RESUMEN

The ubiquitin-proteasome system is frequently employed to degrade viral proteins, thereby inhibiting viral replication and pathogenicity. Through an analysis of the degradation kinetics of all the SARS-CoV-2 proteins, our study revealed rapid degradation of several proteins, particularly NSP5. Additionally, we identified FBXO22, an E3 ubiquitin ligase, as the primary regulator of NSP5 ubiquitination. Moreover, we validated the interaction between FBXO22 and NSP5, demonstrating that FBXO22-mediated ubiquitination of NSP5 facilitated its recognition by the proteasome, leading to subsequent degradation. Specifically, FBXO22 catalyzed the formation of K48-linked polyubiquitin chains on NSP5 at lysine residues 5 and 90. Knockdown of FBXO22 resulted in decreased NSP5 ubiquitination levels, increased stability, and enhanced ability to evade the host innate immune response. Notably, the protein level of FBXO22 were negatively correlated with SARS-CoV-2 load, highlighting its importance in inhibiting viral replication. This study elucidates the molecular mechanism by which FBXO22 mediates the degradation of NSP5 and underscores its critical role in limiting viral replication. The identification of FBXO22 as a regulator of NSP5 stability provides new insights and potential avenues for targeting NSP5 in antiviral strategies.

Asunto(s)

Complejo de la Endopetidasa Proteasomal , SARS-CoV-2 , Ubiquitinación , Replicación Viral , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , SARS-CoV-2/fisiología , SARS-CoV-2/metabolismo , COVID-19/virología , COVID-19/metabolismo , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Células HEK293 , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteolisis , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Receptores Citoplasmáticos y Nucleares

RESUMEN

Introduction: Pathologists rely on whole slide images (WSIs) to diagnose cancer by identifying tumor cells and subtypes. Deep learning models, particularly weakly supervised ones, classify WSIs using image tiles but may overlook false positives and negatives due to the heterogeneous nature of tumors. Both cancerous and healthy cells can proliferate in patterns that extend beyond individual tiles, leading to errors at the tile level that result in inaccurate tumor-level classifications. Methods: To address this limitation, we introduce NATMIL (Neighborhood Attention Transformer Multiple Instance Learning), which utilizes the Neighborhood Attention Transformer to incorporate contextual dependencies among WSI tiles. NATMIL enhances multiple instance learning by integrating a broader tissue context into the model. Our approach enhances the accuracy of tumor classification by considering the broader tissue context, thus reducing errors associated with isolated tile analysis. Results: We conducted a quantitative analysis to evaluate NATMIL's performance against other weakly supervised algorithms. When applied to subtyping non-small cell lung cancer (NSCLC) and lymph node (LN) tumors, NATMIL demonstrated superior accuracy. Specifically, NATMIL achieved accuracy values of 89.6% on the Camelyon dataset and 88.1% on the TCGA-LUSC dataset, outperforming existing methods. These results underscore NATMIL's potential as a robust tool for improving the precision of cancer diagnosis using WSIs. Discussion: Our findings demonstrate that NATMIL significantly improves tumor classification accuracy by reducing errors associated with isolated tile analysis. The integration of contextual dependencies enhances the precision of cancer diagnosis using WSIs, highlighting NATMILs´ potential as a robust tool in pathology.

RESUMEN

Inflammation is the response of the human body to injury, infection, or other abnormal states, which is involved in the development of many diseases. As a member of the Krüppel-like transcription factors (KLFs) family, KLF4 plays a crucial regulatory role in physiological and pathological processes due to its unique dual domain of transcriptional activation and inhibition. A growing body of evidence has demonstrated that KLF4 plays a pivotal role in the pathogenesis of various inflammatory disorders, including inflammatory bowel disease, osteoarthritis, renal inflammation, pneumonia, neuroinflammation, and so on. Consequently, KLF4 has emerged as a promising new therapeutic target for inflammatory diseases. This review systematically generalizes the molecular regulatory network, specific functions, and mechanisms of KLF4 to elucidate its complex roles in inflammatory diseases. An in-depth study on the biological function of KLF4 is anticipated to offer a novel research perspective and potential intervention strategies for inflammatory diseases.

