RESUMO
OBJECTIVE: Determine whether automated changes in electronic screen color temperature of personal electronic devices is associated with changes in objective and self-reported indices of sleep and mental health in young adults, as well as determine feasibility and acceptability of the experimental manipulation. PARTICIPANTS: A single-blind randomized controlled trial was conducted at a large public university in the Pacific Northwest region of the United States. Fifty-five participants (female=78%, mean age=19.45 years) who reported using a smartphone and/or laptop computer two hours before bedtime were randomized into either an experimental group (EG; n=29) or active control group (ACG; n=26). METHODS: Both the EG and ACG had installed on their devices a piece of software that automatically lowers the color temperature of these devices' screens as the day progresses ("f.lux"). However, only the EG had the blue-light-reducing features activated, and participants were blind to condition. Before and after the one-week long experimental manipulation period, participants completed the Pittsburgh Sleep Quality Index (PSQI), Pediatric Daytime Sleepiness Scale (PDSS), Pre-Sleep Arousal Scale (PSAS), and Patient Health Questionnaire (PHQ) and wore an actiwatch for seven consecutive nights. RESULTS: Participants in the EG did not show greater improvement in objective sleep, self-reported sleep, or mental health compared to participants in the ACG. Participants in the EG rated the software as more distracting and purposely disabled the software more often compared to participants in the ACG. CONCLUSIONS: Automated diurnal variation in electronic screen temperature in personal devices did not improve sleep or mental health in young adults.
Assuntos
Qualidade do Sono , Sono , Adulto , Criança , Eletrônica , Feminino , Humanos , Método Simples-Cego , Temperatura , Estados Unidos , Adulto JovemRESUMO
HYPOTHESIS: The purpose of this study was to determine the prevalence and responsiveness of common patient-reported outcome (PRO) tools in patients undergoing primary total shoulder arthroplasty (TSA) for glenohumeral arthritis. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of anatomic and reverse TSA studies from PubMed, SportDiscus, Cochrane, and CINAHL was performed. Studies on primary TSA for glenohumeral arthritis that reported at least 1 PRO tool were included in the final analysis. A subgroup analysis of studies that reported preoperative and postoperative PRO scores with at least 2-year follow-up data was evaluated to compare the responsiveness between the different PRO instruments. RESULTS: After full-text review of 490 articles, 74 articles met all inclusion criteria and were included in the final analysis. Anatomic TSA was evaluated in 35 studies, reverse TSA in 32 studies, and both anatomic and reverse in 7 studies. There were a total of 7624 patients, and 25 different PRO tools were used. The most commonly reported PRO tools were the American Shoulder and Elbow Surgeons (44 studies), Constant (42 studies), the visual analog scale for pain (23 studies), and the Simple Shoulder Test (17 studies). A median of 3.0 PRO instruments were used in each study. All instruments had large effect sizes. The University of California at Los Angeles (UCLA) score was found to be the most responsive instrument, and the Single Assessment Numeric Evaluation score was least responsive. The American Shoulder and Elbow Surgeons score was the most responsive instrument that required only patient-reported data. CONCLUSION: Overall, the UCLA score was found to be the most responsive followed by the Adjusted Constant. However, both the UCLA and Adjusted Constant scores require strength and range of motion assessment that may limit their widespread clinical use. The increased responsiveness of these measures, which include objective clinical testing, speaks to the predicted increases in strength and range of motion after shoulder arthroplasty. Of the measures that can be administered without in-person clinical evaluation, the American Shoulder and Elbow Surgeons score and Western Ontario Osteoarthritis of the Shoulder index were the most responsive.
