RESUMO
Ion channels play a central role in the regulation of nearly every cellular process. Dating back to the classic 1952 Hodgkin-Huxley model of the generation of the action potential, ion channels have always been thought of as independent agents. A myriad of recent experimental findings exploiting advances in electrophysiology, structural biology, and imaging techniques, however, have posed a serious challenge to this long-held axiom, as several classes of ion channels appear to open and close in a coordinated, cooperative manner. Ion channel cooperativity ranges from variable-sized oligomeric cooperative gating in voltage-gated, dihydropyridine-sensitive CaV1.2 and CaV1.3 channels to obligatory dimeric assembly and gating of voltage-gated NaV1.5 channels. Potassium channels, transient receptor potential channels, hyperpolarization cyclic nucleotide-activated channels, ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3Rs) have also been shown to gate cooperatively. The implications of cooperative gating of these ion channels range from fine-tuning excitation-contraction coupling in muscle cells to regulating cardiac function and vascular tone, to modulation of action potential and conduction velocity in neurons and cardiac cells, and to control of pacemaking activity in the heart. In this review, we discuss the mechanisms leading to cooperative gating of ion channels, their physiological consequences, and how alterations in cooperative gating of ion channels may induce a range of clinically significant pathologies.
Assuntos
Ativação do Canal Iônico , Canal de Liberação de Cálcio do Receptor de Rianodina , Potenciais de Ação , Humanos , Ativação do Canal Iônico/fisiologia , NeurôniosRESUMO
The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was <1 mM, which is eightfold to 10-fold lower than previously estimated. Accordingly, ATP-sensitive K+ (KATP) channels were active at physiological [ATP]i. Cells exhibited two distinct types of ATP fluctuations during an action potential: net increases (Mode 1) or decreases (Mode 2) in [ATP]i. Mode 1 [ATP]i increases necessitated Ca2+ entry and release from the sarcoplasmic reticulum (SR) and were associated with increases in mitochondrial Ca2+. By contrast, decreases in mitochondrial Ca2+ accompanied Mode 2 [ATP]i decreases. Down-regulation of the protein mitofusin 2 reduced the magnitude of [ATP]i fluctuations, indicating that SR-mitochondrial coupling plays a crucial role in the dynamic control of ATP levels. Activation of ß-adrenergic receptors decreased [ATP]i, underscoring the energetic impact of this signaling pathway. Finally, our work suggests that cross-bridge cycling is the largest consumer of ATP in a ventricular myocyte during an action potential. These findings provide insights into the energetic demands of EC coupling and highlight the dynamic nature of ATP concentrations in cardiac muscle.
Assuntos
Trifosfato de Adenosina , Cálcio , Acoplamento Excitação-Contração , Ventrículos do Coração , Miócitos Cardíacos , Miócitos Cardíacos/metabolismo , Trifosfato de Adenosina/metabolismo , Acoplamento Excitação-Contração/fisiologia , Animais , Cálcio/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/citologia , Potenciais de Ação/fisiologia , Retículo Sarcoplasmático/metabolismo , Frequência Cardíaca/fisiologia , Humanos , Canais KATP/metabolismo , Contração Miocárdica/fisiologia , CamundongosRESUMO
Membrane contact sites between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are found in all eukaryotic cells. In excitable cells they play unique roles in organizing diverse forms of Ca2+ signaling as triggered by membrane depolarization. ER-PM junctions underlie crucial physiological processes such as excitation-contraction coupling, smooth muscle contraction and relaxation, and various forms of activity-dependent signaling and plasticity in neurons. In many cases the structure and molecular composition of ER-PM junctions in excitable cells comprise important regulatory feedback loops linking depolarization-induced Ca2+ signaling at these sites to the regulation of membrane potential. Here, we describe recent findings on physiological roles and molecular composition of native ER-PM junctions in excitable cells. We focus on recent studies that provide new insights into canonical forms of depolarization-induced Ca2+ signaling occurring at junctional triads and dyads of striated muscle, as well as the diversity of ER-PM junctions in these cells and in smooth muscle and neurons.
