Interaction of Shiga Toxin with the A-domains and Multimers of von Willebrand Factor

Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli causes diarrhea-associated hemolytic-uremic syndrome (DHUS), a severe renal thrombotic microangiopathy. We investigated the interaction between Stx and von Willebrand Factor (VWF), a multimeric plasma glycoprotein that mediates platelet adhesion, activation, and aggregation. Stx bound to ultra-large VWF (ULVWF) secreted from and anchored to stimulated human umbilical vein endothelial cells, as well as to immobilized VWF-rich human umbilical vein endothelial cell supernatant. This Stx binding was localized to the A1 and A2 domain of VWF monomeric subunits and reduced the rate of ADAMTS-13-mediated cleavage of the Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ peptide bond in the A2 domain. Stx-VWF interaction and the associated delay in ADAMTS-13-mediated cleavage of VWF may contribute to the pathophysiology of DHUS.     

Increased socially mediated plasticity in gene expression accompanies rapid adaptive evolution

Recent theory predicts that increased phenotypic plasticity can facilitate adaptation as traits respond to selection. When genetic adaptation alters the social environment, socially mediated plasticity could cause co‐evolutionary feedback dynamics that increase adaptive potential. We tested this by asking whether neural gene expression in a recently arisen, adaptive morph of the field cricket Teleogryllus oceanicus is more responsive to the social environment than the ancestral morph. Silent males (flatwings) rapidly spread in a Hawaiian population subject to acoustically orienting parasitoids, changing the population's acoustic environment. Experimental altering crickets’ acoustic environments during rearing revealed broad, plastic changes in gene expression. However, flatwing genotypes showed increased socially mediated plasticity, whereas normal‐wing genotypes exhibited negligible expression plasticity. Increased plasticity in flatwing crickets suggests a coevolutionary process coupling socially flexible gene expression with the abrupt spread of flatwing. Our results support predictions that phenotypic plasticity should rapidly evolve to be more pronounced during early phases of adaptation.     

Dissimilar numerical responses of macroinvertebrates to disturbance from drying and predatory sunfish

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His Bundle Activates Faster than Ventricular Myocardium during Prolonged Ventricular Fibrillation

Background

The Purkinje fiber system has recently been implicated as an important driver of the rapid activation rate during long duration ventricular fibrillation (VF>2 minutes). The goal of this study is to determine whether this activity propagates to or occurs in the proximal specialized conduction system during VF as well.

Methods and Results

An 8×8 array with 300 µm spaced electrodes was placed over the His bundles of isolated, perfused rabbit hearts (n = 12). Ventricular myocardial (VM) and His activations were differentiated by calculating Laplacian recordings from unipolar signals. Activation rates of the VM and His bundle were compared and the His bundle conduction velocity was measured during perfused VF followed by 8 minutes of unperfused VF. During perfused VF the average VM activation rate of 11.04 activations/sec was significantly higher than the His bundle activation rate of 6.88 activations/sec (p<0.05). However from 3–8 minutes of unperfused VF the His system activation rate (6.16, 5.53, 5.14, 5.22, 6.00, and 4.62 activations/sec significantly faster than the rate of the VM (4.67, 3.63, 2.94, 2.24, 3.45, and 2.31 activations/sec) (p<0.05). The conduction velocity of the His system immediately decreased to 94% of the sinus rate during perfused VF then gradually decreased to 67% of sinus rhythm conduction at 8 minutes of unperfused VF.

Conclusion

During prolonged VF the activation rate of the His bundle is faster than that of the VM. This suggests that the proximal conduction system, like the distal Purkinje system, may be an important driver during long duration VF and may be a target for interventional therapy.     

