150 research outputs found
Delayed Dynamical Systems: Networks, Chimeras and Reservoir Computing
We present a systematic approach to reveal the correspondence between time
delay dynamics and networks of coupled oscillators. After early demonstrations
of the usefulness of spatio-temporal representations of time-delay system
dynamics, extensive research on optoelectronic feedback loops has revealed
their immense potential for realizing complex system dynamics such as chimeras
in rings of coupled oscillators and applications to reservoir computing.
Delayed dynamical systems have been enriched in recent years through the
application of digital signal processing techniques. Very recently, we have
showed that one can significantly extend the capabilities and implement
networks with arbitrary topologies through the use of field programmable gate
arrays (FPGAs). This architecture allows the design of appropriate filters and
multiple time delays which greatly extend the possibilities for exploring
synchronization patterns in arbitrary topological networks. This has enabled us
to explore complex dynamics on networks with nodes that can be perfectly
identical, introduce parameter heterogeneities and multiple time delays, as
well as change network topologies to control the formation and evolution of
patterns of synchrony
Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?
This is the final version. Available on open access from Springer via the DOI in this recordAvailable evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo âhumanisedâ mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the âbenignâ islet autoimmunity of healthy individuals.Leona M. and Harry B. Helmsley Charitable TrustJDRFFondation Francophone pour la Recherche sur le DiabĂšteFondation pour la Recherche MĂ©dicaleAgence Nationale de la RechercheDiabetes UKMedical Research Council (MRC)Innovative Medicines Initiative 2 Joint UndertakingEuropean Union Horizon 2020European Federation of Pharmaceutical Industries Association
Elevated soluble Flt1 mediates an anti-angiogenic state in patients with ANCA-associated vasculitis
International audiencen.
Visualizing the Template of a Chaotic Attractor
Chaotic attractors are solutions of deterministic processes, of which the
topology can be described by templates. We consider templates of chaotic
attractors bounded by a genus-1 torus described by a linking matrix. This
article introduces a novel and unique tool to validate a linking matrix, to
optimize the compactness of the corresponding template and to draw this
template. The article provides a detailed description of the different
validation steps and the extraction of an order of crossings from the linking
matrix leading to a template of minimal height. Finally, the drawing process of
the template corresponding to the matrix is saved in a Scalable Vector Graphics
(SVG) file.Comment: Appears in the Proceedings of the 26th International Symposium on
Graph Drawing and Network Visualization (GD 2018
The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3
OBJECTIVEâThe clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-α (HNF1A) gene mutation.
RESEARCH DESIGN AND METHODSâWe analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes.
RESULTSâMissense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10â4). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03).
CONCLUSIONSâThese data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors
Quantifying the extent to which index event biases influence large genetic association studies
This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.As genetic association studies increase in size to 100,000s of individuals, subtle biases may influence conclusions. One possible bias is "index event bias" (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analysing data from 113,203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (BMI-decreasing) and one (near MTNR1B) underestimated (BMI-increasing) associations among 11 type 2 diabetes risk alleles (at Pââ500,000 if the prevalence of those diseases differs byâ>â10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.H.Y., A.R.W. and T.M.F. are supported by the European Research Council grant: 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. Z.K. received financial support from the Leenaards Foundation, the Swiss Institute of Bioinformatics and the Swiss National Science Foundation (31003A-143914) and SystemsX.ch (39). The work of M.P.B was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award no. T32HL007779. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. E.R.P. holds a WT New investigator award 102820/Z/13/Z
Angiopoietin 2 Alters Pancreatic Vascularization in Diabetic Conditions
Islet vascularization, by controlling beta-cell mass expansion in response to increased insulin demand, is implicated in the progression to glucose intolerance and type 2 diabetes. We investigated how hyperglycaemia impairs expansion and differentiation of the growing pancreas. We have grafted xenogenic (avian) embryonic pancreas in severe combined immuno-deficient (SCID) mouse and analyzed endocrine and endothelial development in hyperglycaemic compared to normoglycaemic conditions.
14 dpi chicken pancreases were grafted under the kidney capsule of normoglycaemic or hyperglycaemic, streptozotocin-induced, SCID mice and analyzed two weeks later. Vascularization was analyzed both quantitatively and qualitatively using either in situ hybridization with both mouse- and chick-specific RNA probes for VEGFR2 or immunohistochemistry with an antibody to nestin, a marker of endothelial cells that is specific for murine cells. To inhibit angiopoietin 2 (Ang2), SCID mice were treated with 4 mg/kg IP L1-10 twice/week.
In normoglycaemic condition, chicken-derived endocrine and exocrine cells developed well and intragraft vessels were lined with mouse endothelial cells. When pancreases were grafted in hyperglycaemic mice, growth and differentiation of the graft were altered and we observed endothelial discontinuities, large blood-filled spaces. Vessel density was decreased. These major vascular anomalies were associated with strong over-expression of chick-Ang2. To explore the possibility that Ang2 over-expression could be a key step in vascular disorganization induced by hyperglycaemia, we treated mice with L1-10, an Ang-2 specific inhibitor. Inhibition of Ang2 improved vascularization and beta-cell density.
this work highligghted an important role of Ang2 in pancreatic vascular defects induced by hyperglycemia
Conventional and Neo-Antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors.
The Clinical Variability of Maternally Inherited Diabetes and Deafness Is Associated with the Degree of Heteroplasmy in Blood Leukocytes
Context: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue.
Objective: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes.
Participants: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded.
Results: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA1c was also found and remained significant after adjustment for age at molecular sampling and gender.
Conclusions: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.
Heteroplasmy levels are at least one of the determinants of the severity of the phenotype of maternally inherited diabetes and deafness
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