Proteomic analysis of heart failure hospitalization among patients with chronic kidney disease: The Heart and Soul Study.

BACKGROUND:Patients with chronic kidney disease (CKD) are at increased risk for heart failure (HF). We aimed to investigate differences in proteins associated with HF hospitalizations among patients with and without CKD in the Heart and Soul Study. METHODS AND RESULTS:We measured 1068 unique plasma proteins from baseline samples of 974 participants in The Heart and Soul Study who were followed for HF hospitalization over a median of 7 years. We sequentially applied forest regression and Cox survival analyses to select prognostic proteins. Among participants with CKD, four proteins were associated with HF at Bonferroni-level significance (p<2.5x10(-4)): Angiopoietin-2 (HR[95%CI] 1.45[1.33, 1.59]), Spondin-1 (HR[95%CI] 1.13 [1.06, 1.20]), tartrate-resistant acid phosphatase type 5 (HR[95%CI] 0.65[0.53, 0.78]) and neurogenis locus notch homolog protein 1 (NOTCH1) (HR[95%CI] 0.67[0.55, 0.80]). These associations persisted at p<0.01 after adjustment for age, estimated glomerular filtration and history of HF. CKD was a significant interaction term in the associations of NOTCH1 and Spondin-1 with HF. Pathway analysis showed a trend for higher representation of the Cardiac Hypertrophy and Complement/Coagulation pathways among proteins prognostic of HF in the CKD sub-group. CONCLUSIONS:These results suggest that markers of heart failure differ between patients with and without CKD. Further research is needed to validate novel markers in cohorts of patients with CKD and adjudicated HF events

Characterizing the gut microbiome in trauma: significant changes in microbial diversity occur early after severe injury.

Background:Recent studies have demonstrated the vital influence of commensal microbial communities on human health. The central role of the gut in the response to injury is well described; however, no prior studies have used culture-independent profiling techniques to characterize the gut microbiome after severe trauma. We hypothesized that in critically injured patients, the gut microbiome would undergo significant compositional changes in the first 72 hours after injury. Methods:Trauma stool samples were prospectively collected via digital rectal examination at the time of presentation (0 hour). Patients admitted to the intensive care unit (n=12) had additional stool samples collected at 24 hours and/or 72 hours. Uninjured patients served as controls (n=10). DNA was extracted from stool samples and 16S rRNA-targeted PCR amplification was performed; amplicons were sequenced and binned into operational taxonomic units (OTUs; 97% sequence similarity). Diversity was analyzed using principle coordinates analyses, and negative binomial regression was used to determine significantly enriched OTUs. Results:Critically injured patients had a median Injury Severity Score of 27 and suffered polytrauma. At baseline (0 hour), there were no detectable differences in gut microbial community diversity between injured and uninjured patients. Injured patients developed changes in gut microbiome composition within 72 hours, characterized by significant alterations in phylogenetic composition and taxon relative abundance. Members of the bacterial orders Bacteroidales, Fusobacteriales and Verrucomicrobiales were depleted during 72 hours, whereas Clostridiales and Enterococcus members enriched significantly. Discussion:In this initial study of the gut microbiome after trauma, we demonstrate that significant changes in phylogenetic composition and relative abundance occur in the first 72 hours after injury. This rapid change in intestinal microbiota represents a critical phenomenon that may influence outcomes after severe trauma. A better understanding of the nature of these postinjury changes may lead to the ability to intervene in otherwise pathological clinical trajectories. Level of evidence:III. Study type:Prognostic/epidemiological

Enhancing Vitality in Academic Medicine: Faculty Development and Productivity

The prevalence of low satisfaction and increased stress among faculty in academic medicine makes understanding facuity vitality in this field more important than ever before. To explore the contributors to and outcomes of faculty vitality, we conducted a multi-institutional study of faculty in academic medicine (N = 1,980, 42 percent response rate). Faculty were surveyed about climate and leadership, career and life management, satisfaction, engagement, productivity, and involvement in faculty development. Analysis reveals that controlling for other factors, academic medicine faculty who participate regularly in facuity development activ ities are significantly more satisfied, engaged, and productive

Kahler Stabilized, Modular Invariant Heterotic String Models

We review the theory and phenomenology of effective supergravity theories based on orbifold compactifications of the weakly-coupled heterotic string. In particular, we consider theories in which the four-dimensional theory displays target space modular invariance and where the dilatonic mode undergoes Kahler stabilization. A self-contained exposition of effective Lagrangian approaches to gaugino condensation and heterotic string theory is presented, leading to the development of the models of Binetruy, Gaillard and Wu. Various aspects of the phenomenology of this class of models are considered. These include issues of supersymmetry breaking and superpartner spectra, the role of anomalous U(1) factors, issues of flavor and R-parity conservation, collider signatures, axion physics, and early universe cosmology. For the vast majority of phenomenological considerations the theories reviewed here compare quite favorably to other string-derived models in the literature. Theoretical objections to the framework and directions for further research are identified and discussed.Comment: Invited review article for International Journal of Modern Physic

Heparin-binding Epidermal Growth Factor-like Growth Factor Links Hepatocyte Priming with Cell Cycle Progression during Liver Regeneration

The mechanisms that regulate the transition between the initial priming phase and DNA replication in liver regeneration are poorly understood. To study this transition, we compared events occurring after standard two-thirds partial hepatectomy, which elicits full regeneration, with response to a reduced hepatectomy, one-third partial hepatectomy (1/3PH), which leads to little DNA replication. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between the two procedures, cell cycle progression was significantly blunted in 1/3PH mice. Among the main defects observed in 1/3PH mice were an almost complete deficiency in retinoblastoma phosphorylation and the lack of increase in kinase activity associated with cyclin E. We report that, in two-thirds partial hepatectomy mice, the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) preceded the start of DNA replication and was not detectable in 1/3PH animals. Injection of HB-EGF into 1/3PH mice resulted in a >15-fold increase in DNA replication. Moreover, we show that hepatocyte DNA replication was delayed in HB-EGF knock-out mice. In summary, we show that HB-EGF is a key factor for hepatocyte progression through G(1)/S transition during liver regeneration

Bone mineral density and the subsequent risk of cancer in the NHANES I follow-up cohort

BACKGROUD: Bone mineral density (BMD) is a marker of long-term estrogen exposure. BMD measurement has been used in this context to investigate the association of estrogen with breast cancer risk in three cohorts. In order to assess further BMD as a predictor of estrogen related cancer risk, the association of BMD with colorectal and corpus uteri cancer was investigated in the NHANES I Epidemiologic Followup Study (NHEFS) cohort along with breast cancer and prostate cancer. METHODS: Participants were members of the NHEFS cohort who had BMD measurement in 1974–1975. Age, race, and BMI adjusted rate ratios and 95% confidence intervals were calculated for incidence of cancers of the corpus uterus, breast, colorectum, prostate, and of osteoporosis and hip fracture related to baseline BMD. RESULTS: Data were available for 6046 individuals. One hundred cases of breast cancer, 94 prostate cancers, 115 colorectal cancers, 29 uterine cancers, 110 cases of hip fracture and 103 cases of osteoporosis were reported between 1974 and 1993. Hip fracture and osteoporosis were both significantly inversely associated with BMD. Uterine cancer was positively associated (p = 0.005, test for linear trend) and colorectal cancer negatively associated (p = 0.03) with BMD. No association was found between elevated BMD and incidence of breast cancer (p = 0.74) or prostate cancer (p = 0.37) in the overall cohort, although a weak association was seen between BMD and subsequent breast cancer incidence when BMD was measured in post-menopausal women (p = 0.04). CONCLUSION: The findings related to cancers of the uterus and colorectum as well as the weak association of BMD with breast cancer strengthen the use of BMD as a marker of estrogen exposure and cancer risk

Clades of huge phages from across Earth's ecosystems.

Bacteriophages typically have small genomes1 and depend on their bacterial hosts for replication2. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of more than 200 kilobases (kb), including a genome of 735 kb, which is-to our knowledge-the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR-Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR-Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR-Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth's ecosystems

Prompt atmospheric neutrino fluxes: perturbative QCD models and nuclear effects

We evaluate the prompt atmospheric neutrino flux at high energies using three different frameworks for calculating the heavy quark production cross section in QCD: NLO perturbative QCD, $k_T$ factorization including low-$x$ resummation, and the dipole model including parton saturation. We use QCD parameters, the value for the charm quark mass and the range for the factorization and renormalization scales that provide the best description of the total charm cross section measured at fixed target experiments, at RHIC and at LHC. Using these parameters we calculate differential cross sections for charm and bottom production and compare with the latest data on forward charm meson production from LHCb at $7$ TeV and at $13$ TeV, finding good agreement with the data. In addition, we investigate the role of nuclear shadowing by including nuclear parton distribution functions (PDF) for the target air nucleus using two different nuclear PDF schemes. Depending on the scheme used, we find the reduction of the flux due to nuclear effects varies from $10\%$ to $50 \%$ at the highest energies. Finally, we compare our results with the IceCube limit on the prompt neutrino flux, which is already providing valuable information about some of the QCD models.Comment: 61 pages, 25 figures, 11 table