How benign is sickle cell trait?

This is the final version of the article. It first appeared from Elsevier at http://dx.doi.org/10.1016/j.ebiom.2016.08.023

Lipid metabolism in terminal erythropoiesis.

In this issue of Blood, Huang et al have provided evidence that altered lipid metabolism is critical for terminal erythropoiesis. A key role is proposed for the PHOSPHO1 gene product, a phosphocholine phosphatase. PHOSPHO1 knockouts (KOs) showed reduced erythroblast proliferation and enucleation in both mice and human erythroid tissues, apparently through energy depletion mediated via inhibition of oxidative phosphorylation of fatty acids and reduced adenosine triphosphate (ATP) production in late glycolysis. This work emphasizes that altered expression of genes involving lipid metabolism are important during late red cell maturation

Not All Worms Were Created Equal

[Extract] Whilst we support the need to report safety outcomes from experimental therapy of any kind, including the use of helminths as therapy, we believe that it is important to critically examine the causal relationship of the reported event to the proposed etiology so that a balanced view of the cause and effect be arrived at. This is particularly the case in an uncontrolled setting where formal processes for documenting and reporting experimental therapy may not be in place. Recent reviews of studies with one of the most widely used helminths, the anthropophilic hookworm, Necator americanus, have shown this helminth to be safe and well tolerated in hundreds of individuals by numerous research groups across Australia, the US and Europe (1–3). In BMC Pulmonary Medicine (4), Zeynalyan and colleagues report rapidly progressive respiratory failure in a patient with significant comorbidities, including systemic sclerosis, interstitial lung disease and pulmonary hypertension after self-administration of N. americanus larvae that were purchased over the internet. Here we raise some concerns about this report

Effects of 5-hydroxymethyl-2-furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease.

The heterocyclic aldehyde 5-hydroxymethyl-2-furfural (5HMF) interacts allosterically with the abnormal form of haemoglobin (Hb), HbS, in red blood cells (RBCs) from patients with sickle cell disease (SCD), thereby increasing oxygen affinity and decreasing HbS polymerization and RBC sickling during hypoxia. We hypothesized that should 5HMF also inhibit the main cation pathways implicated in the dehydration of RBCs from SCD patients - the deoxygenation-induced cation pathway (Psickle), the Ca(2+)-activated K(+) channel (the Gardos channel) and the K(+)-Cl(-) cotransporter (KCC) - it would have a synergistic effect in protection against sickling, directly through interacting with HbS, and indirectly through maintaining hydration and reducing [HbS]. This study was therefore designed to investigate the effects of 5HMF on RBC volume and K(+) permeability in vitro. 5HMF markedly reduced the deoxygenation-induced dehydration of RBCs whether in response to maintained deoxygenation or to cyclical deoxygenation/re-oxygenation. 5HMF was found to inhibit Psickle, an effect which correlated with its effects on sickling. Deoxygenation-induced activation of the Gardos channel and exposure of phosphatidylserine were also inhibited, probably indirectly via reduced entry of Ca(2+) through the Psickle pathway. Effects of 5HMF on KCC were more modest with a slight inhibition in N-ethylmaleimide (NEM, 1 mm)-treated RBCs and stimulation in RBCs untreated with NEM. These findings support the hypothesis that 5HMF may also be beneficial through effects on RBC ion and water homeostasis.We thank Action Medical Research and the MRC for financial support. UMC receives a BBSRC studentship.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.277681/abstract

Some Late-time Asymptotics of General Scalar-Tensor Cosmologies

We study the asymptotic behaviour of isotropic and homogeneous universes in general scalar-tensor gravity theories containing a p=-rho vacuum fluid stress and other sub-dominant matter stresses. It is shown that in order for there to be approach to a de Sitter spacetime at large 4-volumes the coupling function, omega(phi), which defines the scalar-tensor theory, must diverge faster than |phi_infty-phi|^(-1+epsilon) for all epsilon>0 as phi rightarrow phi_infty 0 for large values of the time. Thus, for a given theory, specified by omega(phi), there must exist some phi_infty in (0,infty) such that omega -> infty and omega' / omega^(2+epsilon) -> 0 as phi -> 0 phi_infty in order for cosmological solutions of the theory to approach de Sitter expansion at late times. We also classify the possible asymptotic time variations of the gravitation `constant' G(t) at late times in scalar-tensor theories. We show that (unlike in general relativity) the problem of a profusion of ``Boltzmann brains'' at late cosmological times can be avoided in scalar-tensor theories, including Brans-Dicke theory, in which phi -> infty and omega ~ o(\phi^(1/2)) at asymptotically late times.Comment: 14 page

Resolving the Formation of Protogalaxies. I. Virialization

(Abridged) Galaxies form in hierarchically assembling dark matter halos. With cosmological three dimensional adaptive mesh refinement simulations, we explore in detail the virialization of baryons in the concordance cosmology, including optically thin primordial gas cooling. We focus on early protogalaxies with virial temperatures of 10^4 K and their progenitors. Without cooling, virial heating occurs in shocks close to the virial radius for material falling in from voids. Material in dense filaments penetrates deeper to about half that radius. With cooling the virial shock position shrinks and also the filaments reach scales as small as a third the virial radius. The temperatures in protogalaxies found in adiabatic simulations decrease by a factor of two from the center and show flat entropy cores. In cooling halos the gas reaches virial equilibrium with the dark matter potential through its turbulent velocities. We observe turbulent Mach numbers ranging from one to three in the cooling cases. This turbulence is driven by the large scale merging and interestingly remains supersonic in the centers of these early galaxies even in the absence of any feedback processes. The virial theorem is shown to approximately hold over 3 orders of magnitude in length scale with the turbulent pressure prevailing over the thermal energy. The turbulent velocity distributions are Maxwellian and by far dominate the small rotation velocities associated with the total angular momentum of the galaxies. Decomposing the velocity field using the Cauchy-Stokes theorem, we show that ample amounts of vorticity are present around shocks even at the very centers of these objects.Comment: 13 pages, 6 figures. Submitted to ApJ on 8 March 2007. Revised manuscript. Comments welcom

The effect of the antisickling compound GBT1118 on the permeability of red blood cells from patients with sickle cell anemia.

Sickle cell anemia (SCA) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S (HbS) to increase oxygen (O2 ) affinity and reduce sickling. One of these, voxelotor (GBT440), is currently in advanced clinical trials. A structural analogue, GBT1118, was investigated in the current work. As RBC dehydration is important in pathogenesis of SCA, the effect of GBT1118 on RBC cation permeability was also studied. Activities of Psickle , the Gardos channel and the KCl cotransporter (KCC) were all reduced. Gardos channel and KCC activities were also inhibited in RBCs treated with Ca2+ ionophore or the thiol reagent N-ethylmaleimide, indicative of direct effects on these two transport systems. Consistent with its action on RBC membrane transporters, GBT1118 significantly increased RBC hydration. RBC hemolysis was reduced in a nonelectrolyte lysis assay. Further to its direct effects on O2 affinity, GBT1118 was therefore found to reduce RBC shrinkage and fragility. Findings reveal important effects of GBT1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA.Sultanate of Oman His Majesty Sultan Qaboos's 1000 grants British Heart Foundatio