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1.
Nutrients ; 13(8)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445051

RESUMO

Intrauterine growth restriction (IUGR) is associated with reduced placental amino acid transport (AAT). However, it remains to be established if changes in AAT contribute to restricted fetal growth. We hypothesized that reduced in vivo placental AAT precedes the development of IUGR in baboons with maternal nutrient restriction (MNR). Baboons were fed either a control (ad libitum) or MNR diet (70% of control diet) from gestational day (GD) 30. At GD 140, in vivo transplacental AA transport was measured by infusing nine (13)C- or (2)H-labeled essential amino acids (EAAs) as a bolus into the maternal circulation at cesarean section. A fetal vein-to-maternal artery mole percent excess ratio for each EAA was measured. Microvillous plasma membrane (MVM) system A and system L transport activity were determined. Fetal and placental weights were not significantly different between MNR and control. In vivo, the fetal vein-to-maternal artery mole percent excess ratio was significantly decreased for tryptophan in MNR. MVM system A and system L activity was markedly reduced in MNR. Reduction of in vivo placental amino acid transport precedes fetal growth restriction in the non-human primate, suggesting that reduced placental amino acid transfer may contribute to IUGR.


Assuntos
Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Dieta com Restrição de Proteínas , Retardo do Crescimento Fetal/etiologia , Troca Materno-Fetal , Placenta/metabolismo , Animais , Transporte Biológico , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/fisiopatologia , Idade Gestacional , Fenômenos Fisiológicos da Nutrição Materna , Papio , Gravidez
2.
FASEB J ; 35(9): e21788, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34425031

RESUMO

Hypoxia increases fetal hepatic insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR-mediated IGFBP-1 hyperphosphorylation in response to hypoxia requires hypoxia-inducible factor-1α (HIF-1α) and regulated in development and DNA-damage responses-1 (REDD-1) signaling. Western blotting (n = 6) and immunohistochemistry (n = 3) using fetal liver indicated greater expression of HIF-1α, REDD-1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO2 ) (n = 3) induced REDD-1, inhibited mTOR complex-1 (mTORC1) activity and increased IGFBP-1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF-1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia-mediated inhibition of mTORC1 and induction of IGFBP-1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF-1α and also REDD-1 expression, inhibited mTORC1 and increased IGFBP-1 secretion/phosphorylation. Induction of HIF-1α (DMOG) and REDD-1 by Compound 3 inhibited mTORC1, increased IGFBP-1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF-1α induction, increased REDD-1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP-1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia-responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.


Assuntos
Técnicas de Cultura de Células , Modelos Animais de Doenças , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Hipóxia/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Eritropoetina/metabolismo , Peso Fetal , Feto/química , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Técnicas In Vitro , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/química , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Microscopia de Fluorescência , Tamanho do Órgão , Papio , Fosforilação , Proteína Quinase C-alfa/metabolismo , Receptores da Eritropoetina/metabolismo , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Science ; 373(6551): 181-186, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244407

RESUMO

Relatives have more similar gut microbiomes than nonrelatives, but the degree to which this similarity results from shared genotypes versus shared environments has been controversial. Here, we leveraged 16,234 gut microbiome profiles, collected over 14 years from 585 wild baboons, to reveal that host genetic effects on the gut microbiome are nearly universal. Controlling for diet, age, and socioecological variation, 97% of microbiome phenotypes were significantly heritable, including several reported as heritable in humans. Heritability was typically low (mean = 0.068) but was systematically greater in the dry season, with low diet diversity, and in older hosts. We show that longitudinal profiles and large sample sizes are crucial to quantifying microbiome heritability, and indicate scope for selection on microbiome characteristics as a host phenotype.


Assuntos
Bactérias/classificação , Meio Ambiente , Microbioma Gastrointestinal/genética , Papio/microbiologia , Actinobacteria/classificação , Actinobacteria/genética , Actinobacteria/crescimento & desenvolvimento , Actinobacteria/isolamento & purificação , Envelhecimento , Animais , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bacteroidetes/classificação , Bacteroidetes/genética , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/isolamento & purificação , Dieta , Fezes/microbiologia , Feminino , Firmicutes/classificação , Firmicutes/genética , Firmicutes/crescimento & desenvolvimento , Firmicutes/isolamento & purificação , Genótipo , Humanos , Masculino , Papio/genética , Fenótipo , Estações do Ano , Comportamento Social
4.
J Am Assoc Lab Anim Sci ; 60(4): 484-488, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34193333

RESUMO

Alopecia occurs frequently in captive populations of nonhuman primates. Because multiple factors can play a role in alopecia, a better understanding of its etiology will help identify potential welfare concerns. The purpose of this study was to investigate risk factors for alopecia in a breeding colony of baboons with a focus on pregnancy and age. Alopecia was scored on a scale of 0 (no alopecia) to 5 (severe alopecia) in 253 female baboons during routine physicals. The subjects ranged in age from 4 to 23 y (Mean = 9.6) and were categorized as pregnant (n = 83), nursing (n = 60) or control (n = 110). Resulting alopecia scores were combined into 2 categories (mild = 0 or 1; moderate = 2 or 3); no animals scored a 4 or 5. Significantly more pregnant females had moderate alopecia than did control females. There was no effect of age on alopecia. An unexpected outcome was that among nursing females, more of those with female infants had moderate alopecia than did those with male infants. The impact of the infant's sex on alopecia may be due to sex differences in maternal contact or maternal investment. This information adds to our understanding of alopecia risk factors in captive nonhuman primates.


Assuntos
Alopecia , Papio hamadryas , Alopecia/epidemiologia , Alopecia/veterinária , Animais , Feminino , Masculino , Papio , Gravidez
6.
Proc Biol Sci ; 288(1955): 20210839, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34315256

RESUMO

When members of a group differ in locomotor capacity, coordinating collective movement poses a challenge: some individuals may have to move faster (or slower) than their preferred speed to remain together. Such compromises have energetic repercussions, yet research in collective behaviour has largely neglected locomotor consensus costs. Here, we integrate high-resolution tracking of wild baboon locomotion and movement with simulations to demonstrate that size-based variation in locomotor capacity poses an obstacle to the collective movement. While all baboons modulate their gait and move-pause dynamics during collective movement, the costs of maintaining cohesion are disproportionately borne by smaller group members. Although consensus costs are not distributed equally, all group-mates do make locomotor compromises, suggesting a shared decision-making process drives the pace of collective movement in this highly despotic species. These results highlight the importance of considering how social dynamics and locomotor capacity interact to shape the movement ecology of group-living species.


Assuntos
Comportamento Cooperativo , Comportamento Social , Animais , Humanos , Locomoção , Papio
7.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L321-L335, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34105359

RESUMO

Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction and 2) test the safety and efficacy of a novel extracorporeal blood filter to remove proinflammatory molecules and improve organ function. After a dose-finding pilot study, 12 animals were inoculated with Streptococcus pneumoniae [5 × 109 colony-forming units (CFU)], given ceftriaxone at 24 h after inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate (n = 6) or sham treatment (n = 6) for 4 h at 30 h after inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 h, necropsy was performed. Inoculated animals developed severe pneumonia and septic shock. Compared with sham-treated animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock (P < 0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated bronchoalveolar lavage (BAL) CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3 inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines and is renal protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.


Assuntos
Hemofiltração , Heparina/química , Pneumonia Pneumocócica/terapia , Choque Séptico/terapia , Streptococcus pneumoniae/metabolismo , Animais , Citocinas/metabolismo , Masculino , Papio , Projetos Piloto , Pneumonia Pneumocócica/sangue , Choque Séptico/sangue
8.
Vaccine ; 39(30): 4063-4071, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34140172

RESUMO

Respiratory syncytial virus (RSV) is the major viral respiratory pathogen for human infants and children. Despite a severe global burden incurred by annual RSV epidemics, there is no licensed RSV vaccine. We have developed an RSV vaccine from a human RSV strain from which the gene for the viral M protein has been deleted ("Mnull RSV"). RSV infects airway cells and produces each of its proteins. The M protein is responsible for reassembling the various other synthesized viral proteins into new, intact virus. In the absence of the M protein, therefore, reassembly does not occur, and the Mnull RSV does not replicate. We vaccinated 2-week old infant baboons with Mnull RSV either intranasally (IN) or directly into the lung (intratracheal, or IT), then infected these animals by inoculating human RSV directly into the lung. IN vaccination induced inconsistent serum RSV neutralizing antibody (NA) responses, but provided moderate reductions in respiratory rates, overall signs of illness and viral replication in bronchoalveolar lavage (BAL) fluid following infection. Intratracheal vaccination induced much stronger RSV NA responses, which persisted for at least 4-6 months. Following RSV infection, animals vaccinated by the IT route had much greater reductions in tachypnea and work of breathing than animals vaccinated IN, and had undetectable amounts of virus in BAL fluids. These results support the further development of IT Mnull RSV vaccination to reduce the impact of RSV infection in humans.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Criança , Humanos , Lactente , Papio , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinação , Replicação Viral
9.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071951

