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The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing anti-tuberculosis therapy, while aiming to combat tuberculosis (TB), also debilitates innate and adaptive immune components of the host. In this study, we explored how the front-line anti-TB drugs impact the host immune cells by modulating multiple signaling pathways and subsequently leading to disease relapse. Administration of these drugs led to a reduction in innate immune activation and also the cytokines required to trigger protective T cell responses. Moreover, these drugs led to activation-induced cell death in the mycobacterial-specific T cell leading to a reduced killing capacity. Furthermore, these drugs stalled the T cell differentiation into memory subsets by modulating the activation of STAT3, STAT4, FOXO1, and NFκB transcription factors and hampering the Th1 and Th17-mediated long-term host protective memory responses. These findings suggest the urgent need to augment directly observed treatment, short-course (DOTS) therapy with immunomodulatory agents to mitigate the adverse effects linked to the treatment.IMPORTANCEAs a central component of TB eradication initiatives, directly observed treatment, short-course (DOTS) therapy imparts immune-dampening effects during the course of treatment. This approach undermines the host immune system by delaying the activation process and lowering the immune response. In our investigation, we have unveiled the impact of DOTS on specific immune cell populations. Notably, the signaling pathways involving STAT3 and STAT4 critical for memory responses and NFκß associated with pro-inflammation were substantially declined due to the therapy. Consequently, these drugs exhibit limited effectiveness in preventing recurrence of the disease. These observations highlight the imperative integration of immunomodulators to manage TB infection.
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Antituberculosos , Citocinas , Mycobacterium tuberculosis , Tuberculosis , Antituberculosos/uso terapéutico , Antituberculosos/farmacología , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunología , Tuberculosis/microbiología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/inmunología , Humanos , Animales , Ratones , Citocinas/metabolismo , Inmunidad Innata/efectos de los fármacos , Recurrencia , Transducción de Señal/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Femenino , Ratones Endogámicos C57BL , Células TH1/inmunología , Células TH1/efectos de los fármacos , Células Th17/inmunología , Células Th17/efectos de los fármacosRESUMEN
Mycobacterium tuberculosis (M.tb) effectively manipulates the host processes to establish the deadly respiratory disease, Tuberculosis (TB). M.tb has developed key mechanisms to disrupt the host cell health to combat immune responses and replicate efficaciously. M.tb antigens such as ESAT-6, 19kDa lipoprotein, Hip1, and Hsp70 destroy the integrity of cell organelles (Mitochondria, Endoplasmic Reticulum, Nucleus, Phagosomes) or delay innate/adaptive cell responses. This is followed by the induction of cellular stress responses in the host. Such cells can either undergo various cell death processes such as apoptosis or necrosis, or mount effective immune responses to clear the invading pathogen. Further, to combat the infection progression, the host secretes extracellular vesicles such as exosomes to initiate immune signaling. The exosomes can contain M.tb as well as host cell-derived peptides that can act as a double-edged sword in the immune signaling event. The host-symbiont microbiota produces various metabolites that are beneficial for maintaining healthy tissue microenvironment. In juxtaposition to the above-mentioned mechanisms, M.tb dysregulates the gut and respiratory microbiome to support its replication and dissemination process. The above-mentioned interconnected host cellular processes of Immunometabolism, Cellular stress, Host Microbiome, and Extracellular vesicles are less explored in the realm of exploration of novel Host-directed therapies for TB. Therefore, this review highlights the intertwined host cellular processes to control M.tb survival and showcases the important factors that can be targeted for designing efficacious therapy.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Interacciones Huésped-Patógeno , Transducción de Señal , ApoptosisRESUMEN
BACKGROUND: Anatomy is one of the most volatile subjects and needs the learner to understand and retain a lot of information and terms. It is thus very important to continuously upgrade the methodology from the traditional didactive to interactive teaching to make the student an active learner and engage him in the learning process to categorize and analyze anatomical facts and knowledge. AIMS AND OBJECTIVES: The study was done to compare the learning outcomes and perception of medical students towards didactic lectures and interactive quiz-based lectures in anatomy. METHODOLOGY: The study was conducted amongst the 200 Year 1 medical undergraduate students enrolled in the Department of Anatomy at Dr. Ram Manohar Lohia Institute of Medical Sciences, located in Lucknow, India. The 200 students comprised 120 males (60%) and 80 females (40%). The mean age of male students was 19.67 years and of females was 19.52 years. The students were divided into two groups of hundred students each by a method of convenience sampling. Students of group I were taught by an interactive quiz-based lecture and group II by a traditional didactic lecture. A pre- and post-test were conducted for both groups and feedback for both methods was taken by using a pre-validated feedback form based on a 5-point Likert scale. RESULTS: On statistical analysis, it was found that in the post-test the performance of group I taught by the interactive quiz-based study was better as compared to group II taught by traditional didactive teaching, but was not statistically significant (p=0.233, p>0.05). The feedback from students revealed that 45.9% of them strongly agreed and 44.9% agreed with the fact that quiz-based lectures are better than routine lectures. CONCLUSIONS: Results of the present study clearly indicate that the introduction of quiz-based anatomy teaching for undergraduate medical students was well received and appeared to improve their learning outcomes in the form of increased attention and participation during class and would lead to better retention of the topics taught during interactive lectures. To the best of our knowledge, no previous study has been done to document the efficacy of quiz-based teaching for the subject of anatomy.
