Therapeutic targets in systemic sclerosis

The precise aetiology of systemic sclerosis (SSc) remains elusive, but significant advances over the past few years have improved our understanding of the underlying pathogenic processes and identified key pathways and mediators that are potential therapeutic targets. The situation is complicated by the clinical heterogeneity of SSc and the differential pathogenesis that underlies the two commonest subsets, namely diffuse and limited cutaneous disease. However, there are common mediators that could be targeted to provide clinical benefit in both types of disease. To date, clinical success with therapies directed against logical profibrotic mediators, such as connective tissue growth factor and transforming growth factor-beta, is yet to be reported, although studies are ongoing. More promising clinical results have been obtained with the dual endothelin receptor antagonist bosentan, which has been shown to manage two vascular complications of SSc effectively: pulmonary arterial hypertension and digital ulceration. It remains to be determined whether the identification of additional mediators merely furthers our knowledge of the natural history of SSc or presents targets that can be manipulated to manage SSc patients effectively.     

Computational and Functional Analyses of a Small-Molecule Binding Site in ROMK

The renal outer medullary potassium channel (ROMK, or Kir1.1, encoded by KCNJ1) critically regulates renal tubule electrolyte and water transport and hence blood volume and pressure. The discovery of loss-of-function mutations in KCNJ1 underlying renal salt and water wasting and lower blood pressure has sparked interest in developing new classes of antihypertensive diuretics targeting ROMK. The recent development of nanomolar-affinity small-molecule inhibitors of ROMK creates opportunities for exploring the chemical and physical basis of ligand-channel interactions required for selective ROMK inhibition. We previously reported that the bis-nitro-phenyl ROMK inhibitor VU591 exhibits voltage-dependent knock-off at hyperpolarizing potentials, suggesting that the binding site is located within the ion-conduction pore. In this study, comparative molecular modeling and in silico ligand docking were used to interrogate the full-length ROMK pore for energetically favorable VU591 binding sites. Cluster analysis of 2498 low-energy poses resulting from 9900 Monte Carlo docking trajectories on each of 10 conformationally distinct ROMK comparative homology models identified two putative binding sites in the transmembrane pore that were subsequently tested for a role in VU591-dependent inhibition using site-directed mutagenesis and patch-clamp electrophysiology. Introduction of mutations into the lower site had no effect on the sensitivity of the channel to VU591. In contrast, mutations of Val¹⁶⁸ or Asn¹⁷¹ in the upper site, which are unique to ROMK within the Kir channel family, led to a dramatic reduction in VU591 sensitivity. This study highlights the utility of computational modeling for defining ligand-ROMK interactions and proposes a mechanism for inhibition of ROMK.     

A new phylogenetic test for comparing multiple high‐dimensional evolutionary rates suggests interplay of evolutionary rates and modularity in lanternfishes (Myctophiformes; Myctophidae)

The interplay between evolutionary rates and modularity influences the evolution of organismal body plans by both promoting and constraining the magnitude and direction of trait response to ecological conditions. However, few studies have examined whether the best‐fit hypothesis of modularity is the same as the shape subset with the greatest difference in evolutionary rate. Here, we develop a new phylogenetic comparative method for comparing evolutionary rates among high‐dimensional traits, and apply this method to analyze body shape evolution in bioluminescent lanternfishes. We frame the study of evolutionary rates and modularity through analysis of three hypotheses derived from the literature on fish development, biomechanics, and bioluminescent communication. We show that a development‐informed partitioning of shape exhibits the greatest evolutionary rate differences among modules, but that a hydrodynamically informed partitioning is the best‐fit modularity hypothesis. Furthermore, we show that bioluminescent lateral photophores evolve at a similar rate as, and are strongly integrated with, body shape in lanternfishes. These results suggest that overlapping life‐history constraints on development and movement define axes of body shape evolution in lanternfishes, and that the positions of their lateral photophore complexes are likely a passive outcome of the interaction of these ecological pressures.     

Ethics and Rationing Access to Dialysis in Resource‐Limited Settings: The Consequences of Refusing a Renal Transplant in the South African State Sector

Resource constraints in developing countries compel policy makers to ration the provision of healthcare services. This article examines one such set of Guidelines: A patient dialysing in the state sector in South Africa may not refuse renal transplantation when a kidney becomes available. Refusal of transplantation can lead to exclusion from the state‐funded dialysis programme. This Guideline is legally acceptable as related to Constitutional stipulations which allow for rationing healthcare resources in South Africa. Evaluating the ethical merit of the Guideline, and exploring the ethical dilemma it poses, proves a more complex task. We examine the actions of healthcare professionals as constrained by the Guideline. From a best interests framework, we argue that in these circumstances directing patient decision making (pressurising a patient to undergo renal transplantation) is not necessarily unethical or unacceptably paternalistic. We then scrutinise the guideline itself through several different ethical ‘lenses’. Here, we argue that bioethics does not provide a definitive answer as to the moral merit of rationing dialysis under these circumstances, however it can be considered just in this context. We conclude by examining a potential pitfall of the Guideline: Unwilling transplant recipients may not comply with immunosuppressive medication, which raises questions for policies based on resource management and rationing.     

Stomatal conductance and not stomatal density determines the long-term reduction in leaf transpiration of poplar in elevated CO<Subscript>2</Subscript>

Using a free-air CO₂ enrichment (FACE) experiment, poplar trees (Populus × euramericana clone I214) were exposed to either ambient or elevated [CO₂] from planting, for a 5-year period during canopy development, closure, coppice and re-growth. In each year, measurements were taken of stomatal density (SD, number mm⁻²) and stomatal index (SI, the proportion of epidermal cells forming stomata). In year 5, measurements were also taken of leaf stomatal conductance (g _s, μmol m⁻² s⁻¹), photosynthetic CO₂ fixation (A, mmol m⁻² s⁻¹), instantaneous water-use efficiency (A/E) and the ratio of intercellular to atmospheric CO₂ (C_i:C_a). Elevated [CO₂] caused reductions in SI in the first year, and in SD in the first 2 years, when the canopy was largely open. In following years, when the canopy had closed, elevated [CO₂] had no detectable effects on stomatal numbers or index. In contrast, even after 5 years of exposure to elevated [CO₂], g _s was reduced, A/E was stimulated, and C_i:C_a was reduced relative to ambient [CO₂]. These outcomes from the long-term realistic field conditions of this forest FACE experiment suggest that stomatal numbers (SD and SI) had no role in determining the improved instantaneous leaf-level efficiency of water use under elevated [CO₂]. We propose that altered cuticular development during canopy closure may partially explain the changing response of stomata to elevated [CO₂], although the mechanism for this remains obscure.