RESUMO

Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Ciclo-Oxigenase 2/metabolismo , Inflamação/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Celecoxib/farmacologia , Química Farmacêutica/métodos , Feminino , Humanos , Cinética , Ligantes , Imageamento por Ressonância Magnética , Masculino , Camundongos , Papio , Permeabilidade , Ratos
10.
Epilepsy Behav ; 120: 107973, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962250

RESUMO

OBJECTIVE: To evaluate the efficacy of cortical responsive neurostimulation (CRN) in a male baboon with epilepsy and with genetic generalized epilepsy (GGE), as well as the alteration of seizure patterns and their circadian rhythms due to treatment. METHODS: The baboon was implanted with two subdural frontoparietal strips, bridging the medial central sulci bilaterally. Electrocorticography (ECoG) data were downloaded daily during a three-month baseline, then every 2-3 days over a five-month treatment period. Long episodes, reflecting ictal or interictal epileptic discharges, were also quantified. RESULTS: Twenty-three generalized tonic-clonic seizures (GTCS) and 2 episodes of nonconvulsive status epilepticus (NCSE) were recorded at baseline (median 8 events/month), whereas 26 GTCS were recorded under treatment (median 5/month). Similarly, daily indices of long episodes decreased from 0.46 at baseline to 0.29 with treatment. Ictal ECoG patterns and the circadian distribution of GTCS were also altered by RNS therapy. SIGNIFICANCE: This case study provides the proof-of-concept for RNS therapy in the baboon model of GGE. Cortical responsive neurostimulation (CRN) demonstrated a 38% median reduction in GTCS. Distinct ictal patterns were identified, which changed over the treatment period; the circadian pattern of his GTCS also shifted gradually from night to daytime with treatment. Future studies targeting the thalamic nuclei, or combining cortical and subcortical sites, may further improve detection and control of GTCS as well as other generalized seizure types. More broadly, this study demonstrates opportunities for evaluating seizure detection as well as chronic therapeutic interventions over long term in the baboon.


Assuntos
Epilepsia Generalizada , Epilepsia , Estado Epiléptico , Animais , Eletroencefalografia , Humanos , Masculino , Papio , Convulsões
11.
Xenotransplantation ; 28(4): e12700, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34036638

RESUMO

Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs) and expressing "protective" human transgenes are likely sources of organs for transplantation into human recipients. Testing of human sera against red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs has revealed minimal evidence of natural antibody binding. However, unlike humans, baboons exhibit natural antibody binding to TKO pig cells. The xenoantigen specificities of these natural antibodies are postulated to be one or more carbohydrate moieties exposed when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival of renal grafts in baboons from pigs that either expressed Neu5Gc (GTKO pigs; Group1, n = 5) or did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group2, n = 5). An anti-CD40mAb-based immunosuppressive regimen was administered in both groups. Group1 kidneys functioned for 90-260 days (median 237, mean 196 days), with histopathological features of antibody-mediated rejection in two kidneys. Group2 kidneys functioned for 0-183 days (median 35, mean 57), with all of the grafts exhibiting histologic features of antibody-mediated rejection. These findings suggest that the absence of expression of Neu5Gc on pig kidneys impacts graft survival in baboon recipients.


Assuntos
Transplante de Rim , Animais , Animais Geneticamente Modificados , Rejeição de Enxerto , Leucócitos Mononucleares , Ácidos Neuramínicos , Papio , Suínos , Transplante Heterólogo
12.
Xenotransplantation ; 28(4): e12701, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34053125

RESUMO

The current evidence is that sensitization to a pig xenograft does not result in the development of antibodies that cross-react with alloantigens, and therefore, sensitization to a pig xenograft would not be detrimental to the outcome of a subsequent allograft. This evidence relates almost entirely to the transplantation of cells or organs from wild-type or α1,3-galactosyltransferase gene-knockout (GTKO) pigs. However, it is not known whether recipients of triple-knockout (TKO) pig grafts who become sensitized to TKO pig antigens develop antibodies that cross-react with alloantigens and thus be detrimental to a subsequent organ allotransplant. We identified a single baboon (B1317) in which no (or minimal) serum anti-TKO pig antibodies could be measured-in our experience unique among baboons. We sensitized it by repeated subcutaneous injections of TKO pig peripheral blood mononuclear cells (PBMCs) in the absence of any immunosuppressive therapy. After TKO pig PBMC injection, there was a transient increase in anti-TKO pig IgM, followed by a sustained increase in IgG binding to TKO cells. In contrast, there was no serum IgM or IgG binding to PBMCs from any of a panel of baboon PBMCs (n = 8). We conclude that sensitization to TKO pig PBMCs in the baboon did not result in the development of antibodies that also bound to baboon cells, suggesting that there would be no detrimental effect of sensitization on a subsequent organ allotransplant.


Assuntos
Leucócitos Mononucleares , Animais , Animais Geneticamente Modificados , Xenoenxertos , Papio , Suínos , Transplante Heterólogo
13.
Epilepsy Behav ; 121(Pt A): 108012, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34022622

RESUMO

The baboon offers a natural model for genetic generalized epilepsy with photosensitivity. In this review, we will summarize some of the more important clinical, neuroimaging, and elctrophysiological findings form recent work performed at the Southwest National Primate Research Center (SNPRC, Texas Biomedical Research Institute, San Antonio, Texas), which houses the world's largest captive baboon pedigree. Due to the phylogenetic proximity of the baboon to humans, many of the findings are readily translatable, but there may be some important differences, such as the mutlifocality of the ictal and interictal epileptic discharges (IEDs) on intracranial electroencephalography (EEG) and greater parieto-occipital connectivity of baboon brain networks compared to juvenile myoclonic epilepsy in humans. Furthermore, there is still limited knowledge of the natural history of the epilepsy, which could be transformative for research into epileptogenesis in genetic generalized epilepsy (GGE) and sudden unexpected death in epilepsy (SUDEP).


Assuntos
Eletroencefalografia , Epilepsia Generalizada , Animais , Papio , Filogenia , Texas
14.
Elife ; 102021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929318

RESUMO

In a population of wild baboons, a new way to assess biological age reveals a surprising effect of social hierarchy.


Assuntos
Hierarquia Social , Animais , Papio
16.
J Immunol ; 206(8): 1784-1792, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811105

RESUMO

Complement factor H (CFH) is the major inhibitor of the alternative pathway of the complement system and is structurally related to beta2-glycoprotein I, which itself is known to bind to ligands, including coagulation factor XI (FXI). We observed reduced complement activation when FXI activation was inhibited in a baboon model of lethal systemic inflammation, suggesting cross-talk between FXI and the complement cascade. It is unknown whether FXI or its activated form, activated FXI (FXIa), directly interacts with the complement system. We explored whether FXI could interact with and inhibit the activity of CFH. We found that FXIa neutralized CFH by cleavage of the R341/R342 bonds. FXIa reduced the capacity of CFH to enhance the cleavage of C3b by factor I and the decay of C3bBb. The binding of CFH to human endothelial cells was also reduced after incubating CFH with FXIa. The addition of either short- or long-chain polyphosphate enhanced the capacity of FXIa to cleave CFH. FXIa also cleaved CFH that was present on endothelial cells and in the secretome from blood platelets. The generation of FXIa in plasma induced the cleavage of CFH. Moreover, FXIa reduced the cleavage of C3b by factor I in serum. Conversely, we observed that CFH inhibited FXI activation by either thrombin or FXIIa. Our study provides, to our knowledge, a novel molecular link between the contact pathway of coagulation and the complement system. These results suggest that FXIa generation enhances the activity of the complement system and thus may potentiate the immune response.


Assuntos
Plaquetas/metabolismo , Fator H do Complemento/metabolismo , Células Endoteliais/metabolismo , Fator XIa/metabolismo , Inflamação/metabolismo , Animais , Coagulação Sanguínea , Complemento C3b/metabolismo , Via Alternativa do Complemento , Fibrinogênio/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Papio , Ligação Proteica , Receptor Cross-Talk
18.
Blood Cells Mol Dis ; 89: 102561, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744514

