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1.
Curr Issues Personal Psychol ; 12(1): 11-19, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756194

RESUMO

BACKGROUND: Personality traits are known factors that may influence levels of physical activity and other healthy lifestyle measures and behaviors that ultimately lead to health problems later in life. Participants And Procedure: The aim of this study was to examine the association between personality traits (HEXACO) and levels of physical activity and resting heart rate (RHR) - measured using Fitbits, BMI, and a self-reported whole-person healthy lifestyle score for N = 2580 college students. Data were collected and analyzed for students enrolled in a University Success type course from August 2017 to May 2021. The relationships between HEXACO personality traits and various physical activity and healthy lifestyle behaviors were analyzed by building several multiple regression models using R version 4.0.2. Results: In general, students who are extraverted were more physically active and students who are more open to experience had a higher RHR, even when controlling for gender. Females and males however had different profiles as to how personality influenced physical activity and other health-related measures. Male extraverts with high negative emotionality scores tend to be more physically active, whereas females tend to be more physically active when they were high in extroversion and conscientiousness, and low in openness to experience. BMI values were higher for female participants with high honesty-humility and low agreeableness and conscientiousness scores. Females also had a lower RHR for high honesty-humility and emotionality and low conscientiousness scores. CONCLUSIONS: Personality can influence levels of physical activity, RHR, and BMI. This is especially true of women. Being aware of one's personality and the relationship of personality traits to levels of physical activity and other measures of leading a healthy lifestyle can be beneficial in determining strategies to improve long-term health outcomes.

2.
Oper Dent ; 49(3): 290-299, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38632850

RESUMO

PURPOSE: This study's purpose was to evaluate the effect of simulated in vitro hydrostatic pulpal pressure (HPP) on microleakage. METHODS AND MATERIALS: Extracted third molars (n=12) were sectioned 5 mm below the cementoenamel junction, pulp tissue removed, and the sectioned crowns mounted on a Plexiglas plate penetrated by an 18-gauge stainless steel tube. The mounted specimen mesial surface received a 2×4×6 mm Class V preparation followed by restoration with a strongly acidic, one-step dental adhesive and a flowable microfilled resin, following all manufacturers' instructions. Restorations were finished to contour, and tubing was attached to a 20-cm elevated, 0.2% rhodamine G reservoir to the specimen steel tube for 48 hours. Specimens then received a nail polish coating to within 1 mm of the restoration margins and were placed in 2% methylene blue (MB) dye for 24 hours, followed by rinsing, embedding in epoxy resin, and sectioning into 1 mm slices using a diamond saw. Controls were intact molars (n=12) processed as above but without HPP. Specimen slices were evaluated using laser confocal microscopy with images exported to ImageJ software with microleakage assessed as the MB linear penetration as a percentage of the total interfacial wall length. Mean values were evaluated with the Kruskal Wallis/Dunn test at a 95% confidence level. RESULTS: The control specimens demonstrated significantly greater (p<0.0001) MB penetration than experimental specimens with simulated HPP. Under this study's conditions, simulated HPP significantly decreased MB dye penetration. CONCLUSION: Studies accomplished without simulated HPP may overestimate microleakage results.


Assuntos
Resinas Compostas , Infiltração Dentária , Polpa Dentária , Pressão Hidrostática , Humanos , Polpa Dentária/fisiologia , Resinas Compostas/química , Resinas Compostas/uso terapêutico , Microscopia Confocal , Restauração Dentária Permanente/métodos , Preparo da Cavidade Dentária/métodos , Dente Serotino , Cimentos de Resina/química
3.
Aggress Behav ; 50(1): e22120, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37942824

RESUMO

Intimate partner aggression (IPA) is a costly and incompletely understood phenomenon. Negative urgency, the tendency to act impulsively in response to negative affect, is predictive of IPA perpetration. Mindfulness, by virtue of its emphasis on nonreactivity to negative affect, is an opposing force to urgent tendencies that may mitigate the negative urgency-IPA link. Yet, no research to date investigates the interactive effects of negative urgency and mindfulness on IPA perpetration. Two studies were conducted that measured and manipulated multiple facets of mindfulness alongside measures of negative urgency and tendencies of IPA perpetration (combined N = 508 undergraduate students in monogamous intimate relationships). Counter to our preregistered predictions, we found that negative urgency's association with greater IPA perpetration increased at higher levels of mindfulness. These findings suggest that mindfulness may not be a protective factor against IPA perpetration for individuals higher in negative urgency, but rather may serve as a risk factor.


