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BACKGROUND: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. METHODS: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. RESULTS: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. CONCLUSIONS: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU.
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Fenilcetonúrias , Criança , Adolescente , Adulto Jovem , Humanos , Adulto , Consenso , Fenilcetonúrias/diagnóstico , Programas de RastreamentoRESUMO
The health of insect pollinators, particularly the honey bee, Apis mellifera (Linnaeus, 1758), is a major concern for agriculture and ecosystem health. In response to mounting evidence supporting the detrimental effects of neonicotinoid pesticides on pollinators, a novel 'bee safe' butenolide compound, flupyradifurone (FPF) has been registered for use in agricultural use. Although FPF is not a neonicotinoid, like neonicotinoids, it is an excitotoxic nicotinic acetylcholine receptor agonist. In addition, A. mellifera faces threats from pathogens, such as the microsporidian endoparasite, Nosema ceranae (Fries et al. 1996). We therefore sought 1) to increase our understanding of the potential effects of FPF on honey bees by focusing on a crucial behavior, the ability to learn and remember an odor associated with a food reward, and 2) to test for a potential synergistic effect on such learning by exposure to FPF and infection with N. ceranae. We found little evidence that FPF significantly alters learning and memory at short-term field-realistic doses. However, at high doses and at chronic, field-realistic exposure, FPF did reduce learning and memory in an olfactory conditioning task. Infection with N. ceranae also reduced learning, but there was no synergy (no significant interaction) between N. ceranae and exposure to FPF. These results suggest the importance of continued studies on the chronic effects of FPF.
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4-Butirolactona/análogos & derivados , Abelhas/efeitos dos fármacos , Agentes de Controle Biológico/efeitos adversos , Inseticidas/efeitos adversos , Nosema/química , Piridinas/efeitos adversos , Olfato/efeitos dos fármacos , 4-Butirolactona/efeitos adversos , Animais , Abelhas/fisiologia , AprendizagemRESUMO
Cys(2)-His(2) zinc finger proteins (ZFPs) are the largest family of transcription factors in higher metazoans. They also represent the most diverse family with regards to the composition of their recognition sequences. Although there are a number of ZFPs with characterized DNA-binding preferences, the specificity of the vast majority of ZFPs is unknown and cannot be directly inferred by homology due to the diversity of recognition residues present within individual fingers. Given the large number of unique zinc fingers and assemblies present across eukaryotes, a comprehensive predictive recognition model that could accurately estimate the DNA-binding specificity of any ZFP based on its amino acid sequence would have great utility. Toward this goal, we have used the DNA-binding specificities of 678 two-finger modules from both natural and artificial sources to construct a random forest-based predictive model for ZFP recognition. We find that our recognition model outperforms previously described determinant-based recognition models for ZFPs, and can successfully estimate the specificity of naturally occurring ZFPs with previously defined specificities.
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Proteínas de Ligação a DNA/metabolismo , Elementos Reguladores de Transcrição , Fatores de Transcrição/metabolismo , Dedos de Zinco , Inteligência Artificial , Sítios de Ligação , DNA/química , Proteínas de Ligação a DNA/química , Modelos Biológicos , Motivos de Nucleotídeos , Fatores de Transcrição/químicaRESUMO
BACKGROUND: Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor immunity, but its role in melanoma progression warrants further investigation. OBJECTIVE: We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. METHODS: Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. RESULTS: Primary tumors from patients who developed recurrent disease had fewer CD2(+) cells (P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence (P = .008) and overall survival (P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes (P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence (P = .0006) and overall survival (P = .0318). LIMITATIONS: Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. CONCLUSIONS: CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.
