 0.001, respectively). Correlation analysis revealed a weak but significant correlation between rigidity/akinetic-rigid subscores and misidentification numbers for neutral/unpleasant odors (all p < 0.05), with age, gender, LEDD, and disease duration as covariates. All significances were retained in the linear regression analysis. Conclusion: Our results emphasize the link between olfactory impairment of specific emotional valence, neutral/unpleasant odors, and PD severity, particularly with respect to akinetic-rigid symptoms. A concise olfactory test that focuses on both neutral and unpleasant odors may offer deeper insights into PD symptoms.
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Pulmonary fibrosis is a lung disorder characterized by the accumulation of abnormal extracellular matrix, scar tissue formation, and tissue stiffness. Type II alveolar epithelial cells (AEII) play a critical role in repairing lung tissue after injury, and repeated injury to these cells is a key factor in the development of pulmonary fibrosis. Chronic exposure to PM2.5, a type of air pollution, has been shown to increase the incidence and severity of pulmonary fibrosis by enhancing the activation of EMT in lung epithelial cells. Melatonin, a hormone with antioxidant properties, has been shown to prevent EMT and reduce fibrosis in previous studies. However, the mechanism through which melatonin targets EMT to prevent pulmonary fibrosis caused by PM2.5 exposure has not been extensively discussed before. In this current study, we found that melatonin effectively prevented pulmonary fibrosis caused by prolonged exposure to PM2.5 by targeting EMT. The study demonstrated changes in cellular morphology and expression of EMT markers. Furthermore, the cell migratory potential induced by prolonged exposure to PM2.5 was greatly reduced by melatonin treatment. Finally, in vivo animal studies showed reduced EMT markers and improved pulmonary function. These findings suggest that melatonin has potential clinical use for the prevention of pulmonary fibrosis.
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Transición Epitelial-Mesenquimal , Melatonina , Material Particulado , Fibrosis Pulmonar , Melatonina/farmacología , Melatonina/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Animales , Fibrosis Pulmonar/prevención & control , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Material Particulado/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento Celular/efectos de los fármacos , Humanos , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéuticoRESUMEN
Telomeres, which are chromosomal end structures, play a crucial role in maintaining genome stability and integrity in eukaryotes. In the baker's yeast Saccharomyces cerevisiae, the X- and Y'-elements are subtelomeric repetitive sequences found in all 32 and 17 telomeres, respectively. While the Y'-elements serve as a backup for telomere functions in cells lacking telomerase, the function of the X-elements remains unclear. This study utilized the S. cerevisiae strain SY12, which has three chromosomes and six telomeres, to investigate the role of X-elements (as well as Y'-elements) in telomere maintenance. Deletion of Y'-elements (SY12YΔ), X-elements (SY12XYΔ+Y), or both X- and Y'-elements (SY12XYΔ) did not impact the length of the terminal TG1-3 tracks or telomere silencing. However, inactivation of telomerase in SY12YΔ, SY12XYΔ+Y, and SY12XYΔ cells resulted in cellular senescence and the generation of survivors. These survivors either maintained their telomeres through homologous recombination-dependent TG1-3 track elongation or underwent microhomology-mediated intra-chromosomal end-to-end joining. Our findings indicate the non-essential role of subtelomeric X- and Y'-elements in telomere regulation in both telomerase-proficient and telomerase-null cells and suggest that these elements may represent remnants of S. cerevisiae genome evolution. Furthermore, strains with fewer or no subtelomeric elements exhibit more concise telomere structures and offer potential models for future studies in telomere biology.
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Secuencias Repetitivas de Ácidos Nucleicos , Saccharomyces cerevisiae , Telomerasa , Telómero , Saccharomyces cerevisiae/genética , Telómero/metabolismo , Telómero/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Telomerasa/genética , Telomerasa/metabolismo , Homeostasis del Telómero , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Eliminación de SecuenciaRESUMEN
Objective: Preoperative frailty and surgical waiting times are associated with the occurrence of adverse outcomes in patients with hip fractures. Specifically, we aimed to investigate the influence of frailty status and surgical timing on the risk of serious adverse events during hospitalization. Methods: This study utilized an observational single cohort design and included patients aged ≥60 years with a primary diagnosis of hip fracture. Frailty was assessed using the chart-derived frailty index (CFI), which was calculated based on demographic and routine laboratory variables. The primary outcome of interest was the occurrence of in-hospital serious adverse events. A multivariate logistic regression model was utilized to examine the risk factors influencing outcomes. Results: The study included 427 participants, with a mean age of 80.28 ± 8.13 years and 64.2% of whom were female. Patients with high CFI have more comorbidities (P < .001), lower surgical rates (P = .002), and delayed surgical times (P = .033). A total of 239 patients (56.0%) experienced serious adverse events. The high CFI group had a significantly higher occurrence of serious adverse events compared to the low CFI group (73.4% vs 48.5%, P < .001). After adjusting for surgical timing and covariates, the multivariate logistic regression analysis revealed that high frailty significantly increased the risk for serious adverse events (OR = 2.47, 95% CI 1.398-4.412), infection (OR = 1.99, 95% CI 1.146-3.446), acute heart failure (OR = 3.37, 95% CI 1.607-7.045). However, the timing of surgery did not demonstrate any association with these outcomes. In addition, after adjusting for surgical factors, high CFI remains an independent risk factor for these complications. Conclusions: Frailty serves as a reliable predictor of the probability of encountering severe adverse events while hospitalized for elderly individuals with hip fractures. This method has the potential to pinpoint particular modifiable factors that necessitate intervention, whereas the impact of surgical timing remains uncertain and necessitates additional research.
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The standard treatment for early-stage breast cancer involves breast-conserving surgery followed by adjuvant radiotherapy. However, approximately 20 % of patients experience distant metastasis, and adjuvant radiotherapy often leads to radiation-induced skin fibrosis (RISF). In this study, we develop an on-site injectable formulation composed of selenocystamine (SeCA) and hyaluronic acid (HyA), referred to as SeCA cross-linked HyA (SCH) agent, and investigate its potential to mitigate metastasis and prevent RISF associated with breast cancer therapy. SCH agents are synthesized using the nanoprecipitation method to modulate cell-cell tight junctions and tissue inflammation. The toxicity assessments reveal that SCH agents with a higher Se content (Se payload 17.4 µg/mL) are well tolerated by L929 cells compared to SeCA (Se payload 3.2 µg/mL). In vitro, SCH agents significantly enhance cell-cell tight junctions and effectively mitigate migration and invasion of breast cancer cells (4T1). In vivo, SCH agents mitigate distant lung metastasis. Furthermore, in animal models, SCH agents reduce RISF and promote wound repair. These findings highlight the potential of SCH agents as a novel therapeutic formulation for effectively mitigating metastasis and reducing RISF. This holds great promise for improving clinical outcomes in breast cancer patients undergoing adjuvant radiotherapy.
Asunto(s)
Neoplasias de la Mama , Fibrosis , Ácido Hialurónico , Ácido Hialurónico/química , Animales , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Ratones , Fibrosis/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Ratones Endogámicos BALB C , Cistamina/química , Cistamina/farmacología , Piel/efectos de los fármacos , Piel/patología , Piel/efectos de la radiación , Movimiento Celular/efectos de los fármacos , InyeccionesRESUMEN
Sialyltransferase-catalyzed membrane protein and lipid glycosylation plays a vital role as one of the most abundant post-translational modifications and diversification reactions in eukaryotes. However, aberrant sialylation has been associated with cancer malignancy and metastasis. Sialyltransferases thus represent emerging targets for the development of small molecule cancer drugs. Herein, we report the inhibitory effects of a recently discovered lithocholic acid derivative FCW393 on sialyltransferase catalytic activity, integrin sialyation, cancer-associated signal transduction, MDA-MB-231 and B16F10 cell migration and invasion, and in in vivo studies, on tumor growth, metastasis, and angiogenesis. FCW393 showed effective and selective inhibition of the sialyltransferases ST6GAL1 (IC50 = 7.8 µM) and ST3GAL3 (IC50 = 9.45 µM) relative to ST3GAL1 (IC50 > 400 µM) and ST8SIA4 (IC50 > 100 µM). FCW393 reduced integrin sialylation in breast cancer and melanoma cells dose-dependently and downregulated proteins associated with the integrin-regulated FAK/paxillin and GEF/Rho/ROCK pathways, and with the VEGF-regulated Akt/NFκB/HIF-1α pathway. FCW393 inhibited cell migration (IC50 = 2.6 µM) and invasion in in vitro experiments, and in in vivo studies of tumor-bearing mice, FCW393 reduced tumor size, angiogenesis, and metastatic potential. Based on its demonstrated selectivity, cell permeability, relatively low cytotoxicity (IC50 = 55 µM), and high efficacy, FCW393 shows promising potential as a small molecule experimental tool compound and a lead for further development of a novel cancer therapeutic.
Asunto(s)
Movimiento Celular , Sialiltransferasas , Sialiltransferasas/metabolismo , Sialiltransferasas/antagonistas & inhibidores , Humanos , Animales , Ratones , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia , Femenino , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ácido Litocólico/farmacologíaRESUMEN
Background: Olfactory dysfunction in Parkinson's disease (PD) is associated with more severe phenotypes, but trajectories of cognitive function, disease severity, and subdomains of quality-of-life measurements in patients with distinct olfactory profiles remain underexplored. Objective: To analyze the influence of olfaction on trajectories of clinical parameters in patients with PD. Design: Retrospective cohort study. Subjects: From October 2016 to May 2021, the study tracked 58 participants over 3 years. Participants completed follow-up assessments using tools including the Chinese version of the University of Pennsylvania's Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, and the Chinese translation of the 39-item Parkinson's Disease Questionnaire (PDQ-39). Methods: Participants were divided into anosmia (UPSIT < 19) and non-anosmia (UPSIT ≥ 19) groups based on initial scores. Generalized estimating equations and repeated measures correlations were used to examine longitudinal associations and correlations between olfaction and clinical parameters. Results: Divergent cognitive trajectories were observed between groups. The anosmia group exhibited a faster cognitive decline (adjusted B [beta coefficient] = -1.8, p = 0.012) according to the interaction effect of olfaction and time on the MoCA score. The anosmia group exhibited no longitudinal correlation between cognition and olfactory function but showed correlations with age (rrm [coefficient of repeated measures correlation] = -0.464, p = 0.004) and disease duration (rrm = -0.457, p = 0.005). The non-anosmia group's UPSIT scores decreased over time (B = -2.3, p = 0.005) alongside a significant correlation with motor function (rrm = -0.479, p = 0.006). Conclusion: The anosmia group's accelerated cognitive decline correlated with age and disease duration, but not olfactory function, suggesting a poor cognitive outcome in this population despite the lack of longitudinal correlation between cognition and olfaction. The non-anosmia group exhibited progressive olfactory degradation and notable correlations between motor function and UPSIT scores, implying pathological accumulation in the olfactory structure and basal ganglia.
RESUMEN
BACKGROUND: Interactive features of computerized cognitive training (CCT) may enhance adherence to training, providing a relatively low-cost intervention. A robust systematic review on the effectiveness of CCT for improving working memory (WM) among pediatric survivors with cancer is lacking. OBJECTIVE: To summarize the available evidence and determine the effectiveness of CCT for WM among pediatric survivors with cancer. INTERVENTIONS/METHODS: Five databases were searched. The Effective Public Health Practice Project was used to assess the study quality. ReviewerManager was used. The primary outcome was WM performance. Secondary outcomes included processing speed, attention, intervention adherence, and number of adverse events. RESULTS: Six studies were included. Regarding overall quality, 1 study was weak, and 5 studies were moderate. Five studies reported a significant improvement of WM postintervention (P < .05). The meta-analysis of Cogmed interventions on symbolic WM revealed a significant difference between groups (vs placebo), with an overall pooled effect size of 0.71 (95% confidence interval, 0.02-1.41; P = .04). Two and 4 studies investigated the effects of CCT on processing speed and attention, respectively, with conflicting results. Four studies reported adherence of 80% or greater. Two studies reported no adverse events. CONCLUSIONS: Computerized cognitive training using Cogmed has a significant positive effect on WM. The effects of CCT on processing speed and attention remain inconclusive. IMPLICATIONS FOR PRACTICE: More rigorous trials should be conducted to elucidate the cognitive effects of CCT, particularly processing speed and attention, in the pediatric population with cancer. Further studies should consider combining CCT with other existing interventions to strengthen their effectiveness.