Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 124
Filtrar
1.
iScience ; 27(5): 109720, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38706858

RESUMO

In perinatal HIV infection, early antiretroviral therapy (ART) initiation is recommended but questions remain regarding infant immune responses to HIV and its impact on immune development. Using single cell transcriptional and phenotypic analysis we evaluated the T cell compartment at pre-ART initiation of infants with perinatally acquired HIV from Maputo, Mozambique (Towards AIDS Remission Approaches cohort). CD8+ T cell maturation subsets exhibited altered distribution in HIV exposed infected (HEI) infants relative to HIV exposed uninfected infants with reduced naive, increased effectors, higher frequencies of activated T cells, and lower frequencies of cells with markers of self-renewal. Additionally, a cluster of CD8+ T cells identified in HEI displayed gene profiles consistent with cytotoxic T lymphocytes and showed evidence for hyper expansion. Longitudinal phenotypic analysis revealed accelerated maturation of CD8+ T cells was maintained in HEI despite viral control. The results point to an HIV-directed immune response that is likely to influence reservoir establishment.

2.
bioRxiv ; 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-38045254

RESUMO

With the advent of antiretroviral therapy (ART), perinatal HIV infection is declining globally but prevalence in Sub-Saharan Africa is still greater than other nations. The relationship of HIV replication in early infancy and the developing immune system is not well understood. In this study, we investigated cellular components of the innate immune system including Natural Killer (NK) cells, monocytes, and Dendritic Cells (DC) in a cohort of HIV exposed infected (HEI) and age-matched HIV exposed uninfected (HEU) infants from Mozambique. Study entry was at the first visit after delivery at age 1-2 months for HIV diagnosis and initiation of ART. Phenotypic analysis by multi-parameter flow cytometry revealed an expansion of total NK cells and the dysfunctional, CD56-CD16+, NK cell subset; increased activation in monocytes and DC; and higher levels of inflammatory homing receptor CCR5 on circulating DC subsets in the HEI infants. NKG2A, an inhibitory receptor for NK cytolytic function, was reduced in HEI compared to HEU and positively correlated with pre-ART viral load (VL) while expression of CCR2, the inflammatory homing receptor, on NK was negatively correlated with VL. Other subsets exhibited positive correlations with VL including the frequency of intermediate monocytes amongst total monocytes. Longitudinal analysis of VL indicated suboptimal ART adherence in HEI. Regardless of level of viral suppression achieved, the frequencies of specific innate immune subsets in HEI were normalized to HEU by 18m. These data support the notion that in early life, NK cells play a role in virus control and should be explored for functional attributes that are effective against HIV at this time during development. Overall, our study provides high resolution overview of the innate immune system during perinatal HIV infection.

3.
Proc Biol Sci ; 290(2007): 20231349, 2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37752842

RESUMO

Rapid global warming is severely impacting Arctic ecosystems and is predicted to transform the abundance, distribution and genetic diversity of Arctic species, though these linkages are poorly understood. We address this gap in knowledge using palaeogenomics to examine how earlier periods of global warming influenced the genetic diversity of Atlantic walrus (Odobenus rosmarus rosmarus), a species closely associated with sea ice and shallow-water habitats. We analysed 82 ancient and historical Atlantic walrus mitochondrial genomes (mitogenomes), including now-extinct populations in Iceland and the Canadian Maritimes, to reconstruct the Atlantic walrus' response to Arctic deglaciation. Our results demonstrate that the phylogeography and genetic diversity of Atlantic walrus populations was initially shaped by the last glacial maximum (LGM), surviving in distinct glacial refugia, and subsequently expanding rapidly in multiple migration waves during the late Pleistocene and early Holocene. The timing of diversification and establishment of distinct populations corresponds closely with the chronology of the glacial retreat, pointing to a strong link between walrus phylogeography and sea ice. Our results indicate that accelerated ice loss in the modern Arctic may trigger further dispersal events, likely increasing the connectivity of northern stocks while isolating more southerly stocks putatively caught in small pockets of suitable habitat.

