Using statolith elemental signatures to confirm ontogenetic migrations of the squid Doryteuthis gahi around the Falkland Islands (Southwest Atlantic)

This work was supported by the Falkland Islands Government. We thank Dr. Simon Chenery and the British Geological Survey for assistance with the LA-ICP-MS analysis and training and use of their facilities. We are grateful to the scientific observers from the Falkland Islands Fisheries Department for sample collection. We thank the Director of Fisheries, John Barton, and the director of SAERI, Paul Brickle, for supporting this work. We thank Dr. Elena Ieno, Dr. Andreas Winter, Dr. Haseeb Randhawa and three anonymous reviewers for their helpful comments that greatly improved the manuscript.Peer reviewedPostprin

Predicting Progression of IgA Nephropathy: New Clinical Progression Risk Score

IgA nephropathy (IgAN) is a common cause of end-stage renal disease (ESRD) in Asia. In this study, based on a large cohort of Chinese patients with IgAN, we aim to identify independent predictive factors associated with disease progression to ESRD. We collected retrospective clinical data and renal outcomes on 619 biopsy-diagnosed IgAN patients with a mean follow-up time of 41.3 months. In total, 67 individuals reached the study endpoint defined by occurrence of ESRD necessitating renal replacement therapy. In the fully adjusted Cox proportional hazards model, there were four baseline variables with a significant independent effect on the risk of ESRD. These included: eGFR [HR = 0.96(0.95–0.97)], serum albumin [HR = 0.47(0.32–0.68)], hemoglobin [HR = 0.79(0.72–0.88)], and SBP [HR = 1.02(1.00–1.03)]. Based on these observations, we developed a 4-variable equation of a clinical risk score for disease progression. Our risk score explained nearly 22% of the total variance in the primary outcome. Survival ROC curves revealed that the risk score provided improved prediction of ESRD at 24th, 60th and 120th month of follow-up compared to the three previously proposed risk scores. In summary, our data indicate that IgAN patients with higher systolic blood pressure, lower eGFR, hemoglobin, and albumin levels at baseline are at a greatest risk of progression to ESRD. The new progression risk score calculated based on these four baseline variables offers a simple clinical tool for risk stratification

The Elusive Third Subunit IIa of the Bacterial B-Type Oxidases: The Enzyme from the Hyperthermophile Aquifex aeolicus

The reduction of molecular oxygen to water is catalyzed by complicated membrane-bound metallo-enzymes containing variable numbers of subunits, called cytochrome c oxidases or quinol oxidases. We previously described the cytochrome c oxidase II from the hyperthermophilic bacterium Aquifex aeolicus as a ba3-type two-subunit (subunits I and II) enzyme and showed that it is included in a supercomplex involved in the sulfide-oxygen respiration pathway. It belongs to the B-family of the heme-copper oxidases, enzymes that are far less studied than the ones from family A. Here, we describe the presence in this enzyme of an additional transmembrane helix “subunit IIa”, which is composed of 41 amino acid residues with a measured molecular mass of 5105 Da. Moreover, we show that subunit II, as expected, is in fact longer than the originally annotated protein (from the genome) and contains a transmembrane domain. Using Aquifex aeolicus genomic sequence analyses, N-terminal sequencing, peptide mass fingerprinting and mass spectrometry analysis on entire subunits, we conclude that the B-type enzyme from this bacterium is a three-subunit complex. It is composed of subunit I (encoded by coxA2) of 59000 Da, subunit II (encoded by coxB2) of 16700 Da and subunit IIa which contain 12, 1 and 1 transmembrane helices respectively. A structural model indicates that the structural organization of the complex strongly resembles that of the ba3 cytochrome c oxidase from the bacterium Thermus thermophilus, the IIa helical subunit being structurally the lacking N-terminal transmembrane helix of subunit II present in the A-type oxidases. Analysis of the genomic context of genes encoding oxidases indicates that this third subunit is present in many of the bacterial oxidases from B-family, enzymes that have been described as two-subunit complexes

An Observational Cohort Study of the Kynurenine to Tryptophan Ratio in Sepsis: Association with Impaired Immune and Microvascular Function

Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-γ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-γ, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64–235]) compared to controls (36 [28–52]); p<0.0001), and correlated with plasma interferon-γ and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100–286] on day 0 to 89 [65–139] by day 7; p = 0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p<0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology

National Institutes of Health–Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities

Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed

Mutation of the His ligand in mitoNEET stabilizes the 2Fe–2S cluster despite conformational heterogeneity in the ligand environment

The spectroscopic and stability properties and X-ray crystal structure of the H87C mutant of the 2Fe–2S ligand mitoNEET are reported. Strikingly, the single point mutation leads to changes in its absorbance and CD spectra and an increase of around sixfold in the stability of the 2Fe–2S clusters over the pH range 5–7. However, the crystal structure of the H87C mutant displays heterogeneity in a few key residues, including the introduced cysteine ligand. Nonetheless, the cluster is highly stabilized from release

Glomerular hyperfiltration: A new marker of metabolic risk

Chronic kidney disease coexists with metabolic syndrome and this relationship may be apparent before overt manifestations of cardiovascular disease. To investigate early stages of the natural history of associations between renal function and metabolic syndrome, we phenotyped 1572 young (mean age=18.4 years), apparently healthy men for metabolic risk factors and estimated their creatinine clearance based on the Cockcroft–Gault equation. High metabolic risk (clustering of at least three metabolic risk factors) was revealed in 8.7% (137) of the subjects and was associated with a 6.9-fold increase in the odds of glomerular hyperfiltration (95% confidence interval (CI): 3.9–11.5) when compared to reference (from none to two metabolic risk factors). Overweight, elevated blood pressure, and low high-density lipoprotein (HDL) cholesterol increased the multivariate-adjusted odds ratio of glomerular hyperfiltration to 6.6 (95% CI: 3.8–11.6), 1.8 (95% CI: 1.0–3.0), and 2.5 (95% CI: 1.5–4.3), respectively. Systolic and diastolic blood pressures clustered together with leptin in the factor analysis and this blood pressure–adiposity component correlated with estimated creatinine clearance (r=0.329, P<0.0001) and explained on its own 10.2% of the variance in the estimated renal function. Our data reveal the silent epidemics of metabolic risk among young, apparently healthy men. Furthermore, the results indicate that high metabolic risk is associated with glomerular hyperfiltration before overt manifestations of cardiovascular disease