Relational place-based solutions for environmental policy misalignments.

Current reductionist approaches to environmental governance cannot resolve social-ecological crises. Siloed institutions fail to address linked social and ecological processes, thereby neglecting issues of equity, justice, and cumulative effects. Global insights can be gained from Indigenous-led initiatives that support the resilience of relationships within and among places.

Indigenous-led conservation: Pathways to recovery for the nearly extirpated Klinse-Za mountain caribou.

Indigenous Peoples around the northern hemisphere have long relied on caribou for subsistence and for ceremonial and community purposes. Unfortunately, despite recovery efforts by federal and provincial agencies, caribou are currently in decline in many areas across Canada. In response to recent and dramatic declines of mountain caribou populations within their traditional territory, West Moberly First Nations and Saulteau First Nations (collectively, the "Nations") came together to create a new vision for caribou recovery on the lands they have long stewarded and shared. The Nations focused on the Klinse-Za subpopulation, which had once encompassed so many caribou that West Moberly Elders remarked that they were "like bugs on the landscape." The Klinse-Za caribou declined from ~250 in the 1990s to only 38 in 2013, rendering Indigenous harvest of caribou nonviable and infringing on treaty rights to a subsistence livelihood. In collaboration with many groups and governments, this Indigenous-led conservation initiative paired short-term population recovery actions, predator reduction and maternal penning, with long-term habitat protection in an effort to create a self-sustaining caribou population. Here, we review these recovery actions and the promising evidence that the abundance of Klinse-Za caribou has more than doubled from 38 animals in 2013 to 101 in 2021, representing rapid population growth in response to recovery actions. With looming extirpation averted, the Nations focused efforts on securing a landmark conservation agreement in 2020 that protects caribou habitat over a 7986-km2 area. The Agreement provides habitat protection for >85% of the Klinse-Za subpopulation (up from only 1.8% protected pre-conservation agreement) and affords moderate protection for neighboring caribou subpopulations (29%-47% of subpopulation areas, up from 0%-20%). This Indigenous-led conservation initiative has set both the Indigenous and Canadian governments on the path to recover the Klinse-Za subpopulation and reinstate a culturally meaningful caribou hunt. This effort highlights how Indigenous governance and leadership can be the catalyst needed to establish meaningful conservation actions, enhance endangered species recovery, and honor cultural connections to now imperiled wildlife.

Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance.

The lactate transporter SLC16A1/monocarboxylate transporter 1 (MCT1) plays a central role in tumor cell energy homeostasis. In a cell-based screen, we identified a novel class of MCT1 inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246 cancer cell lines and show that hematopoietic tumor cells, in particular diffuse large B-cell lymphoma cell lines, and subsets of solid tumor models are particularly sensitive to MCT1 inhibition. Associated markers of sensitivity were, among others, lack of MCT4 expression, low pleckstrin homology like domain family A member 2, and high pellino E3 ubiquitin protein ligase 1 expression. The antitumor effect of MCT1 inhibition was less pronounced on tumor xenografts, with tumor stasis being the maximal response. BAY-8002 significantly increased intratumor lactate levels and transiently modulated pyruvate levels. In order to address potential acquired resistance mechanisms to MCT1 inhibition, we generated MCT1 inhibitor-resistant cell lines and show that resistance can occur by upregulation of MCT4 even in the presence of sufficient oxygen, as well as by shifting energy generation toward oxidative phosphorylation. These findings provide insight into novel aspects of tumor response to MCT1 modulation and offer further rationale for patient selection in the clinical development of MCT1 inhibitors. Mol Cancer Ther; 17(11); 2285-96. ©2018 AACR.

FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration.

Aberrant centrosome organisation with ensuing alterations of microtubule nucleation capacity enables tumour cells to proliferate and invade despite increased genomic instability. CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here, we report that FBXL13, a binding determinant of SCF (SKP1-CUL1-F-box)-family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin-2, Centrin-3, CEP152 and CEP192. Among these, CEP192 is specifically targeted for proteasomal degradation by FBXL13. Accordingly, induced FBXL13 expression downregulates centrosomal γ-tubulin and disrupts centrosomal microtubule arrays. In addition, depletion of FBXL13 induces high levels of CEP192 and γ-tubulin at the centrosomes with the consequence of defects in cell motility. Together, we characterise FBXL13 as a novel regulator of microtubule nucleation activity and highlight a role in promoting cell motility with potential tumour-promoting implications.