Assuntos
Retículo Endoplasmático , Proteínas de Membrana , Humanos , Proteínas de Membrana/fisiologia , Retículo Endoplasmático/metabolismo , Membrana Celular/metabolismo , Transdução de Sinais , Neurônios/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismoRESUMO
CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.
Assuntos
Angiotensina II , Acoplamento Excitação-Contração , Células Cultivadas , Angiotensina II/metabolismo , Transdução de Sinais , Miócitos Cardíacos/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismoRESUMO
Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIß-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.
Assuntos
Membrana Celular/metabolismo , Complexo de Golgi/metabolismo , Lisossomos/metabolismo , Proteína C1 de Niemann-Pick/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Animais , Transporte Biológico/fisiologia , Células CHO , Linhagem Celular , Colesterol/metabolismo , Cricetulus , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Membranas Intracelulares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Transdução de Sinais/fisiologiaRESUMO
Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.
Assuntos
Benzenossulfonatos/farmacologia , Senescência Celular/efeitos dos fármacos , Histona Acetiltransferases/antagonistas & inibidores , Hidrazinas/farmacologia , Linfoma/tratamento farmacológico , Linfoma/patologia , Sulfonamidas/farmacologia , Acetilação/efeitos dos fármacos , Animais , Benzenossulfonatos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Desenvolvimento de Medicamentos , Fibroblastos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Acetiltransferases/deficiência , Histona Acetiltransferases/genética , Histonas/química , Histonas/metabolismo , Hidrazinas/uso terapêutico , Linfoma/enzimologia , Linfoma/genética , Lisina/química , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: Intimate partner violence (IPV) is a serious public health problem associated with countless adverse physical and mental health outcomes. It places an enormous economic and public health burden on communities. The aim of this study was to examine the associations between psychological states (such as depression or hopeless) and help-seeking experiences of IPV survivors after experiencing IPV, based on the Allegheny County Health Survey (ACHS). METHODS: Data from 2015 to 2016 Allegheny County Health Survey with N = 8,012 adults were analyzed. The 6-item version of the Kessler Psychological Stress Scale, located in Module 11 of the ACHS questionnaire, was used to measure psychological stress in participants. Module 12 of the ACHS questionnaire collected information on participants' experiences of intimate partner violence and help-seeking in the past 12 months. Descriptive statistical analysis, Pearson's chi-square or two sample independent t-tests statistical analysis, and multivariate binary logistic regression models were used to analyze the relationship between IPV experience and psychological distress. RESULTS: A total of 212 of the 8,012 participants had IPV experience, with age, marital status, education, income, and race significantly different from those without IPV experience. The psychological stress of participants feeling hopeless (OR = 2.02, 95% CI = 1.37-2.99), restless or fidgety (OR = 1.83, 95% CI = 1.27-2.65), perceiving everything was an effort (OR = 1.55, 95% CI = 1.08-2.22) and worthless (OR = 1.49, 95% CI = 1.01-2.20) was associated with the IPV experience. Help-seeking behaviors of IPV survivors were associated with psychological distress, such as hopelessness (OR = 6.71, 95% CI = 1.38-32.60). CONCLUSIONS: This study explored the association between IPV experience, help-seeking and psychological distress, and the need to expand community support. It is necessary to implement targeted interventions, enhance training of professionals, and promote the identification of early IPV cases as well as collaboration between healthcare and social support departments to reduce the occurrence of IPV or psychological distress following IPV.
