Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

A proteomic approach to investigating gene cluster expression and secondary metabolite functionality in Aspergillus fumigatus.

A combined proteomics and metabolomics approach was utilised to advance the identification and characterisation of secondary metabolites in Aspergillus fumigatus. Here, implementation of a shotgun proteomic strategy led to the identification of non-redundant mycelial proteins (n = 414) from A. fumigatus including proteins typically under-represented in 2-D proteome maps: proteins with multiple transmembrane regions, hydrophobic proteins and proteins with extremes of molecular mass and pI. Indirect identification of secondary metabolite cluster expression was also achieved, with proteins (n = 18) from LaeA-regulated clusters detected, including GliT encoded within the gliotoxin biosynthetic cluster. Biochemical analysis then revealed that gliotoxin significantly attenuates H2O2-induced oxidative stress in A. fumigatus (p>0.0001), confirming observations from proteomics data. A complementary 2-D/LC-MS/MS approach further elucidated significantly increased abundance (p<0.05) of proliferating cell nuclear antigen (PCNA), NADH-quinone oxidoreductase and the gliotoxin oxidoreductase GliT, along with significantly attenuated abundance (p<0.05) of a heat shock protein, an oxidative stress protein and an autolysis-associated chitinase, when gliotoxin and H2O2 were present, compared to H2O2 alone. Moreover, gliotoxin exposure significantly reduced the abundance of selected proteins (p<0.05) involved in de novo purine biosynthesis. Significantly elevated abundance (p<0.05) of a key enzyme, xanthine-guanine phosphoribosyl transferase Xpt1, utilised in purine salvage, was observed in the presence of H2O2 and gliotoxin. This work provides new insights into the A. fumigatus proteome and experimental strategies, plus mechanistic data pertaining to gliotoxin functionality in the organism

Subcellular optogenetic inhibition of G proteins generates signaling gradients and cell migration

Cells sense gradients of extracellular cues and generate polarized responses such as cell migration and neurite initiation. There is static information on the intracellular signaling molecules involved in these responses, but how they dynamically orchestrate polarized cell behaviors is not well understood. A limitation has been the lack of methods to exert spatial and temporal control over specific signaling molecules inside a living cell. Here we introduce optogenetic tools that act downstream of native G protein–coupled receptor (GPCRs) and provide direct control over the activity of endogenous heterotrimeric G protein subunits. Light-triggered recruitment of a truncated regulator of G protein signaling (RGS) protein or a Gβγ-sequestering domain to a selected region on the plasma membrane results in localized inhibition of G protein signaling. In immune cells exposed to spatially uniform chemoattractants, these optogenetic tools allow us to create reversible gradients of signaling activity. Migratory responses generated by this approach show that a gradient of active G protein αi and βγ subunits is sufficient to generate directed cell migration. They also provide the most direct evidence so for a global inhibition pathway triggered by Gi signaling in directional sensing and adaptation. These optogenetic tools can be applied to interrogate the mechanistic basis of other GPCR-modulated cellular functions

Identification, characterization, and gene expression analysis of nucleotide binding site (NB)-type resistance gene homologues in switchgrass

Abstract Background Switchgrass (Panicum virgatum L.) is a warm-season perennial grass that can be used as a second generation bioenergy crop. However, foliar fungal pathogens, like switchgrass rust, have the potential to significantly reduce switchgrass biomass yield. Despite its importance as a prominent bioenergy crop, a genome-wide comprehensive analysis of NB-LRR disease resistance genes has yet to be performed in switchgrass. Results In this study, we used a homology-based computational approach to identify 1011 potential NB-LRR resistance gene homologs (RGHs) in the switchgrass genome (v 1.1). In addition, we identified 40 RGHs that potentially contain unique domains including major sperm protein domain, jacalin-like binding domain, calmodulin-like binding, and thioredoxin. RNA-sequencing analysis of leaf tissue from ‘Alamo’, a rust-resistant switchgrass cultivar, and ‘Dacotah’, a rust-susceptible switchgrass cultivar, identified 2634 high quality variants in the RGHs between the two cultivars. RNA-sequencing data from field-grown cultivar ‘Summer’ plants indicated that the expression of some of these RGHs was developmentally regulated. Conclusions Our results provide useful insight into the molecular structure, distribution, and expression patterns of members of the NB-LRR gene family in switchgrass. These results also provide a foundation for future work aimed at elucidating the molecular mechanisms underlying disease resistance in this important bioenergy crop

Class IA PI3Kinase Regulatory Subunit, p85α, Mediates Mast Cell Development through Regulation of Growth and Survival Related Genes

Stem cell factor (SCF) mediated KIT receptor activation plays a pivotal role in mast cell growth, maturation and survival. However, the signaling events downstream from KIT are poorly understood. Mast cells express multiple regulatory subunits of class 1A PI3Kinase (PI3K) including p85α, p85β, p50α, and p55α. While it is known that PI3K plays an essential role in mast cells; the precise mechanism by which these regulatory subunits impact specific mast cell functions including growth, survival and cycling are not known. We show that loss of p85α impairs the growth, survival and cycling of mast cell progenitors (MCp). To delineate the molecular mechanism (s) by which p85α regulates mast cell growth, survival and cycling, we performed microarray analyses to compare the gene expression profile of MCps derived from WT and p85α-deficient mice in response to SCF stimulation. We identified 151 unique genes exhibiting altered expression in p85α-deficient cells in response to SCF stimulation compared to WT cells. Functional categorization based on DAVID bioinformatics tool and Ingenuity Pathway Analysis (IPA) software relates the altered genes due to lack of p85α to transcription, cell cycle, cell survival, cell adhesion, cell differentiation, and signal transduction. Our results suggest that p85α is involved in mast cell development through regulation of expression of growth, survival and cell cycle related genes

Hospital Readmission in General Medicine Patients: A Prediction Model

Background: Previous studies of hospital readmission have focused on specific conditions or populations and generated complex prediction models. Objective: To identify predictors of early hospital readmission in a diverse patient population and derive and validate a simple model for identifying patients at high readmission risk. Design: Prospective observational cohort study. Patients: Participants encompassed 10,946 patients discharged home from general medicine services at six academic medical centers and were randomly divided into derivation (n = 7,287) and validation (n = 3,659) cohorts. Measurements: We identified readmissions from administrative data and 30-day post-discharge telephone follow-up. Patient-level factors were grouped into four categories: sociodemographic factors, social support, health condition, and healthcare utilization. We performed logistic regression analysis to identify significant predictors of unplanned readmission within 30 days of discharge and developed a scoring system for estimating readmission risk. Results: Approximately 17.5% of patients were readmitted in each cohort. Among patients in the derivation cohort, seven factors emerged as significant predictors of early readmission: insurance status, marital status, having a regular physician, Charlson comorbidity index, SF12 physical component score, ≥1 admission(s) within the last year, and current length of stay >2 days. A cumulative risk score of ≥25 points identified 5% of patients with a readmission risk of approximately 30% in each cohort. Model discrimination was fair with a c-statistic of 0.65 and 0.61 for the derivation and validation cohorts, respectively. Conclusions: Select patient characteristics easily available shortly after admission can be used to identify a subset of patients at elevated risk of early readmission. This information may guide the efficient use of interventions to prevent readmission

Aerosolized BC-819 Inhibits Primary but Not Secondary Lung Cancer Growth

Despite numerous efforts, drug based treatments for patients suffering from lung cancer remains poor. As a promising alternative, we investigated the therapeutic potential of BC-819 for the treatment of lung cancer in mouse tumor models. BC-819 is a novel plasmid DNA which encodes for the A-fragment of Diphtheria toxin and has previously been shown to successfully inhibit tumor growth in human clinical study of bladder carcinoma. In a first set of experiments, we examined in vitro efficacy of BC-819 in human lung cancer cell-lines NCI-H460, NCI-H358 and A549, which revealed >90% reduction of cell growth. In vivo efficacy was examined in an orthotopic mouse xenograft lung cancer model and in a lung metastasis model using luminescent A549-C8-luc adenocarcinoma cells. These cells resulted in peri- and intra-bronchiolar tumors upon intrabronchial application and parenchymal tumors upon intravenous injection, respectively. Mice suffering from these lung tumors were treated with BC-819, complexed to branched polyethylenimine (PEI) and aerosolized to the mice once per week for a period of 10 weeks. Using this regimen, growth of intrabronchially induced lung tumors was significantly inhibited (p = 0.01), whereas no effect could be observed in mice suffering from lung metastasis. In summary, we suggest that aerosolized PEI/BC-819 is capable of reducing growth only in tumors arising from the luminal part of the airways and are therefore directly accessible for inhaled BC-819

