Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 535
Filtrar
1.
Nature ; 613(7945): 751-758, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36631608

RESUMO

Cognate tRNAs deliver specific amino acids to translating ribosomes according to the standard genetic code, and three codons with no cognate tRNAs serve as stop codons. Some protists have reassigned all stop codons as sense codons, neglecting this fundamental principle1-4. Here we analyse the in-frame stop codons in 7,259 predicted protein-coding genes of a previously undescribed trypanosomatid, Blastocrithidia nonstop. We reveal that in this species in-frame stop codons are underrepresented in genes expressed at high levels and that UAA serves as the only termination codon. Whereas new tRNAsGlu fully cognate to UAG and UAA evolved to reassign these stop codons, the UGA reassignment followed a different path through shortening the anticodon stem of tRNATrpCCA from five to four base pairs (bp). The canonical 5-bp tRNATrp recognizes UGG as dictated by the genetic code, whereas its shortened 4-bp variant incorporates tryptophan also into in-frame UGA. Mimicking this evolutionary twist by engineering both variants from B. nonstop, Trypanosoma brucei and Saccharomyces cerevisiae and expressing them in the last two species, we recorded a significantly higher readthrough for all 4-bp variants. Furthermore, a gene encoding B. nonstop release factor 1 acquired a mutation that specifically restricts UGA recognition, robustly potentiating the UGA reassignment. Virtually the same strategy has been adopted by the ciliate Condylostoma magnum. Hence, we describe a previously unknown, universal mechanism that has been exploited in unrelated eukaryotes with reassigned stop codons.


Assuntos
Anticódon , Códon de Terminação , Células Eucarióticas , Código Genético , Mutação , Fatores de Terminação de Peptídeos , RNA de Transferência , Anticódon/química , Anticódon/genética , Anticódon/metabolismo , Cilióforos/genética , Códon de Terminação/genética , Código Genético/genética , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo , RNA de Transferência de Triptofano/genética , Saccharomyces cerevisiae/genética , RNA de Transferência de Ácido Glutâmico/genética , Trypanosoma brucei brucei/genética
2.
PLoS Biol ; 22(7): e3002715, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39042591

RESUMO

Awards can propel academic careers. They also reflect the culture and values of the scientific community. But do awards incentivize greater transparency, inclusivity, and openness in science? Our cross-disciplinary survey of 222 awards for the "best" journal articles across all 27 SCImago subject areas revealed that journals and learned societies administering such awards generally publish little detail on their procedures and criteria. Award descriptions were brief, rarely including contact details or information on the nominations pool. Nominations of underrepresented groups were not explicitly encouraged, and concepts that align with Open Science were almost absent from the assessment criteria. At the same time, 10% of awards, especially the recently established ones, tended to use article-level impact metrics. USA-affiliated researchers dominated the winner's pool (48%), while researchers from the Global South were uncommon (11%). Sixty-one percent of individual winners were men. Overall, Best Paper awards miss the global calls for greater transparency and equitable access to academic recognition. We provide concrete and implementable recommendations for scientific awards to improve the scientific recognition system and incentives for better scientific practice.


Assuntos
Distinções e Prêmios , Humanos , Pesquisadores , Masculino , Feminino , Ciência , Editoração/normas , Publicações Periódicas como Assunto/normas
3.
Nature ; 568(7751): 226-229, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30894750

RESUMO

The origins of religion and of complex societies represent evolutionary puzzles1-8. The 'moralizing gods' hypothesis offers a solution to both puzzles by proposing that belief in morally concerned supernatural agents culturally evolved to facilitate cooperation among strangers in large-scale societies9-13. Although previous research has suggested an association between the presence of moralizing gods and social complexity3,6,7,9-18, the relationship between the two is disputed9-13,19-24, and attempts to establish causality have been hampered by limitations in the availability of detailed global longitudinal data. To overcome these limitations, here we systematically coded records from 414 societies that span the past 10,000 years from 30 regions around the world, using 51 measures of social complexity and 4 measures of supernatural enforcement of morality. Our analyses not only confirm the association between moralizing gods and social complexity, but also reveal that moralizing gods follow-rather than precede-large increases in social complexity. Contrary to previous predictions9,12,16,18, powerful moralizing 'big gods' and prosocial supernatural punishment tend to appear only after the emergence of 'megasocieties' with populations of more than around one million people. Moralizing gods are not a prerequisite for the evolution of social complexity, but they may help to sustain and expand complex multi-ethnic empires after they have become established. By contrast, rituals that facilitate the standardization of religious traditions across large populations25,26 generally precede the appearance of moralizing gods. This suggests that ritual practices were more important than the particular content of religious belief to the initial rise of social complexity.


Assuntos
Mapeamento Geográfico , Princípios Morais , Religião/história , Bases de Dados Factuais , História Antiga , Humanos , Ciências Sociais
6.
Pediatr Cardiol ; 45(3): 513-519, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38308060

RESUMO

Tissue hypoxia increases erythropoietin production and release of immature erythrocytes that can be measured using nucleated red blood cell counts (nRBC). We hypothesized that hypoxia due to congenital heart disease (CHD) is chronic and is better tolerated than hypoxia due to respiratory disease (RD), which is an acute stress in newborns leading to higher nRBC. This study assesses the utility of nRBC as a marker to differentiate hypoxia due to CHD vs RD in term neonates. This was a single-center, retrospective study of term neonates with cyanosis from 2015 to 2022. Neonates < 37 weeks of gestation, with hypoxic-ischemic encephalopathy, and those with other causes of cyanosis were excluded. The patients were divided into 2 groups: cyanotic CHD and cyanotic RD. Clinical and laboratory data done within 12 h and 24-36 h after birth were collected. Data are represented as median and Interquartile range. Of 189 patients with cyanosis, 80 had CHD and 109 had RD. The absolute nRBC count at ≤ 12 h of age was lower in the CHD (360 cells/mm3) compared to RD group (2340 cells/mm3) despite the CHD group having significantly lower baseline saturations. A value of 1070 cells/mm3 was highly sensitive and specific for differentiating CHD from RD. The positive predictive value for this cut-off value of 1070 cells/mm3 was 0.94 and the negative predictive value was 0.89. The absolute nRBC is a simple screening test and is available worldwide. A nRBC < 1070 cells/mm3 in cyanotic newborns should hasten the search for CHD etiology with the possible need for prostaglandin therapy.


Assuntos
Eritroblastos , Cardiopatias Congênitas , Recém-Nascido , Humanos , Estudos Retrospectivos , Contagem de Eritrócitos , Cianose/diagnóstico , Cianose/etiologia , Hipóxia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico
7.
Rev Cardiovasc Med ; 24(1): 14, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39076861

RESUMO

The evidence that cardiorespiratory fitness (CRF) predicts morbidity and mortality independent of commonly obtained risk factors is beyond dispute. Observations establishing that the addition of CRF to algorithms for estimating cardiovascular disease risk reinforces the clinical utility of CRF. Evidence suggesting that non-exercise estimations of CRF are associated with all-cause mortality provides an opportunity to obtain estimates of CRF in a cost-effective manner. Together with the observation that CRF is substantially improved in response to exercise consistent with guideline recommendations underscores the position that CRF should be included as a routine measure across all health care settings. Here we provide a brief overview of the evidence in support of this position.

8.
Surg Endosc ; 37(11): 8810-8817, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37620650

RESUMO

BACKGROUND: The obesity pandemic has worsened global disease burden, including type 2 diabetes, cardiovascular disease, and cancer. Metabolic/bariatric surgery (MBS) is the most effective and durable obesity treatment, but the mechanisms underlying its long-term weight loss efficacy remain unclear. MBS drives substrate oxidation that has been linked to improvements in metabolic function and improved glycemic control that are potentially mediated by mitochondria-a primary site of energy production. As such, augmentation of intestinal mitochondrial function may drive processes underlying the systemic metabolic benefits of MBS. Herein, we applied a highly sensitive technique to evaluate intestinal mitochondrial function ex vivo in a mouse model of MBS. METHODS: Mice were randomized to surgery, sham, or non-operative control. A simplified model of MBS, ileal interposition, was performed by interposition of a 2-cm segment of terminal ileum into the proximal bowel 5 mm from the ligament of Treitz. After a four-week recovery period, intestinal mucosa of duodenum, jejunum, ileum, and interposed ileum were assayed for determination of mitochondrial respiratory function. Citrate synthase activity was measured as a marker of mitochondrial content. RESULTS: Ileal interposition was well tolerated and associated with modest body weight loss and transient hypophagia relative to controls. Mitochondrial capacity declined in the native duodenum and jejunum of animals following ileal interposition relative to controls, although respiration remained unchanged in these segments. Similarly, ileal interposition lowered citrate synthase activity in the duodenum and jejunum following relative to controls but ileal function remained constant across all groups. CONCLUSION: Ileal interposition decreases mitochondrial volume in the proximal intestinal mucosa of mice. This change in concentration with preserved respiration suggests a global mucosal response to segment specific nutrition signals in the distal bowel. Future studies are required to understand the causes underlying these mitochondrial changes.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Citrato (si)-Sintase/metabolismo , Íleo/cirurgia , Jejuno/cirurgia , Mucosa Intestinal , Obesidade/cirurgia , Mitocôndrias
9.
J Infect Chemother ; 29(7): 646-653, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36898501

RESUMO

BACKGROUND: Community acquired pneumonia (CAP) is the most frequent cause of mortality secondary to infectious etiologies. Recommendations about the use of blood cultures in the diagnosis and treatment of CAP has been a contentious topic of debate and ever-changing recommendations. METHODS: A cohort study was conducted in a community teaching hospital. All the patients that were admitted with a diagnosis of CAP, between January and December of 2019 were included. Sociodemographic and clinical characteristics were obtained. Blood cultures results were obtained, and it was evaluated if they were done in compliance with current recommendations by the Infectious Disease Society of America (IDSA). RESULTS: 721 patients were included in the study. Median age was 68 years and 50% of the patients were male (n = 293). Patients presented from home (84%) and the most common comorbidities were hypertension and diabetes (68% and 31%). 96 patients had positive blood culture and 34% (n = 247) of all the blood cultures were adequately ordered. 80 patients died or went to hospice and the median length of hospital stay in our cohort was 7 days. The multivariate model showed that mortality was associated with positive blood cultures (OR = 3.1 95%CI 1.63-5.87) and appropriateness of blood cultures (OR = 2.96 95% CI 1.2-5.7). CONCLUSION: Adequate use of blood cultures in patients with CAP might have some association with the outcomes of this disease. However, a prospective study evaluating the utility of this test following current IDSA recommendations is needed to understand their impact in mortality and morbidity.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Masculino , Idoso , Feminino , Estudos Retrospectivos , Estudos de Coortes , Hemocultura , Estudos Prospectivos , Pneumonia/diagnóstico , Infecções Comunitárias Adquiridas/diagnóstico , Fidelidade a Diretrizes , Antibacterianos/uso terapêutico
10.
Am J Respir Crit Care Med ; 206(1): 81-93, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35316153

RESUMO

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.


Assuntos
Autoimunidade , Hipertensão Pulmonar , Autoanticorpos , Estudos Transversais , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/genética
11.
Nucleic Acids Res ; 49(14): 8247-8260, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34244755

RESUMO

Transfer RNAs (tRNAs) are key players in protein synthesis. To be fully active, tRNAs undergo extensive post-transcriptional modifications, including queuosine (Q), a hypermodified 7-deaza-guanosine present in the anticodon of several tRNAs in bacteria and eukarya. Here, molecular and biochemical approaches revealed that in the protozoan parasite Trypanosoma brucei, Q-containing tRNAs have a preference for the U-ending codons for asparagine, aspartate, tyrosine and histidine, analogous to what has been described in other systems. However, since a lack of tRNA genes in T. brucei mitochondria makes it essential to import a complete set from the cytoplasm, we surprisingly found that Q-modified tRNAs are preferentially imported over their unmodified counterparts. In turn, their absence from mitochondria has a pronounced effect on organellar translation and affects function. Although Q modification in T. brucei is globally important for codon selection, it is more so for mitochondrial protein synthesis. These results provide a unique example of the combined regulatory effect of codon usage and wobble modifications on protein synthesis; all driven by tRNA intracellular transport dynamics.


