Predicting optimal hematocrit in silico

Optimal hematocrit $H_o$ maximizes oxygen transport. In healthy humans, the average hematocrit $H$ is in the range of 40-45$\%$, but it can significantly change in blood pathologies such as severe anemia (low $H$) and polycythemia (high $H$). Whether the hematocrit level in humans corresponds to the optimal one is a long standing physiological question. Here, using numerical simulations with the Lattice Boltzmann method and two mechanical models of the red blood cell (RBC) we predict the optimal hematocrit, and explore how altering the mechanical properties of RBCs affects $H_o$. We develop a simplified analytical theory that accounts for results obtained from numerical simulations and provides insight into the physical mechanisms determining $H_o$. Our numerical and analytical models can easily be modified to incorporate a wide range of mechanical properties of RBCs as well as other soft particles thereby providing means for the rational design of blood substitutes. Our work lays the foundations for systematic theoretical study of the optimal hematocrit and its link with pathological RBCs associated with various diseases (e.g. sickle cell anemia, diabetes mellitus, malaria, elliptocytosis)

High Temperature Superconductivity

The current status of basic research on the high temperature cuprate superconductors and prospects for technological applications of these materials is discussed. Recent developments concerning other novel superconductors are also briefly described.Comment: 30 pages, 13 figure

BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells

Arsenic exposure constitutes one of the most widespread environmental carcinogens, and is associated with increased risk of many different types of cancers. Here we report that arsenite (As[III]) can induce both replication-dependent DNA double-strand breaks (DSB) and homologous recombination (HR) at doses as low as 5 µM (0.65 mg/l), which are within the typical doses often found in drinking water in contaminated areas. We show that the production of DSBs is dependent on active replication and is likely to be the result of conversion of a DNA single-strand break (SSB) into a toxic DSB when encountered by a replication fork. We demonstrate that HR is required for the repair of these breaks and show that a functional HR pathway protects against As[III]-induced cytotoxicity. In addition, BRCA2-deficient cells are sensitive to As[III] and we suggest that As[III] could be exploited as a therapy for HR-deficient tumours such as BRCA1 and BRCA2 mutated breast and ovarian cancers

Assessing the effects of Ang-(1-7) therapy following transient middle cerebral artery occlusion

The counter-regulatory axis, Angiotensin Converting Enzyme 2, Angiotensin-(1-7), Mas receptor (ACE2/Ang-1-7/MasR), of the renin angiotensin system (RAS) is a potential therapeutic target in stroke, with Ang-(1-7) reported to have neuroprotective effects in pre-clinical stroke models. Here, an extensive investigation of the functional and mechanistic effects of Ang-(1-7) was performed in a rodent model of stroke. Using longitudinal magnetic resonance imaging (MRI) it was observed that central administration of Ang-(1-7) following transient middle cerebral artery occlusion (MCAO) increased the amount of tissue salvage compared to reperfusion alone. This protective effect was not due to early changes in blood brain barrier (BBB) permeability, microglia activation or inflammatory gene expression. However, increases in NADPH oxidase 1 (Nox1) mRNA expression were observed in the treatment group compared to control. In order to determine whether Ang-(1-7) has direct cerebrovascular effects, laser speckle contrast imaging (LSCI) was performed to measure dynamic changes in cortical perfusion following reperfusion. Delivery of Ang-(1-7) did not have any effect on cortical perfusion following reperfusion however; it showed an indication to prevent the ‘steal phenomenon’ within the contralateral hemisphere. The comprehensive series of studies have demonstrated a moderate protective effect of Ang-(1-7) when given alongside reperfusion to increase tissue salvage

The MDM2-p53 pathway is involved in preconditioning-induced neuronal tolerance to ischemia.

Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome. Here, we study the role of MDM2-p53 pathway on PC-induced neuroprotection both in cultured neurons (in vitro) and rat brain (in vivo). Our results show that PC increased neuronal MDM2 protein levels, which prevented ischemiainduced p53 stabilization and neuronal death. Indeed, PC attenuated ischemia-induced activation of the p53/PUMA/caspase-3 signaling pathway. Pharmacological inhibition of MDM2-p53 interaction in neurons abrogated PC-induced neuroprotection against ischemia. Finally, the relevance of the MDM2-p53 pathway was confirmed in rat brain using a PC model in vivo. These findings demonstrate the key role of the MDM2-p53 pathway in PC-induced neuroprotection against a subsequent ischemic insult and poses MDM2 as an essential target in ischemic tolerance

Structural Biology by NMR: Structure, Dynamics, and Interactions

The function of bio-macromolecules is determined by both their 3D structure and conformational dynamics. These molecules are inherently flexible systems displaying a broad range of dynamics on time-scales from picoseconds to seconds. Nuclear Magnetic Resonance (NMR) spectroscopy has emerged as the method of choice for studying both protein structure and dynamics in solution. Typically, NMR experiments are sensitive both to structural features and to dynamics, and hence the measured data contain information on both. Despite major progress in both experimental approaches and computational methods, obtaining a consistent view of structure and dynamics from experimental NMR data remains a challenge. Molecular dynamics simulations have emerged as an indispensable tool in the analysis of NMR data

A Criterion for Brittle Failure of Rocks Using the Theory of Critical Distances

This paper presents a new analytical criterion for brittle failure of rocks and heavily overconsolidated soils. Griffith’s model of a randomly oriented defect under a biaxial stress state is used to keep the criterion simple. The Griffith’s criterion is improved because the maximum tensile strength is not evaluated at the boundary of the defect but at a certain distance from the boundary, known as the critical distance. This fracture criterion is known as the Point Method, and is part of the Theory of Critical Distances, which is utilized in fracture mechanics. The proposed failure criterion has two parameters: the inherent tensile strength, ó0, and the ratio of the half-length of the initial crack/flaw to the critical distance, a/L. These parameters are difficult to measure but they may be correlated with the uniaxial compressive and tensile strengths, óc and ót. The proposed criterion is able to reproduce the common range of strength ratios for rocks and heavily overconsolidated soils (óc/ót=3-50) and the influence of several microstructural rock properties, such as texture and porosity. Good agreement with laboratory tests reported in the literature is found for tensile and low confining stresses.The work presented was initiated during a research project on “Structural integrity assessments of notch-type defects", for the Spanish Ministry of Science and Innovation (Ref.: MAT2010-15721)

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction

Ethnic Related Selection for an ADH Class I Variant within East Asia

The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region.Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best.The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region. The obvious ethnicity-related distributions of ADH1B diversities suggest the existence of some culture-related selective forces that have acted on the ADH1B region