RESUMO
Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.
Assuntos
Células Sanguíneas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Eritropoese/fisiologia , Regulação da Expressão Gênica/fisiologia , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células K562 , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/metabolismo , Mielopoese/fisiologia , Fatores de Transcrição/metabolismo , Transcrição Gênica/fisiologiaRESUMO
Patients with myelodysplastic syndromes (MDSs) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2f/+Vav1cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2f/+Vav1cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2f/+Vav1cre CD4+ T cells (TH22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2f/+Vav1cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.
Assuntos
Anemia/metabolismo , Anticorpos Neutralizantes/farmacologia , Células Eritroides/metabolismo , Eritropoese/efeitos dos fármacos , Interleucinas/antagonistas & inibidores , Síndromes Mielodisplásicas/tratamento farmacológico , Receptores de Interleucina/metabolismo , Anemia/sangue , Anemia/imunologia , Anemia/prevenção & controle , Animais , Células Cultivadas , Microambiente Celular , Modelos Animais de Doenças , Células Eritroides/imunologia , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Receptores de Interleucina/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Interleucina 22RESUMO
Cyclic dinucleotides (CDNs) are a significant and expanding class of secondary messengers that influence several vital bacterial physiological functions. Therefore, an understanding of the process by which CDNs are degraded by their cognate PDEs is crucial for comprehending a variety of cellular processes, such as the formation and dissemination of biofilms. As an alternative, it might be beneficial to create and/or identify non-hydrolyzable CDN derivatives to employ them as chemical probes of cyclic-di-GMP (c-di-GMP) signaling. Cyclic-di-inosine monophosphate, or c-di-IMP, is not a naturally occurring signaling molecule in biological systems, but it has strong adjuvant effects on metazoans and functions as an immunological modulator and stimulant. Here we report the first structural details of c-di-IMP and EAL interaction through high-resolution (2.2 Å) crystal structure of VcEAL in complex with c-di-IMP + Ca2+. Comparison of the VcEAL structures bound with cyclic-di-GMP (c-di-GMP), 3',5'-cyclic-AMP-GMP (cGAMP) and c-di-IMP and the structural variations at the chemical level between these CDNs provides their structural basis of recognition and rate of hydrolysis.
RESUMO
Aims and background: Endotracheal tube cuff pressure (ETCP) is an important factor to determine the development of complications associated with invasive mechanical ventilation. To avoid preventable complications arising out of immobilization, frequent changes in body positioning are necessary. Such variations in body position can affect ETCP in critically ill patients who are on mechanical ventilation. So, our study aimed to assess the effect of changes in body position on ETCP in patients who are on mechanical ventilation. Materials and methods: This prospective observational study included 31 critically ill intubated patients. Each study subject was first placed in a neutral starting position with a 30º head elevation. Then, they were subjected to a sequential change in body position based on the 16 most used positions as part of the critical care unit's (CCUs) daily routine. Endotracheal tube cuff pressure was measured after each position change. Data were analyzed using standard statistical tests. Results: Statistically significant difference in ETCP was observed during anteflexion of neck, hyperextension of neck, left lateral flexion of neck, right lateral flexion of neck, left lateral rotation of neck, right lateral rotation of neck, 10o recumbent position, supine position, Trendelenburg position, and right lateral 30° and 45° positions. Maximum increase in ETCP was seen during anteflexion of neck (31 ± 4.5; 22-42 cm H2O). Conclusion: Our study demonstrates significant deviations in ETCP from the recommended range following changes in the body position of mechanically ventilated patients, highlighting the need for the measurement of ETCP after each position change and maintenance of the same within the target range. How to cite this article: Roy O, Dasgupta S, Chandra A, Biswas P, Choudhury A, Ghosh S, et al. Relationship of Endotracheal Tube Cuff Pressures with Changes in Body Positions of Critically Ill Patients on Mechanical Ventilation: An Observational Study. Indian J Crit Care Med 2024;28(1):36-40.
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Rising incidence of thromboembolism secondary to COVID-19 has become a global concern, with several surveys reporting increased mortality rates. Thrombogenic potential of the SARS-CoV-2 virus has been hypothesised to originate from its ability to produce an exaggerated inflammatory response leading to endothelial dysfunction. Anticoagulants have remained the primary modality of treatment of thromboembolism for decades. However, there is no universal consensus regarding the timing, dosage and duration of anticoagulation in COVID-19 as well as need for postdischarge prophylaxis. This article seeks to review the present guidelines and recommendations as well as the ongoing trials on use of anticoagulants in COVID-19, identify discrepancies between all these, and provide a comprehensive strategy regarding usage of these drugs in the current pandemic.
