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1.
Sci Rep ; 13(1): 12344, 2023 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-37524893

RESUMO

Diastolic dysfunction is increasingly identified as a key, early onset subclinical condition characterizing cardiopathologies of rising prevalence, including diabetic heart disease and heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction characterization has important prognostic value in management of disease outcomes. Validated tools for in vivo monitoring of diastolic function in rodent models of diabetes are required for progress in pre-clinical cardiology studies. 2D speckle tracking echocardiography has emerged as a powerful tool for evaluating cardiac wall deformation throughout the cardiac cycle. The aim of this study was to examine the applicability of 2D speckle tracking echocardiography for comprehensive global and regional assessment of diastolic function in a pre-clinical murine model of cardio-metabolic disease. Type 2 diabetes (T2D) was induced in C57Bl/6 male mice using a high fat high sugar dietary intervention for 20 weeks. Significant impairment in left ventricle peak diastolic strain rate was evident in longitudinal, radial and circumferential planes in T2D mice. Peak diastolic velocity was similarly impaired in the longitudinal and radial planes. Regional analysis of longitudinal peak diastolic strain rate revealed that the anterior free left ventricular wall is particularly susceptible to T2D-induced diastolic dysfunction. These findings provide a significant advance on characterization of diastolic dysfunction in a pre-clinical mouse model of cardiopathology and offer a comprehensive suite of benchmark values for future pre-clinical cardiology studies.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Masculino , Animais , Camundongos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Volume Sistólico , Ecocardiografia/métodos , Miocárdio , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda
2.
Front Genet ; 14: 1198129, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37323671

RESUMO

Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent aneuploidy observed in the human population and represents the most common genetic form of intellectual disability and early-onset Alzheimer's disease (AD). Individuals with DS exhibit a wide spectrum of clinical presentation, with a number of organs implicated including the neurological, immune, musculoskeletal, cardiac, and gastrointestinal systems. Decades of DS research have illuminated our understanding of the disorder, however many of the features that limit quality of life and independence of individuals with DS, including intellectual disability and early-onset dementia, remain poorly understood. This lack of knowledge of the cellular and molecular mechanisms leading to neurological features of DS has caused significant roadblocks in developing effective therapeutic strategies to improve quality of life for individuals with DS. Recent technological advances in human stem cell culture methods, genome editing approaches, and single-cell transcriptomics have provided paradigm-shifting insights into complex neurological diseases such as DS. Here, we review novel neurological disease modeling approaches, how they have been used to study DS, and what questions might be addressed in the future using these innovative tools.

3.
Physiol Behav ; 263: 114117, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36781093

RESUMO

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.


Assuntos
Transtornos Cognitivos , Disfunção Cognitiva , Esquizofrenia , Ratos , Feminino , Animais , Fenciclidina/efeitos adversos , Esquizofrenia/induzido quimicamente , Disfunção Cognitiva/induzido quimicamente , Cognição , Modelos Animais de Doenças
4.
Scand J Rheumatol ; 52(6): 673-682, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36815837

RESUMO

OBJECTIVE: Compare characteristics, sex differences, and management of gout in Sweden and the UK. METHOD: The results from two separate primary care gout surveys from Sweden and the UK were compared. Participants aged ≥18 years with gout were sent a questionnaire asking about lifestyle, gout characteristics, uratelowering therapy (ULT), comorbidities, disability, and disease impact. For sex comparison, participants were pooled across countries. RESULTS: In total, 784 (80% male) participants from Sweden and 500 (87% male) from the UK were included. Swedish patients were significantly older at gout onset, mean (SD) age 72 (12) versus 63 (13) years, (p<0.0001), with more comorbidities, and more frequent use of ULT (48% vs 35%, p=0.0005, age-adjusted). Use of alcohol and diuretics was significantly more common among UK patients, who also reported a higher number of gout flares, mean (SD) 2.2 (1.7) versus 1.6 (3.6), (p=0.003) age-adjusted. Females with gout were older at gout onset, mean (SD) age 67 (13) versus 56 (15), (p<0.0001), more often obese, and reported higher use of diuretics. Furthermore, females reported greater impact of gout, more pain and physical limitations, whereas no sex differences were seen in ULT or flares. CONCLUSIONS: In the UK, gout was more frequently associated with modifiable risk factors. People with gout in Sweden were more commonly taking ULT and had lower frequency of gout flares and impact of gout. Females with gout more commonly took diuretics, had higher body mass index, and reported greater physical disability, which should be considered when managing gout in women.