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Antígenos CD2/imunologia , Melanoma/mortalidade , Melanoma/patologia , Recidiva Local de Neoplasia/mortalidade , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia por Agulha , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/cirurgia , Análise de Sobrevida , Resultado do Tratamento , Melanoma Maligno CutâneoRESUMO
Importance: Buprenorphine is an approved medication for opioid use disorder (MOUD); however, prescribing buprenorphine is limited by a requirement to obtain a waiver to prescribe it (hereinafter, "DATA [Drug Abuse Treatment Act]-waiver") and a lack of knowledge of the best practices among clinicians. Objective: To examine how Project ECHO (Extension for Community Healthcare Outcomes) telementoring is associated with changes in DATA-waiver attainment and buprenorphine prescribing among primary care clinicians in Minnesota. Design, Setting, and Participants: In this retrospective matched-cohort study of 918 clinicians, ECHO-trained clinicians were enrolled on the date they first attended ECHO (January 3, 2018, to June 11, 2020); comparison clinicians were assigned an enrollment date from the distribution of the first ECHO sessions. The baseline period was 12 months preceding enrollment, with follow-up for 18 months or until June 30, 2020. The ECHO-trained clinicians were a population-based sample of primary care clinicians who treated Medicaid patients in Minnesota 12 months prior to the initiation of ECHO training. This analysis used propensity score matching to select comparison clinicians who were similar across demographic and clinical practice characteristics at baseline in a 2:1 ratio. Follow-up was available for 167 ECHO-trained clinicians (54.6%) and 330 comparison clinicians (53.9%) at 18 months. Exposures: ECHO-trained clinicians attended at least 1 weekly, hour-long ECHO session. Comparison clinicians never participated in any ECHO sessions. Main Outcomes and Measures: DATA-waiver attainment, any buprenorphine prescribing, and the percentage of patients with opioid use disorder (OUD) who were prescribed buprenorphine. Results: The final sample included 918 clinicians (ECHO-trained [306]; comparison [612]), of whom 620 (67.5%) practiced outside the metropolitan Twin Cities (Minneapolis-St Paul) region. The mean (SD) age of the ECHO-trained clinicians was 46.0 (12.1) years and that of the comparison clinicians was 45.7 (12.3) years. Relative to the changes among the matched comparison clinicians, the ECHO-trained clinicians were more likely to obtain a DATA-waiver (difference-in-differences, 22.7 percentage points; 95% CI, 15.5-29.9 percentage points; P < .001) and prescribe any buprenorphine (16.5 percentage points; 95% CI, 10.4-22.5 percentage points; P < .001) after 6 quarters of follow-up. ECHO-trained clinicians prescribed buprenorphine to a greater share of patients with OUD (a difference of 7.6 percentage points per month; 95% CI, 4.6-10.6 percentage points per month; P < .001), relative to that prescribed by the comparison clinicians. Conclusions and Relevance: According to the findings of this matched-cohort study, ECHO telementoring may be associated with greater prescribing of buprenorphine by primary care clinicians. These findings suggest that Project ECHO training could be a useful tool for expanding access to MOUD.
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Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Humanos , Estados Unidos , Pessoa de Meia-Idade , Buprenorfina/uso terapêutico , Tratamento de Substituição de Opiáceos , Minnesota/epidemiologia , Estudos de Coortes , Estudos Retrospectivos , Padrões de Prática Médica , Transtornos Relacionados ao Uso de Opioides/diagnóstico por imagem , Atenção Primária à SaúdeRESUMO
There are many liver diseases that could be treated with delivery of therapeutics such as DNA, proteins, or small molecules. Nanoparticles are often proposed as delivery vectors for such therapeutics; however, achieving nanoparticle accumulations in the therapeutically relevant hepatocytes is challenging. In order to address this issue, we have synthesized polymer coated, fluorescent iron oxide nanoparticles that bind and deliver DNA, as well as produce contrast for magnetic resonance imaging (MRI), fluorescence imaging, and transmission electron microscopy (TEM). The composition of the coating can be varied in a facile manner to increase the quantity of poly(ethylene glycol) (PEG) from 0% to 5%, 10%, or 25%, with the aim of reducing opsonization but maintaining DNA binding. We investigated the effect of the nanoparticle coating on DNA binding, cell uptake, cell transfection, and opsonization in vitro. Furthermore, we exploited MRI, fluorescence imaging, and TEM to investigate the distribution of the different formulations in the liver of mice. While MRI and fluorescence imaging showed that each formulation was heavily taken up in the liver at 24 h, the 10% PEG formulation was taken up by the therapeutically relevant hepatocytes more extensively than either the 0% PEG or the 5% PEG, indicating its potential for delivery of therapeutics to the liver.