Asunto(s)

Inflamación , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel , Animales , Humanos , Antiinflamatorios/uso terapéutico , Inflamación/metabolismo , Inflamación/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética

RESUMEN

Accurate prediction of Kirsten rat sarcoma (KRAS) mutation status is crucial for personalized treatment of advanced colorectal cancer patients. However, despite the excellent performance of deep learning models in certain aspects, they often overlook the synergistic promotion among multiple tasks and the consideration of both global and local information, which can significantly reduce prediction accuracy. To address these issues, this paper proposes an innovative method called the Multi-task Global-Local Collaborative Hybrid Network (CHNet) aimed at more accurately predicting patients' KRAS mutation status. CHNet consists of two branches that can extract global and local features from segmentation and classification tasks, respectively, and exchange complementary information to collaborate in executing these tasks. Within the two branches, we have designed a Channel-wise Hybrid Transformer (CHT) and a Spatial-wise Hybrid Transformer (SHT). These transformers integrate the advantages of both Transformer and CNN, employing cascaded hybrid attention and convolution to capture global and local information from the two tasks. Additionally, we have created an Adaptive Collaborative Attention (ACA) module to facilitate the collaborative fusion of segmentation and classification features through guidance. Furthermore, we introduce a novel Class Activation Map (CAM) loss to encourage CHNet to learn complementary information between the two tasks. We evaluate CHNet on the T2-weighted MRI dataset, and achieve an accuracy of 88.93% in KRAS mutation status prediction, which outperforms the performance of representative KRAS mutation status prediction methods. The results suggest that our CHNet can more accurately predict KRAS mutation status in patients via a multi-task collaborative facilitation and considering global-local information way, which can assist doctors in formulating more personalized treatment strategies for patients.

Asunto(s)

Neoplasias Colorrectales , Mutación , Redes Neurales de la Computación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Aprendizaje Profundo , Proteínas Proto-Oncogénicas p21(ras)/genética

RESUMEN

Peptidyl arginine deiminase 4 (PAD4) plays a critical role in many autoimmune diseases including rheumatoid arthritis. Herein, a trypsin assisted highly immunoassay method was established to determine PAD4 activity and screen potent inhibitors from herbal plants extracts and purified natural products. The method was applied to determine endogenous PAD4 activity in both cell and tissue lysates, as well as the inhibitory effects of 20 herbal plants and 50 purified natural products. The Cinnamomi ramulus extract showed strongest inhibitory potency with IC50 value lower than 5 µg/mL. Meanwhile, pyrroloquinoline quinone (PQQ), widely used as a dietary supplement, was discovered as a promising PAD4 inhibitor with an IC50 value lower than 4 µM. The inhibition kinetic analysis, drug affinity response target stability (DARTS) and molecular docking were performed to confirm the interaction between PQQ and PAD4. This method has great potential for researchers to monitor activities and discover potential inhibitors of PAD4.

Asunto(s)

Simulación del Acoplamiento Molecular , Extractos Vegetales , Arginina Deiminasa Proteína-Tipo 4 , Extractos Vegetales/química , Extractos Vegetales/farmacología , Humanos , Arginina Deiminasa Proteína-Tipo 4/antagonistas & inhibidores , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Inmunoensayo/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/análisis , Productos Biológicos/química , Productos Biológicos/farmacología , Tripsina/metabolismo , Tripsina/química , Evaluación Preclínica de Medicamentos , Animales

RESUMEN

Background: Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear. Methods: Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on. Results: We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c-Jun n-terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo. Conclusion: Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