Assuntos
Supressores da Gota , Gota , Humanos , Feminino , Masculino , Adolescente , Adulto , Idoso , Suécia/epidemiologia , Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Gota/epidemiologia , Diuréticos/uso terapêutico , Reino Unido/epidemiologia
5.
Environ Sci Technol ; 56(24): 17902-17912, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36414474

RESUMO

The risk of human exposure to cyanotoxins is partially influenced by the location of toxin-producing cyanobacteria in waterbodies. Cyanotoxin production can occur throughout the water column, with deep water production representing a potential public health concern, specifically for drinking water supplies. Deep cyanobacteria layers are often unreported, and it remains to be seen if lower incident rates reflect an uncommon phenomenon or a monitoring bias. Here, we examine Sunfish Lake, Ontario, Canada as a case study lake with a known deep cyanobacteria layer. Cyanotoxin and other bioactive metabolite screening revealed that the deep cyanobacteria layer was toxigenic [0.03 µg L-1 microcystins (max) and 2.5 µg L-1 anabaenopeptins (max)]. The deep layer was predominantly composed of Planktothrix isothrix (exhibiting a lower cyanotoxin cell quota), with Planktothrix rubescens (exhibiting a higher cyanotoxin cell quota) found at background levels. The co-occurrence of multiple toxigenic Planktothrix species underscores the importance of routine surveillance for prompt identification leading to early intervention. For instance, microcystin concentrations in Sunfish Lake are currently below national drinking water thresholds, but shifting environmental conditions (e.g., in response to climate change or nutrient modification) could fashion an environment favoring P. rubescens, creating a scenario of greater cyanotoxin production. Future work should monitor the entire water column to help build predictive capacities for identifying waterbodies at elevated risk of developing deep cyanobacteria layers to safeguard drinking water supplies.


Assuntos
Cianobactérias , Água Potável , Humanos , Água Potável/metabolismo , Cianobactérias/metabolismo , Microcistinas/metabolismo , Abastecimento de Água , Lagos/microbiologia , Ontário
6.
Cell Stem Cell ; 29(1): 116-130.e7, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34995493

RESUMO

Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) and characterized by a wide range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide "chromosomal introversion," disruption of lamina-associated domains, and global chromatin accessibility changes in response to T21, consistent with the transcriptional and nuclear architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular, and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS.


Assuntos
Síndrome de Down , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Perfilação da Expressão Gênica , Humanos , Transcriptoma/genética
7.
Med Probl Perform Art ; 36(3): 163-175, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34464962

RESUMO

OBJECTIVE: To explore the subjective experiences of student circus arts performers with atraumatic shoulder instability undertaking a 12-week shoulder rehabilitation program during the COVID-19 pandemic lockdown, in Melbourne, Australia. METHODS: Using a qualitative design, 14 circus arts students from the National Institute of Circus Arts (Australia) were individually interviewed via teleconsultation. All interviews were recorded, transcribed, and analysed using inductive thematic analysis. RESULTS: Five overarching themes were identified: (i) impact (physical and mental), (ii) opportunity, (iii) developing routine, (iv) client-therapist relationship, and (v) transformation. All participants reported positive physical changes to their shoulder including increases in strength, stability, range of motion, less pain, "clicking" and "clunking," improved posture, muscle memory, as well as carry-over to functional circus activities. The pandemic's mental impact varied across the cohort, with positive and negative experiences described in relation to cognitive, social, and affective factors. Most performers felt the pandemic provided an opportunity to focus on rehabilitation of their shoulder. The program effects were also underpinned by positive client-therapist relationships and a progressive transformation of learning where students gained knowledge of their condition, developed tools to manage their current shoulder impairment, and learned how to apply this new knowledge to future management of their condition. CONCLUSION: A shoulder exercise intervention delivered via teleconsultation during the COVID-19 pandemic resulted in subjective reports of positive physical changes to the participants' shoulder health complaint. This was facilitated through client-physiotherapist relationships, providing structure during uncertain times, and by providing education to help in understanding their condition and its future management.


Assuntos
COVID-19 , Instabilidade Articular , Articulação do Ombro , Telemedicina , Controle de Doenças Transmissíveis , Humanos , Pandemias , Encaminhamento e Consulta , SARS-CoV-2 , Ombro , Estudantes
8.
Toxins (Basel) ; 13(7)2021 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199141

RESUMO

The understanding of deep chlorophyll layers (DCLs) in the Great Lakes-largely reported as a mix of picoplankton and mixotrophic nanoflagellates-is predominantly based on studies of deep (>30 m), offshore locations. Here, we document and characterize nearshore DCLs from two meso-oligotrophic embayments, Twelve Mile Bay (TMB) and South Bay (SB), along eastern Georgian Bay, Lake Huron (Ontario, Canada) in 2014, 2015, and 2018. Both embayments showed the annual formation of DCLs, present as dense, thin, metalimnetic plates dominated by the large, potentially toxic, and bloom-forming cyanobacteria Planktothrix cf. isothrix. The contribution of P. cf. isothrix to the deep-living total biomass (TB) increased as thermal stratification progressed over the ice-free season, reaching 40% in TMB (0.6 mg/L at 9.5 m) and 65% in South Bay (3.5 mg/L at 7.5 m) in 2015. The euphotic zone in each embayment extended down past the mixed layer, into the nutrient-enriched hypoxic hypolimnia, consistent with other studies of similar systems with DCLs. The co-occurrence of the metal-oxidizing bacteria Leptothrix spp. and bactivorous flagellates within the metalimnetic DCLs suggests that the microbial loop plays an important role in recycling nutrients within these layers, particularly phosphate (PO4) and iron (Fe). Samples taken through the water column in both embayments showed measurable concentrations of the cyanobacterial toxins microcystins (max. 0.4 µg/L) and the other bioactive metabolites anabaenopeptins (max. ~7 µg/L) and cyanopeptolins (max. 1 ng/L), along with the corresponding genes (max. in 2018). These oligopeptides are known to act as metabolic inhibitors (e.g., in chemical defence against grazers, parasites) and allow a competitive advantage. In TMB, the 2018 peaks in these oligopeptides and genes coincided with the P. cf. isothrix DCLs, suggesting this species as the main source. Our data indicate that intersecting physicochemical gradients of light and nutrient-enriched hypoxic hypolimnia are key factors in supporting DCLs in TMB and SB. Microbial activity and allelopathy may also influence DCL community structure and function, and require further investigation, particularly related to the dominance of potentially toxigenic species such as P. cf. isothrix.


Assuntos
Toxinas Bacterianas/análise , Baías/análise , Baías/microbiologia , Lagos/análise , Lagos/microbiologia , Poluentes da Água/análise , Biomassa , Clorofila , Monitoramento Ambiental , Luz , Metais Pesados/análise , Compostos de Nitrogênio/análise , Ontário , Oxigênio , Fosfatos/análise , Planktothrix
9.
Post Reprod Health ; 27(3): 167-173, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34255590