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Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Fígado/citologia , Fígado/metabolismo , Nanopartículas/química , Animais , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Compostos Férricos/química , Compostos Férricos/metabolismo , Compostos Férricos/farmacocinética , Compostos Férricos/toxicidade , Células HEK293 , Meia-Vida , Humanos , Imageamento por Ressonância Magnética , Camundongos , Microscopia Eletrônica de Transmissão , Nanopartículas/toxicidade , Polietilenoglicóis/químicaRESUMO
Social vulnerability analyses have typically relied upon narratives to capture the nuances of the concept. While narratives have enhanced our understanding of the multiple drivers of vulnerability, they have had limited influence on hazards and climate adaptation policy. This is partially a function of the different needs and goals of the policy and research communities. The former prioritises generalised quantitative information, while the latter is more concerned with capturing complexity. A theoretically driven and empirically tested quantitative vulnerability and capacities index (VCI) for use at the local scale is presented to help connect vulnerability research and policy. There are four versions of the index for use in rural and urban contexts at the household and community levels. There can be an infinite number of drivers of vulnerability, but the VCI draws upon 12 indicators to represent material, institutional and attitudinal aspects of differential vulnerability and capacities.
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Clima , Redes Comunitárias , Desastres , Gestão de Riscos , Populações Vulneráveis , Humanos , Índia , Narração , Vigilância da População , População Rural , População UrbanaRESUMO
Biological collectives, like honeybee colonies, can make intelligent decisions and robustly adapt to changing conditions via intricate systems of excitatory and inhibitory signals. In this study, we explore the role of behavioural plasticity and its relationship to network size by manipulating honeybee colony exposure to an artificial inhibitory signal. As predicted, inhibition was strongest in large colonies and weakest in small colonies. This is ecologically relevant for honeybees, for which reduced inhibitory effects may increase robustness in small colonies that must maintain a minimum level of foraging and food stores. We discuss evidence for size-dependent plasticity in other types of biological networks.
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Abelhas , AnimaisRESUMO
INTRODUCTION: Once-weekly (OW) semaglutide was associated with clinically relevant improvements in glycaemic control and body weight versus comparators in the SUSTAIN randomised controlled trials (RCTs). SURE UK, which is one of a series of individual studies that comprise the SURE programme, evaluated the use of OW semaglutide in a real-world patient population with type 2 diabetes (T2D) in the UK. METHODS: In this prospective, observational study, adults (≥ 18 years) with ≥ 1 documented glycated haemoglobin (HbA1c) value ≤ 12 weeks before semaglutide initiation were enrolled. The primary endpoint was change in HbA1c from baseline to end of study (EOS; ~ 30 weeks, although due to the COVID-19 pandemic, visits up to week 52 were permitted). Secondary endpoints included change in body weight, waist circumference and patient-reported outcomes (PROs). Physicians were to report all episodes of documented or severe hypoglycaemia, fatal events, serious adverse drug reactions, pregnancies and adverse events (AEs) in foetuses/newborn infants; other AEs during the study period could be reported on a voluntary basis. RESULT: The estimated mean change in HbA1c from baseline to EOS was - 16.3 mmol/mol [95% confidence interval (CI): - 18.22, - 14.37] (- 1.5%-points [95% CI - 1.67, - 1.31]; p < 0.0001) among the 171 enrolled patients who completed the study on treatment. Mean body weight change was - 5.8 kg (95% CI - 6.75, - 4.94; p < 0.0001). Sensitivity analyses showed similar results. Improvements were also observed in other secondary endpoints, including PROs. No new safety concerns were identified with semaglutide treatment. CONCLUSION: Patients receiving OW semaglutide experienced statistically significant and clinically relevant reductions from baseline in HbA1c and body weight. These results are in line with those of the SUSTAIN RCTs and support the use of OW semaglutide in routine clinical practice in adults with T2D in the UK. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03876015.
