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Colonies of neotropical army ants of the genus Eciton Latreille offer some of the most captivating examples of intricate interactions between species, with hundreds of associated species already described in colonies of Eciton burchellii Westwood. Among this plethora of species found with Eciton colonies, two genera of staphylinid beetles, Ecitomorpha Wasmann, and Ecitophya Wasmann, have evolved to mimic the appearance and parallel the colouration of the most abundant ant worker cast. Here, we study for the first time the association of these ant-mimicking beetles with their ant host in an evolutionary and population genetics framework. The central emphasis is on colonies of E. burchellii, the only Eciton species that harbours both genera of ant-mimicking beetles. Phylogenetic and population structure analyses using the same mtDNA COI region (802 bp) for ants and beetles indicated that speciation patterns of the myrmecophiles were congruent with specialization to a particular Eciton (sub)species. Therefore, current taxonomic treatments of Eciton and its Ecitomorpha and Ecitophya associates need revision. Molecular clock analyses suggested that diversification of the Eciton hosts pre-date that of their guests, with a possible earlier association of Ecitophya (found with a large number of Eciton species) than with Ecitomorpha (found only with E. burchellii colonies). Population-level analyses revealed that patterns of diversification for the myrmecophiles are also consistent with specialisation to a particular host across broad geographical areas but not at small geographical scales, with gene flow within each species found between host colonies, even across landscape features that are strong barriers for Eciton female-mediated gene flow. [ABSTRACT FROM AUTHOR]

We give a simple sufficient condition for consistency of the standard OLS-based estimate of the disturbance variance in the linear regression model with autocorrelated disturbances. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD- GRN ). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD- GRN , namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD- GRN -associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD- GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD- GRN and potentially other CNS disorders.

Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE -/- and ApoE +/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE -/- mice, characterized by an open blood-brain barrier, but not in their ApoE +/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE -/- and ApoE +/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.