circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan.

Circular RNAs (circRNAs) are an emerging class of non-coding RNA molecules that are thought to regulate gene expression and human disease. Despite the observation that circRNAs are known to accumulate in older organisms and have been reported in cellular senescence, their role in aging remains relatively unexplored. Here, we have assessed circRNA expression in aging human blood and followed up age-associated circRNA in relation to human aging phenotypes, mammalian longevity as measured by mouse median strain lifespan and cellular senescence in four different primary human cell types. We found that circRNAs circDEF6, circEP300, circFOXO3 and circFNDC3B demonstrate associations with parental longevity or hand grip strength in 306 subjects from the InCHIANTI study of aging, and furthermore, circFOXO3 and circEP300 also demonstrate differential expression in one or more human senescent cell types. Finally, four circRNAs tested showed evidence of conservation in mouse. Expression levels of one of these, circPlekhm1, was nominally associated with lifespan. These data suggest that circRNA may represent a novel class of regulatory RNA involved in the determination of aging phenotypes, which may show future promise as both biomarkers and future therapeutic targets for age-related disease

Classification of Wildfires from MODIS Data Using Neural Networks

Wildfires are destructive to both life and property, which necessitates an approach to quickly and autonomously detect these events from orbital observatories. This talk will introduce a neural network based approach for classifying wildfires in MODIS multispectral data, and will show how it could be applied to a constellation of low-cost CubeSats. The approach combines training a deep neural network on the ground using high performance consumer GPUs, with a highly optimized inference system running on a flight-proven embedded processor. Normally neural networks execute on hardware orders of magnitude more powerful than anything found in a space-based computer, therefore the inference system is designed to be performance even on the most modest of platforms. This implementation is able to be significantly more accurate than previous neural network implementations, while also approaching the accuracy of the state-of-the-art MODFIRE data products

Genetic algorithm with logistic regression for prediction of progression to Alzheimer\u27s disease

Assessment of risk and early diagnosis of Alzheimer\u27s disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development. This study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.</p

Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1

AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier

Analysis of Different Views and Conceptualizations of the Literacy Practices of Pupils, Families, and Teachers in Costa Rican Primary Education

This article is based on a socio-cultural discourse model of literacy, whereby literacy events are regarded as being situated within social practices, creating various formal, informal, and non-formal literacy events that are part of 10multiliteracies. The aim of the research was to analyze primary pupils ’ literacy practices (8–12 years) from the perspectives of 1,354 primary pupils, 1,020 family members, and 96 teachers in Costa Rica, using an ex-post facto design and a survey method. The findings indicate that the three groups of participants (pupils, family members, and teachers) have different views on 15and conceptualizations of literacy practices in school and in the community. The results show that young learners develop their literacy practices according to their different communicative needs inside and outside school. A multimodal literacy is promoted outside school to meet students’ daily communicative needs. However, the school promotes a monomodal lit20eracy, which allows pupils to respond essentially to school needs

Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

Chronostratigraphy, site formation, and palaeoenvironmental context of late pleistocene and holocene occupations at grassridge rock shelter (Eastern Cape, South Africa)

© 2020 The Author(s). Grassridge rock shelter is located in the high elevation grassland foothills of the Stormberg Mountains in the Eastern Cape of South Africa. This places Grassridge at an important biogeoclimatic intersec-tion between the Drakensberg Mountains, the South African coastal zone, and the interior arid lands of southern Africa. First excavated in 1979, the approximately 1.5 m stratigraphic sequence was divided into two major occupational components: a 50–70 cm thick Later Stone Age component dating between 7–6 ka and an underlying 50–80 cm thick Middle Stone Age component dated to 36 ka at the base. Here we present a reanalysis of the Grassridge stratigraphic sequence that combines new optically stimulated luminescence and radiocarbon age estimates with sedimentological and microbotanical analyses to evalu-ate site formation processes and the palaeoenvironmental context of human occupations. Results indicate a complex history of geogenic, anthropogenic, and biogenic inputs to the depositional sequence that are interspersed with pulsed human occupation from 43–28 ka, 13.5–11.6 ka, and 7.3–6.8 ka. Microbotanical remains indicate a cooler, drier grassland environment in MIS 3 that transitions to a warmer, moister grassland environment dominated by summer rainfall in the middle of MIS 1. The pulsed occupational sequence identified at Grassridge is characteristic of the Pleistocene and Holocene record across the greater high elevation grassland region of South Africa, which, based on comparison with other currently available evidence, seems linked to a complex system of forager mobility entwined with rapidly fluctuating palaeoenvironments across the last glacial to interglacial transition