RESUMO
The human microbiome is an integral component of the human body and a co-determinant of several health conditions1,2. However, the extent to which interpersonal relations shape the individual genetic makeup of the microbiome and its transmission within and across populations remains largely unknown3,4. Here, capitalizing on more than 9,700 human metagenomes and computational strain-level profiling, we detected extensive bacterial strain sharing across individuals (more than 10 million instances) with distinct mother-to-infant, intra-household and intra-population transmission patterns. Mother-to-infant gut microbiome transmission was considerable and stable during infancy (around 50% of the same strains among shared species (strain-sharing rate)) and remained detectable at older ages. By contrast, the transmission of the oral microbiome occurred largely horizontally and was enhanced by the duration of cohabitation. There was substantial strain sharing among cohabiting individuals, with 12% and 32% median strain-sharing rates for the gut and oral microbiomes, and time since cohabitation affected strain sharing more than age or genetics did. Bacterial strain sharing additionally recapitulated host population structures better than species-level profiles did. Finally, distinct taxa appeared as efficient spreaders across transmission modes and were associated with different predicted bacterial phenotypes linked with out-of-host survival capabilities. The extent of microorganism transmission that we describe underscores its relevance in human microbiome studies5, especially those on non-infectious, microbiome-associated diseases.
Assuntos
Bactérias , Transmissão de Doença Infecciosa , Microbioma Gastrointestinal , Ambiente Domiciliar , Microbiota , Boca , Feminino , Humanos , Lactente , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Microbioma Gastrointestinal/genética , Metagenoma , Microbiota/genética , Mães , Boca/microbiologia , Transmissão Vertical de Doenças Infecciosas , Características da Família , Envelhecimento , Fatores de Tempo , Viabilidade MicrobianaRESUMO
BACKGROUND: Respiratory symptoms after exercise are frequently reported by asthmatic patients, and exercise-induced bronchoconstriction (EIB) is a frequent cause, which requires objective testing for diagnosis. Eucapnic voluntary hyperpnea (EVH) is recommended as a surrogate stimulus for this purpose. Its short-term reproducibility is not yet established in children and young adolescents with asthma. OBJECTIVE: To evaluate the short-term test-retest agreement and reproducibility of FEV1 changes after EVH in this population. METHODS: Asthmatic patients aged between 10 and 20 years underwent EVH for EIB diagnosis on two occasions 2-4 days apart at a specialized university clinic. FEV1 was measured at 5, 15, and 30 min after EVH with a target ventilation rate 21 times the baseline FEV1 . EIB was diagnosed as a decrease ≥10% in FEV1 from baseline. RESULTS: A total of 26 of 62 recruited individuals tested positive for EIB on both visits (positive group) and 17 on one visit only (divergent group), while 19 tested negative on both visits (negative group). The overall agreement was 72.5% (95%CI 61.6%, 83.6%), and Cohen's kappa coefficient was 0.452. Low bias (0.87%) and high intra-class correlation coefficient (0.854, 95%CI 0.758,0.912; p < .001) for FEV1 response between test days were found, but with wide limits of agreement (±20.72%). There were no differences in pre-challenge FEV1 or achieved ventilation rate between visits either between groups (p = .097 and p = .461) or within groups (p = .828 and p = .780). There were no safety issues. CONCLUSIONS: More than one EVH test should be performed in children and young adolescents with asthma to exclude EIB and minimize misdiagnosis and mistreatment.
Assuntos
Asma Induzida por Exercício , Asma , Adolescente , Adulto , Asma/diagnóstico , Asma Induzida por Exercício/diagnóstico , Broncoconstrição , Criança , Volume Expiratório Forçado , Humanos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
OBJECTIVE: To review the clinical and scientific literature on the subjective ways of assessing burn scars and describe their main characteristics. DATA SOURCES: The Latin American, Caribbean Health Sciences Literature, Nursing Database, PubMed, CINAHL, and Scopus and Web of Science databases were used to search for studies published between 2014 and 2018 using descriptors in Portuguese, Spanish, and English. STUDY SELECTION: After establishing the research question and the location and definition of the studies, as well as accounting for differences among databases and application of filters based on inclusion and exclusion criteria, 886 references remained. DATA EXTRACTION: Investigators reviewed the titles and abstracts of the sample and selected 188 relevant studies for full review. DATA SYNTHESIS: Twenty-six subjective forms of assessment were found; most research concerned the Patient and Observer Scar Assessment Scale and the Vancouver Scar Scale. CONCLUSIONS: The Patient and Observer Scar Assessment Scale and the Vancouver Scar Scale are the most common scales for assessing burn scars and have similar evaluation points such as vascularization, pliability, pigmentation, and height, which are the main parameters that contribute to the general assessment and severity of a scar. There is a need to improve instructions for application of the scales to facilitate better understanding and improve agreement among evaluators.
Assuntos
Queimaduras/complicações , Cicatriz/enfermagem , Cicatriz/classificação , Cicatriz/diagnóstico , Competência Clínica/normas , Competência Clínica/estatística & dados numéricos , HumanosRESUMO
BACKGROUND: Malaria remains a significant public health problem in Guinea-Bissau, West Africa. Government control measures include bed net distribution campaigns, however, local knowledge, attitudes and practices towards bed nets and malaria are uncharacterized on the remote Bijagos Archipelago. METHODS: Knowledge, attitude and practice questionnaires were conducted with household heads, aiming to explore the understanding of malaria and factors influencing bed net uptake and usage. Nets were observed in situ to appraise net quality and behaviour. All 14 villages and one semi-urban neighbourhood on Bubaque Island were included. One in 5 households containing school-aged children were randomly selected. RESULTS: Of 100 participants, 94 were aware of malaria and 66 of those considered it a significant or severe problem, primarily because of its impact on health and income. Transmission, symptoms and risk factors were well known, however, 28.0% of participants felt under-informed. Some 80.0% reported contact with distribution campaigns, with inter-village variability. Campaign contact was associated with feeling well informed (OR 3.44; P = 0.024) and inversely with perceiving malaria a household (OR 0.18; P = 0.002) or regional problem (OR 0.25; P = 0.018). Every household contained nets; every identifiable example was a long-lasting insecticide-treated net (LLIN), however, 23.0% of households contained at least one expired net. Replacements were in demand; 89.0% of households reported that all residents used nets, and average occupancy was 2.07 people per net; 65.2% stated that the repurposing of bed nets was common. Correctly using bed nets, defined by age, integrity and demonstration, was 35.0% and strongly associated with completing intermittent preventative treatment in pregnancy (RR 3.63; P = 0.014). CONCLUSIONS: Knowledge of malaria is good in these communities. Bed nets are used widely and are valued for their role in preventing malaria. However, their use is frequently sub-optimal and offers a target for improving malaria control by adapting popular distribution campaigns to provide more education alongside fresh LLINs. The impact of this could be significant as LLINs represent the mainstay of malaria prevention in Guinea-Bissau; however, the persistence of malaria despite the high uptake of LLINs seen in this study suggests that novel supplementary approaches must also be considered.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Malária/psicologia , Controle de Mosquitos/estatística & dados numéricos , Mosquiteiros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Guiné-Bissau , Humanos , Ilhas , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Bubaque is the most populous island of the Bijagos archipelago, a group of malaria-endemic islands situated off the coast of Guinea-Bissau, West Africa. Malaria vector control on Bubaque relies almost exclusively on the use of long-lasting insecticidal nets (LLINs). However, there is little information on local vector bionomics and insecticide resistance. METHODS: A survey of mosquito species composition was performed at the onset of the wet season (June/July) and the beginning of the dry season (November/December). Sampling was performed using indoor adult light-traps and larval dipping. Anopheles mosquitoes were identified to species level and assessed for kdr allele frequency by TaqMan PCR. Females were analysed for sporozoite positivity by CSP-ELISA. Resistance to permethrin and α-cypermethrin was measured using the CDC-bottle bioassay incorporating the synergist piperonyl-butoxide. RESULTS: Several Anopheles species were found on the island, all belonging to the Anopheles gambiae sensu lato (s.l.) complex, including An. gambiae sensu stricto, Anopheles coluzzii, Anopheles melas, and An. gambiae/An. coluzzii hybrids. Endophagic Anopheles species composition and abundance showed strong seasonal variation, with a majority of An. gambiae (50% of adults collected) caught in June/July, while An. melas was dominant in November/December (83.9% of adults collected). Anopheles gambiae had the highest sporozoite rate in both seasons, with infection rates of 13.9% and 20% in June/July and November/December, respectively. Moderate frequencies of the West African kdr allele were found in An. gambiae (36%), An. coluzzii (35%), An. gambiae/An. coluzzii hybrids (42%). Bioassays suggest moderate resistance to α-cypermethrin, but full susceptibility to permethrin. CONCLUSIONS: The island of Bubaque maintained an An. gambiae s.l. population in both June/July and November/December. Anopheles gambiae was the primary vector at the onset of the wet season, while An. melas is likely to be responsible for most dry season transmission. There was moderate kdr allele frequency and synergist assays suggest likely metabolic resistance, which could reduce the efficacy of LLINs. Future control of malaria on the islands should consider the seasonal shift in mosquito species, and should employ continuous monitoring for insecticide resistance.
Assuntos
Anopheles/classificação , Resistência a Inseticidas , Malária/transmissão , Mosquitos Vetores/classificação , Animais , Anopheles/enzimologia , Anopheles/genética , Bioensaio/métodos , DNA/isolamento & purificação , Feminino , Técnicas de Genotipagem , Guiné-Bissau , Resistência a Inseticidas/genética , Ilhas , Malária/prevenção & controle , Mosquitos Vetores/enzimologia , Mosquitos Vetores/genética , Projetos Piloto , Estações do Ano , Inquéritos e Questionários , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Epidemics of dengue, Zika, and other arboviral diseases are increasing in frequency and severity. Current efforts to rapidly identify and manage these epidemics are limited by the short diagnostic window in acute infection, the extensive serologic cross-reactivity among flaviviruses, and the lack of point-of-care diagnostic tools to detect these viral species in primary care settings. The Partnership for Dengue Control organized a workshop to review the current landscape of Flavivirus diagnostic tools, identified current gaps, and developed strategies to accelerate the adoption of promising novel technologies into national programs. The rate-limiting step to bringing new diagnostic tools to the market is access to reference materials and well-characterized clinical samples to facilitate performance evaluation. We suggest the creation of an international laboratory-response consortium for flaviviruses with a decentralized biobank of well-characterized samples to facilitate assay validation. Access to proficiency panels are needed to ensure quality control, in additional to in-country capacity building.
Assuntos
Anticorpos Antivirais/sangue , Dengue/diagnóstico , Infecção por Zika virus/diagnóstico , Anticorpos Antivirais/imunologia , Qualidade de Produtos para o Consumidor , Dengue/história , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Vírus da Dengue/isolamento & purificação , Ensaio de Imunoadsorção Enzimática/história , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/tendências , História do Século XX , História do Século XXI , Humanos , Vigilância da População , Reação em Cadeia da Polimerase Via Transcriptase Reversa/história , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/tendências , Sensibilidade e Especificidade , Zika virus/genética , Zika virus/imunologia , Zika virus/isolamento & purificação , Infecção por Zika virus/história , Infecção por Zika virus/virologiaRESUMO
Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Vírus/imunologia , Endopeptidases/metabolismo , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imunidade Inata/imunologia , Espectrometria de Massas , Fases de Leitura Aberta/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Especificidade por Substrato , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Vírus/metabolismoRESUMO
NKG2C is an activating receptor that is preferentially expressed on natural killer (NK) cells. The gene encoding NKG2C (killer cell lectin-like receptor C2, KLRC2) is present at different copy numbers in the genomes of different individuals. Deletion at the NKG2C locus was investigated in a case-control study of 1522 individuals indigenous to East- and West-Africa and the association with the ocular Chlamydia trachomatis infection and its sequelae was explored. The frequency of homozygous KLRC2 deletion was 13.7 % in Gambians and 4.7 % in Tanzanians. A significantly higher frequency of the deletion allele was found in West-Africans from the Gambia and Guinea-Bissau (36.2 % p = 2.105 × 10(-8), 26.8 % p = 0.050; respectively) in comparison to East-African Tanzanians where the frequency of the deletion is comparable to other human populations (20.9 %). We found no evidence for an association between the numbers of KLRC2 gene copies and the clinical manifestations of trachoma (follicular trachoma or conjunctival scarring). A new method for imputation of KLRC2 genotypes from single nucleotide polymorphism (SNP) data in 2621 individuals from the Gambia further confirmed these results. Our data suggest that NKG2C does not play a major role in trachomatous disease. We found that the deletion allele is present at different frequencies in different populations but the reason behind these differences is currently not understood. The new method offers the potential to use SNP arrays from genome wide association studies to study the frequency of KLRC2 deletion in other populations and its association with other diseases.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Tracoma/genética , Adolescente , Adulto , África Ocidental , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Feminino , Genótipo , Homozigoto , Humanos , Lactente , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Deleção de Sequência/genética , Tracoma/epidemiologia , Tracoma/patologiaRESUMO
Natural killer (NK) cells differentiate and mature during the human life course; human cytomegalovirus (HCMV) infection is a known driver of this process. We have explored human NK cell phenotypic and functional maturation in a rural African (Gambian) population with a high prevalence of HCMV. The effect of age on the frequency, absolute number, phenotype, and functional capacity of NK cells was monitored in 191 individuals aged from 1 to 49 years. Increasing frequencies of NK cells with age were associated with increased proportions of CD56dim cells expressing the differentiation marker CD57 and expansion of the NKG2C+ subset. Frequencies of NK cells responding to exogenous cytokines declined with age in line with a decreased proportion of CD57- cells. These changes coincided with a highly significant drop in anti-HCMV IgG titers by the age of 10 years, suggesting that HCMV infection is brought under control as NK cells differentiate (or vice versa). Deletion at the NKG2C locus was associated with a gene dose-dependent reduction in proportions of CD94+ and CD57+ NK cells. Importantly, anti-HCMV IgG titers were significantly elevated in NKG2C-/- children, suggesting that lack of expression of NKG2C may be associated with altered control of HCMV in childhood.
Assuntos
Infecções por Citomegalovirus/metabolismo , Citomegalovirus/metabolismo , Deleção de Genes , Células Matadoras Naturais/citologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Adolescente , Adulto , Antígenos CD57/metabolismo , Diferenciação Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Lactente , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fenótipo , Adulto JovemRESUMO
BACKGROUND: Exercise-induced bronchoconstriction (EIB) occurs in up to 90% of young people with asthma and can be diagnosed using serial measurements of forced expiratory volume in 1 second (FEV1) after standardized exercise, usually treadmill running (TR). Eucapnic voluntary hyperventilation (EVH) is a guideline-recommended alternative challenge for EIB diagnosis. The 2 methods have not been compared for EIB diagnosis in this population. OBJECTIVE: To compare 2 methods of EIB diagnosis in children and adolescents with asthma. METHODS: Thirty-four children 8 to 18 years of age attending the allergy clinic of the Hospital das Clínicas (Recife, Brazil) from September through December 2013 were examined. All underwent a basal FEV1 determination followed by TR for 8 minutes or EVH for 6 minutes on consecutive days. The first challenge was chosen at random. Serial FEV1 determinations were obtained at 3, 5, 7, 10, 15, and 30 minutes after the challenge and the test result was considered positive if at least 2 consecutive FEV1 measurements decreased at least 10% below the basal value. RESULTS: Thirteen patients responded to the 2 challenges, 6 only after TR and 4 exclusively after EVH (agreement 71%, κ = 0.41). The 95% limits of agreement of FEV1 decreasing after the challenges were widely spread (mean 0.1%, limits 19.8% to -19.6%). CONCLUSION: The 2 tests cannot be used interchangeably and the reproducibility of the FEV1 response to the EVH challenge has to be properly evaluated to better understand its role in EIB diagnosis.
Assuntos
Asma Induzida por Exercício/diagnóstico , Broncoconstrição/fisiologia , Corrida/fisiologia , Adolescente , Criança , Teste de Esforço , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Hiperventilação , Masculino , EspirometriaRESUMO
Introduction: Malaria parasites increasingly develop resistance to all drugs available in the market, hampering the goal of reducing malaria burden. Methods: Herein, we evaluated the impact of a single-nucleotide variant, E738K, present in the 26S proteasome regulatory subunit rpn2 gene, identified in Plasmodium chabaudi resistant parasites. Plasmids carrying a functional rpn2 interspecies chimeric gene with 5' recombination region from P. falciparum and 3' from P. chabaudi were constructed and transfected into Dd2 P. falciparum parasites. Results and discussion: The 738K variant parasite line presented increased parasite survival when subjected to dihydroartemisinin (DHA), as well as increased chymotrypsin-like activity and decreased accumulation of polyubiquitinated proteins. We thus conclude that the ubiquitin-proteasome pathway, including the 738K variant, play an important role in parasite response to DHA, being the first report of a mutation in a potential DHA drug target enhancing parasite survival and contributing to a significant advance in the understanding the biology of artemisinin resistance.
Assuntos
Antimaláricos , Artemisininas , Plasmodium falciparum , Antimaláricos/farmacologia , Artemisininas/farmacologia , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismoRESUMO
The development of new cancer treatment options, such as multifunctional devices, allows for a more personalized treatment, avoiding the known severe side effects of conventional options. In this context, on-demand drug delivery systems can actively control the rate of drug release offering a precise control of treatment. Magnetically and thermally controlled drug delivery systems have been explored as on-demand devices to treat chronic diseases and cancer tumors. In the present work, dual-stimuli responsive systems were developed by incorporating Fe3O4 magnetic nanoparticles (NPs) and poly(N-isopropylacrylamide) (PNIPAAm) microgels into electrospun polymeric fibers for application in cancer treatment. First, Fe3O4 NPs with an average diameter of 8 nm were synthesized by chemical precipitation technique and stabilized with dimercaptosuccinic acid (DMSA) or oleic acid (OA). PNIPAAm microgels were synthesized by surfactant-free emulsion polymerization (SFEP). Poly(vinyl alcohol) (PVA) was used as a fiber template originating fibers with an average diameter of 179 ± 14 nm. Stress tests of the membranes showed that incorporating both microgels and Fe3O4 NPs in electrospun fibers increases their Young's modulus. Swelling assays indicate that PVA membranes have a swelling ratio of around 3.4 (g/g) and that the presence of microgels does not affect its swelling ability. However, with the incorporation of Fe3O4 NPs, the swelling ratio of the membranes decreases. Magnetic hyperthermia assays show that a higher concentration of NPs leads to a higher heating ability. The composite membrane with the most promising results is the one incorporated with DMSA-coated NPs, since it shows the highest temperature variation, 5.1 °C. To assess the membranes biocompatibility and ability to promote cell proliferation, indirect and direct contact cell viability assays were performed, as well as cell adhesion assays. Following an extract method viability assay, all membrane designs did not reveal cytotoxic effects on dermal fibroblasts and melanoma cancer cells, after 48 h exposure and support long-term viability. The present work demonstrates the potential of dual-stimuli composite membranes for magnetic hyperthermia and may in the future be used as an alternative cancer treatment particularly in anatomically reachable solid tumors.
Assuntos
Hipertermia Induzida , Microgéis , Nanofibras , Neoplasias , Álcool de Polivinil , Fenômenos MagnéticosRESUMO
Following integrated malaria control interventions, malaria burden on the Bijagós Archipelago has significantly decreased. Understanding the genomic diversity of circulating Plasmodium falciparum malaria parasites can assist infection control, through identifying drug resistance mutations and characterising the complexity of population structure. This study presents the first whole genome sequence data for P. falciparum isolates from the Bijagós Archipelago. Amplified DNA from P. falciparum isolates sourced from dried blood spot samples of 15 asymptomatic malaria cases were sequenced. Using 1.3 million SNPs characterised across 795 African P. falciparum isolates, population structure analyses revealed that isolates from the archipelago cluster with samples from mainland West Africa and appear closely related to mainland populations; without forming a separate phylogenetic cluster. This study characterises SNPs associated with antimalarial drug resistance on the archipelago. We observed fixation of the PfDHFR mutations N51I and S108N, associated with resistance to sulphadoxine-pyrimethamine, and the continued presence of PfCRT K76T, associated with chloroquine resistance. These data have relevance for infection control and drug resistance surveillance; particularly considering expected increases in antimalarial drug use following updated WHO recommendations, and the recent implementation of seasonal malaria chemoprevention and mass drug administration in the region.
Assuntos
Antimaláricos , Antagonistas do Ácido Fólico , Malária Falciparum , Malária , Humanos , Plasmodium falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Guiné-Bissau , Filogenia , Proteínas de Protozoários/genética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Pirimetamina/farmacologia , Pirimetamina/uso terapêutico , Malária/parasitologia , Mutação , Resistência a Medicamentos/genética , Combinação de Medicamentos , Dinâmica PopulacionalRESUMO
Aicardi-Goutières syndrome (AGS) is a rare inherited autoimmune disease caused by mutations in genes encoding the RNase H2 subunits A, B, and C; the DNase three prime repair exonuclease 1 (TREX1); and sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1). Using unbiased affinity purification coupled to protein mass spectrometry, we identify SAMHD1 as a nucleic-acid-binding protein displaying a preference for RNA over DNA. In contrast to TREX1 and the RNase H2 complex, SAMHD1 has no obvious nuclease activity. In addition, interrogating truncation mutants of SAMHD1 observed in AGS patients, we map the nucleic-acid-binding domain to residues 164-442, thus overlapping with the HD domain. Furthermore, we show that although wild-type SAMHD1 displays almost exclusive nuclear localization, 11 of 12 SAMHD1 mutants show at least partial mislocalization to the cytosol. Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.
Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Imunofluorescência , Predisposição Genética para Doença/genética , Humanos , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação , Proteína 1 com Domínio SAM e Domínio HDRESUMO
TANK-binding kinase 1 (TBK1) is of central importance for the induction of type-I interferon (IFN) in response to pathogens. We identified the DEAD-box helicase DDX3X as an interaction partner of TBK1. TBK1 and DDX3X acted synergistically in their ability to stimulate the IFN promoter, whereas RNAi-mediated reduction of DDX3X expression led to an impairment of IFN production. Chromatin immunoprecipitation indicated that DDX3X is recruited to the IFN promoter upon infection with Listeria monocytogenes, suggesting a transcriptional mechanism of action. DDX3X was found to be a TBK1 substrate in vitro and in vivo. Phosphorylation-deficient mutants of DDX3X failed to synergize with TBK1 in their ability to stimulate the IFN promoter. Overall, our data imply that DDX3X is a critical effector of TBK1 that is necessary for type I IFN induction.
Assuntos
RNA Helicases DEAD-box/fisiologia , Imunidade Inata , Interferon Tipo I/imunologia , Proteínas Serina-Treonina Quinases/fisiologia , Sequência de Aminoácidos , Linhagem Celular , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Humanos , Interferon Tipo I/biossíntese , Interferon Tipo I/genética , Listeria monocytogenes/fisiologia , Listeriose/imunologia , Listeriose/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
OBJECTIVE: This article reviews the epidemiology and treatment of bone metastases. Also, it revisits the mechanism of action, indications, benefits, and complications of antiresorptive agents; discusses the adverse event profile of these agents; and addresses the prevention and management of these side effects. DATA SOURCES: For this review, peer-reviewed articles, research publications, and relevant clinical guidelines identified from PubMed were used. CONCLUSION: Bone metastases are common in advanced cancer and much more frequently than in primary bone cancer, especially in adults. Bisphosphonates and Denosumab are potent antiresorptives and significantly reduce the risk of skeletal-related events. These complications are related to poor quality of life, bone pain, functional disability, and decreased survival. Prolonged therapy with these antiresorptive agents in patients with advanced malignancy is generally well tolerated, but some side effects are potentially serious and require periodic monitoring. Furthermore, some of them can be avoided. IMPLICATIONS FOR NURSING PRACTICE: The role of health care providers and specially nurses on identifying patients at risk of complications from these antiresorptive agents, and providing information on how to prevent them, is essential for health and quality of life maintenance in these patients.
Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Segunda Neoplasia Primária , Adulto , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Denosumab/efeitos adversos , Humanos , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/tratamento farmacológico , Qualidade de VidaRESUMO
Encapsulation in agriculture today is practically focused on agrochemicals such as pesticides, herbicides, fungicides, or fertilizers to enhance the protective or nutritive aspects of the entrapped active ingredients. However, one of the most promising and environmentally friendly technologies, biostimulants, is hardly explored in this field. Encapsulation of biostimulants could indeed be an excellent means of counteracting the problems posed by their nature: they are easily biodegradable, and most of them run off through the soil, losing most of the compounds, thus becoming inaccessible to plants. In this respect, encapsulation seems to be a practical and profitable way to increase the stability and durability of biostimulants under field conditions. This review paper aims to provide researchers working on plant biostimulants with a quick overview of how to get started with encapsulation. Here we describe different techniques and offer protocols and suggestions for introduction to polymer science to improve the properties of biostimulants for future agricultural applications.
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OBJECTIVE: This study aimed to compare the effects of therapeutic ultrasound and paraffin with or without vacuum massage on the biomechanical properties of grafted skin after a burn. METHODS: A total of 44 patients with deep second- and third-degree burns, with a mean age of 35.89 (±11.53) years, who visited the Hospital Burn Unity, were included in the study. The therapeutic interventions were randomly defined by drawing lots, with a crossover design (crossover), and a minimum interval of 7 days (washout) between interventions. Skin biomechanical parameters such as distensibility (R0) and viscoelasticity (R6) were noninvasively evaluated by Cutometer before and after 0, 10, 20, and 30 min of intervention with therapeutic ultrasound and paraffin alone, as well as associated with negative pressure therapy of the skin (vacuum therapy). In this study, all groups showed increased distensibility (R0) in the period immediately after the application of the resources and a progressive reduction in the effects in the consecutive tests. Participants with skin grafts showed a decrease in viscoelasticity (R6) in all groups, except therapeutic paraffin and therapeutic ultrasound and vacuum massage. CONCLUSION: The biomechanical properties of grafted skin after a burn are altered after therapeutic intervention with ultrasound alone or associated with vacuum massage, such as intervention with paraffin associated with vacuum massage, for both parameters evaluated, skin distensibility (R0) and skin viscoelasticity (R6). However, the same did not occur for the intervention with isolated paraffin. There was no significant difference between the interventions therapeutic ultrasound and therapeutic paraffin.
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Queimaduras , Terapia por Ultrassom , Humanos , Adulto , Parafina , Pele , Queimaduras/terapia , MassagemRESUMO
The delivery of multiple anti-cancer agents holds great promise for better treatments. The present work focuses on developing multifunctional materials for simultaneous and local combinatory treatment: Chemotherapy and hyperthermia. We first produced hybrid microgels (MG), synthesized by surfactant-free emulsion polymerization, consisting of Poly (N-isopropyl acrylamide) (PNIPAAm), chitosan (40 wt.%), and iron oxide nanoparticles (NPs) (5 wt.%) as the inorganic component. PNIPAAm MGs with a hydrodynamic diameter of about 1 µm (in their swollen state) were successfully synthesized. With the incorporation of chitosan and NPs in PNIPAAm MG, a decrease in MG diameter and swelling capacity was observed, without affecting their thermosensitivity. We then sought to produce biocompatible and mechanically robust membranes containing these dual-responsive MG. To achieve this, MG were incorporated in poly (vinyl pyrrolidone) (PVP) fibers through colloidal electrospinning. The presence of NPs in MG decreases the membrane swelling ratio from 10 to values between 6 and 7, and increases the material stiffness, raising its Young modulus from 20 to 35 MPa. Furthermore, magnetic hyperthermia assay shows that PVP-MG-NP composites perform better than any other formulation, with a temperature variation of about 1 °C. The present work demonstrates the potential of using multifunctional colloidal membranes for magnetic hyperthermia and may in the future be used as an alternative treatment for cancer.
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Distribution of long-lasting insecticide-treated nets (LLINs), passive detection and treatment with artemisinin-based combination therapy (ACT), and intermittent preventive treatment in pregnancy (IPTp) are the mainstay malaria control measures of Guinea-Bissau's national control programme. This study aimed to estimate the prevalence of Plasmodium falciparum on Bubaque, the most populous island of the country's remote Bijagos archipelago. A cross-sectional survey was performed at the start of the rainy season in August 2017. Participants were recruited using systematic random sampling in a two-stage stratified cluster design. Malaria parasitemia was detected using rapid diagnostic tests (RDTs) and quantitative PCR (qPCR). Data on housing, education, larval source management, socioeconomic status, anemia, and malaria preventive measures were collected. Multivariable logistic regression models were constructed to identify associations with P. falciparum infection. Four hundred four persons (aged 6 months-79 years, median 17 years) were enrolled in the study. The prevalence of P. falciparum parasitemia was 5.8% by RDT (95% CI: 3.55-9.33) and 16.9% by qPCR (95% CI: 13.09-21.71). The prevalence of anemia was 74.3% (95% CI: 69.04-78.85) as defined by the WHO criteria. All sampled houses were found to have open eaves; 99.5% of the surveyed population reported sleeping under a bednet (95% CI: 97.8-99.9). Although reported LLIN use is high, there remains an appreciable prevalence of malaria, suggesting that transmission is ongoing and further tools are required to reduce the burden of the disease.