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In patients with breast cancer, lower bone mineral density increases the risk of bone metastasis. Although the relationship between bone-matrix mineralization and tumour-cell phenotype in breast cancer is not well understood, mineralization-induced rigidity is thought to drive metastatic progression via increased cell-adhesion forces. Here, by using collagen-based matrices with adjustable intrafibrillar mineralization, we show that, unexpectedly, matrix mineralization dampens integrin-mediated mechanosignalling and induces a less proliferative stem-cell-like phenotype in breast cancer cells. In mice with xenografted decellularized physiological bone matrices seeded with human breast tumour cells, the presence of bone mineral reduced tumour growth and upregulated a gene-expression signature that is associated with longer metastasis-free survival in patients with breast cancer. Our findings suggest that bone-matrix changes in osteogenic niches regulate metastatic progression in breast cancer and that in vitro models of bone metastasis should integrate organic and inorganic matrix components to mimic physiological and pathologic mineralization.
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Neoplasias de la Mama , Calcinosis , Neoplasias Mamarias Animales , Humanos , Ratones , Animales , Femenino , Matriz Ósea/patología , Integrinas , Neoplasias de la Mama/patología , Calcificación Fisiológica/fisiología , ColágenoRESUMEN
AIMS: In the SUSTAIN 6 cardiovascular outcomes trial, once-weekly semaglutide was associated with a statistically significant reduction in major adverse cardiovascular events compared with placebo. To date, no studies have assessed how accurately existing diabetes models predict the outcomes observed in SUSTAIN 6. The aims of this analysis were to investigate the performance of the IQVIA Core Diabetes Model when used to predict the SUSTAIN 6 trial outcomes, to calibrate the model such that projected outcomes reflected observed outcomes, and to examine the impact of calibration on the cost-effectiveness of once-weekly semaglutide from a UK healthcare payer perspective. METHODS: The IQVIA Core Diabetes Model was calibrated to ensure that the projected non-fatal stroke event rates reflected the non-fatal stroke event rates observed in SUSTAIN 6 over a two-year time horizon. Cost-effectiveness analyses of once-weekly semaglutide versus placebo plus standard of care were conducted over a lifetime horizon using the uncalibrated and calibrated models to assess the impact on cost-effectiveness outcomes. RESULTS: To replicate the non-fatal stroke event rate in SUSTAIN 6, calibration of the model through the application of relative risks for stroke of 1.07 and 1.65 with once-weekly semaglutide and placebo, respectively, was required. In the long-term cost-effectiveness analysis, the uncalibrated model projected an incremental cost-effectiveness ratio for once-weekly semaglutide versus placebo plus standard of care of GBP 22,262 per quality-adjusted life year (QALY) gained, which fell to GBP 17,594 per QALY gained when the calibrated model was used. CONCLUSIONS: The requirement for calibration to replicate the outcomes observed in SUSTAIN 6 suggests that the reductions in risk of cardiovascular complications observed with once-weekly semaglutide cannot be solely explained by differences in conventional risk factors. Accurate estimation of the risk of diabetes-related complications using methods such as calibration is important to ensure accurate cost-effectiveness analyses are conducted.
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Accidente Cerebrovascular , Humanos , Calibración , Péptidos Similares al Glucagón , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Ensayos Clínicos como AsuntoRESUMEN
Tuberculosis (TB) still tops the list of global health burdens even after COVID-19. However, it will sooner transcend the current pandemic due to the prevailing risk of reactivation of latent TB in immunocompromised individuals. The indiscriminate misuse and overuse of antibiotics have resulted in the emergence of deadly drug-resistant variants of Mycobacterium tuberculosis (M.tb). This study aims to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM) in generating long-lasting immunity against TB. BPM treatment significantly boosted the activation status of the innate immune arm-macrophages by augmenting p38 signaling. Macrophages further primed and activated the adaptive immune cells CD4+ and CD8+ T-cells in the lung and spleen of the infected mice model. Furthermore, BPM treatment significantly amplified the polarization of T lymphocytes toward inflammatory subsets, such as Th1 and Th17. The treatment also helped generate a long-lived central memory T-cell subset. The generation of central memory T lymphocyte subset upon BPM treatment in the murine model led to a significant curtailing in the recurrence of TB due to reactivation and reinfection. These results suggest the potentiality of BPM as a potent adjunct immunomodulator to improve host defense against M.tb by enriching long-term protective memory cells. IMPORTANCE Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) tops the list of infectious killers around the globe. The emergence of drug-resistant variants of M.tb has been a major hindrance toward realizing the "END TB" goal. Drug resistance has amplified the global burden toward the quest for novel drug molecules targeting M.tb. Host-directed therapy (HDT) offers a lucrative alternative to tackle emerging drug resistance and disease relapse by strengthening the host's immunity. Through our present study, we have tried to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM). BPM treatment significantly augmented long-lasting immunity against TB by boosting the innate and adaptive immune arms. The generation of long-lived central memory T lymphocyte subset significantly improved the disease outcome and provided sterilizing immunity in the murine model of TB. The present investigation's encouraging results have helped us depict BPM as a potent adjunct immunomodulator for treating TB.
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COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Animales , Ratones , Linfocitos T CD8-positivos , Antibacterianos/uso terapéutico , Carbapenémicos/uso terapéutico , Modelos Animales de Enfermedad , Tuberculosis/microbiología , Inmunidad , Factores InmunológicosRESUMEN
Bacille Calmette-Guerin (BCG) generates limited long-lasting adaptive memory responses leading to short-lived protection against adult pulmonary tuberculosis (TB). Here, we show that host sirtuin 2 (SIRT2) inhibition by AGK2 significantly enhances the BCG vaccine efficacy during primary infection and TB recurrence through enhanced stem cell memory (TSCM) responses. SIRT2 inhibition modulated the proteome landscape of CD4+ T cells affecting pathways involved in cellular metabolism and T-cell differentiation. Precisely, AGK2 treatment enriched the IFNγ-producing TSCM cells by activating ß-catenin and glycolysis. Furthermore, SIRT2 specifically targeted histone H3 and NF-κB p65 to induce proinflammatory responses. Finally, inhibition of the Wnt/ß-catenin pathway abolished the protective effects of AGK2 treatment during BCG vaccination. Taken together, this study provides a direct link between BCG vaccination, epigenetics, and memory immune responses. We identify SIRT2 as a key regulator of memory T cells during BCG vaccination and project SIRT2 inhibitors as potential immunoprophylaxis against TB.
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Mesenchymal stem cells (MSCs) play diverse roles ranging from regeneration and wound healing to immune signaling. Recent investigations have indicated the crucial role of these multipotent stem cells in regulating various aspects of the immune system. MSCs express unique signaling molecules and secrete various soluble factors that play critical roles in modulating and shaping immune responses, and in some other cases, MSCs can also exert direct antimicrobial effects, thereby helping with the eradication of invading organisms. Recently, it has been demonstrated that MSCs are recruited at the periphery of the granuloma containing Mycobacterium tuberculosis and exert "Janus"-like functions by harboring pathogens and mediating host protective immune responses. This leads to the establishment of a dynamic balance between the host and the pathogen. MSCs function through various immunomodulatory factors such as nitric oxide (NO), IDO, and immunosuppressive cytokines. Recently, our group has shown that M.tb uses MSCs as a niche to evade host protective immune surveillance mechanisms and establish dormancy. MSCs also express a large number of ABC efflux pumps; therefore, dormant M.tb residing in MSCs are exposed to a suboptimal dose of drugs. Therefore, it is highly likely that drug resistance is coupled with dormancy and originates within MSCs. In this review, we discussed various immunomodulatory properties of MSCs, their interactions with important immune cells, and soluble factors. We also discussed the possible roles of MSCs in the outcome of multiple infections and in shaping the immune system, which may provide insight into therapeutic approaches using these cells in different infection models.
