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Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.

Comprising more than 1400 species, bats possess adaptations unique among mammals including powered flight, unexpected longevity given small body size, and extraordinary immunity. Some of the molecular mechanisms underlying these unique adaptations includes DNA repair, metabolism and immunity. However, analyses have been limited to a few divergent lineages, reducing the scope of inferences on gene family evolution across the Order Chiroptera. We conducted an exhaustive comparative genomic study of 37 bat species encompassing a large number of lineages, with a particular emphasis on multi-gene family evolution across immune system and metabolic genes. In agreement with previous analyses, we found lineage-specific expansions of the APOBEC3 and MHC-I gene families, and loss of the proinflammatory PYHIN gene family. We inferred more than 1,000 gene losses unique to bats, including genes involved in the regulation of inflammasome pathways such as epithelial defense receptors, the natural killer gene complex and the interferon-gamma induced pathway. Gene set enrichment analyses revealed genes lost in bats are involved in defense response against pathogen-associated molecular patterns and damage-associated molecular patterns. Gene family evolution and selection analyses indicate bats have evolved fundamental functional differences compared to other mammals in both innate and adaptive immune system, with the potential to enhance anti-viral immune response while dampening inflammatory signaling. In addition, metabolic genes have experienced repeated expansions related to convergent shifts to plant-based diets. Our analyses support the hypothesis that, in tandem with flight, ancestral bats had evolved a unique set of immune adaptations whose functional implications remain to be explored.

The etiology of CNS diseases including multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis remains elusive despite decades of research resulting in treatments with only symptomatic effects. In this study, we provide evidence that a metabolic shift from glucose to lipid is a key mechanism in neurodegeneration. We show that, by downregulating the metabolism of lipids through the key molecule carnitine palmitoyl transferase 1 (CPT1), it is possible to reverse or slowdown disease progression in experimental models of autoimmune encephalomyelitis-, SOD1G93A and rotenone models, mimicking these CNS diseases in humans. The effect was seen both when applying a CPT1 blocker or by using a Cpt1a P479L mutant mouse strain. Furthermore, we show that diet, epigenetics, and microbiota are key elements in this metabolic shift. Finally, we present a systemic model for understanding the complex etiology of neurodegeneration and how different regulatory systems are interconnected through a central metabolic pathway that becomes deregulated under specific conditions.

Bats account for ~20% of all extant mammal species and are considered exceptional given their extraordinary adaptations, including biosonar, true flight, extreme longevity, and unparalleled immune systems. To understand these adaptations, we generated reference-quality genomes of six species representing the key divergent lineages. We assembled these genomes with a novel pipeline incorporating state-of-the-art long-read and long-range sequencing and assembly techniques. The genomes were annotated using a maximal evidence approach, de novo predictions, protein/mRNA alignments, Iso-seq long read and RNA-seq short read transcripts, and gene projections from our new TOGA pipeline, retrieving virtually all (>99%) mammalian BUSCO genes. Phylogenetic analyses of 12,931 protein coding-genes and 10,857 conserved non-coding elements identified across 48 mammalian genomes helped to resolve bats’ closest extant relatives within Laurasiatheria, supporting a basal position for bats within Scrotifera. Genome-wide screens along the bat ancestral branch revealed (a) selection on hearing-involved genes (e.g LRP2, SERPINB6, TJP2), which suggest that laryngeal echolocation is a shared ancestral trait of bats; (b) selection (e.g INAVA, CXCL13, NPSR1) and loss of immunity related proteins (e.g. LRRC70, IL36G), including pro-inflammatory NF-kB signalling; and (c) expansion of the APOBEC family, associated with restricting viral infection, transposon activity and interferon signalling. We also identified unique integrated viruses, indicating that bats have a history of tolerating viral pathogens, lethal to other mammal species. Non-coding RNA analyses identified variant and novel microRNAs, revealing regulatory relationships that may contribute to phenotypic diversity in bats. Together, our reference-quality genomes, high-quality annotations, genome-wide screens and in-vitro tests revealed previously unknown genomic adaptations in bats that may explain their extraordinary traits.

Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our ‘Tool to infer Orthologs from Genome Alignments’ (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease1., Reference-quality genomes for six bat species shed light on the phylogenetic position of Chiroptera, and provide insight into the genetic underpinnings of the unique adaptations of this clade.

Autologus augmentation of wound remodeling with platelet concentrate is a burgeoning field with promising results. We hypothesized that the addition of filtered platelet concentrate (fPC) to an acellular biologic graft would improve crural healing and tissue integrity in hiatal hernia repair. Sixteen healthy Yorkshire female pigs were divided into three groups: hiatus repair (HR) (n = 7), HR with biologic graft (HRM; n = 8, and HR with biologic graft and fPC (fPC; n = 9). Surgeries were performed by a single surgeon. Animals were euthanized at 8 weeks, and the distal esophagus with hiatus was harvested en-block. Tissue was graded by a histopathologist on collagen deposition, vascularization, and inflammation at the graft–hiatal interface. Tensile strength testing was performed using the Teststar IIs (MTS), coupled with a strain extensometer (Epsilon). Samples of equal dimensions were preloaded to 1 N and deformed at a constant rate of 0.2 mm/s. Statistical analysis was performed via Kruskal–Wallis one-way analysis of variance. Aspirate analysis revealed a mean platelet count of 3 million platelets/1 mL of aspirate. Animals in the fPC group had significantly increased mean chronic inflammation (3.1 ± 1.1 vs. 1.8 ± 1.6, 1.2 ± 1.2, p = 0.04) compared to HR alone and HR + biologic graft. Vascular deposition did not differ between groups (p = 0.8). A trend toward increased collagen deposition was demonstrated for the fPC group (1.4 ± 1.1 vs. 2.0 ± 0.6 in HR group and 3.0 ± 1.2 in HRM group, p = 0.06). There was a statistically significant increase in tensile strength, yield force, and Young’s modulus in the fPC group compared with HR and HR + biologic mesh (p

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-β (IFN-β), IFN-β had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-β and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment.

Multiple sclerosis is a complex neurodegenerative disease, thought to arise through autoimmunity against antigens of the central nervous system. The autoimmunity hypothesis fails to explain why genetic and environmental risk factors linked to the disease in one population tend to be unimportant in other populations. Despite great advances in documenting the cell and molecular mechanisms underlying MS pathophysiology, the autoimmunity framework has also been unable to develop a comprehensive explanation of the etiology of the disease. I propose a new framework for understanding MS as a dysfunction of the metabolism of lipids. Specifically, the homeostasis of lipid metabolism collapses during acute-phase inflammatory response triggered by a pathogen, trauma, or stress, starting a feedback loop of increased oxidative stress, inflammatory response, and proliferation of cytoxic foam cells that cross the blood brain barrier and both catabolize myelin and prevent remyelination. Understanding MS as a chronic metabolic disorder illuminates four aspects of disease onset and progression: 1) its pathophysiology; 2) genetic susceptibility; 3) environmental and pathogen triggers; and 4) the skewed sex ratio of patients. It also suggests new avenues for treatment.

Disease detection in historical samples currently relies on DNA extraction and amplification, or immunoassays. These techniques only establish pathogen presence rather than active disease. We report the first use of shotgun proteomics to detect the protein expression profile of buccal swabs and cloth samples from two 500-year-old Andean mummies. The profile of one of the mummies is consistent with immune system response to severe pulmonary bacterial infection at the time of death. Presence of a probably pathogenic Mycobacterium sp. in one buccal swab was confirmed by DNA amplification, sequencing, and phylogenetic analyses. Our study provides positive evidence of active pathogenic infection in an ancient sample for the first time. The protocol introduced here is less susceptible to contamination than DNA-based or immunoassay-based studies. In scarce forensic samples, shotgun proteomics narrows the range of pathogens to detect using DNA assays, reducing cost. This analytical technique can be broadly applied for detecting infection in ancient samples to answer questions on the historical ecology of specific pathogens, as well as in medico-legal cases when active pathogenic infection is suspected.

Identifying drivers of deforestation in tropical biodiversity hotspots is critical to assess threats to particular ecosystems and species and proactively plan for conservation. We analyzed land cover change between 2002 and 2007 in the northern Andes, Choco, and Amazon forests of Colombia, the largest producer of coca leaf for the global cocaine market, to quantify the impact of this illicit crop on forest dynamics, evaluate the effectiveness of protected areas in this context, and determine the effects of eradication on deforestation. Landscape-level analyses of forest conversion revealed that proximity to new coca plots and a greater proportion of an area planted with coca increased the probability of forest loss in southern Colombia, even after accounting for other covariates and spatial autocorrelation. We also showed that protected areas successfully reduced forest conversion in coca-growing regions. Neither eradication nor coca cultivation predicted deforestation rates across municipalities. Instead, the presence of new coca cultivation was an indicator of municipalities, where increasing population led to higher deforestation rates. We hypothesize that poor rural development underlies the relationship between population density and deforestation in coca-growing areas. Conservation in Colombia's vast forest frontier, which overlaps with its coca frontier, requires a mix of protected areas and strategic rural development to succeed.

