Gemischte Least-Squares-FEM für Elastoplastizität

[no abstract

Enhancing Humoral Responses Against HIV Envelope Trimers via Nanoparticle Delivery with Stabilized Synthetic Liposomes

An HIV vaccine capable of eliciting durable neutralizing antibody responses continues to be an important unmet need. Multivalent nanoparticles displaying a high density of envelope trimers may be promising immunogen forms to elicit strong and durable humoral responses to HIV, but critical particle design criteria remain to be fully defined. To this end, we developed strategies to covalently anchor a stabilized gp140 trimer, BG505 MD39, on the surfaces of synthetic liposomes to study the effects of trimer density and vesicle stability on vaccine-elicited humoral responses in mice. CryoEM imaging revealed homogeneously distributed and oriented MD39 on the surface of liposomes irrespective of particle size, lipid composition, and conjugation strategy. Immunization with covalent MD39-coupled liposomes led to increased germinal center and antigen-specific T follicular helper cell responses and significantly higher avidity serum MD39-specific IgG responses compared to immunization with soluble MD39 trimers. A priming immunization with liposomal-MD39 was important for elicitation of high avidity antibody responses, regardless of whether booster immunizations were administered with either soluble or particulate trimers. The stability of trimer anchoring to liposomes was critical for these effects, as germinal center and output antibody responses were further increased by liposome compositions incorporating sphingomyelin that exhibited high in vitro stability in the presence of serum. Together these data highlight key liposome design features for optimizing humoral immunity to lipid nanoparticle immunogens.National Institute of Allergy and Infectious Diseases (U.S.) (Award UM1AI100663)National Institutes of Health (U.S.) (Award P01-AI104715)National Institutes of Health (U.S.) (Award P01-AI048240)National Cancer Institute (U.S.) (Grant P30-CA14051

Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo

Autoreactive B lymphocytes first encountering self-antigens in peripheral tissues are normally regulated by induction of anergy or apoptosis. According to the “two-signal” model, antigen recognition alone should render B cells tolerant unless T cell help or inflammatory signals such as lipopolysaccharide are provided. However, no such signals seem necessary for responses to T-independent type 2 (TI-2) antigens, which are multimeric antigens lacking T cell epitopes and Toll-like receptor ligands. How then do mature B cells avoid making a TI-2–like response to multimeric self-antigens? We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid–binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid “missing self”–responses to unsialylated multimeric antigens. The results suggest use of siglec ligand antigen constructs as an approach for inducing tolerance

Exploring the potential of virtual reality technology to investigate the health and well being benefits of group singing

There is a growing body of academic research aiming to quantify and understand the associated health and well being benefits of group singing. The social interaction is known to strongly contribute to perceived improvements to mental and physical health but there are also indications that singing together elicits better well being outcomes that other community activities. This paper introduces the Vocal Interaction in an Immersive Virtual Acoustic (VIIVA) system, which allows the user to take part in a group singing activity in 360 degree virtual reality, hearing themselves in the recorded venue alongside the other singers. The VIIVA is intended to make group singing accessible to those unable to attend real community choirs but also as a tool for experimental research into the health and well being benefits of group singing. This paper describes the system and presents a number of methodologies and applications which are discussed in relation to three ongoing research projects. Preliminary work indicates that the VIIVA system and the devised setups provide a promising tool with which to study the health and well being benefits of group singing, and in particular to control for the social interactions inherent in real group singing activities

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case-control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran-Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10(-4) (rs3815676) and for ABCB4 it was 4.6×10(-7)(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility

regression.data

outcomes of staged encounters with crayfish of known size and strength. Variables are as follows: A) crayfish ID; B & C) mean.size estimated as a score for PC1 and mean.force of the focal crayfish's pair of claws; D) random effect of focal crayfish from model of force predicted by size; E) mean residual force of the pair of claws from a regression of force onto size; F & G) minimal and maximal residual force (i.e., residua strength of weaker and stronger claw, respectively); H) difference in residual strength of stronger and weaker claw; I) ID of opponent crayfish; J) random effect of opponent crayfish from model of force predicted by size; L) opponents size estimate as a score for PC1; M) force of opponent's claws expected from their mean size; N) outcome of encounter, where 0 means focal crayfish fled and 1 means it escalated aggression; O) difference in mean size between focal crayfish and its opponent; P) difference in mean force between focal crayfish and its opponent; Q) difference between mean force of focal crayfish and the expected force of its opponent, given the opponent's mean claw size

PCA.data

Seven linear measurements of claw size and one estimate of maximal claw force for left and right claws of crayfis

Self-deception in nonhuman animals: weak crayfish escalated aggression as if they were strong

Humans routinely deceive themselves when communicating to others, but no one knows whether other animals do the same. We ask whether dishonest signaling between crayfish meets a condition required for self-deception: dishonest individuals and honest individuals escalate aggression according to their signals of strength rather than actual strength. Using game theory, we predicted how an animal’s knowledge of its strength should affect its decision to escalate aggression. At the evolutionary equilibrium, an animal that knows its strength should escalate aggression according to its strength, relative to the expected strength of its opponent. By contrast, an animal that knows only its size should escalate aggression according to its size, relative to the size of its opponent. We tested these predictions by staging encounters between male crayfish (Cherax dispar) of known sizes and strengths. Consistent with a model of self-deception, crayfish escalated aggression based on the sizes of their claws relative to those of their opponents, despite the fact that size poorly predicts strength. Males who were weak for their size escalated disputes less often, but their aggression far exceeded the level predicted by a model of self-awareness, suggesting these crayfish were largely ignorant of their deception. Animals that fail to recognize their own dishonest signals may win disputes with stronger opponents without engaging in costly combat. Our game-theoretical approach can be used to identify potential cases of self-deception in nonhuman animals, enabling comparative studies of this behavior

Data from: Self-deception in nonhuman animals: weak crayfish escalated aggression as if they were strong

Humans routinely deceive themselves when communicating to others, but no one knows whether other animals do the same. We ask whether dishonest signaling between crayfish meets a condition required for self-deception: dishonest individuals and honest individuals escalate aggression according to their signals of strength rather than actual strength. Using game theory, we predicted how an animal’s knowledge of its strength should affect its decision to escalate aggression. At the evolutionary equilibrium, an animal that knows its strength should escalate aggression according to its strength, relative to the expected strength of its opponent. By contrast, an animal that knows only its size should escalate aggression according to its size, relative to the size of its opponent. We tested these predictions by staging encounters between male crayfish (Cherax dispar) of known sizes and strengths. Consistent with a model of self-deception, crayfish escalated aggression based on the sizes of their claws relative to those of their opponents, despite the fact that size poorly predicts strength. Males who were weak for their size escalated disputes less often, but their aggression far exceeded the level predicted by a model of self-awareness, suggesting these crayfish were largely ignorant of their deception. Animals that fail to recognize their own dishonest signals may win disputes with stronger opponents without engaging in costly combat. Our game-theoretical approach can be used to identify potential cases of self-deception in nonhuman animals, enabling comparative studies of this behavior