RESUMO
The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill defined. To address this gap, we performed genome-scale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E). These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, sterol regulatory element-binding protein (SREBP) signaling, bone morphogenetic protein (BMP) signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins. We identified an absolute requirement for the VMP1, TMEM41, and TMEM64 (VTT) domain-containing protein transmembrane protein 41B (TMEM41B) for infection by SARS-CoV-2 and three seasonal coronaviruses. This human coronavirus host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus pandemics.
Assuntos
Infecções por Coronavirus/genética , Estudo de Associação Genômica Ampla , SARS-CoV-2/fisiologia , Células A549 , Linhagem Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Coronavirus Humano 229E/fisiologia , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/fisiologia , Coronavirus Humano OC43/fisiologia , Técnicas de Inativação de Genes , Células HEK293 , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Proteínas de Membrana/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Mapeamento de Interação de ProteínasRESUMO
Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFß. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.
Assuntos
Neoplasias Pulmonares , Metástase Neoplásica , Animais , Camundongos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Ciclo Celular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos T/imunologia , Fator de Crescimento Transformador beta , Células Matadoras Naturais/imunologiaRESUMO
CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, ß-cell-specific CD8 T cells destroy insulin-producing ß-cells. Here we followed the fate of ß-cell-specific CD8 T cells in non-obese diabetic mice throughout the course of type 1 diabetes. We identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators. pLN autoimmune mediators migrate to the pancreas, where they differentiate further and destroy ß-cells. Whereas transplantation of as few as 20 autoimmune progenitors induced type 1 diabetes, as many as 100,000 pancreatic autoimmune mediators did not. Pancreatic autoimmune mediators are short-lived, and stem-like autoimmune progenitors must continuously seed the pancreas to sustain ß-cell destruction. Single-cell RNA sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from autoimmune progenitor to autoimmune mediator. Strategies aimed at targeting the stem-like autoimmune progenitor pool could emerge as novel and powerful immunotherapeutic interventions for type 1 diabetes.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Células Secretoras de Insulina/imunologia , Células-Tronco/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Autorrenovação Celular , Células Clonais/imunologia , Células Clonais/metabolismo , Células Clonais/patologia , Modelos Animais de Doenças , Feminino , Glucose-6-Fosfatase/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Células Secretoras de Insulina/patologia , Linfonodos/imunologia , Masculino , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Célula Única , Transplante de Células-Tronco , Células-Tronco/imunologia , Células-Tronco/metabolismo , TranscriptomaRESUMO
Cancers develop as a result of driver mutations1,2 that lead to clonal outgrowth and the evolution of disease3,4. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes5 and therapeutic vulnerabilities6. However, the serial genetic evolution of mutant cancer genes7,8 and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.
Assuntos
Carcinogênese/genética , Modelos Genéticos , Mutação , Neoplasias/genética , Oncogenes/genética , Alelos , Animais , Feminino , Genes p53/genética , Humanos , Camundongos , Seleção Genética , Telomerase/genéticaRESUMO
The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of α-ketoglutarate (αKG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable αKG. Increased levels of the αKG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of αKG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase-an enzyme of the tricarboxylic acid cycle-specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of αKG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that αKG is an effector of p53-mediated tumour suppression, and that the accumulation of αKG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.
Assuntos
Carcinoma Ductal Pancreático , Diferenciação Celular/genética , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pancreáticas , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/fisiopatologia , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Ácidos Cetoglutáricos/farmacologia , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/fisiopatologia , Ligação Proteica , Ácido Succínico/metabolismo , Ativação TranscricionalRESUMO
Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile preclinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9a cancer target whose clinical development has been hampered by compounds with poorly understood target specificity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve significant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.
Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Quinase 9 Dependente de Ciclina/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Interferência de RNARESUMO
Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell- and T-cell-specific factors. Additionally, Phf6KO cells show significant down-regulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.