Exploring the functional role of the CHRM2 gene in human cognition: results from a dense genotyping and brain expression study

<p>Abstract</p> <p>Background</p> <p>The <it>CHRM2 </it>gene, located on the long arm of chromosome 7 (7q31-35), is involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release, and has been implicated in higher cognitive processing. The aim of this study is the identification of functional (non)coding variants underlying cognitive phenotypic variation.</p> <p>Methods</p> <p>We previously reported an association between polymorphisms in the 5'UTR regions of the <it>CHRM2 </it>gene and intelligence.. However, no functional variants within this area have currently been identified. In order to identify the relevant functional variant(s), we conducted a denser coverage of SNPs, using two independent Dutch cohorts, consisting of a children's sample (N = 371 ss; mean age 12.4) and an adult sample (N= 391 ss; mean age 37.6). For all individuals standardized intelligence measures were available. Subsequently, we investigated genotype-dependent <it>CHRM2 </it>gene expression levels in the brain, to explore putative enhancer/inhibition activity exerted by variants within the muscarinic acetylcholinergic receptor.</p> <p>Results</p> <p>Using a test of within-family association two of the previously reported variants – rs2061174, and rs324650 – were again strongly associated with intelligence (<it>P </it>< 0.01). A new SNP (rs2350780) showed a trend towards significance. SNP rs324650, is located within a short interspersed repeat (SINE). Although the function of short interspersed repeats remains contentious, recent research revealed potential functionality of SINE repeats in a gene-regulatory context. Gene-expression levels in post-mortem brain material, however were not dependent on rs324650 genotype.</p> <p>Conclusion</p> <p>Using a denser coverage of SNPs in the <it>CHRM2 </it>gene, we confirmed the 5'UTR regions to be most interesting in the context of intelligence, and ruled out other regions of this gene. Although no correlation between genomic variants and gene expression was found, it would be interesting to examine allele-specific effects on CHRM2 transcripts expression in much more detail, for example in relation to transcripts specific halve-life and their relation to LTP and memory.</p

Widespread Climate Change in the Himalayas and Associated Changes in Local Ecosystems

Background: Climate change in the Himalayas, a biodiversity hotspot, home of many sacred landscapes, and the source of eight largest rivers of Asia, is likely to impact the well-being of $\sim$20% of humanity. However, despite the extraordinary environmental, cultural, and socio-economic importance of the Himalayas, and despite their rapidly increasing ecological degradation, not much is known about actual changes in the two most critical climatic variables: temperature and rainfall. Nor do we know how changes in these parameters might impact the ecosystems including vegetation phenology. Methodology/Principal Findings: By analyzing temperature and rainfall data, and NDVI (Normalized Difference Vegetation Index) values from remotely sensed imagery, we report significant changes in temperature, rainfall, and vegetation phenology across the Himalayas between 1982 and 2006. The average annual mean temperature during the 25 year period has increased by 1.5$^\circ$C with an average increase of 0.06$^\circ$C yr$^{−1}$. The average annual precipitation has increased by 163 mm or 6.52 mmyr$^{−1}$. Since changes in temperature and precipitation are immediately manifested as changes in phenology of local ecosystems, we examined phenological changes in all major ecoregions. The average start of the growing season (SOS) seems to have advanced by 4.7 days or 0.19 days yr$^{−1}$ and the length of growing season (LOS) appears to have advanced by 4.7 days or 0.19 days yr$^{−1}$, but there has been no change in the end of the growing season (EOS). There is considerable spatial and seasonal variation in changes in climate and phenological parameters. Conclusions/Significance: This is the first time that large scale climatic and phenological changes at the landscape level have been documented for the Himalayas. The rate of warming in the Himalayas is greater than the global average, confirming that the Himalayas are among the regions most vulnerable to climate change