The past and future of experimental speciation

Speciation is the result of evolutionary processes that generate barriers to gene flow between populations, facilitating reproductive isolation. Speciation is typically studied via theoretical models and “snap-shot” tests in natural populations. Experimental speciation enables real-time direct tests of speciation theory and has been long-touted as a critical complement to other approaches. We argue that, despite its promise to elucidate the evolution of reproductive isolation, experimental speciation has been underutilised and lags behind other contributions to speciation research. We review recent experiments and outline a framework for how experimental speciation can be implemented to address current outstanding questions that are otherwise challenging to answer. Greater uptake of this approach is necessary to rapidly advance understanding of speciation

Extrapolating from model organisms in pharmacology

In this chapter we explore the process of extrapolating causal claims from model organisms to humans in pharmacology. We describe and compare four strategies of extrapolation: enumerative induction, comparative process tracing, phylogenetic reasoning, and robustness reasoning. We argue that evidence of mechanisms plays a crucial role in several strategies for extrapolation and in the underlying logic of extrapolation: the more directly a strategy establishes mechanistic similarities between a model and humans, the more reliable the extrapolation. We present case studies from the research on atherosclerosis and the development of statins, that illustrate these strategies and the role of mechanistic evidence in extrapolation

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT

Intracellular Concentrations of Borrelia burgdorferi Cyclic Di-AMP Are Not Changed by Altered Expression of the CdaA Synthase.

The second messenger nucleotide cyclic diadenylate monophosphate (c-di-AMP) has been identified in several species of Gram positive bacteria and Chlamydia trachomatis. This molecule has been associated with bacterial cell division, cell wall biosynthesis and phosphate metabolism, and with induction of type I interferon responses by host cells. We demonstrate that B. burgdorferi produces a c-di-AMP synthase, which we designated CdaA. Both CdaA and c-di-AMP levels are very low in cultured B. burgdorferi, and no conditions were identified under which cdaA mRNA was differentially expressed. A mutant B. burgdorferi was produced that expresses high levels of CdaA, yet steady state borrelial c-di-AMP levels did not change, apparently due to degradation by the native DhhP phosphodiesterase. The function(s) of c-di-AMP in the Lyme disease spirochete remains enigmatic