Assuntos
Mitocôndrias/genética , Conformação de Ácido Nucleico , Nucleosídeo Q/genética , RNA de Transferência/genética , Anticódon/genética , Núcleo Celular/genética , Núcleo Celular/ultraestrutura , Códon/genética , Citoplasma/genética , Citoplasma/ultraestrutura , Guanosina/genética , Biossíntese de Proteínas/genética , Processamento Pós-Transcricional do RNA/genética , RNA de Transferência/ultraestrutura , Trypanosoma brucei brucei/genética
12.
Nucleic Acids Res ; 49(22): 12986-12999, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34883512

RESUMO

Every type of nucleic acid in cells undergoes programmed chemical post-transcriptional modification. Generally, modification enzymes use substrates derived from intracellular metabolism, one exception is queuine (q)/queuosine (Q), which eukaryotes obtain from their environment; made by bacteria and ultimately taken into eukaryotic cells via currently unknown transport systems. Here, we use a combination of molecular, cell biology and biophysical approaches to show that in Trypanosoma brucei tRNA Q levels change dynamically in response to concentration variations of a sub-set of amino acids in the growth media. Most significant were variations in tyrosine, which at low levels lead to increased Q content for all the natural tRNAs substrates of tRNA-guanine transglycosylase (TGT). Such increase results from longer nuclear dwell time aided by retrograde transport following cytoplasmic splicing. In turn high tyrosine levels lead to rapid decrease in Q content. Importantly, the dynamic changes in Q content of tRNAs have negligible effects on global translation or growth rate but, at least, in the case of tRNATyr it affected codon choice. These observations have implications for the occurrence of other tunable modifications important for 'normal' growth, while connecting the intracellular localization of modification enzymes, metabolites and tRNAs to codon selection and implicitly translational output.


Assuntos
Códon/metabolismo , Nucleosídeo Q/metabolismo , Nutrientes/metabolismo , RNA de Transferência/metabolismo , Trypanosoma brucei brucei/metabolismo , Aminoácidos/metabolismo , Cromatografia Líquida/métodos , Códon/genética , Guanina/análogos & derivados , Guanina/metabolismo , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Splicing de RNA , RNA de Transferência/genética , RNA de Transferência de Tirosina/genética , RNA de Transferência de Tirosina/metabolismo , Espectrometria de Massas em Tandem/métodos , Trypanosoma brucei brucei/genética , Tirosina/metabolismo
13.
Proc Natl Acad Sci U S A ; 117(34): 20689-20695, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788345

RESUMO

RNA abasic sites and the mechanisms involved in their regulation are mostly unknown; in contrast, DNA abasic sites are well-studied. We found surprisingly that, in yeast and human cells, RNA abasic sites are prevalent. When a base is lost from RNA, the remaining ribose is found as a closed-ring or an open-ring sugar with a reactive C1' aldehyde group. Using primary amine-based reagents that react with the aldehyde group, we uncovered evidence for abasic sites in nascent RNA, messenger RNA, and ribosomal RNA from yeast and human cells. Mass spectroscopic analysis confirmed the presence of RNA abasic sites. The RNA abasic sites were found to be coupled to R-loops. We show that human methylpurine DNA glycosylase cleaves N-glycosidic bonds on RNA and that human apurinic/apyrimidinic endonuclease 1 incises RNA abasic sites in RNA-DNA hybrids. Our results reveal that, in yeast and human cells, there are RNA abasic sites, and we identify a glycosylase that generates these sites and an AP endonuclease that processes them.


Assuntos
Sequência de Bases/genética , RNA/química , RNA/genética , Sítios de Ligação , DNA/química , Dano ao DNA/genética , DNA Glicosilases/metabolismo , Reparo do DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Desoxirribonuclease I/metabolismo , Humanos , Nucleotídeos/genética , Estruturas R-Loop/genética , Saccharomyces cerevisiae/genética , Especificidade por Substrato , Leveduras/genética
14.
Crit Rev Biochem Mol Biol ; 55(6): 525-540, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32933330

RESUMO

Every type of nucleic acid in cells may undergo some kind of post-replicative or post-transcriptional chemical modification. Recent evidence has highlighted their importance in biology and their chemical complexity. In the following pages, we will describe new discoveries of modifications, with a focus on tRNA and mRNA. We will highlight current challenges and advances in modification detection and we will discuss how changes in nucleotide post-transcriptional modifications may affect cell homeostasis leading to malfunction. Although, RNA modifications prevail in all forms of life, the present review will focus on eukaryotic systems, where the great degree of intracellular compartmentalization provides barriers and filters for the level at which a given RNA is modified and will of course affect its fate and function. Additionally, although we will mention rRNA modification and modifications of the mRNA 5'-CAP structure, this will only be discussed in passing, as many substantive reviews have been written on these subjects. Here we will not spend much time describing all the possible modifications that have been observed; truly a daunting task. For reference, Bujnicki and coworkers have created MODOMICS, a useful repository for all types of modifications and their associated enzymes. Instead we will discuss a few examples, which illustrate our arguments on the connection of modifications, metabolism and ultimately translation. The fact remains, a full understanding of the long reach of nucleic acid modifications in cells requires both a global and targeted study of unprecedented scale, which at the moment may well be limited only by technology.


Assuntos
Nucleotídeos/metabolismo , RNA Mensageiro/metabolismo , RNA de Transferência/metabolismo , Animais , Humanos , Processamento Pós-Transcricional do RNA/fisiologia
15.
J Biol Chem ; 297(1): 100825, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029594

RESUMO

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.


Assuntos
Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Biogênese de Organelas , Oxigênio/metabolismo , Animais , Hipóxia Celular , DNA Mitocondrial/genética , Regulação para Baixo/genética , Coração/embriologia , Insuficiência Cardíaca/genética , Ventrículos do Coração/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Oxirredução , Fosforilação Oxidativa , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Receptor ERRalfa Relacionado ao Estrogênio
16.
Circ Res ; 127(2): 284-297, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32345129

RESUMO

RATIONALE: ZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown. OBJECTIVE: To determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function. METHODS AND RESULTS: We generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL. CONCLUSIONS: ZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.


Assuntos
Bloqueio Atrioventricular/metabolismo , Nó Atrioventricular/metabolismo , Função Ventricular , Proteína da Zônula de Oclusão-1/metabolismo , Animais , Bloqueio Atrioventricular/fisiopatologia , Nó Atrioventricular/fisiologia , Caderinas/genética , Caderinas/metabolismo , Conexinas/genética , Conexinas/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Vinculina/genética , Vinculina/metabolismo , Proteína da Zônula de Oclusão-1/genética , alfa Catenina/genética , alfa Catenina/metabolismo
17.
CMAJ ; 194(9): E324-E331, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35256388

RESUMO

BACKGROUND: Efforts to manage obesity through weight loss are often unsuccessful as most adults are not able to sustain the major changes in behaviour that are required to maintain weight loss long term. We sought to determine whether small changes in physical activity and diet prevent weight gain in adults with overweight and obesity. METHODS: We randomized 320 sedentary adults with overweight or obesity to monitoring alone (MA, n = 160) or a small change approach (SCA, n = 160). In Phase I (2 yr), MA participants were asked to maintain their normal lifestyle and SCA participants were counselled to make small changes in diet and physical activity, namely a suggested increase in daily step count of 2000 steps with a decrease in energy intake of 100 kcal per day, with group and individual support. Phase II (1 yr) was a passive follow-up period. The difference in change in body weight between groups at 24 and 36 months from baseline was the primary outcome. Additional outcomes included waist circumference and cardiorespiratory fitness. RESULTS: Overall, 268 participants (83.8%) completed the 2-year intervention, and 239 (74.7%) returned at the end of the follow-up period at 3 years. The difference in body weight change between the SCA and MA groups was significant at 3, 6, 12 and 15 months from baseline, but was no longer significant at 24 months (mean change 0.9 [standard error (SE) 0.5] kg v. -0.4 [SE 0.5] kg; difference -0.6, 95% confidence interval [CI] -1.9 to 0.8) or at 36 months (-1.2 [SE 0.8] v. -0.7 [SE 0.8] kg; difference -0.5, 95% CI -2.2 to 1.2). Changes in waist circumference and cardiorespiratory fitness were not significantly different between groups at 24 or 36 months (both p > 0.1). INTERPRETATION: The SCA did not prevent weight gain compared with monitoring alone at 2 or 3 years in adults with overweight or obesity. On average, we observed prevention of weight gain in both arms of the trial. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT02027077.


Assuntos
Obesidade , Sobrepeso , Adulto , Exercício Físico , Humanos , Obesidade/prevenção & controle , Sobrepeso/prevenção & controle , Aumento de Peso , Redução de Peso
19.
Mem Cognit ; 50(2): 425-434, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34453286

RESUMO

The classical account of reasoning posits that analytic thinking weakens belief in COVID-19 misinformation. We tested this account in a demographically representative sample of 742 Australians. Participants completed a performance-based measure of analytic thinking (the Cognitive Reflection Test) and were randomized to groups in which they either rated the perceived accuracy of claims about COVID-19 or indicated whether they would be willing to share these claims. Half of these claims were previously debunked misinformation, and half were statements endorsed by public health agencies. We found that participants with higher analytic thinking levels were less likely to rate COVID-19 misinformation as accurate and were less likely to be willing to share COVID-19 misinformation. These results support the classical account of reasoning for the topic of COVID-19 misinformation and extend it to the Australian context.


Assuntos
COVID-19 , Austrália , Comunicação , Humanos , SARS-CoV-2
20.
Diabetes Spectr ; 35(4): 484-490, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36561649

RESUMO

Objective: Diabetic ketoacidosis and hyperosmolar hyperglycemic state are life-threatening hyperglycemic crises often requiring intensive care unit (ICU) management. Treatment includes intravenous (IV) insulin with a transition to subcutaneous (SC) insulin upon resolution. Hypoglycemia is a common complication associated with treatment of hyperglycemic crises, but risk factors have not been well established. This study aimed to assess risk factors associated with hypoglycemia during treatment for hyperglycemic crises. Methods: This case-control study included ICU patients admitted with hyperglycemic crises at a single Veterans Affairs health system from 1 January 2013 to 31 March 2020. Patients who developed hypoglycemia during insulin treatment were compared with a control group. Odds of hypoglycemia were assessed based on risk factors, including BMI, comorbidities, and type of SC insulin used. Results: Of the 216 cases of hyperglycemic crises included, hypoglycemia occurred in 61 cases (44 on SC insulin, 11 on IV insulin, and 6 on both). Odds for hypoglycemia were significantly higher for underweight patients (odds ratio 4.52 [95% CI 1.05-19.55]), type 1 diabetes (4.02 [2.09-7.73]), chronic kidney disease (1.94 [1.05-3.57]), those resumed on the exact chronic SC insulin regimen following resolution (2.91 [1.06-7.95]), and patients who received NPH versus glargine insulin (5.13 [1.54-17.06]). No significant differences were seen in the other evaluated variables. Conclusion: This study found several factors associated with hypoglycemia during hyperglycemic crises treatment, many of which are not addressed in consensus statement recommendations. These findings may help ICU clinicians prevent complications related to hyperglycemic crisis management and generate hypotheses for future studies.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA