Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain.\ua0Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery

What do you mean, ‘megafire’?

BACKGROUND : ‘Megafire’ is an emerging concept commonly used to describe fires that are extreme in terms of size, behaviour, and/or impacts, but the term’s meaning remains ambiguous. APPROACH : We sought to resolve ambiguity surrounding the meaning of ‘megafire’ by conducting a structured review of the use and definition of the term in several languages in the peer-reviewed scientific literature. We collated definitions and descriptions of megafire and identified criteria frequently invoked to define megafire. We recorded the size and location of megafires and mapped them to reveal global variation in the size of fires described as megafires. RESULTS : We identified 109 studies that define the term ‘megafire’ or identify a megafire, with the term first appearing in the peer-reviewed literature in 2005. Seventy-one (~65%) of these studies attempted to describe or define the term. There was considerable variability in the criteria used to define megafire, although definitions of megafire based on fire size were most common. Megafire size thresholds varied geographically from > 100–100,000 ha, with fires > 10,000 ha the most common size threshold (41%, 18/44 studies). Definitions of megafire were most common from studies led by authors from North America (52%, 37/71). We recorded 137 instances from 84 studies where fires were reported as megafires, the vast majority (94%, 129/137) of which exceed 10,000 ha in size. Megafires occurred in a range of biomes, but were most frequently described in forested biomes (112/137, 82%), and usually described single ignition fires (59% 81/137). CONCLUSION : As Earth’s climate and ecosystems change, it is important that scientists can communicate trends in the occurrence of larger and more extreme fires with clarity. To overcome ambiguity, we suggest a definition of megafire as fires > 10,000 ha arising from single or multiple related ignition events. We introduce two additional terms – gigafire (> 100,000 ha) and terafire (> 1,000,000 ha) – for fires of an even larger scale than megafires.DATA AVAILABILITY STATEMENT: A list of the references from which the data were extracted can be found in the Appendix A: Data sources. The data used in this study are openly available at zenodo.org: https://doi.org/10.5281/zenodo.6252145.Threatened Species Recovery Hub; NSW Bushfire Risk Management Research Hub; Australian Wildlife Society; World Wildlife Fund.http://wileyonlinelibrary.com/journal/gebZoology and Entomolog

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Critical Illness Myopathy and Polyneuropathy

Neuromuscular weakness commonly develops in the setting of critical illness. This weakness delays recovery and often causes prolonged ventilator dependence. An axonal sensory-motor polyneuropathy, critical illness polyneuropathy (CIP), is seen in up to one third of critically ill patients with the systemic inflammatory response syndrome (usually due to sepsis). An acute myopathy, critical illness myopathy (CIM), frequently develops in a similar setting, often in association with the use of corticosteroids and/or nondepolarizing neuromuscular blocking agents. These patients are often difficult to evaluate due to the limitations imposed by the critical care setting and may be further complicated by the presence of both CIP and CIM in varying degrees. This paper reviews the clinical and electrophysiologic features of these disorders, as well as the putative pathophysiology. In the case of CIM, an animal model has provided evidence that weakness in this disorder is caused by muscle membrane inexcitability due to altered membrane sodium currents and loss of myosin thick filaments

Critical Illness Myopathy and Polyneuropathy

Neuromuscular weakness commonly develops in the setting of critical illness. This weakness delays recovery and often causes prolonged ventilator dependence. An axonal sensory-motor polyneuropathy, critical illness polyneuropathy (CIP), is seen in up to one third of critically ill patients with the systemic inflammatory response syndrome (usually due to sepsis). An acute myopathy, critical illness myopathy (CIM), frequently develops in a similar setting, often in association with the use of corticosteroids and/or nondepolarizing neuromuscular blocking agents. These patients are often difficult to evaluate due to the limitations imposed by the critical care setting and may be further complicated by the presence of both CIP and CIM in varying degrees. This paper reviews the clinical and electrophysiologic features of these disorders, as well as the putative pathophysiology. In the case of CIM, an animal model has provided evidence that weakness in this disorder is caused by muscle membrane inexcitability due to altered membrane sodium currents and loss of myosin thick filaments

CANOMAD Presenting as Bilateral Sixth Nerve Palsies

A 67-year-old man reported 1 day of binocular horizontal diplopia associated with 1 week of bilateral periorbital pain, worse in the right eye. He felt otherwise well without any constitutional symptoms. Four days prior, he had undergone a partial right nephrectomy for grade II papillary renal cell carcinoma. Visual acuity was 20/20 in each eye, and the remainder of his ophthalmic examination was normal except for mildly limited abduction bilaterally, with a 16-prism diopter esotropia in primary gaze. Brain MRI, acetylcholine receptor antibodies, and thyroid-stimulating hormone level were normal