Determinants of the Generalized Trust Radius in Scripted Fragile Sub-Saharan African States

Trust between strangers does not come easily in collectivist societies governed by coercive institutions and subject to unstable market forces. More than one-third of all states are fragile, yet the trust literature has shown little interest in explaining the variability of generalized trust among them; instead fixating on social capital, the consequence of the expansion of generalized trust, putting the cart before the horse and leaving unexamined many of its causes. The enhanced accuracy of the reconfigured World Values Survey trust question has generated new research opportunities to address this concern. This dissertation advances the trust literature through identifying, measuring, and explaining the full social effect on generalized trust in fragile states through group proximity and civil society power differential. Sociological institutionalism and social capital theory provide the theoretical framework for modeling and explaining structural social effects leading to the improbable expansion of generalized trust in the highly scripted fragile sub-Saharan African states of Burkina Faso, Ethiopia, and Nigeria. These purposefully deviant and least likely test cases are examined using within- and cross-case analysis of necessary and sufficient conditions through most similar multiple comparative case analysis, affirming or confirming most hypotheses. The expansion of generalized trust requires sustained and usually incentivized positive inter-group interaction. In fragile states, most inter-group interaction is conflictual and occurs through civil society because individuals have little capital with which to engage in the market and the state is dysfunctional. The generalized trust radius is likely to widen the more proximate and consociational its civil society is, regardless of how fragile the state is. This dissertation enlarges and strengthens the social explanation for generalized trust variability in fragile states, filling a significant gap in the literature and establishing a research design and model for future research to replicate in other fragile regions

Notecarin D Binds Human Factor V and Factor V-a with High Affinity in the Absence of Membranes

Notecarin D (NotD) is a prothrombin (ProT) activator in the venom of the tiger snake, Notechis scutatus, and a factor Xa (FXa) homolog. NotD binds specifically to the FXa binding site expressed on factor V (FV) upon activation to factor Va (FVa) by thrombin. NotD active site-labeled with 5-fluorescein ([5F]FFR-NotD) binds FV and FVa with remarkably high affinity in the absence of phospholipids (K(D) 12 and ≤ 0.01 nm, respectively). In the presence of membranes, the affinity of [5F]FFR-NotD for FVa is similar, but increased ∼55-fold for FV. Binding of FXa active site-labeled with Oregon Green to FV and FVa in the presence of phospholipids is ∼5,000- and ∼80-fold weaker than [5F]FFR-NotD, respectively. NotD reports FVa and not FV binding by a 3-fold increase in tripeptide substrate hydrolysis, demonstrating allosteric regulation by FVa. The NotD·FVa·membrane complex activates ProT with K(m)((app)) similar to prothrombinase, and ∼85-fold weaker without membranes. Active site-blocked NotD exhibits potent anticoagulant activity in plasma thrombin generation assays, representing inhibition of productive prothrombinase assembly and possible disruption of FXa inhibition by the tissue factor pathway inhibitor. The results show that high affinity binding of NotD to FVa is membrane-independent, unlike the strict membrane dependence of FXa for high affinity FVa binding

Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes

Poly(ADP-ribose) polymerases (PARPs) are NAD(+) dependent enzymes that were identified as DNA repair proteins, however, today it seems clear that PARPs are responsible for a plethora of biological functions. Sirtuins (SIRTs) are NAD(+)-dependent deacetylase enzymes involved in the same biological processes as PARPs raising the question whether PARP and SIRT enzymes may interact with each other in physiological and pathophysiological conditions. Hereby we review the current understanding of the SIRT-PARP interplay in regard to the biochemical nature of the interaction (competition for the common NAD(+) substrate, mutual posttranslational modifications and direct transcriptional effects) and the physiological, or pathophysiological consequences of the interactions (metabolic events, oxidative stress response, genomic stability and ageing). Finally, we give an overview of the possibilities of pharmacological intervention to modulate PARP and SIRT enzymes either directly, or through modulating NAD(+) homeostasis