Assuntos
Violência por Parceiro Íntimo , Atenção Plena , Humanos , Agressão , Relações Interpessoais , Comportamento Sexual , Parceiros Sexuais
4.
Artigo em Inglês | MEDLINE | ID: mdl-37526802

RESUMO

As first generation (FG)/low income (LI) students enter the elite profession of medicine, schools make presumptions about how FGLI students allocate their time. However, their lives are markedly different compared to their peers. This study argues that while all forms of capital are necessary for success, time as a specific form keeps classism in place. Using constructivist grounded theory techniques, we interviewed 48 FGLI students to understand where, why and how they allocated their time, and the perceived impact it had on them. Using open coding and constant comparison, we developed an understanding of FGLI students' relationship to time and then contextualized it within larger conversations on how time is conceptualized in a capitalist system that demands time efficiency, and the activities where time is needed in medical school. When students discussed time, they invoked the concept of 'time famine;' having too much to do and not enough time. In attempting to meet medicine's expectations, they conceptualized time as something that was 'spent' or 'given/taken' as they traversed different marketplaces, using their time as a form of currency to make up for the social capital expected of them. This study shows that because medical education was designed around the social elite, a strata of individuals who have generational resources, time is a critical aspect separating FGLI students from their peers. This study undergirds the idea that time is a hidden organizational framework that helps to maintain classism, thus positioning FGLI students at a disadvantage.

5.
Genome Biol ; 24(1): 172, 2023 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-37480112

RESUMO

BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype-phenotype relationship is required to support newborn screening (NBS) and guide treatment. RESULTS: We collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient's genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population. CONCLUSIONS: These results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype-phenotype relationships and NBS.


Assuntos
Leucodistrofia Metacromática , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Fenótipo , Genótipo , Alelos , Gravidade do Paciente
6.
J Natl Med Assoc ; 114(4): 456-464, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35728993

RESUMO

OBJECTIVE: Professional identity formation (PIF) is considered a fundamental process in the development of healthcare providers. In medical education, the PIF literature has historically centered on medicine's socialization practices involving white male physicians. However, recently researchers have begun to reveal how larger socio-historical contexts influence PIF in minoritized physicians. To better understand what influences Black/African American physicians' PIF, this study compares their PIF experiences to a group of minoritized physician assistants (PAs). In comparing Black physicians' experiences to another provider, this study explored what PIF experiences may be attributed to participants' minoritized status and what might be attributed to the culture of medicine. METHODS: In this cross-case analysis, 45 minoritized PA students and practicing PAs were recruited from several Southeastern universities. The PA participants included 23 Black/African Americans, 12 Latinx, 4 Indigenous/Native, and 6 of mixed races/ethnicities. Interview data were then compared to previously collected data from 41 Black/African American medical trainees and physicians. Using constant comparative method, similarities and differences in PIF were explored. RESULTS: Similarities between the two groups included the importance of participants' racial/ethnic identity to patient care, experiences on-going microaggressions from patients and peers, and a desire to engage in racial uplift. However, one marked difference was found, namely that PAs felt they could bring their entire selves to the profession, whereas physicians described feeling splintered early in their training. CONCLUSIONS: Several possibilities that might explain why Black physicians and minoritized PAs have this one marked difference in their PIF experience, including identity threat, internalization of different discourses, and length of training for physicians. While this study was not designed to answer this question, it is clear that there is something in the culture of medicine and the training of physicians that signals to Black physicians that they cannot bring their whole selves to the profession.


