Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen.

Cell Syst. 2017 Jun 14;:

Authors: Québatte M, Christen M, Harms A, Körner J, Christen B, Dehio C

Abstract
The Bartonella gene transfer agent (BaGTA) is an archetypical example for domestication of a phage-derived element to permit high-frequency genetic exchange in bacterial populations. Here we used multiplexed transposon sequencing (TnSeq) and single-cell reporters to globally define the core components and transfer dynamics of BaGTA. Our systems-level analysis has identified inner- and outer-circle components of the BaGTA system, including 55 regulatory components, as well as an additional 74 and 107 components mediating donor transfer and recipient uptake functions. We show that the stringent response signal guanosine-tetraphosphate (ppGpp) restricts BaGTA induction to a subset of fast-growing cells, whereas BaGTA particle uptake depends on a functional Tol-Pal trans-envelope complex that mediates outer-membrane invagination upon cell division. Our findings suggest that Bartonella evolved an efficient strategy to promote genetic exchange within the fittest subpopulation while disfavoring exchange of deleterious genetic information, thereby facilitating genome integrity and rapid host adaptation.

PMID: 28624614 [PubMed - as supplied by publisher]

Intestinal Fungal Dysbiosis Associates With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats.

Gastroenterology. 2017 Jun 14;:

Authors: Botschuijver S, Roeselers G, Levin E, Jonkers DM, Welting O, Heinsbroek SE, de Weerd HH, Boekhout T, Fornai M, Masclee AA, Schuren FHJ, de Jonge WJ, Seppen J, van den Wijngaard RM

Abstract
BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity.
METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble β-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1.
RESULTS: α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble β-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate β-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine.
CONCLUSIONS: In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble β-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.

PMID: 28624575 [PubMed - as supplied by publisher]

Dissecting the chloroplast proteome of chickpea (Cicer arietinum L.) provides new insights into classical and non-classical functions.

J Proteomics. 2017 Jun 14;:

Authors: Lande NV, Subba P, Barua P, Gayen D, Keshava Prasad TS, Chakraborty S, Chakraborty N

Abstract
Chloroplast, the energy organelle unique to plant cells, is a dynamic entity which integrates an array of metabolic pathways and serves as first level for energy conversion for the entire ecological hierarchy. Increasing amount of sequence data and evolution of mass spectrometric approaches has opened up new avenues for opportune exploration of the global proteome of this organelle. In our study, we aimed at generation of a comprehensive catalogue of chloroplast proteins in a grain legume, chickpea and provided a reference proteome map. To accurately assign the identified proteins, purity of chloroplast-enriched fraction was stringently monitored by multiple chemical and immunological indexes, besides pigment and enzyme analyses. The proteome analysis led to the identification of 2451 proteins, including 27 isoforms, which include predicted and novel chloroplast constituents. The identified proteins were validated through their sequence analysis. Extensive sequence based localization prediction revealed more than 50% proteins to be chloroplast resident by at least two different algorithms. Chromosomal distribution of identified proteins across nuclear and chloroplast genome unveiled the presence of 55 chloroplast encoded gene. In depth comparison of our dataset with the non-redundant set of chloroplast proteins identified so far across other species revealed novel as well as overlapping candidates.
BIOLOGICAL SIGNIFICANCE: Pulses add large amount of nitrogen to the soil and has very low water footprint and therefore, contributes to fortification of sustainable agriculture. Chickpea is one of the earliest cultivated legumes and serves as an energy and protein source for humans and animals. Chloroplasts are the unique organelles which conduct photosynthesis. Investigation on chloroplast proteome is of particular significance, especially to plant biologists, as it would allow a better understanding of chloroplast function in plants. Generation of a saturated proteome map would not only validate the proteome inventory from its genome sequencing, but also serve as a comprehensive catalogue for future studies. We identified 2451 proteins, encoded by both the nuclear as well as chloroplast genomes, presumably involved in multivariate metabolic processes. The chloroplast deduced proteome and putative chloroplast proteins identified in this study would provide a foundation for future investigation of the expression and function of the chloroplast proteins of chickpea in specific and other crops species in general.