Growth chronologies of white sucker, Catostomuscommersoni, and lake trout, Salvelinusnamaycush: a comparison among lakes and between trophic levels

A growth chronology index was used to determine whether changes in ecosystem structure and function in lakes could be associated with fish growth histories. Growth chronologies were compared for white suckers, Catostomus commersoni, from Little Moose (oligotrophic), Oneida (eutrophic), and Cayuga (mesotrophic) lakes (New York) from opercular bone growth increments, and for lake trout, Salvelinus namaycush, from Little Moose Lake using otolith growth. The longevity of these species allowed the development of chronologies from 17 to 33 years in length using only contemporary collections. We used these chronologies to examine whether fish growth histories could be used as an index for ecosystem-scale changes. Specifically, we examined whether zebra mussel, Dreissena polymorpha, invasion in Oneida and Cayuga lakes in the early 1990s, and treatment of sewage effluent from dwellings around Little Moose Lake beginning during the late 1980s could be detected in white sucker and lake trout growth chronologies. White sucker growth in Oneida and Cayuga Lakes did not differ before and after zebra mussel invasions. Neither white sucker nor lake trout growth chronologies from Little Moose Lake reflect changes in growth expected with reduced productivity levels associated with improved sewage treatment. Growth chronologies of these two species did not detect the ecosystem-scale changes that occurred in the study lakes.     

Runaway sexual selection without genetic correlations: social environments and flexible mate choice initiate and enhance the fisher process

Female mating preferences are often flexible, reflecting the social environment in which they are expressed. Associated indirect genetic effects (IGEs) can affect the rate and direction of evolutionary change, but sexual selection models do not capture these dynamics. We incorporate IGEs into quantitative genetic models to explore how variation in social environments and mate choice flexibility influence Fisherian sexual selection. The importance of IGEs is that runaway sexual selection can occur in the absence of a genetic correlation between male traits and female preferences. Social influences can facilitate the initiation of the runaway process and increase the rate of trait elaboration. Incorporating costs to choice do not alter the main findings. Our model provides testable predictions: (1) genetic covariances between male traits and female preferences may not exist, (2) social flexibility in female choice will be common in populations experiencing strong sexual selection, (3) variation in social environments should be associated with rapid sexual trait divergence, and (4) secondary sexual traits will be more elaborate than previously predicted. Allowing feedback from the social environment resolves discrepancies between theoretical predictions and empirical data, such as why indirect selection on female preferences, theoretically weak, might be sufficient for preferences to become elaborated.     

Evolutionary models of extended phenotypes

A variety of theoretical models incorporate phenotypes expressed in the external environment, but a core question is whether such traits generate dynamics that alter evolution. This has proven to be a challenging and controversial proposition. However, several recent modelling frameworks provide insight: indirect genetic effect (IGE) models, niche construction models, and evolutionary feedback models. These distinct approaches converge upon the observation that gene action at a distance generates feedback that expands the range of trait values and evolutionary rates that we should expect to observe in empirical studies. Such conceptual replication provides solid evidence that traits with extended effects have important evolutionary consequences, but more empirical work is needed to evaluate the predictive power of different modelling approaches.     

A Novel MHC-I Surface Targeted for Binding by the MCMV m06 Immunoevasin Revealed by Solution NMR

As part of its strategy to evade detection by the host immune system, murine cytomegalovirus (MCMV) encodes three proteins that modulate cell surface expression of major histocompatibility complex class I (MHC-I) molecules: the MHC-I homolog m152/gp40 as well as the m02-m16 family members m04/gp34 and m06/gp48. Previous studies of the m04 protein revealed a divergent Ig-like fold that is unique to immunoevasins of the m02-m16 family. Here, we engineer and characterize recombinant m06 and investigate its interactions with full-length and truncated forms of the MHC-I molecule H2-L^d by several techniques. Furthermore, we employ solution NMR to map the interaction footprint of the m06 protein on MHC-I, taking advantage of a truncated H2-L^d, “mini-H2-L^d,” consisting of only the α1α2 platform domain. Mini-H2-L^d refolded in vitro with a high affinity peptide yields a molecule that shows outstanding NMR spectral features, permitting complete backbone assignments. These NMR-based studies reveal that m06 binds tightly to a discrete site located under the peptide-binding platform that partially overlaps with the β₂-microglobulin interface on the MHC-I heavy chain, consistent with in vitro binding experiments showing significantly reduced complex formation between m06 and β₂-microglobulin-associated MHC-I. Moreover, we carry out NMR relaxation experiments to characterize the picosecond-nanosecond dynamics of the free mini-H2-L^d MHC-I molecule, revealing that the site of interaction is highly ordered. This study provides insight into the mechanism of the interaction of m06 with MHC-I, suggesting a structural manipulation of the target MHC-I molecule at an early stage of the peptide-loading pathway.