Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work ...has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD.
Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. We investigated immunogenicity and protective efficacy of a multi-antigen (MA) universal ...influenza DNA vaccine consisting of HA, M2, and NP antigens in cynomolgus macaques. Following challenge with a heterologous pandemic H1N1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. The MA DNA vaccine induced robust serum and mucosal antibody responses but these high antibody titers were not broadly neutralizing. In contrast, the vaccine induced broadly-reactive NP specific T cell responses that cross-reacted with the challenge virus and inversely correlated with lower viral loads and inflammation. These results demonstrate that a MA DNA vaccine that induces strong cross-reactive T cell responses can, independent of neutralizing antibody, mediate significant cross-protection in a nonhuman primate model and further supports development as an effective approach to induce broad protection against circulating and emerging influenza strains.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Intensivists are increasingly attuned to the postdischarge outcomes experienced by families because patient recovery and family outcomes are interdependent after childhood critical ...illness. In this scoping review of international contemporary literature, we describe the evidence of family effects and functioning postpediatric intensive care unit (PICU) as well as outcome measures used to identify strengths and weaknesses in the literature.
Methods
We reviewed all articles published between 1970 and 2017 in PubMed, Embase, PsycINFO, Cumulative Index of Nursing and Allied Health Literature (CINAHL), or the Cochrane Controlled Trials Registry. Our search used a combination of terms for the concept of “critical care/illness” combined with additional terms for the prespecified domains of social, cognitive, emotional, physical, health-related quality of life (HRQL), and family functioning.
Results
We identified 71 articles reporting on the postPICU experience of more than 2400 parents and 3600 families of PICU survivors in 8 countries. These articles used 101 different metrics to assess the various aspects of family outcomes; 34 articles also included open-ended interviews. Overall, most families experienced significant disruption in at least five out of six of our family outcomes subdomains, with themes of decline in mental health, physical health, family cohesion, and family finances identified. Almost all articles represented relatively small, single-center, or disease-specific observational studies. There was a disproportionate representation of families of higher socioeconomic status (SES) and Caucasian race, and there was much more data about mothers compared to fathers. There was also very limited information regarding outcomes for siblings and extended family members after a child's PICU stay.
Conclusions
Significant opportunities remain for research exploring family functioning after PICU discharge. We recommend that future work include more diverse populations with respect to the critically ill child as well as family characteristics, include more intervention studies, and enrich existing knowledge about outcomes for siblings and extended family.
A new version of the Century ecosystem model, modified to better represent chemically and physically recalcitrant organic amendments by allowing the addition of organic waste products (OWP) as a ...mixture of plant material and surface slow soil organic matter (SOM) controlled by the Indicator of Residual Organic Carbon (IROC), and field observations from a 16‐year wheat corn rotation experiment near Paris, France, were used to assess the long‐term impacts of applying agricultural and municipal organic waste products (OWP) on soil carbon (C) sequestration, grain C and nutrient content, and soil nutrient status. Sixteen years of observed grain C, nitrogen (N), phosphorus (P), and potassium (K) and soil C and nutrient data were used to calibrate and validate the performance of IROC‐Century. A suite of future management scenarios, simulated using this calibrated model, explored multiple frequencies of applications of OWP and fertilizer to evaluate their long‐term impacts on grain C and nutrient content, soil C sequestration, and NO3− leaching. The model effectively simulated the impact of biennial additions of four OWP types on soil C, N, P, and K during the 16‐year experiment. Measured and simulated OWP +fertilizer resulted in higher soil C (highest for well‐decomposed 55% vs. less‐decomposed 37% OWP) and N content, while total soil accumulation of N, P, and K was determined by the content of the OWP, regardless of IROC, and OWP greatly reduced the need to add chemical fertilizer while increasing crop production and N, P, and K uptake by the crop. Simulation scenarios using IROC‐Century for future management suggest that the optimal cropping management system to maintain high corn and wheat production and reduce NO3− leaching is to apply OWP biennially for 12 years along with fertilizer and then reduce OWP to every fourth year while continuing to add fertilizer to the wheat crop only. However, reducing the number of OWP additions in these scenarios did decrease the rate of soil carbon sequestration.
Core Ideas
Observed and simulated biennial addition of organic waste products (OWP) increased grain carbon (C), nitrogen, phosphorus, and potassium by >40%.
Observed and simulated biennial additions of OWP during a 16‐year period increased soil C by >38%.
Maximum corn grain C occurred after biennial OWP applications over 16 years.
Soil carbon stabilization is greater for composted OWP than fresh manure and increases with compost age.
To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors ...peroxisome proliferator-activated receptor α (PPARα; muscle creatine kinase MCK-PPARα) or PPARβ/δ (MCK-PPARβ/δ). MCK-PPARβ/δ mice are known to have enhanced exercise performance, whereas MCK-PPARα mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase b (Ldhb)/Ldha gene expression ratio is increased in MCK-PPARβ/δ muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARβ/δ gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARβ/δ, but not PPARα, interacts with the exercise-inducible kinase AMP-activated protein kinase (AMPK) to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A) in a PPARβ/δ ligand-independent manner. MCK-PPARβ/δ muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation, suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARβ/δ mice persistently oxidized glucose compared with nontransgenic controls, while exhibiting supranormal performance. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training.
Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of ...proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and IFN-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.
This paper investigates peer effects at the level of individual connections, leveraging the approach to shed light on peer mechanisms. In a field experiment using college freshmen, we elicited best ...friends and offered monetary incentives for gym visits to a treated subset. We find large spillovers from treated subjects to treated best friends but none from treated subjects to control best friends. We also find evidence of a mechanism: Subjects coordinate by visiting the gym with best friends, indicating that the intervention harnesses complementarities in utility or commitment mechanisms. Results highlight subtle peer effects and mechanisms that often go undetected.
•This field experiment identifies large spillovers from treated subjects to treated best friends•This experiment finds no spillover from treated subjects to control best friends•Subjects coordinate by visiting the gym with best friends•The intervention harnesses complementarities in utility or commitment mechanisms•The results highlight subtle peer effects and mechanisms that often go undetected
Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors ...include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).
In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2
tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy.
Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (
= 4) and 32.7 months in cohort 2 (
= 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS.
VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.
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