Anil Kumar Dasanna

Slow closure of denaturation bubbles in DNA: twist matters.

The closure of long equilibrated denaturation bubbles in DNA is studied using Brownian dynamics simulations. A minimal mesoscopic model is used where the double helix is made of two interacting bead-spring freely rotating strands, with a nonzero torsional modulus in the duplex state, κ(φ)=200 to 300k(B)T. For DNAs of lengths N=40 to 100 base pairs (bps) with a large initial bubble in their middle, long closure times of 0.1 to 100μs are found. The bubble starts winding from both ends until it reaches a ≈10 bp metastable state due to the large elastic energy stored in the bubble. The final closure is limited by three competing mechanisms depending on κ(φ) and N: arms diffusion until their alignment, bubble diffusion along the DNA until one end is reached, or local Kramers process (crossing over a torsional energy barrier). For clamped ends or long DNAs, the closure occurs via this last temperature-activated mechanism, yielding a good quantitative agreement with the experiments.

Modeling cytoadhesion of Plasmodium falciparum‐infected erythrocytes and leukocytes—common principles and distinctive features

Cytoadhesion of Plasmodium falciparum‐infected erythrocytes to the microvascular endothelial lining shares striking similarities to cytoadhesion of leukocytes. In both cases, adhesins are presented in structures that raise them above the cell surface. Another similarity is the enhancement of adhesion under physical force (catch bonding). Here, we review recent advances in our understanding of the molecular and biophysical mechanisms underlying cytoadherence in both cellular systems. We describe how imaging, flow chamber experiments, single‐molecule measurements, and computational modeling have been used to decipher the relevant processes. We conclude that although the parasite seems to induce processes that resemble the cytoadherence of leukocytes, the mechanics of erythrocytes is such that the resulting behavior in shear flow is fundamentally different.

Multifractal analysis of HIV-1 genomes

Pathogens like HIV-1, which evolve into many closely related variants displaying differential infectivity and evolutionary dynamics in a short time scale, require fast and accurate classification. Conventional whole genome sequence alignment-based methods are computationally expensive and involve complex analysis. Alignment-free methodologies are increasingly being used to effectively differentiate genomic variations between viral species. Multifractal analysis, which explores the self-similar nature of genomes, is an alignment-free methodology that has been applied to study such variations. However, whether multifractal analysis can quantify variations between closely related genomes, such as the HIV-1 subtypes, is an open question. Here we address the above by implementing the multifractal analysis on four retroviral genomes (HIV-1, HIV-2, SIVcpz, and HTLV-1), and demonstrate that individual multifractal properties can differentiate between different retrovirus types easily. However, the individual multifractal measures do not resolve within-group variations for different known subtypes of HIV-1 M group. We show here that these known subtypes can instead be classified correctly using a combination of the crucial multifractal measures. This method is simple and computationally fast in comparison to the conventional alignment-based methods for whole genome phylogenetic analysis.

Differential time-dependent volumetric and surface area changes and delayed induction of new permeation pathways in P. falciparum-infected hemoglobinopathic erythrocytes

During intraerythrocytic development, Plasmodium falciparum increases the ion permeability of the erythrocyte plasma membrane to an extent that jeopardizes the osmotic stability of the host cell. A previously formulated numeric model has suggested that the parasite prevents premature rupture of the host cell by consuming hemoglobin (Hb) in excess of its own anabolic needs. Here, we have tested the colloid‐osmotic model on the grounds of time‐resolved experimental measurements on cell surface area and volume. We have further verified whether the colloid‐osmotic model can predict time‐dependent volumetric changes when parasites are grown in erythrocytes containing the hemoglobin variants S or C. A good agreement between model‐predicted and empirical data on both infected erythrocyte and intracellular parasite volume was found for parasitized HbAA and HbAC erythrocytes. However, a delayed induction of the new permeation pathways needed to be taken into consideration for the latter case. For parasitized HbAS erythrocyte, volumes diverged from model predictions, and infected erythrocytes showed excessive vesiculation during the replication cycle. We conclude that the colloid‐osmotic model provides a plausible and experimentally supported explanation of the volume expansion and osmotic stability of P. falciparum‐infected erythrocytes. The contribution of vesiculation to the malaria‐protective function of hemoglobin S is discussed.

