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1.
JAMA Pediatr ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566672

RESUMO

Importance: Despite increasing access to vaccination, invasive pneumococcal disease (IPD) is responsible for approximately 826 000 deaths worldwide in children younger than 5 years each year. To allow early identification and prevention, an improved understanding of risk factors for IPD is needed. Objectives: To review the literature on the prevalence of primary immunodeficiency (PID) in children younger than 18 years presenting with IPD without another predisposing condition and to inform guidelines for immunologic evaluation after the first episode of IPD based on published evidence. Evidence Review: A literature search of PubMed, Embase (inception [1974] to February 28, 2019), and MEDLINE (inception [1946] to February 28, 2019) was conducted using the terms Streptococcus pneumonia, Streptococcus pneumoniae, pneumococcal infection, Streptococcus infection, pneumococcal meningitis, immunodeficiency, immune response, immunocompromised, susceptib*, precursor, predispose*, recurren*, newborn, neonat*, infan*, toddler, child, preschooler, adolescen*, and pediatric. Publications reporting original data on immunodeficiency in children with microbiologically confirmed primary or recurrent IPD were included. Strength of clinical data was graded according to the 5-point scale of the Oxford Centre for Evidence-Based Medicine. Findings: In 6022 unique children with primary IPD, 5 of 393 (1.3%) to 17 of 162 (10.5%) of all children and 14 of 53 (26.4%) of those older than 2 years had a PID identified. Higher rates of PID, up to 10 of 15 (66.7%), were found in children with recurrent IPD. Antibody deficiency was the most common immunodeficiency, followed by complement deficiency, asplenia, and rarer defects in T-cell signaling. The site of infection was a key indicator for the risk of underlying PID, with the greatest risk of PID in children with meningitis or complicated pneumonia. Conclusions and Relevance: Results of this study suggest that invasive pneumococcal disease, and particularly recurrent IPD, is an important marker of underlying PID in children without other risk factors. The findings also suggest that children older than 2 years with pneumococcal meningitis or complicated pneumonia and all children with recurrent IPD should be referred for an immune evaluation. Trial Registration: PROSPERO identifier: CRD42017075978.

2.
Gigascience ; 8(9)2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31531675

RESUMO

BACKGROUND: Penguins (Sphenisciformes) are a remarkable order of flightless wing-propelled diving seabirds distributed widely across the southern hemisphere. They share a volant common ancestor with Procellariiformes close to the Cretaceous-Paleogene boundary (66 million years ago) and subsequently lost the ability to fly but enhanced their diving capabilities. With ∼20 species among 6 genera, penguins range from the tropical Galápagos Islands to the oceanic temperate forests of New Zealand, the rocky coastlines of the sub-Antarctic islands, and the sea ice around Antarctica. To inhabit such diverse and extreme environments, penguins evolved many physiological and morphological adaptations. However, they are also highly sensitive to climate change. Therefore, penguins provide an exciting target system for understanding the evolutionary processes of speciation, adaptation, and demography. Genomic data are an emerging resource for addressing questions about such processes. RESULTS: Here we present a novel dataset of 19 high-coverage genomes that, together with 2 previously published genomes, encompass all extant penguin species. We also present a well-supported phylogeny to clarify the relationships among penguins. In contrast to recent studies, our results demonstrate that the genus Aptenodytes is basal and sister to all other extant penguin genera, providing intriguing new insights into the adaptation of penguins to Antarctica. As such, our dataset provides a novel resource for understanding the evolutionary history of penguins as a clade, as well as the fine-scale relationships of individual penguin lineages. Against this background, we introduce a major consortium of international scientists dedicated to studying these genomes. Moreover, we highlight emerging issues regarding ensuring legal and respectful indigenous consultation, particularly for genomic data originating from New Zealand Taonga species. CONCLUSIONS: We believe that our dataset and project will be important for understanding evolution, increasing cultural heritage and guiding the conservation of this iconic southern hemisphere species assemblage.

