Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p < 0.01). Among patients undergoing HCT who develop respiratory failure and require advanced therapeutic support, neutrophil recovery at time of IMV and/or presence of a respiratory pathogen should not be used as determining factors when counseling families about survival

Picomolar beta-amyloid modulates hippocampal synaptic plasticity via inhibitor of apoptosis protein regulation of caspase-3 activity and RhoGDP dissociation inhibitor

Picomolar beta-amyloid modulates hippocampal synaptic plasticity via inhibitor of apoptosis protein regulation of caspase-3 activity and RhoGDP dissociation inhibitor. Pero M.E., Ribe E.M., Jean Y.Y., Troy C.M. Picomolar beta-amyloid (Abeta) positively modulates hippocampal synaptic plasticity and memory, whereas nanomolar and higher concentrations lead to inhibition of long-term potentiation, loss of spines and eventually neuronal death. We have previously shown that the toxic effects of Abeta are mediated by activation of caspase-2, despite concurrent activation of caspase-3 (caspase-3 is neither necessary nor sufficient for toxicity). In the current work we examine the function of caspase-3 in the effects of pM Abeta. Treatment of primary hippocampal neurons with pM Abeta leads to a rapid increase in spine density that is accompanied by a rapid increase in caspase-3 activity in purified synaptosomes. Effects are seen within 30 minutes of treatment of the cultures. As this effect is rapid, we posited that the synapses contain cleaved (activated) caspase-3 that is inhibited by endogenous inhibitor of apoptosis proteins, IAPs. We found that the synaptosomal fraction contains cIAP1 and XIAP, and co-immunoprecipitation shows that there are complexes of cIAP1-cleaved caspase-3 and XIAP-cleaved caspase-3. Treatment of cultures with pM Abeta induces a decrease in the cIAP1-cleaved caspase-3 interaction, but no change in the XIAP-cleaved caspase-3 interaction, suggesting that the increase in caspase-3 activity is modulated by cIAP1. Actin, the major component of spines, is a substrate of caspase-3, and we find that pM Abeta leads to an increase in cleaved actin. siRNA knockdown of caspase-3 prevents the effects of pM Abeta and siRNA knockdown of cIAP1 potentiates the effects of pM Abeta on spine density. Surprisingly we found that siRNA knockdown of XIAP prevented the effects of pM Abeta. A recent study has shown that XIAP can bind to RhoGDI (Rho GDP dissociation inhibitor), leading to an increase in f-actin. Co-IP shows that pM Abeta increases the XIAP-RhoGDI interaction. Our data show that spine dynamics can be regulated by pM Abeta through both induction of caspase-3 activity and sequestration of RhoGDI by XIAP

Detecting sexual conflict and sexually antagonistic coevolution

We begin by providing an operational definition of sexual conflict that applies to both inter- and intralocus conflict. Using this definition, we examine a series of simple coevolutionary models to elucidate fruitful approaches for detecting interlocus sexual conflict and resultant sexually antagonistic coevolution. We then use published empirical examples to illustrate the utility of these approaches. Three relevant attributes emerge. First, the dynamics of sexually antagonistic coevolution may obscure the conflict itself. Second, competing models of inter-sexual coevolution may yield similar population patterns near equilibria. Third, a variety of evolutionary forces underlying competing models may be acting simultaneously near equilibria. One main conclusion is that studies of emergent patterns in extant populations (e.g. studies of population and/or female fitness) are unlikely to allow us to distinguish among competing coevolutionary models. Instead, we need more research aimed at identifying the forces of selection acting on shared traits and sexually antagonistic traits. More specifically, we need a greater number of functional studies of female traits as well as studies of the consequences of both male and female traits for female fitness. A mix of selection and manipulative studies on these is likely the most promising route