Differential time‐dependent volumetric and surface area changes and delayed induction of new permeation pathways in haemoglobinopathic erythrocytes

During intraerythrocytic development, Plasmodium falciparum increases the ion permeability of the erythrocyte plasma membrane to an extent that jeopardizes the osmotic stability of the host cell. A previously formulated numeric model has suggested that the parasite prevents premature rupture of the host cell by consuming hemoglobin (Hb) in excess of its own anabolic needs. Here, we have tested the colloid‐osmotic model on the grounds of time‐resolved experimental measurements on cell surface area and volume. We have further verified whether the colloid‐osmotic model can predict time‐dependent volumetric changes when parasites are grown in erythrocytes containing the hemoglobin variants S or C. A good agreement between model‐predicted and empirical data on both infected erythrocyte and intracellular parasite volume was found for parasitized HbAA and HbAC erythrocytes. However, a delayed induction of the new permeation pathways needed to be taken into consideration for the latter case. For parasitized HbAS erythrocyte, volumes diverged from model predictions, and infected erythrocytes showed excessive vesiculation during the replication cycle. We conclude that the colloid‐osmotic model provides a plausible and experimentally supported explanation of the volume expansion and osmotic stability of P. falciparum‐infected erythrocytes. The contribution of vesiculation to the malaria‐protective function of hemoglobin S is discussed.

Multiscale Modeling of Malaria-Infected Red Blood Cells

Malaria is a parasitic disease which takes approximately half a million lives every year. The unicellular parasites are transmitted by mosquitoes and mainly affect vascular blood flow by invading red blood cells (RBCs). The pathogenicity of malaria primarily results from substantial changes in the stiffness of infected RBCs and their ability to adhere to endothelial cells and other circulating blood cells, leading to a substantial disruption of normal blood circulation and inflammation of the vascular endothelium. Multiscale modeling of malaria has proved to contribute significantly to the understanding of this devastating disease. In particular, modeling on the level of single infected RBCs allows quantification of their mechanics, cytoadherence, and individual as well as collective behavior in blood flow. Recent modeling advances in this direction are discussed. We show how computational models in malaria are validated and used for the interpretation of experimental observations or the establishment of new physical hypotheses. Such computational models have a strong potential to elucidate a number of physical mechanisms relevant for malaria and to aid in the development of novel diagnostic tools and treatment strategies.

Differential time-dependent volumetric and surface area changes and delayed induction of new permeation pathways inP. falciparum-infected hemoglobinopathic erythrocytes: Volumeric and surface area changes inP. falciparum-infected erythrocytes

During intraerythrocytic development, Plasmodium falciparum increases the ion permeability of the erythrocyte plasma membrane to an extent that jeopardizes the osmotic stability of the host cell. A previously formulated numeric model has suggested that the parasite prevents premature rupture of the host cell by consuming hemoglobin (Hb) in excess of its own anabolic needs. Here, we have tested the colloid‐osmotic model on the grounds of time‐resolved experimental measurements on cell surface area and volume. We have further verified whether the colloid‐osmotic model can predict time‐dependent volumetric changes when parasites are grown in erythrocytes containing the hemoglobin variants S or C. A good agreement between model‐predicted and empirical data on both infected erythrocyte and intracellular parasite volume was found for parasitized HbAA and HbAC erythrocytes. However, a delayed induction of the new permeation pathways needed to be taken into consideration for the latter case. For parasitized HbAS erythrocyte, volumes diverged from model predictions, and infected erythrocytes showed excessive vesiculation during the replication cycle. We conclude that the colloid‐osmotic model provides a plausible and experimentally supported explanation of the volume expansion and osmotic stability of P. falciparum‐infected erythrocytes. The contribution of vesiculation to the malaria‐protective function of hemoglobin S is discussed.