Assuntos
Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/fisiopatologia , Animais , Linhagem Celular Tumoral , Linhagem da Célula/genética , Cromatina/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Inativação de Genes , Linfoma não Hodgkin/genética , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas Repressoras , Transdução de Sinais/genéticaRESUMO
Recent advances in genome editing technologies are allowing investigators to engineer and study cancer-associated mutations in their endogenous genetic contexts with high precision and efficiency. Of these, base editing and prime editing are quickly becoming gold-standards in the field due to their versatility and scalability. Here, we review the merits and limitations of these precision genome editing technologies, their application to modern cancer research, and speculate how these could be integrated to address future directions in the field.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Neoplasias , Humanos , Edição de Genes/métodos , Neoplasias/genética , Neoplasias/terapia , Mutação , Animais , Medicina de Precisão , Genoma HumanoRESUMO
Reactivation of p53 in established tumors typically results in one of two cell fates, cell cycle arrest or apoptosis, but it remains unclear how this cell fate is determined. We hypothesized that high mitochondrial priming prior to p53 reactivation would lead to apoptosis, while low priming would lead to survival and cell cycle arrest. Using a panel of Kras-driven, p53 restorable cell lines derived from genetically engineered mouse models of lung adenocarcinoma and sarcoma (both of which undergo cell cycle arrest upon p53 restoration), as well as lymphoma (which instead undergo apoptosis), we show that the level of mitochondrial apoptotic priming is a critical determinant of p53 reactivation outcome. Cells with high initial priming (e.g., lymphomas) lacked sufficient reserve antiapoptotic capacity and underwent apoptosis after p53 restoration. Forced BCL-2 or BCL-XL expression reduced priming and resulted in survival and cell cycle arrest. Cells with low initial priming (e.g., lung adenocarcinoma and sarcoma) survived and proceeded to arrest in the cell cycle. When primed by inhibition of their antiapoptotic proteins using genetic (BCL-2 or BCL-XL deletion or BAD overexpression) or pharmacologic (navitoclax) means, apoptosis resulted upon p53 restoration in vitro and in vivo. These data demonstrate that mitochondrial apoptotic priming is a key determining factor of cell fate upon p53 activation. Moreover, it is possible to enforce apoptotic cell fate following p53 activation in less primed cells using p53-independent drugs that increase apoptotic priming, including BH3 mimetic drugs.
Assuntos
Adenocarcinoma de Pulmão/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Neoplasias Pulmonares/metabolismo , Mitocôndrias/metabolismo , Sarcoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Mitocôndrias/genética , Mitocôndrias/patologia , Sarcoma/genética , Sarcoma/patologia , Proteína Supressora de Tumor p53/genéticaRESUMO
INTRODUCTION: There is a gap in the literature on the romantic relationships of adopted adolescents. To address this issue, the present study has three aims: (1) to explore differences between adopted and non-adopted adolescents in terms of their involvement in and the length of their romantic relationships; (2) to explore the quality of these relationships; and (3) to analyze associations between affective relationships and well-being in both groups. METHOD: The sample comprised 276 adopted (64.5% girls; mean age 16.3 years, 73.9% international adoptees) and 276 non-adopted (48.3% girls; mean age 16.3 years) adolescents, all of whom participated in the Spanish Health Behaviour in School-aged Children survey. RESULTS: Similar romantic relationship rates and lengths were found among adoptees and non-adoptees, as well as between international and domestic adoptees. Adoptees reported more emotional support and conflicts in their romantic relationships than their non-adopted peers. Finally, associations between the quality of the romantic relationships and well-being were similar for both groups, with more conflicts being linked to lower levels of well-being, and more emotional support and affection correlating with higher levels of well-being. DISCUSSION: The data suggest more similarities than differences between adopted and non-adopted adolescents. However, although this indicates that romantic relationships are yet another example of recovery for adopted boys and girls, further research is required, with larger and more diverse samples from multiple countries, to explore the differences observed in more detail.