RESUMO

OBJECTIVES: Studies investigating the safety of hormone replacement therapy in cervical cancer have predominantly included patients with squamous disease. Pathological studies have identified estrogen receptor positivity in cervical adenocarcinomas. A recent small case-control study suggested a trend towards reduced survival with hormone replacement therapy in cervical adenocarcinomas. Our objective was to determine if hormone replacement therapy use in patients treated for cervical adenocarcinomas is detrimental to survival. STUDY DESIGN: A retrospective review of all women under the age of 50 with stage 1B-2B cervical adenocarcinomas diagnosed between 1 November 2000 and 24 September 2019. Women were categorised into three groups: ovaries conserved (OVCON); or iatrogenic menopause with (IM-HRT) or without (IM-NOHRT) hormone replacement therapy. Hormone replacement therapy use was defined on an intention to treat basis. Statistical analysis was performed using Kaplan-Meier and Cox proportional hazards methods. MAIN OUTCOME MEASURES: Overall (OS), disease specific (DSS) and progression free (PFS) survival. RESULTS: A total of 58 women (mean age 38.5 ± 6.6) were included in the study of whom 25 (43.1%) had OVCON, 20 (34.4%) had IM-HRT and 13 (22.4%) had IM-NOHRT. No menopause-associated deaths occurred. Although five-year DSS was 73% in IM-NOHRT compared to 95% in IM-HRT and 95% in OVCON, these differences were not statistically significant. Five-year PFS was 68% in IM-NOHRT compared to 90% in IM-HRT and 81% in OVCON but again, these differences were not statistically significant. CONCLUSION: In this small study, hormone replacement therapy does not appear to be detrimental to survival in cervical adenocarcinomas. There is a trend towards improved survival with hormone replacement therapy. Larger studies are required to substantiate these findings.


Assuntos
Adenocarcinoma , Neoplasias do Colo do Útero , Adulto , Estudos de Casos e Controles , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Mol Syst Biol ; 16(12): e9819, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33289969

RESUMO

Alzheimer's disease (AD) is characterized by the appearance of amyloid-ß plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem cell-derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.


Assuntos
Inflamação/patologia , Microglia/metabolismo , Degeneração Neural/patologia , Fosfoproteínas/metabolismo , Proteômica , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Anticorpos/metabolismo , Morte Celular , Linhagem Celular , Humanos , Inflamação/metabolismo , Interferon gama/metabolismo , Camundongos Transgênicos , Microglia/patologia , Degeneração Neural/metabolismo , Peptídeos/metabolismo , Fagocitose , Fosfotirosina/metabolismo , Proteoma/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química , Transdução de Sinais , Regulação para Cima
11.
Int J Nanomedicine ; 15: 6421-6432, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922009

RESUMO

PURPOSE: Expanded research on the biomedical applications of graphene has shown promising results, although interactions between cells and graphene are still unclear. The current study aims to dissect the cellular and molecular effects of graphene nanocomposite in photothermal therapy against cancer, and to evaluate its efficacy. METHODS: In this study, a reduced graphene oxide and iron oxide (rGO-Fe3O4) nanocomposite was obtained by chemical synthesis. The nanocomposite was fully characterized by Raman spectroscopy, TEM, VSM and thermal profiling. Cell-nanocomposite interaction was evaluated by confocal microscopy and viability assays on cancer cell line HeLa. The efficacy of the thermal therapy and changes in gene expression of Bcl-2 and Hsp70 was assessed. RESULTS: The resulting rGO-Fe3O4 nanocomposite exhibited superparamagnetic properties and the capacity to increase the surrounding temperature by 18-20°C with respect to the initial temperature. The studies of cell-nanocomposite interaction showed that rGO-Fe3O4 attaches to cell membrane but there is a range of concentration at which the nanomaterial preserves cell viability. Photothermal therapy reduced cell viability to 32.6% and 23.7% with 50 and 100 µg/mL of nanomaterial, respectively. The effect of treatment on the molecular mechanism of cell death demonstrated an overexpression of anti-apoptotic proteins Hsp70 and Bcl-2 as an initial response to the therapy and depending on the aggressiveness of the treatment. CONCLUSION: The results of this study contribute to understanding the interactions between cell and graphene and support its application in photothermal therapy against cancer due to its promising results.


Assuntos
Compostos Férricos/química , Grafite/química , Hipertermia Induzida , Nanocompostos/química , Neoplasias/terapia , Fototerapia , Apoptose/genética , Comunicação Celular , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Nanocompostos/ultraestrutura , Neoplasias/genética , Neoplasias/patologia , Oxirredução , Análise Espectral Raman , Temperatura , Resultado do Tratamento
12.
J Health Pollut ; 10(26): 200604, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32509405

RESUMO

BACKGROUND: Gold mining activities in forested areas across Guyana have been a common practice for more than a century. The intensification of artisanal and small-scale gold mining (ASGM) in recent decades caused by global market demand is contributing to the mobilization of mercury into aquatic systems. Indigenous populations who consume high levels of locally sourced fish are greater at risk for methylmercury poisoning from ingestion of contaminated fish. OBJECTIVES: The aim of the present study was to investigate the levels of mercury contamination and identify the risk factors associated with hair mercury levels in four indigenous communities in Guyana. METHODS: Concentrations of total mercury were measured in hair samples from 99 participants from four indigenous communities in the south Rupununi region in Guyana. The findings of this study were compared with those of previous studies to assess the prevalence of mercury contamination in indigenous communities across Guyana. RESULTS: Hair mercury levels were found to be above the World Health Organization (WHO) reference value for residents who live close to ASGM activities and who consume high quantities of locally sourced fish. Our results are not only consistent with those obtained in previous studies, but also evidence that mercury poisoning has become a generalized problem for indigenous communities in Guyana. CONCLUSIONS: Fish is the main source of protein for many riverine communities and consumption of mercury-contaminated fish poses a serious health hazard for these vulnerable populations. The situation is especially dire for community members of Parabara with 100% of participants showing elevated (>15 µg*g-1) hair mercury levels. It is therefore crucial that Parabara residents be evaluated by relevant health agencies for clinical symptoms related to mercury toxicity. PARTICIPANT CONSENT: Obtained. ETHICS APPROVAL: The study protocol was approved by the Institutional Review Board of the Ministry of Public Health, Guyana. COMPETING INTERESTS: The authors declare no competing financial interests.

13.
Shoulder Elbow ; 12(3): 203-211, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32565922

RESUMO

BACKGROUND: A simple modification to standard rotator cuff exercises using an additional resistance band around the scapula has been recommended in the clinical setting, postulated to encourage activation of the posterior scapular stabilisers and increase rotator cuff activation. The aim of this clinical laboratory study was to compare scapular and rotator cuff muscle activation between standard and modified exercises. METHODS: Electromyographic data were collected from 10 healthy adults via surface and intramuscular electrodes from the scapular and rotator cuff muscles. Internal and external rotation exercises of the shoulder with the arm abducted to 0°, 45° and 90° were performed using one handheld resistance band (standard) or two bands with the additional band applied to the scapula (modified). RESULTS: Activation of the trapezii and rhomboid muscles during the modified exercises at 0° and 45° of abduction was significantly greater when compared to the standard exercises (P < 0.05). No significant differences were found in rotator cuff muscle activation. DISCUSSION: Applying resistance to the posterior scapula increases activation of some scapular stabilising muscles particularly in lower ranges of abduction. This study provides preliminary evidence that this simple modification can elicit greater scapular muscle activity, potentially producing enhanced exercise outcomes with minimal additional effort.

14.
Nat Commun ; 11(1): 2484, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424276

RESUMO

DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer's disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Dano ao DNA , DNA Glicosilases/metabolismo , Histona Desacetilase 1/metabolismo , Estresse Oxidativo , Acetilação , Envelhecimento/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Sequência de Bases , Benzofenonas/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Ontologia Genética , Guanina/análogos & derivados , Guanina/metabolismo , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Regiões Promotoras Genéticas/genética
15.
J Chem Phys ; 152(12): 124108, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32241152