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Enfermedades Transmisibles , Células Madre Mesenquimatosas , Mycobacterium tuberculosis , Tuberculosis , Humanos , Citocinas , Inmunomodulación , Células Madre Mesenquimatosas/fisiologíaRESUMEN
IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Endorribonucleasas , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinasas , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/genética , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Neoplasias Pulmonares/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
OBJECTIVE: This study aims to characterize the gender distribution of first authors, senior authors, and editorial board members across several high-impact factor journals in PCCM. METHODS: In this cross-sectional study, we analysed gender disparities in critical care authorship and editorial boards, based on publications from 1 January 2019 to 31 December 2021 from the top 20 high impact journals based on the Journal of Citation Reports. RESULTS: Among 20 journals (median impact factor of 6.66), 25% of editors-in-chief and 28.8% of editorial board members were female. From 2019 to 2021, a total of 23,994 articles were published. Female first authors and last authors made up 29.1% and 21.2% of the authorship, respectively (n = 6637 articles). CONCLUSIONS: Our study demonstrates significant gender disparities in critical care authorship and editorial boards, with males predominantly filling the roles of editors in chief, editorial members, and first and senior authors. Despite this significant difference in gender distribution, there was no statistically significant correlation between authorship and editor gender.
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Autoria , Cuidados Críticos , Equidad de Género , Neumología , Humanos , Edición , Publicaciones Periódicas como Asunto , Diversidad, Equidad e Inclusión , LiderazgoRESUMEN
Mycobacterium szulgai is a nontuberculous pathogen found in the environment that rarely affects immunocompetent hosts but can cause multiorgan disease in immunocompromised hosts. Here, we report a rare case of disseminated M. szulgai in an immunocompromised patient with a liver transplant and drug-induced neutropenia who initially presented with cutaneous lesions on his arms and right upper extremity joint pain.
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Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Animales , Ratones , Linfocitos T , Quimiocinas , Neoplasias Pancreáticas/tratamiento farmacológico , Microambiente TumoralRESUMEN
Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent. SIGNIFICANCE: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483.
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Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama Triple Negativas/genética , Transcriptoma , Negro o Afroamericano/genética , BiologíaRESUMEN
Somatic copy-number alterations (CNA) promote cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded proteins are considered. mRNAs can act as competitive endogenous RNAs (ceRNA), which sponge miRNAs to posttranscriptionally regulate gene expression in a protein coding-independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted melanoma progression and metastasis at least in part through overexpression of three mRNAs with ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced melanoma metastasis by sequestering tumor suppressor miRNAs. Orthogonal genetic assays with miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q ceRNA-mediated miRNA sequestration alleviated the repression of several prometastatic target genes. This regulatory RNA network was evident in other cancer types, suggesting chromosome 1q ceRNA deregulation as a common driver of cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs. SIGNIFICANCE: The function of CEP170, NUCKS1, and ZC3H11A mRNAs as competitive endogenous RNAs that sequester tumor suppressor microRNAs underlies the oncogenic activity of chromosome 1q gains.
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Melanoma , MicroARNs , ARN Largo no Codificante , Carcinogénesis/genética , Cromosomas , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Melanoma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Mensajero/genéticaRESUMEN
Cyclic AMP (cAMP) signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. Here, we present a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncover a nuclear cAMP microdomain that activates a tumor-suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397 and export of YAP from the nucleus with no change in YAP protein stability. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer; thus, drugs directed at the nuclear cAMP microdomain may provide avenues for the treatment of cancer.
