The Stomach Divalent Ion-sensing Receptor SCAR Is a Modulator of Gastric Acid Secretion

Divalent cation receptors have recently been identified in a wide variety of tissues and organs, yet their exact function remains controversial. We have previously identified a member of this receptor family in the stomach and have demonstrated that it is localized to the parietal cell, the acid secretory cell of the gastric gland. The activation of acid secretion has been classically defined as being regulated by two pathways: a neuronal pathway (mediated by acetylcholine) and an endocrine pathway (mediated by gastrin and histamine). Here, we identified a novel pathway modulating gastric acid secretion through the stomach calcium-sensing receptor (SCAR) located on the basolateral membrane of gastric parietal cells. Activation of SCAR in the intact rat gastric gland by divalent cations (Ca(2+) or Mg(2+)) or by the potent stimulator gadolinium (Gd(3+)) led to an increase in the rate of acid secretion through the apical H+,K+ -ATPase. Gd(3+) was able to activate acid secretion through the omeprazole-sensitive H+,K+ -ATPase even in the absence of the classical stimulator histamine. In contrast, inhibition of SCAR by reduction of extracellular cations abolished the stimulatory effect of histamine on gastric acid secretion, providing evidence for the regulation of the proton secretory transport protein by the receptor. These studies present the first example of a member of the divalent cation receptors modulating a plasma membrane transport protein and may lead to new insights into the regulation of gastric acid secretion

Oligotyping and metagenome analyses reveal a high-resolution recurrence that frames potential ecological strategies of North Sea bacterioplankton

Temperate coastal marine habitats are replete with complex biotic and abiotic interactions that mediate relationships and niche space between resident microbial community members. The dynamics of these interactions are amplified during spring and summer when phytoplankton form massive blooms and heterotrophic bacterioplankton respond to the successional release of high molecular weight dissolved organic matter (DOM, e.g., proteins, polysaccharides, lipids) as algal cells lyse. Dedicated clades of copiotrophic bacterioplankton adapted to high nutrient loads employ a suite of specialized enzymes and transporters for the degradation and uptake of large complex molecules like polysaccharides. Functional profiles of these carbohydrate active enzymes (CAZymes) reveal successions of niche spaces determined through substrate availability during bloom periods. As bacterioplankton process these substrates, algal-derived DOM is effectively incorporated into bacterioplankton biomass where it can be re-assimilated by higher protozoans and thus recycled within the food web or rapidly exported to sediments below. The net result is an enhancement of system-level efficiency and carbon export, respectively. In order to parse potential niche space in such a dynamic system, we first present diversity data derived from high-resolution temporal sampling (weekly to bi-weekly intervals) using the high-resolution oligotyping method Minimum Entropy Decomposition (MED) to cluster OTUs from 3 replicated sampling years 2010-2012. Differential abundance of MED OTUs >99% similar reveals a granularity of potential niche resolution that would not have been retrieved by traditional OTU clustering. Implementation of MED effectively extracts only those polymorphisms most relevant to in situ environmental selection pressure, essentially providing an ecological fingerprint of resident North Sea bacterioplankton. Despite inter-annual variation in phytoplankton blooms, we see a population of recurrent heterotrophic bacterioplankton during both baseline and bloom periods that is remarkably constrained in composition, relative community abundance and time of appearance each year for both abundant and rare OTUs. These robustly recurrent patterns reflect the selective power of seasonal forcing in shaping temperate microbial communities with low-frequency temperature-driven seasonal shifts. Superimposing effects of temperature are higher frequency shifts in OTUs during dynamic bloom events when substrate-induced forcing drives copiotrophic bacterioplankton communities, particularly within the Gammaproteobacteria and Flavobacteriia. Metagenome data from monthly sampling during spring blooms from these same years supports 16S rRNA diversity analyses revealing recurrent groups of specialized bloom taxa with highly constrained repertories of CAZymes. We demonstrate that even though there is substantial inter-annual variation of phytoplankton bloom intensity and taxonomic composition, the accompanying succession of bacterial clades is not a purely stochastic process, but also governed by deterministic principles such as temperature and substrate-induced forcing. The result is a resident bacterioplankton community containing as few as 6-14 dominant taxa each spring responsible for a vast majority of the diversity and thus potential function in a system previously thought to be considerably more stochastic and complex

Recurring patterns in bacterioplankton dynamics during coastal spring algae blooms

A process of global importance in carbon cycling is the remineralization of algae biomass by heterotrophic bacteria, most notably during massive marine algae blooms. Such blooms can trigger secondary blooms of planktonic bacteria that consist of swift successions of distinct bacterial clades, most prominently members of the Flavobacteriia, Gammaproteobacteria and the alphaproteobacterial Roseobacter clade. We investigated such successions during spring phytoplankton blooms in the southern North Sea (German Bight) for four consecutive years. Dense sampling and high-resolution taxonomic analyses allowed the detection of recurring patterns down to the genus level. Metagenome analyses also revealed recurrent patterns at the functional level, in particular with respect to algal polysaccharide degradation genes. We demonstrate that even though there is substantial inter-annual variation between spring phytoplankton blooms, the accompanying succession of bacterial clades is not a purely stochastic process, but also governed by deterministic principles such as substrate-induced forcing

Concordance between Comprehensive Cancer Genome Profiling in Plasma and Tumor Specimens

Introduction: Detection of somatic genomic alterations in the plasma of patients with cancer (liquid biopsy) are increasingly being used in the clinic. However, the concordance of alterations identified in liquid biopsies with those detected in cancer specimens is not routinely being determined. Methods: We sought to systematically compare alterations found by a massively parallel sequencing liquid biopsy assay covering 39 genes (NEOliquid [NEO New Oncology GmbH, Koln, Germany]) with those identified through routine diagnostic testing in a certified central pathology laboratory in a cohort of patients with nonsquamous NSCLC. NEOliquid is based on enrichment of the genomic territory of interest by hybrid capture and is thus capable of detecting point mutations, small insertions and deletions, copy number alterations, and gene rearrangements/fusions in a single assay. Results: In a cohort of 82 patients with matched blood/tissue samples, the concordance between NEOliquid and tissue-based routine testing was 98%, the sensitivity of NEOliquid was higher than 70%, and the specificity was 100%. Discordant cases included those with insufficient amounts of circulaating tumor DNA in plasma and cases in which known driver mutations (e.g., isocitrate dehydrogenase (NADP(+)), 1 systolic gene [IDH1] R132H, kinesin family member 5B gene [KIFSb-ret proto-oncogene [RET], or MNNG HOS Transforming gene [MET] exon 14) were found in the plasma but were not interrogated by routine tissue analyses. Conclusions: In summary, NEOliquid offers accurate and reliable detection of clinically relevant driver alterations in plasma of patients with cancer. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved