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1.
Rev Med Liege ; 76(9): 689-696, 2021 Sep.
Artigo em Francês | MEDLINE | ID: mdl-34477341

RESUMO

Since the early 1970s, the concept of quality of life has been the subject of increasing interest in the medical field, although no scientific consensus has emerged on how to define and measure it. The aim of this narrative review of the literature is to decrypt the notion of quality of life in the medical field, in order to enable clinicians-researchers and clinicians who use quality of life measurement instruments in clinical practice to form an informed and nuanced opinion on the issue. To do so, the paper is divided into three parts. Firstly, a brief overview of the origin of the concept in the medical field is given by exposing the main factors explaining its emergence and its rise in importance. Next, the plurality of definitions of quality of life and its derivatives (e.g. health-related quality of life), as well as its measurement instruments in the medical field, are explored. Finally, some benchmarks for the use of health-related quality of life instruments in clinical practice are presented.


Assuntos
Qualidade de Vida , Semântica , Humanos
2.
Curr Opin Neurol ; 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34392299

RESUMO

PURPOSE OF REVIEW: An intronic G4C2 expansion mutation in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Although there are currently no treatments for this insidious, fatal disease, intense research has led to promising therapeutic strategies, which will be discussed here. RECENT FINDINGS: Therapeutic strategies for C9-ALS/FTD have primarily focused on reducing the toxic effects of mutant expansion RNAs or the dipeptide repeat proteins (DPRs). The pathogenic effects of G4C2 expansion transcripts have been targeted using approaches aimed at promoting their degradation, inhibiting nuclear export or silencing transcription. Other promising strategies include immunotherapy to reduce the DPRs themselves, reducing RAN translation, removing the repeats using DNA or RNA editing and manipulation of downstream disease-altered stress granule pathways. Finally, understanding the molecular triggers that lead to pheno-conversion may lead to opportunities that can delay symptomatic disease onset. SUMMARY: A large body of evidence implicates RAN-translated DPRs as a main driver of C9-ALS/FTD. Promising therapeutic strategies for these devastating diseases are being rapidly developed with several approaches already in or approaching clinical trials.

3.
Mol Neurodegener ; 16(1): 53, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376242

RESUMO

BACKGROUND: Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question. METHODS: Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes. RESULTS: Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits. CONCLUSIONS: Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.

4.
Mol Ecol ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34192383

RESUMO

Transmissible cancers are parasitic malignant cell lineages that have acquired the ability to infect new hosts from the same species, or sometimes related species. First described in dogs and Tasmanian devils, transmissible cancers were later discovered in some marine bivalves affected by a leukaemia-like disease. In Mytilus mussels, two lineages of bivalve transmissible neoplasia (BTN) have been described to date (MtrBTN1 and MtrBTN2), both of which emerged in a Mytilus trossulus founder individual. Here, we performed extensive screening of genetic chimerism, a hallmark of transmissible cancer, by genotyping 106 single nucleotide polymorphisms of 5,907 European Mytilus mussels. Genetic analysis allowed us to simultaneously obtain the genotype of hosts - Mytilus edulis, M. galloprovincialis or hybrids - and the genotype of tumours of heavily infected individuals. In addition, a subset of 222 individuals were systematically genotyped and analysed by histology to screen for possible nontransmissible cancers. We detected MtrBTN2 at low prevalence in M. edulis, and also in M. galloprovincialis and hybrids although at a much lower prevalence. No MtrBTN1 or new BTN were found, but eight individuals with nontransmissible neoplasia were observed at a single polluted site on the same sampling date. We observed a diversity of MtrBTN2 genotypes that appeared more introgressed or more ancestral than MtrBTN1 and reference healthy M. trossulus individuals. The observed polymorphism is probably due to somatic null alleles caused by structural variations or point mutations in primer-binding sites leading to enhanced detection of the host alleles. Despite low prevalence, two sublineages divergent by 10% fixed somatic null alleles and one nonsynonymous mtCOI (mitochondrial cytochrome oxidase I) substitution are cospreading in the same geographical area, suggesting a complex diversification of MtrBTN2 since its emergence and host species shift.

5.
Biochem Soc Trans ; 49(2): 775-792, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33729487

RESUMO

Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.

6.
Commun Biol ; 4(1): 93, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473151

RESUMO

Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Descoberta de Drogas , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/química , COVID-19/virologia , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/química , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , SARS-CoV-2/enzimologia , Relação Estrutura-Atividade
7.
Aging Cell ; 20(1): e13281, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33314575

RESUMO

Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation to studying mechanisms and potential therapies aiming to preserve neuronal health. Here, we show that induced astrocytes from fibroblasts donors in their childhood or adulthood display age-related transcriptional differences and functionally diverge in a spectrum of age-associated features, such as altered nuclear compartmentalisation, nucleocytoplasmic shuttling properties, oxidative stress response and DNA damage response. Remarkably, we also show an age-related differential response of induced neural progenitor cells derived astrocytes (iNPC-As) in their ability to support neurons in co-culture upon pro-inflammatory stimuli. These results show that iNPC-As are a renewable, readily available resource of human glia that retain the age-related features of the donor fibroblasts, making them a unique and valuable model to interrogate human astrocyte function over time in human CNS health and disease.


Assuntos
Astrócitos/metabolismo , Fibroblastos/metabolismo , Envelhecimento , Sistema Nervoso Central , Humanos
8.
Curr Alzheimer Res ; 17(7): 667-679, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33023447

RESUMO

BACKGROUND: Research indicates that polygenic indices of risk of Alzheimer's disease are linked to clinical profiles. OBJECTIVE: Given the "genetic centrality" of the APOE gene, we tested whether this held true for both APOE-ε4 carriers and non-carriers. METHODS: A polygenic hazard score (PHS) was extracted from 784 non-demented participants recruited in the Alzheimer's Disease Neuroimaging Initiative and stratified by APOE ε4 status. Datasets were split into sub-cohorts defined by clinical (unimpaired/MCI) and amyloid status (Aß+/Aß-). Linear models were devised in each sub-cohort and for each APOE-ε4 status to test the association between PHS and memory, executive functioning and grey-matter volumetric maps. RESULTS: PHS predicted memory and executive functioning in ε4ε3 MCI patients, memory in ε3ε3 MCI patients, and memory in ε4ε3 Aß+ participants. PHS also predicted volume in sensorimotor regions in ε3ε3 Aß+ participants. CONCLUSION: The link between polygenic hazard and neurocognitive variables varies depending on APOE-ε4 allele status. This suggests that clinical phenotypes might be influenced by complex genetic interactions.

9.
Nat Rev Neurol ; 16(8): 440-456, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32669685

RESUMO

Globally, there is a huge unmet need for effective treatments for neurodegenerative diseases. The complexity of the molecular mechanisms underlying neuronal degeneration and the heterogeneity of the patient population present massive challenges to the development of early diagnostic tools and effective treatments for these diseases. Machine learning, a subfield of artificial intelligence, is enabling scientists, clinicians and patients to address some of these challenges. In this Review, we discuss how machine learning can aid early diagnosis and interpretation of medical images as well as the discovery and development of new therapies. A unifying theme of the different applications of machine learning is the integration of multiple high-dimensional sources of data, which all provide a different view on disease, and the automated derivation of actionable insights.

10.
Environ Microbiol ; 22(10): 4323-4341, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32363732

RESUMO

In the marine environment, bivalve mollusks constitute habitats for bacteria of the Vibrionaceae family. Vibrios belong to the microbiota of healthy oysters and mussels, which have the ability to concentrate bacteria in their tissues and body fluids, including the hemolymph. Remarkably, these important aquaculture species respond differently to infectious diseases. While oysters are the subject of recurrent mass mortalities at different life stages, mussels appear rather resistant to infections. Thus, Vibrio species are associated with the main diseases affecting the worldwide oyster production. Here, we review the current knowledge on Vibrio-bivalve interaction in oysters (Crassostrea sp.) and mussels (Mytilus sp.). We discuss the transient versus stable associations of vibrios with their bivalve hosts as well as technical issues limiting the monitoring of these bacteria in bivalve health and disease. Based on the current knowledge of oyster/mussel immunity and their interactions with Vibrio species pathogenic for oyster, we discuss how differences in immune effectors could contribute to the higher resistance of mussels to infections. Finally, we review the multiple strategies evolved by pathogenic vibrios to circumvent the potent immune defences of bivalves and how key virulence mechanisms could have been positively or negatively selected in the marine environment through interactions with predators.