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AIMS: We have previously found no effect of moderate-volume aerobic exercise training (approximately 3 hrs*wk(-1)) on postprandial oxidative stress. It is possible that a higher volume of exercise is needed to impact postprandial oxidative stress in young, otherwise healthy individuals. Our purpose was to compare blood triglycerides (TAGs) and oxidative stress biomarkers in 10 healthy untrained and 10 healthy highly aerobically trained (eg, >or= 40 miles running*wk(-1) or >or= 150 miles cycling*wk(-1)) men and women following ingestion of a lipid meal. METHODS: Blood samples were collected before (in a 10-hour fasted state), and 1, 2, 4, and 6 hours after ingestion of a lipid load (heavy whipping cream at 1 g*kg(-1)). Blood samples were analyzed for TAGs, malondialdehyde (MDA), hydrogen peroxide (H(2)O(2)), and nitrate/nitrite (NOx). RESULTS: No training status or interaction effects were noted for TAGs, MDA, H2O2, or NOx (P > 0.05). However, a time effect was noted for TAGs (P = 0.01), with values higher at 2 hours (67 +/- 6 mg*dL(-1)) compared with premeal (41 +/- 6 mg*dL(-1)). A time effect was also noted for H2O2 (P = 0.0001), with values higher at 2 hours (24 +/- 3 micromol*L(-1)), 4 hours (23 +/- 3 micromol*L(-1)), and 6 hours (21 +/- 3 mumol.L(-1)) compared with premeal (7 +/- 2 micromol*L(-1)). The time effect for MDA approached significance (P = 0.07), with values peaking at 4 hours post-meal (1.59 +/- 0.16 micromol*L(-1)) compared with premeal (0.99 +/- 0.15 micromol*L(-1)). CONCLUSION: These data indicate that aerobic exercise training (even when performed at a relatively high volume) does not attenuate postprandial lipemia or oxidative stress as compared with no exercise when healthy men and women consume a lipid load in the form of heavy whipping cream. Fasting TAG values may be most important in this regard. It is possible that long-term exercise may be capable of attenuating postprandial lipemia or oxidative stress in older individuals, those with chronic disease, or those with elevated fasting TAG values. Future work is needed to confirm these hypotheses.
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Gorduras na Dieta/metabolismo , Exercício Físico/fisiologia , Estresse Oxidativo/fisiologia , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aptidão Física , Adulto JovemRESUMO
BACKGROUND: Sublethal exposure to neonicotinoids, a popular class of agricultural pesticides, can lead to behavioral effects that impact the health of pollinators. Therefore, new compounds, such as flupyradifurone (FPF), have recently been developed as 'safer' alternatives. FPF is an excitotoxic nicotinic acetylcholine receptor agonist, similar to neonicotinoids. Given the novelty of FPF, what data exist are focused mostly on assessing the effect of FPF on pollinator mortality. One important avenue for investigation is the potential effect of FPF on the sensitivity of nectar foragers, such as Apis mellifera, to sucrose concentrations. Neonicotinoids can alter this sucrose responsiveness and disrupt foraging. Compounding this effect, neonicotinoid-containing solutions are preferred by A. mellifera over pure sucrose solutions. We therefore conducted four studies, administering FPF under both acute and chronic conditions, and at field-realistic and higher than field-realistic doses, to assess the influence of FPF exposure on sucrose responsiveness and sucrose solutions with FPF in A. mellifera nectar foragers. RESULTS: We found no evidence that FPF exposure under acute or chronic field-realistic conditions significantly altered sucrose responsiveness, and we did not find that bees exposed to FPF consumed more of the solution. However, at the much higher median lethal dose (48 h), among bees that survived, FPF-exposed foragers responded to significantly lower concentrations of sucrose than controls and responded at significantly higher rates to all concentrations of sucrose than controls. CONCLUSION: We found no evidence that FPF alters the sucrose responsiveness of nectar foragers at field-realistic doses during winter or early spring, but caution and further investigation are warranted, particularly on the effects of FPF in conjunction with other stressors. © 2019 Society of Chemical Industry.
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Abelhas , 4-Butirolactona/análogos & derivados , Animais , Inseticidas , Neonicotinoides , Piridinas , SacaroseRESUMO
BACKGROUND: Patient's satisfaction has been regarded as a subjective reflection of the quality of care received by patients during their hospital stay. However, which factors may influence patient satisfaction in different healthcare settings needs to be determined. METHODS: Cross-sectional investigation of satisfaction at the time of discharge in 52 consecutive patients admitted in a UK Referral Centre for Thoracic Surgery for either elective (41 patients) or acute (11 patients) procedures. We evaluated patients' satisfaction with the inpatient service through the European Organisation for the Research and Treatment of Cancer IN-PATSAT32 standardised questionnaire. Major cardiopulmonary complications were defined according to the definition of the European Society of Thoracic Surgeons database. We focused on the General Patient Satisfaction Scale of the questionnaire to explore its relationship with several demographic and clinical factors. Relationships were tested using univariate regression analyses. RESULTS: General inpatient satisfaction was lower in patients with complications rather than those without (P=0.006) and in males rather than females (P=0.04). Living area, sex, and complications explained 22% of the variation in general inpatient satisfaction (P=0.006). CONCLUSIONS: Regardless of the diagnosis, post-operative complications were associated with a lower patient satisfaction following thoracic surgery in our group of patients. This was particularly so for males and patients from rural areas. Research should focus on different clinical groups in our speciality to determine the specific strategies warranted to improve their quality of care and hence increase their satisfaction with inpatient services.
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Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by an inability to metabolize the amino acid phenylalanine (Phe). If left untreated, an accumulation of Phe results in neurodevelopmental, neurological and psychological impairments. Advancements in detection and treatment of PKU have improved outcomes and life expectancy for these patients, emphasizing the need for life-long, specialized care. Due to the paucity of adult-focused PKU clinics, patients who are well into adulthood are still being treated in pediatric centers. This retrospective study evaluates the perceived expectations, benefits and challenges of 50 adult PKU patients (mean age 31.3 ± 10.4 years) transitioning from a pediatric to adult care setting using a transition questionnaire administered at the first clinic visit at the adult PKU care center. Patients reported a lack of access to adult resources and adult-specific PKU educational material in their pediatric PKU clinic. In contrast, the established relationships with the pediatric health care team and familiarity with treatment plans were aspects of pediatric care that patients enjoyed. The results from this study will contribute to the optimization of adult PKU patient care, establishment of strategies for transitioning adults with PKU and other metabolic disorders from pediatric to adult care, and support the need to establish adult-only PKU care facilities.
