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2.
Biomacromolecules ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38869359

RESUMO

Acute myeloid leukemia (AML) is often associated with poor prognosis and survival. Small molecule inhibitors, though widening the treatment landscape, have limited monotherapy efficacy. The combination therapy, however, shows suboptimal clinical outcomes due to low bioavailability, overlapping systemic toxicity and drug resistance. Here, we report that CXCR4-mediated codelivery of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor sorafenib (SOR) via T22 peptide-tagged disulfide cross-linked polymeric micelles (TM) achieves synergistic treatment of FLT3-ITD AML. TM-VS with a VEN/SOR weight ratio of 1/4 and T22 peptide density of 20% exhibited an extraordinary inhibitory effect on CXCR4-overexpressing MV4-11 AML cells. TM-VS at a VEN/SOR dosage of 2.5/10 mg/kg remarkably reduced leukemia burden, prolonged mouse survival, and impeded bone loss in orthotopic MV4-11-bearing mice, outperforming the nontargeted M-VS and oral administration of free VEN/SOR. CXCR4-mediated codelivery of BCL-2 and FLT3 inhibitors has emerged as a prospective clinical treatment for FLT3-ITD AML.

3.
J Glob Health ; 14: 05019, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38843040

RESUMO

Background: In this study, we assessed the general population's fears towards various diseases and events, aiming to inform public health strategies that balance health-seeking behaviours. Methods: We surveyed adults from 30 countries across all World Health Organization (WHO) regions between July 2020 and August 2021. Participants rated their fear of 11 factors on an 11-point Likert scale. We stratified the data by age and gender and examined variations across countries and regions through multidimensional preference analysis. Results: Of the 16 512 adult participants, 62.7% (n = 10 351) were women. The most feared factor was the loss of family members, reported by 4232 participants (25.9%), followed by cancer (n = 2248, 13.7%) and stroke (n = 1416, 8.7%). The highest weighted fear scores were for loss of family members (mean (x̄) = 7.46, standard deviation (SD) = 3.04), cancer (x̄ = 7.00, SD = 3.09), and stroke (x̄ = 6.61, SD = 3.24). The least feared factors included animals/insects (x̄ = 3.72, SD = 2.96), loss of a mobile phone (x̄ = 4.27, SD = 2.98), and social isolation (x̄ = 4.83, SD = 3.13). Coronavirus disease 2019 (COVID-19) was the sixth most feared factor (x̄ = 6.23, SD = 2.92). Multidimensional preference analyses showed distinct fears of COVID-19 and job loss in Australia and Burundi. The other countries primarily feared loss of family members, cancer, stroke, and heart attacks; this ranking was consistent across WHO regions, economic levels, and COVID-19 severity levels. Conclusions: Fear of family loss can improve public health messaging, highlighting the need for bereavement support and the prevention of early death-causing diseases. Addressing cancer fears is crucial to encouraging the use of preventive services. Fear of non-communicable diseases remains high during health emergencies. Top fears require more resources and countries with similar concerns should collaborate internationally for effective fear management.


Assuntos
COVID-19 , Medo , Humanos , COVID-19/psicologia , COVID-19/epidemiologia , Feminino , Medo/psicologia , Masculino , Estudos Transversais , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Acontecimentos que Mudam a Vida , SARS-CoV-2 , Inquéritos e Questionários , Adolescente , Saúde Global , Neoplasias/psicologia
4.
Pathol Res Pract ; 260: 155409, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38917707