Assuntos
Violência por Parceiro Íntimo , Angústia Psicológica , Adulto , Humanos , Ansiedade , Inquéritos e Questionários , Inquéritos Epidemiológicos , Fatores de RiscoRESUMO
The number and activity of Cav1.2 channels in the cardiomyocyte sarcolemma tunes the magnitude of Ca2+-induced Ca2+ release and myocardial contraction. ß-Adrenergic receptor (ßAR) activation stimulates sarcolemmal insertion of CaV1.2. This supplements the preexisting sarcolemmal CaV1.2 population, forming large "superclusters" wherein neighboring channels undergo enhanced cooperative-gating behavior, amplifying Ca2+ influx and myocardial contractility. Here, we determine this stimulated insertion is fueled by an internal reserve of early and recycling endosome-localized, presynthesized CaV1.2 channels. ßAR-activation decreased CaV1.2/endosome colocalization in ventricular myocytes, as it triggered "emptying" of endosomal CaV1.2 cargo into the t-tubule sarcolemma. We examined the rapid dynamics of this stimulated insertion process with live-myocyte imaging of channel trafficking, and discovered that CaV1.2 are often inserted into the sarcolemma as preformed, multichannel clusters. Similarly, entire clusters were removed from the sarcolemma during endocytosis, while in other cases, a more incremental process suggested removal of individual channels. The amplitude of the stimulated insertion response was doubled by coexpression of constitutively active Rab4a, halved by coexpression of dominant-negative Rab11a, and abolished by coexpression of dominant-negative mutant Rab4a. In ventricular myocytes, ßAR-stimulated recycling of CaV1.2 was diminished by both nocodazole and latrunculin-A, suggesting an essential role of the cytoskeleton in this process. Functionally, cytoskeletal disruptors prevented ßAR-activated Ca2+ current augmentation. Moreover, ßAR-regulation of CaV1.2 was abolished when recycling was halted by coapplication of nocodazole and latrunculin-A. These findings reveal that ßAR-stimulation triggers an on-demand boost in sarcolemmal CaV1.2 abundance via targeted Rab4a- and Rab11a-dependent insertion of channels that is essential for ßAR-regulation of cardiac CaV1.2.
Assuntos
Canais de Cálcio Tipo L/metabolismo , Miócitos Cardíacos/metabolismo , Receptores Adrenérgicos beta/metabolismo , Sarcolema/metabolismo , Proteínas rab4 de Ligação ao GTP/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Células Cultivadas , Endossomos/metabolismo , Feminino , Ventrículos do Coração/citologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Nocodazol/farmacologia , Transporte Proteico , Tiazolidinas/farmacologiaRESUMO
Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease-causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.
Assuntos
Cálcio/metabolismo , Morte Celular/fisiologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Mitocôndrias/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Lisossomos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Presenilina-1/metabolismoRESUMO
Finding the optimal balance between survival and reproduction is a central puzzle in life-history theory. The terminal investment hypothesis predicts that when individuals encounter a survival threat that compromises future reproductive potential, they will increase immediate reproductive investment to maximise fitness. Despite decades of research on the terminal investment hypothesis, findings remain mixed. We examined the terminal investment hypothesis with a meta-analysis of studies that measured reproductive investment of multicellular iteroparous animals after a non-lethal immune challenge. We had two main aims. The first was to investigate whether individuals, on average, increase reproductive investment in response to an immune threat, as predicted by the terminal investment hypothesis. We also examined whether such responses vary adaptively on factors associated with the amount of reproductive opportunities left (residual reproductive value) in the individuals, as predicted by the terminal investment hypothesis. The second was to provide a quantitative test of a novel prediction based on the dynamic threshold model: that an immune threat increases between-individual variance in reproductive investment. Our results provided some support for our hypotheses. Older individuals, who are expected to have lower residual reproductive values, showed stronger mean terminal investment response than younger individuals. In terms of variance, individuals showed a divergence in responses, leading to an increase in variance. This increase in variance was especially amplified in longer-living species, which was consistent with our prediction that individuals in longer-living species should respond with greater individual variation due to increased phenotypic plasticity. We find little statistical evidence of publication bias. Together, our results highlight the need for a more nuanced view on the terminal investment hypothesis and a greater focus on the factors that drive individual responses.