Studies in molecular ecology depend on field-collected samples for genetic information, and the tissue sampled and preservation conditions strongly affect the quality of the DNA obtained. DNA yields from different tissue types have seldom been compared, and the relative performance of storage media has never been directly tested, even though these media may influence DNA degradation under field conditions. We analyzed DNA yield from buccal swabs and wing punches harvested from live bats using nucleic acid quantification as well as quantitative PCR for a single-copy nuclear locus. We also compared DNA yields from wing tissue preserved in three media: ethanol, NaCl-saturated dimethyl sulfoxide (DMSO), and silica desiccant. Wing punches yielded more total DNA than did buccal swabs, and wing tissues preserved in silica beads yielded significantly more total and nuclear DNA than those preserved in DMSO or ethanol. These results show that tissue type and preservation media strongly influence the quantity of DNA obtained from non-lethal genetic samples, and based on these effects we provide recommendations for field collection of tissues for genetic analyses.

With the advent of the so-called genomic revolution and improved techniques of DNA analysis, combined with a rapidly vanishing biodiversity, the systematic community has been facing a remarkable—and often neglected—challenge for the past 50 years: to preserve genetic resources issued from research. The preservation and long-term storage of biological specimens’ derived materials (e.g., DNA extracts) and associated data are essential to ensure comparability and reproducibility in all areas of biological research. Natural history museums and herbaria around the world are now in a position to face the exciting and challenging task of preserving the genetic library of life for generations to come. However, the lack and/or poor condition of preservation of molecular vouchers generated from often fragile and rare specimens have been problems too often underestimated or unable to be addressed due to lack of funding or, more pointedly, lack of interest in preservation of these important research materials. The present article does not seek to reiterate the plea for genetic resource collections introduce by Dessauer et al. in 1984 (and more recently by Sheldon, 2001, and Savolainen and Reeves, 2004). It seeks to bring these collections, and the issues of preservation of genetic resources, to the awareness of the systematic biology community through the case study of the American Museum of Natural History new cryogenic repository, the Ambrose Monell Collection for Molecular and Microbial Research (AMCC; website: http://research.amnh.org/ amcc/).

Since 2004 five new species have been described in the nectar-feeding phyllostomid bat genus Lonchophylla. All the new species are endemic to one Neotropical ecoregion, suggesting that more species remain to be discovered among collected specimens currently referred to several widespread taxa. Herein we describe a new species, Lonchophylla orienticollina, endemic to the middle elevations of the eastern Andes of Venezuela, Colombia, and Ecuador. The new species superficially resembles its sympatric congener L. robusta, but its cranial morphology and combination of measurements are distinctive. Throughout its range, L. orienticollina is sympatric with L. robusta, and it also overlaps with L. handleyi in the Cordillera Oriental of Ecuador. The evolutionary processes leading to the divergence among Lonchophylla species, as well as the ecological mechanisms that enable multiple, subtly different species to coexist will remain obscure without new field and phylogenetic studies.

With the advent of the “genomic revolution” and the rapid refinement of techniques of molecular biology, academic institutions, such as museums and university collections, are at the forefront of specimen analysis. However, the lack and/or poor condition of preservation of molecular voucher generated from often fragile and rare specimens is a problem rarely addressed. To remedy this problem, the AMNH launched a frozen tissue collection, the Ambrose Monell Cryocollection (AM-CC) in May 2001. The AM-CC maintains specimens below -150 o Celsius and supports ongoing genetic research across taxa, from ancient to modern samples, by insuring that all research materials are vouchered (i.e. they point back to a specimen in a curated collection), a much-needed service that the Museum extends to the entire scientific community. Scientists using the Monell Collection have access to legally collected, authoritatively identified and properly documented specimens for use in their research, complete with Museum catalog numbers to reference in their scholarly publications. Researcher are also offered the possibility of vouchering their research by depositing the DNA or tissue samples gathered for their studies