SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability ...of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.
Romanian Culture Houses of Students are state structures meant to continue the process of education and to contribute to artistic and civic culture formation of the young generation via their ...cultural, artistic and similar non-formal activities. The artistic-cultural activity cannot be supported and encouraged without an adequate financial potential. Insufficient financial support, every year felt with more intensity, obliged many Houses of Culture in Romania to abandon their activity or to give it less importance, replacing it with adjacent activities capable of creating their own incomes. The insufficient financing from the state budget requires indentifying and capitalizing extra-budgetary resources, making an effort to complement the institutions with their own necessary funds. The paper, primarily, highlights the legislative void regarding the financing strategies of the culture houses of Romanian students and secondarily, proposes some methods to reduce the impact of this lack of financing.
This study was conducted to evaluate the effect of polymer used with different nitrogen and potassium sources on the growth and nutrition of chrysanthemum (Dendranthema grandiforum, var. "Virginal") ...and on chemical characteristics of substrate. Two substrates were evaluated: 1) composite with 50 % organic soil, 45 % sand, and 5 % composted tobacco; 2) plow layer soil (0-20 cm depth; red oxisol typical dystrophic). The experimental design was a factorial (4x2x2) and included four polymer rates (0, 1, 2, and 4 g kg-1of substrate), two nitrogen ((NH4)2SO4 and (H2N)2CO), and two potassium (KCl and K2SO4) sources. Dry biomass, flower number, and concentration of K, Ca, and Mg were evaluated. Inverse relationships between polymer rates and plant biomass, macronutrient uptake were noticed, regardless substrate or nutrient source.
O polímero agrícola tem um grande potencial de uso como condicionador de solo para produção de mudas. Contudo, pouco conhecimento existe sobre seu uso e interação com fertilizantes.Visando avaliar o efeito do polímero com diferentes fontes de abubações nitrogenadas e potássicas, no crescimento e nutrição do crisântemo (var. "Virginal") e características químicas dos substratos, um experimento foi montado. A instalação foi em casa de vegetação da Empresa CONSPIZZA HIDROSSEMEADURA Ltda., situada no município de Colombo-PR, no verão de 2001. Dois substratos foram testados: 1) composto de 50% de solo orgânico, 45% de areia e 5% de fumo compostado; 2) camada superficial (0-20cm) de um LATOSSOLO VERMELHO Distrófico típico, do município de Ponta Grossa. O delineamento experimental foi em blocos ao acaso, com 5 repetições, em esquema fatorial 4x2x2, sendo 4 doses de polímero (0; 1; 2 e 4g kg-1 de substrato), 2 fontes nitrogenadas (NH4)2SO4 e (H2N)2CO e duas fontes potássicas (KCl e K2SO4), respectivamente. Determinou-se massa seca de ramos, folhas e teores de K, Ca e Mg. Os substratos foram avaliados quanto aos teores de K, Ca , Mg, valores de pH e condutividade elétrica (CE). Foram observados relações inversas entre doses de polímero e biomassa, absorção de K, Ca e Mg independente do substrato e fonte de fertilizante. Com exceção do K solúvel, cujos valores foram maiores em até 5 vezes em relação à testemunha, as demais características químicas do solo foram pouco afetadas. Foi observado um ligeiro aumento na CE, com o aumento nas doses de polímero em ambos os substratos. No substrato-1 os teores de todos os nutrientes analisados foram superiores aos observados no substrato-2. Mas, contrariamente, o crescimento das plantas foi melhor no substrato-2, indicando um provável desbalanço nutricional, principalmente associado às relações K/Ca e K/Mg. É possível também que o meio de crescimento do substrato 1 apresentava alguma característica não detectada que desfavoreceu o desenvolvimento da espécie testada. O polímero afetou negativamente a absorção de nutrientes e produção de biomassa, mas contribuiu substancialmente com o aumento de K nos substratos. Sugere-se novas pesquisas envolvendo outras espécies e substratos.
Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with ...wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.
Pneumococcal colonisation is regarded as a pre-requisite for developing pneumococcal disease. In children previous studies have reported pneumococcal colonisation to be a symptomatic event and ...described a relationship between symptom severity/frequency and colonisation density. The evidence for this in adults is lacking in the literature. This study uses the experimental human pneumococcal challenge (EHPC) model to explore whether pneumococcal colonisation is a symptomatic event in healthy adults.
Healthy participants aged 18-50 were recruited and inoculated intra-nasally with either Streptococcus pneumoniae (serotypes 6B, 23F) or saline as a control. Respiratory viral swabs were obtained prior to inoculation. Nasal and non-nasal symptoms were then assessed using a modified Likert score between 1 (no symptoms) to 7 (cannot function). The rate of symptoms reported between the two groups was compared and a correlation analysis performed.
Data from 54 participants were analysed. 46 were inoculated with S. pneumoniae (29 with serotype 6B, 17 with serotype 23F) and 8 received saline (control). In total, 14 became experimentally colonised (30.4%), all of which were inoculated with serotype 6B. There was no statistically significant difference in nasal (p = 0.45) or non-nasal symptoms (p = 0.28) between the inoculation group and the control group. In those who were colonised there was no direct correlation between colonisation density and symptom severity. In the 22% (12/52) who were co-colonised, with pneumococcus and respiratory viruses, there was no statistical difference in either nasal or non-nasal symptoms (virus positive p = 0.74 and virus negative p = 1.0).
Pneumococcal colonisation using the EHPC model is asymptomatic in healthy adults, regardless of pneumococcal density or viral co-colonisation.
Abstract Background Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 ...receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. Methods and findings In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. Conclusion Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
The morbidity and mortality related to respiratory tract diseases is enormous, with hundreds of millions of individuals afflicted and four million people dying each year. Understanding the ...immunological processes in the mucosa that govern outcome following pathogenic encounter could lead to novel therapies. There is a need to study responses at mucosal surfaces in humans for two reasons: (i) Immunological findings in mice, or other animals, often fail to translate to humans. (ii) Compartmentalization of the immune system dictates a need to study sites where pathogens reside. In this manuscript, we describe two novel non-invasive nasal mucosal microsampling techniques and their use for measuring immunological parameters: 1) using nasal curettes to collect cells from the inferior turbinate and; 2) absorptive matrices to collect nasal lining fluid. Both techniques were well tolerated and yielded reproducible and robust data. We demonstrated differences in immune populations and activation state in nasal mucosa compared to blood as well as compared to nasopharyngeal lumen in healthy adults. We also found superior cytokine detection with absorptive matrices compared to nasal wash. These techniques are promising new tools that will facilitate studies of the immunological signatures underlying susceptibility and resistance to respiratory infections.
Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of ...fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19.
This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing.
The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18–102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 11% of 741 vs 119 16% of 756); relative risk RR 0·68; 95% Bayesian credible interval 95% BCI: 0·52–0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53–0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21–0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio OR 0·68, 95% CI: 0·36–1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01–0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups.
Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.
FastGrants and The Rainwater Charitable Foundation.
For the Portuguese translation of the abstract see Supplementary Materials section.
Neural language networks at birth Perani, Daniela; Saccuman, Maria C; Scifo, Paola ...
Proceedings of the National Academy of Sciences - PNAS,
09/2011, Letnik:
108, Številka:
38
Journal Article
Recenzirano
Odprti dostop
The ability to learn language is a human trait. In adults and children, brain imaging studies have shown that auditory language activates a bilateral frontotemporal network with a left hemispheric ...dominance. It is an open question whether these activations represent the complete neural basis for language present at birth. Here we demonstrate that in 2-d-old infants, the language-related neural substrate is fully active in both hemispheres with a preponderance in the right auditory cortex. Functional and structural connectivities within this neural network, however, are immature, with strong connectivities only between the two hemispheres, contrasting with the adult pattern of prevalent intrahemispheric connectivities. Thus, although the brain responds to spoken language already at birth, thereby providing a strong biological basis to acquire language, progressive maturation of intrahemispheric functional connectivity is yet to be established with language exposure as the brain develops.
Background The Framingham 10-year cardiovascular disease risk score, which is based on age, sex, smoking, total cholesterol, high-density lipoprotein-cholesterol, blood pressure, and diabetes, has ...been found to be associated with cognitive health, but these findings have not been validated in a representative sample in the United States. We aimed to examine the associations of Framingham risk score with cognitive function among older adults in a nationally representative sample, as well as by race or ethnicity, education, and family income. Methods and Results A total of 2254 older adults ≥60 years (57% female, 79% non-Hispanic White) in the National Health and Nutrition Examination Survey 2011 to 2014 were included in the final sample for analysis. All components of the Framingham risk score were obtained with questionnaire or measured in the laboratory. Cognitive function was examined using the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Task (immediate and delayed memory), Digit Symbol Substitution Test, and Animal Fluency Test. Multivariable linear regression models were used to assess the associations between Framingham risk score and test-specific and global cognition
scores. Each incremental 5% in Framingham 10-year cardiovascular disease risk was associated with lower
scores for Digit Symbol Substitution Test (β=-0.06 95% CI, -0.09 to -0.03), delayed memory (β=-0.05 95% CI, -0.08 to -0.01), immediate memory (β=-0.07 95% CI, -0.10 to -0.03), and global cognition (β=-0.05 95% CI, -0.09 to -0.02). Socioeconomic status, particularly race or ethnicity and monthly income levels, were strong effect measure modifiers of the associations. Conclusions Lower cardiovascular risk factors are associated with better cognitive function.
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