RESUMEN

Protein citrullination is an irreversible post-translational modification process regulated by peptidylarginine deiminases (PADs) in the presence of Ca2+. This process is closely related to the occurrence and development of autoimmune diseases, cancers, neurological disorders, cardiovascular and cerebrovascular diseases, and other major diseases. The analysis of protein citrullination by biomass spectrometry confronts great challenges owing to its low abundance, lack of affinity tags, small mass-to-charge ratio change, and susceptibility to isotopic and deamidation interferences. The methods commonly used to study the protein citrullination mainly involve the chemical derivatization of the urea group of the guanine side chain of the peptide to increase the mass-to-charge ratio difference of the citrullinated peptide. Affinity-enriched labels are then introduced to effectively improve the sensitivity and accuracy of protein citrullination by mass spectrometry. 2,3-Butanedione or phenylglyoxal compounds are often used as derivatization reagents to increase the mass-to-charge ratio difference of the citrullinated peptide, and the resulting derivatives have been observed to contain α-dicarbonyl structures. To date, however, no relevant studies on the reactivity of dicarbonyl compounds with citrullinated peptides have been reported. In this study, we determined whether six α-dicarbonyl and two ß-dicarbonyl compounds undergo derivatization reactions with standard citrullinated peptides using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Among the α-dicarbonyl compounds, 2,3-butanedione and glyoxal reacted efficiently with several standard citrullinated peptides, but yielded a series of by-products. Phenylglyoxal, methylglyoxal, 1,2-cyclohexanedione, and 1,10-phenanthroline-5,6-dione also derivated efficiently with standard citrullinated peptides, generating a single derivative. Thus, a new derivatization method that could yield a single derivative was identified. Among the ß-dicarbonyl compounds, 1,3-cyclohexanedione and 2,4-pentanedione successfully reacted with the standard citrullinated peptides, and generated a single derivative. However, their reaction efficiency was very low, indicating that the ß-dicarbonyl compounds are unsuitable for the chemical derivatization of citrullinated peptides. The above results indicate that the α-dicarbonyl structure is necessary for realizing the efficient and specific chemical derivatization of citrullinated peptides. Moreover, the side chains of the α-dicarbonyl structure determine the structure of the derivatives, derivatization efficiency, and generation (or otherwise) of by-products. Therefore, the specific enrichment and precise identification of citrullinated peptides can be achieved by synthesizing α-dicarbonyl structured compounds containing affinity tags. The proposed method enables the identification of citrullinated proteins and their modified sites by MS, thereby providing a better understanding of the distribution of citrullinated proteins in different tissues. The findings will be beneficial for studies on the mechanism of action of citrullinated proteins in a variety of diseases.

Asunto(s)

Citrulinación , Péptidos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Péptidos/química

RESUMEN

Cancer is a serious global public health issue, and a great deal of research has been made to treat cancer. Of these, discovery of promising compounds that effectively fight cancer always has been the main point of interest in pharmaceutical research. Carnosic acid (CA) is a phenolic diterpenoid compound widely present in Lamiaceae plants such as Rosemary (Rosmarinus officinalis L.). In recent years, there has been increasing evidence that CA has significant anti-cancer activity, such as leukaemia, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, lymphoma, prostate cancer, oral cancer, etc. The potential mechanisms involved by CA, including inhibiting cell proliferation, inhibiting metastasis, inducing cell apoptosis, stimulating autophagy, regulating the immune system, reducing inflammation, regulating the gut microbiota, and enhancing the effects of other anti-cancer drugs. This article reviews the biosynthesis, pharmacokinetics and metabolism, safety and toxicity, as well as the molecular mechanisms and signaling pathways of the anticancer activity of CA. This will contribute to the development of CA or CA-containing functional foods for the prevention and treatment of cancer, providing important advances in the advancement of cancer treatment strategies.