3.
Mol Phylogenet Evol ; 139: 106563, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323335

RESUMO

The study of systematics in wide-ranging seabirds can be challenging due to the vast geographic scales involved, as well as the possible discordance between molecular, morphological and behavioral data. In the Southern Ocean, macaroni penguins (Eudyptes chrysolophus) are distributed over a circumpolar range including populations in Antarctic and sub-Antarctic areas. Macquarie Island, in its relative isolation, is home to a closely related endemic taxon - the royal penguin (Eudyptes schlegeli), which is distinguishable from E. chrysolophus mainly by facial coloration. Although these sister taxa are widely accepted as representing distinct species based on morphological grounds, the extent of their genome-wide differentiation remains uncertain. In this study, we use genome-wide Single Nucleotide Polymorphisms to test genetic differentiation between these geographically isolated taxa and evaluate the main drivers of population structure among breeding colonies of macaroni/royal penguins. Genetic similarity observed between macaroni and royal penguins suggests they constitute a single evolutionary unit. Nevertheless, royal penguins exhibited a tendency to cluster only with macaroni individuals from Kerguelen Island, suggesting that dispersal occurs mainly between these neighboring colonies. A stepping stone model of differentiation of macaroni/royal populations was further supported by a strong pattern of isolation by distance detected across its whole distribution range, possibly driven by large geographic distances between colonies as well as natal philopatry. However, we also detected intraspecific genomic differentiation between Antarctic and sub-Antarctic populations of macaroni penguins, highlighting the role of environmental factors together with geographic distance in the processes of genetic differentiation between Antarctic and sub-Antarctic waters.

4.
Pediatr Transplant ; 23(6): e13517, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271477

RESUMO

TCR α+ ß+ /CD19+ cell depletion is an emerging technique for ex vivo graft manipulation in HSCT. We report 20 pediatric patients who underwent TCR α+ ß+ /CD19+ cell-depleted HSCT in four Australian centers. Conditioning regimen was dependent on HSCT indication, which included immunodeficiency (n = 14), Fanconi anemia (n = 3), and acute leukemia (n = 3). Donor sources were haploidentical parent (n = 17), haploidentical sibling (n = 2), or matched unrelated donor (n = 1). Mean cell dose was 8.2 × 108 /kg TNC, 12.1 × 106 /kg CD34+ cells, and 0.4 × 105 /kg TCR α+ ß+ cells. All patients achieved primary neutrophil and platelet engraftment, with average time to neutrophil engraftment 11 days (range 8-22) and platelet engraftment 24 days (range 12-69). TRM at 1 year was 15%. Rate of grade II-IV aGVHD at 1 year was 20% with no grade III-IV aGVHD seen. CMV reactivation occurred in 81% of CMV-positive recipients, with one patient developing CMV disease. Average time to CD4 recovery (>400 × 106 /L) was 258 days. Overall survival for the cohort at 5 years was 80%. This report highlights the initial experience of TCR α+ ß+ /CD19+ cell-depleted HSCT in Australian centers, with high rates of engraftment, low rates of aGVHD, and acceptable TRM.

5.
J Clin Immunol ; 39(5): 505-511, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31172381

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with primary immune deficiency (PID). Haploidentical donors have historically been associated with higher rates of graft-versus-host disease (GvHD) and graft failure. Use of T cell receptor (TCR) α+ß+/CD19+-depleted grafts has resulted in improved haploidentical HSCT outcomes. We sought to evaluate outcomes of TCR α+ß+/CD19+-depleted haploidentical HSCT in pediatric patients with PID at a single center in Australia. Specifically, we evaluated immune reconstitution, looking at time to T cell and B cell reconstitution, and B cell function post-HSCT. Eleven patients with a mean age of 7.92 years (range 0.33-17.17 years) were included. The median time to B cell recovery was 93 days (range 41-205 days), and the median time to cessation of immunoglobulin replacement was 281.5 days (range 41-205 days). All patients who had ceased immunoglobulin replacement had an adequate response to pneumococcal conjugate (Prevenar 13) vaccine. The median time to CD4+ recovery was 132 days (range 30-296 days), and naive T cells were present in all surviving patients by 4 months post-HSCT. Eight of 11 patients are surviving, with six patients having whole blood chimerism greater than 95%, one patient with whole blood chimerism of 82.8%, and another with 76.0%. All of these patients clinically had no evidence of underlying immunodeficiency. Likelihood of overall survival at 2 years post-HSCT was 81.8%. Cumulative incidence of acute GvHD was 27.3%. Cumulative incidence of CMV viremia was 63.6%. All patients previously exposed to CMV had reactivation post-HSCT, but were controlled with pre-emptive CMV treatment. Assuming most children with PID have a haploidentical donor available, use of this technique is likely to result in good outcomes for patients who do not have a suitable matched sibling or matched unrelated donor.