RESUMO

Linc00265, a long intergenic non-coding RNA, has garnered significant research attention due to its involvement in various human diseases, particularly cancer. It exhibits tissue-specific and dysregulated expression across multiple cancer types, including blood malignancies, colorectal, gastric, bladder, osteosarcoma, and hepatocellular carcinoma. This dysregulation is often associated with tumor aggressiveness, metastasis, and poor prognosis. Moreover, aberrant expression of Linc00265 has been reported in inflammation-related diseases such as osteoarthritis and sepsis. Mechanistically, Linc00265 acts as a competing endogenous RNA (CeRNA), sequestering specific microRNAs and thereby modulating their downstream targets. Additionally, it influences critical signaling pathways by mediating the key effectors within these pathways. Importantly, the dysregulation of Linc00265 shows promising potential as a diagnostic and prognostic biomarker in several human diseases. This review aims to comprehensively analyze the expression patterns, regulatory mechanisms, and potential biomarker roles of Linc00265 in human diseases, with a particular focus on cancer. By elucidating the functional implications of Linc00265, we can deepen our understanding of its roles in human diseases, potentially paving the way for novel therapeutic interventions in disease management.

5.
Plant Cell ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38701330

RESUMO

Grain and flag leaf size are two important agronomic traits that influence grain yield in rice (Oryza sativa). Many QTLs and genes that regulate these traits individually have been identified, however, few QTLs and genes that simultaneously control these two traits have been identified. In this study, we conducted a genome-wide association analysis in rice and detected a major locus, WIDTH OF LEAF AND GRAIN (WLG), that associated with both grain and flag leaf width. WLG encodes a RING-domain E3 ubiquitin ligase. WLGhap.B, which possesses five SNP variations compared to WLGhap.A, encodes a protein with enhanced ubiquitination activity that confers increased rice leaf width and grain size, whereas mutation of WLG leads to narrower leaves and smaller grains. Both WLGhap.A and WLGhap.B interact with LARGE2, a HETC-type E3 ligase, however, WLGhap.B exhibits stronger interaction with LARGE2, thus higher ubiquitination activity towards LARGE2 compared with WLGhap.A. Lysine1021 is crucial for the ubiquitination of LARGE2 by WLG. Loss-of-function of LARGE2 in wlg-1 phenocopies large2-c in grain and leaf width, suggesting that WLG acts upstream of LARGE2. These findings reveal the genetic and molecular mechanism by which the WLG-LARGE2 module mediates grain and leaf size in rice, and suggest the potential of WLGhap.B in improving rice yield.

6.
Prog Mater Sci ; 1422024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38745676

RESUMO

Possessing a unique combination of properties that are traditionally contradictory in other natural or synthetical materials, Ga-based liquid metals (LMs) exhibit low mechanical stiffness and flowability like a liquid, with good electrical and thermal conductivity like metal, as well as good biocompatibility and room-temperature phase transformation. These remarkable properties have paved the way for the development of novel reconfigurable or stretchable electronics and devices. Despite these outstanding properties, the easy oxidation, high surface tension, and low rheological viscosity of LMs have presented formidable challenges in high-resolution patterning. To address this challenge, various surface modifications or additives have been employed to tailor the oxidation state, viscosity, and patterning capability of LMs. One effective approach for LM patterning is breaking down LMs into microparticles known as liquid metal particles (LMPs). This facilitates LM patterning using conventional techniques such as stencil, screening, or inkjet printing. Judiciously formulated photo-curable LMP inks or the introduction of an adhesive seed layer combined with a modified lift-off process further provide the micrometer-level LM patterns. Incorporating porous and adhesive substrates in LM-based electronics allows direct interfacing with the skin for robust and long-term monitoring of physiological signals. Combined with self-healing polymers in the form of substrates or composites, LM-based electronics can provide mechanical-robust devices to heal after damage for working in harsh environments. This review provides the latest advances in LM-based composites, fabrication methods, and their novel and unique applications in stretchable or reconfigurable sensors and resulting integrated systems. It is believed that the advancements in LM-based material preparation and high-resolution techniques have opened up opportunities for customized designs of LM-based stretchable sensors, as well as multifunctional, reconfigurable, highly integrated, and even standalone systems.

