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2.
Sci Rep ; 11(1): 16591, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400712

RESUMO

Lipidomics is advantageous in the study of sebum perturbations occurring in acne. An extended evaluation of the sebum lipid profiles in acne-prone sebaceous areas is lacking in dark skin. Yet, there is a void space in understanding how the building blocks of sebum lipids, i.e. individual fatty acids (FAs), are intertwined with acne-prone skin. We aimed to determine the sebum lipidome in facial areas of adolescents with and without acne in Nigeria. A cross-sectional analytical study was conducted in 60 adolescents/young adults divided in 30 acne patients (15F, 15M) and 30 age and sex-matched controls. Sebum samples obtained from foreheads and cheeks were analysed separately by gas chromatography-mass spectrometry (GCMS) and thin layer chromatography (HPTLC). Distributions of sebum components were investigated with multivariate ANOVA-simultaneous component analysis (ASCA). Sebum incretion in acne was paralleled by significantly higher abundance of triglycerides, wax esters, and squalene together with monounsaturated FAs (MUFAs), and straight chain saturated FAs (SFAs), especially those with odd-carbon chain, i.e. C13:0, C15:0, and C17:0. Profiling weight/weight percentage of individual components revealed that, in acne, the free FAs (FFAs) array was shifted towards higher relative abundance of the SFAs C15:0, C16:0, and C17:0 and lower percentage of the anteiso-branched FFAs with 12, 14, 16, and 18 carbons. In acne patients, MUFAs and PUFAs were quantitatively increased and decreased on foreheads and cheeks, respectively. Relative abundance of fatty alcohols was decreased in acne independent on the site. The results indicated that acne associates with site-specific derangement of the pathways regulating the balance among odd straight-chain and branched-chain SFAs, MUFAs, which included sapienate (C16:1n-10), PUFAs, and squalene.

3.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445526

RESUMO

Among disorders of pigmentation, vitiligo is the most common, with an estimated prevalence between 0.5% and 1%. The disease has gathered increased attention in the most recent years, leading to a better understanding of the disease's pathophysiology and its implications and to the development of newer therapeutic strategies. A better, more integrated approach is already in use for other chronic inflammatory dermatological diseases such as psoriasis, for which metabolic comorbidities are well-established and part of the routine clinical evaluation. The pathogenesis of these might be linked to cytokines which also play a role in vitiligo pathogenesis, such as IL-1, IL-6, TNF-α, and possibly IL-17. Following the reports of intrinsic metabolic alterations reported by our group, in this brief review, we analyze the available data on metabolic comorbidities in vitiligo, accompanied by our single-center experience. Increased awareness of the metabolic aspects of vitiligo is crucial to improving patient care.


Assuntos
Doenças Metabólicas/epidemiologia , Vitiligo/epidemiologia , Ensaios Clínicos como Assunto , Comorbidade , Humanos , Doenças Metabólicas/patologia , Vitiligo/patologia
4.
Front Public Health ; 9: 683683, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249847

RESUMO

Background: During the lockdown for COVID-19, a massive decrease in hospital admissions for acute coronary syndrome (ACS) and a drop in air pollution were both detected in Italy. Our aim was to investigate the possible association between these two events at the Province of Terni, one of the most polluted urban and industrial area in Central Italy. Methods: We analyzed data of daily 24-h urban air concentrations of particulate matter (PM)10 and PM2.5 from fixed station monitoring network located in the main city centers of the Terni province, and accesses for ACS at the catheterization laboratory of the Cardiological Hub Center of the Terni University Hospital during lockdown. A comparison was made with data corresponding to the same lockdown time period of years 2019, 2018, and 2017. Results: Invasive procedures for ACS decreased in 2020 (n = 49) as compared with previous years (n = 93 in 2019, n = 109 in 2018, and n = 89 in 2017, p < 0.001). Conversely, reductions in average PM10 (20.7 µg/m3) and PM2.5 (14.7 µg/m3) in 2020 were consistent with a long-term decreasing trend, being comparable to those recorded in 2019 and 2018 (all p > 0.05) and slightly lower than 2017 (p < 0.05). The Granger-causality test demonstrated the lack of association between time-varying changes in air pollution and the number of procedures for ACS. Conclusions: Our results did not support the hypothesis that reduction in invasive procedures for ACS during lockdown was linked to an air cleaning effect. Reasons other than reduced air pollution should be sought to explain the observed decrease in ACS procedures.


Assuntos
Síndrome Coronariana Aguda , Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Síndrome Coronariana Aguda/epidemiologia , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Cidades , Controle de Doenças Transmissíveis , Monitoramento Ambiental , Humanos , Itália/epidemiologia , SARS-CoV-2
5.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299118

RESUMO

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Catecóis/farmacologia , Diferenciação Celular , Inflamação/tratamento farmacológico , Compostos Organometálicos/farmacologia , Psoríase/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Ligantes , Psoríase/metabolismo , Psoríase/patologia , Pele/metabolismo , Pele/patologia
6.
Elife ; 102021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34009123

RESUMO

Genes encoding glycosyltransferases can be under relatively high selection pressure, likely due to the involvement of the glycans synthesized in host-microbe interactions. Here, we used mice as an experimental model system to investigate whether loss of α-1,3-galactosyltransferase gene (GGTA1) function and Galα1-3Galß1-4GlcNAcß1-R (αGal) glycan expression affects host-microbiota interactions, as might have occurred during primate evolution. We found that Ggta1 deletion shaped the composition of the gut microbiota. This occurred via an immunoglobulin (Ig)-dependent mechanism, associated with targeting of αGal-expressing bacteria by IgA. Systemic infection with an Ig-shaped microbiota inoculum elicited a less severe form of sepsis compared to infection with non-Ig-shaped microbiota. This suggests that in the absence of host αGal, antibodies can shape the microbiota towards lower pathogenicity. Given the fitness cost imposed by bacterial sepsis, we infer that the observed reduction in microbiota pathogenicity upon Ggta1 deletion in mice may have contributed to increase the frequency of GGTA1 loss-of-function mutations in ancestral primates that gave rise to humans.


Assuntos
Bactérias/metabolismo , Evolução Molecular , Microbioma Gastrointestinal , Intestinos/microbiologia , Polissacarídeos/metabolismo , Primatas/microbiologia , Animais , Bactérias/imunologia , Bactérias/patogenicidade , Feminino , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Interações Hospedeiro-Patógeno , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Mutação com Perda de Função , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polissacarídeos/imunologia , Primatas/genética , Primatas/imunologia , Primatas/metabolismo , Seleção Genética , Sepse/genética , Sepse/imunologia , Sepse/metabolismo , Sepse/microbiologia
7.
Cell Host Microbe ; 29(3): 347-361.e12, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33497603

RESUMO

Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide α-1,3-galactosyltransferase enzyme, which synthesizes Gal-α1-3Gal-ß1-4GlcNAc (α-gal) and are thus tolerant to this self-expressed glycan. Old World primates including humans, however, carry loss-of-function mutations in GGTA1 and lack α-gal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of α-gal-specific immunity, conferring resistance to α-gal-expressing pathogens. Here, we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of α-Gal-specific immunity. Rather, the absence of α-gal from IgG-associated glycans increases IgG effector function via a mechanism associated with enhanced IgG-Fc gamma receptor (FcγR) binding. The ensuing survival advantage against sepsis comes alongside a cost of accelerated reproductive senescence in Ggta1-deleted mice. Mathematical modeling of this trade-off suggests that high exposure to virulent pathogens exerts sufficient selective pressure to fix GGTA1 loss-of-function mutations, as likely occurred during the evolution of primates toward humans.


Assuntos
Evolução Biológica , Dissacarídeos , Sepse/microbiologia , Animais , Bactérias , Proteínas de Transporte , Proteínas de Ligação a DNA , Feminino , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Glicoproteínas , Hominidae , Humanos , Imunoglobulina G/imunologia , Masculino , Mamíferos/imunologia , Camundongos , Camundongos Knockout , Polissacarídeos , Primatas
8.
Gigascience ; 9(10)2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084878

RESUMO

BACKGROUND: Some natural systems are big in size, complex, and often characterized by convoluted mechanisms of interaction, such as epistasis, pleiotropy, and trophism, which cannot be immediately ascribed to individual natural events or biological entities but that are often derived from group effects. However, the determination of important groups of entities, such as genes or proteins, in complex systems is considered a computationally hard task. RESULTS: We present Pyntacle, a high-performance framework designed to exploit parallel computing and graph theory to efficiently identify critical groups in big networks and in scenarios that cannot be tackled with traditional network analysis approaches. CONCLUSIONS: We showcase potential applications of Pyntacle with transcriptomics and structural biology data, thereby highlighting the outstanding improvement in terms of computational resources over existing tools.

9.
Am J Med Genet A ; 182(3): 508-512, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31880396

RESUMO

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) is a rare autosomal recessive neuromuscular disorder characterized by arthrogryposis multiplex congenita and prenatal fractures of the long bones, with poor prognosis. The most affected patients present with biallelic loss-of-function nucleotide variants in ASCC1 gene, coding a subunit of the transcriptional coactivator ASC-1 complex, although the exact pathogenesis is yet unknown. This work describes the first case of SMABF2 in a stillbirth with documented evolution of the disease in the prenatal period. A microdeletion copy number variant (CNV) of about 64 Kb, involving four exons of ASCC1, was firstly detected by microarray analysis, requested for arthrogryposis and hydrops. Subsequent exome analysis disclosed a nucleotide variant of the same gene [c.1027C>T; (p. Arg343*)], resulting in the introduction of a premature termination codon. This stillbirth represents the first case of ASCC1 compound heterozygosity, due to an exonic microdeletion and a nucleotide variant, expanding the mutational spectrum of this gene. It also provides further evidence that exonic CNVs are an underestimated cause of disease-alleles and that the integrated use of the last generation genetic analysis tools, together with careful clinical evaluations, are fundamental for the characterization of rare diseases even in the prenatal setting.


Assuntos
Proteínas de Transporte/genética , Anormalidades Congênitas/genética , Fraturas Ósseas/genética , Atrofia Muscular Espinal/genética , Códon sem Sentido/genética , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/fisiopatologia , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/fisiopatologia , Estudos de Associação Genética , Testes Genéticos , Humanos , Masculino , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Gravidez , Natimorto/epidemiologia , Natimorto/genética , Sequenciamento Completo do Exoma
10.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533246

RESUMO

Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomic, proteomic, and functional properties of ultradian and circadian subsets. We found hallmarks of the three oscillating gene subsets, including different (i) functional annotation, (ii) proteomic and electrochemical features, and (iii) transcription factor binding motifs in upstream regions of 8-h and 12-h oscillating genes that seemingly allow the link of the ultradian gene sets to a known circadian network. Our multifaceted bioinformatics analysis of circadian and ultradian genes suggests that the different rhythmicity of gene expression impacts physiological outcomes and may be related to transcriptional, translational and post-translational dynamics, as well as to phylogenetic and evolutionary components.


Assuntos
Genômica , Mamíferos/genética , Mamíferos/metabolismo , Proteômica , Animais , Sítios de Ligação , Biomarcadores , Mapeamento Cromossômico , Biologia Computacional/métodos , Epigênese Genética , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Anotação de Sequência Molecular , Filogenia , Regiões Promotoras Genéticas , Proteoma , Proteômica/métodos , Fatores de Tempo , Fatores de Transcrição
11.
Evol Bioinform Online ; 15: 1176934319850144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205410

RESUMO

In several fields of research, molecular dynamics simulation techniques are exploited to evaluate the temporal motion of particles constituting water, ions, small molecules, macromolecules, or more complex systems over time. These techniques are considered difficult to setup, computationally demanding and require high specialization and scientific skills. Moreover, they need specialized computing infrastructures to run faster and make the simulation of big systems feasible. Here, we have simulated 3 systems of increasing sizes on scientific- and gaming-enabled graphic processing unit (GPU) cards with Amber, GROMACS, and NAMD and measured their performance accounting also for the market prices of the GPU cards where they were run on.

12.
Front Microbiol ; 9: 1179, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29922262

RESUMO

The yeast Candida albicans is an important opportunistic human pathogen. For C. albicans strain typing or drug susceptibility testing, a single colony recovered from a patient sample is normally used. This is insufficient when multiple strains are present at the site sampled. How often this is the case is unclear. Previous studies, confined to oral, vaginal and vulvar samples, have yielded conflicting results and have assessed too small a number of colonies per sample to reliably detect the presence of multiple strains. We developed a next-generation sequencing (NGS) modification of the highly discriminatory C. albicans MLST (multilocus sequence typing) method, 100+1 NGS-MLST, for detection and typing of multiple strains in clinical samples. In 100+1 NGS-MLST, DNA is extracted from a pool of colonies from a patient sample and also from one of the colonies. MLST amplicons from both DNA preparations are analyzed by high-throughput sequencing. Using base call frequencies, our bespoke DALMATIONS software determines the MLST type of the single colony. If base call frequency differences between pool and single colony indicate the presence of an additional strain, the differences are used to computationally infer the second MLST type without the need for MLST of additional individual colonies. In mixes of previously typed pairs of strains, 100+1 NGS-MLST reliably detected a second strain. Inferred MLST types of second strains were always more similar to their real MLST types than to those of any of 59 other isolates (22 of 31 inferred types were identical to the real type). Using 100+1 NGS-MLST we found that 7/60 human samples, including three superficial candidiasis samples, contained two unrelated strains. In addition, at least one sample contained two highly similar variants of the same strain. The probability of samples containing unrelated strains appears to differ considerably between body sites. Our findings indicate the need for wider surveys to determine if, for some types of samples, routine testing for the presence of multiple strains is warranted. 100+1 NGS-MLST is effective for this purpose.

13.
Mol Plant Microbe Interact ; 30(2): 138-149, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28027026

RESUMO

Increased resilience of pasture grasses mediated by fungal Epichloë endophytes is crucial to pastoral industries. The underlying mechanisms are only partially understood and likely involve very different activities of the endophyte in different plant tissues and responses of the plant to these. We analyzed the transcriptomes of Epichloë festucae and its host, Lolium perenne, in host tissues of different function and developmental stages. The endophyte contributed approximately 10× more to the transcriptomes than to the biomass of infected tissues. Proliferating mycelium in growing host tissues highly expressed genes involved in hyphal growth. Nonproliferating mycelium in mature plant tissues, transcriptionally equally active, highly expressed genes involved in synthesizing antiherbivore compounds. Transcripts from the latter accounted for 4% of fungal transcripts. Endophyte infection systemically but moderately increased transcription of L. perenne genes with roles in hormone biosynthesis and perception as well as stress and pathogen resistance while reducing expression of genes involved in photosynthesis. There was a good correlation between transcriptome-based observations and physiological observations. Our data indicate that the fitness-enhancing effects of the endophyte are based both on its biosynthetic activities, predominantly in mature host tissues, and also on systemic alteration of the host's hormonal responses and induction of stress response genes. [Formula: see text] Copyright © 2017 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .


Assuntos
Endófitos/fisiologia , Meio Ambiente , Epichloe/fisiologia , Interações Hospedeiro-Patógeno , Lolium/imunologia , Lolium/microbiologia , Reguladores de Crescimento de Plantas/metabolismo , Núcleo Celular/metabolismo , Cloroplastos/metabolismo , DNA de Plantas/metabolismo , Endófitos/genética , Epichloe/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes Fúngicos , Herbivoria , Hifas/genética , Lolium/crescimento & desenvolvimento , Fases de Leitura Aberta/genética , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/metabolismo , Simbiose/genética , Transcrição Genética , Transcriptoma/genética
14.
Genetics ; 203(3): 1249-64, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27182943

RESUMO

HDAC4 is a potent memory repressor with overexpression of wild type or a nuclear-restricted mutant resulting in memory deficits. Interestingly, reduction of HDAC4 also impairs memory via an as yet unknown mechanism. Although histone deacetylase family members are important mediators of epigenetic mechanisms in neurons, HDAC4 is predominantly cytoplasmic in the brain and there is increasing evidence for interactions with nonhistone proteins, suggesting HDAC4 has roles beyond transcriptional regulation. To that end, we performed a genetic interaction screen in Drosophila and identified 26 genes that interacted with HDAC4, including Ubc9, the sole SUMO E2-conjugating enzyme. RNA interference-induced reduction of Ubc9 in the adult brain impaired long-term memory in the courtship suppression assay, a Drosophila model of associative memory. We also demonstrate that HDAC4 and Ubc9 interact genetically during memory formation, opening new avenues for investigating the mechanisms through which HDAC4 regulates memory formation and other neurological processes.


Assuntos
Encéfalo/metabolismo , Proteínas de Drosophila/genética , Histona Desacetilases/genética , Memória de Longo Prazo , Enzimas de Conjugação de Ubiquitina/genética , Animais , Encéfalo/crescimento & desenvolvimento , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Histona Desacetilases/metabolismo , Interferência de RNA , Sumoilação/genética , Enzimas de Conjugação de Ubiquitina/metabolismo
15.
PLoS One ; 7(11): e50240, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23209685

RESUMO

Nucleotides are involved in several cellular processes, ranging from the transmission of genetic information, to energy transfer and storage. Both sequence and structure based methods have been developed to predict the location of nucleotide-binding sites in proteins. Here we propose a novel methodology that leverages the observation that nucleotide-binding sites have a modular structure. Nucleotides are composed of identifiable fragments, i.e. the phosphate, the nucleobase and the carbohydrate moieties. These fragments are bound by specific structural motifs that recur in proteins of different fold. Moreover these motifs behave as modules and are found in different combinations across fold space. Our method predicts binding sites for each nucleotide fragment by comparing a query protein with a database of templates extracted from proteins of known structure. Whenever a similarity is found the fragment bound by the template is transferred on the query protein, thus identifying a putative binding site. Predictions falling inside the surface of the protein are discarded, and the remaining ones are scored using clustering and conservation. The method is able to rank as first a correct prediction in the 48%, 48% and 68% of the analyzed proteins for the nucleobase, carbohydrate and phosphate respectively, while considering the first five predictions the performances change to 71%, 65% and 86% respectively. Furthermore we attempted to reconstruct the full structure of the binding site, starting from the predicted positions of the fragments. We calculated that in the 59% of the analyzed proteins the method ranks as first a reconstructed binding site or a part of it. Finally we tested the reliability of our method in a real world case in which it has to predict nucleotide-binding sites in unbound proteins. We analyzed proteins whose structure has been solved with and without the nucleotide and observed only little variations in the method performance.


Assuntos
Nucleotídeos/química , Proteínas/química , Animais , Proteínas de Bactérias/química , Sítios de Ligação , Carboidratos/química , Biologia Computacional/métodos , Bases de Dados de Proteínas , Humanos , Nucleotídeos/genética , Fosfatos/química , Proteínas de Plantas/química , Ligação Proteica , Dobramento de Proteína , Reprodutibilidade dos Testes , Software , Solventes/química
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