Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy

Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the α1 domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/−1.7 vs. 54.7 +/−3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.

The contribution of trait-mediated indirect effects to the net effects of a predator

Many prey modify traits in response to predation risk and this modification of traits can influence the prey's resource acquisition rate. A predator thus can have a “nonlethal” impact on prey that can lead to indirect effects on other community members. Such indirect interactions are termed trait-mediated indirect interactions because they arise from a predator's influence on prey traits, rather than prey density. Because such nonlethal predator effects are immediate, can influence the entire prey population, and can occur over the entire prey lifetime, we argue that nonlethal predator effects are likely to contribute strongly to the net indirect effects of predators (i.e., nonlethal effects may be comparable in magnitude to those resulting from killing prey). This prediction was supported by an experiment in which the indirect effects of a larval dragonfly (Anax sp.) predator on large bullfrog tadpoles (Rana catesbeiana), through nonlethal effects on competing small bullfrog tadpoles, were large relative to indirect effects caused by density reduction of the small tadpoles (the lethal effect). Treatments in which lethal and nonlethal effects of Anax were manipulated independently indicated that this result was robust for a large range of different combinations of lethal and nonlethal effects. Because many, if not most, prey modify traits in response to predators, our results suggest that the magnitude of interaction coefficients between two species may often be dynamically related to changes in other community members, and that many indirect effects previously attributed to the lethal effects of predators may instead be due to shifts in traits of surviving prey.

Postembryonic segregation of the germ line in sea urchins in relation to indirect development.

The four small micromeres of the sea urchin embryo contribute only to the coelomic sacs, which produce major components of the adult body plan during postembryonic development. To test the proposition that the small micromeres are the definitive primordial germ cell lineage of the sea urchin, we deleted their 4th cleavage parents, and raised the deleted embryos through larval life and metamorphosis to sexual maturity. Almost all of the experimental animals produced functional gametes, excluding the possibility that the germ cell lineage arises exclusively and obligatorily from descendants of the small micromeres; rather, the germ cell lineage arises during the postembryonic development of the rudiment. A survey of the literature indicates that there is no known case of an embryonic primordial germ cell lineage in a bilaterian species that displays maximal indirect development.

Recognition of diverse sequences by class I zinc fingers: asymmetries and indirect effects on specificity in the interaction between CF2II and A+T-rich elements.

The Drosophila CF2II protein, which contains zinc fingers of the Cys2His2 type and recognizes an A+T-rich sequence, behaves in cell culture as an activator of a reporter chloramphenicol acetyltransferase gene. This activity depends on C-terminal but not N-terminal zinc fingers, as does in vitro DNA binding. By site-specific mutagenesis and binding site selection, we define the critical amino acid-base interactions. Mutations of single amino acid residues at the leading edge of the recognition helix are rarely neutral: many result in a slight change in affinity for the ideal DNA target site; some cause major loss of affinity; and others change specificity for as many as two bases in the target site. Compared to zinc fingers that recognize G+C-rich DNA, CF2II fingers appear to bind to A+T-rich DNA in a generally similar manner, but with additional flexibility and amino acid-base interactions. The results illustrate how zinc fingers may be evolving to recognize an unusually diverse set of DNA sequences.

Indirect coupling of phosphate release to de novo tension generation during muscle contraction.

A key question in muscle contraction is how tension generation is coupled to the chemistry of the actomyosin ATPase. Biochemical and mechanochemical experiments link tension generation to a change in structure associated with phosphate release. Length-jump and temperature-jump experiments, on the other hand, implicate phase 2slow, a significantly faster, markedly strain-sensitive kinetic process in tension generation. We use a laser temperature jump to probe the kinetics and mechanism of tension generation in skinned rabbit psoas fibers--an appropriate method since both phosphate release and phase 2slow are readily perturbed by temperature. Kinetics characteristic of the structural change associated with phosphate release are observed only when phosphate is added to fibers. When present, it causes a reduction in fiber tension; otherwise, no force is generated when it is perturbed. We therefore exclude this step from tension generation. The kinetics of de novo tension generation by the temperature-jump equivalent of phase 2slow appear unaffected by phosphate binding. We therefore propose that phosphate release is indirectly coupled to de novo tension generation via a steady-state flux through an irreversible step. We conclude that tension generation occurs in the absence of chemical change as the result of an entropy-driven transition between strongly bound crossbridges in the actomyosin-ADP state. The mechanism resembles the operation of a clock, with phosphate release providing the energy to tension the spring, and the irreversible step functions as the escapement mechanism, which is followed in turn by tension generation as the movement of the hands.

Direct versus indirect channels: Differentiated loss aversion in a high‐involvement, non‐frequently purchased hedonic product

Purpose – This article aims to investigate whether intermediaries reduce loss aversion in the context of a high-involvement non-frequently purchased hedonic product (tourism packages). Design/methodology/approach – The study incorporates the reference-dependent model into a multinomial logit model with random parameters, which controls for heterogeneity and allows representation of different correlation patterns between non-independent alternatives. Findings – Differentiated loss aversion is found: consumers buying high-involvement non-frequently purchased hedonic products are less loss averse when using an intermediary than when dealing with each provider separately and booking their services independently. This result can be taken as identifying consumer-based added value provided by the intermediaries. Practical implications – Knowing the effect of an increase in their prices is crucial for tourism collective brands (e.g. “sun and sea”, “inland”, “green destinations”, “World Heritage destinations”). This is especially applicable nowadays on account of the fact that many destinations have lowered prices to attract tourists (although, in the future, they will have to put prices back up to their normal levels). The negative effect of raising prices can be absorbed more easily via indirect channels when compared to individual providers, as the influence of loss aversion is lower for the former than the latter. The key implication is that intermediaries can – and should – add value in competition with direct e-tailing. Originality/value – Research on loss aversion in retailing has been prolific, exclusively focused on low-involvement and frequently purchased products without distinguishing the direct or indirect character of the distribution channel. However, less is known about other types of products such as high-involvement non-frequently purchased hedonic products. This article focuses on the latter and analyzes different patterns of loss aversion in direct and indirect channels.

Causal Maps and Indirect Influences Analysis in the Diagnosis of Second-Home Tourism Impacts

This paper proposes a method for diagnosing the impacts of second-home tourism and illustrates it for a Mediterranean Spanish destination. This method proposes the application of network analysis software to the analysis of causal maps in order to create a causal network model based on stakeholder-identified impacts. The main innovation is the analysis of indirect relations in causal maps for the identification of the most influential nodes in the model. The results show that the most influential nodes are of a political nature, which contradicts previous diagnoses identifying technical planning as the ultimate cause of problems.

Políticas europeas para la competitividad, salarios mìnimos y tutela del poder adquisitivo de las retribuciones en Italia tras el acuerdo de noviembre de 2012 [European Policies for competitiveness, minimum wages and purchasing power protection in Italy after the November 2012 agreement]. WP C.S.D.L.E. “Massimo D’Antona”.INT – 99/2013

On the floor of the Global Wage Report 2012/2013 by ILO, entitled Wages and equitable growth, the A. thinks that the wage regulation has to take into account competitiveness without compressing global aggregate demand. Therefore, International and European rules are necessary to avoid the spiral towards the wages dampen, which is bad for the economic development. The rules in action at the different levels are inadequate. The A. proposes an interpretation of Article 153 and Article 155 TFEU that is more suitable for a European regulation promoting better minimum wages and more coherent with the current legal framework of the right to pay, which can be considered, even if partially, as a social right.