Assuntos
Reprodução , Animais , Reprodução/fisiologiaRESUMO
Collaborative efforts to directly replicate empirical studies in the medical and social sciences have revealed alarmingly low rates of replicability, a phenomenon dubbed the 'replication crisis'. Poor replicability has spurred cultural changes targeted at improving reliability in these disciplines. Given the absence of equivalent replication projects in ecology and evolutionary biology, two inter-related indicators offer the opportunity to retrospectively assess replicability: publication bias and statistical power. This registered report assesses the prevalence and severity of small-study (i.e., smaller studies reporting larger effect sizes) and decline effects (i.e., effect sizes decreasing over time) across ecology and evolutionary biology using 87 meta-analyses comprising 4,250 primary studies and 17,638 effect sizes. Further, we estimate how publication bias might distort the estimation of effect sizes, statistical power, and errors in magnitude (Type M or exaggeration ratio) and sign (Type S). We show strong evidence for the pervasiveness of both small-study and decline effects in ecology and evolution. There was widespread prevalence of publication bias that resulted in meta-analytic means being over-estimated by (at least) 0.12 standard deviations. The prevalence of publication bias distorted confidence in meta-analytic results, with 66% of initially statistically significant meta-analytic means becoming non-significant after correcting for publication bias. Ecological and evolutionary studies consistently had low statistical power (15%) with a 4-fold exaggeration of effects on average (Type M error rates = 4.4). Notably, publication bias reduced power from 23% to 15% and increased type M error rates from 2.7 to 4.4 because it creates a non-random sample of effect size evidence. The sign errors of effect sizes (Type S error) increased from 5% to 8% because of publication bias. Our research provides clear evidence that many published ecological and evolutionary findings are inflated. Our results highlight the importance of designing high-power empirical studies (e.g., via collaborative team science), promoting and encouraging replication studies, testing and correcting for publication bias in meta-analyses, and adopting open and transparent research practices, such as (pre)registration, data- and code-sharing, and transparent reporting.
Assuntos
Biologia , Viés , Viés de Publicação , Reprodutibilidade dos Testes , Estudos Retrospectivos , Metanálise como AssuntoRESUMO
This white paper is the outcome of the seventh UC Davis Cardiovascular Research Symposium on Systems Approach to Understanding Cardiovascular Disease and Arrhythmia. This biannual meeting aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2022 Symposium was 'Cell Diversity in the Cardiovascular System, cell-autonomous and cell-cell signalling'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies, and challenges in examining cell and signal diversity, co-ordination and interrelationships involved in cardiovascular function. This paper originates from the topics of formal presentations and informal discussions from the Symposium, which aimed to develop a holistic view of how the multiple cell types in the cardiovascular system integrate to influence cardiovascular function, disease progression and therapeutic strategies. The first section describes the major cell types (e.g. cardiomyocytes, vascular smooth muscle and endothelial cells, fibroblasts, neurons, immune cells, etc.) and the signals involved in cardiovascular function. The second section emphasizes the complexity at the subcellular, cellular and system levels in the context of cardiovascular development, ageing and disease. Finally, the third section surveys the technological innovations that allow the interrogation of this diversity and advancing our understanding of the integrated cardiovascular function and dysfunction.
Assuntos
Doenças Cardiovasculares , Células Endoteliais , Humanos , Arritmias Cardíacas , Miócitos CardíacosRESUMO
Most studies assessing rates of phenotypic change focus on population mean trait values, whereas a largely overlooked additional component is changes in population trait variation. Theoretically, eco-evolutionary dynamics mediated by such changes in trait variation could be as important as those mediated by changes in trait means. To date, however, no study has comprehensively summarised how phenotypic variation is changing in contemporary populations. Here, we explore four questions using a large database: How do changes in trait variances compare to changes in trait means? Do different human disturbances have different effects on trait variance? Do different trait types have different effects on changes in trait variance? Do studies that established a genetic basis for trait change show different patterns from those that did not? We find that changes in variation are typically small; yet we also see some very large changes associated with particular disturbances or trait types. We close by interpreting and discussing the implications of our findings in the context of eco-evolutionary studies.