PMID: 28624520 [PubMed - as supplied by publisher]

Evaluation of whole exome sequencing by targeted gene sequencing and Sanger sequencing.

Clin Chim Acta. 2017 Jun 14;:

Authors: Chang YS, Huang HD, Yeh KT, Chang JG

Abstract
BACKGROUND: Targeted gene sequencing (TGS) and whole exome sequencing (WES) are being used in clinical testing in laboratories. We compared the performances of TGS and WES using the same DNA samples.
METHODS: DNA was extracted from 10 endometrial tumor tissue specimens. Sequencing were performed with an Illumina HiSeq 2000. We randomly selected variants to confirm through Sanger sequencing or mutant-enriched PCR with Sanger sequencing.
RESULTS: We found that the variants identified in both TGS and WES were true positives (47/47), regardless of the sequencing depth. Most variants found in TGS only were true positives (34/40), and most of the variants found by WES only were false positives (8/18). From these results, we suggest that the sequencing depth may not play important role in the accuracy of NGS-based methods. After analysis, we found that WES had a sensitivity of 72.70%, specificity of 96.27%, precision of 99.44%, and accuracy of 75.03%.
CONCLUSIONS: The results of NGS-based methods must currently be validated, especially for important reported variants regardless of the methods used, and for the use of WES in cancers a higher false negative rate must be considered. More sensitive methods should be used to confirm the NGS results in uneven cancer tissues.

PMID: 28624499 [PubMed - as supplied by publisher]

Letter to the Editor: A response to Horne and Lucey (2017).

J Dairy Sci. 2017 Jul;100(7):5121-5124

Authors: Carver JA, Thorn DC, Ecroyd H, Holt C

PMID: 28624068 [PubMed - in process]

36 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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"systems biology"

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"systems biology"

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"systems biology"

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"systems biology"

These pubmed results were generated on 2017/06/14

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23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/06/13

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Permeability-driven selection in a semi-empirical protocell model: the roots of prebiotic systems evolution.

Sci Rep. 2017 Jun 09;7(1):3141

Authors: Piedrafita G, Monnard PA, Mavelli F, Ruiz-Mirazo K

Abstract
The origin-of-life problem has been traditionally conceived as the chemical challenge to find the type of molecule and free-solution reaction dynamics that could have started Darwinian evolution. Different autocatalytic and 'self-replicative' molecular species have been extensively investigated, together with plausible synthetic pathways that might have led, abiotically, to such a minimalist scenario. However, in addition to molecular kinetics or molecular evolutionary dynamics, other physical and chemical constraints (like compartmentalization, differential diffusion, selective transport, osmotic forces, energetic couplings) could have been crucial for the cohesion, functional integration, and intrinsic stability/robustness of intermediate systems between chemistry and biology. These less acknowledged mechanisms of interaction and molecular control might have made the initial pathways to prebiotic systems evolution more intricate, but were surely essential for sustaining far-from-equilibrium chemical dynamics, given their functional relevance in all modern cells. Here we explore a protocellular scenario in which some of those additional constraints/mechanisms are addressed, demonstrating their 'system-level' implications. In particular, an experimental study on the permeability of prebiotic vesicle membranes composed of binary lipid mixtures allows us to construct a semi-empirical model where protocells are able to reproduce and undergo an evolutionary process based on their coupling with an internal chemistry that supports lipid synthesis.

PMID: 28600550 [PubMed - in process]

Conserved amino acid networks modulate discrete functional properties in an enzyme superfamily.

