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Spinal cord injury (SCI) results in significant neurological deficits, and curative therapies are lacking. Neural progenitor cell (NPC) transplantation shows promise, as graft-derived neurons (GDNs) can integrate into host spinal cord and support axon regeneration. Here, we examined the synaptic integration of GDNs into hindlimb motor circuits in a mouse thoracic contusion SCI model. Transsynaptic tracing revealed that GDNs form synaptic connections with host motor circuits. Axon mapping showed distinct termination patterns of cholinergic and V2a interneurons within host spinal cord. Chemogenetic activation of GDNs induced muscle activity in a subset of transplanted animals, but NPC transplantation alone did not improve locomotor recovery. These findings indicate that GDNs can integrate into and modulate activity of host circuits, yet limited synaptic connectivity constrains functional recovery. Future studies should enhance graft-host connectivity and refine transplantation strategies to maximize therapeutic benefit for SCI. Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

Indigenous people living in the Circumpolar North rely, to varying degrees, on the natural environment and the resources it provides for their lifestyle and livelihoods. As a consequence, these Northern Indigenous peoples may be more sensitive to global climate change, which has implications for food security, cultural practices, and health and well-being. To date, most research on the human dimensions of climate change in the Circumpolar North has focused on biophysical issues and their consequences, such as changing sea ice regimes affecting travel to hunting grounds or the effects of melting permafrost on built infrastructure. Less is known about how these changes in the environment affect mental health and well-being. In this paper, we build upon existing research, combined with our community-based research and professional mental health practices, to outline some pathways and mechanisms through which climate change may adversely impact mental health and well-being in the Circumpolar North. Our analysis indicates that mental health may be affected by climate change due to changes to land, ice, snow, weather, and sense of place; impacts to physical health; damage to infrastructure; indirect impacts via media, research, and policy; and through the compounding of existing stress and distress. We argue that climate change is likely an emerging mental health challenge for Circumpolar Indigenous populations and efforts to respond through research, policy, and mental health programming should be a priority. We conclude by identifying next steps in research, outlining points for policy, and calling for additional mental health resources that are locally responsive and culturally relevant.

Abstract Efficient interrogation of neurobiology remains bottlenecked by obtaining mature neurons. Immortalized cell lines still require lengthy differentiation periods to obtain neuron-like cells, which may not efficiently differentiate and are challenging to transfect with plasmids relative to other cell lines such as HEK-293’s. To overcome challenges with limited access to cells that express mature neuronal proteins, we knocked out the RE1-silencing transcription factor (REST) from HEK-293’s to create a novel neuron-like cell, which we name Neuro293. RNA-sequencing and bioinformatics analyses revealed a significant upregulation of genes associated with neurobiology and membrane excitability including pre-/post-synaptic proteins, voltage gated ion channels, neuron-cytoskeleton, as well as neurotransmitter synthesis, packaging, and release. Western blot validated the upregulation of Synapsin-1 (Syn1) and Snap-25 as two neuron-restricted proteins, as well as the potassium channel Kv1.2. Immunocytochemistry against Neurofilament 200 kd revealed a significant upregulation and accumulation in singular processes extending from Neuro293’s cell body. Similarly, while Syn1 increased in the cell body, Syn1 protein accumulated at the ends of processes extruding from Neuro293’s. Neuro293’s express reporter-genes through the Syn1 promoter after infection with adeno-associated viruses (AAV). However, transient transfection with AAV2 plasmids led to leaky expression through promoter-independent mechanisms. Despite an upregulation of many voltage-gated ion channels, Neuro293’s do not possess excitable membranes. Collectively, REST-knockout in HEK-293’s induces a quickly dividing and easily transfectable cell line that expresses neuron-restricted and mature neuronal proteins which can be used for high-throughput biochemical interrogation, however, without further modifications neither HEK-293’s or Neuro293’s exhibit properties of excitable membranes.

Neural progenitor cell (NPC) transplantation is a promising therapeutic strategy for replacing lost neurons following spinal cord injury (SCI). However, how graft cellular composition influences regeneration and synaptogenesis of host axon populations, or recovery of motor and sensory functions after SCI, is poorly understood. We transplanted developmentally-restricted spinal cord NPCs, isolated from E11.5-E13.5 mouse embryos, into sites of adult mouse SCI and analyzed graft axon outgrowth, cellular composition, host axon regeneration, and behavior. Earlier-stage grafts exhibited greater axon outgrowth, enrichment for ventral spinal cord interneurons and Group-Z spinal interneurons, and enhanced host 5-HT + axon regeneration. Later-stage grafts were enriched for late-born dorsal horn interneuronal subtypes and Group-N spinal interneurons, supported more extensive host CGRP + axon ingrowth, and exacerbated thermal hypersensitivity. Locomotor function was not affected by any type of NPC graft. These findings showcase the role of spinal cord graft cellular composition in determining anatomical and functional outcomes following SCI. In a mouse model of spinal cord injury, the developmental stage of transplanted neural progenitor cells is shown to influence anatomical and behavioral outcomes after spinal cord injury

Defining subpopulations using genetics has traditionally used data from microsatellite markers to investigate population structure; however, single‐nucleotide polymorphisms (SNPs) have emerged as a tool for detection of fine‐scale structure. In Hudson Bay, Canada, three polar bear (Ursus maritimus) subpopulations (Foxe Basin (FB), Southern Hudson Bay (SH), and Western Hudson Bay (WH)) have been delineated based on mark–recapture studies, radiotelemetry and satellite telemetry, return of marked animals in the subsistence harvest, and population genetics using microsatellites. We used SNPs to detect fine‐scale population structure in polar bears from the Hudson Bay region and compared our results to the current designations using 414 individuals genotyped at 2,603 SNPs. Analyses based on discriminant analysis of principal components (DAPC) and STRUCTURE support the presence of four genetic clusters: (i) Western—including individuals sampled in WH, SH (excluding Akimiski Island in James Bay), and southern FB (south of Southampton Island); (ii) Northern—individuals sampled in northern FB (Baffin Island) and Davis Strait (DS) (Labrador coast); (iii) Southeast—individuals from SH (Akimiski Island in James Bay); and (iv) Northeast—individuals from DS (Baffin Island). Population structure differed from microsatellite studies and current management designations demonstrating the value of using SNPs for fine‐scale population delineation in polar bears. Using SNPs, we investigate fine‐scale population structure in polar bears of the Hudson Bay region of Canada and compare these findings to subpopulation designations. Based on 414 samples and 2,603 SNPs, we conclude there are four genetic clusters that differ from current management.

Homelessness in the Beaufort-Delta represents a significant problem that is underserved by government, market, and nonprofit agencies. Based on research conducted during 2011-2012, this article outlines the breadth and scope of the housing problem and details extant service provision networks for homeless and hard-to-house (HtH) persons with addiction and mental health problems. A critique of neoliberal governance on housing development and social services suggests that significant effort is needed to deal with the problems associated with centralization on the one hand and the isolation associated with Arctic life on the other. The authors conclude by making recommendations for the future role of nonprofit agencies in the Beaufort-Delta through the adoption of a housing first approach. Dans le delta de Beaufort, l’itinérance pose un sérieux défi que négligent les secteurs gouvernemental, commercial et sans but lucratif. Cet article se fonde sur une étude menée en 2011-2012 qui souligne l’envergure du problème de logement et recense les réseaux actuels qui desservent les sans-abris et les personnes difficiles à héberger souffrant de problèmes de dépendance et de santé mentale. Il s’ensuit dans cet article la critique d’une politique néolibérale envers la fourniture de logements et de services sociaux. Cette critique suggère qu’un effort important est requis pour surmonter les problèmes reliés à la centralisation des services d’une part et à l’isolement du milieu arctique d’autre part. Pour conclure, l’article propose un rôle futur pour les agences à but non lucratif dans le delta de Beaufort en recommandant à ces dernières une approche qui met l’accent sur les logements avant tout. 

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε‐amino group of lysine or hydroxylysine on collagen side‐chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS‐5153A, a novel mechanism based, fast‐acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS‐5153A dose‐dependently reduced LOXL2‐mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet‐induced, PXS‐5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS‐5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.

Background Compared with the E3 allele of Apolipoprotein E (APOE), E4 increases late‐onset Alzheimer’s Disease (AD) risk up to 15‐fold, while the E2 allele substantially decreases risk. In the CNS, ApoE is predominantly synthesized by astrocytes and microglia, making these two cell types promising targets for ApoE‐directed therapeutic approaches. Our lab has generated an inducible “switch” mouse model (APOE4s2) in which we can conditionally replace E4 with the protective E2 in a cell‐specific manner. To elucidate potential mechanisms by which astrocytes and microglia expressing E2 or E4may modulate AD risk, we characterized the immuno‐metabolic response of astrocyte‐ and microglia‐specific “switch” mice to a variety of CNS‐related challenges. Method Aged APOE4s2 mice were administered tamoxifen to induce an in vivo transition from expression of E4 to E2 selectively in astrocytes (Aldh1l1‐CreERT2) or microglia (Tmem119‐CreERT2). A separate cohort of APOE4s2 mice received LPS to induce an inflammatory response 24 hours prior to tissue collection. Immunohistochemical analysis of gliosis (GFAP, IBA1), cytokine measurements, and targeted metabolomics and lipidomics were performed on brain tissue from these groups. Additionally, a cohort of 6‐week‐old microglia‐APOE4s2 mice were administered lysophosphatidylcholine (LPC) via intracranial injections to promote demyelination. Mice were sacrificed 10 days post‐LPC injection, and myelin content and glial reactivity were quantified via staining of myelin basic protein (MBP), degraded MBP (dMBP), and Luxol Fast Blue (LFB). Result As measured by plasma and brain cytokine levels, the inflammatory response was not modified by glial E2 expression in either age or LPS. However, aged E4 mice in which only astrocytes selectively expressed E2 showed decreased microglia reactivity (Iba1 immunoreactivity) compared to mice expressing E4 in all cell types. In contrast, aged mice in which only the microglia express E2 showed increased microglia reactivity relative to E4 expressing controls. Interestingly, a similar increase in Iba1 signal was noted in mice expressing only astrocytic E2 following an acute exposure to LPS. Finally, E2 expressing microglia appear to have higher levels of myelin following LPC injections compared to E4 expressing microglia. Conclusion Glial cell‐specific expression of E2 alters microglia reactivity in response to various pathological challenges, including aging, inflammatory stimuli, and demyelination.