Asunto(s)

Abietanos , Antineoplásicos Fitogénicos , Neoplasias , Transducción de Señal , Humanos , Abietanos/uso terapéutico , Abietanos/farmacología , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/farmacología

RESUMEN

Dysregulation of peptidyl arginine deiminase 4 (PAD4) is involved in a variety of diseases including rheumatoid arthritis (RA) and Alzheimer's disease (AD), and it has emerged as potential and promising therapeutic target. However, no PAD4 inhibitor is ready for clinical use. Immobilized enzyme screening technology has gained increasing attention due to its low cost, reusability, easy separation from the reaction mixture, and resistance to changes in environmental conditions. In this study, PAD4 was immobilized on the magnetic nanoparticles (MNP) to prolong its activity stability, and a simple and rapid screening strategy of traditional Chinese medicine inhibitors based on immobilized PAD4 was established. The PAD4 enzyme was immobilized on magnetic nanoparticles (MNP) via Schiff base reaction using glutaraldehyde (GA) as crosslinking agent. Compared with free PAD4, the resulting MNP@GA@PAD4 exhibited an enhanced tolerance to temperature and storage stability, and its reusability was greatly improved with 66 % of initial enzyme activity after being recycled 10 times. The inhibitory activity of the immobilized PAD4 was assessed using two known PAD4 inhibitors GSK484 and BB-Cl-amidine. The semi-maximum inhibitory concentrations (IC50) of GSK484 and BB-Cl-amidine for MNP@GA@PAD4 were 1.00 and 0.97 µM, respectively, for free PAD4 were 0.64 and 0.85 µM, respectively. Finally, the MNP@GA@PAD4 was employed to rapid screen of natural PAD4 inhibitors from forty traditional Chinese medicines (TCMs). Under the same conditions, the controlled experiment was conducted with free PAD4. The screening results of TCMs inhibitors on MNP@GA@PAD4 and free PAD4 were similar, the alcohol extracts of Cinnamomi Cortex and Caryophylli Flos had significant inhibitory effects on PAD4 enzyme activity. The IC50 values of Cinnamomi Cortex extract for MNP@GA@PAD4 and free PAD4 were determined as 27 and 48 µg/mL, respectively. The IC50 values of Caryophylli Flos extracts for MNP@GA@PAD4 and free PAD4 were determined as 48 and 32 µg/mL, respectively. For the first time, this study proposed a method to immobilize PAD4 on magnetic materials, and developed a rapid, reusable and feasible strategy to screening natural PAD4 inhibitors from TCMs.

Asunto(s)

Inhibidores Enzimáticos , Enzimas Inmovilizadas , Nanopartículas de Magnetita , Arginina Deiminasa Proteína-Tipo 4 , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Enzimas Inmovilizadas/antagonistas & inhibidores , Nanopartículas de Magnetita/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Arginina Deiminasa Proteína-Tipo 4/antagonistas & inhibidores , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Arginina Deiminasa Proteína-Tipo 4/química , Humanos , Medicina Tradicional China , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Evaluación Preclínica de Medicamentos

RESUMEN

Peptidyl arginine deiminase 4 (PAD4) is a promising target for the treatment of metabolic diseases associated with autoimmune and central nervous system disease. By now there are limited numbers of PAD4 inhibitors, and no one is ready for clinical use. This study aims to find efficient and specific PAD4 inhibitors from traditional herbal medicines and to investigate their inhibitory mechanisms. The inhibitory effects of forty-eight extracts from sixteen traditional herbal medicines which are widely used in traditional herbal medicines were investigated. Salvia miltiorrhiza was found to have the most potent PAD4 inhibitory activity. After that, a practical bioactivity-guided fractionation coupling with a chemical profiling strategy was used to identify the fractions from Salvia miltiorrhiza with strong PAD4 inhibition activity, and the major constituents in these bioactive fractions were characterized by LC-MS/MS. Seven compounds were found to have inhibition on PAD4 with IC50 values ranging from 33.52 µM to 667 µM, in which salvianolic acid A showed the most potent inhibitory activity, with an IC50 value of 33.52 µM. Inhibition kinetic analyses indicated that salvianolic acid A effectively inhibited PAD4 in a mixed inhibitory manner, and computer simulation analyses demonstrated that salvianolic acid A binds to PAD4 mainly using hydrogen bonding. Overall, our results suggest that salvianolic acid A from Salvia miltiorrhiza is a potent inhibitor of PAD4, and that salvianolic acid A can be used as a promising lead compound for the development of more potent PAD4 inhibitors.

Asunto(s)

Simulación del Acoplamiento Molecular , Arginina Deiminasa Proteína-Tipo 4 , Salvia miltiorrhiza , Arginina Deiminasa Proteína-Tipo 4/antagonistas & inhibidores , Salvia miltiorrhiza/química , Estructura Molecular , Plantas Medicinales/química , Humanos , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Extractos Vegetales/farmacología , Extractos Vegetales/química

RESUMEN

Psychiatric disorders with dysfunction of the lateral habenula (LHb) show sleep disturbance, especially a disinhibition of rapid eye movement (REM) sleep in major depression. However, the role of LHb in physiological sleep control and how LHb contributes to sleep disturbance in major depression remain elusive. Here, we found that functional manipulations of LHb glutamatergic neurons bidirectionally modulated both non-REM (NREM) sleep and REM sleep. Activity recording revealed heterogeneous activity patterns of LHb neurons across sleep/wakefulness cycles, but LHb neurons were preferentially active during REM sleep. Using an activity-dependent tagging method, we selectively labeled a population of REM sleep-active LHb neurons and demonstrated that these neurons specifically promoted REM sleep. Neural circuit studies showed that LHb neurons regulated REM sleep via projections to the ventral tegmental area but not to the rostromedial tegmental nucleus. Furthermore, we found that the increased REM sleep in a depression mouse model was associated with a potentiation of REM sleep-active LHb neurons, including an increased proportion, elevated spike firing, and altered activity mode. Importantly, inhibition of REM sleep-active LHb neurons not only attenuated the increased REM sleep but also alleviated depressive-like behaviors in a depression mouse model. Thus, our results demonstrated that REM sleep-active LHb neurons selectively promoted REM sleep, and a potentiation of these neurons contributed to depression-associated sleep disturbance.

Asunto(s)

Habénula , Neuronas , Sueño REM , Animales , Habénula/fisiología , Habénula/fisiopatología , Sueño REM/fisiología , Ratones , Neuronas/fisiología , Masculino , Ratones Endogámicos C57BL , Trastornos del Sueño-Vigilia/fisiopatología , Depresión/fisiopatología

RESUMEN

Rabies, caused by lyssavirus rabies (Rabies lyssavirus, RABV), is a fatal disease among humans and almost all warm-blooded animals. In this study, we found that RABV infection induces the up-regulation of receptor transporter protein 4 (RTP4) in mouse brains and different cells of nervous tissue. Over-expression of RTP4 reduces the viral titer of RABV in different neuronal cells. Furthermore, a recombinant RABV expressing RTP4, named rRABV-RTP4, was constructed and displayed a lower viral titer in different neuronal cells due to the expression of RTP4. Moreover, the survival rates of mice infected with rRABV-RTP4 were significantly higher than those of mice infected with parent virus rRABV or control virus rRABV-RTP4(-). In terms of mechanism, RTP4 could bind viral genomic RNA (vRNA) of RABV, and suppress the whole viral genome amplification. In addition, we found that the zinc finger domain (ZFD) of RTP4 exerts the antiviral function by truncation analysis, and an important amino acids site (C95) in the RTP4 3CxxC motif which is essential for its antiviral function was identified by mutation analysis. This study contributes to our understanding of how RTP4 or other RTP proteins play a role in defense against the invasion of RABV or other viruses.

