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  • 1
    Publication Date: 2018-07-18
    Description: Vaccine-elicited immunoglobulin G (IgG) has been shown to be important for protection against simian-human immunodeficiency virus (SHIV) infection in rhesus monkeys. However, it remains unclear whether vaccine-elicited IgA responses are beneficial or detrimental for protection. In this study, we evaluated the kinetics, magnitude, breadth, and linear epitope specificities of vaccine-elicited IgG and IgA responses in serum and mucosal secretions following intramuscular immunization with adenovirus 26 (Ad26) prime, Env protein boost vaccination regimens. The systemic and mucosal antibody responses exhibited kinetics similar to those of the serum antibody responses but lower titers than the serum antibody responses. Moreover, the IgG and IgA responses were correlated, both in terms of the magnitude of the responses and in terms of the antibody specificities against linear human immunodeficiency virus type 1 (HIV-1) Env, Gag, and Pol epitopes. These data suggest that IgG and IgA responses are highly coordinated in both peripheral blood and mucosal compartments following Ad26/Env vaccination in rhesus monkeys. IMPORTANCE Vaccine-elicited IgG responses are important for protection against simian-human immunodeficiency virus (SHIV) infection in nonhuman primates. However, much less is known about the role and function of IgA, despite it being the predominant antibody in mucosal sites. There is debate as to whether HIV-1-specific IgA responses are beneficial or detrimental, since serum anti-Env IgA titers were shown to be inversely correlated with protection in the RV144 clinical trial. We thus assessed vaccine-elicited IgG and IgA antibody responses in peripheral blood and mucosal secretions following vaccination with the Ad26/Env vaccine.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 2
    Publication Date: 2012-05-19
    Description: Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (1 every 17 bases) and geographically localized, so that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. We conclude that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319976/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319976/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nelson, Matthew R -- Wegmann, Daniel -- Ehm, Margaret G -- Kessner, Darren -- St Jean, Pamela -- Verzilli, Claudio -- Shen, Judong -- Tang, Zhengzheng -- Bacanu, Silviu-Alin -- Fraser, Dana -- Warren, Liling -- Aponte, Jennifer -- Zawistowski, Matthew -- Liu, Xiao -- Zhang, Hao -- Zhang, Yong -- Li, Jun -- Li, Yun -- Li, Li -- Woollard, Peter -- Topp, Simon -- Hall, Matthew D -- Nangle, Keith -- Wang, Jun -- Abecasis, Goncalo -- Cardon, Lon R -- Zollner, Sebastian -- Whittaker, John C -- Chissoe, Stephanie L -- Novembre, John -- Mooser, Vincent -- T32 HG002536/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2012 Jul 6;337(6090):100-4. doi: 10.1126/science.1217876. Epub 2012 May 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Quantitative Sciences, GlaxoSmithKline (GSK), Research Triangle Park, NC 27709, USA. matthew.r.nelson@gsk.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22604722" target="_blank"〉PubMed〈/a〉
    Keywords: African Americans/genetics ; Asian Continental Ancestry Group ; Disease/*genetics ; European Continental Ancestry Group/genetics ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; *Genetic Variation ; *Genome, Human ; Geography ; High-Throughput Nucleotide Sequencing ; Humans ; Molecular Targeted Therapy ; Multifactorial Inheritance ; Mutation Rate ; Pharmacogenetics ; Phenotype ; Polymorphism, Single Nucleotide ; Population Growth ; Sample Size ; Selection, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    ISSN: 1432-0428
    Keywords: Keywords Insulin ; autoantibodies ; autoreactivity ; T-lymphocytes ; insulin-dependent diabetes mellitus.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin-dependent diabetes mellitus (IDDM) is the result of a T-cell mediated autoimmune beta-cell destruction,which is accompanied by autoantibodies. We analysed the cellular and humoral immune response to insulin and insulin peptides in patients with recent-onset IDDM, IDDM patients treated with insulin, non-diabetic first degree relatives and unrelated control subjects. There were no differences in T-cell reactivity to whole insulin or insulin peptides in general between age-matched groups of IDDM patients, relatives or healthy control subjects. In contrast to investigations in NOD mice, no immunodominant or disease-specific insulin peptide could be identified. Surprisingly, a positive correlation of T-cell responses to insulin with age was noted (p 〈 0.005). This resulted in an inverse relation of insulin autoantibodies (IAA) and insulin reactive T-cells (p 〈 0.001) together with the well-described negative correlation of IAA with age. Interestingly, insulin-treated patients differed from age-matched recent-onset IDDM patients: first, simultaneous immune recognition of insulin with T-cells and IAA was only seen in patients treated for 6 months with insulin; second, insulin-treated patients rarely responded to whole insulin; third, they displayed less determinant spreading, and finally, recognition of multiple insulin peptides was not accompanied by crossreactivity to whole insulin. These distinct observations in insulin-treated IDDM patients, together with the inverse correlation between humoral and cellular responses to insulin, may result from activation or modulation of different T-cell subsets, and may be of relevance to insulin therapy trials, in which selective activation of non-destructive T-cell subsets may be a key to successful intervention. [Diabetologia (1997) 40: 564–572]