Assuntos
COVID-19 , Tromboembolia , Tromboembolia Venosa , Assistência ao Convalescente , Anticoagulantes/uso terapêutico , Humanos , Alta do Paciente , SARS-CoV-2 , Tromboembolia/tratamento farmacológico , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Tromboembolia Venosa/etiologiaRESUMO
Mycobacteriophages infect mycobacteria, resulting in their death. Therefore, the possibility of using them as therapeutic agents against the deadly mycobacterial disease tuberculosis (TB) is of great interest. To obtain better insight into the dynamics of mycobacterial inactivation by mycobacteriophages, this study was initiated using mycobacteriophage D29 and Mycobacterium smegmatis as the phage-host system. Here, we implemented a goal-oriented iterative cycle of experiments on one hand and mathematical modeling combined with Monte Carlo simulations on the other. This integrative approach lends valuable insight into the detailed kinetics of bacterium-phage interactions. We measured time-dependent changes in host viability during the growth of phage D29 in M. smegmatis at different multiplicities of infection (MOI). The predictions emerging out of theoretical analyses were further examined using biochemical and cell biological assays. In a phage-host interaction system where multiple rounds of infection are allowed to take place, cell counts drop more rapidly than expected if cell lysis is considered the only mechanism for cell death. The phenomenon could be explained by considering a secondary factor for cell death in addition to lysis. Further investigations reveal that phage infection leads to the increased production of superoxide radicals, which appears to be the secondary factor. Therefore, mycobacteriophage D29 can function as an effective antimycobacterial agent, the killing potential of which may be amplified through secondary mechanisms.
Assuntos
Micobacteriófagos/fisiologia , Mycobacterium smegmatis/crescimento & desenvolvimento , Mycobacterium smegmatis/virologia , Radicais Livres/metabolismo , Cinética , Viabilidade Microbiana , Mycobacterium smegmatis/química , Mycobacterium smegmatis/metabolismoRESUMO
BACKGROUND: Preclinical experiments suggest protective effects of omega-3 fatty acids and their metabolites in lung injury and fibrosis. Whether higher intake of omega-3 fatty acids is associated with disease progression and survival in humans with pulmonary fibrosis is unknown. RESEARCH QUESTION: What are the associations of plasma omega-3 fatty acid levels (a validated marker of omega-3 nutritional intake) with disease progression and transplant-free survival in pulmonary fibrosis? STUDY DESIGN AND METHODS: Omega-3 fatty acid levels were measured from plasma samples of patients with clinically diagnosed pulmonary fibrosis from the Pulmonary Fibrosis Foundation Patient Registry (n = 150), University of Virginia (n = 58), and University of Chicago (n = 101) cohorts. The N-3 index (docosahexaenoic acid + eicosapentaenoic acid) was the primary exposure variable of interest. Linear-mixed effects models with random intercept and slope were used to examine associations of plasma omega-3 fatty acid levels with changes in FVC and diffusing capacity for carbon monoxide over a period of 12 months. Cox proportional hazards models were used to examine transplant-free survival. Stratified analyses by telomere length were performed in the University of Chicago cohort. RESULTS: Most of the cohort were patients with idiopathic pulmonary fibrosis (88%) and male patients (74%). One-unit increment in log-transformed N-3 index plasma level was associated with a change in diffusing capacity for carbon monoxide of 1.43 mL/min/mm Hg per 12 months (95% CI, 0.46-2.41) and a hazard ratio for transplant-free survival of 0.44 (95% CI, 0.24-0.83). Cardiovascular disease history, smoking, and antifibrotic usage did not significantly modify associations. Omega-3 fatty acid levels were not significantly associated with changes in FVC. Higher eicosapentaenoic acid plasma levels were associated with longer transplant-free survival among University of Chicago participants with shorter telomere length (P value for interaction = .02). INTERPRETATION: Further research is needed to investigate underlying biological mechanisms and whether omega-3 fatty acids are a potential disease-modifying therapy.
Assuntos
Ácidos Graxos Ômega-3 , Fibrose Pulmonar Idiopática , Humanos , Masculino , Ácido Eicosapentaenoico , Monóxido de Carbono , Progressão da DoençaRESUMO
Mammalian sirtuin 6 (SIRT6) regulates a spectrum of vital biological processes and has long been implicated in the progression of cancer. However, the mechanisms underlying the regulation of SIRT6 in tumorigenesis remain elusive. Here, we report that the tumor-suppressive function of SIRT6 in non-small cell lung cancer (NSCLC) is regulated by acetylation. Specifically, males absent on the first (MOF) acetylates SIRT6 at K128, K160, and K267, resulting in a decreased deacetylase activity of SIRT6 and attenuated SIRT6 tumor-suppressive function in NSCLC. Mechanistically, MOF-mediated SIRT6 acetylation hinders the interaction between SIRT6 and transcriptional factor FOXA2, which in turn leads to the transcriptional activation of ZEB2, thus promoting NSCLC progression. Collectively, these data indicate an acetylation-dependent mechanism that modulates SIRT6 tumor-suppressive function in NSCLC. Our findings suggest that the MOF-SIRT6-ZEB2 axis may represent a promising therapeutic target for the management of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sirtuínas , Humanos , Masculino , Acetilação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Sirtuínas/genética , Sirtuínas/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
Right-sided native valve infective endocarditis is common in patients with congenital or valvular heart disease, intracardiac device, central venous catheter and intravenous drug abuse, usually manifesting in adulthood. However, in the absence of predisposing risk factors and in younger age groups, this disease may pose a diagnostic challenge. We report a case series of three juvenile patients with isolated tricuspid valve infective endocarditis without any risk factors and paucity of cardiovascular findings in two of them, in an attempt to highlight the importance of maintaining a high index of suspicion to arrive a timely diagnosis.
Assuntos
Endocardite Bacteriana , Endocardite , Doenças das Valvas Cardíacas , Abuso de Substâncias por Via Intravenosa , Adulto , Endocardite/diagnóstico , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/tratamento farmacológico , Humanos , Abuso de Substâncias por Via Intravenosa/complicações , Valva Tricúspide/diagnóstico por imagemRESUMO
Electrical injuries can have myriad presentations, including significant cardiac involvement. Arrhythmias are the most frequently experienced cardiac affliction, of which sinus tachycardia or bradycardia, ventricular fibrillation, atrial or ventricular premature beats and bundle branch block are most commonly reported. A 50-year-old man, with no prior history of cardiac disease, presented with palpitations following low voltage electrical injury. On examination, he was tachycardic with an irregularly irregular pulse. An ECG confirmed atrial fibrillation with rapid ventricular rate. Chemical cardioversion was attempted successfully, following which the patient reverted to sinus rhythm. Atrial fibrillation following electrical injury has been rarely described in the literature, and is rarer so without associated high voltage electrical exposure or pre-existing cardiac ailment.
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Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Traumatismos por Eletricidade/complicações , Fibrilação Atrial/terapia , Eletrocardiografia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The spectrum of central nervous system demyelinating disorders is vast and heterogeneous and, often, with overlapping clinical presentations. Misdiagnosis might occur in some cases with serious therapeutic repercussions. However, introduction of several new biomarkers such as aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG has made distinction between diseases such as multiple sclerosis and myelin oligodendrocyte glycoprotein antibody-associated disorder easier. Here, we report a case of a 15-year-old male patient with subacute multifocal neurological presentation without encephalopathy, eventually diagnosed as myelin oligodendrocyte glycoprotein antibody-associated disorder.
Assuntos
Ataxia/etiologia , Disartria/etiologia , Glicoproteína Mielina-Oligodendrócito , Doenças Neurodegenerativas/diagnóstico , Adolescente , Aquaporina 4 , Autoanticorpos , Humanos , MasculinoRESUMO
Mycobacteriophages are phages that infect and kill Mycobacteria, several of which, Mycobacterium tuberculosis (Mtb), for example, cause the disease tuberculosis. Although genomes of many such phages have been sequenced, we have very little insight into how they express their genes in a controlled manner. To address this issue, we have raised a temperature-sensitive (ts) mutant of phage D29 that can grow at 37°C but not at 42°C and used it to perform differential gene expression and proteome analysis studies. Our analysis results indicate that expression of genes located in the right arm, considered to be early expressed, was lowered as the temperature was shifted from 37°C to 42°C. In contrast, expression of those on the left, the late genes were only marginally affected. Thus, we conclude that transcription of genes from the two arms takes place independently of each other and that a specific factor must be controlling the expression of the right arm genes. We also observe that within the right arm itself; there exists a mechanism to ensure high-level synthesis of Gp48, a thymidylate synthase X. Enhanced presence of this protein in infected cells results in delayed lysis and higher phage yields.