4.
PLoS One ; 18(9): e0291032, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37747844

RESUMO

BACKGROUND: Snakebites are a neglected public health problem that pose a significant burden on affected individuals and communities in many sub-Saharan African countries, including Uganda. However, the barriers and facilitators to snakebite management within healthcare settings are not as well understood and well-documented. The aim of this study was to explore the experiences and perspectives of healthcare workers involved in handling snakebite incidents at individual and health system levels in Arua and Gulu districts in Northern Uganda. We sought to understand how healthcare workers manage snakebite cases, what challenges they encounter, and what opportunities they perceive for improvement. METHODS: We conducted a qualitative study using in-depth interviews with 18 healthcare workers from different cadres, seniority levels, and facility types. We used iterative thematic analysis to explore the management procedures, challenges, and opportunities for snakebite management. Using thematic analysis, we identified the overarching themes and subthemes related to snakebite management and associated barriers and opportunities. RESULTS: The main barriers to snakebite management identified by healthcare workers were inadequate knowledge and skills; limited availability of antivenom; lack of protocols for snakebite management; delayed treatment-seeking for patients; and poor referral systems. The main opportunities for improvement were regular in-service training; increasing public education and awareness about snakebite prevention and management; and increased funding and research. CONCLUSION: This study highlights the need for interventions to address the identified barriers while leveraging the existing opportunities to enhance snakebite management in Uganda. Specifically, we recommend the provision of regular training and support to healthcare workers, developing clinical guidelines, and improving the availability of antivenoms.


Assuntos
Acessibilidade aos Serviços de Saúde , Mordeduras de Serpentes , Humanos , Antivenenos/uso terapêutico , População Negra , Pessoal de Saúde , Mordeduras de Serpentes/epidemiologia , Mordeduras de Serpentes/terapia , Uganda/epidemiologia , Atitude do Pessoal de Saúde
5.
Acta Parasitol ; 68(4): 782-792, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37603125

RESUMO

PURPOSE: To identify and describe any new nematode species of the genus Heterakis Dujardin, 1845 (Heterakidae Railliet & Henry, 1914) found in bandicoots (Peramelidae Gray, 1825) collected from Australia and Papua New Guinea and held in the South Australian Museum, Adelaide. METHODS: All the relevant specimens registered in the South Australian Museum were examined as temporary wet mounts, after clearing in lactophenol, using an Olympus BH-2 microscope with differential interference optics. Measurements were made with an eyepiece micrometer and figures drawn using a drawing tube. RESULTS: Heterakis balamukensis n. sp. was described from Echymipera kabulu (Lesson, 1828) collected from Balamuk station, Bensbach River, Papua New Guinea and Heterakis oweni n. sp. was described from Isoodon macrourus (Gould, 1842) collected from Papua New Guinea, and Queensland, Australia. Heterakis sp. females were identified from I. macrourus from the Northern Territory and Perameles pallescens Thomas, 1923 from Queensland, Australia. A key to the valid species of Heterakis from mammals is given. CONCLUSIONS: The heterakid fauna of mammals now comprises eight species: the cosmopolitan species Heterakis spumosa Schneider, 1886 as well as H. balamukensis n. sp., H. fieldingi Smales, 1996, H. oweni n. sp. and H. sirawii Smales, 2016 from Australasia, H. dahomensis (Gendre, 1911) from Africa, and H. inglisi Gupta & Trevadi, 1982 and H. yamagutii Gupta & Trevadi, 1982 from India. Two species have been declared species inquirenda; H. equispicularis Uphadyyay, 2017 and H. verrucosa Molin, 1860, while H. rattui Ghambir, Gyaneswori, Tarnita, Indrani & Zenith, 2008 falls as a junior synonym of H. spumosa. No infections of the cosmopolitan species infecting rodent hosts, Heterakis spumosa Schneider, 1866, were found in bandicoots.


Assuntos
Ascaridídios , Nematoides , Feminino , Animais , Papua Nova Guiné , Austrália , Roedores
6.
Cell Rep ; 42(3): 112196, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36871219

RESUMO

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism and provide valuable, interactive resources for discovery and validation research.


Assuntos
Doença de Alzheimer , Microglia , Camundongos , Animais , Humanos , Microglia/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteína E4/metabolismo , Neuroglia/metabolismo , Encéfalo/metabolismo , Proteínas Amiloidogênicas/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Apolipoproteína E3/metabolismo
7.
Int J Infect Dis ; 127: 129-136, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36476348

RESUMO

BACKGROUND: The persistence of HIV-1-infected cells during antiretroviral therapy is well documented but may be modulated by early initiation of antiretroviral therapy in infants. METHODS: Here, we longitudinally analyzed the proviral landscape in nine infants with vertical HIV-1 infection from Mozambique over a median period of 24 months, using single-genome, near full-length, next-generation proviral sequencing. RESULTS: We observed a rapid decline in the frequency of intact proviruses, leading to a disproportional under-representation of intact HIV-1 sequences within the total number of HIV-1 DNA sequences after 12-24 months of therapy. In addition, proviral integration site profiling in one infant demonstrated clonal expansion of infected cells harboring intact proviruses and indicated that viral rebound was associated with an integration site profile dominated by intact proviruses integrated into genic and accessible chromatin locations. CONCLUSION: Together, these results permit rare insight into the evolution of the HIV-1 reservoir in infants infected with HIV-1 and suggest that the rapid decline of intact proviruses, relative to defective proviruses, may be attributed to a higher vulnerability of genome-intact proviruses to antiviral immunity. Technologies to analyze combinations of intact proviral sequences and corresponding integration sites permit a high-resolution analysis of HIV-1 reservoir cells after early antiretroviral treatment initiation in infants.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Lactente , HIV-1/genética , Moçambique/epidemiologia , DNA Viral/genética , Provírus/genética , Linfócitos T CD4-Positivos , Carga Viral
8.
Alzheimers Dement ; 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36479795

RESUMO

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.

10.
J Plast Reconstr Aesthet Surg ; 75(9): 3078-3084, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35931618

RESUMO

BACKGROUND: The female breast comes in many different shapes and sizes. The literature remains inconclusive on the ideal breast size. This study aims to investigate and compare breast size preferences among three cohorts (patients, plastic surgeons, and laypeople) to provide a better understanding of Western European ideals. METHODS: Patients, plastic surgeons, and laypeople were interviewed using a survey containing three-dimensional simulations of nine females, each depicted using five simulations with increasing breast size (1 = natural breast without breast implants, 2 = moderate, 3 = moderate plus, 4 = high, and 5 = ultra-high). Linear regression models were performed to define statistically significant associations between preferred breast size and predictor variables. RESULTS: In total, 28 patients, 45 plastic surgeons, and 100 laypeople (50 males and 50 females) participated in this study. On average, patients (3.5 ± 0.7) preferred larger breast sizes compared to surgeons (3.0 ± 0.7) and laypeople (3.1 ± 0.8). The difference between patients and surgeons was statistically significant. Overall, males preferred larger breast sizes than women. Patients of older age and with a higher BMI preferred larger breast sizes, while higher educational level was significantly associated with smaller breast size preference. Female plastic surgeons would undergo breast augmentation, while male plastic surgeons and female lay participants seem more skeptical. CONCLUSIONS: Significant preferential differences exist between patients and surgeons. It is important for professionals to be aware of societal ideals and preferential differences to adequately consult patients and achieve more satisfactory results.


Assuntos
Implante Mamário , Implantes de Mama , Mamoplastia , Cirurgiões , Cirurgia Plástica , Mama/cirurgia , Implante Mamário/métodos , Feminino , Humanos , Masculino , Inquéritos e Questionários
11.
PLoS One ; 17(7): e0269244, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35776718

RESUMO

A number of studies have highlighted physiological data from the first surge in critically unwell Covid-19 patients but there is a paucity of data describing emerging variants of SARS-CoV-2, such as B.1.1.7. We compared ventilatory parameters, biochemical and physiological data and mortality between the first and second COVID-19 surges in the United Kingdom, where distinct variants of SARS-CoV-2 were the dominant stain. We performed a retrospective cohort study investigating critically unwell patients admitted with COVID-19 across three tertiary regional ICUs in London, UK. Of 1782 adult ICU patients screened, 330 intubated and ventilated patients diagnosed with COVID-19 were included. In the second wave where B.1.1.7 variant was the dominant strain, patients were had increased severity of ARDS whilst compliance was greater (p<0.05) and d-dimer lower. The 28-day mortality was not statistically significant (1st wave: 42.2% vs 2nd wave: 39.8%). However, when adjusted for key covariates, the hazard ratio for 28-day mortality in those patients with B.1.1.7 was 3.79 (CI 1.04-13.8; p = 0.043) compared to the original strain. During the second surge in the UK, where the COVID-19 variant B.1.1.7 was most prevalent, significantly more patients presented to critical care with severe ARDS. Furthermore, mortality risk was significantly greater in our ICU population during the second wave of the pandemic in those patients with B.1.1.7. As ICUs are experiencing further waves (particularly by the delta (B.1.617.2) variant), we highlight the urgent need for prospective studies describing immunological and pathophysiological differences across novel emerging variants.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Adulto , Cuidados Críticos , Humanos , Estudos Prospectivos , Estudos Retrospectivos , SARS-CoV-2
12.
Acta Parasitol ; 67(3): 1230-1236, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35616830