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords Autoreactivity ; autoimmunity ; human T-cells ; GAD65 ; GAD autoantibodies ; insulin-dependent diabetes ; molecular mimicry.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary GAD65 is one of the major autoantigens associated with insulin-dependent diabetes mellitus (IDDM). The two peptides p17 and p18 of GAD65 that share sequence similarity with coxsackie virus (amino acid sequence identity: PEVKEK) appeared to be the major determinants of GAD65 recognized preferably by T cells from new-onset IDDM patients and their first degree relatives. In contrast, in our study unrelated control subjects frequently recognized the two GAD peptides (55 %, 16/29), similar to first degree relatives (41 %, 12/29) and IDDM patients post-onset (68 %, 15/22). However, recent-onset IDDM patients, responded less frequently (25 %, 4/16) compared with IDDM patients post-onset (p 〈 0.03) or unrelated control subjects (borderline significant) confirming previous observations in humans and NOD mice that T-cell reactivity to GADp17/p18 at diabetes onset is decreased. Moreover, this study demonstrated a positive correlation of T-cell proliferation to GAD p17 (amino acid 247–266) and p18 (amino acid 260–279) with simultaneous responses to both peptides in 13 % of all subjects tested (n = 97) (p 〈 0.001). T-cell proliferation to GAD p17 was higher than to p18 in recent-onset diabetic patients, first degree relatives and unrelated control subjects (p 〈 0.02, p 〈 0.004, p 〈 0.002, respectively). However, in post-onset IDDM patients, the two peptides were recognized equally well. Our results show that T-cell reactivity to GAD65 peptides homologous with coxsackie protein is very frequently observed, but not primarily associated with IDDM. The temporary decline of T-cell proliferation is not associated with the beta-cell destruction process, but with clinical manifestation. The positive correlation of reactivity to the two peptides in the viral motif implicates that PEVKEK is an immunogenic epitope. [Diabetologia (1997) 40: 332–338]
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1436-5073
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Eine Reihe von 15 anionenselektiven Membranen, beruhend auf unterschiedlichen quaternären Ammoniumionen und auf verschiedenen Weichmachern, führt auch bei voneinander abweichenden Membranzusammensetzungen durchwegs zur Selektivitätssequenz: $$ClO_4 - 〉 SCN - 〉 I - 〉 NO_3 - 〉 Br - 〉 Cl - 〉 HCO_3 - \sim OAc - \sim SO_4 ^2 - \sim HPO_4 ^2 - .$$ . Eine umfassende Analyse zeigt, daß das Selektivitätsmuster solcher Systeme nur dann grundlegend verändert werden kann, wenn a) mobile, positiv geladene Austauschzentren mit hinreichend starker, spezifischer Wechselwirkung mit Anionen eingesetzt werden und/oder b) elektrisch neutrale anionenselektive Membrankomponenten gewählt werden.
    Notes: Summary A series of 15 anion-selective membranes, based on quaternary ammonium compounds of different constitution and on a variety of plasticizers in different compositions of the solvent polymeric membranes, lead throughout to the selectivity sequence $$ClO_4 - 〉 SCN - 〉 I - 〉 NO_3 - 〉 Br - 〉 Cl - 〉 HCO_3 - \sim OAc - \sim SO_4 ^2 - \sim HPO_4 ^2 - .$$ . A detailed analysis demonstrates that the selectivity pattern of such systems may be drastically modified only if a) a mobile, positively charged site with a sufficiently strong and specific interaction with anions is chosen and/or b) an electrically neutral anion-selective membrane component is used.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0029-554X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Physics
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0003-2670
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 8
    Publication Date: 2018-06-01
    Description: Little is known regarding the first people to enter the Americas and their genetic legacy. Genomic analysis of the oldest human remains from the Americas showed a direct relationship between a Clovis-related ancestral population and all modern Central and South Americans as well as a deep split separating them from North Americans in Canada. We present 91 ancient human genomes from California and Southwestern Ontario and demonstrate the existence of two distinct ancestries in North America, which possibly split south of the ice sheets. A contribution from both of these ancestral populations is found in all modern Central and South Americans. The proportions of these two ancestries in ancient and modern populations are consistent with a coastal dispersal and multiple admixture events.
    Keywords: Anthropology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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