Assuntos
Adoção , Relações Interpessoais , Humanos , Adolescente , Masculino , Feminino , Adoção/psicologia , Espanha , Inquéritos e Questionários , Comportamento do Adolescente/psicologiaRESUMO
AIM: The aim of this study was to review the existing evidence on burnout levels in midwives and the main related factors. DESIGN: Mixed studies systematic review. DATA SOURCES: PubMed, Scopus and Web of Science were sourced from 2018 and 2023. REVIEW METHODS: Inclusion criteria: quantitative cross-sectional or qualitative articles published in English within the last 5 years. EXCLUSION CRITERIA: studies with undergraduate or trainee midwives, studies examining the factors in a pandemic setting and those not answering the research question. Potential risk of bias was assessed using the Mixed Methods Assessment Tool (MMAT). A convergent synthesis design was followed through a thematic synthesis using Thomas and Harden's three-step method: inductive coding of the text, development of descriptive themes and generation of analytical themes. Qualitative approaches adopted exploratory descriptive studies and participatory action research. RESULTS: Thirty-six studies were included, with a total of 17,364 participants. There were higher levels of burnout in midwives who were single, under 35-40 years of age, with less than 10 years of experience and those with young children. Stress, anxiety and depression, as well as the emotional impact of traumatic events, have been described as related psychological factors. CONCLUSION: Although extrinsic work factors such as shifts, workload, pay and interpersonal relationships increase burnout, intrinsic factors such as lack of autonomy and recognition are the main factors related to it. IMPACT: What problem did the study address? Burnout among healthcare workers has been recognized as a global crisis requiring urgent attention, specifically in midwives. What were the main findings? There is a persistent shortage of midwives that is attributed in part to chronic retention difficulties related to job burnout expressed by these professionals. Where and on whom will the research have an impact? We seek to address the paucity of research on burnout in midwives in the current crisis in the profession. Work factors such as lack of autonomy or recognition in the profession carry an associated risk of burnout and job attrition. Understanding the factors that contribute to burnout will enable healthcare organizations to reduce the current problem. REPORTING METHOD: PREFERRED: Reporting items for systematic review and meta-analyses (PRISMA). PATIENT OF PUBLIC CONTRIBUTION: No patient or public contribution.
RESUMO
In 1926, during an economic crisis that severely impacted the mining industry, Guggenheim Brothers, the Guggenheim family business, implemented a new technological system to extract saltpeter from the Atacama Desert in northern Chile. Known as the Guggenheim system, this cutting-edge technological innovation had a significant impact on regional society and facilitated the introduction of Chilean saltpeter into the global fertilizer market. For this system to succeed, however, it had to incorporate a sociopolitical strategy based on a highly hierarchical and well-controlled labor force. Through their political and cultural influence in the region, the Guggenheim family's industry transformed a remote area into a state periphery, creating new ways of inhabiting the desert within a strict framework in which workers' lives were regulated by company-imposed labor discipline. With more political power than the state, the Guggenheim family sought to suppress any social agency deemed dangerous to the production of saltpeter.
