Biology subjects

Grand, J.

Publications and source records attributed to Grand, J..

3 recordsLinked to original sources

bioRxiv2023

Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation

BackgroundAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. MethodsRight atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. ResultsIn human patients with AF, PPP1R12C expression was increased two-fold versus SR controls (P=2.0x10-2, n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation (P=1.4x10-6, n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9x10-2 and 6.7x10-3 respectively, n=8,8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls (P=5.0x10-6, n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls (P=1.8x10-2 and 4.1x10-2 respectively, n= 6,6,5). ConclusionsAF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

molecular biology↗

bioRxiv2023

A framework for linking hemispheric, full annual cycle prioritizations to local conservation actions for migratory birds

The conservation of migratory birds poses a fundamental challenge: their conservation requires coordinated action across the hemisphere, but those actions must be designed and implemented locally. To address this challenge, we describe a multi-level framework for linking broad-scale, full annual cycle prioritizations to local conservation actions for migratory birds. We developed hemisphere-scale spatial prioritizations for the full annual cycle of migratory birds that breed in six different ecosystems in North America. The full annual cycle prioritizations provide a hemispheric context within which regional priorities can be identifieed. Finer resolution, regional prioritizations can then inform local conservation actions more effectively. We describe the importance of local conservation practitioner contributions at each level of the process and provide two examples of regional spatial prioritizations that were developed to guide local action. The fierst example focused on coastal North and South Carolina, USA, and used information on marsh birds, shorebirds, ecological integrity, and co-benefiets for people to identify Cape Romain, South Carolina as a high-priority site for conservation action. The second example in Colombia used information on migrant and resident birds to identify the Cauca Valley as a high priority site. The multi-level conceptual framework we describe is one pathway for identifying sites for implementation of local conservation actions that are guided by conservation priorities for migratory birds across their full annual cycle.

ecology↗

bioRxiv2023

Where, who, and what counts under area-based conservation targets: A framework for identifying opportunities that benefit biodiversity, climate mitigation, and human communities

O_LIArea-based conservation targets, such as 30-30, if strategically applied, can increase resiliency to climate change and provide co-benefits to people and biodiversity. However, protected areas historically were not designated within the context of global change, and human communities at highest risk are often overlooked in conservation planning. C_LIO_LITo inform 30-30 conservation planning in the United States (i.e., America the Beautiful; ATB), we evaluated where US conservation opportunities exist by identifying habitats that can simultaneously benefit climate change mitigation and bird populations, as well as who lives in these areas and how conservation actions could both improve human well-being or potentially be at odds with local communities. To inform the equitable implementation of area-based conservation targets, we integrated maps of critical habitat for birds now and under a changing climate with carbon stocks and sinks and developed a prioritization framework to investigate the spatial alignment of these locations with areas identified as important for both human well-being and land-dependent human communities. C_LIO_LIAlthough nearly 30% of US lands have some level of protection, only 6% of US lands (143 million acres) are managed for biodiversity and align with Bird and Carbon (BC) priorities, and <3% of protected US lands (59 million acres) align with priorities for Birds, Carbon, and Human well-being (BCH). C_LIO_LIOf the 312 million acres of BCH priorities identified, 71% lack known protection or formal conservation plans (14% of US lands) and should be considered conservation opportunities that could simultaneously address the biodiversity and climate crises, and social inequities. Targeting these BCH areas for conservation action would contribute to more equitable benefits to marginalized communities, and could fulfill the Justice 40 commitment, which aims to allocate 40% of federal investments in climate benefits to marginalized communities (which, for the 30% goal under ATB equates to 12% of US lands). C_LIO_LIAt least 80% of all BCH priorities co-occur with Indigenous peoples and local communities (IPLCs) who have strong cultural and socioeconomic ties to the land, making it imperative to work with local communities to define what counts as conservation actions towards the 30% goal and what successful conservation outcomes that benefit biodiversity, climate change mitigation, and human communities look like. C_LI

ecology↗