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Abstract Wildfires in the southwestern United States are increasingly frequent and severe, but whether these trends exceed historical norms remains contested. Here we combine dendroecological records, satellite-derived burn severity, and field measured tree mortality to compare historical (1700-1880) and contemporary (1985-2020) fire regimes at tree-ring fire-scar sites in Arizona and New Mexico. We found that contemporary fire frequency, including recent, record fire years, is still

IntroductionClimate change is predicted to increase the frequency of extreme single-day fire spread events, with major ecological and social implications. In contrast with well-documented spatio-temporal patterns of wildfire ignitions and perimeters, daily progression remains poorly understood across continental spatial scales, particularly for extreme single-day events (“blow ups”). Here, we characterize daily wildfire spread across North America, including occurrence of extreme single-day events, duration and seasonality of fire and extremes, and ecoregional climatic niches of fire in terms of Actual Evapotranspiration (AET) and Climatic Water Deficit (CWD) annual climate normals.MethodsRemotely sensed daily progression of 9,636 wildfires ≥400 ha was used to characterize ecoregional patterns of fire growth, extreme single-day events, duration, and seasonality. To explore occurrence, extent, and impacts of single-day extremes among ecoregions, we considered complementary ecoregional and continental extreme thresholds (Ecoregional or Continental Mean Daily Area Burned + 2SD). Ecoregional spread rates were regressed against AET and CWD to explore climatic influence on spread.ResultsWe found three-fold differences in mean Daily Area Burned among 10 North American ecoregions, ranging from 260 ha day−1 in the Marine West Coast Forests to 751 ha day−1 in Mediterranean California. Ecoregional extreme thresholds ranged from 3,829 ha day−1 to 16,626 ha day−1, relative to a continental threshold of 7,173 ha day−1. The ~3% of events classified as extreme cumulatively account for 16–55% of total area burned among ecoregions. We observed four-fold differences in mean fire duration, ranging from 2.7 days in the Great Plains to 10.5 days in Northwestern Forested Mountains. Regions with shorter fire durations also had greater daily area burned, suggesting a paradigm of fast-growing short-duration fires in some regions and slow-growing long-duration fires elsewhere. CWD had a weak positive relationship with spread rate and extreme thresholds, and there was no pattern for AET.DiscussionRegions with shorter fire durations had greater daily area burned, suggesting a paradigm of fast-growing short-duration fires in some regions and slow-growing long-duration fires elsewhere. Although climatic conditions can set the stage for ignition and influence vegetation and fuels, finer-scale mechanisms likely drive variation in daily spread. Daily fire progression offers valuable insights into the regional and seasonal distributions of extreme single-day spread events, and how these events shape net fire effects.

Abstract The historical role of fire in sagebrush (Artemisia tridentata) landscapes remains poorly understood, yet is important to inform management and conservation of obligate species such as the threatened Gunnison Sage‐grouse (GUSG; Centrocercus minimus). We reconstructed fire histories from tree‐ring fire scars at sagebrush–forest ecotones (10 sites, 111 trees) to better understand the role of fire in sagebrush landscapes of the Upper Gunnison Basin (UGB), Colorado, and how fire may have changed following Euro‐American settlement. We assessed likely influences of historical fire by surveying plant composition and structure at 100 sagebrush sites with and without recent (2001–2020) fires. Tree‐ring fire scars revealed a history of repeated low‐severity fire at sagebrush–forest ecotones until 1892, followed by over a century without fire. Between 1684 and 1892, the mean fire interval (MFI) among sites averaged 49.6 years (ranging from 18.2 to 119 years). Fire over this period occurred synchronously at two or more sites on average every 23.6 years, potentially indicative of spread between sites. Most (70%) of the historical fires burned in the early growing season, consistent with times of strong wind. Recent burns exhibited reductions in sagebrush cover (5% vs. 25% in unburned sites) and concomitant increases in herbaceous cover (55% vs. 40%). These differences declined over time but persisted for at least two decades. Burned sites were dominated by native perennial grasses, forbs, and resprouting shrub species. Historically, such openings may have served as seasonal GUSG habitat. Our results indicate that parts of the UGB sagebrush landscapes were characterized historically by frequent fire and dynamic vegetation mosaics that included open, grassy patches. These findings support the use of prescribed fire to restore and maintain this ecological process and vegetation heterogeneity. However, the contemporary context for fire has changed and now includes substantially reduced, Endangered Species Act (ESA)‐listed GUSG populations, increased risk of non‐native plant invasion, and climate warming. These circumstances highlight new risks, information needs, and opportunities for key knowledge co‐production via management–research partnerships.

Abstract Fire regimes in North American forests are diverse and modern fire records are often too short to capture important patterns, trends, feedbacks, and drivers of variability. Tree‐ring fire scars provide valuable perspectives on fire regimes, including centuries‐long records of fire year, season, frequency, severity, and size. Here, we introduce the newly compiled North American tree‐ring fire‐scar network (NAFSN), which contains 2562 sites, >37,000 fire‐scarred trees, and covers large parts of North America. We investigate the NAFSN in terms of geography, sample depth, vegetation, topography, climate, and human land use. Fire scars are found in most ecoregions, from boreal forests in northern Alaska and Canada to subtropical forests in southern Florida and Mexico. The network includes 91 tree species, but is dominated by gymnosperms in the genus Pinus. Fire scars are found from sea level to >4000‐m elevation and across a range of topographic settings that vary by ecoregion. Multiple regions are densely sampled (e.g., >1000 fire‐scarred trees), enabling new spatial analyses such as reconstructions of area burned. To demonstrate the potential of the network, we compared the climate space of the NAFSN to those of modern fires and forests; the NAFSN spans a climate space largely representative of the forested areas in North America, with notable gaps in warmer tropical climates. Modern fires are burning in similar climate spaces as historical fires, but disproportionately in warmer regions compared to the historical record, possibly related to under‐sampling of warm subtropical forests or supporting observations of changing fire regimes. The historical influence of Indigenous and non‐Indigenous human land use on fire regimes varies in space and time. A 20th century fire deficit associated with human activities is evident in many regions, yet fire regimes characterized by frequent surface fires are still active in some areas (e.g., Mexico and the southeastern United States). These analyses provide a foundation and framework for future studies using the hundreds of thousands of annually‐ to sub‐annually‐resolved tree‐ring records of fire spanning centuries, which will further advance our understanding of the interactions among fire, climate, topography, vegetation, and humans across North America.