Assuntos
Artroplastia do Ombro , Osteoartrite , Articulação do Ombro , Humanos , Ontário , Osteoartrite/cirurgia , Medidas de Resultados Relatados pelo Paciente , Amplitude de Movimento Articular , Estudos Retrospectivos , Articulação do Ombro/cirurgia , Resultado do TratamentoRESUMO
Cardiac sympathetic nerves undergo cholinergic transdifferentiation following reperfused myocardial infarction (MI), whereby the sympathetic nerves release both norepinephrine (NE) and acetylcholine (ACh). The functional electrophysiological consequences of post-MI transdifferentiation have never been explored. We performed MI or sham surgery in wild-type (WT) mice and mice in which choline acetyltransferase was deleted from adult noradrenergic neurons [knockout (KO)]. Electrophysiological activity was assessed with optical mapping of action potentials (AP) and intracellular Ca2+ transients (CaT) in innervated Langendorff-perfused hearts. KO MI hearts had similar NE content but reduced ACh content compared with WT MI hearts (0.360 ± 0.074 vs. 0.493 ± 0.087 pmol/mg; KO, n = 6; WT, n = 4; P < 0.05). KO MI hearts also had higher basal ex vivo heart rates versus WT MI hearts (328.5 ± 35.3 vs. 247.4 ± 62.4 beats/min; KO, n = 8; WT, n = 6; P < 0.05). AP duration at 80% repolarization was significantly shorter in the remote and border zones of KO MI versus WT MI hearts, whereas AP durations (APDs) were similar in infarct regions. This APD heterogeneity resulted in increased APD dispersion in the KO MI versus WT MI hearts (11.9 ± 2.7 vs. 8.2 ± 2.3 ms; KO, n = 8; WT, n = 6; P < 0.05), which was eliminated with atropine. CaT duration at 80% and CaT alternans magnitude were similar between groups both with and without sympathetic nerve stimulation. These results indicate that cholinergic transdifferentiation following MI prolongs APD in the remote and border zone and reduces APD heterogeneity.NEW & NOTEWORTHY Cardiac sympathetic neurons undergo cholinergic transdifferentiation following myocardial infarction; however, the electrophysiological effects of corelease of norepinephrine and acetylcholine (ACh) have never been assessed. Using a mouse model in which choline acetyltransferase was deleted from adult noradrenergic neurons and optical mapping of innervated hearts, we found that corelease of ACh reduces dispersion of action potential duration, which may be antiarrhythmic.
Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Transdiferenciação Celular/fisiologia , Neurônios Colinérgicos/metabolismo , Infarto do Miocárdio/fisiopatologia , Sistema Nervoso Simpático/metabolismo , Neurônios Adrenérgicos/metabolismo , Animais , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Coração/inervação , Camundongos , Camundongos Knockout , Infarto do Miocárdio/metabolismoRESUMO
With legalization efforts across the United States, cannabis use is becoming increasingly mainstream. Various studies have documented the effects of acute and chronic cannabis use on brain structure and cognitive performance, including within the frontal executive control network, but little attention has been given to the effects on the cerebellum. Recent evidence increasingly points to the role of the cerebellum in various nonmotor networks, and the cerebellum's expression of cannabinoid receptors may pose particular vulnerabilities to the consequences of cannabis use. Using a combined approach of resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the present study aims to assess how cannabis use relates to the cerebellum's intrinsic functional connectivity and underlying white matter structure and whether these properties are associated with craving or severity of cannabis use. Resting-state fMRI and DTI data, as well as self-reports of substance use history, were analyzed from a sample of 26 adults at risk for cannabis use disorder (CUD) and an age- and sex-matched comparison group of 25 cannabis-naïve adults (control). Results demonstrated that individuals at risk for a CUD showed key differences in cerebellar functional connectivity, with specific impacts on the dorsal attention and default mode networks. In addition, group differences in white matter were localized to the middle cerebellar peduncle (MCP), with a relationship between lower MCP diffusivity and higher levels of self-reported craving. These findings lend further support to the cerebellum's role in key cognitive networks and potential consequences for substance use disorders.
Assuntos
Cannabis/efeitos adversos , Cerebelo/diagnóstico por imagem , Imagem de Tensor de Difusão , Imageamento por Ressonância Magnética , Abuso de Maconha/diagnóstico por imagem , Adulto , Função Executiva , Feminino , Humanos , Masculino , Abuso de Maconha/psicologia , Vias Neurais/diagnóstico por imagem , Risco , Inquéritos e Questionários , Substância Branca/diagnóstico por imagem , Adulto JovemRESUMO
Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.
Assuntos
Dinoprostona/metabolismo , Músculo Esquelético/fisiologia , Mioblastos Esqueléticos/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos , Músculo Esquelético/citologia , Mioblastos Esqueléticos/citologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The aim of this study was to test moderators of therapeutic improvement in an adolescent cognitive-behavioral and mindfulness-based group sleep intervention. Specifically, we examined whether the effects of the program on postintervention sleep outcomes were dependent on participant gender and/or measures of sleep duration, anxiety, depression, and self-efficacy prior to the interventions. METHOD: Secondary analysis of a randomized controlled trial conducted with 123 adolescent participants (female = 59.34%; mean age = 14.48 years, range 12.04-16.31 years) who had elevated levels of sleep problems and anxiety symptoms. Participants were randomized into either a group sleep improvement intervention (n = 63) or group active control 'study skills' intervention (n = 60). The sleep intervention ('Sleep SENSE') was cognitive behavioral in approach, incorporating sleep education, sleep hygiene, stimulus control, and cognitive restructuring, but also had added anxiety-reducing, mindfulness, and motivational interviewing elements. Components of the active control intervention ('Study SENSE') included personal organization, persuasive writing, critical reading, referencing, memorization, and note taking. Participants completed the Pittsburgh Sleep Quality Index (PSQI), Spence Children's Anxiety Scale (SCAS), Center for Epidemiologic Studies Depression Scale (CES-D), and General Self-Efficacy Scale (GSE) and wore an actigraph and completed a sleep diary for five school nights prior to the interventions. Sleep assessments were repeated at postintervention. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612001177842; http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12612001177842&isBasic=True). RESULTS: The results showed that compared with the active control intervention, the effect of the sleep intervention on self-reported sleep quality (PSQI global score) at postintervention was statistically significant among adolescents with relatively moderate to high SCAS, CES-D, and GSE prior to the intervention, but not among adolescents with relatively low SCAS, CES-D, and GSE prior to the intervention. The results were consistent across genders. However, the effects of the sleep intervention on actigraphy-measured sleep onset latency and sleep diary-measured sleep efficiency at postintervention were not dependent on actigraphy-measured total sleep time, SCAS, CES-D, or GSE prior to the intervention. CONCLUSIONS: This study provides evidence that some sleep benefits of adolescent cognitive-behavioral sleep interventions are greatest among those with higher levels of anxiety and depressive symptoms, suggesting that this may be an especially propitious group to whom intervention efforts could be targeted. Furthermore, adolescents with lower levels of self-efficacy may need further targeted support (e.g. additional motivational interviewing) to help them reach treatment goals.
Assuntos
Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Depressão/terapia , Autoeficácia , Transtornos do Sono-Vigília/terapia , Adolescente , Criança , Feminino , Humanos , Masculino , Atenção Plena/métodos , Entrevista Motivacional/métodos , Psicoterapia de Grupo/métodosRESUMO
We report a combined experimental and computational study of the synthesis and electronic structure of titanium borylimido compounds. Three new synthetic routes to this hitherto almost unknown class of Group 4 imide are presented. The double-deprotonation reaction of the borylamine H2NB(NAr'CH)2 (Ar' = 2,6-C6H3iPr2) with Ti(NMe2)2Cl2 gave Ti{NB(NAr'CH)2}Cl2(NHMe2)2, which was easily converted to Ti{NB(NAr'CH)2}Cl2(py)3. This compound is an entry point to other borylimides, for example, reacting with Li2N2pyrNMe to form Ti(N2pyrNMe){NB(NAr'CH)2}(py)2 and with 2 equiv of NaCp to give Cp2Ti{NB(NAr'CH)2}(py) (23). Borylamine-tert-butylimide exchange between H2NB(NAr'CH)2 and Cp*Ti(NtBu)Cl(py) under forcing conditions afforded Cp*Ti{NB(NAr'CH)2}Cl(py), which could be further substituted with guanidinate or pyrrolide-amine ligands to give Cp*Ti(hpp){NB(NAr'CH)2} (16) and Cp*Ti(NpyrNMe2){NB(NAr'CH)2} (17). The Ti-Nim distances in compounds with the NB(NAr'CH)2 ligand were comparable to those of the corresponding arylimides. Dialkyl- or diaryl-substituted borylamines do not undergo the analogous double-deprotonation or imide-amine exchange reactions. Reaction of (Cpâ³2Ti)2(µ2:η1,η1-N2) with N3BMes2 gave the base-free, diarylborylimide Cpâ³2Ti(NBMes2) (26) by an oxidative route; this compound has a relatively long Ti-Nim bond and large Cpâ³-Ti-Cpâ³ angle. Reaction of 16 with H2NtBu formed equilibrium mixtures with H2NB(NAr'CH)2 and Cp*Ti(hpp)(NtBu) (ΔrG = -1.0 kcal mol-1). In contrast, the dialkylborylimide Cp*Ti{MeC(NiPr)2}(NBC8H14) (2) reacted quantitatively with H2NtBu to give the corresponding tert-butylimide and borylamine. The electronic structures and imide-amine exchange reactions of half-sandwich and sandwich titanium borylimides have been evaluated using density functional theory (DFT), supported by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis, and placed more generally in context with the well-established alkyl- and arylimides and hydrazides. The calculations find that Ti-Nim bonds for borylimides are stronger and more covalent than in their organoimido or hydrazido analogues, and are strongest for alkyl- and arylborylimides. Borylamine-tert-butylimide exchange reactions fail for H2NBR2 (R = hydrocarbyl) but not for H2NB(NAr'CH)2 because the increased strength of the new Ti-Nim bond for the former is outweighed by the increased net H-N bond strengths in the borylamine. Variation of the Ti-Nim bond length over short distances is dominated by π-interactions with any appropriate orbital on the Nim atom organic substituent. However, over the full range of imides and hydrazides studied, overall bond energies do not correlate with bond length but with the Ti-Nim σ-bond character and the orthogonal π-interaction.
