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1.
Fam Cancer ; 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38954285

RESUMO

Family-history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention and Early Detection (SPED). The online patient-facing cancer Family History Questionnaire Service (cFHQS) is a digitalised, resource efficient tool for family history data capture to facilitate this. The capturing of digital data from cFHQS allows for data interrogation of patients referred to Clinical Genetics for the purposes of service improvement. Digital data from 4,044 cFHQS respondents over a three-year period was collected and interrogated with respect to the number and type of familial tumour diagnoses to enable service improvement and streamlining of referral pathways. 81% of colorectal and 71% of breast screening assessments were population- or moderate-risk. Most patients who completed cFHQS reported more than one diagnosis of cancer/tumour/polyps in their family. 2.5% of family history assessment patients had a second indication that required assessment that would have been missed if single tumour type assessment was undertaken. Implementation of an innovative, digital family history data collection pathway has allowed large scale interrogation of referral patterns and assessment outcomes to enable service development. The high volume of inappropriate referrals to Clinical Genetics for population and moderate risk patients highlighted the need for dedicated secondary care pathway provision for these patients. The use of cFHQS streamlined family history assessment allows for redistribution of resources to improve equity and access to genetic cancer risk assessment.

2.
BJGP Open ; 7(4)2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37591554

RESUMO

BACKGROUND: Family history assessment can identify individuals above population-risk for cancer to enable targeted Screening, Prevention, and Early Detection (SPED). Family History Questionnaire Service (FHQS) is a resource-efficient patient-facing online tool to facilitate this. In the UK, cancer risk assessment is usually only offered to concerned individuals proactively self-presenting to their GP, leading to inequity in accessing SPED in the community. AIM: To improve access to community cancer genetic risk assessment and explore barriers to uptake. DESIGN & SETTING: Service development project of a digital pathway using the FHQS for cancer risk assessment across four general practices within the clinical remit of the South West Thames Centre for Genomics (SWTCG). METHOD: 3100 individuals aged 38-50 years were invited to complete the FHQS through either text message or email. A random selection of 100 non-responders were contacted to determine barriers to uptake. RESULTS: In total, n = 304/3100 (10%) registered for the FHQS. Responders were more likely to be British (63% vs 47%, P<0.001), speak English as their main language (92% vs 76%, P<0.001), and not require an interpreter (99.6% vs 94.9%, P = 0.001). Of 304 responders, 158 (52%) were automatically identified as at population-risk without full family history review. Of the remaining 146 responders, 52 (36%) required either additional screening referral (n = 23), genetics referral (n = 15), and/or advice to relatives (n = 18). Of 100 non-responders contacted, eight had incorrect contact details and 53 were contactable. Reasons for not responding included not receiving invitation details (n = 26), losing the invitation (n = 5), or forgetting (n = 4). CONCLUSION: The FHQS can be used as part of a low-resource primary care pathway to identify individuals in the community above population-risk for cancer requiring action. This study highlighted barriers to uptake requiring consideration to maximise impact and minimise inequity.

3.
Int Urogynecol J ; 34(8): 1697-1704, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36695860

RESUMO

INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are common pelvic floor disorders (PFDs). Owing to significant adverse events associated with mesh-related pelvic floor procedures (PFPs) in a proportion of the surgically treated population, and deficits in collection and reporting of these events, the Australian Government identified an urgent need for a tracking mechanism to improve safety and quality of care. The Australasian Pelvic Floor Procedure Registry (APFPR) was recently established following the 2018 Senate Committee Inquiry with the aim of tracking outcomes of PFP involving the use of devices and/or prostheses, with the objective of improving the health outcomes of women who undergo these procedures. This paper will describe the APFPR's aims, development, implementation and possible challenges on the way to its establishment. METHODS: The APFPR has been developed and implemented in accordance with the national operating principles of clinical quality registries (CQRs). The minimum datasets (MDS) for the registry's database have been developed using a modified Delphi process, and data are primarily being collected from participating surgeons. Patient recruitment is based on an opt-out approach or a waiver of consent. Patient-reported outcome measures (PROMs) providing additional health and outcome information will be obtained from participating women to support safety monitoring of mesh-related adverse events. RESULTS: Currently in the Australasian Pelvic Floor Procedure Registry (APFPR) there are 32 sites from various jurisdictions across Australia, that have obtained relevant ethics and governance approvals to start patient recruitment and data collection as of January 2023. Additionally, there are two sites that are awaiting governance review and five sites that are having documentation compiled for submission. Seventeen sites have commenced patient registration and have entered data into the database. Thus far, we have 308 patients registered in the APFPR database. The registry also published its first status report and a consumer-friendly public report in 2022. CONCLUSIONS: The registry will act as a systematic tracking mechanism by collecting outcomes on PFP, especially those involving devices and/or prostheses to improve safety and quality of care.


Assuntos
Prolapso de Órgão Pélvico , Incontinência Urinária por Estresse , Humanos , Feminino , Diafragma da Pelve/cirurgia , Austrália , Prolapso de Órgão Pélvico/complicações , Incontinência Urinária por Estresse/terapia , Sistema de Registros
4.
Nat Commun ; 13(1): 790, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145079

RESUMO

High-calorie diet-induced nutrient stress promotes thiol oxidative stress and the reprogramming of blood monocytes, giving rise to dysregulated, obesogenic, proatherogenic monocyte-derived macrophages. We report that in chow-fed, reproductively senescent female mice but not in age-matched male mice, deficiency in the thiol transferase glutaredoxin 1 (Grx1) promotes dysregulated macrophage phenotypes as well as rapid weight gain and atherogenesis. Grx1 deficiency derepresses distinct expression patterns of reactive oxygen species and reactive nitrogen species generators in male versus female macrophages, poising female but not male macrophages for increased peroxynitrate production. Hematopoietic Grx1 deficiency recapitulates this sexual dimorphism in high-calorie diet-fed LDLR-/- mice, whereas macrophage-restricted overexpression of Grx1 eliminates the sex differences unmasked by high-calorie diet-feeding and protects both males and females against atherogenesis. We conclude that loss of monocytic Grx1 activity disrupts the immunometabolic balance in mice and derepresses sexually dimorphic oxidative stress responses in macrophages. This mechanism may contribute to the sex differences reported in cardiovascular disease and obesity in humans.


Assuntos
Aterosclerose/metabolismo , Glutarredoxinas/deficiência , Glutarredoxinas/metabolismo , Monócitos/metabolismo , Obesidade/metabolismo , Substâncias Protetoras/metabolismo , Animais , Feminino , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nutrientes , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transcriptoma
5.
Clin Dysmorphol ; 31(1): 11-17, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34654017

RESUMO

DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.


Assuntos
Diabetes Mellitus Tipo 1 , Doenças Neurodegenerativas , Adolescente , Criança , Deficiências do Desenvolvimento , Proteínas de Choque Térmico HSP40/genética , Humanos , Insulina , Mutação
6.
Antioxidants (Basel) ; 10(8)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34439409

RESUMO

Ursolic acid (UA) is a well-studied natural pentacyclic triterpenoid found in herbs, fruit and a number of traditional Chinese medicinal plants. UA has a broad range of biological activities and numerous potential health benefits. In this review, we summarize the current data on the bioavailability and pharmacokinetics of UA and review the literature on the biological activities of UA and its closest analogues in the context of inflammation, metabolic diseases, including liver and kidney diseases, obesity and diabetes, cardiovascular diseases, cancer, and neurological disorders. We end with a brief overview of UA's main analogues with a special focus on a newly discovered naturally occurring analogue with intriguing biological properties and potential health benefits, 23-hydroxy ursolic acid.

7.
Am J Med Genet A ; 185(12): 3740-3753, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34331327

RESUMO

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype-phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.


Assuntos
Anormalidades Congênitas/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Antígenos de Histocompatibilidade Menor/genética , Convulsões/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Mutação de Sentido Incorreto/genética , Fenótipo , Convulsões/diagnóstico , Convulsões/patologia , Sequenciamento do Exoma
8.
Am J Hum Genet ; 108(6): 1138-1150, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33909992

RESUMO

ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.


Assuntos
Anormalidades Craniofaciais/etiologia , Heterozigoto , Deficiência Intelectual/etiologia , Transtornos do Desenvolvimento da Linguagem/etiologia , Mutação com Perda de Função , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Haploinsuficiência , Humanos , Lactente , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Linhagem , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Síndrome , Adulto Jovem
9.
J Virol ; 94(13)2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32295916

RESUMO

During the replication of parainfluenza virus 5 (PIV5), copyback defective virus genomes (DVGs) are erroneously produced and are packaged into "infectious" virus particles. Copyback DVGs are the primary inducers of innate intracellular responses, including the interferon (IFN) response. While DVGs can interfere with the replication of nondefective (ND) virus genomes and activate the IFN-induction cascade before ND PIV5 can block the production of IFN, we demonstrate that the converse is also true, i.e., high levels of ND virus can block the ability of DVGs to activate the IFN-induction cascade. By following the replication and amplification of DVGs in A549 cells that are deficient in a variety of innate intracellular antiviral responses, we show that DVGs induce an uncharacterized IFN-independent innate response(s) that limits their replication. High-throughput sequencing was used to characterize the molecular structure of copyback DVGs. While there appears to be no sequence-specific break or rejoining points for the generation of copyback DVGs, our findings suggest there are region, size, and/or structural preferences selected for during for their amplification.IMPORTANCE Copyback defective virus genomes (DVGs) are powerful inducers of innate immune responses both in vitro and in vivo They impact the outcome of natural infections, may help drive virus-host coevolution, and promote virus persistence. Due to their potent interfering and immunostimulatory properties, DVGs may also be used therapeutically as antivirals and vaccine adjuvants. However, little is known of the host cell restrictions which limit their amplification. We show here that the generation of copyback DVGs readily occurs during parainfluenza virus 5 (PIV5) replication, but that their subsequent amplification is restricted by the induction of innate intracellular responses. Molecular characterization of PIV5 copyback DVGs suggests that while there are no genome sequence-specific breaks or rejoin points for the generation of copyback DVGs, genome region, size, and structural preferences are selected for during their evolution and amplification.


Assuntos
Imunidade Inata/imunologia , Vírus da Parainfluenza 5/genética , Vírus da Parainfluenza 5/imunologia , Células A549 , Animais , Sequência de Bases/genética , Linhagem Celular , Chlorocebus aethiops , Citoplasma , Vírus Defeituosos/genética , Genoma Viral/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Interferons/genética , RNA Viral/genética , Células Vero , Vírion/genética , Viroses/genética , Replicação Viral/genética
10.
Zootaxa ; 4695(1): zootaxa.4695.1.1, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31719362

RESUMO

Caridina biyiga sp. nov. is described from Leichhardt Springs, Kakadu National Park, Northern Territory, Australia, based on morphological and molecular data. The new species is highly distinctive among its congeners in having the dactylus of pereiopod 5 similar to the dactyli of pereiopods 3-4 and lacking the comb-like row of spiniform setae typical of the genus. The branchial formula is also distinctive for the genus in lacking an arthrobranch at the base of pereiopod 1 and in having a vestigial epipod on maxilliped 1.                Despite the distinctive morphology of the new species, the molecular data did not provide strong support for the recognition of a new genus. Phylogenetic analyses of Australian Caridina using the mitochondrial 16S rDNA gene fragment placed the new species in a well-supported clade containing at least one typical species of Caridina. Within this clade, referred to as the 'thermophila' group, Kimura 2-parameter (K2P) genetic distances of 16S rDNA between the new species and sister taxa ranged from 5.1-6.0%. Analyses using the mitochondrial 3' COI gene fragment from species of the 'thermophila' group yielded K2P genetic distances between the new species and its sister taxa ranging from 10.4-15.1%.                A preliminary illustrated key to Northern Territory Caridina is provided. The conservation significance of Leichhardt Springs and its aquatic fauna are also briefly discussed.