Assuntos
Crassostrea/microbiologia , Interações Hospedeiro-Patógeno/imunologia , Mytilus/microbiologia , Vibrio/patogenicidade , Animais , Crassostrea/imunologia , Hemolinfa/microbiologia , Interações Hospedeiro-Patógeno/fisiologia , Microbiota , Mytilus/imunologia , Vibrio/imunologia
11.
Environ Microbiol ; 22(10): 4264-4278, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32219965

RESUMO

A major debate in evolutionary biology is whether virulence is maintained as an adaptive trait and/or evolves to non-virulence. In the environment, virulence traits of non-obligatory parasites are subjected to diverse selective pressures and trade-offs. Here, we focus on a population of Vibrio splendidus that displays moderate virulence for oysters. A MARTX (Multifunctional-autoprocessing repeats-in-toxin) and a type-six secretion system (T6SS) were found to be necessary for virulence toward oysters, while a region (wbe) involved in O-antigen synthesis is necessary for resistance to predation against amoebae. Gene inactivation within the wbe region had major consequences on the O-antigen structure, conferring lower immunogenicity, competitive advantage and increased virulence in oyster experimental infections. Therefore, O-antigen structures that favour resistance to environmental predators result in an increased activation of the oyster immune system and a reduced virulence in that host. These trade-offs likely contribute to maintaining O-antigen diversity in the marine environment by favouring genomic plasticity of the wbe region. The results of this study indicate an evolution of V. splendidus towards moderate virulence as a compromise between fitness in the oyster as a host, and resistance to its predators in the environment.


Assuntos
Antígenos O/metabolismo , Ostreidae/microbiologia , Sistemas de Secreção Tipo VI/genética , Vibrio/patogenicidade , Amoeba/metabolismo , Animais , Cadeia Alimentar , Antígenos O/imunologia , Ostreidae/imunologia , Alimentos Marinhos/microbiologia , Vibrio/imunologia , Virulência/genética , Virulência/fisiologia
12.
Diabetes Metab ; 46(2): 129-136, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31163275

RESUMO

AIM: In hepatocytes, the peroxisome proliferator-activated receptor (PPAR)-α and insulin receptor (IR) are critical for transcriptional responses to fasting and feeding, respectively. The present report analyzes the effects of nutritional status (fasting vs feeding) on the expression of a large panel of hepatokines in hepatocyte-specific PPAR-α (Pparαhep-/-) and IR (IRhep-/-) null mice. METHODS: Pparαhep-/- and IRhep-/- mice, and their wild-type littermates, were subjected to fasting or feeding metabolic challenges, then analyzed for hepatokine gene expression. Experiments were conducted in mice of both genders. RESULTS: Our data confirmed that PPAR-α is essential for regulating fasting-induced Fgf21 and Angptl4 expression. In mice lacking PPAR-α, fasting led to increased Igfbp1 and Gdf15 gene expression. In the absence of hepatic IR, feeding induced overexpression of Igfbp1, follistatin (Fst) and adropin (Enho), and reduced activin E (Inhbe) expression. Gender had only a modest influence on hepatokine gene expression in the liver. CONCLUSION: The present results highlight the potential roles of hepatokines as a class of hormones that substantially influence nutritional regulation in both female and male mice.

13.
Patient Educ Couns ; 103(1): 5-14, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31447194

RESUMO

OBJECTIVES: Several concepts on collaboration between patients and healthcare systems have emerged in the literature but there is little consensus on their meanings and differences. In this study, "patient participation" and related concepts were studied by focusing on the dimensions that compose them. This review follows two objectives: (1) to produce a detailed and comprehensive overview of the "patient participation" dimensions; (2) to identify differences and similarities between the related concepts. METHODS: A scoping review was performed to synthesize knowledge into a conceptual framework. An electronic protocol driven search was conducted in two bibliographic databases and a thematic analysis was used to analyse the data. RESULTS: The search process returned 39 articles after exclusion for full data extraction and analysis. Through the thematic analysis, the dimensions, influencing factors and expected outcomes of "patient participation" were determined. Finally, differences between the included concepts were identified. CONCLUSION: This global vision of "patient participation" allows us to go beyond the distinctions between the existing concepts and reveals their common goal to include the patient in the healthcare system. PRACTICE IMPLICATIONS: This scoping review provides useful information to propose a conceptual model of "patient participation", which could impact clinical practice and medical training programs.


Assuntos
Participação do Paciente , Humanos
14.
Environ Microbiol ; 22(10): 4183-4197, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31386262

RESUMO

Vibrios are ubiquitous in marine environments and opportunistically colonize a broad range of hosts. Strains of Vibrio tasmaniensis present in oyster farms can thrive in oysters during juvenile mortality events and behave as facultative intracellular pathogen of oyster haemocytes. Herein, we wondered whether V. tasmaniensis LGP32 resistance to phagocytosis is specific to oyster immune cells or contributes to resistance to other phagocytes, like marine amoebae. To address this question, we developed an integrative study, from the first description of amoeba diversity in oyster farms to the characterization of LGP32 interactions with amoebae. An isolate of the Vannella genus, Vannella sp. AP1411, which was collected from oyster farms, is ubiquitous, and belongs to one clade of Vannella that could be found associated with Vibrionaceae. LGP32 was shown to be resistant to grazing by Vannella sp. AP1411 and this phenotype depends on some previously identified virulence factors: secreted metalloprotease Vsm and copper efflux p-ATPase CopA, which act at different steps during amoeba-vibrio interactions, whereas some other virulence factors were not involved. Altogether, our work indicates that some virulence factors can be involved in multi-host interactions of V. tasmaniensis ranging from protozoans to metazoans, potentially favouring their opportunistic behaviour.


Assuntos
Amebozoários/fisiologia , Ostreidae/microbiologia , Vibrio/fisiologia , Amoeba/fisiologia , Animais , Proteínas de Bactérias/genética , Comportamento Predatório , Vibrio/genética , Vibrio/patogenicidade , Fatores de Virulência/genética
15.
Opt Express ; 27(21): 30989-31000, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684340

RESUMO

We present the design and performance of an active stabilization system for attosecond pump-probe setups based on a Mach-Zehnder interferometer configuration. The system employs a CW laser propagating coaxially with the pump and probe beams in the interferometer. The stabilization is achieved with a standalone feedback controller that adjusts the length of one of its arms to maintain a constant relative phase between the CW beams. With this system, the time delay between the pump and probe beams is stabilized within 10 as rms over several hours. The system is easy to operate and only requires a few minutes to set up before any pump/probe measurements.

17.
Proc Natl Acad Sci U S A ; 116(28): 14238-14247, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31221761

RESUMO

Vibrio species cause infectious diseases in humans and animals, but they can also live as commensals within their host tissues. How Vibrio subverts the host defenses to mount a successful infection remains poorly understood, and this knowledge is critical for predicting and managing disease. Here, we have investigated the cellular and molecular mechanisms underpinning infection and colonization of 2 virulent Vibrio species in an ecologically relevant host model, oyster, to study interactions with marine Vibrio species. All Vibrio strains were recognized by the immune system, but only nonvirulent strains were controlled. We showed that virulent strains were cytotoxic to hemocytes, oyster immune cells. By analyzing host and bacterial transcriptional responses to infection, together with Vibrio gene knock-outs, we discovered that Vibrio crassostreae and Vibrio tasmaniensis use distinct mechanisms to cause hemocyte lysis. Whereas V. crassostreae cytotoxicity is dependent on a direct contact with hemocytes and requires an ancestral gene encoding a protein of unknown function, r5.7, V. tasmaniensis cytotoxicity is dependent on phagocytosis and requires intracellular secretion of T6SS effectors. We conclude that proliferation of commensal vibrios is controlled by the host immune system, preventing systemic infections in oysters, whereas the successful infection of virulent strains relies on Vibrio species-specific molecular determinants that converge to compromise host immune cell function, allowing evasion of the host immune system.


Assuntos
Interações Hospedeiro-Patógeno/genética , Ostreidae/microbiologia , Vibrioses/genética , Vibrio/genética , Animais , Citoplasma/genética , Citoplasma/microbiologia , Hemócitos/microbiologia , Fagocitose/genética , Especificidade da Espécie , Vibrio/patogenicidade , Vibrioses/patologia
18.
Rev Med Liege ; 74(5-6): 241-247, 2019 05.
Artigo em Francês | MEDLINE | ID: mdl-31206260

RESUMO

The epidemiological data about alcohol consumption show that the current preventive measures have their limits. Worryingly, the morbidity and mortality associated remain significant in the world. Two main types of preventive approaches, based on individual affect exist: the negative approach based on fear and threat and the so-called Social Norm Approach (SNA). The last original and more positive approach has been used across the Atlantic for thirty years and shows to be efficient. It aims to reduce an individual's consumption of addictive substance by confronting his own social norm (what he thinks people drink, quantities generally overestimated) to the real norm of consumption by a reference social group. A cross-border project is currently evaluating the feasibility of this approach in the Euregio Meuse-Rhin.


Assuntos
Consumo de Bebidas Alcoólicas , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Humanos , Masculino
19.
PLoS Pathog ; 15(3): e1007647, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30893368

RESUMO

Selective pressures between hosts and their parasites can result in reciprocal evolution or adaptation of specific life history traits. Local adaptation of resident hosts and parasites should lead to increase parasite infectivity/virulence (higher compatibility) when infecting hosts from the same location (in sympatry) than from a foreign location (in allopatry). Analysis of geographic variations in compatibility phenotypes is the most common proxy used to infer local adaptation. However, in some cases, allopatric host-parasite systems demonstrate similar or greater compatibility than in sympatry. In such cases, the potential for local adaptation remains unclear. Here, we study the interaction between Schistosoma and its vector snail Biomphalaria in which such discrepancy in local versus foreign compatibility phenotype has been reported. Herein, we aim at bridging this gap of knowledge by comparing life history traits (immune cellular response, host mortality, and parasite growth) and molecular responses in highly compatible sympatric and allopatric Schistosoma/Biomphalaria interactions originating from different geographic localities (Brazil, Venezuela and Burundi). We found that despite displaying similar prevalence phenotypes, sympatric schistosomes triggered a rapid immune suppression (dual-RNAseq analyses) in the snails within 24h post infection, whereas infection by allopatric schistosomes (regardless of the species) was associated with immune cell proliferation and triggered a non-specific generalized immune response after 96h. We observed that, sympatric schistosomes grow more rapidly. Finally, we identify miRNAs differentially expressed by Schistosoma mansoni that target host immune genes and could be responsible for hijacking the host immune response during the sympatric interaction. We show that despite having similar prevalence phenotypes, sympatric and allopatric snail-Schistosoma interactions displayed strong differences in their immunobiological molecular dialogue. Understanding the mechanisms allowing parasites to adapt rapidly and efficiently to new hosts is critical to control disease emergence and risks of Schistosomiasis outbreaks.


Assuntos
Biomphalaria/genética , Schistosoma/genética , Simpatria/fisiologia , Adaptação Fisiológica , Animais , Evolução Biológica , Biomphalaria/imunologia , Biomphalaria/parasitologia , Vetores de Doenças , Evolução Molecular , Perfilação da Expressão Gênica , Interações Hospedeiro-Parasita , Fenômenos do Sistema Imunológico , Imunidade Celular/genética , Imunidade Celular/imunologia , Prevalência , Schistosoma/parasitologia , Simpatria/genética , Virulência
20.
EBioMedicine ; 40: 626-635, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711519

RESUMO

BACKGROUND: Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration. METHODS: We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity. ADEVs were isolated from iAstrocyte conditioned medium via ultracentrifugation and resuspended in fresh astrocyte medium before testing ADEV impact on HB9-GFP+ mouse motor neurons (Hb9-GFP+ MN). We used post-mortem brain and spinal cord tissue from 3 sporadic ALS and 3 non-ALS cases for PCR analysis. FINDINGS: We report that EV formation and miRNA cargo are dysregulated in C9ORF72-ALS iAstrocytes and this affects neurite network maintenance and MN survival in vitro. In particular, we have identified downregulation of miR-494-3p, a negative regulator of semaphorin 3A (SEMA3A) and other targets involved in axonal maintenance. We show here that by restoring miR-494-3p levels through expression of an engineered miRNA mimic we can downregulate Sema3A levels in MNs and increases MN survival in vitro. Consistently, we also report lower levels of mir-494-3p in cortico-spinal tract tissue isolated from sporadic ALS donors, thus supporting the pathological importance of this pathway in MNs and its therapeutic potential. INTERPRETATION: ALS ADEVs and their miRNA cargo are involved in MN death in ALS and we have identified miR-494-3p as a potential therapeutic target. FUNDING: Thierry Latran Fondation and Academy of Medical Sciences.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Astrócitos/metabolismo , Proteína C9orf72/genética , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Degeneração Neural/genética , Degeneração Neural/metabolismo , Adulto , Idoso , Esclerose Amiotrófica Lateral/diagnóstico , Animais , Autopsia , Biópsia , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Vesículas Extracelulares/ultraestrutura , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , Modelos Biológicos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Mutação , Interferência de RNA , Semaforina-3A/genética , Semaforina-3A/metabolismo , Pele/metabolismo , Pele/patologia
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