RESUMO
Reduction of indium boryl precursors to give two- and three-dimensional M-M bonded networks is influenced by the choice of supporting ligand. While the unprecedented nanoscale cluster [In68 (boryl)12 ]- (with an In12 @In44 @In12 (boryl)12 concentric structure), can be isolated from the potassium reduction of a bis(boryl)indium(III) chloride precursor, analogous reduction of the corresponding (benzamidinate)InIII Br(boryl) system gives a near-planar (and weakly aromatic) tetranuclear [In4 (boryl)4 ]2- system.
RESUMO
By employing strongly σ-donating boryl ancillary ligands, the oxidative addition of H2 to a single site Sn(II) system has been achieved for the first time, generating (boryl)2SnH2. Similar chemistry can also be achieved for protic and hydridic E-H bonds (N-H/O-H, Si-H/B-H, respectively). In the case of ammonia (and water, albeit more slowly), E-H oxidative addition can be shown to be followed by reductive elimination to give an N- (or O-)borylated product. Thus, in stoichiometric fashion, redox-based bond cleavage/formation is demonstrated for a single main group metal center at room temperature. From a mechanistic viewpoint, a two-step coordination/proton transfer process for N-H activation is shown to be viable through the isolation of species of the types Sn(boryl)2·NH3 and [Sn(boryl)2(NH2)](-) and their onward conversion to the formal oxidative addition product Sn(boryl)2(H)(NH2).
RESUMO
Reduction of Fp2 (Fp = CpFe(CO)2) or [Co(CO)3(PCy3)]2 (15) with Mg-mercury amalgam gave [Mg{TM(L)}2(THF)]2 (TM(L) = Fp or Co(CO)3(PCy3) (19)) in which the TM is bonded to two Mg atoms. Reduction of 15 with Ca-, Sr-, Ba-, Yb-, Eu- and Sm-mercury amalgam gave a series of compounds "M{Co(CO)3(PCy3)}2(THF)n" (M = Ae or Ln) in which the M-Co bonding varies with the charge-to-size ratio of M. For M = Ca or Yb (24), each metal forms one M-Co bond and one M(µ-OC)Co η(1)-isocarbonyl linkage. With M = Sr (21) or Eu (25), a switch from M-Co bonding to side-on (η(2)) CO ligand coordination is found. Sm(II){Co(CO)3(PCy3)}2(THF)3 disproportionates in pentane to form Sm(III){Co(CO)3(PCy3)}3(THF)3 containing two Sm(III)-Co bonds, in contrast with 25, showing the importance of the Ln charge on Ln-TM bonding. Diffusion NMR spectroscopy found that in solution, 21 and 24 are dimeric compounds [M{Co(CO)3(PCy3)}2(THF)3]2 that, according to DFT calculations, contain either one (Ae = Ca) or two (Ae = Sr) Ae-Co bonds per Co atom. DFT calculations in combination with Ziegler Rauk energy decomposition and atoms in molecules analysis were used to assess the nature and energy of Ae-Co bonding in a series of model compounds. The Ae-Co interaction energies decrease from Be to Sr, and toward the bottom of the group, side-on (η(2)) CO ligand coordination competes with Ae-Co bonding. The PCy3 ligand plays a pivotal role by increasing solubility in nondonor solvents and the Ae-Co interaction energy.
RESUMO
Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein (APP) producing the neurotoxic Amyloid-ß (Aß) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of APP-like (APPL) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased ß-cleavage of endogenous APPL by the ß-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of APPL-derived Aß production but rather may be caused by a mechanism common to both α and ß-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous APPL maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer's disease.