Assuntos
Decápodes , Animais , Água Doce , Northern Territory , Parques Recreativos , Filogenia
11.
AIDS Res Ther ; 15(1): 18, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409215

RESUMO

BACKGROUND: The widespread global access to antiretroviral drugs has led to considerable reductions in morbidity and mortality but, unfortunately, the risk of virologic failure increases with the emergence, and potential transmission, of drug resistant viruses. Detecting and quantifying HIV-1 drug resistance has therefore become the standard of care when designing new antiretroviral regimens. The sensitivity of Sanger sequencing-based HIV-1 genotypic assays is limited by its inability to identify minority members of the quasispecies, i.e., it only detects variants present above ~ 20% of the viral population, thus, failing to detect minority variants below this threshold. It is clear that deep sequencing-based HIV-1 genotyping assays are an important step change towards accurately monitoring HIV-infected individuals. METHODS: We implemented and verified a clinically validated HIV-1 genotyping assay based on deep sequencing (DEEPGEN™) in two clinical laboratories in the United Kingdom: St. George's University Hospitals Healthcare NHS Foundation Trust (London) and at NHS Lothian (Edinburgh), to characterize minority HIV-1 variants in 109 plasma samples from ART-naïve or -experienced individuals. RESULTS: Although subtype B HIV-1 strains were highly prevalent (44%, 48/109), most individuals were infected with non-B subtype viruses (i.e., A1, A2, C, D, F1, G, CRF02_AG, and CRF01_AE). DEEPGEN™ was able to accurately detect drug resistance-associated mutations not identified using standard Sanger sequencing-based tests, which correlated significantly with patient's antiretroviral treatment histories. A higher proportion of minority PI-, NRTI-, and NNRTI-resistance mutations was detected in NHS Lothian patients compared to individuals from St. George's, mainly M46I/L and I50 V (associated with PIs), D67 N, K65R, L74I, M184 V/I, and K219Q (NRTIs), and L100I (NNRTIs). Interestingly, we observed an inverse correlation between intra-patient HIV-1 diversity and CD4+ T cell counts in the NHS Lothian patients. CONCLUSIONS: This is the first study evaluating the transition, training, and implementation of DEEPGEN™ between three clinical laboratories in two different countries. More importantly, we were able to characterize the HIV-1 drug resistance profile (including minority variants), coreceptor tropism, subtyping, and intra-patient viral diversity in patients from the United Kingdom, providing a rigorous foundation for basing clinical decisions on highly sensitive and cost-effective deep sequencing-based HIV-1 genotyping assays in the country.


Assuntos
Farmacorresistência Viral , Variação Genética , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , Tropismo Viral , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Genes Virais , Infecções por HIV/tratamento farmacológico , HIV-1/classificação , HIV-1/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Filogenia , Reino Unido/epidemiologia , Carga Viral
12.
Front Immunol ; 8: 958, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28878765

RESUMO

Monocytes and the recruitment of monocyte-derived macrophages into sites of inflammation play a key role in atherogenesis and other chronic inflammatory diseases linked to cardiometabolic syndrome and obesity. Previous studies from our group have shown that metabolic stress promotes monocyte priming, i.e., enhanced adhesion and accelerated chemotaxis of monocytes in response to chemokines, both in vitro and in dyslipidemic LDLR-/- mice. We also showed that metabolic stress-induced monocyte dysfunction is, at least to a large extent caused by the S-glutathionylation, inactivation, and subsequent degradation of mitogen-activated protein kinase phosphatase 1. Here, we analyzed the effects of a Western-style, dyslipidemic diet (DD), which was composed of high levels of saturated fat, cholesterol, and simple sugars, on monocyte (dys)function in non-human primates (NHPs). We found that similar to mice, a DD enhances monocyte chemotaxis in NHP within 4 weeks, occurring concordantly with the onset of hypercholesterolemia but prior to changes in triglycerides, blood glucose, monocytosis, or changes in monocyte subset composition. In addition, we identified transitory decreases in the acetylation of histone H3 at the lysine residues 18 and 23 in metabolically primed monocytes, and we found that monocyte priming was correlated with the acetylation of histone H3 at lysine 27 after an 8-week DD regimen. Our data show that metabolic stress promotes monocyte priming and hyper-chemotactic responses in NHP. The histone modifications accompanying monocyte priming in primates suggest a reprogramming of the epigenetic landscape, which may lead to dysregulated responses and functionalities in macrophages derived from primed monocytes that are recruited to sites of inflammation.

13.
Arterioscler Thromb Vasc Biol ; 37(10): 1840-1848, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28798141

RESUMO

OBJECTIVE: Despite the early promising results of 18F-fluorodeoxyglucose positron emission tomography for assessment of vessel wall inflammation, its accuracy in prospective identification of vulnerable plaques has remained limited. Additionally, previous studies have indicated that 18F-fluorodeoxyglucose uptake alone may not allow for accurate identification of specific macrophage activation states. We aimed to determine whether combined measurement of glucose and glutamine accumulation-the 2 most important bioenergetic substrates for macrophages-improves the distinction of macrophage inflammatory states and can be utilized to image atherosclerosis. APPROACH AND RESULTS: Murine peritoneal macrophages (MΦ) were activated ex vivo into proinflammatory states with either lipopolysaccharide (MΦLPS) or interferon-γ+tumor necrosis factor-α (MΦIFN-γ+TNF-α). An alternative polarization phenotype was induced with interleukin-4 (MΦIL-4). The pronounced increase in 2-deoxyglucose uptake distinguishes MΦLPS from MΦIFN-γ+TNF-α, MΦIL-4, and unstimulated macrophages (MΦ0). Despite having comparable levels of 2-deoxyglucose accumulation, MΦIL-4 can be distinguished from both MΦIFN-γ+TNF-α and MΦ0 based on the enhanced glutamine accumulation, which was associated with increased expression of a glutamine transporter, Slc1a5. Ex vivo autoradiography experiments demonstrated distinct and heterogenous patterns of 18F-fluorodeoxyglucose and 14C-glutamine accumulation in atherosclerotic lesions of low-density lipoprotein receptor-null mice fed a high-fat diet. CONCLUSIONS: Combined assessment of glutamine and 2-deoxyglucose accumulation improves the ex vivo identification of macrophage activation states. Combined ex vivo metabolic imaging demonstrates heterogenous and distinct patterns of substrate accumulation in atherosclerotic lesions. Further studies are required to define the in vivo significance of glutamine uptake in atherosclerosis and its potential application in identification of vulnerable plaques.


Assuntos
Aterosclerose/diagnóstico por imagem , Desoxiglucose/metabolismo , Fluordesoxiglucose F18 , Glutamina/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aterosclerose/metabolismo , Autorradiografia , Camundongos , Placa Aterosclerótica/metabolismo
14.
Eur J Cell Biol ; 96(2): 182-197, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28256270

RESUMO

The yeast dynamin Vps1 acts cooperatively with many proteins at diverse cellular locations for endocytosis, protein sorting, and membrane fusion and fission. It has been proposed that Vps1 is functionally linked to clathrin heavy chain 1 (Chc1), but the question of how, where, and when they function together remains unknown. Here we report that Vps1 arrives at the Golgi after clathrin, and that loss of Vps1 leads to a shift in the cellular localization of clathrin to the late endosome and vacuole, not vice versa. Our two-hybrid-based approach provides evidence that full-length Vps1 and its truncated versions bind to the C-terminal region of the Chc1. Cells lacking both Vps1 and Chc1 displayed more severe defects in carboxypeptidase Y (CPY) sorting at the Golgi than those in Vps1-deficient cells. Further, these Vps1 fragments became dominant-negative for CPY sorting upon overexpression. These results suggest that Vps1 binds to Chc1 and functions together at the Golgi for efficient Golgi-to-endosome membrane trafficking. In addition, we found that Vps1, without the aid of clathrin, plays a role in controlling the number and turnover of late Golgi.


Assuntos
Clatrina/metabolismo , Dinaminas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Complexo de Golgi/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Ligação ao GTP/genética , Homeostase , Saccharomyces cerevisiae/genética , Proteínas de Transporte Vesicular/genética
15.
Cell Biol Int ; 41(5): 484-494, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28185357

RESUMO

The dynamin-like protein, Vps1, is a GTPase involved in cargo sorting and membrane remodeling in multiple cellular trafficking pathways. Recently, Vps1 has been shown to genetically interact with ESCRT subunits. We tested the hypothesis that the functional connection of Vps1 with some of these subunits of ESCRT complexes occurs via a physical interaction. By utilizing the yeast two-hybrid system, we revealed that Vps1 physically interacts with the ESCRT-II subunits, Vps22 and Vps36, and the ESCRT-III subunit Vps24. We found that Vps1 and ESCRT-II components colocalize with Pep12, an endosomal marker. Additionally, loss of Vps1 or depletion of the GTPase activity of Vps1 results in a moderate defect in Cps1 targeting to the vacuole. Here, we discussed the potential implications of Vps1 and ESCRT interaction and their roles in the endosome-to-vacuole traffic. In summary, yeast dynamin interacts with ESCRT II and III complexes, and it functions in Cps1 trafficking toward the vacuole.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Ligação ao GTP/química , Modelos Biológicos , Mutação/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Subunidades Proteicas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Proteínas de Transporte Vesicular/química
16.
Radiology ; 283(1): 87-97, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27849433

RESUMO

Purpose To determine the divergence of immunometabolic phenotypes of macrophages stimulated with macrophage colony-stimulating factor (M-CSF) and granulocyte-M-CSF (GM-CSF) and its implications for fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging of atherosclerosis. Materials and Methods This study was approved by the animal care committee. Uptake of 2-deoxyglucose and various indexes of oxidative and glycolytic metabolism were evaluated in nonactivated murine peritoneal macrophages (MΦ0) and macrophages stimulated with M-CSF (MΦM-CSF) or GM-CSF (MΦGM-CSF). Intracellular glucose flux was measured by using stable isotope tracing of glycolytic and tricyclic acid intermediary metabolites. 18F-FDG uptake was evaluated in murine atherosclerotic aortas after stimulation with M-CSF or GM-CSF by using quantitative autoradiography. Results Despite inducing distinct activation states, GM-CSF and M-CSF stimulated progressive but similar levels of increased 2-deoxyglucose uptake in macrophages that reached up to sixfold compared with MΦ0. The expression of glucose transporters, oxidative metabolism, and mitochondrial biogenesis were induced to similar levels in MΦM-CSF and MΦGM-CSF. Unexpectedly, there was a 1.7-fold increase in extracellular acidification rate, a 1.4-fold increase in lactate production, and overexpression of several critical glycolytic enzymes in MΦM-CSF compared with MΦGM-CSF with associated increased glucose flux through glycolytic pathway. Quantitative autoradiography demonstrated a 1.6-fold induction of 18F-FDG uptake in murine atherosclerotic plaques by both M-CSF and GM-CSF. Conclusion The proinflammatory and inflammation-resolving activation states of macrophages induced by GM-CSF and M-CSF in either cell culture or atherosclerotic plaques may not be distinguishable by the assessment of glucose uptake. © RSNA, 2016 Online supplemental material is available for this article.


Assuntos
Fluordesoxiglucose F18 , Glucose/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Inflamação/diagnóstico por imagem , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Inflamação/metabolismo , Camundongos , Compostos Radiofarmacêuticos
17.
J Nanosci Nanotechnol ; 16(5): 5207-17, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27483901

RESUMO

Carbon nanomaterials (CNMs), which include carbon nanotubes (CNTs) and their derivatives, have diverse technological and biomedical applications. The potential toxicity of CNMs to cells and tissues has become an important emerging question in nanotechnology. To assess the toxicity of CNTs and fullerenol C60(OH)24, we in the present work used the budding yeast Saccharomyces cerevisiae, one of the simplest eukaryotic organisms that share fundamental aspects of eukaryotic cell biology. We found that treatment with CNMs, regardless of their physical shape, negatively affected the growth rates, end-point cell densities and doubling times of CNM-exposed yeast cells when compared to unexposed cells. To investigate potential mechanisms behind the CNMs-induced growth defects, we performed RNA-Seq dependent transcriptional analysis and constructed global gene expression profiles of fullerenol C60(OH)24- and CNT-treated cells. When compared to non-treated control cells, CNM-treated cells displayed differential expression of genes whose functions are implicated in membrane transporters and stress response, although differentially expressed genes were not consistent between CNT- and fullerenol C60(OH)24-treated groups, leading to our conclusion that CNMs could serve as environmental toxic factors to eukaryotic cells.

18.
Aust N Z J Obstet Gynaecol ; 56(4): 432-5, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27363343

RESUMO

This observational case series in 65 premenopausal women with abnormal uterine bleeding evaluated whether transvaginal ultrasound followed by saline infusion sonohysterography (SIS) prevented unnecessary hysteroscopy. Although SIS indicated that hysteroscopy was unnecessary in eight women, this benefit was offset by the invasive nature of the scan, the number of endometrial abnormalities falsely detected by SIS and the cost of the additional investigation.


