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Parasites impose a permanent threat for hosts. As a consequence, immune defenses are important for host fitness. However, the immune response can also produce self-damage and impair host fitness if not properly regulated. Effectors that up-and downregulate the immune response should, therefore, evolve in concert, and be under the action of correlational selection. To address this issue, we assessed the shape of the selection operating on pro-and anti-inflammatory effectors following andoi:10.1111/j.1558-5646.2012.01708.x pmid:23002997 fatcat:rhxwqat6zrgafoperz6xxtzrjm
more »... ory challenge in laboratory mice. We found that selection acts on the combination of these two traits as individuals that produced large amount of pro-inflammatory cytokines could achieve relatively high fitness (survival) only if also producing a large amount of anti-inflammatory effectors. To our knowledge, this is the first study providing evidence for correlational selection on immunity. K E Y W O R D S : Cytokines, Darwinian medicine, evolutionary immunology, IL-6, IL-10, immunopathology, inflammation, survival.
Sens., 45, 4, 905-924. 41 .Figure 1 : 411 Zakharova E.A., Fleury S., Guerreiro K., Willmes S., Rémy R., Kouraev A., Heinemann G., 2015. ... L'épaisseur de neige à la surface de la banquise (Figure 2) peut être estimée en 136 combinant des données altimétriques [Guerreiro et al., 2016]. ...doi:10.4267/2042/62170 fatcat:dziqb4cwxjhqbb4hpdfwzv6kym
Lupton, Kristelle Brown, Kevin Morgan, John Powell, Andrew Singleton, and John Hardy. ... Figure 7 . 7 A Road Map of APP Processing and Ab Production CONSORTIA The members of the AESG (Alzheimer's Exome Sequencing Group) are Rita Guerreiro, José Brá s, Celeste Sassi, J. ...doi:10.1016/j.celrep.2013.12.005 pmid:24373285 pmcid:PMC4004174 fatcat:ibuuknqw5fcyzemg7ew7scielm
However, recent in situ observations have demonstrated that snow depth has thinned by 50 % over first-year ice relative to the W99 climatology Guerreiro et al., 2016) . ... Guerreiro et al.: Comparison of CryoSat-2 and ENVISAT radar freeboard over Arctic sea ice Over the past decade, satellite radar altimeters have been used to estimate basin-scale sea-ice thickness. ...doi:10.5194/tc-11-2059-2017 fatcat:g2664pg7fjglhhx5hecxkg5r2q
et al., 2010a; Guerreiro et al., 2010b) . ... reassessed the pathogenicity of variants described in the genes known to more frequently harbor Alzheimer's disease and frontotemporal dementia causative mutations (APP, PSEN1, PSEN2, GRN and MAPT) (Guerreiro ...doi:10.1101/270686 fatcat:lf6beznv5ren7brhr5bu3sutcy
., 2013; Guerreiro et al., 2016) . ...doi:10.5194/tc-2016-293 fatcat:xkdrdcjnzfatpoxi7fjo26qmxa
Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer's disease (LOAD) were genotyped on the NeuroChipdoi:10.1038/s41398-019-0485-7 pmid:31127079 pmcid:PMC6534556 fatcat:oroo4d3jufa63cg6olva2et26q
more »... array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer's Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.
The Leeuwin Current System (LCS) along the coast of Western Australia consists of the poleward-flowing Leeuwin Current (LC), the equatorward-flowing Leeuwin Undercurrent (LUC), and neighboring flows in the south Indian Ocean (SIO). Using geostrophic currents obtained from a highly resolved ( 1 /88) hydrographic climatology [CSIRO Atlas of Regional Seas (CARS)], this study describes the spatial structure and annual variability of the LC, LUC, and SIO zonal currents, estimates their transports,doi:10.1175/jpo-d-16-0170.1 fatcat:6i7deu5fpvdanleg3zvgm5w5hu
more »... d identifies linkages among them. In CARS, the LC is supplied partly by water from the tropics (an annual mean of 0.3 Sv; 1 Sv [ 10 6 m 3 s 21 ) but mostly by shallow (&200 m) eastward flows in the SIO (4.7 Sv), and it loses water by downwelling across the bottom of this layer (3.4 Sv). The downwelling is so strong that, despite the large SIO inflow, the horizontal transport of the LC does not much increase to the south (from 0.3 Sv at 228S to 1.5 Sv at 348S). This LC transport is significantly smaller than previously reported. The LUC is supplied by water from south of Australia (0.2 Sv), by eastward inflow from the SIO south of 288S (1.6 Sv), and by the downwelling from the LC (1.6 Sv) and in response strengthens northward, reaching a maximum near 288S (3.4 Sv). North of 288S it loses water by outflow into subsurface westward flow (23.6 Sv between 288 and 228S) and despite an additional downwelling from the LC (1.9 Sv), it decreases to the north (1.7 Sv at 228S). The seasonality of the LUC is described for the first time.
Chemical modification of proteins is essential for a variety of important diagnostic and therapeutic applications. Many strategies developed to date lack chemoand regioselectivity as well as result in non-native linkages that may suffer from instability in vivo and adversely affect the protein's structure and function. We describe here the reaction of N-nucleophiles with the amino acid dehydroalanine (Dha) in a protein context. When Dha is chemically installed in proteins, the addition of adoi:10.1021/jacs.7b10702 pmid:29206031 pmcid:PMC5799870 fatcat:a5nt5was5bepzjmjwoet6vaeye
more »... -range N-nucleophiles enables the rapid formation of amine linkages (secondary and tertiary) in a chemoselective manner under mild, biocompatible conditions. These new linkages are stable at a wide range of pH values (pH 2.8 to 12.8), under reducing conditions (biological thiols such as glutathione) and in human plasma. This method is demonstrated for three proteins and is shown to be fully compatible with disulfide bridges, as evidenced by the selective modification of recombinant albumin that displays 17 structurally relevant disulfides. The practicability and utility of our approach is further demonstrated by the construction of a chemically modified C2A domain of Synaptotagmin-I protein that retains its ability to preferentially bind to apoptotic cells at a level comparable to the native protein. Importantly, the method was useful for building a homogeneous antibody-drug conjugate with a precise drug-to-antibody ratio of 2. The kinase inhibitor crizotinib was directly conjugated to Dha through its piperidine motif, and its antibody-mediated intracellular delivery results in 10-fold improvement of its cancer cell-killing efficacy. The simplicity and exquisite site-selectivity of the aza-Michael ligation described herein allows the construction of stable secondary and tertiary amine-linked protein conjugates without affecting the structure and function of biologically relevant proteins.
Guerreiro); and the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disease and Stroke, National Institutes of Health (Department of Health and ... Appendix The authors and their affiliations are as follows: Rita Guerreiro, Ph.D., University College London (UCL) Institute of Neurology, London, ...doi:10.1056/nejmoa1211851 pmid:23150934 pmcid:PMC3631573 fatcat:nu2itnljrvdd3glejvfdnuln7a
99 words Main Text: 1721 words Tables: 3 East NRES committee 08/H0704/128+5 and has deemed all approved requests for tissue to have been approved by the committee. The work presented here was funded by an ARUK Major Project Grant to KM and PTF.doi:10.3233/jad-180191 pmid:29914034 fatcat:nvrrtyb25jgltmaglg24i26xna
Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 cosegregating with andoi:10.1038/s41380-018-0091-8 pmid:29988083 fatcat:nbwzt2rwarairnuw2bs7dxznli
more »... pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD. Fig. 4 APP expression is negatively correlated with ADAM17 expression in human brain. Average log 2 of ADAM17 gene expression against average log 2 of APP gene expression was plotted. a NBB sample set; b MUC sample set A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease
contribution to Section 4.1; Jean Tournadre to Section 4.2 ;and Kevin Guerreiro to Section 4.3. On geodesy, Walter H. F. Smith contributed to Section 5. ...doi:10.3390/rs10020163 fatcat:ty2shtipqzbzfgvfd7ghg7moum
., 2003; Guerreiro et al., 2017) . ... Guerreiro et al. (2017), and Paul et al. (2018) both used TFRMA for retracking ice floe echoes from Envisat. have either only a numerical solution or to have an analytical solution as well. ...doi:10.5194/tc-2018-148 fatcat:nkgpjm27r5bexiopyp4anbb3di
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