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Fenilcetonúrias/terapia , Transição para Assistência do Adulto , Adulto , Feminino , Humanos , Masculino , Fenilcetonúrias/psicologia , Inquéritos e Questionários , Adulto JovemRESUMO
A 3-year study was conducted to determine if testing mosquitoes collected in modified sentinel chicken boxes for West Nile virus (WNV) or testing sentinel chickens for WNV antibody would detect WNV activity before onset of human cases in East Baton Rouge Parish, LA. In each year mosquitoes tested positive for WNV before the onset of human cases were detected, but seroconversions of sentinel chickens were detected after the human cases occurred. In 1 year we also compared the effectiveness of Centers for Disease Control and Prevention (CDC) light traps, gravid traps, and sentinel chicken box traps for collecting WNV-positive mosquitoes. Gravid traps collected more WNV-positive mosquitoes than CDC light traps or sentinel chicken box traps. However, WNV was detected earlier in mosquitoes collected from sentinel chicken box traps than in mosquitoes collected with gravid traps or CDC light traps. In total, 1,222 pools containing 19,353 mosquito specimens representing 18 species were tested for WNV. West Nile virus was detected in 59 mosquito pools from 4 species; 87% of the positive pools were detected from Culex quinquefasciatus, which was the most abundant species collected in all 3 years.
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Culicidae/virologia , Doenças das Aves Domésticas/prevenção & controle , Febre do Nilo Ocidental/veterinária , Vírus do Nilo Ocidental/isolamento & purificação , Animais , Galinhas/parasitologia , Humanos , Louisiana , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/virologia , Vigilância de Evento Sentinela , Febre do Nilo Ocidental/epidemiologia , Febre do Nilo Ocidental/prevenção & controleRESUMO
Congenital neutropenias due to mutations in ELANE, SBDS or HAX1 or in the setting of glycogen storage disease (GSD) which is caused by SLC37A4 mutation, often require prolonged granulocyte colony stimulating factor (G-CSF) therapy to prevent recurrent infections and hospital admission. There has been emerging evidence that prolonged exposure to G-CSF in cases with congenital neutropenia other than GSD is associated with transformation to myelodysplastic syndrome/acute myeloid leukemia.
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Minichromosome maintenance (MCM) proteins are essential for DNA replication in eukaryotes. A subcomplex of the MCM2-7 family members, initially characterized in yeast, is thought to serve as a eukaryotic DNA replicative helicase. MCM8 is a new family member, not present in yeast, which may function alone or with other family members in aspects of DNA metabolism, including replication initiation and elongation. Through the use of chromatin immunoprecipitation, we find that MCM8, like MCM7, colocalizes on a specific DNA segment of the c-MYC replication initiation zone (c-MYC replicator) with Cdc6, a protein potentially involved in loading MCM proteins onto DNA. The association between MCM8 and MCM7 peaks in mid G1, at the time of assembly of the prereplication complex. The association of both MCM proteins with Cdc6, however, continues even after DNA replication is complete. We also find that MCM8 colocalizes at the c-MYC replicator with chromatin-bound Cdk2. Our data indicate that any role MCM8 may play in elongation is likely to be discontinuous, in its association with DNA, from a potential role in initiation. Using immunogold electron microscopy we show that MCM8 and MCM7 differ in spatial relation to RPA70 during S phase. Our data strongly suggest that MCM8 functions with other known replication proteins in processes which accompany DNA replication, especially initiation, and which are specifically adapted to suit higher eukaryotes.
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Proteínas de Ciclo Celular/metabolismo , Imunoprecipitação da Cromatina/métodos , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Células HeLa , Humanos , Imuno-Histoquímica , Microscopia Eletrônica , Componente 7 do Complexo de Manutenção de Minicromossomo , Proteínas de Manutenção de Minicromossomo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína de Replicação A/metabolismoRESUMO
Filtering of redundant or stable inputs is a critical function of all sensory pathways. Normal sensory gating can allow processing resources to be differentially devoted to changing or otherwise biologically significant stimuli. In olfaction, short-term odor habituation is mediated by a metabotropic glutamate receptor (mGluR)-mediated depression of afferent synapses in the piriform cortex. Given the role of early experience in shaping cortical function and anatomy, the present experiments examined the effects of chronic habituation disruption during development on behavior and local circuit anatomy. Rats were chronically intra-cerebrally infused with the mGluR group III antagonist (RS)-a-cyclopropyl-4-phosphonophenylglycine (CPPG) during early development. The results demonstrated that early onset mGluRIII blockade resulted in a long-lasting decrement in odor habituation compared to controls, evident for at least 2 weeks post-infusion offset. Odor investigation time in the youngest animals was correlated with cortical laminar thickness, though the long-lasting behavioral effect showed no such correlation. No changes in apical dendritic spine density in the piriform cortex were detected. Combined with previous work, these results suggest that sensory gating disruption during development can have both immediate and long-lasting effects on sensory-guided behavior.