Assuntos
Endossonografia/métodos , Hemorragia Uterina/diagnóstico por imagem , Útero/diagnóstico por imagem , Adulto , Endossonografia/economia , Feminino , Humanos , Histeroscopia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Cloreto de Sódio/administração & dosagem , Vagina
19.
Antioxid Redox Signal ; 25(15): 816-835, 2016 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-27288099

RESUMO

SIGNIFICANCE: Monocyte and macrophage dysfunction plays a critical role in a wide range of inflammatory disease processes, including obesity, impaired wound healing diabetic complications, and atherosclerosis. Emerging evidence suggests that the earliest events in monocyte or macrophage dysregulation include elevated reactive oxygen species production, thiol modifications, and disruption of redox-sensitive signaling pathways. This review focuses on the current state of research in thiol redox signaling in monocytes and macrophages, including (i) the molecular mechanisms by which reversible protein-S-glutathionylation occurs, (ii) the identification of bona fide S-glutathionylated proteins that occur under physiological conditions, and (iii) how disruptions of thiol redox signaling affect monocyte and macrophage functions and contribute to atherosclerosis. Recent Advances: Recent advances in redox biochemistry and biology as well as redox proteomic techniques have led to the identification of many new thiol redox-regulated proteins and pathways. In addition, major advances have been made in expanding the list of S-glutathionylated proteins and assessing the role that protein-S-glutathionylation and S-glutathionylation-regulating enzymes play in monocyte and macrophage functions, including monocyte transmigration, macrophage polarization, foam cell formation, and macrophage cell death. CRITICAL ISSUES: Protein-S-glutathionylation/deglutathionylation in monocytes and macrophages has emerged as a new and important signaling paradigm, which provides a molecular basis for the well-established relationship between metabolic disorders, oxidative stress, and cardiovascular diseases. FUTURE DIRECTIONS: The identification of specific S-glutathionylated proteins as well as the mechanisms that control this post-translational protein modification in monocytes and macrophages will facilitate the development of new preventive and therapeutic strategies to combat atherosclerosis and other metabolic diseases. Antioxid. Redox Signal. 25, 816-835.


Assuntos
Macrófagos/metabolismo , Monócitos/metabolismo , Oxirredução , Proteínas/metabolismo , Transdução de Sinais , Compostos de Sulfidrila/metabolismo , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Glutationa/metabolismo , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo , Processamento de Proteína Pós-Traducional , Espécies Reativas de Oxigênio/metabolismo
20.
N Z Med J ; 129(1434): 59-68, 2016 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-27349264

RESUMO

AIM: To evaluate the safety and effectiveness of a clinical pathway for investigation of postmenopausal bleeding (PMB), managed primarily by general practitioners. Women with an endometrial thickness (ET) ≥5mm on transvaginal ultrasound (TVUS) require either a pipelle biopsy in primary care or referral for specialist care. METHOD: Data on 241 women with PMB were reviewed retrospectively over a 5-year follow-up period. Twenty-five women were excluded as they did not satisfy PMB clinical pathway criteria. RESULTS: TVUS showed 121 women had an ET <5mm, 83 an ET ≥5mm, and 12 an endometrial polyp. In the women with ET ≥5mm, 38 had a pipelle biopsy performed in primary care, 36 were referred directly to secondary care, and 9 declined further investigations. Only 17 pipelle biopsies provided sufficient tissue, with the remaining 21 women referred to secondary care. Seven cases of endometrial cancer were identified, 4 by pipelle biopsy and 3 by hysteroscopy. Of the study cohort, 68% were managed solely by their general practitioner to the point of diagnosis, while 81% with an ET ≥5mm required management in secondary care at some stage. No further cases of endometrial cancer were identified in reviews of patient medical records and cancer registries. CONCLUSION: Community-based investigation of PMB is an alternative model of care with no evidence of additional risks to the patient. Targeted education of general practitioners on pipelle biopsies is essential to maximise the effectiveness of the pathway.


Assuntos
Endométrio/diagnóstico por imagem , Endométrio/patologia , Clínicos Gerais , Pós-Menopausa , Hemorragia Uterina/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Nova Zelândia , Estudos Retrospectivos , Ultrassonografia , Hemorragia Uterina/etiologia
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