6.
Mol Biol Evol ; 36(8): 1671-1685, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31028398

RESUMO

Speciation through homoploid hybridization (HHS) is considered extremely rare in animals. This is mainly because the establishment of reproductive isolation as a product of hybridization is uncommon. Additionally, many traits are underpinned by polygeny and/or incomplete dominance, where the hybrid phenotype is an additive blend of parental characteristics. Phenotypically intermediate hybrids are usually at a fitness disadvantage compared with parental species and tend to vanish through backcrossing with parental population(s). It is therefore unknown whether the additive nature of hybrid traits in itself could lead successfully to HHS. Using a multi-marker genetic data set and a meta-analysis of diet and morphology, we investigated a potential case of HHS in the prions (Pachyptila spp.), seabirds distinguished by their bills, prey choice, and timing of breeding. Using approximate Bayesian computation, we show that the medium-billed Salvin's prion (Pachyptila salvini) could be a hybrid between the narrow-billed Antarctic prion (Pachyptila desolata) and broad-billed prion (Pachyptila vittata). Remarkably, P. salvini's intermediate bill width has given it a feeding advantage with respect to the other Pachyptila species, allowing it to consume a broader range of prey, potentially increasing its fitness. Available metadata showed that P. salvini is also intermediate in breeding phenology and, with no overlap in breeding times, it is effectively reproductively isolated from either parental species through allochrony. These results provide evidence for a case of HHS in nature, and show for the first time that additivity of divergent parental traits alone can lead directly to increased hybrid fitness and reproductive isolation.

7.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

8.
J Allergy Clin Immunol ; 144(1): 236-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30738173

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis. OBJECTIVE: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. METHODS: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling. RESULTS: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic. CONCLUSION: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.

9.
Glob Chang Biol ; 25(5): 1733-1745, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30706600

RESUMO

Comprehending ecological dynamics requires not only knowledge of modern communities but also detailed reconstructions of ecosystem history. Ancient DNA (aDNA) metabarcoding allows biodiversity responses to major climatic change to be explored at different spatial and temporal scales. We extracted aDNA preserved in fossil rodent middens to reconstruct late Quaternary vegetation dynamics in the hyperarid Atacama Desert. By comparing our paleo-informed millennial record with contemporary observations of interannual variations in diversity, we show local plant communities behave differentially at different timescales. In the interannual (years to decades) time frame, only annual herbaceous expand and contract their distributional ranges (emerging from persistent seed banks) in response to precipitation, whereas perennials distribution appears to be extraordinarily resilient. In contrast, at longer timescales (thousands of years) many perennial species were displaced up to 1,000 m downslope during pluvial events. Given ongoing and future natural and anthropogenically induced climate change, our results not only provide baselines for vegetation in the Atacama Desert, but also help to inform how these and other high mountain plant communities may respond to fluctuations of climate in the future.


Assuntos
Biodiversidade , Mudança Climática , Clima Desértico , Plantas , Chile , DNA Antigo/análise , Ecossistema , Fósseis , Dispersão Vegetal , Plantas/classificação , Plantas/genética , Dinâmica Populacional
10.
Mol Biol Evol ; 36(4): 784-797, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30722030

RESUMO

The emergence of islands has been linked to spectacular radiations of diverse organisms. Although penguins spend much of their lives at sea, they rely on land for nesting, and a high proportion of extant species are endemic to geologically young islands. Islands may thus have been crucial to the evolutionary diversification of penguins. We test this hypothesis using a fossil-calibrated phylogeny of mitochondrial genomes (mitogenomes) from all extant and recently extinct penguin taxa. Our temporal analysis demonstrates that numerous recent island-endemic penguin taxa diverged following the formation of their islands during the Plio-Pleistocene, including the Galápagos (Galápagos Islands), northern rockhopper (Gough Island), erect-crested (Antipodes Islands), Snares crested (Snares) and royal (Macquarie Island) penguins. Our analysis also reveals two new recently extinct island-endemic penguin taxa from New Zealand's Chatham Islands: Eudyptes warhami sp. nov. and a dwarf subspecies of the yellow-eyed penguin, Megadyptes antipodes richdalei ssp. nov. Eudyptes warhami diverged from the Antipodes Islands erect-crested penguin between 1.1 and 2.5 Ma, shortly after the emergence of the Chatham Islands (∼3 Ma). This new finding of recently evolved taxa on this young archipelago provides further evidence that the radiation of penguins over the last 5 Ma has been linked to island emergence. Mitogenomic analyses of all penguin species, and the discovery of two new extinct penguin taxa, highlight the importance of island formation in the diversification of penguins, as well as the extent to which anthropogenic extinctions have affected island-endemic taxa across the Southern Hemisphere's isolated archipelagos.


