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The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4+) and non-containing (XO4−) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4− microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.

Successful ovulation and implantation processes play a crucial role in female fertility. Adamts-1, a matrix metalloproteinase with disintegrin and thrombospondin motifs, has been suggested to be regulated by the progesterone receptor in the hormonal pathway leading to ovulation. With the primary aim of investigating the role of Adamts-1 in female fertility, we generated Adamts-1 null mice. Forty-five percent of the newborn Adamts-1 null mice die, with death most likely caused by a kidney malformation that becomes apparent at birth. Surviving female null mice were subfertile, whereas males reproduced normally. Ovulation in null females was impaired because of mature oocytes remaining trapped in ovarian follicles. No uterine phenotype was apparent in Adamts-1 null animals. Embryo implantation occurred normally, the uteri were capable of undergoing decidualization, and no morphological changes were observed. These results demonstrate that a functional Adamts-1 is required for normal ovulation to occur, and hence the Adamts-1 gene plays an important role in female fertility, primarily during the tissue remodeling process of ovulation.

Background A robust molecular phylogeny is fundamental for developing a stable classification and providing a solid framework to understand patterns of diversification, historical biogeography, and character evolution. As the sixth largest angiosperm family, Lamiaceae, or the mint family, consitutes a major source of aromatic oil, wood, ornamentals, and culinary and medicinal herbs, making it an exceptionally important group ecologically, ethnobotanically, and floristically. The lack of a reliable phylogenetic framework for this family has thus far hindered broad-scale biogeographic studies and our comprehension of diversification. Although significant progress has been made towards clarifying Lamiaceae relationships during the past three decades, the resolution of a phylogenetic backbone at the tribal level has remained one of the greatest challenges due to limited availability of genetic data. Results We performed phylogenetic analyses of Lamiaceae to infer relationships at the tribal level using 79 protein-coding plastid genes from 175 accessions representing 170 taxa, 79 genera, and all 12 subfamilies. Both maximum likelihood and Bayesian analyses yielded a more robust phylogenetic hypothesis relative to previous studies and supported the monophyly of all 12 subfamilies, and a classification for 22 tribes, three of which are newly recognized in this study. As a consequence, we propose an updated phylogenetically informed tribal classification for Lamiaceae that is supplemented with a detailed summary of taxonomic history, generic and species diversity, morphology, synapomorphies, and distribution for each subfamily and tribe. Conclusions Increased taxon sampling conjoined with phylogenetic analyses based on plastome sequences has provided robust support at both deep and shallow nodes and offers new insights into the phylogenetic relationships among tribes and subfamilies of Lamiaceae. This robust phylogenetic backbone of Lamiaceae will serve as a framework for future studies on mint classification, biogeography, character evolution, and diversification. Graphical abstract

Elf5 is an epithelial-specific ETS factor. Embryos with a null mutation in the Elf5 gene died before embryonic day 7.5, indicating that Elf5 is essential during mouse embryogenesis. Elf5 is also required for proliferation and differentiation of mouse mammary alveolar epithelial cells during pregnancy and lactation. The loss of one functional allele led to complete developmental arrest of the mammary gland in pregnant Elf5 heterozygous mice. A quantitative mRNA expression study and Western blot analysis revealed that decreased expression of Elf5 correlated with the downregulation of milk proteins in Elf5 þ /À mammary glands. Mammary gland transplants into Rag À/À mice demonstrated that Elf5 þ /À mammary alveolar buds failed to develop in an Elf5 þ / þ mammary fat pad during pregnancy, demonstrating an epithelial cell autonomous defect. Elf5 expression was reduced in Prolactin receptor (Prlr) heterozygous mammary glands, which phenocopy Elf5 þ /À glands, suggesting that Elf5 and Prlr are in the same pathway. Our data demonstrate that Elf5 is essential for developmental processes in the embryo and in the mammary gland during pregnancy.

In this study, we systematically examined in vitro frequencies and spectra of the spontaneous mutations in Helicobacter pylori that confer resistance to clarithromycin (Cla r Antibiotic resistance is an increasing problem for the treatment of infectious diseases. Bacteria have evolved diverse mechanisms (pathways) of resistance to antimicrobial agents, including control of uptake and efflux of drugs, modification and detoxification of drugs, alteration and protection of the target sites, and acquisition of heterologous resistance genes from external sources. In Helicobacter pylori, the etiological agent of a wide range of gastric diseases, genetic determinants for resistance to several antibiotics, including clarithromycin, metronidazole, ciprofloxacin, and rifampin, have been determined. Remarkably, the known mechanisms of antibiotic resistance in H. pylori are all due to mutations in chromosomal genes. Clarithromycin resistance is associated with mutations in the 23S rRNA gene (22,25), which inhibit the binding of clarithromycin to the ribosome. Ciprofloxacin resistance is due to mutations in the gyrA gene, which encodes the A subunit of DNA gyrase (16), and rifampin resistance results from mutations in the rpoB gene, encoding the ␤ subunit of RNA polymerase (7). For metronidazole resistance, although several different mechanisms may exist, the predominant determinant has been shown to be the mutational inactivation of the rdxA gene that encodes an oxygen-insensitive NADPH nitroreductase (4, 9, 10, 13, 21).)The importance of de novo mutation in developing antibiotic resistance prompted us to ask how mutations occur in H. pylori (28). The first step in elucidating the mechanisms of mutagenesis is to define the background of frequency and specificity of spontaneous mutations. From the pioneering works of Luria and Delbruck (14) and recent developments in determining mutation rates of bacterial populations, it is known that determination of mutation rates is not simple (15,17), and determination of mutation spectra is particularly tedious. In this study we systematically examined the in vitro frequencies and spectra of spontaneous mutations in H. pylori that confer resistance to clarithromycin, metronidazole, amoxicillin, ciprofloxacin, and rifampin. MATERIALS AND METHODSH. pylori strains, growth medium, and antibiotics. H. pylori reference strains 26695, NCTC11639, and UA802 (26), as well as some isolates from University of Alberta Hospital, were used; all are susceptible to the antibiotics tested in this study. H. pylori strains were grown on BHI-YE broth (3.7% brain heart infusion with 0.3% yeast extract and 5% animal serum) or agar plates at 37°C under microaerobic conditions (5% CO 2 , 5% H 2 , and 90% N 2 ). Antibiotics used in this study include clarithromycin (Bayer), metronidazole (Sigma), ciprofloxacin (Bayer), rifampin (Sigma), and amoxicillin (Sigma).MIC test. H. pylori cells were grown for 2 days and suspended in sterile BHI-YE liquid medium, and the turbidity of the suspensions was adjusted to that...

Expression of Ets2, a proto-oncogene and transcription factor, occurs in a variety of cell types. During murine development it is highly expressed in newly forming cartilage, including in the skull precursor cells and vertebral primordia. Ets2 is located on human chromosome 21 (ref. 8) and is overexpressed in Down's syndrome (trisomy 21). Here we generate transgenic mice to investigate the consequences of overexpression of Ets2. We find that mice with less than 2-fold Ets2 overexpression in particular organs develop neurocranial, viscerocranial and cervical skeletal abnormalities. These abnormalities have similarities with the skeletal anomalies found in trisomy-16 mice and humans with Down's syndrome, in which the gene dosage of Ets2 is increased. Our results indicate that Ets2 has a role in skeletal development and implicate the overexpression of Ets2 in the genesis of some skeletal abnormalities that occur in Down's syndrome.