RESUMO

Multisite phosphorylation plays an important role in regulating switch-like protein activity and has been used widely in mathematical models. With the development of new experimental techniques and more molecular data, molecular phosphorylation processes emerge in many systems with increasing complexity and sizes. These developments call for simple yet valid stochastic models to describe various multisite phosphorylation processes, especially in large and complex biochemical networks. To reduce model complexity, this work aims at simplifying the multisite phosphorylation mechanism by a stochastic Hill function model. Furthermore, this work optimizes regions of parameter space to match simulation results from the stochastic Hill function with the distributive multisite phosphorylation process. While traditional parameter optimization methods have been focusing on finding the best parameter vector, in most circumstances, modelers would like to find a set of parameter vectors that generate similar system dynamics and results. This paper proposes a general α-ß-γ rule to return an acceptable parameter region of the stochastic Hill function based on a quasi-Newton stochastic optimization algorithm. Different objective functions are investigated characterizing different features of the simulation-based empirical data, among which the approximate maximum log-likelihood method is recommended for general applications. Numerical results demonstrate that with an appropriate parameter vector value, the stochastic Hill function model depicts the multisite phosphorylation process well except the initial (transient) period.


Assuntos
Modelos Químicos , Proteínas/química , Algoritmos , Fosforilação , Processos Estocásticos
16.
J Colloid Interface Sci ; 558: 95-99, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31585226

RESUMO

The behavior of Janus particles fabricated from core silica particles decorated with gold nanoparticles on one hemisphere is studied at the air/water interface. An unexpected reduction in the effective surface tension is observed in the presence of these chemically-modified Janus particles. Experiments on the interfacial behavior of a variety of control particles, including the physically-modified Janus particles made from the same core silica particles coated with a thin gold layer, do not exhibit significant surface tension effects. We hypothesize that the chemical modification of particles in form of a Janus structure is needed to alter the surface tension and attribute the surfactant-like behavior of these particles to the presence of immersion forces.

17.
Curr Oncol ; 26(4): e503-e509, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548818

RESUMO

Background: The collection of patient reported outcomes (pros) is a standard of care in many cancer organizations. In Alberta, pros have been integrated into routine clinical practice since 2012. This longitudinal collection of pros provides a wealth of data and a unique research opportunity to improve cancer care. The goal of this pro data initiative is to establish a robust repository of information for ongoing clinical care and research focused on pros. In this paper, we describe the rationale, scope, and design of this initiative. Implementation: The initiative consists of pros and other administrative health data from the province of Alberta. Retrieval of health data from a variety of provincially governed sources will create a platform of information on pros, health outcomes, cancer data, other health conditions, and demographics. The aims of the initiative are to use the data to inform best practices at the point of care; to conduct health services research, particularly clinical epidemiology studies; and to evaluate a variety of pro-related outcomes. Discussion: Because this effort represents our first to integrate routinely collected pros with other administrative health data, a unique and robust data repository will be created. The ability to integrate various types of data will provide a comprehensive mechanism to evaluate a variety of outcomes. Because cancer care in Alberta is governed by a single health care system, the data linkages will include population health and psychosocial cancer data. We anticipate that research related to this initiative will ultimately help to inform more patient-centred care.


Assuntos
Pesquisa sobre Serviços de Saúde/métodos , Medidas de Resultados Relatados pelo Paciente , Alberta , Bases de Dados Factuais , Humanos , Neoplasias , Assistência Centrada no Paciente , Guias de Prática Clínica como Assunto , Qualidade da Assistência à Saúde , Padrão de Cuidado
18.
J Autism Dev Disord ; 49(6): 2447-2460, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937735

RESUMO

We examined language profiles of 2571 children, 30-68 months old, with autism spectrum disorder (ASD), other developmental disabilities (DD), and typical development from the general population (POP). Children were categorized as expressive dominant (ED), receptive dominant (RD), or nondominant (ND). Within each group, the ED profile was the least frequent. However, children in the ASD group were more likely to display an ED profile than those in the DD or POP groups, and these children were typically younger, had lower nonverbal cognitive skills, and displayed more severe social-affect symptoms of ASD compared to their peers with RD or ND profiles. These findings have research and clinical implications related to the focus of interventions targeting young children with ASD and other DDs.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/psicologia , Desenvolvimento Infantil/fisiologia , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/psicologia , Idioma , Transtorno do Espectro Autista/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Masculino
19.
Br J Oral Maxillofac Surg ; 56(7): 611-614, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30017576