RESUMO

PURPOSE: To confirm the identity of Longicollum edmondsi Golvan, 1969, Pomphorhynchidae Yamaguti, 1939, from Australia. METHODS: All the relevant specimens registered in Australian museums were examined. Those held as permanent slide preparations were examined directly and those stored in 70% ethanol were examined as temporary wet mounts, after clearing in lactophenol, using an Olympus BH-2 microscope with differential interference optics. Measurements were made with an eyepiece micrometer and figures drawn using a drawing tube. RESULTS: All the material registered as either Longicollum edmondsi or Paralongicollum sp. was determined to be Paralongicollum edmondsi (Golvan, 1969) comb. nov. based, amongst other characters, on the morphology of the neck. DISCUSSION: The significance of known host species of P. edmondsi and their geographical distribution around the Australian coast was analysed. The geographical distribution of the genus Paralongicollum, Amin, Bauer & Siderov, 1991, across the Indo Pacific was compared to that of the acanthocephalan genus Sclerocollum Schmidt & Paperna, 1978.


Assuntos
Acantocéfalos , Ascomicetos , Animais , Austrália , Especificidade de Hospedeiro , Microscopia
13.
Syst Parasitol ; 99(2): 241-251, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35089482

RESUMO

We report on Neoechinorhynchus aldrichettae Edmonds, 1971 (Acanthocephala: Neoechinorhynchidae), obtained from yellow-eye mullet Aldrichetta forsteri (Valenciennes) (Mugiliformes: Mugilidae) from the Huon River, Tasmania, Australia. We provide new 18S and 28S rDNA gene sequence data for N. aldrichettae, assess its phylogenetic position relative to other species of Neoechinorhynchus and provide an updated morphological account of this species including detail of features omitted in the type-description, specifically of the apical organ, a collar at the base of the neck and a para-receptacle structure associated with the proboscis receptacle. We determine that eggs in this species are ovoid, without polar prolongations of fertilisation membrane, which permits assignment of N. aldrichettae to the subgenus Neoechinorhynchus. Our phylogenetic analyses place N. (N.) aldrichettae in a clade with other species of Neoechinorhynchus which parasitise mullets in marine and estuarine waters. We find that, in terms of monophyletic clades, the current subgeneric classification system for Neoechinorhynchus is not reflected in our phylogenetic analyses.


Assuntos
Acantocéfalos , Doenças dos Peixes , Helmintíase Animal , Smegmamorpha , Animais , Austrália , Filogenia , Especificidade da Espécie , Tasmânia
15.
J Mech Behav Biomed Mater ; 126: 104984, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857491

RESUMO

Developing a shear wave tensiometer capable of non-invasively measuring ligament tension holds promise for enhancing research and clinical assessments of ligament function. Such development would benefit from tunable test specimens fabricated from well-characterized and consistent materials. Although previous work found that yarn can replicate the mechanical behavior of collateral ligaments, it is not obvious whether yarn-based phantoms would be suitable for development of a shear wave tensiometer for measuring ligament tension. Accordingly, the primary objective of this study was to characterize the mechanical properties and shear wave speed - stress relationships of ligament phantoms fabricated from yarn and silicone, and compare these results to published data from biological ligaments. We measured the mechanical properties and shear wave speeds during axial loading in nine phantoms with systematically varied material properties. We performed a simple linear regression between shear wave speed squared and axial stress to determine the shear wave speed - stress relationship for each phantom. We found comparable elastic moduli, hysteresis, and shear wave speed squared - stress regression parameters between the phantoms and collateral ligaments. For example, the ranges of the coefficients of determination (R2) and slopes across the nine phantoms were 0.84-0.95, and 0.78-1.27 kPa/m2/s2, respectively, which overlapped with the ranges found in a prior study in porcine collateral ligaments (0.84-0.996 and 0.34-1.18 kPa/m2/s2, respectively). Additionally, the shear wave speed squared - stress regression parameters varied predictably with the density of the phantom and the shear modulus of the silicone. In summary, we found that yarn-based phantoms serve as mechanical analogs for ligaments (i.e., are ligament mimicking), and thus, should prove beneficial for investigations into ligament structure-function relationships and in the development of a shear wave tensiometer for measuring ligament tension.