Assuntos
Educação Médica , Medicina , Médicos , Humanos , Masculino , Identificação Social , Socialização
7.
Can Med Educ J ; 13(1): 96-98, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35291450

RESUMO

The Education Innovation Institute (EII) of Medical College of Georgia, Augusta University, hosted a conference on Twitter about Professional Identity Formation (PIF), #MCGConf2021PIF, on February 25, 2021. The conference featured five presentations by 15 authors from Canada and the U.S. A Twitter conference is a versatile, affordable, and accessible digital option for medical education groups interested in diversifying conference offerings and reaching a broader audience. It was low-cost, organized in six months, and garnered over 9,000 Twitter impressions. Small networks and interest groups can organize Twitter conferences for their constituencies and larger conference organizations can host online mini-conferences to supplement in-person events.


Le 25 février 2021, l'Educational Innovation Institute (EII) du Medical College of Georgia de l'Université Augusta a tenu une conférence sur la construction de l'identité professionnelle sur le réseau social Twitter (#MCGConf2021PIF). Cinq communications y ont été présentées par 15 chercheurs du Canada et des États-Unis. Elle a été organisée en six mois, à coût modeste, et elle a recueilli plus de 9000 impressions sur Twitter. La conférence Twitter s'avère être une option numérique polyvalente, abordable et accessible pour les membres du milieu de l'éducation médicale désireux de diversifier leur offre de symposiums et de toucher un public plus large. Twitter offre aux petits réseaux et groupes d'intérêt la possibilité de convier leurs membres à des conférences restreintes et aux organisateurs de conférences plus importantes la possibilité de tenir des mini-conférences en ligne pour compléter leurs activités en personne.

8.
Photodermatol Photoimmunol Photomed ; 38(5): 478-488, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35073443

RESUMO

Clothing is recognized by leading health agencies as a primary method to protect against the harmful effects of photodamage caused by ultraviolet (UV) radiation and visible light. The photoprotective capacity of clothing is commonly measured as the ultraviolet protective factor (UPF). While the technology driving photoprotective clothing has been well-established, there continues to be efforts to discover new materials to improve the UPF of clothing. Here, we show increased Google searches for photoprotective clothing over the last decade, suggesting a high level of public interest in photoprotective clothing. In addition, we investigate the frequency of UPF-graded photoprotective clothing sold by large retail stores featured in Fortune 1000. We review factors that alter the UPF of clothing and describe emerging textile technologies used to increase clothing's photoprotective capacity. Finally, we compare how photoprotective clothing is regulated among different countries, the importance of photoprotective clothing in occupational health, and research in visible light and clothing photoprotection.


Assuntos
Roupa de Proteção , Raios Ultravioleta , Humanos , Têxteis , Raios Ultravioleta/efeitos adversos
9.
Nat Commun ; 12(1): 2224, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850126

RESUMO

Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10-8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.


Assuntos
Genes , Preparações Farmacêuticas , Descoberta de Drogas , Nanismo/genética , Estudos de Associação Genética , Humanos , Peptídeo Natriurético Tipo C/genética , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor IGF Tipo 1/genética , Receptores do Fator Natriurético Atrial/genética , Proteína de Homoeobox de Baixa Estatura/genética
10.
Phys Rev E ; 102(1-1): 012401, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32795061

RESUMO

The balance between stretching and bending deformations characterizes shape transitions of thin elastic sheets. While stretching dominates the mechanical response in tension, bending dominates in compression after an abrupt buckling transition. Recently, experimental results in suspended living epithelial monolayers have shown that, due to the asymmetry in surface stresses generated by molecular motors across the thickness e of the epithelium, the free edges of such tissues spontaneously curl out-of-plane, stretching the sheet in-plane as a result. This suggests that a competition between bending and stretching sets the morphology of the tissue margin. In this paper, we use the framework of non-Euclidean plates to incorporate active pre-strain and spontaneous curvature to the theory of thin elastic shells. We show that, when the spontaneous curvature of the sheet scales like 1/e, stretching and bending energies have the same scaling in the limit of a vanishingly small thickness and therefore both compete, in a way that is continuously altered by an external tension, to define the three-dimensional shape of the tissue.


Assuntos
Fenômenos Mecânicos , Modelos Biológicos , Fenômenos Biomecânicos , Sobrevivência Celular
11.
J Immunotoxicol ; 17(1): 153-162, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32634062

RESUMO

Exposure to organic dust increases chronic airway inflammatory disorders. Effective treatment strategies are lacking. It has been reported that hog barn dust extracts (HDE) induce TNFα through protein kinase C (PKC) activation and that lung inflammation is enhanced in scavenger receptor A (SRA/CD204) knockout (KO) mice following HDE. Because interleukin (IL)-10 production can limit excessive inflammation, it was hypothesized here that HDE-induced IL-10 would require CD204 to effect inflammatory responses. C57BL/6 wild-type (WT), SRA KO, and IL-10 KO mice were intranasally challenged daily for 8 days with HDE and subsequently rested for 3 days with/without recombinant IL-10 (rIL-10) treatment. Primary peritoneal macrophages (PM) and murine alveolar macrophages (MH-S cells) were treated in vitro with HDE, SRA ligand (fucoidan), rIL-10, and/or PKC isoform inhibitors. HDE induced in vivo lung IL-10 in WT, but not SRA KO mice, and similar trends were demonstrated in isolated PM from same treated mice. Lung lymphocyte aggregates and neutrophils were elevated in in vivo HDE-treated SRA and IL-10 KO mice after a 3-d recovery, and treatment during recovery with rIL-10 abrogated these responses. In vitro rIL-10 treatment reduced HDE-stimulated TNFα release in MH-S and WT PM. In SRA KO macrophages, there was reduced IL-10 and PKC zeta (ζ) activity and increased TNFα following in vitro HDE stimulation. Similarly, blocking SRA (24 hr fucoidan pre-treatment) resulted in enhanced HDE-stimulated macrophage TNFα and decreased IL-10 and PKCζ activation. PKCζ inhibitors blocked HDE-stimulated IL-10, but not TNFα. Collectively, HDE stimulates IL-10 by an SRA- and PKCζ-dependent mechanism to regulate TNFα. Enhancing resolution of dust-mediated lung inflammation through targeting IL-10 and/or SRA may represent new approaches to therapeutic interventions.


Assuntos
Poeira/imunologia , Pulmão de Fazendeiro/imunologia , Interleucina-10/metabolismo , Lesão Pulmonar/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Administração Intranasal , Animais , Linhagem Celular , Modelos Animais de Doenças , Pulmão de Fazendeiro/tratamento farmacológico , Pulmão de Fazendeiro/patologia , Humanos , Interleucina-10/genética , Pulmão/patologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Macrófagos Alveolares , Macrófagos Peritoneais , Masculino , Camundongos , Camundongos Knockout , Polissacarídeos/administração & dosagem , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/genética
12.
Hum Mutat ; 40(9): 1519-1529, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31342580

RESUMO

The NAGLU challenge of the fourth edition of the Critical Assessment of Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict the impact of variants of unknown significance (VUS) on the enzymatic activity of the lysosomal hydrolase α-N-acetylglucosaminidase (NAGLU). Deficiencies in NAGLU activity lead to a rare, monogenic, recessive lysosomal storage disorder, Sanfilippo syndrome type B (MPS type IIIB). This challenge attracted 17 submissions from 10 groups. We observed that top models were able to predict the impact of missense mutations on enzymatic activity with Pearson's correlation coefficients of up to .61. We also observed that top methods were significantly more correlated with each other than they were with observed enzymatic activity values, which we believe speaks to the importance of sequence conservation across the different methods. Improved functional predictions on the VUS will help population-scale analysis of disease epidemiology and rare variant association analysis.


Assuntos
Acetilglucosaminidase/metabolismo , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Acetilglucosaminidase/genética , Humanos , Modelos Genéticos , Análise de Regressão
13.
Sci Rep ; 9(1): 9523, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266997

RESUMO

Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) activates numerous signal transduction pathways using its C-terminal activating regions. We reported that LMP1 increased global levels of sumoylated proteins, which aided the oncogenic nature of LMP1. Because increased protein sumoylation is detected in numerous cancers, we wanted to elucidate additional mechanisms by which LMP1 modulates the sumoylation machinery. Results indicated that SUMO-protease activity decreased in a LMP1-dependent manner, so we hypothesized that LMP1 inhibits SUMO-protease activity, resulting in reduced de-sumoylation of cellular proteins, which contributes to the detected accumulation of sumoylated proteins in EBV-positive lymphomas. Focusing on SENP2, findings revealed that LMP1 expression corresponded with increased sumoylation of SENP2 at K48 and K447 in a CTAR-dependent manner. Interestingly, independent of LMP1-induced sumoylation of SENP2, LMP1 also decreased SENP2 activity, decreased SENP2 turnover, and altered the localization of SENP2, which led us to investigate if LMP1 regulated the biology of SENP2 by a different post-translational modification, specifically ubiquitination. Data showed that expression of LMP1 inhibited the ubiquitination of SENP2, and inhibition of ubiquitination was sufficient to mimic LMP1-induced changes in SENP2 activity and trafficking. Together, these findings suggest that LMP1 modulates different post-translational modifications of SENP2 in order to modulate its biology and identify a third member of the sumoylation machinery that is manipulated by LMP1 during latent EBV infections, which can affect oncogenesis.


Assuntos
Cisteína Endopeptidases/metabolismo , Herpesvirus Humano 4/metabolismo , Proteínas da Matriz Viral/metabolismo , Linhagem Celular Tumoral , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Células HEK293 , Humanos , Linfoma/metabolismo , Linfoma/patologia , Mutagênese , Membrana Nuclear/metabolismo , Estabilidade Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sumoilação , Ubiquitinação , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas da Matriz Viral/genética
14.
Sci Rep ; 9(1): 208, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659232

RESUMO

Epstein-Barr Virus latent membrane protein-1 (LMP1) interacts with the SUMO-conjugating enzyme Ubc9, which induces protein sumoylation and may contribute to LMP1-mediated oncogenesis. After analyzing human lymphoma tissues and EBV-positive cell lines, we now document a strong correlation between LMP1 and sumo-1/2/3 or SUMO-1/2/3 levels, and show that LMP1-induced sumo expression requires the activation of NF-κB signaling through CTAR1 and CTAR2. Together, these results point to a second mechanism by which LMP1 dysregulates sumoylation processes and adds EBV-associated lymphomas to the list of malignancies associated with increased SUMO expression.


Assuntos
Proteína SUMO-1/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Proteínas da Matriz Viral/metabolismo , Linhagem Celular , Células HEK293 , Herpesvirus Humano 4/metabolismo , Humanos , Linfoma/metabolismo , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Ligação Proteica , Proteína SUMO-1/genética , Transdução de Sinais , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Sumoilação , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinas/metabolismo , Proteínas da Matriz Viral/fisiologia
15.
Med Mycol ; 57(1): 23-29, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29390156

RESUMO

In Northern Ireland there are concerns about candidaemia, with rates higher than those reported in England and Wales. Our aim was to explore the epidemiology of candidaemia during a 10 year period and the clinical management upon suspicion of cases during a one year enhanced investigation in Northern Ireland.Candidaemia reports to the Public Health Agency were validated during 2002-2011 and used to examine incidence and antifungal sensitivity trends (during 2007-2011). A clinical proforma was used to collate information for all patients with candidaemia in 2011.The majority (96%) of isolates were captured through voluntary laboratory reporting. There was a year-on-year increase in candidaemia from 2002-2011, from 80 to 131 episodes (incidence rate ratio 1.09 95% CI 1.05-1.13). Rates were highest in males under 1 year and over 75 years. 83/98 (85%) of case notes were available from candidaemia patients during 2011. The most prevalent risk factors were patients on total parenteral nutrition (26 people, 31.3%), surgery in the two months prior to the candidaemia (25 people, 30.1%), significant steroid use in the previous 3 months (24 people, 28.9%) and active neoplastic disease (23 people, 27.7%),This study confirmed an increase in candidaemia rates over time, with the observed incidence in 2011 higher than England and Wales. We identified areas for improvement around the clinical management of candidaemia. We recommend raising the awareness of guidelines for fundoscopy, echocardiography and central venous catheter removal.


Assuntos
Antifúngicos/uso terapêutico , Candidemia/tratamento farmacológico , Candidemia/epidemiologia , Antifúngicos/farmacologia , Candida/classificação , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candidemia/prevenção & controle , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Testes de Sensibilidade Microbiana/tendências , Irlanda do Norte/epidemiologia , Estudos Retrospectivos , Fatores de Risco
16.
PLoS One ; 13(7): e0200008, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29979746

RESUMO

Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested this idea on a rare, monogenic, lysosomal storage disorder, Sanfilippo Type B (Mucopolysaccharidosis type IIIB). Sanfilippo Type B is caused by mutations in the gene encoding α-N-acetylglucosaminidase (NAGLU). There were 189 NAGLU missense variants found in the ExAC dataset that comprises roughly 60,000 individual exomes. Only 24 of the 189 missense variants were known to be pathogenic; the remaining 165 variants were of unknown significance (VUS), and their potential contribution to disease is unknown. To address this problem, we measured enzymatic activities of 164 NAGLU missense VUS in the ExAC dataset and developed a statistical framework for estimating disease incidence with associated confidence intervals. We found that 25% of VUS decreased the activity of NAGLU to levels consistent with Sanfilippo Type B pathogenic alleles. We found that a substantial fraction of Sanfilippo Type B incidence (67%) could be accounted for by novel mutations not previously identified in patients, illustrating the utility of combining functional activity data for VUS with population-wide allele frequency data in estimating disease incidence.


Assuntos
Exoma/genética , Variação Genética , Mucopolissacaridose III/genética , Acetilglucosaminidase/química , Acetilglucosaminidase/genética , Acetilglucosaminidase/metabolismo , Humanos , Incidência , Modelos Moleculares , Mucopolissacaridose III/enzimologia , Mutação de Sentido Incorreto , Conformação Proteica
17.
Genome Biol ; 17(1): 184, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27604469

RESUMO

BACKGROUND: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. RESULTS: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. CONCLUSIONS: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.


Assuntos
Biologia Computacional , Proteínas/química , Software , Relação Estrutura-Atividade , Algoritmos , Bases de Dados de Proteínas , Ontologia Genética , Humanos , Anotação de Sequência Molecular , Proteínas/genética
18.
Environ Microbiol Rep ; 8(1): 45-52, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26487515

RESUMO

Hydrophilins are proteins that occur in all domains of life and protect cells and organisms against drought and other stresses. They include most of the late embryogenesis abundant (LEA) proteins and the heat shock protein (HSP) Hsp12. Here, the role of a predicted LEA-like protein (LeamA) and two Hsp12 proteins (Hsp12A and Hsp12B) of Neosartorya fischeri was studied. This filamentous fungus forms ascospores that belong to the most stress-resistant eukaryotic cells described to date. Heterologous expression of LeamA, Hsp12A and Hsp12B resulted in increased tolerance against salt and osmotic stress in Escherichia coli. These proteins were also shown to protect lactate dehydrogenase against dry heat and freeze-thaw cycles in vitro. Deletion of leamA caused diminished viability of sexual ascospores after drought and heat. This is the first report on functionality of Hsp12 and putative LeamA proteins derived from filamentous fungi, and their possible role in N. fischeri ascospore resistance against desiccation, high temperature and osmotic stress is discussed.


