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Ascomycete yeasts are metabolically diverse, with great potential for biotechnology. Here, we report the comparative genome analysis of 29 taxonomically and biotechnologically important yeasts, including 16 newly sequenced. We identify a genetic code change, CUG-Ala, in Pachysolen tannophilus in the clade sister to the known CUG-Ser clade. Our well-resolved yeast phylogeny shows that some traits, such as methylotrophy, are restricted to single clades, whereas others, such as l-rhamnose utilization, have patchy phylogenetic distributions. Gene clusters, with variable organization and distribution, encode many pathways of interest. Genomics can predict some biochemical traits precisely, but the genomic basis of others, such as xylose utilization, remains unresolved. Our data also provide insight into early evolution of ascomycetes. We document the loss of H3K9me2/3 heterochromatin, the origin of ascomycete mating-type switching, and panascomycete synteny at the MAT locus. These data and analyses will facilitate the engineering of efficient biosynthetic and degradative pathways and gateways for genomic manipulation.
Human evolution is widely thought to have involved a particular expansion of prefrontal cortex. This popular notion has recently been challenged, although controversies remain. Here we show that the prefrontal region of both human and nonhuman primates holds about 8% of cortical neurons, with no clear difference across humans and other primates in the distribution of cortical neurons or white matter cells along the anteroposterior axis. Further, we find that the volumes of human prefrontal gray and white matter match the expected volumes for the number of neurons in the gray matter and for the number of other cells in the white matter compared with other primate species. These results indicate that prefrontal cortical expansion in human evolution happened along the same allometric trajectory as for other primate species, without modification of the distribution of neurons across its surface or of the volume of the underlying white matter. We thus propose that the most distinctive feature of the human prefrontal cortex is its absolute number of neurons, not its relative volume.
Various immunohistochemical panels are used as aids to distinguish between primary hepatocellular malignancies and metastatic tumors and between benign lesions and carcinomas. We compared the immunohistochemical spectrum of hepatocellular lesions in mice with that of human hepatocellular carcinoma (HCC). Specifically, we compared the staining parameters of 128 murine foci of cellular alteration (FCA) and tumors (adenoma and HCC) from archival tissue blocks of 3 transgenic mouse models (LFABP-cyclin D1, Alb1-TGFβ1, and LFABP-cyclin D1 × Alb1-TGFβ1) with those of archival human HCC (n = 5). Antibodies were chosen according to their published performance and characterization in human hepatocellular tumor diagnosis and included: arginase 1 (Arg1), β-catenin, glutamine synthetase (GS), glypican 3, hepatocyte paraffin 1 (HepPar1), and cytokeratin 19 (CK19). GS was the single best immunostain for identifying hepatocellular tumors in mice, with 100% positive staining. Data showed a trend toward loss of normal function (staining) with Arg1, with a higher percentage of positive staining in FCA than in adenomas and HCC. All FCA lacked murine β-catenin nuclear translocation, which was present in 2 of the 7 adenomas and 22 of the 96 HCC tested. HepPar1 staining was lower than anticipated, except in trabecular HCC (16 of 22 samples were positive). Glyp3 stained very lightly, and only scattered CK19-positive cells were noted (4 of 44 cases of mouse trabecular HCC). Thus, GS appears to be the most useful marker for identifying neoplasia in the transgenic mouse models we tested and should be included in immunohistochemistry assessing hepatocellular neoplasia development.
PURPOSE - Helicobacter pylori infection and a high dietary salt intake are each risk factors for the development of gastric cancer. We hypothesize that changes in environmental salt concentrations lead to alterations in the H. pylori membrane proteome.
EXPERIMENTAL DESIGN - Label-free and iTRAQ methods were used to identify H. pylori proteins that change in abundance in response to alterations in environmental salt concentrations. In addition, we biotinylated intact bacteria that were grown under high- or low-salt conditions, and thereby analyzed salt-induced changes in the abundance of surface-exposed proteins.
RESULTS - Proteins with increased abundance in response to high salt conditions included CagA, the outer membrane protein HopQ, and fibronectin domain-containing protein HP0746. Proteins with increased abundance in response to low salt conditions included VacA, two VacA-like proteins (ImaA and FaaA), outer-membrane iron transporter FecA3, and several proteins involved in flagellar activity. Consistent with the proteomic data, bacteria grown in high salt conditions exhibited decreased motility compared to bacteria grown in lower salt conditions.