Assuntos
Envelhecimento , Precursor de Proteína beta-Amiloide/metabolismo , Relógios Circadianos/genética , Regulação da Expressão Gênica/genética , Fatores Etários , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Geneticamente Modificados , Sistema Nervoso Central/citologia , Desintegrinas/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Análise de Fourier , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Longevidade , Metaloendopeptidases/metabolismo , Atividade Motora/genética , Neurônios/metabolismo , Proteínas Circadianas Period/metabolismoRESUMO
Monomeric five-valence-electron bis(boryl) complexes of gallium, indium, and thallium undergo oxidative M-C bond formation with 2,3-dimethylbutadiene, in a manner consistent with both the redox properties expected for M(II) species and with metal-centered radical character. The weaker nature of the M-C bond for the heavier two elements leads to the observation of reversibility in M-C bond formation (for indium) and to the isolation of products resulting from subsequent B-C reductive elimination (for both indium and thallium).
RESUMO
This paper presents the results of a one-year study on mastery of assistive technology (AT). This study sought to develop a conceptual framework for talking about mastery of AT and to create an instrument for measuring individual mastery. A Delphi Study was conducted with individuals with disabilities considered to be "power users" of AT, practitioners, and researchers. Participants were asked to: identify factors that are predictors and indicators of AT mastery, determine how to measure these factors and determine criteria for each factor for the stages of AT mastery (e.g. novice, context-dependent, transitional, and power user). The resulting measure is called the Continuum of AT Mastery (CATM).
RESUMO
With advances in sample preparation, small-volume liquid dispensing technologies, high-resolution MS/MS instrumentation, and data acquisition methodologies, it has become increasingly possible to confidently investigate the heterogeneous proteome found within individual cells. In this chapter, we present an automated high-throughput sample preparation workflow based on the Tecan Uno instrument for quantitative single-cell mass spectrometry-based proteomics. Cells are analyzed by the Single-Cell Proteome Analysis platform (SCREEN), which was introduced earlier and provides deeper proteome coverage across single cells.
Assuntos
Proteoma , Proteômica , Análise de Célula Única , Espectrometria de Massas em Tandem , Fluxo de Trabalho , Análise de Célula Única/métodos , Proteômica/métodos , Humanos , Proteoma/análise , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodosRESUMO
Si in sight: a one-pot, single-step synthesis of an acyclic silylsilylene, Si{Si(SiMe(3))(3)}{N(SiMe(3))Dipp} (Dipp=2,6-iPr(2)C(6)H(3)), from a silicon(IV) starting material is reported, together with evidence for a mechanism involving alkali metal silylenoid intermediates.
RESUMO
Sympathetic nerve loss in the heart predicts the risk of ventricular arrhythmias after myocardial infarction (MI) in patients. Sympathetic denervation after cardiac ischemia-reperfusion is sustained by matrix components chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. We showed that 4,6-sulfation of CSPGs was critical for preventing nerve growth into the scar. Promoting early reinnervation with therapeutics reduces arrhythmias during the first 2 weeks after MI, but the longer-term consequences of restoring innervation are unknown. Therefore, we asked if the beneficial effects of early reinnervation were sustained. We compared cardiac function and arrhythmia susceptibility 40 days after MI in mice treated on Days 3-10 with vehicle or with intracellular sigma peptide to restore innervation. Surprisingly, both groups had normal innervation density in the cardiac scar 40 days after MI, indicating delayed reinnervation of the infarct in vehicle-treated mice. That coincided with similar cardiac function and arrhythmia susceptibility in the two groups. We investigated the mechanism allowing delayed reinnervation of the cardiac scar. We found that CSPG 4,6-sulfation, which is elevated early after ischemia-reperfusion, was reduced to control levels allowing reinnervation of the infarct. Thus, remodeling of extracellular matrix weeks after injury leads to remodeling of sympathetic neurons in the heart.
Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Isquemia Miocárdica , Animais , Camundongos , Cicatriz , Isquemia , Reperfusão , Proteoglicanas de Sulfatos de CondroitinaRESUMO
Sympathetic denervation of the heart following ischemia/reperfusion induced myocardial infarction (MI) is sustained by chondroitin sulfate proteoglycans (CSPGs) in the cardiac scar. Denervation predicts risk of sudden cardiac death in humans. Blocking CSPG signaling restores sympathetic axon outgrowth into the cardiac scar, decreasing arrhythmia susceptibility. Axon growth inhibition by CSPGs can depend on the sulfation status of the glycosaminoglycan (CS-GAG) side chains. Tandem sulfation of CS-GAGs at the 4th (4S) and 6th (6S) positions of n-acetyl-galactosamine inhibits outgrowth in several types of central neurons, but we don't know if sulfation is similarly critical during peripheral nerve regeneration. We asked if CSPG sulfation prevented sympathetic axon outgrowth after MI. Reducing 4S with the 4-sulfatase enzyme Arylsulfatase-B (ARSB) enhanced outgrowth of dissociated rat sympathetic neurons over CSPGs. Likewise, reducing 4S with ARSB restored axon outgrowth from mouse sympathetic ganglia co-cultured with cardiac scar tissue. We quantified enzymes responsible for adding and removing sulfation, and found that CHST15 (4S dependent 6-sulfotransferase) was upregulated, and ARSB was downregulated after MI. This suggests a mechanism for production and maintenance of sulfated CSPGs in the cardiac scar. We decreased 4S,6S CS-GAGs in vivo by transient siRNA knockdown of Chst15 after MI, and found that reducing 4S,6S restored tyrosine hydroxylase (TH) positive sympathetic nerve fibers in the cardiac scar. Reinnervation reduced isoproterenol induced arrhythmias. Our results suggest that modulating CSPG-sulfation after MI may be a therapeutic target to promote sympathetic nerve regeneration in the cardiac scar and reduce post-MI cardiac arrhythmias.
Assuntos
Infarto do Miocárdio , N-Acetilgalactosamina-4-Sulfatase , Enxofre/metabolismo , Animais , Antígenos , Proteoglicanas de Sulfatos de Condroitina/química , Cicatriz , Camundongos , Regeneração Nervosa/fisiologia , Proteoglicanas , RatosRESUMO
Chondroitin sulfate proteoglycans (CSPGs) prevent sympathetic nerve regeneration in the heart after myocardial infarction and prevent central nerve regrowth after traumatic brain injury and spinal cord injury. Currently, there are no small-molecule therapeutics to promote nerve regeneration through CSPG-containing scars. CSPGs bind to monomers of receptor protein tyrosine phosphatase sigma (PTPσ) on the surface of neurons, enhancing the ability of PTPσ to bind and dephosphorylate tropomyosin receptor kinases (Trks), inhibiting their activity and preventing axon outgrowth. Targeting PTPσ-Trk interactions is thus a potential therapeutic target. Here, we describe the development and synthesis of small molecules (HJ-01 and HJ-02) that disrupt PTPσ interactions with Trks, enhance Trk signaling, and promote sympathetic nerve regeneration over CSPGs.
Assuntos
Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Traumatismos da Medula Espinal , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Humanos , Regeneração Nervosa/fisiologia , Monoéster Fosfórico Hidrolases , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Traumatismos da Medula Espinal/metabolismoRESUMO
Myocardial infarction (MI) triggers an inflammatory response that transitions from pro-inflammatory to reparative over time. Restoring sympathetic nerves in the heart after MI prevents arrhythmias. This study investigated if reinnervation altered the immune response after MI. This study used quantitative multiplex immunohistochemistry to identify the immune cells present in the heart 2 weeks after ischemia-reperfusion. Two therapeutics stimulated reinnervation, preventing arrhythmias and shifting the immune response from inflammatory to reparative, with fewer pro-inflammatory macrophages and more regulatory T cells and reparative macrophages. Treatments did not alter macrophage phenotype in vitro, which suggested reinnervation contributed to the altered immune response.
RESUMO
Reaction of calcium or ytterbium amalgam with [CpFe(CO)(2)](2) (Fp(2)) gave the isostructural heavy alkaline earth or divalent rare earth compounds [MFp(2)(THF)(3)](2) (M = Ca or Yb) containing two direct Ca-Fe (3.0185(6) Å) or Yb-Fe (2.9892(4) Å) bonds. Density functional theory supports experiment in finding shorter Yb-Fe than Ca-Fe distances, and Ziegler-Rauk, molecular orbital, and atoms-in-molecules analyses find the M-Fe bonding to be predominantly electrostatic in nature. The Yb-Fe interaction energy and bond critical point electron density are slightly larger than for Ca-Fe, in agreement with the shorter M-Fe bond in the former. The corresponding reaction for magnesium gave MgFp(2)(THF)(4) with two O-bound Fp moieties and no Mg-Fe bond.