Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Multiple mechanism based constitutive modeling of gradient nanograined material

Gradient nano-grained (GNG) materials, inside which grain size increases gradually from nanoscale in the surface to micro-scale in the substrate, have shown synergetic strength and ductility. The extra strain hardening of GNG materials is considered to result from both geometrically necessary dislocations (GNDs) accommodating nonuniform plastic deformation and superior kinematic hardening characterized by back stress. However, few quantitative investigations were performed to evaluate the contribution of various strengthening mechanisms to the mechanical response of GNG materials. In this work, we develop a multiple-mechanism-based constitutive model, in which constitutive laws for GNDs and back stress at both grain level and sample level are established. Microstructure-based finite element simulation successfully predicts the uniaxial tensile behavior of a GNG interstitial-free (IF) steel sheet. The simulation results demonstrate that GNDs and back stress at sample level have little influence on the strengthening of the GNG IF-steel, while the back stress induced by pileup GNDs contributes about 35% to the flow stress. The uniform elongation of the GNG sample is improved by the constraint of coarsegrained core on GNG layer. This work helps to understand the contributions of deformation mechanisms to the synergetic strength and ductility of GNG materials and to guide the microstructure design and optimization for improved strength-ductility combination