Efficacy and Renal Outcomes of SGLT2 Inhibitors in Patients with Type 2 Diabetes and Chronic Kidney Disease

Objective: To review glucose-lowering efficacy and changes in renal function associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Data sources: A literature search of MEDLINE and Cochrane databases was performed from 2000 to August 2018 using search terms: SGLT2 inhibitors, sodium glucose co-transporter 2, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and chronic kidney disease. References of identified articles were also reviewed. Study selection and data extraction: English-language studies investigating glucose-lowering endpoints and/or changes in renal function with one of four U.S. approved SGLT2 inhibitors were included. A total of 10 studies met inclusion criteria and are included in this review. Results: In patients with T2DM and CKD, SGLT2 inhibitors are modestly effective in lowering hemoglobin A1C and fasting plasma glucose compared to placebo. Small reductions in eGFR are seen shortly after initiating therapy with SGLT2 inhibitors, but return to baseline levels after discontinuation. SGLT2 inhibitors are associated with a substantial reduction in albuminuria and reduced risk of progression to albuminuria. Conclusions: In patients with T2DM and CKD, SGLT2 inhibitors have a decreased glucose-lowering effect compared to patients without CKD. Renal benefits among patients with CKD are similar to those without CKD and include a significant reduction in albuminuria and reduced incidence of worsening albuminuria. Given that CKD and T2DM are both associated with increased cardiovascular risk, we believe these agents should considered as preferred add-on agents in most patients with uncontrolled T2DM and eGFR \u3e30 ml/min/1.73 m2. Ongoing studies will provide additional information as to whether these agents should be added to the current standard of care for CKD patients, with and without T2DM

Effects of GLP-1 Receptor Agonists on Cardiovascular Outcomes in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Aim To evaluate the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD). Materials and Methods We searched PubMed, Ovid MEDLINE, CINAHL, and Web of Science databases for randomized controlled trials reporting event rates for a composite cardiovascular outcome of cardiovascular death, myocardial infarction, and stroke in patients with T2DM and CKD receiving GLP1-RA or placebo. Studies were restricted to those reporting specific event rates for patients with CKD separately from the overall population. We conducted a meta-analysis using a random-effects model. This meta-analysis was registered on PROSPERO (CRD42022320157). Results A total of four studies comprising 7130 patients was included in our analysis. Four different GLP1-RA were assessed in a population with CKD defined as estimated glomerular filtration rate (eGFR) \u3c60 ml/min/1.73 m2. Treatment with GLP1-RA was not associated with a significant reduction in the composite cardiovascular end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (odds ratio (OR) 0.80; 95% confidence interval (CI), 0.59–1.07; p = 0.13) among patients with T2DM and CKD. Individual components of the composite cardiovascular end point were assessed in two trials and did not show evidence of an effect of GLP1-RA in reducing cardiovascular end points. Conclusions Pooled analysis of clinical trials reporting separate cardiovascular events rates in patients with T2DM and CKD did not find GLP1-RA to be associated with a reduction in composite cardiovascular event rates. Select GLP1-RA may offer cardiovascular event reduction in patients with T2DM and CKD, but this does not appear to be a class effect. Use of GLP1-RA with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk

Genome-wide analysis of the PreA/PreB (QseB/QseC) regulon of Salmonella enterica serovar Typhimurium

<p>Abstract</p> <p>Background</p> <p>The <it>Salmonella </it>PreA/PreB two-component system (TCS) is an ortholog of the QseBC TCS of <it>Escherichia coli</it>. In both <it>Salmonella </it>and <it>E. coli</it>, this system has been shown to affect motility and virulence in response to quorum-sensing and hormonal signals, and to affect the transcription of the <it>Salmonella enterica </it>serovar Typhimurium (<it>S</it>. Typhimurium) <it>pmrAB </it>operon, which encodes an important virulence-associated TCS.</p> <p>Results</p> <p>To determine the PreA/PreB regulon in <it>S</it>. Typhimurium, we performed DNA microarrays comparing the wild type strain and various <it>preA </it>and/or <it>preB </it>mutants in the presence of ectopically expressed <it>preA </it>(<it>qseB</it>). These data confirmed our previous findings of the negative effect of PreB on PreA gene regulation and identified candidate PreA-regulated genes. A proportion of the activated loci were previously identified as PmrA-activated genes (<it>yibD</it>, <it>pmrAB</it>, <it>cptA</it>, etc.) or were genes located in the local region around <it>preA</it>, including the <it>preAB </it>operon. The transcriptional units were defined in this local region by RT-PCR, suggesting three PreA activated operons composed of <it>preA-preB</it>, <it>mdaB-ygiN</it>, and <it>ygiW</it>-STM3175. Several putative virulence-related phenotypes were examined for <it>preAB </it>mutants, resulting in the observation of a host cell invasion and slight virulence defect of a <it>preAB </it>mutant. Contrary to previous reports on this TCS, we were unable to show a PreA/PreB-dependent effect of the quorum-sensing signal AI-2 or of epinephrine on <it>S</it>. Typhimurium with regard to bacterial motility.</p> <p>Conclusion</p> <p>This work further characterizes this unorthadox OmpR/EnvZ class TCS and provides novel candidate regulated genes for further study. This first in-depth study of the PreA/PreB regulatory system phenotypes and regulation suggests significant comparative differences to the reported function of the orthologous QseB/QseC in <it>E. coli</it>.</p

Factors Determining Mortality of Adult Chaparral Shrubs in an Extreme Drought Year in California

We measured dieback and mortality in a chaparral shrub community at a chaparral/desert ecotone following four years of below-average rainfall. Ecotones are important systems in which to examine plant and community responses to extreme and prolonged drought conditions and the potential impact of global change on plant distributions and community composition. Following a particularly severe drought year, dieback and mortality were documented for seven co-dominant shrub species. We examined whether mortality was related to species ecology, leaf traits, or water relations. Dieback and mortality were greatest in two non-sprouting species. These species also had high xylem cavitation resistance and low specific leaf area compared to several sprouting species. Among two sprouting congeners, mortality was greater in the more shallowly rooted species, even though this species was more cavitation resistant. Across all species, those that were more resistant to cavitation had greater mortality. Evidently, high resistance to xylem cavitation does not prevent adult plant mortality at chaparral/desert ecotones. A series of extreme drought years could preferentially reduce or eliminate non-sprouting species from mixed chaparral populations, causing a shift in community structure and contributing to desertification

The Salmonella effector SseJ disrupts microtubule dynamics when ectopically expressed in Normal Rat Kidney cells

Salmonella effector protein SseJ is secreted by Salmonella into the host cell cytoplasm where it can then modify host cell processes. Whilst host cell small GTPase RhoA has previously been shown to activate the acyl-transferase activity of SseJ we show here an un-described effect of SseJ protein production upon microtubule dynamism. SseJ prevents microtubule collapse and this is independent of SseJ's acyl-transferase activity. We speculate that the effects of SseJ on microtubules would be mediated via its known interactions with the small GTPases of the Rho family

Consensus Guidelines for Advancing Coral Holobiont Genome and Specimen Voucher Deposition

Coral research is being ushered into the genomic era. To fully capitalize on the potential discoveries from this genomic revolution, the rapidly increasing number of high-quality genomes requires effective pairing with rigorous taxonomic characterizations of specimens and the contextualization of their ecological relevance. However, to date there is no formal framework that genomicists, taxonomists, and coral scientists can collectively use to systematically acquire and link these data. Spurred by the recently announced “Coral symbiosis sensitivity to environmental change hub” under the “Aquatic Symbiosis Genomics Project” - a collaboration between the Wellcome Sanger Institute and the Gordon and Betty Moore Foundation to generate gold-standard genome sequences for coral animal hosts and their associated Symbiodiniaceae microalgae (among the sequencing of many other symbiotic aquatic species) - we outline consensus guidelines to reconcile different types of data. The metaorganism nature of the coral holobiont provides a particular challenge in this context and is a key factor to consider for developing a framework to consolidate genomic, taxonomic, and ecological (meta)data. Ideally, genomic data should be accompanied by taxonomic references, i.e., skeletal vouchers as formal morphological references for corals and strain specimens in the case of microalgal and bacterial symbionts (cultured isolates). However, exhaustive taxonomic characterization of all coral holobiont member species is currently not feasible simply because we do not have a comprehensive understanding of all the organisms that constitute the coral holobiont. Nevertheless, guidelines on minimal, recommended, and ideal-case descriptions for the major coral holobiont constituents (coral animal, Symbiodiniaceae microalgae, and prokaryotes) will undoubtedly help in future referencing and will facilitate comparative studies. We hope that the guidelines outlined here, which we will adhere to as part of the Aquatic Symbiosis Genomics Project sub-hub focused on coral symbioses, will be useful to a broader community and their implementation will facilitate cross- and meta-data comparisons and analyses.CV acknowledges funding from the German Research Foundation (DFG), grants 433042944 and 458901010. Open Access publication fees are covered by an institutional agreement of the University of Konstanz

Global Systems-Level Analysis of Hfq and SmpB Deletion Mutants in Salmonella: Implications for Virulence and Global Protein Translation

Using sample-matched transcriptomics and proteomics measurements it is now possible to begin to understand the impact of post-transcriptional regulatory programs in Enterobacteria. In bacteria post-transcriptional regulation is mediated by relatively few identified RNA-binding protein factors including CsrA, Hfq and SmpB. A mutation in any one of these three genes, csrA, hfq, and smpB, in Salmonella is attenuated for mouse virulence and unable to survive in macrophages. CsrA has a clearly defined specificity based on binding to a specific mRNA sequence to inhibit translation. However, the proteins regulated by Hfq and SmpB are not as clearly defined. Previous work identified proteins regulated by hfq using purification of the RNA-protein complex with direct sequencing of the bound RNAs and found binding to a surprisingly large number of transcripts. In this report we have used global proteomics to directly identify proteins regulated by Hfq or SmpB by comparing protein abundance in the parent and isogenic hfq or smpB mutant. From these same samples we also prepared RNA for microarray analysis to determine if alteration of protein expression was mediated post-transcriptionally. Samples were analyzed from bacteria grown under four different conditions; two laboratory conditions and two that are thought to mimic the intracellular environment. We show that mutants of hfq and smpB directly or indirectly modulate at least 20% and 4% of all possible Salmonella proteins, respectively, with limited correlation between transcription and protein expression. These proteins represent a broad spectrum of Salmonella proteins required for many biological processes including host cell invasion, motility, central metabolism, LPS biosynthesis, two-component regulatory systems, and fatty acid metabolism. Our results represent one of the first global analyses of post-transcriptional regulons in any organism and suggest that regulation at the translational level is widespread and plays an important role in virulence regulation and environmental adaptation for Salmonella

Selection of Salmonella enterica Serovar Typhi Genes Involved during Interaction with Human Macrophages by Screening of a Transposon Mutant Library

The human-adapted Salmonella enterica serovar Typhi (S. Typhi) causes a systemic infection known as typhoid fever. This disease relies on the ability of the bacterium to survive within macrophages. In order to identify genes involved during interaction with macrophages, a pool of approximately 105 transposon mutants of S. Typhi was subjected to three serial passages of 24 hours through human macrophages. Mutants recovered from infected macrophages (output) were compared to the initial pool (input) and those significantly underrepresented resulted in the identification of 130 genes encoding for cell membrane components, fimbriae, flagella, regulatory processes, pathogenesis, and many genes of unknown function. Defined deletions in 28 genes or gene clusters were created and mutants were evaluated in competitive and individual infection assays for uptake and intracellular survival during interaction with human macrophages. Overall, 26 mutants had defects in the competitive assay and 14 mutants had defects in the individual assay. Twelve mutants had defects in both assays, including acrA, exbDB, flhCD, fliC, gppA, mlc, pgtE, typA, waaQGP, SPI-4, STY1867-68, and STY2346. The complementation of several mutants by expression of plasmid-borne wild-type genes or gene clusters reversed defects, confirming that the phenotypic impairments within macrophages were gene-specific. In this study, 35 novel phenotypes of either uptake or intracellular survival in macrophages were associated with Salmonella genes. Moreover, these results reveal several genes encoding molecular mechanisms not previously known to be involved in systemic infection by human-adapted typhoidal Salmonella that will need to be elucidated