Assuntos
Evolução Biológica , Variação Biológica da População , Humanos , FenótipoRESUMO
AIM: Non-surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short-term intensive glucose-lowering therapy. METHODS: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time-to-event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. RESULTS: The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40-0.81; p = .002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14-3.24) and 1.83 (1.03-3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00-3.53) at 48 weeks and 2.05 (0.98-4.29) at 64 weeks. CONCLUSIONS: A 12-week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Insulina Glargina/efeitos adversos , Hemoglobinas Glicadas , Glicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Resultado do TratamentoRESUMO
In a relaxed and awake state with the eyes closed, 8-12 Hz neural oscillations are the dominant rhythm, most prominent in parietal-occipital regions. Resting-state (RS) alpha is associated with processing speed and is also thought to be central to how networks process information. Unfortunately, the RS eyes-closed (EC) exam can only be used with individuals who can remain awake with their eyes closed for an extended period. As such, infants, toddlers, and individuals with intellectual disabilities are usually excluded from RS alpha studies. Previous research suggests obtaining RS alpha measures in a dark room with the eyes open as a viable alternative to the traditional RS EC exam. To further explore this, RS EC and RS dark room (DR) eyes-open alpha activity was recorded using magnetoencephalography in children with typical development (TD; N = 37) and children with autism spectrum disorder (ASD; N = 30) 6.9-12.6 years old. Findings showed good reliability for the RS EC and DR peak alpha frequency (frequency with strongest alpha power; interclass correlation (ICC) = 0.83). ICCs for posterior alpha power were slightly lower (ICCs in the 0.70 s), with an ~ 5% reduction in posterior alpha power in the DR than EC condition. No differences in the EC and DR associations were observed between the TD and ASD groups. Finally, age was associated with both EC and DR peak alpha frequency. Findings thus indicate the DR exam as a viable way to obtain RS alpha measures in populations frequently excluded from electrophysiology RS studies.
Assuntos
Transtorno do Espectro Autista , Lactente , Humanos , Criança , Reprodutibilidade dos Testes , Magnetoencefalografia , Lobo Occipital , Lobo ParietalRESUMO
BACKGROUND: In recent years, there has been a tendency toward an "endovascular-first" approach for the treatment for femoropopliteal arterial disease. The purpose of this study is to determine if there are patients that are better served with an initial femoropopliteal bypass (FPB) rather than an endovascular attempt at revascularization. METHODS: A retrospective analysis of all patients undergoing FPB between June 2006 - December 2014 was performed. Our primary endpoint was primary graft patency, defined as patent using ultrasound or angiography without secondary intervention. Patients with <1-year follow-up were excluded. Univariate analysis of factors significant for 5-year patency was performed using χ2 tests for binary variables. A binary logistic regression analysis incorporating all factors identified as significant by univariate analysis was used to identify independent risk factors for 5-year patency. Event-free graft survival was evaluated using Kaplan-Meier models. RESULTS: We identified 241 patients undergoing FPB on 272 limbs. FPB indication was disabling claudication in 95 limbs, chronic limb-threatening ischemia (CLTI) in 148, and popliteal aneurysm in 29. In total, 134 FPB were saphenous vein grafts (SVG), 126 were prosthetic grafts, 8 were arm vein grafts, and 4 were cadaveric/xenografts. There were 97 bypasses with primary patency at 5 or more years of follow-up. Grafts patent at 5 years by Kaplan-Meier analysis were more likely to have been performed for claudication or popliteal aneurysm (63% 5-year patency) as compared with CLTI (38%, P < 0.001). Statistically significant predictors (using log rank test) of patency over time were use of SVG (P = 0.015), surgical indication of claudication or popliteal aneurysm (P < 0.001), Caucasian race (P = 0.019) and no history of COPD (P = 0.026). Multivariable regression analysis confirmed these 4 factors as significant independent predictors of 5-year patency. Of note, there was no statistical correlation between FPB configuration (above or below knee anastomosis, in-situ versus reversed saphenous vein) and 5-year patency. There were 40 FPBs in Caucasian patients without a history of COPD receiving SVG for claudication or popliteal aneurysm that had a 92% estimated 5-year patency by Kaplan-Meier survival analysis. CONCLUSIONS: Long-term primary patency that was substantial enough to consider open surgery as a first intervention was demonstrated in Caucasian patients without COPD, having good quality saphenous vein, and who underwent FPB for claudication or popliteal artery aneurysm.
