As a key variance partitioning tool, linear mixed models (LMMs) using genome-based restricted maximum likelihood (GREML) allow both fixed and random effects. Classic LMMs assume independence between ...random effects, which can be violated, causing bias. Here we introduce a generalized GREML, named CORE GREML, that explicitly estimates the covariance between random effects. Using extensive simulations, we show that CORE GREML outperforms the conventional GREML, providing variance and covariance estimates free from bias due to correlated random effects. Applying CORE GREML to UK Biobank data, we find, for example, that the transcriptome, imputed using genotype data, explains a significant proportion of phenotypic variance for height (0.15, p-value = 1.5e-283), and that these transcriptomic effects correlate with the genomic effects (genome-transcriptome correlation = 0.35, p-value = 1.2e-14). We conclude that the covariance between random effects is a key parameter for estimation, especially when partitioning phenotypic variance by multi-omics layers.
Summary Sex chromosome aneuploidies are a common group of disorders that are characterised by an abnormal number of X or Y chromosomes. However, many individuals with these disorders are not ...diagnosed, despite established groups of core features that include aberrant brain development and function. Clinical presentations often include characteristic profiles of intellectual ability, motor impairments, and rates of neurological and psychiatric disorders that are higher than those of the general population. Advances in genetics and neuroimaging have substantially expanded knowledge of potential mechanisms that underlie these phenotypes, including a putative dose effect of sex chromosome genes on neuroanatomical structures and cognitive abilities. Continuing attention to emerging trends in research of sex chromosome aneuploidies is important for clinicians because it informs appropriate management of these common genetic disorders. Furthermore, improved understanding of underlying neurobiological processes has much potential to elucidate sex-related factors associated with neurological and psychiatric disease in general.
Chromosomal rearrangements of
resulting in gene fusions (
gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically,
gene fusions involve both ...inter- and intrachromosomal fusions of the 5' regions of a variety of genes with the 3' regions of
genes leading to TRK fusion proteins with constitutive, ligand-independent activation of the intrinsic tyrosine kinase. The incidence of
gene fusions can range from the majority of cases in certain rare cancers to lower rates in a wide range of more common cancers. Two small-molecule TRK inhibitors have recently received regulatory approval for the treatment of patients with solid tumors harboring
gene fusions, including the selective TRK inhibitor larotrectinib and the TRK/ROS1/ALK multikinase inhibitor entrectinib. In this review, we consider the practicalities of detecting tumors harboring
gene fusions, the pharmacologic properties of TRK inhibitors currently in clinical development, the clinical evidence for larotrectinib and entrectinib efficacy, and possible resistance mechanisms.
Can Rating Pre-K Programs Predict Children's Learning? Sabol, T. J.; Hong, S. L. Soliday; Pianta, R. C. ...
Science (American Association for the Advancement of Science),
08/2013, Letnik:
341, Številka:
6148
Journal Article
Recenzirano
Systems intended to rate the quality of early education programs may not actually reflect impacts on learning.
Early childhood education programs e.g., prekindergarten (pre-K)—characterized by ...stimulating and supportive teacher-child interactions in enriched classroom settings—promote children's learning and school readiness (
1
–
3
). But in the United States, most children, particularly those from low-income backgrounds, attend programs that may not be of sufficient quality to improve readiness for school success (
4
). States are adopting Quality Rating and Improvement Systems (QRISs) as a market-based approach for improving early education, but few states have evaluated the extent to which their QRIS relates to child outcomes. We studied the ability of several QRISs to distinguish among meaningful differences in quality that support learning.
•Currently 75% of tyres, 55% of plastics, 75% of glass, 47% of fly ash and 60% of C&D wastes are disposed in landfills.•Crumb rubber in concrete can degrade physical and mechanical properties but ...improve thermal and dynamic properties.•Recycling is the best practice of managing waste plastics followed by landfill and incineration.•Waste glass could be a good alternative to replace natural sands in concrete.•Recycling 10,000 tons of waste can create 9.2 jobs while this number is only 2.8 if disposed in landfill.
The world is moving towards a circular economy that focuses on reducing wastes and keeping materials in use for the longest time possible. This paper critically reviewed three of the largest volume of landfill waste materials (tyres, plastics and glass) that are becoming a major concern for many countries. At present, crumb rubbers (from tyres) and glass sands (from crushed waste glass) are being used in concrete and road constructions while plastics are often used in manufacturing civil structures. However, only 10% tyres, 19.5% plastics and 21% glass are currently recycled globally. The massive volume of remaining unused wastes goes to landfill creating environmental problems. Therefore, finding new strategies of utilising these landfill wastes is vital. The global and country specific production, recycling and landfilling rates of these waste are summarised to understand the present situation of global waste crisis. Future strategies for improved waste management, potential investment and research directions are highlighted. New options for recycling wastes tyres, plastics and glass in construction are also presented to provide practical and economical solutions to extract maximum value and ensure their continued use in a closed loop system.
