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1.
bioRxiv ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38405840

RESUMO

Histopathological heterogeneity in human pancreas has been well documented; however, functional evidence at the tissue level is scarce. Herein we investigated in situ glucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in no diabetes (ND, n=15), single islet autoantibody-positive (1AAb+, n=7), and type 1 diabetes donors (T1D, <14 months duration, n=5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features were comparable across the regions in ND. In T1D, insulin secretion and beta-cell volume were significantly reduced within all regions, while glucagon and enzymes were unaltered. Beta-cell volume was lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ were consistent across PH, PB and PT. This study supports low inter-regional variation in pancreas slice function and potentially, increased metabolic demand in 1AAb+.

2.
Commun Biol ; 7(1): 55, 2024 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-38184755

RESUMO

The aesthetic values that individuals place on visual images are formed and shaped over a lifetime. However, whether the formation of visual aesthetic value is solely influenced by environmental exposure is still a matter of debate. Here, we considered differences in aesthetic value emerging across three visual domains: abstract images, scenes, and faces. We examined variability in two major dimensions of ordinary aesthetic experiences: taste-typicality and evaluation-bias. We build on two samples from the Australian Twin Registry where 1547 and 1231 monozygotic and dizygotic twins originally rated visual images belonging to the three domains. Genetic influences explained 26% to 41% of the variance in taste-typicality and evaluation-bias. Multivariate analyses showed that genetic effects were partially shared across visual domains. Results indicate that the heritability of major dimensions of aesthetic evaluations is comparable to that of other complex social traits, albeit lower than for other complex cognitive traits. The exception was taste-typicality for abstract images, for which we found only shared and unique environmental influences. Our study reveals that diverse sources of genetic and environmental variation influence the formation of aesthetic value across distinct visual domains and provides improved metrics to assess inter-individual differences in aesthetic value.


Assuntos
Benchmarking , Exposição Ambiental , Humanos , Austrália , Estética , Individualidade
3.
J Sports Med Phys Fitness ; 64(1): 73-77, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37902807

RESUMO

BACKGROUND: Mass gatherings are a commonly occurring event, especially on college campuses. Any mass gathering gives rise to possible small- or large-scale emergencies. Mass gathering medicine is an integral part of emergency medical services (EMS). An assessment was performed to see if collegiate stadiums possess capabilities for advanced medical care when emergencies arise among attendees. METHODS: A standardized survey was sent by a single researcher to all National Collegiate Athletic Association (NCAA) Division I programs regarding medical services they currently have in place at their stadiums during Saturday football games. A follow-up inquiry was made at each local community office of emergency management (OEM) to confirm responses or obtain missing data. RESULTS: Only 21.5% (N.=17) of stadium facilities reported having physicians solely dedicated to the care of fans and other support staff. Most stadiums (N.=70, 88.6%) offered ALS services for their fans, with the remaining ALS services provided by paramedics (N.=46, 58.2%) or registered nurses (N.=7, 8.9%). The remaining stadiums only offered BLS services (N.=6, 7.6%) or basic first aid (N.=3, 3.8%). One stadium offered athletic trainer services to its fan in addition to the ALS care. CONCLUSIONS: Given the potential for a large influx of patients at sporting events, almost all stadiums have some degree of prehospital emergency care on site. More than a 10% of stadiums lacked ALS services and very few stadiums have physicians on site. Many stadiums were unaware of the resources available during these events. The ability to have ALS services on site who can provide rapid, advanced care to spectators is important due to likely delays in 911 response. At a minimum ALS services should be available within the stadium with consideration of physician coverage as well.


Assuntos
Serviços Médicos de Emergência , Futebol Americano , Instalações Esportivas e Recreacionais , Humanos , Emergências , Serviços Médicos de Emergência/organização & administração , Instalações Esportivas e Recreacionais/organização & administração
4.
F1000Res ; 12: 417, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37954063

RESUMO

Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.


Assuntos
Tumor Carcinoide , Neoplasias Intestinais , Tumores Neuroendócrinos , Humanos , Multiômica , Tumor Carcinoide/genética , Tumor Carcinoide/patologia , Tumor Carcinoide/secundário , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Ubiquitina-Proteína Ligases
5.
Nat Commun ; 14(1): 6078, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770433

RESUMO

Identification of regulators of Toxoplasma gondii bradyzoite development and cyst formation is the most direct way to address the importance of parasite development in long-term persistence and reactivation of this parasite. Here we show that a T. gondii gene (named Regulator of Cystogenesis 1; ROCY1) is sufficient for T. gondii bradyzoite formation in vitro and in vivo. ROCY1 encodes an RNA binding protein that has a preference for 3' regulatory regions of hundreds of T. gondii transcripts, and its RNA-binding domains are required to mediate bradyzoite development. Female mice infected with ΔROCY1 parasites have reduced (>90%) cyst burden. While viable parasites can be cultivated from brain tissue for up to 6 months post-infection, chronic brain-resident ΔROCY1 parasites have reduced oral infectivity compared to wild type. Despite clear defects in bradyzoite formation and oral infectivity, ΔROCY1 parasites were able to reactivate with similar timing and magnitude as wild type parasites for up to 5 months post-infection. Therefore while ROCY1 is a critical regulator of the bradyzoite developmental pathway, it is not required for parasite reactivation, raising new questions about the persisting life stage responsible for causing recrudescent disease.


Assuntos
Toxoplasma , Feminino , Animais , Camundongos , Toxoplasma/metabolismo , Redes Reguladoras de Genes , Recidiva Local de Neoplasia , Encéfalo/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo
6.
Eur Eat Disord Rev ; 31(6): 802-812, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37406031

RESUMO

OBJECTIVE: In April 2022 the Calorie Labelling (Out of Home) Regulations came into effect in England where cafés, restaurants, and takeaways with over 250 employees were required to provide calorie labelling on menus. Concerns have been raised regarding the potential negative impact this could have on individuals with eating disorders (EDs), yet this has not been explored using qualitative methodology. METHOD: Eleven participants with a current or previously diagnosed restrictive ED were interviewed in September 2022. Interpretative Phenomenological Analysis (IPA) was used to explore their experience of the introduction of calories on menus. RESULTS: Using IPA we established six themes and seven subordinate themes. These included the introduction of calories on menus as an 'attack' on individuals with EDs; the prominent visual display of calories as an attentional pull; normalising of calories counting; the impact on behaviour; and associated strategies for managing. CONCLUSION: This contributes to research surrounding the implications for public health policies on individuals with EDs, especially their ability to reinforce and amplify disordered thoughts and behaviours, and the need for greater consideration of how to minimise impact and potential harm of large public health campaigns.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos , Rotulagem de Alimentos , Humanos , Rotulagem de Alimentos/métodos , Ingestão de Energia , Comportamento Alimentar , Restaurantes
7.
Adv Mater ; 35(40): e2300812, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37357903

RESUMO

Immune therapeutics holds great promise in the treatment of type 1 diabetes (T1D). Nonetheless, their progress is hampered by limited efficacy, equipoise, or issues of safety. To address this, a novel and specific nanodelivery platform for T1D that targets high endothelial venules (HEVs) presented in the pancreatic lymph nodes (PLNs) and pancreas is developed. Data indicate that the pancreata of nonobese diabetic (NOD) mice and patients with T1D are unique in their expression of newly formed HEVs. Anti-CD3 mAb is encapsulated in poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles (NPs), the surfaces of which are conjugated with MECA79 mAb that recognizes HEVs. Targeted delivery of these NPs improves accumulation of anti-CD3 mAb in both the PLNs and pancreata of NOD mice. Treatment of hyperglycemic NOD mice with MECA79-anti-CD3-NPs results in significant reversal of T1D compared to those that are untreated, treated with empty NPs, or provided free anti-CD3. This effect is associated with a significant reduction of T effector cell populations in the PLNs and a decreased production of pro-inflammatory cytokine in the mice treated with MECA79-anti-CD3-NPs. In summary, HEV-targeted therapeutics may be used as a means by which immune therapeutics can be delivered to PLNs and pancreata to suppress autoimmune diabetes effectively.


Assuntos
Diabetes Mellitus Tipo 1 , Humanos , Camundongos , Animais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Camundongos Endogâmicos NOD , Pâncreas
8.
ACS Chem Biol ; 18(5): 1124-1135, 2023 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-37144894

RESUMO

The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and phosphorylated tau accumulation in cultured cells. Three compounds, representing divergent clogP values, were evaluated for in vivo blood-brain barrier penetration and tau reduction in an ex vivo brain slice model. AL69, the compound with the lowest clogP and the lowest membrane retention in a parallel artificial membrane permeability assay (PAMPA), reduced phosphorylated tau accumulation. Our results suggest that benzothiazole substitutions of JG-98 that increase hydrophilicity may increase the efficacy of these Hsp70 inhibitors to reduce phosphorylated tau.


Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Benzotiazóis/farmacologia , Proteínas de Choque Térmico HSP70 , Chaperonas Moleculares , Proteínas tau/metabolismo , Tauopatias/metabolismo
9.
Sci Data ; 10(1): 323, 2023 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-37237059

RESUMO

The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Doadores de Tecidos , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Genômica , Pâncreas
10.
Matern Child Health J ; 27(7): 1254-1263, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37029891

RESUMO

INTRODUCTION: Pregnancy is a time of increased vulnerability to mental health disorders. Additionally, the COVID-19 pandemic has increased the incidence of depression and anxiety. Thus, we aimed to assess mental health and associated healthy behaviors of pregnant people in California during the pandemic in order to contextualize prenatal well-being during the first pandemic of the twenty-first century. METHODS: We conducted an online cross-sectional study of 433 pregnant people from June 6 through July 29, 2020. We explored 3 hypotheses: (1) mental health would be worse during the pandemic than in general pregnant samples to date; (2) first-time pregnant people would have worse mental health; and (3) healthy behaviors would be positively related to mental health. RESULTS: Many of our participants (22%) reported clinically significant depressive symptoms and 31% reported clinically significant anxiety symptoms. Multiparous pregnant people were more likely to express worries about their own health and wellbeing and the process of childbirth than were primiparous pregnant people. Additionally, as pregnancy advanced, sleep and nutrition worsened, while physical activity increased. Lastly, anxious-depressive symptomology was significantly predictive of participant sleep behaviors, nutrition, and physical activity during the past week. DISCUSSION: Pregnant people had worse mental health during the pandemic, and this was associated with worse health-promoting behaviors. Given that the COVID-19 pandemic and associated risks are likely to persist due to low vaccination rates and the emergence of variants with high infection rates, care that promotes mental and physical well-being for the pregnant population should be a public health priority.


Assuntos
COVID-19 , Pandemias , Feminino , Gravidez , Humanos , Estudos Transversais , COVID-19/epidemiologia , Comportamentos Relacionados com a Saúde , California/epidemiologia , Ansiedade/epidemiologia , Depressão/epidemiologia
11.
Diabetes Res Clin Pract ; 196: 110228, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36549505

RESUMO

AIMS: We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS). METHODS: Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP). RESULTS: Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP. CONCLUSIONS: A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.


Assuntos
Adiponectina , Hormônio do Crescimento Humano , Humanos , Secreção de Insulina , Síndrome , Insulina , Hormônio do Crescimento Humano/metabolismo , Glucose , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Fenótipo , Fator de Crescimento Insulin-Like I/metabolismo
12.
Matern Child Nutr ; 19(1): e13446, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36218286

RESUMO

This study evaluated the collateral, or unanticipated, impacts of Smart Beginnings (SB), a two-site, tiered intervention designed to promote responsive parenting and school readiness, on breastfeeding intensity in a low-income sample. Impact analyses for the SB intervention were conducted using an intent-to-treat design leveraging a two-arm random assignment structure. Mothers assigned to the SB intervention group were more than three times more likely to give breastmilk as the only milk source at infant age 6 months than mothers assigned to the control group at one site, an effect not evident at the other study site. As development and growth are the two most salient domains of child health, understanding how interventions impact subsequent parenting practices across both domains is critical to address long-term economic and racial/ethnic disparities. Implications of the findings are discussed for improving the efficacy of interventions based on paediatric primary care.


Assuntos
Aleitamento Materno , Mães , Lactente , Feminino , Criança , Humanos , Poder Familiar , Desenvolvimento Infantil , Instituições Acadêmicas
13.
Dis Model Mech ; 16(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36579626

RESUMO

Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ∼100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.


Assuntos
Glaucoma de Ângulo Aberto , Glaucoma , Humanos , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/metabolismo , Glaucoma/genética , Glaucoma/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Mutação/genética
14.
J Am Coll Health ; 71(7): 2031-2037, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34293273

RESUMO

Objective: Despite the growing student parent population, many postsecondary institutions in the United States (U.S.) lack sufficient lactation policies for students. The objective of this study was to explore breastfeeding students' perceived awareness and use of on-campus lactation rooms and identify barriers and facilitators to expressing milk on campus.Participants:A convenience sample of breastfeeding students enrolled in colleges/universities in the U.S.Methods:Information about students' experiences expressing milk on campus was collected via an online survey. Thematic analysis was used to qualitatively analyze self-reported barriers/facilitators to expressing.Results:Ninety-three participants representing 68 unique institutions completed the survey. Barriers to expressing on campus included inadequate lactation spaces, lack of storage for breast pump equipment/expressed milk, and lack of time to express. Conversely, access to adequate lactation spaces, having appropriate breast pump equipment, and on-campus social support, were important facilitators.Conclusion:Comprehensive lactation policies may improve on-campus breastfeeding experiences among students.

15.
Eat Behav ; 46: 101660, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35933925

RESUMO

Research suggests that the COVID-19 pandemic is negatively impacting mental health, with rates of eating disorder referrals in particular rising steeply during the pandemic. This study aimed to examine 8-month changes in body image and disordered eating during the COVID-19 pandemic, and explore whether any changes were moderated by gender, age, or eating disorder history. This study used a longitudinal survey design in which 587 adults living in the UK (85 % women; mean age = 32.87 years) completed assessments every two months over five timepoints from May/June 2020 to January/February 2021. Measures included body esteem, disordered eating, and psychological distress. Mixed effect models showed small but significant improvements in body esteem and disordered eating symptoms from May/June 2020 to January/February 2021. These improvements were independent of changes in psychological distress, and did not vary by gender, age or eating disorder history. Whilst poor body image and disordered eating may have been elevated in the early period of the pandemic, this study suggests improvements, rather than worsening, of these outcomes over time. This may reflect adaptation to this changing context.


Assuntos
COVID-19 , Transtornos da Alimentação e da Ingestão de Alimentos , Adulto , Imagem Corporal/psicologia , COVID-19/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Feminino , Humanos , Masculino , Pandemias , Reino Unido/epidemiologia
16.
Front Psychol ; 13: 782033, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846638

RESUMO

When experienced in-person, engagement with art has been associated-in a growing body of evidence-with positive outcomes in wellbeing and mental health. This represents an exciting new field for psychology, curation, and health interventions, suggesting a widely-accessible, cost-effective, and non-pharmaceutical means of regulating factors such as mood or anxiety. However, can similar impacts be found with online presentations? If so, this would open up positive outcomes to an even-wider population-a trend accelerating due to the current COVID-19 pandemic. Despite its promise, this question, and the underlying mechanisms of art interventions and impacts, has largely not been explored. Participants (N = 84) were asked to engage with one of two online exhibitions from Google Arts and Culture (a Monet painting or a similarly-formatted display of Japanese culinary traditions). With just 1-2 min exposure, both improved negative mood, state-anxiety, loneliness, and wellbeing. Stepdown analysis suggested the changes can be explained primarily via negative mood, while improvements in mood correlated with aesthetic appraisals and cognitive-emotional experience of the exhibition. However, no difference was found between exhibitions. We discuss the findings in terms of applications and targets for future research.

17.
J Biol Inorg Chem ; 27(6): 553-564, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35831671

RESUMO

Myocilin is secreted from trabecular meshwork cells to an eponymous extracellular matrix that is critical for maintaining intraocular pressure. Missense mutations found in the myocilin olfactomedin domain (OLF) lead to intracellular myocilin misfolding and are causative for the heritable form of early-onset glaucoma. The OLF domain contains a unique internal, hetero-dinuclear calcium site. Here, we tested the hypothesis that calcium dysregulation causes wild-type (WT) myocilin misfolding reminiscent of that observed for disease variants. Using two cellular models expressing WT myocilin, we show that the Ca2+ ATPase channel blocker thapsigargin inhibits WT myocilin secretion. Intracellular WT myocilin is at least partly insoluble and aggregated in the endoplasmic reticulum (ER), and stains positively with an amyloid dye. By comparing the effect of thapsigargin on WT myocilin to that on a de novo secretion-competent Ca2+-free variant D478S, we discern that non-secretion of WT myocilin is due initially to calcium dysregulation, and is potentiated further by resultant ER stress. In E. coli, depletion of calcium leads to recombinant expression of misfolded isolated WT OLF but the D478S variant is still produced as a folded monomer. Treatment of cells expressing a double mutant composed of D478S and either disease variants P370L or Y437H with thapsigargin promotes its misfolding and aggregation, demonstrating the limits of D478S to correct secretion defects. Taken together, the heterodinuclear calcium site is a liability for proper folding of myocilin. Our study suggests a molecular mechanism by which WT myocilin misfolding may contribute broadly to glaucoma-associated ER stress. This study explores the effect of calcium depletion on myocilin olfactomedin domain folding.


Assuntos
Cálcio , Glaucoma , Proteínas do Citoesqueleto , Escherichia coli/metabolismo , Proteínas do Olho/química , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Glaucoma/genética , Glaucoma/metabolismo , Glicoproteínas , Humanos , Mutação , Tapsigargina/farmacologia
18.
Hum Mutat ; 43(11): 1590-1608, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35510381

RESUMO

While whole-genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA-level data fails to identify the underlying genetic etiology. Specifically, patients of non-White race and non-European ancestry are disproportionately affected by "variants of unknown/uncertain significance" (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non-neoplastic diseases.


Assuntos
Predisposição Genética para Doença , Variação Genética , Perfilação da Expressão Gênica , Testes Genéticos , Humanos , Íntrons , RNA
19.
Disaster Med Public Health Prep ; 17: e179, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35492019

RESUMO

OBJECTIVE: Researchers and public health professionals need to better understand individual engagement in coronavirus disease 2019 (COVID-19) mitigation behaviors to reduce the human and societal costs of the current pandemic and prepare for future respiratory pandemics. We suggest that developing measures of individual mitigation behaviors and testing them among high-risk individuals, including pregnant people, may help to reduce overall morbidity and mortality by quickly identifying targets for messaging around mitigation until sufficient vaccination uptake is reached. METHODS: We surveyed pregnant people in California over 2 waves of the COVID-19 pandemic to explore mitigation behaviors. We developed and validated a novel Viral Respiratory Illness Mitigation Scale (VRIMS). RESULTS: Seven measures loaded onto a single factor with good psychometric properties. The overall sample scale average was high over both waves, indicating that most pregnant Californians engaged in most of the strategies most of the time. Older participants, minoritized participants, those living in more urban contexts, and those surveyed during a surge reported engaging in these strategies most frequently. CONCLUSIONS: Clinicians and researchers should consider using reliable, validated measures like the VRIMS to identify individuals and communities that may benefit from additional education on reducing risk for COVID-19, future respiratory pandemics, or even seasonal flu.


Assuntos
COVID-19 , Gravidez , Feminino , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2 , Saúde Pública , Vacinação
20.
Vaccine ; 40(19): 2755-2760, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35361501

RESUMO

BACKGROUND: A key mitigation strategy to the COVID-19 pandemic has been the development and roll-out of vaccines. However, pregnant and lactating people were not included in initial vaccine trials and this population is hesitant to receive the vaccine, despite contrary recommendations from the American College of Obstetrics and Gynecology and the Centers for Disease Control and Prevention. Understanding the reasons behind this hesitancy is vital to promote vaccine uptake. METHODS: We surveyed pregnant people in California from December 2020 to January 2021 (n = 387) to describe cognitions and decision-making regarding COVID-19 vaccination. Using descriptive, regression-based analyses, we examined rates of planned uptake and reasoning among individuals who reported COVID-19 vaccine hesitancy. RESULTS: Overall, the pregnant Californians that we surveyed were aware of the COVID-19 vaccines. Of 387 participants, 43% reported planning to get the vaccine as soon as possible. The remaining 57% were hesitant: 27% responded that they would not receive the vaccine. Some demographic features did predict more COVID-19 vaccine hesitancy, particularly younger age (AOR = 0.95, p = 0.025) and living in a less urban context (AOR = 0.80, p = 0.041). Essential worker status also was associated with vaccine hesitancy. Having had, or intending to have, a flu vaccine was negatively associated with COVID-19 vaccine hesitancy (p < 0.001). The most commonly reported reason for COVID-19 vaccine hesitancy was "I don't know enough about the vaccine." Low levels of self-reported knowledge were highly predictive of hesitancy. CONCLUSIONS: Terms like "vaccine hesitance" and "anti-vax" do not adequately characterize decisions regarding delaying COVID-19 vaccination. Rather, these decisions are largely based on the lack of knowledge about the impacts of vaccination on pregnancy, fetal development, and later child wellbeing. This lack of knowledge should be countered by conversations between individual healthcare providers and their pregnant patients, and better inclusion of pregnant people and children in vaccine trials.


Assuntos
COVID-19 , Vacinas contra Influenza , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Criança , Estudos Transversais , Feminino , Humanos , Lactação , Pandemias , Gravidez , SARS-CoV-2 , Estados Unidos , Vacinação
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