Assuntos
Aneurisma , Artéria Poplítea , Humanos , Estudos Retrospectivos , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/cirurgia , Grau de Desobstrução Vascular , Isquemia/diagnóstico por imagem , Isquemia/cirurgia , Isquemia/etiologia , Resultado do Tratamento , Extremidade Inferior/irrigação sanguínea , Claudicação Intermitente/diagnóstico por imagem , Claudicação Intermitente/cirurgia , Claudicação Intermitente/etiologia , Aneurisma/diagnóstico por imagem , Aneurisma/cirurgia , Aneurisma/complicaçõesRESUMO
OBJECTIVE: Despite documented racial disparities in all facets of the criminal justice system, recent laboratory attempts to investigate racial bias in legal settings have produced null effects or racial-bias reversals. These counterintuitive findings may be an artifact of laboratory participants' attempts to appear unprejudiced in response to social norms that proscribe expressions of racial bias against Black individuals. Furthermore, given pervasive stereotypes linking Black people with crime and heightened attention to issues of racial injustice in the legal system, laboratory participants may be especially likely to attempt to appear unprejudiced in studies examining judgments of Black individuals in legal as opposed to nonlegal contexts. HYPOTHESES: We predicted that counterintuitive race effects (null and pro-Black effects) are more likely to occur in laboratory research examining race in legal than in nonlegal contexts. METHOD: We conducted a quantitative review of race effects in three leading social psychology and legal psychology journals over the last four decades (Personality and Social Psychology Bulletin [PSPB]; Law and Human Behavior [LHB]; Psychology, Public Policy, and Law [PPPL]). We then conducted two experiments in which students (N = 314; Experiment 1) and Mechanical Turk workers (N = 695; Experiment 2) read descriptions of White and Black targets in either legal or nonlegal contexts and rated each target along various characteristics (e.g., dangerous, trustworthy). RESULTS: Our analysis of the literature indicated that counterintuitive race effects were more frequent in studies examining race in legal compared with nonlegal contexts. Our experiments likewise revealed that pro-Black race effects were stronger in legal than in nonlegal contexts. CONCLUSIONS: Laboratory research on racial bias against Black people-especially in legal settings-may produce misleading conclusions about the effects of race on important real-world outcomes. Methodological innovations for studying racial bias are needed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Assuntos
População Negra , Racismo , Humanos , Crime , Racismo/psicologia , População BrancaRESUMO
OBJECTIVE: Recently, experimental work on racial bias in legal settings has diverged from real-world field data demonstrating racial disparities, instead often producing null or potential overcorrection effects favoring Black individuals over White individuals. We explored the role of social desirability in these counterintuitive effects and tested whether allowing participants to establish nonracist moral credentials increased their willingness to convict a Black defendant. HYPOTHESES: We predicted that establishing nonracist moral credentials would increase convictions of Black defendants-especially for participants likely to harbor racial bias and external motivation to control it. METHOD: In two experiments, we randomly assigned White mock jurors (Study 1: N = 1,018; Study 2: N = 1,253) to establish nonracist moral credentials by acquitting a Black defendant in an initial case, acquit a White defendant in the same case, or see no prior case. Next, they judged an ambiguous case against a Black (Studies 1 and 2) or White (Study 2) defendant. After choosing verdicts, they provided open-ended guesses of what the study was about. Participants completed measures of explicit prejudice, motivations to control prejudice, and political orientation. RESULTS: Most participants who were asked to judge at least one Black defendant guessed that the study was about racial bias and convicted Black defendants less often than did those who guessed the study was about something else. White participants who established nonracist credentials were