Divalent cations promote huntingtin fibril formation on endoplasmic reticulum derived and model membranes.

Huntington's Disease (HD) is caused by an abnormal expansion of the polyglutamine (polyQ) domain within the first exon of the huntingtin protein (htt). This expansion promotes disease-related htt aggregation into amyloid fibrils and the formation of proteinaceous inclusion bodies within neurons. Fibril formation is a complex heterogenous process involving an array of aggregate species such as oligomers, protofibrils, and fibrils. In HD, structural abnormalities of membranes of several organelles develop. In particular, the accumulation of htt fibrils near the endoplasmic reticulum (ER) impinges upon the membrane, resulting in ER damage, altered dynamics, and leakage of Ca2+. Here, the aggregation of htt at a bilayer interface assembled from ER-derived liposomes was investigated, and fibril formation directly on these membranes was enhanced. Based on these observations, simplified model systems were used to investigate mechanisms associated with htt aggregation on ER membranes. As the ER-derived liposome fractions contained residual Ca2+, the role of divalent cations was also investigated. In the absence of lipids, divalent cations had minimal impact on htt structure and aggregation. However, the presence of Ca2+ or Mg2+ played a key role in promoting fibril formation on lipid membranes despite reduced htt insertion into and association with lipid interfaces, suggesting that the ability of divalent cations to promote fibril formation on membranes is mediated by induced changes to the lipid membrane physicochemical properties. With enhanced concentrations of intracellular calcium being a hallmark of HD, the ability of divalent cations to influence htt aggregation at lipid membranes may play a role in aggregation events that lead to organelle abnormalities associated with disease.

The polyglutamine domain is the primary driver of seeding in huntingtin aggregation.

Huntington's Disease (HD) is a fatal, neurodegenerative disease caused by aggregation of the huntingtin protein (htt) with an expanded polyglutamine (polyQ) domain into amyloid fibrils. Htt aggregation is modified by flanking sequences surrounding the polyQ domain as well as the binding of htt to lipid membranes. Upon fibrillization, htt fibrils are able to template the aggregation of monomers into fibrils in a phenomenon known as seeding, and this process appears to play a critical role in cell-to-cell spread of HD. Here, exposure of C. elegans expressing a nonpathogenic N-terminal htt fragment (15-repeat glutamine residues) to preformed htt-exon1 fibrils induced inclusion formation and resulted in decreased viability in a dose dependent manner, demonstrating that seeding can induce toxic aggregation of nonpathogenic forms of htt. To better understand this seeding process, the impact of flanking sequences adjacent to the polyQ stretch, polyQ length, and the presence of model lipid membranes on htt seeding was investigated. Htt seeding readily occurred across polyQ lengths and was independent of flanking sequence, suggesting that the structured polyQ domain within fibrils is the key contributor to the seeding phenomenon. However, the addition of lipid vesicles modified seeding efficiency in a manner suggesting that seeding primarily occurs in bulk solution and not at the membrane interface. In addition, fibrils formed in the presence of lipid membranes displayed similar seeding efficiencies. Collectively, this suggests that the polyQ domain that forms the amyloid fibril core is the main driver of seeding in htt aggregation.

Improving the quality of pressure ulcer management in a skilled nursing facility.

Pressure ulcers (PUs) are a serious health care problem for nursing home residents and a key quality metric for regulators. Three initiatives were introduced at a 128-bed facility to improve PU prevention. First, a Quality Assurance and Performance Improvement project and a Root Cause Analysis were conducted to improve the facility's wound care programme. Second, a digital wound care management solution was adopted to track wound management. Third, the role of skin integrity coordinator was created as a central point of accountability for wound care-related activities and related performance metrics. Improvements in PU prevention were tracked using Centers of Medicare and Medicaid data, specifically (a) the percentage of long-stay high-risk residents with PUs and (b) the percentage of short-stay residents with PUs that are new or have worsened. PU prevalence for long-stay high-risk residents was 12.99% (Q4 2016), and upon implementation of these initiatives, the facility saw continued reductions in PU prevalence to 2.9% (Q4 2017), while PUs for short-stay residents were maintained at zero throughout this period. This study highlights the power of effective management combined with real-time data analytics, as enabled by digital wound care management, to make significant improvements in health care delivery.