Assuntos
Técnicas de Imagem por Elasticidade , Ligamentos , Animais , Módulo de Elasticidade , Imagens de Fantasmas , Estresse Mecânico , Suínos , Suporte de Carga
16.
Aerosp Med Hum Perform ; 92(11): 864-872, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34819212

RESUMO

BACKGROUND: Transcutaneous measurement of carbon dioxide (CO2) has been proposed for physiological monitoring of tactical jet aircrew because in some clinical settings it mirrors arterial CO2 partial pressure (Paco2). End-tidal monitoring in laboratory settings is known to give high-fidelity estimates of Paco2.METHODS: The correspondence between end-tidal (PETco2) and transcutaneous Pco2 (tcPco2) was examined in healthy volunteers under laboratory conditions of hyperoxia and hypoxia. Rest and exercise, skin heating and cooling, hyperventilation, and induced CO2 retention were employed.RESULTS: Neither measure followed all known changes in Paco2 and tcPco2 changed when the skin temperature near the probe changed. Bland-Altman analysis showed significant nonzero slopes under most conditions. Regression analysis indicated that oxygen partial pressure (Po2) in tissue measured as transcutaneous Po2 (tcPo2) is an important explanatory variable for tcPco2 in addition to PETco2, and that local skin temperature also has an effect. Additionally, absorption atelectasis from breathing 100% O2 may cause PETco2 to deviate from Paco2.DISCUSSION: Even as a trend indicator for Paco2, tcPco2 is not useful under conditions that resemble those in the highly dynamic tactical jet aircraft environment. PETco2 is also not a good indicator of CO2 status in pilots who breathe nearly 100% O2.Shykoff BE, Lee LR, Gallo M, Griswold CA. Transcutaneous and end-tidal CO2 measurements in hypoxia and hyperoxia. Aerosp Med Hum Perform. 2021; 92(11):864-872.


Assuntos
Dióxido de Carbono , Hiperóxia , Gasometria , Humanos , Hipóxia , Respiração
17.
Aging (Albany NY) ; 13(19): 22772-22791, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635604

RESUMO

Anti-retroviral therapy (ART) improves life expectancy in people living with HIV (PWH), but it remains unclear how chronic HIV infection affects normal aging of the immune system. Plasma cell-free protein expression and immune phenotypes were assessed in blood from ART treated PWH (19-77yrs, n = 106) and age-matched, HIV-negative controls (HC, n = 103). Using univariate spearman correlation, we identified 277 and 491 age-associated parameters out of a total 1,357 in HC and PWH, respectively. PWH exhibited shared and distinct age-associated immune profiles compared to HC highlighting the effect of HIV infection on immunological aging. Our analysis resulted in an 8-parameter, plasma-detectable inflammatory index that correlated with chronological age of all study participants but was higher overall in PWH. Additionally, predictive modeling for age in HC participants and age-associated parameters generated a 25-parameter signature, IMAP-25, with 70% and 53% accuracy in HC and PWH, respectively. Applying the IMAP-25 signature to immunological data from PWH revealed accelerated aging in PWH by 5.6 yrs. Overall, our results demonstrate that immune signatures, easily monitored in human blood samples, can be used as an indicator of one's 'immunological age' during ART-treated HIV infection and can be applied to other disease states that affect the immune system.


Assuntos
Envelhecimento/imunologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adulto , Idoso , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto Jovem
18.
Mol Neurodegener ; 16(1): 62, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488832

RESUMO

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. RESULTS: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. CONCLUSIONS: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.