Assuntos
Clima Desértico , Mineração , Chile , Mineração/história , História do Século XX , Nitratos/história , Humanos , PolíticaRESUMO
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Progressão da Doença , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Nicho de Células-Tronco , Proteínas Wnt/biossíntese , Via de Sinalização Wnt , Adenocarcinoma de Pulmão , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Taxa de Sobrevida , Proteínas Wnt/química , Proteínas Wnt/metabolismoRESUMO
The coronavirus disease pandemic, which profoundly reshaped the world in 2019 (COVID-19), and is currently ongoing, has affected over 200 countries, caused over 500 million cumulative cases, and claimed the lives of over 6.4 million people worldwide as of August 2022. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Depicting this virus' life cycle and pathogenic mechanisms, as well as the cellular host factors and pathways involved during infection, has great relevance for the development of therapeutic strategies. Autophagy is a catabolic process that sequesters damaged cell organelles, proteins, and external invading microbes, and delivers them to the lysosomes for degradation. Autophagy would be involved in the entry, endo, and release, as well as the transcription and translation, of the viral particles in the host cell. Secretory autophagy would also be involved in developing the thrombotic immune-inflammatory syndrome seen in a significant number of COVID-19 patients that can lead to severe illness and even death. This review aims to review the main aspects that characterize the complex and not yet fully elucidated relationship between SARS-CoV-2 infection and autophagy. It briefly describes the key concepts regarding autophagy and mentions its pro- and antiviral roles, while also noting the reciprocal effect of viral infection in autophagic pathways and their clinical aspects.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Autofagia , Antivirais/farmacologia , Lisossomos/metabolismoRESUMO
Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the function of which is unclear. Whether collagen can activate DDR1 in OLs has not been studied. Here, we assessed the expression of DDR1 during in vitro OL differentiation, including collagen IV incubation, and the capability of collagen IV to induce DDR1 phosphorylation. Experiments were performed using two in vitro models of OL differentiation: OLs derived from adult rat neural stem cells (NSCs) and the HOG16 human oligodendroglial cell line. Immunocytofluorescence, western blotting, and ELISA were performed to analyze these questions. The differentiation of OLs from NSCs was addressed using oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP). In HOG16 OLs, collagen IV induced DDR1 phosphorylation through slow and sustained kinetics. In NSC-derived OLs, DDR1 was found in a high proportion of differentiating cells (MBP+/Olig2+), but its protein expression was decreased in later stages. The addition of collagen IV did not change the number of DDR1+/MBP+ cells but did accelerate OL branching. Here, we provide the first demonstration that collagen IV mediates the phosphorylation of DDR1 in HOG16 cells and that the in vitro co-expression of DDR1 and MBP is associated with accelerated branching during the differentiation of primary OLs.
Assuntos
Receptor com Domínio Discoidina 1 , Receptores Proteína Tirosina Quinases , Ratos , Humanos , Animais , Receptor com Domínio Discoidina 1/metabolismo , Ligantes , Colágeno Tipo IV/metabolismo , Oligodendroglia/metabolismoRESUMO
In this paper I have chosen the topic of psychoanalysis in the age of neuroscience, with the aim of showing why the cultural history of psychoanalysis still matters. To make myself better understood I shall refrain from evaluating the current findings in neuroscience and limit myself to reporting briefly on them. Although I do not regard myself by any means as an expert in that field, I may be permitted to offer a few ideas about it. In this regard, there is presently a significant predominance of biological ideologies and practices regarding the treatment of mental illness, which implies an increase in the interest in etiology, nosology, definitions, and the effectivity of treatments. Even so, those psychoanalytic historians and/or analysts among us who are committed to psychoanalysis and its therapeutic implications, irrespective of what drugs might be prescribed and what the research findings might conclude, believe that patients still want to be listened to in depth and always will. For that reason, it is justified to ask why the cultural history of psychoanalysis still matters in a contemporary mental health environment that is ever more oriented towards the neurosciences.
Assuntos
Transtornos Mentais , Neurociências , Psicanálise , HumanosRESUMO
Life expectancy in humans is increasing, resulting in a growing aging population, that is accompanied by an increased disposition to develop cognitive deterioration. Hypometabolism is one of the multiple factors related to inefficient brain function during aging. This review emphasizes the metabolic interactions between glial cells (astrocytes, oligodendrocytes, and microglia) and neurons, particularly, during aging. Glial cells provide support and protection to neurons allowing adequate synaptic activity. We address metabolic coupling from the expression of transporters, availability of substrates, metabolic pathways, and mitochondrial activity. In aging, the main metabolic exchange machinery is altered with inefficient levels of nutrients and detrimental mitochondrial activity that results in high reactive oxygen species levels and reduced ATP production, generating a highly inflammatory environment that favors deregulated cell death. Here, we provide an overview of the glial-to-neuron mechanisms, from the molecular components to the cell types, emphasizing aging as the crucial risk factor for developing neurodegenerative/neuroinflammatory diseases.