Asunto(s)

ARN Viral , Virus de la Rabia , Rabia , Animales , Humanos , Ratones , Encéfalo/virología , Línea Celular , Genoma Viral , Lyssavirus/genética , Neuronas/virología , Rabia/virología , Virus de la Rabia/genética , Virus de la Rabia/fisiología , Virus de la Rabia/patogenicidad , ARN Viral/genética , Replicación Viral

RESUMEN

BACKGROUND: Early detection of cognitive impairment or dementia is essential to reduce the incidence of severe neurodegenerative diseases. However, currently available diagnostic tools for detecting mild cognitive impairment (MCI) or dementia are time-consuming, expensive, or not widely accessible. Hence, exploring more effective methods to assist clinicians in detecting MCI is necessary. OBJECTIVE: In this study, we aimed to explore the feasibility and efficiency of assessing MCI through movement kinetics under tablet-based "drawing and dragging" tasks. METHODS: We iteratively designed "drawing and dragging" tasks by conducting symposiums, programming, and interviews with stakeholders (neurologists, nurses, engineers, patients with MCI, healthy older adults, and caregivers). Subsequently, stroke patterns and movement kinetics were evaluated in healthy control and MCI groups by comparing 5 categories of features related to hand motor function (ie, time, stroke, frequency, score, and sequence). Finally, user experience with the overall cognitive screening system was investigated using structured questionnaires and unstructured interviews, and their suggestions were recorded. RESULTS: The "drawing and dragging" tasks can detect MCI effectively, with an average accuracy of 85% (SD 2%). Using statistical comparison of movement kinetics, we discovered that the time- and score-based features are the most effective among all the features. Specifically, compared with the healthy control group, the MCI group showed a significant increase in the time they took for the hand to switch from one stroke to the next, with longer drawing times, slow dragging, and lower scores. In addition, patients with MCI had poorer decision-making strategies and visual perception of drawing sequence features, as evidenced by adding auxiliary information and losing more local details in the drawing. Feedback from user experience indicates that our system is user-friendly and facilitates screening for deficits in self-perception. CONCLUSIONS: The tablet-based MCI detection system quantitatively assesses hand motor function in older adults and further elucidates the cognitive and behavioral decline phenomenon in patients with MCI. This innovative approach serves to identify and measure digital biomarkers associated with MCI or Alzheimer dementia, enabling the monitoring of changes in patients' executive function and visual perceptual abilities as the disease advances.

Asunto(s)

Disfunción Cognitiva , Humanos , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Pruebas Neuropsicológicas/estadística & datos numéricos , Pruebas Neuropsicológicas/normas , Mano/fisiopatología , Anciano de 80 o más Años , Encuestas y Cuestionarios , Investigación Cualitativa

RESUMEN

Mitogen-Activated Protein Kinases (MAPKs) are serine/threonine protein kinases that play a crucial role in transmitting extracellular signals to the intracellular environment, influencing a wide range of cellular processes including proliferation, differentiation, apoptosis, metabolic activities, immune function and stress response. MAPK4, a non-classical MAPK, is frequently overexpressed in various malignancies, including prostate, breast, cervix, thyroid, and gliomas. It orchestrates cell proliferation, migration, and apoptosis via the AKT/mTOR and/or PDK1 signaling pathways, thus facilitating tumor cell growth. Furthermore, MAPK4 expression is closely associated with the effectiveness of specific inhibitors like PI3K and PARP1, and also correlate with the survival rates of cancer patients. Increasing evidence highlights MAPK4's involvement in the tumor microenvironment, modulating immune response and inflammation-related diseases. This review comprehensively explores the structure, function, and oncogenic role of MAPK4, providing a deeper understanding of its activation and mechanisms of action in tumorigenesis, which might be helpful for the development of innovative therapeutic strategies for cancer management.