significantly more likely to convict Black defendants compared with White participants who did not establish nonracist credentials. Subsequent analyses revealed that conservatives showed this predicted credentialing pattern, whereas liberals did not. Credentialed liberals' convictions of Black defendants remained low; instead, they convicted White defendants more than did noncredentialed liberals. CONCLUSIONS: Social desirability plays a clear role in whether White people acquit Black defendants in experiments, which does not align with persistent racial bias in the legal system. Research participants' concern about looking prejudiced might undermine the validity of experiments investigating racial bias in legal settings by artificially inflating pro-Black judgments. The opportunity to credential oneself as nonracist, however, might make conservatives more comfortable making anti-Black legal judgments-whereas credentialed liberals continue to judge Black individuals more favorably than White individuals in legal settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Assuntos
Racismo , Desejabilidade Social , Humanos , Julgamento , Negro ou Afro-Americano , Credenciamento , Tomada de DecisõesRESUMO
Oral clefts are common birth defects. Individuals with oral clefts who have identical genetic mutations regularly present with variable penetrance and severity. Epigenetic or chromatin-mediated mechanisms are commonly invoked to explain variable penetrance. However, specific examples of these are rare. Two functional copies of the MOZ (KAT6A, MYST3) gene, encoding a MYST family lysine acetyltransferase chromatin regulator, are essential for human craniofacial development, but the molecular role of MOZ in this context is unclear. Using genetic interaction and genomic studies, we have investigated the effects of loss of MOZ on the gene expression program during mouse development. Among the more than 500 genes differentially expressed after loss of MOZ, 19 genes had previously been associated with cleft palates. These included four distal-less homeobox (DLX) transcription factor-encoding genes, Dlx1, Dlx2, Dlx3 and Dlx5 and DLX target genes (including Barx1, Gbx2, Osr2 and Sim2). MOZ occupied the Dlx5 locus and was required for normal levels of histone H3 lysine 9 acetylation. MOZ affected Dlx gene expression cell-autonomously within neural crest cells. Our study identifies a specific program by which the chromatin modifier MOZ regulates craniofacial development.
Assuntos
Ossos Faciais/embriologia , Proteínas de Homeodomínio/genética , Desenvolvimento Maxilofacial/genética , Crânio/embriologia , Fatores de Transcrição/genética , Animais , Desenvolvimento Ósseo/genética , Células Cultivadas , Embrião de Mamíferos , Ossos Faciais/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Histona Acetiltransferases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Crânio/metabolismoRESUMO
Damage can be signalled by extracellular ATP (eATP) using plasma membrane (PM) receptors to effect cytosolic free calcium ion ([Ca2+ ]cyt ) increase as a second messenger. The downstream PM Ca2+ channels remain enigmatic. Here, the Arabidopsis thaliana Ca2+ channel subunit CYCLIC NUCLEOTIDE-GATED CHANNEL2 (CNGC2) was identified as a critical component linking eATP receptors to downstream [Ca2+ ]cyt signalling in roots. Extracellular ATP-induced changes in single epidermal cell PM voltage and conductance were measured electrophysiologically, changes in root [Ca2+ ]cyt were measured with aequorin, and root transcriptional changes were determined by quantitative real-time PCR. Two cngc2 loss-of-function mutants were used: cngc2-3 and defence not death1 (which expresses cytosolic aequorin). Extracellular ATP-induced transient depolarization of Arabidopsis root elongation zone epidermal PM voltage was Ca2+ dependent, requiring CNGC2 but not CNGC4 (its channel co-subunit in immunity signalling). Activation of PM Ca2+ influx currents also required CNGC2. The eATP-induced [Ca2+ ]cyt increase and transcriptional response in cngc2 roots were significantly impaired. CYCLIC NUCLEOTIDE-GATED CHANNEL2 is required for eATP-induced epidermal Ca2+ influx, causing depolarization leading to [Ca2+ ]cyt increase and damage-related transcriptional response.