Chapter A Fuzzy Logic Approach for Remote Healthcare Monitoring by Learning and Recognizing Human Activities of Daily Living

Systems analysis & desig

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma.

International audience: BackgroundIt is well established that inflammation promotes cancer, including melanoma, although the exact mechanisms involved are less known. In this study, we tested the hypothesis that inflammatory factors affect the cancer stem cell (CSC) compartment responsible for tumor development and relapse.ResultsUsing an inducible histone 2B-GFP fusion protein as a tracer of cell divisional history, we determined that tumor necrosis factor (TNF), which is a classical pro-inflammatory cytokine, enlarged the CSC pool of GFP-positive label-retaining cells (LRCs) in tumor-like melanospheres. Although these cells acquired melanoma stem cell markers, including ABCB5 and CD271, and self-renewal ability, they lost their capacity to differentiate, as evidenced by the diminished MelanA expression in melanosphere cells and the loss of pigmentation in a skin equivalent model of human melanoma. The undifferentiated cell phenotype could be reversed by LY294002, which is an inhibitor of the PI3K/AKT signaling pathway, and this reversal was accompanied by a significant reduction in CSC phenotypic markers and functional properties. Importantly, the changes induced by a transient exposure to TNF were long-lasting and observed for many generations after TNF withdrawal.ConclusionsWe conclude that pro-inflammatory TNF targets the quiescent/slow-cycling melanoma SC compartment and promotes PI3K/AKT-driven expansion of melanoma SCs most likely by preventing their asymmetrical self-renewal. This TNF effect is maintained and transferred to descendants of LRC CSCs and is manifested in the absence of TNF, suggesting that a transient exposure to inflammatory factors imprints long-lasting molecular and/or cellular changes with functional consequences long after inflammatory signal suppression. Clinically, these results may translate into an inflammation-triggered accumulation of quiescent/slow-cycling CSCs and a post-inflammatory onset of an aggressive tumor

Systematic research is needed on the potential effects of lifelong technology experience on cognition: a mini-review and recommendations

Digital technology now occupies a fundamental space in human life. Increasingly sophisticated access to information and social interactions has enabled a sort of offloading of many aspects of cognition, and for many people, this technology use has been lifelong. While the global development of technologies advances exponentially as part of the Fourth Industrial Revolution, researchers have not yet fully characterized the human effects of this technology-centric revolution at the same pace. In this mini-review, we consider three important higher-level cognitive functions: creativity, adaptability, and decision-making, and discuss their potential relationship to lifelong digital technology experience, which here includes both passive exposure and active use of electronic devices. We then articulate the gaps in related literature and knowledge, and outline general considerations, suggestions, and challenges for future research avenues. In general, we found that prior research has investigated uses of specific technology products on lower-level cognition (e.g., how does the use of online search engines affect memory?), but there is a lack of research assessing the overall effects of technology experience on cognitive functioning, particularly complex cognition

Detecting change in the Indonesian Seas

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sprintall, J., Gordon, A. L., Wijffels, S. E., Feng, M., Hu, S., Koch-Larrouy, A., Phillips, H., Nugroho, D., Napitu, A., Pujiana, K., Susanto, R. D., Sloyan, B., Yuan, D., Riama, N. F., Siswanto, S., Kuswardani, A., Arifin, Z., Wahyudi, A. J., Zhou, H., Nagai, T., Ansong, J. K., Bourdalle-Badie, R., Chanuts, J., Lyard, F., Arbic, B. K., Ramdhani, A., & Setiawan, A. Detecting change in the Indonesian Seas. Frontiers in Marine Science, 6, (2019):257, doi:10.3389/fmars.2019.00257.The Indonesian seas play a fundamental role in the coupled ocean and climate system with the Indonesian Throughflow (ITF) providing the only tropical pathway connecting the global oceans. Pacific warm pool waters passing through the Indonesian seas are cooled and freshened by strong air-sea fluxes and mixing from internal tides to form a unique water mass that can be tracked across the Indian Ocean basin and beyond. The Indonesian seas lie at the climatological center of the atmospheric deep convection associated with the ascending branch of the Walker Circulation. Regional SST variations cause changes in the surface winds that can shift the center of atmospheric deep convection, subsequently altering the precipitation and ocean circulation patterns within the entire Indo-Pacific region. Recent multi-decadal changes in the wind and buoyancy forcing over the tropical Indo-Pacific have directly affected the vertical profile, strength, and the heat and freshwater transports of the ITF. These changes influence the large-scale sea level, SST, precipitation and wind patterns. Observing long-term changes in mass, heat and freshwater within the Indonesian seas is central to understanding the variability and predictability of the global coupled climate system. Although substantial progress has been made over the past decade in measuring and modeling the physical and biogeochemical variability within the Indonesian seas, large uncertainties remain. A comprehensive strategy is needed for measuring the temporal and spatial scales of variability that govern the various water mass transport streams of the ITF, its connection with the circulation and heat and freshwater inventories and associated air-sea fluxes of the regional and global oceans. This white paper puts forward the design of an observational array using multi-platforms combined with high-resolution models aimed at increasing our quantitative understanding of water mass transformation rates and advection within the Indonesian seas and their impacts on the air-sea climate system. IntroductionJS acknowledges funding to support her effort by the National Science Foundation under Grant Number OCE-1736285 and NOAA’s Climate Program Office, Climate Variability and Predictability Program under Award Number NA17OAR4310257. SH was supported by the National Natural Science Foundation of China (Grant 41776018) and the Key Research Program of Frontier Sciences, CAS (QYZDB-SSW-SYS023). HP acknowledges support from the Australian Government’s National Environmental Science Programme. HZ acknowledges support from National Science Foundation under Grant No. 41876009. RS was supported by National Science Foundation Grant No. OCE-07-25935; Office of Naval Research Grant No. N00014-08-01-0618 and National Aeronautics and Space Administration Grant No. 80NSSC18K0777. SW, MF, and BS were supported by Center for Southern Hemisphere Oceans Research (CSHOR), which is a joint initiative between the Qingdao National Laboratory for Marine Science and Technology (QNLM), CSIRO, University of New South Wales and University of Tasmania

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead