Blackwood

Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo . Here, using a mouse model of myocardial ischemia/reperfusion, we showed that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 was also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a first-in-class proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.

The sarco/endoplasmic reticulum (SR/ER) of cardiomyocytes is a critical site of protein synthesis and folding, as most secreted and membrane proteins including receptors, growth factors, ion channels, and calcium-handling proteins are made at this location. Myocardial ischemia induces ER stress, during which toxic, misfolded proteins accumulate in the SR/ER and contribute to cardiomyocyte death. The branch of the ER stress response mediated by the transcription factor, ATF6, induces ER chaperones that restore SR/ER protein folding. We found that ATF6 also induces mesencephalic astrocyte-derived neurotrophic factor (MANF), a novel, ubiquitously expressed, ER-luminal protein of unknown function. MANF is structurally unique, thus its function cannot be inferred by structural analogy to known proteins. Since it is ATF6-inducible, and resides in the ER lumen, we hypothesized that MANF is an ER chaperone required for optimal viability of cardiac myocytes during ER stresses, including ischemia. The characteristics of MANF gene induction by ER stress, and the effects of MANF knockdown on the ER stress response and cell viability were determined in cultured neonatal rat ventricular myocytes (NRVM). The ability of recombinant MANF to restore structure and function to model misfolded proteins was also examined. Finally, the effects of MANF loss-of-function in the ischemic heart, in vivo , were determined by generating a transgenic mouse model that expresses a cardiomyocyte-specific MANF-targeted microRNA. MANF induction and functional characteristics phenocopied those of a well-studied ER chaperone, glucose-regulated protein 78 (Grp78). Like Grp78, MANF was induced by ER stress in an ATF6-dependent manner. Like knockdown of Grp78, knockdown of MANF in NRVM increased myocyte death in response to ER stress. Like recombinant Grp78, recombinant MANF exhibited a robust ability to restore structure and function to model misfolded proteins, in vitro. Finally, MANF knockdown in the heart, in vivo , increased damage in a mouse model of myocardial infarction. These results suggest that MANF is an SR/ER-resident chaperone required for restoration of SR/ER protein folding during the adaptive ER stress response, and decreasing tissue damage in the ischemic heart.

Iron-deficiency anaemia is the most common nutritional deficiency around the world. This article looks at the presentation, causes and management of a common and potentially serious condition in general practice.

There are two main types of skin cancer: malignant melanoma and non-melanoma skin cancers (NMSC). More than 100 000 new cases of skin cancer are diagnosed every year. The major cause of skin cancers is overexposure to ultraviolet radiation. Prevention strategies are important in reducing the occurrence of skin cancers. They include environmental measures as well as public education campaigns about sun safety and early detection.

Rotary forging has been used to produce high-density bonded magnets from rapidly quenched Nd-Fe-B based ribbons [MQP-D, of nominal composition 28%Nd-56%Fe-15%Co-1%B (wt %)]. Polytetrafluoroethylene (PTFE), when used as an additive (5%–15% by volume) has been found to act as an effective binder and greatly enhances the forgeability of the MQI, allowing higher forging pressures to be used. Densities of up to 98% of the fully dense composite have been achieved. The forging process can be undertaken in air at room temperature. Magnetically, the compacts are comparable to conventional epoxy resin bonded MQI, with energy products of up to 84 kJ/m3. Equivalent volume fractions of MQI (∼83.5 vol %) have been achieved in the compacts with increased PTFE content due to the displacement of pores by the PTFE. The effect of PTFE content on the mechanical strength of the compacts has been assessed and it has been found that strength increases with increasing PTFE content, consistent with the reduction in porosity.

A contribution to an IEE conference on distribution switchgear in 1978 contained the seeds of developments which led to the range of equipment reviewed here