RESUMO

In 2009 we evaluated the publication of research presented at annual scientific meetings of the British Association of Oral and Maxillofacial Surgeons (BAOMS) 2002-2006, inclusive. Since then, the format of these meetings has changed, there has been a rapid increase in the number of online-only journals, and restraints on time during training and consultant practice have continued. We have therefore investigated the pattern of publication after presentation at these meetings between 2010 and 2014. All abstracts accepted for oral presentations or posters were included, and publication had to follow no more than four years later. We searched PubMed for papers in peer-reviewed journals and compared the data with those from 2002-2006. A total of 975 abstracts were accepted (2010-2014) of which 221 (23%) went on to be published. The median (IQR) delay to publication was 13 (4-25) months. Most were clinical papers from groups based in the UK (p<0.001) and most were published in BJOMS (p<0.001). The rate of publication has not changed significantly between the two periods (23% compared with 24%), and patterns in the type of papers, delays, journals, and research groups, were similar. Despite consistent rates of publication within the specialty, OMFS produces fewer publications after presentation than other surgical specialties. Further research is required to evaluate this more fully.


Assuntos
Congressos como Assunto , Pesquisa em Odontologia , Editoração/estatística & dados numéricos , Cirurgia Bucal , Indexação e Redação de Resumos , Animais , Inglaterra , Humanos , Sociedades Odontológicas
20.
Health Serv Res ; 53(6): 4584-4608, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29740807

RESUMO

OBJECTIVE: To assess frequency, type, and extent of behavioral health (BH) nonquantitative treatment limits (NQTLs) before and after implementation of the Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA). DATA SOURCES: Secondary administrative data for Optum carve-out and carve-in plans. STUDY DESIGN: Cross-tabulations and "two-part" regression models were estimated to assess associations of parity period with NQTLs. DATA COLLECTION/EXTRACTION METHODS: Optum provided four proprietary BH databases, including 2008-2013 data for 40 carve-out and 385 carve-in employers from Optum's claims processing databases and 2010 data from interviews conducted by Optum's parity compliance team with 49 carve-out employers. PRINCIPAL FINDINGS: Preparity, carve-out plans required preauthorization for in-network inpatient/intermediate care; otherwise coverage was denied. Postparity, 73 percent would review later by request and half charged no penalty for late authorization. Outpatient visit authorization requirements virtually disappeared. For carve-out out-of-network inpatient/intermediate care, and for carve-ins, plans changed penalties to match medical service policies, but this did not necessarily lead to fewer requirements or lower penalties. CONCLUSION: After 2011, MHPAEA was associated with the transformation of BH care management, including much less restrictive preauthorization requirements, especially for in-network care provided by carve-out plans.


Assuntos
Planos de Assistência de Saúde para Empregados , Cobertura do Seguro , Seguro Saúde , Transtornos Mentais , Serviços de Saúde Mental , Bases de Dados Factuais , Planos de Assistência de Saúde para Empregados/economia , Planos de Assistência de Saúde para Empregados/legislação & jurisprudência , Planos de Assistência de Saúde para Empregados/estatística & dados numéricos , Gastos em Saúde , Humanos , Cobertura do Seguro/economia , Cobertura do Seguro/legislação & jurisprudência , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/economia , Seguro Saúde/legislação & jurisprudência , Seguro Saúde/estatística & dados numéricos , Programas de Assistência Gerenciada , Transtornos Mentais/economia , Transtornos Mentais/terapia , Serviços de Saúde Mental/economia , Serviços de Saúde Mental/legislação & jurisprudência , Serviços de Saúde Mental/estatística & dados numéricos , Transtornos Relacionados ao Uso de Substâncias/economia , Transtornos Relacionados ao Uso de Substâncias/terapia , Estados Unidos
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