CONCLUSION AND CLINICAL RELEVANCE - Alterations in the H. pylori membrane proteome in response to high salt conditions may contribute to the increased risk of gastric cancer associated with a high salt diet.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
When functioning properly, the intestine is one of the key interfaces between the human body and its environment. It is responsible for extracting nutrients from our food and excreting our waste products. It provides an environment for a host of healthful microbes and serves as a first defense against pathogenic ones. These processes require tight homeostatic controls, which are provided by the interactions of a complex mix of epithelial, stromal, neural and immune cells, as well as the resident microflora. This homeostasis can be disrupted by invasive microbes, genetic lesions, and carcinogens, resulting in diseases such Clostridium difficile infection, inflammatory bowel disease (IBD) and cancer. Enormous strides have been made in understanding how this important organ functions in health and disease using everything from cell culture systems to animal models to human tissue samples. This has resulted in better therapies for all of these diseases, but there is still significant room for improvement. In the United States alone, 14,000 people per year die of C. difficile, up to 1.6 million people suffer from IBD, and more than 50,000 people die every year from colon cancer. Because these and other intestinal diseases arise from complex interactions between the different components of the gut ecosystem, we propose that systems approaches that address this complexity in an integrative manner may eventually lead to improved therapeutics that deliver lasting cures. This review will discuss the use of systems biology for studying intestinal diseases in vivo with particular emphasis on mouse models. Additionally, it will focus on established experimental techniques that have been used to drive this systems-level analysis, and emerging techniques that will push this field forward in the future.
We performed high-throughput mass spectrometry at high spatial resolution from individual regions (anterior cingulate and primary motor, somatosensory, and visual cortices) and layers of the neocortex (layers III, IV, and V) and cerebellum (granule cell layer), as well as the caudate nucleus in humans and chimpanzees. A total of 39 mass spectrometry peaks were matched with probable protein identifications in both species, allowing for comparison in expression. We explored how the pattern of protein expression varies across regions and cortical layers to provide insights into the differences in molecular phenotype of these neural structures between species. The expression of proteins differed principally in a region- and layer-specific pattern, with more subtle differences between species. Specifically, human and chimpanzee brains were similar in their distribution of proteins related to the regulation of transcription and enzyme activity but differed in their expression of proteins supporting aerobic metabolism. Whereas most work assessing molecular expression differences in the brains of primates has been performed on gene transcripts, this dataset extends current understanding of the differential molecular expression that may underlie human cognitive specializations.
© 2015 Wiley Periodicals, Inc.
The primate corticobasal ganglia circuits are understood to be segregated into parallel anatomically and functionally distinct loops. Anatomical and physiological studies in macaque monkeys are summarized as showing that an oculomotor loop begins with projections from the frontal eye fields (FEF) to the caudate nucleus, and a motor loop begins with projections from the primary motor cortex (M1) to the putamen. However, recent functional and structural neuroimaging studies of the human corticostriatal system report evidence inconsistent with this organization. To obtain conclusive evidence, we directly compared the pattern of connectivity between cortical motor areas and the striatum in humans and macaques in vivo using probabilistic diffusion tractography. In macaques we found that FEF is connected with the head of the caudate and anterior putamen, and M1 is connected with more posterior sections of the caudate and putamen, corroborating neuroanatomical tract tracing findings. However, in humans FEF and M1 are connected to largely overlapping portions of posterior putamen and only a small portion of the caudate. These results demonstrate that the corticobasal connectivity for the oculomotor and primary motor loop is not entirely segregated for primates at a macroscopic level and that the description of the anatomical connectivity of corticostriatal motor systems in humans does not parallel that of macaques, perhaps because of an expansion of prefrontal projections to striatum in humans.
Copyright © 2015 the American Physiological Society.
Phospholipase D is a ubiquitous protein in eukaryotes that hydrolyzes phospholipids to generate the signaling lipid phosphatidic acid (PtdOH). PldA, a Pseudomonas aeruginosa PLD, is a secreted protein that targets bacterial and eukaryotic cells. Here we have characterized the in vitro factors that modulate enzymatic activity of PldA, including divalent cations and phosphoinositides. We have identified several similarities between the eukaryotic-like PldA and the human PLD isoforms, as well as several properties in which the enzymes diverge. Notable differences include the substrate preference and transphosphatidylation efficiency for PldA. These findings offer new insights into potential regulatory mechanisms of PldA and its role in pathogenesis.