RESUMO

Increased expression of developmentally silenced fetal globin (HBG) reduces the clinical severity of ß-hemoglobinopathies. Benserazide has a relatively benign safety profile having been approved for 50 years in Europe and Canada for Parkinson's disease treatment. Benserazide was shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed fetal hemoglobin (HbF) induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice containing the entire human ß-globin gene (ß-YAC) and anemic baboons. The goal of this study is to evaluate efficacies and plasma exposure profiles of benserazide racemate and its enantiomers to select the chemical form for clinical development. Intermittent treatment with all forms of benserazide in ß-YAC mice significantly increased proportions of red blood cells expressing HbF and HbF protein per cell with similar pharmacokinetic profiles and with no cytopenia. These data contribute to the regulatory justification for development of the benserazide racemate. Additionally, dose ranges and frequencies required for HbF induction using racemic benserazide were explored. Orally administered escalating doses of benserazide in an anemic baboon induced γ-globin mRNA up to 13-fold and establish an intermittent dose regimen for clinical studies as a therapeutic candidate for potential treatment of ß-hemoglobinopathies.


Assuntos
Anemia Falciforme/tratamento farmacológico , Benserazida/farmacologia , Dopaminérgicos/farmacologia , Hemoglobina Fetal/genética , Regulação para Cima/efeitos dos fármacos , Talassemia beta/tratamento farmacológico , Anemia Falciforme/genética , Animais , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papio , Talassemia beta/genética , gama-Globinas/genética
19.
Neurosci Res ; 171: 19-26, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33744333

RESUMO

The corpus callosum enables integration and coordination of cognitive processing between the cerebral hemispheres. In the aging human brain, these functions are affected by progressive axon and myelin deteriorations, reflected as atrophy of the midsagittal corpus callosum in old age. In non-human primates, these degenerative processes are less pronounced as previous morphometric studies on capuchin monkey, rhesus monkeys, and chimpanzees do not find old-age callosal atrophy. In the present study, we extend these previous findings by studying callosal development of the olive baboon (Papio anubis) across the lifespan and compare it to chimpanzee and human data. For this purpose, total relative (to forebrain volume) midsagittal area, subsectional area, and regional thickness of the corpus callosum were assessed in 91 male and female baboons using non-invasive MRI-based morphometry. The studied age range was 2.5-26.6 years and lifespan trajectories were fitted using general additive modelling. Relative area of the total and anterior corpus callosum showed a positive linear trajectory. That is, both measures increased slowly but continuously from childhood into old age, and no decline was observed in old age. Thus, comparable with all other non-human primates studied to-date, baboons do not show callosal atrophy in old age. This observation lends supports to the notion that atrophy of the corpus callosum is a unique characteristic of human brain aging.


Assuntos
Corpo Caloso , Longevidade , Animais , Corpo Caloso/diagnóstico por imagem , Estudos Transversais , Feminino , Imageamento por Ressonância Magnética , Masculino , Papio , Papio anubis
20.
J Mol Biol ; 433(10): 166923, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33713677

RESUMO

How retroviral Gag proteins recognize the packaging signals (Psi) on their genomic RNA (gRNA) is a key question that we addressed here using Mason-Pfizer monkey virus (MPMV) as a model system by combining band-shift assays and footprinting experiments. Our data show that Pr78Gag selects gRNA against spliced viral RNA by simultaneously binding to two single stranded loops on the MPMV Psi RNA: (1) a large purine loop (ssPurines), and (2) a loop which partially overlaps with a mostly base-paired purine repeat (bpPurines) and extends into a GU-rich binding motif. Importantly, this second Gag binding site is located immediately downstream of the major splice donor (mSD) and is thus absent from the spliced viral RNAs. Identifying elements crucial for MPMV gRNA packaging should help in understanding not only the mechanism of virion assembly by retroviruses, but also facilitate construction of safer retroviral vectors for human gene therapy.


Assuntos
Produtos do Gene gag/química , Guanina/química , Vírus dos Macacos de Mason-Pfizer/química , RNA Viral/química , Uracila/química , Animais , Pareamento de Bases , Sequência de Bases , Sítios de Ligação , Ensaio de Desvio de Mobilidade Eletroforética , Regulação Viral da Expressão Gênica , Produtos do Gene gag/genética , Produtos do Gene gag/metabolismo , Guanina/metabolismo , Interações Hospedeiro-Patógeno , Vírus dos Macacos de Mason-Pfizer/genética , Vírus dos Macacos de Mason-Pfizer/metabolismo , Conformação de Ácido Nucleico , Papio , Ligação Proteica , Conformação Proteica , Pegadas de Proteínas , RNA Viral/genética , RNA Viral/metabolismo , Transdução de Sinais , Uracila/metabolismo
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