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Adaptação Fisiológica/fisiologia , Comportamento Animal/fisiologia , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/crescimento & desenvolvimento , Habituação Psicofisiológica/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Fatores Etários , Animais , Córtex Cerebral/efeitos dos fármacos , Espinhas Dendríticas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Habituação Psicofisiológica/efeitos dos fármacos , Masculino , Odorantes , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/ultraestrutura , Percepção Olfatória/efeitos dos fármacos , Percepção Olfatória/fisiologia , Ratos , Ratos Long-Evans , Coloração pela Prata/métodos , Fatores de TempoRESUMO
While foraging, animals can form inter- and intraspecific social signalling networks to avoid similar predators. We report here that foragers of different native Asian honey bee species can detect and use a specialized alarm pheromone component, benzyl acetate (BA), to avoid danger. We analysed the volatile alarm pheromone produced by attacked workers of the most abundant native Asian honey bee, Apis cerana and tested the responses of other bee species to these alarm signals. As compared to nest guards, A. cerana foragers produced 3.38 fold higher levels of BA. In foragers, BA and (E)-dec-2-en-1-yl acetate (DA) generated the strongest antennal electrophysiological responses. BA was also the only compound that alerted flying foragers and inhibited A. cerana foraging. BA thereby decreased A. cerana foraging for risky sites. Interestingly, although BA occurs only in trace amounts and is nearly absent in sympatric honeybee species (respectively only 0.07% and 0.44% as much in A. dorsata and A. florea), these floral generalists detected and avoided BA as strongly as they did to their own alarm pheromone on natural inflorescences. These results demonstrate that competing pollinators can take advantage of alarm signal information provided by other species.
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Abelhas/fisiologia , Compostos de Benzil/metabolismo , Comportamento Competitivo/fisiologia , Comportamento Alimentar/fisiologia , Feromônios/biossíntese , Animais , Abelhas/classificação , Compostos de Benzil/análise , Reação de Fuga/fisiologia , Flores/fisiologia , Feromônios/análise , Polinização/fisiologia , SimpatriaRESUMO
Rats with juvenile play experience display a greater ability in coordinating their movements with social partners than those deprived of such experience, and this may be due to the play-induced neural restructuring of the medial prefrontal cortex (mPFC). The present study investigates the role of the mPFC in interanimal coordination. Rats with and without bilateral mPFC lesions were tested on a robbing-and-dodging task. This food protection task measures the ability of rats to protect pieces of food by gaining and maintaining an interanimal distance between themselves and the rat attempting to rob the food. Given that mPFC lesions have been associated with sensory and motor deficits, the same rats were also subjected to a task to measure skilled motor movements. Rats with bilateral mPFC lesions had more food stolen and displayed an inability to maintain interanimal distance with partner, but did not exhibit any motor or sensory deficits. These findings suggest that the mPFC is involved in interanimal coordination and that the play-induced neural restructuring of this area may account for the enhanced coordination seen in rats with prior play experience.
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Comportamento Competitivo/fisiologia , Córtex Pré-Frontal/fisiologia , Desempenho Psicomotor/fisiologia , Análise de Variância , Animais , Alimentos , Masculino , Córtex Pré-Frontal/lesões , Ratos Long-EvansRESUMO
A patient tells you she's "starting to worry" that getting pregnant won't be as easy as she'd hoped. Before you provide a referral, look for clues in the couple's histories.