Abstract In utero hematopoietic cell transplantation (IUHCT) utilizes fetal immune tolerance to achieve durable chimerism without conditioning or immunosuppression during a unique window in fetal development. Though donor cells have been observed within the nervous system following in utero injection, the timeline and distribution of cellular trafficking across the blood-brain barrier following IUHCT is not well understood. We injected 20 × 106 adult bone marrow mononuclear cells intravenously at gestational age (GA) 12–17 days and found that donor cells were maximally concentrated in the brain with treatment between GA 13–14. Donor cell engraftment persisted within the brain at every timepoint analyzed and concentrated within the hindbrain with significantly more grafted cells than in the forebrain. Additionally, transplanted cells terminally differentiated into various nervous system cellular morphologies and also populated the enteric nervous system. This study is the first to document the timeline and distribution of donor cell trafficking into the immune-protected nervous system and serves as a foundation for the application of IUHCT to treat neurogenetic diseases.

IntroductionChronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients.MethodsBrain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms.ResultsAnalyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or “zebra bodies” consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice.DiscussionOur findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB) is a recessive genetic disorder that severely affects the brain due to a deficiency in the enzyme α-N-acetylglucosaminidase (NAGLU), leading to intra-lysosomal accumulation of partially degraded heparan sulfate. There are no effective treatments for this disorder. In this project, we carried out an ex vivo correction of neural stem cells derived from Naglu−/− mice (iNSCs) induced pluripotent stem cells (iPSC) using a modified enzyme in which human NAGLU is fused to an insulin-like growth factor II receptor binding peptide in order to improve enzyme uptake. After brain transplantation of corrected iNSCs into Naglu−/− mice and long-term evaluation of their impact, we successfully detected NAGLU-IGFII activity in all transplanted animals. We found decreased lysosomal accumulation and reduced astrocytosis and microglial activation throughout transplanted brains. We also identified a novel neuropathological phenotype in untreated Naglu−/− brains with decreased levels of the neuronal marker Map2 and accumulation of synaptophysin-positive aggregates. Upon transplantation, we restored levels of Map2 expression and significantly reduced formation of synaptophysin-positive aggregates. Our findings suggest that genetically engineered iNSCs can be used to effectively deliver the missing enzyme to the brain and treat Sanfilippo type B-associated neuropathology.

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Abstract Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1 −/−) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1 −/− mice compared to normal animals. Cln1 −/− mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency.

BackgroundThe Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation.MethodsWe have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of PPT1 function (i.e., the classical infantile form) and of the classical juvenile CLN3 phenotype. These two forms of NCL represent early onset and rapidly progressing vs. late onset and slowly progressing disease modalities respectively.ResultsDespite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and postmortem studies reveal strikingly different time courses and distributions of disease propagation. Data from CLN1 disease are indicative of disease propagation from the body, with early effects within the spinal cord and subsequently within the brainstem, the cerebral hemispheres, cerebellum and retina. In contrast, the retina appears to be the most vulnerable organ in CLN3, and the site where pathology is first present. Pathology subsequently is present in the occipital connectome of the CLN3 brain, followed by a top-down propagation in which cerebral and cerebellar atrophy in early adolescence is followed by involvement of the peripheral nerves in later adolescence/early twenties, with the extrapyramidal system also affected during this time course.DiscussionThe propagation of disease in these two NCLs therefore has much in common with the “Brain-first” vs. “Body-first” models of alpha-synuclein propagation in Parkinson's disease. CLN1 disease represents a “Body-first” or bottom-up disease propagation and CLN3 disease having a “Brain-first” and top-down propagation. It is noteworthy that the varied phenotypes of CLN1 disease, whether it starts in infancy (infantile form) or later in childhood (juvenile form), still fit with our proposed hypothesis of a bottom-up disease propagation in CLN1. Likewise, in protracted CLN3 disease, where both cognitive and motor declines are delayed, the initial manifestations of disease are also seen in the outer retinal layers, i.e., identical to classical Juvenile NCL disease.

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional “neuron-centric” view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research.

Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by the high failure rate of translation from rodent-derived therapeutics to clinically effective human neurological interventions. Improved translation is demonstrated using higher order mammals with more complex/comparable neuroanatomy. These animals effectually span this translational disparity and increase confidence in factors including routes of administration/dosing and ability to scale, such that potential therapeutics will have successful outcomes when moving to patients. Coupled with advancements in genetic engineering to produce genetically tailored models, livestock are increasingly being used to bridge this translational gap. Approach: In order to aid in standardising characterisation of such models, we provide comprehensive neurological assessment protocols designed to inform on neuroanatomical dysfunction and/or lesion(s) for large animal species. We also describe the applicability of these exams in different large animals to help provide a better understanding of the practicalities of cross species neurological disease modelling. Recommendation: We would encourage the use of these assessments as a reference framework to help standardise neurological clinical scoring of large animal models.