Asunto(s)

Neoplasias , Humanos , Neoplasias/enzimología , Neoplasias/tratamiento farmacológico , Animales , Microambiente Tumoral , Transducción de Señal , Proliferación Celular , Carcinogénesis , Regulación Neoplásica de la Expresión Génica , Apoptosis

RESUMEN

Men who have sex with men and people living with HIV are disproportionately affected in the 2022 multi-country monkeypox epidemic. The smallpox vaccine can induce cross-reactive antibodies against the monkeypox virus (MPXV) and reduce the risk of infection. Data on antibodies against MPXV induced by historic smallpox vaccination in people with HIV are scarce. In this observational study, plasma samples were collected from people living with and without HIV in Shenzhen, China. We measured antibodies binding to two representative proteins of vaccinia virus (VACV; A27L and A33R) and homologous proteins of MPXV (A29L and A35R) using an enzyme-linked immunosorbent assay. We compared the levels of these antibodies between people living with and without HIV. Stratified analyses were performed based on the year of birth of 1981 when the smallpox vaccination was stopped in China. Plasma samples from 677 people living with HIV and 746 people without HIV were tested. A consistent pattern was identified among the four antibodies, regardless of HIV status. VACV antigen-reactive and MPXV antigen-reactive antibodies induced by historic smallpox vaccination were detectable in the people born before 1981, and antibody levels reached a nadir during or after 1981. The levels of smallpox vaccine-induced antibodies were comparable between people living with HIV and those without HIV. Our findings suggest that the antibody levels against MPXV decreased in both people living with and without HIV due to the cessation of smallpox vaccination.

Asunto(s)

Anticuerpos Antivirales , Infecciones por VIH , Monkeypox virus , Vacuna contra Viruela , Humanos , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Masculino , Vacuna contra Viruela/inmunología , Vacuna contra Viruela/administración & dosificación , Infecciones por VIH/inmunología , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Adulto , Femenino , China/epidemiología , Persona de Mediana Edad , Monkeypox virus/inmunología , Viruela/inmunología , Viruela/prevención & control , Viruela/epidemiología , Viruela/historia , Vacunación , Mpox/inmunología , Mpox/epidemiología , Mpox/historia , Reacciones Cruzadas/inmunología , Adulto Joven , Ensayo de Inmunoadsorción Enzimática , Virus Vaccinia/inmunología

RESUMEN

OBJECTIVES: In Chinese culture, family members are the main decision maker on end-of-life (EoL) issues for patients with advanced cancer. Yet little is known about Chinese families' confidence in making EoL decisions and its associated factors. This study aims to investigate the status and associated factors of Chinese family members' confidence in making EoL decisions for patients with advanced cancer. METHODS: This cross-sectional study used a convenience sample of 147 family members of patients with stage III or stage IV cancer from a tertiary cancer center in Guangzhou, China. The questionnaires included demographic information of patients and their family members, patients' EoL preferences, and the Chinese version of the Family Decision-Making Self-Efficacy (FDMSE) Scale. RESULTS: A total of145 family members (98.64%) completed the questionnaires. The average score of FDMSE was 3.92 ± 0.53. A multiple regression analysis showed that the factors associated with FDMSE included patients' duration of disease, health insurance, participation in EoL decision-making, the expression of unfilled wishes, and family members' employment status. SIGNIFICANCE OF RESULTS: Chinese family members were not confident enough in making EoL decisions for patients with advanced cancer. It is recommended to develop cultural-tailored advanced care planning models to clarify patient preferences and to enhance the family members' self-efficacy in making EoL decisions with or for patients with advanced cancer.