Assuntos
Especiação Genética , Genoma Mitocondrial , Ilhas , Spheniscidae/genética , Animais , Fósseis , Nova Zelândia , Filogeografia
11.
Mol Phylogenet Evol ; 131: 72-79, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30367976

RESUMO

Human impacts have substantially reduced avian biodiversity in many parts of the world, particularly on isolated islands of the Pacific Ocean. The New Zealand archipelago, including its five subantarctic island groups, holds breeding grounds for a third of the world's penguin species, including several representatives of the diverse crested penguin genus Eudyptes. While this species-rich genus has been little studied genetically, recent population estimates indicate that several Eudyptes taxa are experiencing demographic declines. Although crested penguins are currently limited to southern regions of the New Zealand archipelago, prehistoric fossil and archaeological deposits suggest a wider distribution during prehistoric times, with breeding ranges perhaps extending to the North Island. Here, we analyse ancient, historic and modern DNA sequences to explore two hypotheses regarding the recent history of Eudyptes in New Zealand, testing for (1) human-driven extinction of Eudyptes lineages; and (2) reduced genetic diversity in surviving lineages. From 83 prehistoric bone samples, each tentatively identified as 'Eudyptes spp.', we genetically identified six prehistoric penguin taxa from mainland New Zealand, including one previously undescribed genetic lineage. Moreover, our Bayesian coalescent analyses indicated that, while the range of Fiordland crested penguin (E. pachyrhynchus) may have contracted markedly over the last millennium, genetic DNA diversity within this lineage has remained relatively constant. This result contrasts with human-driven biodiversity reductions previously detected in several New Zealand coastal vertebrate taxa.

12.
J Exp Med ; 215(8): 2073-2095, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30018075

RESUMO

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

13.
Proc Natl Acad Sci U S A ; 115(30): 7771-7776, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29987016

RESUMO

New Zealand's geographic isolation, lack of native terrestrial mammals, and Gondwanan origins make it an ideal location to study evolutionary processes. However, since the archipelago was first settled by humans 750 y ago, its unique biodiversity has been under pressure, and today an estimated 49% of the terrestrial avifauna is extinct. Current efforts to conserve the remaining fauna rely on a better understanding of the composition of past ecosystems, as well as the causes and timing of past extinctions. The exact temporal and spatial dynamics of New Zealand's extinct fauna, however, can be difficult to interpret, as only a small proportion of animals are preserved as morphologically identifiable fossils. Here, we conduct a large-scale genetic survey of subfossil bone assemblages to elucidate the impact of humans on the environment in New Zealand. By genetically identifying more than 5,000 nondiagnostic bone fragments from archaeological and paleontological sites, we reconstruct a rich faunal record of 110 species of birds, fish, reptiles, amphibians, and marine mammals. We report evidence of five whale species rarely reported from New Zealand archaeological middens and characterize extinct lineages of leiopelmatid frog (Leiopelma sp.) and kakapo (Strigops habroptilus) haplotypes lost from the gene pool. Taken together, this molecular audit of New Zealand's subfossil record not only contributes to our understanding of past biodiversity and precontact Maori subsistence practices but also provides a more nuanced snapshot of anthropogenic impacts on native fauna after first human arrival.


Assuntos
Biodiversidade , Osso e Ossos , DNA/genética , Fósseis , Pool Gênico , Animais , DNA/química , DNA/isolamento & purificação , Nova Zelândia
15.
Artigo em Inglês | MEDLINE | ID: mdl-29800648

RESUMO

BACKGROUND: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown. OBJECTIVE: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies. METHODS: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV. RESULTS: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70. CONCLUSIONS: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.

18.
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