Assuntos
Neuroglia , Neurônios , Astrócitos/metabolismo , Encéfalo/metabolismo , Metabolismo Energético , Neuroglia/fisiologia , Neurônios/metabolismoRESUMO
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is among the most common cancer types worldwide, yet patients with HCC have limited treatment options. There is an urgent need to identify drug targets that specifically inhibit the growth of HCC cells. APPROACH AND RESULTS: We used a CRISPR library targeting ~2,000 druggable genes to perform a high-throughput screen and identified adenylosuccinate lyase (ADSL), a key enzyme involved in the de novo purine synthesis pathway, as a potential drug target for HCC. ADSL has been implicated as a potential oncogenic driver in some cancers, but its role in liver cancer progression remains unknown. CRISPR-mediated knockout of ADSL impaired colony formation of liver cancer cells by affecting AMP production. In the absence of ADSL, the growth of liver tumors is retarded in vivo. Mechanistically, we found that ADSL knockout caused S-phase cell cycle arrest not by inducing DNA damage but by impairing mitochondrial function. Using data from patients with HCC, we also revealed that high ADSL expression occurs during tumorigenesis and is linked to poor survival rate. CONCLUSIONS: Our findings uncover the role of ADSL-mediated de novo purine synthesis in fueling mitochondrial ATP production to promote liver cancer cell growth. Targeting ADSL may be a therapeutic approach for patients with HCC.
Assuntos
Adenilossuccinato Liase/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Purinas/biossíntese , Trifosfato de Adenosina/biossíntese , Adenilossuccinato Liase/genética , Adenilossuccinato Liase/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Taxa de SobrevidaRESUMO
PURPOSE: The objectives of this study were to analyze the psychometric properties of the Sense of Coherence scale (SOC-13), determine the role of the method effect in the performance of the instrument, and identify the relationship with health perception, quality of life, and sleep quality in patients at cardiovascular risk. METHODS: The final sample consisted of 293 patients at cardiovascular risk, with a mean age of 61.9 years (SD = 8.8), 49.8% of whom were women. The SOC-13, the Patient Health Questionnaire (PHQ-9), and the Medical Outcomes Study-Sleep Scale (MOS-Sleep) were administered. In addition, the participant's self-perceived health and quality of life were also evaluated. All analyses were carried out with SPSS 26.0 and EQS 6.1 statistical software. RESULTS: The results showed adequate reliability for the SOC-13, with a Cronbach's alpha of .789. The fit of the structures was not adequate in any of the cases (.26 to .62 for one factor, .26 to.73 for three factors, .20 to .54 for one second-order factor, and .25, .42, and .54 for three first-order factors). The three structure models showed an improved fit when adding a latent factor resulting from the method effect (.6 to .85 for one factor, .11 to.90 for three factors, and .11 to .96 for one second-order factor). Moreover, positive correlations were found with health perception, perceived quality of life, and perceived sleep quality. CONCLUSION: The SOC-13 is a suitable instrument for patients with cardiovascular risk in Spain, and it is also an indicator of health perception, quality of life, and perceived quality of sleep. Control of the method effect improves the fit of the instrument's structure. As a future direction, it is recommended to conduct new studies in this and other samples and using different versions of the SOC. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number: ISRCTN76069254, 08/04/2015 retrospectively registered.
Assuntos
Senso de Coerência , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Qualidade de Vida , Reprodutibilidade dos Testes , Qualidade do Sono , Inquéritos e QuestionáriosRESUMO
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent disorders in children and adolescents. Neurofeedback, a nonpharmaceutical treatment, has shown promising results. To review the evidence of efficacy of neurofeedback as a treatment for children and adolescents with ADHD. A systematic review of the specific scientific studies published in 1995-2021, identifying and analyzing randomized controlled trials (RCT). A total of 1636 articles were identified and 165 met inclusion criteria, of which 67 were RCTs. Neurofeedback training was associated with significant long-term reduction in symptoms of ADHD. Though limitations exist regarding conclusions about the specific effects of neurofeedback, the review documents improvements in school, social, and family environments.