Sci Rep. 2017 Jun 09;7(1):3207

Authors: Narayanan C, Gagné D, Reynolds KA, Doucet N

Abstract
In this work, we applied the sequence-based statistical coupling analysis approach to characterize conserved amino acid networks important for biochemical function in the pancreatic-type ribonuclease (ptRNase) superfamily. This superfamily-wide analysis indicates a decomposition of the RNase tertiary structure into spatially distributed yet physically connected networks of co-evolving amino acids, termed sectors. Comparison of this statistics-based description with new NMR experiments data shows that discrete amino acid networks, termed sectors, control the tuning of distinct functional properties in different enzyme homologs. Further, experimental characterization of evolutionarily distant sequences reveals that sequence variation at sector positions can distinguish homologs with a conserved dynamic pattern and optimal catalytic activity from those with altered dynamics and diminished catalytic activities. Taken together, these results provide important insights into the mechanistic design of the ptRNase superfamily, and presents a structural basis for evolutionary tuning of function in functionally diverse enzyme homologs.

PMID: 28600532 [PubMed - in process]

Synergistic action of auxin and cytokinin mediates aluminum-induced root growth inhibition in Arabidopsis.

EMBO Rep. 2017 Jun 09;:

Authors: Yang ZB, Liu G, Liu J, Zhang B, Meng W, Müller B, Hayashi KI, Zhang X, Zhao Z, De Smet I, Ding Z

Abstract
Auxin acts synergistically with cytokinin to control the shoot stem-cell niche, while both hormones act antagonistically to maintain the root meristem. In aluminum (Al) stress-induced root growth inhibition, auxin plays an important role. However, the role of cytokinin in this process is not well understood. In this study, we show that cytokinin enhances root growth inhibition under stress by mediating Al-induced auxin signaling. Al stress triggers a local cytokinin response in the root-apex transition zone (TZ) that depends on IPTs, which encode adenosine phosphate isopentenyltransferases and regulate cytokinin biosynthesis. IPTs are up-regulated specifically in the root-apex TZ in response to Al stress and promote local cytokinin biosynthesis and inhibition of root growth. The process of root growth inhibition is also controlled by ethylene signaling which acts upstream of auxin. In summary, different from the situation in the root meristem, auxin acts with cytokinin in a synergistic way to mediate aluminum-induced root growth inhibition in Arabidopsis.

PMID: 28600354 [PubMed - as supplied by publisher]

miRTarVis+: Web-based interactive visual analytics tool for microRNA target predictions.

Methods. 2017 Jun 06;:

Authors: L'Yi S, Jung D, Oh M, Kim B, Freishtat RJ, Giri M, Hoffman E, Seo J

Abstract
In this paper, we present miRTarVis+, a Web-based interactive visual analytics tool for miRNA target predictions and integrative analyses of multiple prediction results. Various microRNA (miRNA) target prediction algorithms have been developed to improve sequence-based miRNA target prediction by exploiting miRNA-mRNA expression profile data. There are also a few analytics tools to help researchers predict targets of miRNAs. However, there still is a need for improving the performance for miRNA prediction algorithms and more importantly for interactive visualization tools for an integrative analysis of multiple prediction results. miRTarVis+ has an intuitive interface to support the analysis pipeline of load, filter, predict, and visualize. It can predict targets of miRNA by adopting Bayesian inference and maximal information-based nonparametric exploration (MINE) analyses as well as conventional correlation and mutual information analyses. miRTarVis+ supports an integrative analysis of multiple prediction results by providing an overview of multiple prediction results and then allowing users to examine a selected miRNA-mRNA network in an interactive treemap and node-link diagram. To evaluate the effectiveness of miRTarVis+, we conducted two case studies using miRNA-mRNA expression profile data of asthma and breast cancer patients and demonstrated that miRTarVis+ helps users more comprehensively analyze targets of miRNA from miRNA-mRNA expression profile data. miRTarVis+ is available at http://hcil.snu.ac.kr/research/mirtarvisplus.

PMID: 28600227 [PubMed - as supplied by publisher]

Clinicopathologic and molecular markers in cervical carcinoma; a prospective cohort study.

Am J Obstet Gynecol. 2017 Jun 06;:

Authors: Halle MK, Ojesina AI, Engerud H, Woie K, Tangen IL, Holst F, Høivik E, Kusonmano K, Haldorsen IS, Vintermyr OK, Trovik J, Bertelsen BI, Salvesen HB, Krakstad C

Abstract
BACKGROUND: Cervical cancer is a major health problem worldwide. Identification of effective clinicopathologic and molecular markers is vital to improve treatment stratification.
OBJECTIVES: To validate a set of well-defined clinicopathologic features in a large population based, prospectively collected cervical cancer cohort to support their use in the clinic. Further, we explore p53 and HER2 as potential prognostic markers in cervical cancer.
STUDY DESIGN: Tissue was collected from 401 cervical cancer patients. Clinical data including follow-up were collected from patient journals. Histopathologic data were evaluated and revised by an expert pathologist. Prognostic impact of selected clinicopathologic variables was analyzed in the whole cohort. Tissue microarrays (TMAs) were prepared from 292 carcinomas and p53 and HER2 protein levels were evaluated by immunohistochemistry. Fresh frozen samples from overlapping cervical carcinomas were previously subjected to HPV typing (n=94), whole exome (n=100) and RNA (n=79) sequencing, and results were available for our analyses.
RESULTS: Among the clinicopathologic variables, vascular space invasion, histologic type and tumor size verified as strong independent prognostic markers. High p53 protein levels were significantly associated with markers for aggressive phenotype and survival, also in multivariate survival analysis, but did not reflect TP53 mutational status. High HER2 protein levels were identified in 21% of all tumors. ERBB2 amplification was associated with poor outcome (p = 0.003), HER2 protein level was not.
CONCLUSIONS: Our findings support that FIGO guidelines should include vascular space invasion and tumor size 2-4 cm and that careful selection of histologic type is essential for stratification of patient risk groups. High p53 independently predict poor survival, yet do not reflect mutational status in cervical cancer. Amplified ERBB2 significantly links to poor survival, while HercepTest do not. With optimal stratification, HER2-based therapy may improve cervical cancer treatment.

PMID: 28599900 [PubMed - as supplied by publisher]

30 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/06/10

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25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/06/09

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Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach.

Cancers (Basel). 2017 Jun 06;9(6):

Authors: Nikitaki Z, Pavlopoulou A, Holá M, Donà M, Michalopoulos I, Balestrazzi A, Angelis KJ, Georgakilas AG

Abstract
The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a 'plant radiation biodosimeter', that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana-based plant system monitoring the role of cancer-related DNA repair genes BRCA1, BARD1 and PARP1 in processing DNA lesions.

PMID: 28587301 [PubMed]

Stem Cells in Neuroendocrinology

Book. 2016

Authors: Pfaff D, Christen Y

Abstract
The hypothalamus controls many homeostatic and instinctive physiological processes, including the sleep-wake cycle, food intake, and sexually dimorphic behaviors. These behaviors are regulated by environmental and physiological cues, although the molecular and cellular mechanisms that underlie these effects are still poorly understood. Recently, it has become clear that both the juvenile and adult hypothalamus exhibit neurogenesis, which modifies homeostatic neural circuitry. In this manuscript, we report data addressing the role of sex-specific and dietary factors in controlling neurogenesis in the mediobasal hypothalamus. We report that a high fat diet (HFD) activates neurogenesis in the median eminence (ME) of young adult female, but not male mice, and that focal irradiation of the ME in HFD-fed mice reduces weight gain in females, but not males. These results suggest that some physiological effects of HFD are mediated by sexually dimorphic neurogenesis in the ME. We present these findings in the context of other studies on the cellular and molecular mechanisms that regulate neurogenesis in postnatal and adult hypothalamus.

PMID: 28590702