7.
Kidney Dis (Basel) ; 10(2): 153-166, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38751796

RESUMO

Background: Acute kidney injury (AKI) is a severe condition marked by rapid renal function deterioration and elevated mortality, with traditional biomarkers lacking sensitivity and specificity. Rare tubulointerstitial diseases encompass a spectrum of disorders, primarily including monogenic diseases, immune-related conditions, and drug-induced tubulointerstitial diseases. The clinical manifestations vary from electrolyte and acid-base imbalances to kidney function insufficiency, which is associated with AKI in up to 20% of cases. Evidence indicated that rare tubulointerstitial diseases might provide new conceptual insights and perspectives for novel biomarkers and potential therapeutic strategies for AKI. Summary: Autosomal dominant tubulointerstitial kidney disease (ADTKD) and Fanconi syndrome (FS) are rare tubulointerstitial diseases. In ADTKD, UMOD and REN are closely related to AKI by affecting oxidative stress and tubuloglomerular feedback, which provide potential new biomarkers for AKI. Both rare tubulointerstitial diseases and AKI share etiologies and treatment responses. From the mechanism standpoint, rare tubulointerstitial diseases and AKI involve tubular transporter injury, initially manifesting as tubular dysfunction in tubulointerstitial disorder and progressing to AKI because of the programmed cell death with apoptosis, pyroptosis, or necroptosis of proximal tubule cells. Additionally, mitochondrial dysfunction has been identified as a common mechanism in both tubulointerstitial diseases and AKI induced by drugs, pSS, or monoclonal diseases. In the end, both AKI and FS patients and animal models responded well to the therapy of the primary diseases. Key Messages: In this review, we describe an overview of ADTKD and FS to identify their associations with AKI. Mitochondrial dysfunction contributes to rare tubulointerstitial diseases and AKI, which might provide a potential therapeutic target.

8.
Water Res X ; 23: 100224, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38711798

RESUMO

The ongoing evolution of SARS-CoV-2 is a significant concern, especially with the decrease in clinical sequencing efforts, which impedes the ability of public health sectors to prepare for the emergence of new variants and potential COVID-19 outbreaks. Wastewater-based epidemiology (WBE) has been proposed as a surveillance program to detect and monitor the SARS-CoV-2 variants being transmitted in communities. However, research is limited in evaluating the effectiveness of wastewater collection at sentinel sites for monitoring disease prevalence and variant dynamics, especially in terms of inferring the epidemic patterns on a broader scale, such as at the state/province level. This study utilized a multiplexed tiling amplicon-based sequencing (ATOPlex) to track the longitudinal dynamics of variant of concern (VOC) in wastewater collected from municipalities in Queensland, Australia, spanning from 2020 to 2022. We demonstrated that wastewater epidemiology measured by ATOPlex exhibited a strong and consistent correlation with the number of daily confirmed cases. The VOC dynamics observed in wastewater closely aligned with the dynamic profile reported by clinical sequencing. Wastewater sequencing has the potential to provide early warning information for emerging variants. These findings suggest that WBE at sentinel sites, coupled with sensitive sequencing methods, provides a reliable and long-term disease surveillance strategy.

