Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including C1QA and C3 are increased in the brain of western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity induced brain pathology, female and male mice deficient in complement component 1qa (C1QA), an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared to WD-fed WT mice, and to C1qa knockout (KO) and WT mice fed a control diet (CD). C1qa KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls.y-induced brain pathology. The complement pathway is an attractive therapeutic target to prevent cognitive decline and reduction of dementia risk caused by obesity. Copyright © 2020 Graham et al.Mild traumatic brain injury (TBI) is common and associated with a range of diffuse, non-specific symptoms including headache, nausea, dizziness, fatigue, hypersomnolence, attentional difficulties, photosensitivity and phonosensitivity, irritability and depersonalisation. Although these symptoms usually resolve within 3 months, 5%-15% of patients are left with chronic symptoms. We argue that simply labelling such symptoms as 'postconcussional' is of little benefit to patients. Instead, we suggest that detailed assessment, including investigation, both of the severity of the 'mild' injury and of the individual symptom syndromes, should be used to tailor a rehabilitative approach to symptoms. To complement such an approach, we have developed a self-help website for patients with mild TBI, based on neurorehabilitative and cognitive behavioural therapy principles, offering information, tips and tools to guide recovery www.headinjurysymptoms.org. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action. Copyright © 2020 the Author(s). Published by PNAS.Alkylation of guanine bases in DNA is detrimental to cells due to its high mutagenic and cytotoxic potential and is repaired by the alkyltransferase AGT. Additionally, alkyltransferase-like proteins (ATLs), which are structurally similar to AGTs, have been identified in many organisms. While ATLs are per se catalytically inactive, strong evidence has suggested that ATLs target alkyl lesions to the nucleotide excision repair system (NER). Using a combination of single-molecule and ensemble approaches, we show here recruitment of UvrA, the initiating enzyme of prokaryotic NER, to an alkyl lesion by ATL. We further characterize lesion recognition by ATL and directly visualize DNA lesion search by highly motile ATL and ATL-UvrA complexes on DNA at the molecular level. Based on the high similarity of ATLs and the DNA-interacting domain of AGTs, our results provide important insight in the lesion search mechanism, not only by ATL but also by AGT, thus opening opportunities for controlling the action of AGT for therapeutic benefit during chemotherapy.Polyploidy, which results from whole genome duplication (WGD), has shaped the long-term evolution of eukaryotic genomes in all kingdoms. Polyploidy is also implicated in adaptation, domestication, and speciation. Yet when WGD newly occurs, the resulting neopolyploids face numerous challenges. A particularly pernicious problem is the segregation of multiple chromosome copies in meiosis. Evolution can overcome this challenge, likely through modification of chromosome pairing and recombination to prevent deleterious multivalent chromosome associations, but the molecular basis of this remains mysterious. We study mechanisms underlying evolutionary stabilization of polyploid meiosis using Arabidopsis arenosa, a relative of A. thaliana with natural diploid and meiotically stable autotetraploid populations. Here we investigate the effects of ancestral (diploid) versus derived (tetraploid) alleles of two genes, ASY1 and ASY3, that were among several meiosis genes under selection in the tetraploid lineage. These genes encode interacting proteins critical for formation of meiotic chromosome axes, long linear multiprotein structures that form along sister chromatids in meiosis and are essential for recombination, chromosome segregation, and fertility. We show that derived alleles of both genes are associated with changes in meiosis, including reduced formation of multichromosome associations, reduced axis length, and a tendency to more rod-shaped bivalents in metaphase I. Thus, we conclude that ASY1 and ASY3 are components of a larger multigenic solution to polyploid meiosis in which individual genes have subtle effects. Our results are relevant for understanding polyploid evolution and more generally for understanding how meiotic traits can evolve when faced with challenges.  https://www.selleckchem.com/products/chir-98014.html  Copyright © 2020 the Author(s). Published by PNAS.