Assuntos
Aerobiose , Apolipoproteína E4/fisiologia , Glucose/metabolismo , Glicólise , Sintomas Prodrômicos , Adolescente , Adulto , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E4/genética , Astrócitos/metabolismo , Sequência de Bases , Química Encefálica , Células Cultivadas , Diagnóstico Precoce , Metabolismo Energético , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Técnicas de Introdução de Genes , Humanos , Metabolômica , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Oxirredução , Fosforilação Oxidativa , Consumo de Oxigênio/genética , Caracteres Sexuais , Análise de Célula Única , Adulto Jovem
19.
Front Immunol ; 12: 720697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531866

RESUMO

HIV eradication is hindered by the existence of latent HIV reservoirs in CD4+ T cells. Therapeutic strategies targeting latent cells are required to achieve a functional cure, however the study of latently infected cells from HIV infected persons is extremely challenging due to the lack of biomarkers that uniquely characterize them. In this study, the dual reporter virus HIVGKO was used to investigate latency establishment and maintenance in lymphoid-derived CD4+ T cells. Single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression were integrated to identify and analyze latently infected cells. FDA-approved, JAK1/2 inhibitors were tested in this system as a potential therapeutic strategy to target the latent reservoir. Latent and productively infected tonsillar CD4+ T cells displayed similar activation profiles as measured by expression of CD69, CD25, and HLADR, however latent cells showed higher CXCR5 expression 3 days post-infection. Single cell analysis revealed a small set of genes, including HIST1-related genes and the inflammatory cytokine, IL32, that were upregulated in latent compared to uninfected and productively infected cells suggesting a role for these molecular pathways in persistent HIV infection. In vitro treatment of HIV-infected CD4+ T cells with physiological concentrations of JAK1/2 inhibitors, ruxolitinib and baricitinib, used in clinical settings to target inflammation, reduced latent and productive infection events when added 24 hr after infection and blocked HIV reactivation from latent cells. Our methods using an established model of HIV latency and lymphoid-derived cells shed light on the biology of latency in a crucial anatomical site for HIV persistence and provides key insights about repurposing baricitinib or ruxolitinib to target the HIV reservoir.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Inibidores de Janus Quinases/farmacologia , Latência Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Perfilação da Expressão Gênica , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Imunofenotipagem , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Ativação Linfocitária/imunologia , Tonsila Palatina , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Transcriptoma , Ativação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
20.
Syst Parasitol ; 98(4): 399-412, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34050496

RESUMO

Gorgorhynchoides pseudocarangis n. sp. (Isthmosacanthidae), is described from the intestine of the white trevally Pseudocaranx dentex (Bloch & Schneider) (Carangiformes: Carangidae) collected in Moreton Bay, Queensland, Australia. The new species has a proboscis armature of 27-28 rows of 16-17 hooks. It is most similar morphologically to Gorgorhynchoides bullocki Cable & Marafachisi, 1970 and Gorgorhynchoides gnathanodontos Smales, 2014 but differs from the former in having a longer proboscis with more rows of hooks, ventral hooks 6/7-12 with notched tips and trunk spines which do not extend onto the anterior bulbous swelling, and from the latter in having a longer proboscis, ventral hooks 6/7-12 with notched tips, more circles of trunk spines, larger eggs and a proboscis armature with all hooks lacking manubria. Previous molecular phylogenetic analyses have shown that the genus Serrasentis Van Cleave, 1923 is sister to Gorgorhynchoides Cable & Linderoth, 1963, although some have failed to resolve these two lineages in separate monophyletic clades. We performed novel single-gene and concatenated phylogenetic analyses using cox1 mtDNA, 18S and 28S rDNA gene-sequences, resolving Gorgorhynchoides and Serrasentis in monophyletic sister clades and demonstrating that Gorgorhynchoides pseudocarangis n. sp. is phylogenetically distinct from related species for which molecular sequence data are available. We view the previous amendment of the Isthmosacanthidae to include the genera Golvanorhynchus Noronha, Fabio & Pinto, 1987, Gorgorhynchoides, Isthmosacanthus Smales 2014 and Serrasentis, and the transfer of the family to the Polymorphida, as the most satisfactory classification at present, although additional molecular evidence would provide greater stability.


Assuntos
Acantocéfalos/classificação , Peixes/parasitologia , Acantocéfalos/anatomia & histologia , Acantocéfalos/genética , Animais , Queensland , RNA Ribossômico 18S/genética , RNA Ribossômico 28S/genética , Especificidade da Espécie
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...