9.
J Med Internet Res ; 26: e53321, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38805704

RESUMO

BACKGROUND: The pandemic has accelerated digital work transformation, yet little is known about individuals' willingness to sustain such digital modes and its associated factors. A better understanding of this willingness and its drivers is crucial for guiding the development of future digital work infrastructure, training programs, and strategies to monitor and prevent related health issues. OBJECTIVE: This study aims to quantify the general population's willingness to sustain pandemic-induced digital work, identify its associated factors, and examine how screen time moderates these relationships. METHODS: A cross-sectional study was conducted targeting Hong Kong residents aged ≥18 years who have increased engagement in digital work since the pandemic. Data were collected through self-reported, web-based surveys. Descriptive statistics determined prevalence rates, while structured multiphase logistic regression identified associated factors and explored the moderating effects of screen hour levels. RESULTS: This unfunded study enrolled 1014 participants from May 2 to June 24, 2022, and completed data analysis within 3 months after data collection. A total of 391 (38.6%; 95% CI 35.6%-41.6%) participants expressed willingness to sustain digital work. Positive factors associated with this willingness included being an employee (odds ratio [OR] 3.12, 95% CI 1.59-6.45; P=.001), being health professionals (OR 3.32, 95% CI 1.49-7.82; P=.004), longer screen hours (OR 1.09, 95% CI 1.03-1.15; P=.002), and higher depression levels (OR 1.20, 95% CI 1.01-1.44; P=.04). Conversely, negatively associated factors included older age (OR 0.87, 95% CI 0.81-0.94; P=.001), extroversion (OR 0.66, 95% CI 0.51-0.86; P=.002), higher eHealth literacy (OR 0.96, 95% CI 0.93-0.98; P<.001), perceived greater susceptibility to COVID-19 (OR 0.84, 95% CI 0.74-0.96; P=.009), residence in a high-severity COVID-19 community (OR 0.73, 95% CI 0.63-0.84; P<.001), having infected individuals in the immediate social circle (OR 0.64, 95% CI 0.46-0.88; P=.006), higher BMI (OR 0.94, 95% CI 0.90-0.99; P=.02), feelings of being out of control (OR 0.96, 95% CI 0.93-0.98; P=.002), and higher fear of COVID-19 (OR 0.96, 95% CI 0.94-0.98; P=.001). In addition, a moderating effect of screen hour level (high: >8 h/d; low: ≤8 h/d) influenced the association among 10 factors related to willingness to sustain pandemic-induced digital work, including age, education level, household size, needs for regular medical care, BMI, frequency of both vigorous and moderate physical activities, perceived COVID-19 severity, immediate social circle COVID-19 presence, and fear of COVID-19 (all P values for interaction <.05). CONCLUSIONS: The substantial willingness of the general population to sustain digital work after the pandemic highlights the need for robust telework infrastructure, thorough monitoring of adverse health outcomes, and the potential to expand telehealth services among this group. The identification of factors influencing this willingness and the moderating role of screen hours inform the development of personalized strategies to enhance digital work acceptance where needed.


Assuntos
COVID-19 , Pandemias , Tempo de Tela , Humanos , Estudos Transversais , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Hong Kong/epidemiologia , COVID-19/epidemiologia , COVID-19/psicologia , COVID-19/prevenção & controle , Prevalência , Adulto Jovem , Adolescente , SARS-CoV-2 , Inquéritos e Questionários , Idoso
10.
Sci Rep ; 14(1): 11362, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38762613

RESUMO

Topographic Rossby waves (TRWs) dominate the low-frequency variability of deep ocean currents and play a crucial role in energy exchange and material mixing. On the continental slope of the southwestern South China Sea, a deep-water mooring was deployed to observe TRWs for a period of ~ 40 days. The TRWs, with a wavelength of 109 km, account for 41.3% of the subinertial variations. A ray-tracing model was applied to investigate the propagation and energy source. The results showed that the TRWs propagated from the northeast of the mooring location and were most likely caused by the mesoscale eddy disturbances off the Vietnam coast. This study provides a new perspective on examining the impact of mesoscale eddies off Vietnam on abyssal currents.

11.
Clin Transl Med ; 14(5): e1699, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38783408

RESUMO

BACKGROUND: The gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear. METHODS: Ileocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV-negative controls, nine immunological responders (IRs), and three immunological non-responders (INRs) and were analyzed using single-cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T-cell counts and the activation of T cells. RESULTS: This study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T-cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor-ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells. CONCLUSIONS: Our study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs. KEY POINTS: An investigation was carried out at the single-cell-level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.


Assuntos
Infecções por HIV , Mucosa Intestinal , Plasmócitos , Humanos , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Masculino , Plasmócitos/imunologia , Mucosa Intestinal/imunologia , Feminino , Adulto , Pessoa de Meia-Idade , Células B de Memória/imunologia , Linfócitos B/imunologia
12.
Gels ; 10(5)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38786250

RESUMO

Intervertebral disc degeneration (IVDD) is a worldwide disease that causes low back pain and reduces quality of life. Biotherapeutic strategies based on tissue engineering alternatives, such as intervertebral disc scaffolds, supplemented by drug-targeted therapy have brought new hope for IVDD. In this study, to explore the role and mechanism of MnO2/GelMA composite hydrogels in alleviating IVDD, we prepared composite hydrogels with MnO2 and methacrylate gelatin (GelMA) and characterized them using compression testing and transmission electron microscopy (TEM). Annulus fibrosus cells (AFCs) were cultured in the composite hydrogels to verify biocompatibility by live/dead and cytoskeleton staining. Cell viability assays and a reactive oxygen species (ROS) probe were used to analyze the protective effect of the composite hydrogels under oxidative damage. To explore the mechanism of improving the microenvironment, we detected the expression levels of antioxidant and autophagy-related genes and proteins by qPCR and Western blotting. We found that the MnO2/GelMA composite hydrogels exhibited excellent biocompatibility and a porous structure, which promoted cell proliferation. The addition of MnO2 nanoparticles to GelMA cleared ROS in AFCs and induced the expression of antioxidant and cellular autophagy through the common SIRT1/NRF2 pathway. Therefore, the MnO2/GelMA composite hydrogels, which can improve the disc microenvironment through scavenging intracellular ROS and resisting oxidative damage, have great application prospects in the treatment of IVDD.

13.
Int J Biol Macromol ; 267(Pt 1): 131438, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38583845

RESUMO

A glutenin (G)-chitosan (CS) complex (G-CS) was cross-linked by water annealing with aim to prepare structured 3D porous cultured meat scaffolds (CMS) here. The CMS has pore diameters ranging from 18 to 67 µm and compressive moduli from 16.09 to 60.35 kPa, along with the mixing ratio of G/CS. SEM showed the porous organized structure of CMS. FTIR and CD showed the increscent content of α-helix and ß-sheet of G and strengthened hydrogen-bondings among G-CS molecules, which strengthened the stiffness of G-CS. Raman spectra exhibited an increase of G concentration resulted in higher crosslinking of disulfide-bonds in G-CS, which aggrandized the bridging effect of G-CS and maintained its three-dimensional network. Cell viability assay and immuno-fluorescence staining showed that G-CS effectively facilitated the growth and myogenic differentiation of porcine skeletal muscle satellite cells (PSCs). CLSM displayed that cells first occupied the angular space of hexagon and then ring-growth circle of PSCs were orderly formed on G-CS. The texture and color of CMS which loaded proliferated PSCs were fresh-meat like. These results showed that physical cross-linked G-CS scaffolds are the biocompatible and stable adaptable extracellular matrix with appropriate architectural cues and natural micro-environment for structured CM models.


Assuntos
Quitosana , Carne , Alicerces Teciduais , Quitosana/química , Animais , Alicerces Teciduais/química , Porosidade , Suínos , Engenharia Tecidual/métodos , Sobrevivência Celular/efeitos dos fármacos , Materiais Biocompatíveis/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Carne in vitro
14.
Sci Total Environ ; 929: 172320, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38614352