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AMP Cíclico , Neoplasias , Humanos , Línea Celular , AMP Cíclico/metabolismo , Vía de Señalización Hippo , Fosforilación , Proteínas Serina-Treonina Quinasas , Serina/metabolismoRESUMEN
Polycomb and Trithorax group proteins (PcG, TrxG) epigenetically regulate developmental genes. These proteins bind with specific DNA elements, the Polycomb Response Element (PRE). Apart from mutations in polycomb/ trithorax proteins, altered cis-elements like PRE underlie the modified function and thus disease etiology. PREs are well studied in Drosophila, while only a few human PREs have been reported. We have identified a polycomb responsive DNA element, hPRE-HoxA3, in the intron of the HoxA3 gene. The hPRE-HoxA3 represses luciferase reporter activity in a PcG-dependent manner. The endogenous hPRE-HoxA3 element recruits PcG proteins and is enriched with repressive H3K27me3 marks, demonstrating that hPRE-HoxA3 is a part of the PcG-dependent gene regulatory network. Furthermore, it interacts with D11-12, the well-known PRE in the human Hox cluster. hPRE-Hox3 is a part of the 3-dimensional chromosomal domain organization as it is involved in the long-range interaction with other PcG enriched regions of Hox A, B, C, and D clusters.
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Proteínas de Drosophila , Histonas , Animales , Drosophila/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Genómica , Histonas/genética , Histonas/metabolismo , Humanos , Luciferasas/metabolismo , Complejo Represivo Polycomb 1/genética , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Elementos de Respuesta , Factores de Transcripción/genéticaRESUMEN
Japanese encephalitis virus (JEV), a single-stranded, enveloped RNA virus, is a health concern across Asian countries, associated with severe neurological disorders, especially in children. Primarily, pigs, bats, and birds are the natural hosts for JEV, but humans are infected incidentally. JEV requires a few host proteins for its entry and replication inside the mammalian host cell. The endoplasmic reticulum (ER) plays a significant role in JEV genome replication and assembly. During this process, the ER undergoes stress due to its remodelling and accumulation of viral particles and unfolded proteins, leading to an unfolded protein response (UPR). Here, we review the overall strategy used by JEV to infect the host cell and various cytopathic effects caused by JEV infection. We also highlight the role of JEV structural proteins (SPs) and non-structural proteins (NSPs) at various stages of the JEV life cycle that are involved in up- and downregulation of different host proteins and are potentially relevant for developing efficient therapeutic drugs.
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Virus de la Encefalitis Japonesa (Especie) , Encefalitis Japonesa , Animales , Línea Celular , Niño , Virus de la Encefalitis Japonesa (Especie)/genética , Humanos , Mamíferos , Porcinos , Respuesta de Proteína Desplegada , Replicación ViralRESUMEN
There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors. Trajectory analysis of single-cell melanoma CD8+ TILs also identified a high fraction of memory/resident memory-scoring TILs in anti-PD-1 responders, which expanded post therapy. In contrast, TILs scoring highly for early T cell activation, but not exhaustion, associated with non-response. Late/persistent, but not early activation signatures, prognosticate melanoma survival, and co-express with dendritic cell and IFN-γ response programs. These data identify an activation-like state associated to poor response and suggest successful memory conversion, above resuscitation of exhaustion, is an under-appreciated aspect of successful anti-tumoral immunity.
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Linfocitos Infiltrantes de Tumor , Melanoma , Animales , Linfocitos T CD8-positivos , Diferenciación Celular , Humanos , Melanoma/genética , Melanoma/terapia , Ratones , Receptor de Muerte Celular Programada 1RESUMEN
Perturbations to the epigenome are known drivers of tumorigenesis. In melanoma, alterations in histone methyltransferases that catalyze methylation at histone 3 lysine 9 and histone 3 lysine 27-two sites of critical post-translational modification-have been reported. To study the function of these methyltransferases in melanoma, we engineered melanocytes to express histone 3 lysine-to-methionine mutations at lysine 9 and lysine 27, which are known to inhibit the activity of histone methyltransferases, in a zebrafish melanoma model. Using this system, we found that loss of histone 3 lysine 9 methylation dramatically suppressed melanoma formation and that inhibition of histone 3 lysine 9 methyltransferases in human melanoma cells increased innate immune response signatures. In contrast, loss of histone 3 lysine 27 methylation significantly accelerated melanoma formation. We identified FOXD1 as a top target of PRC2 that is silenced in melanocytes and found that aberrant overexpression of FOXD1 accelerated melanoma onset. Collectively, these data demonstrate how histone 3 lysine-to-methionine mutations can be used to uncover critical roles for methyltransferases.