Assuntos
Regulação Viral da Expressão Gênica , Genes Virais/genética , Micobacteriófagos/genética , Mutação , Micobacteriófagos/metabolismo , TemperaturaRESUMO
The SARS-CoV-2 has wreaked havoc globally and has claimed innumerable lives all over the world. The symptoms of this disease may range from mild influenza-like symptoms to severe acute respiratory distress syndrome with high morbidity and mortality. With improved diagnostic techniques and better disease understanding, an increased number of cases are being reported with extrapulmonary manifestations of this disease ranging from renal and gastrointestinal to cardiac, hepatic, neurological and haematological dysfunction. Subacute thyroiditis is a self-limiting and painful thyroid gland inflammation most often secondary to viral infections. We report a case of subacute thyroiditis in a 58-year-old gentleman presenting with a painful swelling in the neck who was subsequently detected to be positive for SARS-CoV-2. We seek to highlight the broad clinical spectrum of the COVID-19 by reporting probably the first case of subacute thyroiditis possibly induced by SARS-CoV-2 infection from India.
Assuntos
Amidas/administração & dosagem , Azitromicina/administração & dosagem , Tratamento Farmacológico da COVID-19 , COVID-19 , Prednisolona/administração & dosagem , Pirazinas/administração & dosagem , SARS-CoV-2/isolamento & purificação , Glândula Tireoide/diagnóstico por imagem , Tireoidite Subaguda , Antivirais/administração & dosagem , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/fisiopatologia , Diagnóstico Diferencial , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia/métodos , Testes de Função Tireóidea/métodos , Tireoidite Subaguda/diagnóstico , Tireoidite Subaguda/fisiopatologia , Tireoidite Subaguda/terapia , Tireoidite Subaguda/virologia , Resultado do Tratamento , Ultrassonografia Doppler em Cores/métodosRESUMO
Mammalian sirtuin 6 (Sirt6) is a conserved NAD+-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6-deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging.
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Haploinsuficiência , Longevidade , Sirtuínas/deficiência , Proteína Supressora de Tumor p53/genética , Animais , Feminino , Masculino , CamundongosRESUMO
The sirtuin proteins constitute class III histone deacetylases (HDACs). These evolutionarily conserved NAD(+)-dependent enzymes form an important component in a variety of cellular and biological processes with highly divergent as well as convergent roles in maintaining metabolic homeostasis, safeguarding genomic integrity, regulating cancer metabolism and also inflammatory responses. Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging. The roles of sirtuins in various cellular processes have been extrapolated to draw inter-linkage with anti-aging mechanisms. Also, the latest findings on sirtuins which might have potential effects in the process of aging have been reviewed.
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Senilidade Prematura/enzimologia , Senilidade Prematura/genética , Longevidade/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo , Animais , HumanosRESUMO
The nuclear lamins are essential for various molecular events in the nucleus, such as chromatin organization, DNA replication, and provision of mechanical support. A specific point mutation in the LMNA gene creates a truncated prelamin A termed progerin, causing Hutchinson-Gilford progeria syndrome (HGPS). SIRT6 deficiency leads to defective genomic maintenance and accelerated aging similar to HGPS, suggesting a potential link between lamin A and SIRT6. Here, we report that lamin A is an endogenous activator of SIRT6 and facilitates chromatin localization of SIRT6 upon DNA damage. Lamin A promotes SIRT6-dependent DNA-PKcs (DNA-PK catalytic subunit) recruitment to chromatin, CtIP deacetylation, and PARP1 mono-ADP ribosylation in response to DNA damage. The presence of progerin jeopardizes SIRT6 activation and compromises SIRT6-mediated molecular events in response to DNA damage. These data reveal a critical role for lamin A in regulating SIRT6 activities, suggesting that defects in SIRT6 functions contribute to impaired DNA repair and accelerated aging in HGPS.
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Reparo do DNA , Lamina Tipo A/fisiologia , Sirtuínas/metabolismo , Dano ao DNA , Proteína Quinase Ativada por DNA/metabolismo , Ativação Enzimática , Células HEK293 , Humanos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Sirtuínas/químicaRESUMO
Premature aging disorders, like Werner syndrome, Bloom's syndrome, and Hutchinson-Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways involved in the maintenance of genomic integrity, thus suggesting a profound impact of the nuclear lamina in nuclear organization, chromatin dynamics, regulation of gene expression and epigenetics.