RESUMO

With China's commitment to reach carbon peak by 2030 and achieve carbon neutrality by 2060, it is particularly important to obtain terrestrial ecosystem carbon fluxes with low uncertainty both globally and in China. The use of more observation data may help reduce the uncertainty of inverting carbon fluxes. This study uses the observation data from global stations, background stations and provincial stations in China, as well as the OCO-2 satellite, and uses the China Carbon Monitoring, Verification and Supporting System for Global (CCMVS-G) to estimate the carbon fluxes of global and Chinese terrestrial ecosystems from 2019 to 2021. The results revealed that the global terrestrial ecosystem carbon sink was approximately -3.40 Pg C/yr from 2019 to 2021. The carbon sinks in the Northern Hemisphere are large, especially in Asia, North America, and Europe. From 2019 to 2021, the carbon sink of China's terrestrial ecosystem was approximately -0.44 Pg C/yr. Carbon sinks exhibit significant seasonal and interannual variations in China. After assimilating the observation data, the uncertainty of the posterior flux is smaller than that of the prior flux, a more reasonable distribution of carbon sources and sinks can be obtained, and more accurate boundary conditions can be provided for the China Carbon Monitoring, Verification and Supporting System for Regional (CCMVS-R). In the future, it is important to establish a well-designed CO2 ground-based observation network.

15.
J Glob Health ; 14: 04068, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38606605

RESUMO

Background: Central and bridge nodes can drive significant overall improvements within their respective networks. We aimed to identify them in 16 prevalent chronic diseases during the coronavirus disease 2019 (COVID-19) pandemic to guide effective intervention strategies and appropriate resource allocation for most significant holistic lifestyle and health improvements. Methods: We surveyed 16 512 adults from July 2020 to August 2021 in 30 territories. Participants self-reported their medical histories and the perceived impact of COVID-19 on 18 lifestyle factors and 13 health outcomes. For each disease subgroup, we generated lifestyle, health outcome, and bridge networks. Variables with the highest centrality indices in each were identified central or bridge. We validated these networks using nonparametric and case-dropping subset bootstrapping and confirmed central and bridge variables' significantly higher indices through a centrality difference test. Findings: Among the 48 networks, 44 were validated (all correlation-stability coefficients >0.25). Six central lifestyle factors were identified: less consumption of snacks (for the chronic disease: anxiety), less sugary drinks (cancer, gastric ulcer, hypertension, insomnia, and pre-diabetes), less smoking tobacco (chronic obstructive pulmonary disease), frequency of exercise (depression and fatty liver disease), duration of exercise (irritable bowel syndrome), and overall amount of exercise (autoimmune disease, diabetes, eczema, heart attack, and high cholesterol). Two central health outcomes emerged: less emotional distress (chronic obstructive pulmonary disease, eczema, fatty liver disease, gastric ulcer, heart attack, high cholesterol, hypertension, insomnia, and pre-diabetes) and quality of life (anxiety, autoimmune disease, cancer, depression, diabetes, and irritable bowel syndrome). Four bridge lifestyles were identified: consumption of fruits and vegetables (diabetes, high cholesterol, hypertension, and insomnia), less duration of sitting (eczema, fatty liver disease, and heart attack), frequency of exercise (autoimmune disease, depression, and heart attack), and overall amount of exercise (anxiety, gastric ulcer, and insomnia). The centrality difference test showed the central and bridge variables had significantly higher centrality indices than others in their networks (P < 0.05). Conclusion: To effectively manage chronic diseases during the COVID-19 pandemic, enhanced interventions and optimised resource allocation toward central lifestyle factors, health outcomes, and bridge lifestyles are paramount. The key variables shared across chronic diseases emphasise the importance of coordinated intervention strategies.


Assuntos
Doenças Autoimunes , COVID-19 , Eczema , Hipertensão , Síndrome do Intestino Irritável , Hepatopatias , Infarto do Miocárdio , Estado Pré-Diabético , Doença Pulmonar Obstrutiva Crônica , Distúrbios do Início e da Manutenção do Sono , Adulto , Humanos , Colesterol , Doença Crônica , COVID-19/epidemiologia , Estilo de Vida , Avaliação de Resultados em Cuidados de Saúde , Pandemias , Qualidade de Vida , Úlcera
16.
Eur J Med Chem ; 270: 116345, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38564826

RESUMO

Several generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed for the treatment of non-small cell lung cancer (NSCLC) in clinic. However, emerging drug resistance mediated by new EGFR mutations or activations by pass, leads to malignant progression of NSCLC. Proteolysis targeting chimeras (PROTACs) have been utilized to overcome the drug resistance acquired by mutant EGFR, newly potent and selective degraders are still need to be developed for clinical applications. Herein, we developed autophagosome-tethering compounds (ATTECs) in which EGFR can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of the LC3 ligand GW5074. A series of EGFR-ATTECs have been designed and synthesized. Biological evaluations showed that these compounds could degrade EGFR and exhibited moderate inhibitory effects on certain NSCLC cell lines. The ATTEC 12c potently induced the degradation of EGFR with a DC50 value of 0.98 µM and a Dmax value of 81% in HCC827 cells. Mechanistic exploration revealed that the lysosomal pathway was mainly involved in this degradation. Compound 12c also exhibited promising inhibitory activity, as well as degradation efficiency in vivo. Our study highlights that EGFR-ATTECs could be developed as a new expandable EGFR degradation tool and also reveals a novel potential therapeutic strategy to prevent drug resistance acquired EGFR mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proliferação de Células , Autofagossomos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Linhagem Celular Tumoral , Receptores ErbB , Mutação , Resistencia a Medicamentos Antineoplásicos
17.
Front Hum Neurosci ; 18: 1342931, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38681742

RESUMO

Objectives: The auditory spatial processing abilities mature throughout childhood and degenerate in older adults. This study aimed to compare the differences in onset cortical auditory evoked potentials (CAEPs) and location-evoked acoustic change complex (ACC) responses among children, adults, and the elderly and to investigate the impact of aging and development on ACC responses. Design: One hundred and seventeen people were recruited in the study, including 57 typically-developed children, 30 adults, and 30 elderlies. The onset-CAEP evoked by white noise and ACC by sequential changes in azimuths were recorded. Latencies and amplitudes as a function of azimuths were analyzed using the analysis of variance, Pearson correlation analysis, and multiple linear regression model. Results: The ACC N1'-P2' amplitudes and latencies in adults, P1'-N1' amplitudes in children, and N1' amplitudes and latencies in the elderly were correlated with angles of shifts. The N1'-P2' and P2' amplitudes decreased in the elderly compared to adults. In Children, the ACC P1'-N1' responses gradually differentiated into the P1'-N1'-P2' complex. Multiple regression analysis showed that N1'-P2' amplitudes (R2 = 0.33) and P2' latencies (R2 = 0.18) were the two most variable predictors in adults, while in the elderly, N1' latencies (R2 = 0.26) explained most variances. Although the amplitudes of onset-CAEP differed at some angles, it could not predict angle changes as effectively as ACC responses. Conclusion: The location-evoked ACC responses varied among children, adults, and the elderly. The N1'-P2' amplitudes and P2' latencies in adults and N1' latencies in the elderly explained most variances of changes in spatial position. The differentiation of the N1' waveform was observed in children. Further research should be conducted across all age groups, along with behavioral assessments, to confirm the relationship between aging and immaturity in objective ACC responses and poorer subjective spatial performance. Significance: ACCs evoked by location changes were assessed in adults, children, and the elderly to explore the impact of aging and development on these differences.

18.
Comput Biol Med ; 174: 108326, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38599066

RESUMO

Accurate and expeditious segmentation of stroke lesions can greatly assist physicians in making accurate medical diagnoses and administering timely treatments. However, there are two limitations to the current deep learning methods. On the one hand, the attention structure utilizes only local features, which misleads the subsequent segmentation; on the other hand, simple downsampling compromises task-relevant detailed semantic information. To address these challenges, we propose a novel feature refinement and protection network (FRPNet) for stroke lesion segmentation. FRPNet employs a symmetric encoding-decoding structure and incorporates twin attention gate (TAG) and multi-dimension attention pooling (MAP) modules. The TAG module leverages the self-attention mechanism and bi-directional attention to extract both global and local features of the lesion. On the other hand, the MAP module establishes multidimensional pooling attention to effectively mitigate the loss of features during the encoding process. Extensive comparative experiments show that, our method significantly outperforms the state-of-the-art approaches with 60.16% DSC, 36.20px HD and 85.72% DSC, 27.02px HD on two ischemic stroke datasets that contain all stroke stages and several sequences of stroke images. The excellent results that exceed those of existing methods illustrate the efficacy and generalizability of the proposed method. The source code is released on https://github.com/wu2ze2lin2/FRPNet.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral , Humanos , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodos , Algoritmos
19.
Medicine (Baltimore) ; 103(17): e37930, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38669364

RESUMO

BACKGROUND: In recent years, the incidence of menopause insomnia has gradually increased, seriously affecting women's physical and mental health. METHODS: Total 82 climacteric insomnia patients received from January 2021 to January 2023 were divided into 2 groups at random. In control group, 41 cases received conventional Western medicine, and in study group, 41 cases received acupuncture combined with Ningshen mixture. Clinical effectiveness of both groups was compared, neurotransmitter levels, TCM syndrome integral and Pittsburgh Sleep Quality Index (PSQI) were assessed in both groups. Meanwhile, the recurrence rate and safety were evaluated in 2 groups. RESULTS: The curative effect in study group was better than that in control group (P < .05). After treatment, the expressions of 5-hydroxytryptamine and ß-endorphin (ß-EP) in study group were higher than control group (P < .05); TCM syndrome scores and PSQI scores in study group were lower than control group (P < .05). The total recurrence rate in study group was obviously lower than control group at 3 months after treatment (P < .05). There were no serious adverse reactions in both group, and no distinct difference between 2 groups was found (P > .05). CONCLUSION: Acupuncture united with Ningshen mixture has a significant therapeutic effect and high safety in climacteric insomnia patients. It can effectively improve the neurotransmitter levels, clinical symptoms and sleep quality, and reduce the recurrence rate of climacteric insomnia patients, which has high clinical application value and is worthy of clinical promotion.


Assuntos
Terapia por Acupuntura , Medicamentos de Ervas Chinesas , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/terapia , Feminino , Terapia por Acupuntura/métodos , Pessoa de Meia-Idade , Medicamentos de Ervas Chinesas/uso terapêutico , Terapia Combinada , Menopausa , Resultado do Tratamento , Qualidade do Sono , beta-Endorfina/sangue , beta-Endorfina/metabolismo , Serotonina/metabolismo
20.
J Hazard Mater ; 471: 134363, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38663291

RESUMO

Degradation of organics in high-salinity wastewater is beneficial to meeting the requirement of zero liquid discharge for coking wastewater treatment. Creating efficient and stable performance catalysts for high-salinity wastewater treatment is vital in catalytic ozonation process. Compared with ozonation alone, Mn and Ce co-doped γ-Al2O3 could remarkably enhance activities of catalytic ozonation for chemical oxygen demand (COD) removal (38.9%) of brine derived from a two-stage reverse osmosis treatment. Experimental and theoretical calculation results indicate that introducing Mn could increase the active points of catalyst surface, and introducing Ce could optimize d-band electronic structures and promote the electron transport capacity, enhancing HO• bound to the catalyst surface ([HO•]ads) generation. [HO•]ads plays key roles for degrading the intermediates and transfer them into low molecular weight organics, and further decrease COD, molecular weights and number of organics in reverse osmosis concentrate. Under the same reaction conditions, the presence of Mn/γ-Al2O3 catalyst can reduce ΔO3/ΔCOD by at least 37.6% compared to ozonation alone. Furthermore, Mn-Ce/γ-Al2O3 catalytic ozonation can reduce the ΔO3/ΔCOD from 2.6 of Mn/γ-Al2O3 catalytic ozonation to 0.9 in the case of achieving similar COD removal. Catalytic ozonation has the potential to treat reverse osmosis concentrate derived from bio-treated coking wastewater reclamation.

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