RESUMEN

A distinct rise of global interest in the role of cultural and creative industries in post-industrial urban development calls for the transformation of our industrial heritage into creative clusters. Despite many factories being removed in deindustrialization, some enterprises still preserve and reuse the former industrial lands. However, the inconclusive judgments on the performances of creative clusters call for an in-depth examination of the underlying mechanism of transforming dilapidated urban industrial spaces. In addition, few empirical studies have revealed the commonalities and differences of market entities employing both the top-down and bottom-up approaches during the redevelopment. In this article, a multilevel transformation, and the consequent spatial performance in three postindustrial lands in Beijing have been examined based on big data analysis, field observation and in-depth interviews. We reached three conclusions. First, in addition to the angle of participatory planning, the deep exploration of specific market entities as an intermediate joint among different parties in protecting and reusing the postindustrial lands uncovers a distinct perspective of urban revitalization. Second, the finding of the enterprises' role in mitigating the conflicts between bottom-up and top-down approaches further testifies to a less-dichotomous perspective in urban regeneration studies. Last, though the examination of the multilevel transformation mechanism reflecting the difference between state and nonstate enterprises in property-led management, a generic paradigm behind the trend of relying on enterprises in revitalizing the large-scale postindustrial lands is revealed.

RESUMEN

HMG (high mobility group) proteins are a diverse family of nonhistone chromosomal proteins that interact with DNA and a wide range of transcriptional regulators to regulate the structural architecture of DNA. HMGXB4 (also known as HMG2L1) is an HMG protein family member that contains a single HMG box domain. Our previous studies have demonstrated that HMGXB4 suppresses smooth muscle differentiation and exacerbates endotoxemia by promoting a systemic inflammatory response in mice. However, the expression of Hmgxb4 in vivo has not fully examined. Herein, we generated a mouse model that harbors a gene trap in the form of a lacZ gene insertion into the Hmgxb4 gene. This mouse enables the visualization of endogenous HMGXB4 expression in different tissues via staining for the ß-galactosidase activity of LacZ which is under the control of the endogenous Hmgxb4 gene promoter. We found that HMGXB4 is widely expressed in mouse tissues and is a nuclear protein. Furthermore, the Hmgxb4 gene trap mice exhibit normal cardiac function and blood pressure. Measurement of ß-galactosidase activity in the Hmgxb4 gene trap mice demonstrated that the arterial injury significantly induces Hmgxb4 expression. In summary, the Hmgxb4 gene trap reporter mouse described here provides a valuable tool to examine the expression level of endogenous Hmgxb4 in both physiological and pathological settings in vivo.

Asunto(s)

Proteínas del Grupo de Alta Movilidad , Ratones Endogámicos C57BL , Animales , Masculino , Ratones , beta-Galactosidasa/metabolismo , beta-Galactosidasa/genética , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Operón Lac/genética , Ratones Transgénicos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo

RESUMEN

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Asunto(s)

Procedimiento de Fontan , Células Estrelladas Hepáticas , Hepatocitos , Hepatopatías , Humanos , Epigenómica , Procedimiento de Fontan/efectos adversos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hepatocitos/metabolismo , Hígado/patología , Hígado/metabolismo , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Hepatopatías/etnología , Hepatopatías/patología , Multiómica , Análisis de la Célula Individual , Transcriptoma

RESUMEN

Liver disease is a common and serious threat to human health. The progression of liver diseases is influenced by many physiologic processes, including oxidative stress, inflammation, bile acid metabolism, and autophagy. Various factors lead to the dysfunction of these processes and basing on the different pathogeny, pathology, clinical manifestation, and pathogenesis, liver diseases are grouped into different categories. Specifically, Sirtuin1 (SIRT1), a member of the sirtuin protein family, has been extensively studied in the context of liver injury in recent years and are confirmed the significant role in liver disease. SIRT1 has been found to play a critical role in regulating key processes in liver injury. Further, SIRT1 seems to cause divers outcomes in different types of liver diseases. Recent studies have showed some therapeutic strategies involving modulating SIRT1, which may bring a novel therapeutic target. To elucidate the mechanisms underlying the role of sirtuin1 in liver injury and its potentiality as a therapeutic target, this review outlines the key signaling pathways associated with sirtuin1 and liver injury, and discusses recent advances in therapeutic strategies targeting sirtuin1 in liver diseases.

Asunto(s)

Hepatopatías , Sirtuina 1 , Humanos , Sirtuina 1/genética , Hepatopatías/terapia , Inflamación , Transducción de Señal