Purpose of review There are no current drug therapies to limit abdominal aortic aneurysm (AAA) growth. This review summarizes evidence suggesting that inhibiting proprotein convertase ...subtilisin/kexin type 9 (PCSK9) may be a drug target to limit AAA growth. Recent findings Mendelian randomization studies suggest that raised LDL and non-HDL-cholesterol are causal in AAA formation. PCSK9 was reported to be upregulated in human AAA samples compared to aortic samples from organ donors. PCSK9 gain of function viral vectors promoted aortic expansion in C57BL/6 mice infused with angiotensin II. The effect of altering PCSK9 expression in the aortic perfusion elastase model was reported to be inconsistent. Mutations in the gene encoding PCSK9, which increase serum cholesterol, were associated with increased risk of human AAA. Patients with AAA also have a high risk of cardiovascular death, myocardial infarction and stroke. Recent research suggests that PCSK9 inhibition would substantially reduce the risk of these events. Summary Past research suggests that drugs that inhibit PCSK9 have potential as a novel therapy for AAA to both limit aneurysm growth and reduce risk of cardiovascular events. A large multinational randomized controlled trial is needed to test if PCSK9 inhibition limits AAA growth and cardiovascular events.
Schizophrenia is a complex disorder caused by both genetic and environmental factors. Using 9,087 affected individuals, 12,171 controls and 915,354 imputed SNPs from the Schizophrenia Psychiatric ...Genome-Wide Association Study (GWAS) Consortium (PGC-SCZ), we estimate that 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. We show that a substantial proportion of this variation must be the result of common causal variants, that the variance explained by each chromosome is linearly related to its length (r = 0.89, P = 2.6 × 10(-8)), that the genetic basis of schizophrenia is the same in males and females, and that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 × 10(-8)). These results are consistent with a polygenic genetic architecture and imply more individual SNP associations will be detected for this disease as sample size increases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aspergillus section Nidulantes includes species with striking morphological characters, such as biseriate conidiophores with brown-pigmented stipes, and if present, the production of ascomata ...embedded in masses of Hülle cells with often reddish brown ascospores. The majority of species in this section have a sexual state, which were named Emericella in the dual name nomenclature system. In the present study, strains belonging to subgenus Nidulantes were subjected to multilocus molecular phylogenetic analyses using internal transcribed spacer region (ITS), partial β-tubulin (BenA), calmodulin (CaM) and RNA polymerase II second largest subunit (RPB2) sequences. Nine sections are accepted in subgenus Nidulantes including the new section Cavernicolus. A polyphasic approach using morphological characters, extrolites, physiological characters and phylogeny was applied to investigate the taxonomy of section Nidulantes. Based on this approach, section Nidulantes is subdivided in seven clades and 65 species, and 10 species are described here as new. Morphological characters including colour, shape, size, and ornamentation of ascospores, shape and size of conidia and vesicles, growth temperatures are important for identifying species. Many species of section Nidulantes produce the carcinogenic mycotoxin sterigmatocystin. The most important mycotoxins in Aspergillus section Nidulantes are aflatoxins, sterigmatocystin, emestrin, fumitremorgins, asteltoxins, and paxillin while other extrolites are useful drugs or drug lead candidates such as echinocandins, mulundocandins, calbistrins, varitriols, variecolins and terrain. Aflatoxin B1 is produced by four species: A. astellatus, A. miraensis, A. olivicola, and A. venezuelensis.
Given the potential clinical impact of circulating tumor cells (CTCs) in blood as a clinical biomarker for the diagnosis and prognosis of various cancers, a myriad of detection methods for CTCs have ...been recently introduced. Among those, a series of microfluidic devices are particularly promising as they uniquely offer micro-scale analytical systems that are highlighted by low consumption of samples and reagents, high flexibility to accommodate other cutting-edge technologies, precise and well-defined flow behaviors, and automation capability, presenting significant advantages over conventional larger scale systems. In this review, we highlight the advantages of microfluidic devices and their potential for translation into CTC detection methods, categorized by miniaturization of bench-top analytical instruments, integration capability with nanotechnologies, and
in situ
or sequential analysis of captured CTCs. This review provides a comprehensive overview of recent advances in CTC detection achieved through application of microfluidic devices and the challenges that these promising technologies must overcome to be clinically impactful.
Detection of circulating tumor cells (CTCs) in blood has been extensively investigated to use them as a biomarker for the diagnosis and prognosis of various cancers. This review provides a comprehensive overview of recent advances in CTC detection achieved through application of microfluidic devices and the challenges that these promising technologies must overcome to be clinically impactful.
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