Assuntos
Desidratação , Proteínas Fúngicas/metabolismo , Neosartorya/fisiologia , Estresse Fisiológico , Clonagem Molecular , Secas , Escherichia coli/genética , Escherichia coli/fisiologia , Proteínas Fúngicas/genética , Deleção de Genes , Expressão Gênica , Temperatura Alta , L-Lactato Desidrogenase/análise , Viabilidade Microbiana/efeitos dos fármacos , Neosartorya/efeitos dos fármacos , Neosartorya/genética , Neosartorya/efeitos da radiação , Pressão Osmótica
19.
Int Immunopharmacol ; 27(1): 76-84, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25921030

RESUMO

Hypercapnia is known to have immunoregulatory effects within the lung. Cell culture systems demonstrate this in both macrophages and alveolar cell lines, suggesting that the alveoli are affected by changes in CO2 levels. We hypothesized that hypercapnia would also modulate human bronchial epithelial cell immune responses. Innate immune responses to Pam3CSK4 (TLR2 ligand), LPS (TLR4 ligand) and a complex innate immune stimulus, an extract from the organic dust of swine confinement barns (barn dust extract or BDE), were tested in a human bronchial epithelial cell line, BEAS-2B. Both TLR ligands showed a decrease in IL-6 and IL-8 production, and an increase in MCP-1 in response to elevated CO2 indicating an enhancement in cytokine production to hypercapnia. This change was not reflected in expression levels of TLR receptor RNA which remained unchanged in response to elevated CO2. Interestingly, barn dust showed an increase in IL-6, IL-8 and MCP-1 response at 9% CO2, suggesting that elevated CO2 exerts different effects on different stimuli. Our results show that airway epithelial cell immune responses to barn dust respond differently to hypercapnic conditions than individual TLR ligands.


Assuntos
Brônquios/patologia , Dióxido de Carbono/sangue , Hipercapnia/imunologia , Mucosa Respiratória/metabolismo , Poluição do Ar em Ambientes Fechados/efeitos adversos , Animais , Linhagem Celular , Quimiocina CCL2/metabolismo , Poeira/imunologia , Imunidade Inata , Mediadores da Inflamação/metabolismo , Interleucina-8/metabolismo , Lipopeptídeos/farmacologia , Lipopolissacarídeos/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Suínos , Receptor 2 Toll-Like/agonistas , Receptor 4 Toll-Like/agonistas
20.
Pulm Pharmacol Ther ; 31: 55-62, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25681618

RESUMO

Inhalation of agricultural occupational dusts from swine confinement facilities can result in lung inflammation. The innate immune response to organic barn dusts results in production of a number of pro-inflammatory factors in the lungs of barn workers such as cytokines, chemokines, and an influx of neutrophils. Many of these inflammatory factors are influenced by the chemokine CXCL8/IL-8 (KC or MIP-2 in mice). Previously, we have demonstrated that an endotoxin-independent component of swine barn dust extract (SBE) elevates lung chemokines in a protein kinase C (PKC)-dependent manner resulting in the significant formation of lung inflammatory cell infiltrates in a mouse model of SBE injury. In this study we test the ability of a CXCR1/CXCR2 antagonist, CXCL8(3-74)K11R/G31P (G31P) to block many of the features of lung-inflammation in response to challenge with SBE in an established mouse exposure system. Injection of G31P concurrent with SBE nasal instillation over a course of 3 weeks significantly reduced neutrophil accumulation in the lungs of barn dust exposed animals compared to those given SBE alone. There was a similar reduction in pro-inflammatory cytokines and chemokines IL-6, KC, and MIP-2 in SBE plus G31P-treated mice. In addition to excreted products, the receptors ICAM-1, CXCR1, and CXCR2, which all were elevated with SBE exposure, were also decreased with G31P treatment. SBE activation of PKCα and PKCε was reduced as well with G31P treatment. Thus, G31P was found to be highly effective at reducing several features of lung inflammation in mice exposed to barn dust extracts.


Assuntos
Quimiocinas CXC/antagonistas & inibidores , Inflamação/fisiopatologia , Interleucina-8/farmacologia , Fragmentos de Peptídeos/farmacologia , Criação de Animais Domésticos , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Poeira , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Doenças Profissionais/fisiopatologia , Proteína Quinase C/metabolismo , Suínos
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