Landau Level Splitting in Graphene in High Magnetic Fields

The quantum Hall (QH) effect in two-dimensional (2D) electrons and holes in high quality graphene samples is studied in strong magnetic fields up to 45 T. QH plateaus at filling factors $\nu=0,\pm 1,\pm 4$ are discovered at magnetic fields $B>$20 T, indicating the lifting of the four-fold degeneracy of the previously observed QH states at $\nu=\pm(|n|+1/2)$, where $n$ is the Landau level index. In particular, the presence of the $\nu=0, \pm 1$ QH plateaus indicates that the Landau level at the charge neutral Dirac point splits into four sublevels, lifting sublattice and spin degeneracy. The QH effect at $\nu=\pm 4$ is investigated in tilted magnetic field and can be attributed to lifting of the spin-degeneracy of the $n=1$ Landau level.Comment: 11 pages including 4 figures, to appear in PR

Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in Glioblastoma

SummaryTumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies

Oxidation of Cellular Amino Acid Pools Leads to Cytotoxic Mistranslation of the Genetic Code

Aminoacyl-tRNA synthetases use a variety of mechanisms to ensure fidelity of the genetic code and ultimately select the correct amino acids to be used in protein synthesis. The physiological necessity of these quality control mechanisms in different environments remains unclear, as the cost vs benefit of accurate protein synthesis is difficult to predict. We show that in Escherichia coli, a non-coded amino acid produced through oxidative damage is a significant threat to the accuracy of protein synthesis and must be cleared by phenylalanine-tRNA synthetase in order to prevent cellular toxicity caused by mis-synthesized proteins. These findings demonstrate how stress can lead to the accumulation of non-canonical amino acids that must be excluded from the proteome in order to maintain cellular viability

Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium

Background: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity. Objectives: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability. Methods: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells. Results: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μg/mL, but did not induce IL-1β. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β. Conclusions: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity

Fifteen years of the Australian imaging, biomarkers and lifestyle (AIBL) study: Progress and observations from 2,359 older adults spanning the spectrum from cognitive normality to Alzheimer\u27s disease

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer\u27s disease dementia (AD)) as an \u27Inception cohort\u27 who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an \u27Enrichment cohort\u27 (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

The quality of options in strategic decision making: a study about creativity and completeness in business decision making

A qualidade das decisões estratégicas dos empresários está diretamente relacionada à capacidade que eles demonstram para encontrar alternativas criativas quando enfrentam os problemas de suas empresas. Essas alternativas podem ser geradas intuitivamente, utilizando heurísticas. As pesquisas sobre geração de alternativas têm indicado consistentemente que as pessoas não são eficientes nessa atividade. As explicações para esse fato, contidas na literatura sobre decisão, não são conclusivas e permitem especulações a respeito. Para explorar essa questão e relacioná-la ao administrador brasileiro, foi idealizado um experimento com 174 alunos de quatro cursos de MBA para avaliar a originalidade e a completude das alternativas. O experimento e a respectiva análise basearam-se na confluência da pesquisa experimental, oriunda da psicologia cognitiva da decisão, com as visões da ciência da decisão organizacional tradicional e o novo campo de estudo das decisões intuitivas ou naturalísticas. Para mensurar a criatividade das alternativas apresentadas durante o experimento, empregou-se o conceito de árvore hierárquica, que demonstrou ser uma poderosa ferramenta para a tipologia de alternativas. O resultado desse experimento confirmou o baixo desempenho em geração de alternativas dos gerentes e, ao mesmo tempo, indicou que, provavelmente, a etapa de geração de alternativas isolada da etapa de escolha pode melhorar a qualidade das alternativas. A heurística, por sua vez, não demonstrou influenciar o conjunto de alternativas geradas. _________________________________________________________________________________________ ABSTRACT: The quality of strategic decisions of executives is directly related to the ability they have to find creative alternatives when facing business problems. These alternatives could be generated intuitively, using heuristics. On the other hand, the researches on alternatives generation have consistently indicated that people are not efficient on this duty. The argument for that, contained in the decision’s literature, is not conclusive and it allows speculation about it. To explore this issue and relate it to the Brazilian Administration, an experiment was designed for 174 students of four courses of MBA. The experiment and the analysis were resulted from the confluence between the experimental research from decision cognitive psychology with science’s vision of the traditional organizational decision and the new field of study on naturalistic or intuitive decisions. To measure the creativity of the alternatives presented during the experiment, the concept of hierarchical tree was utilized and it has proved a powerful tool to the typology of alternatives. The result of this experiment confirmed the poor performance in alternatives generation by managers and at the same time, indicated that probably, the generation of options isolated of analysis can produce better quality of alternatives. The heuristic, do not demonstrated any influence on options generated