The prognostic value of the furosemide stress test in predicting delayed graft function following deceased donor kidney transplantation

Objectives and methods: The Furosemide Stress Test (FST) is a novel dynamic assessment of tubular function that has been shown in preliminary studies to predict patients who will progress to advanced stage acute kidney injury, including those who receive renal replacement therapy (RRT). The aim of this study is to investigate if the urinary response to a single intraoperative dose of intravenous furosemide predicts delayed graft function (DGF) in patients undergoing deceased donor kidney transplant.

Results: On an adjusted multiple logistic regression, a single 100?mg dose of intraoperative furosemide after the anastomosis of the renal vessels (FST) predicted the need for RRT at 2 and 6?h post kidney transplantation (KT). Recipient urinary output was measured at 2 and 6?h post furosemide administration. In receiver-operating characteristic (ROC) analysis, the FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cut-off of <600 mls at 6?h with a sensitivity of and a specificity of 83% and 74%, respectively.

Conclusions: The FST is a predictor of DGF post kidney transplant and has the potential to identify patients requiring RRT early after KT.     

Quantifying HDL proteins by mass spectrometry: how many proteins are there and what are their functions?

Introduction: Many lines of evidence indicate that low levels of HDL cholesterol increase the risk of cardiovascular disease (CVD). However, recent clinical studies of statin-treated subjects with established atherosclerosis cast doubt on the hypothesis that elevating HDL cholesterol levels reduces CVD risk.

Areas covered: It is critical to identify new HDL metrics that capture HDL’s proposed cardioprotective effects. One promising approach is quantitative MS/MS-based HDL proteomics. This article focuses on recent studies of the feasibility and challenges of using this strategy in translational studies. It also discusses how lipid-lowering therapy and renal disease alter HDL’s functions and proteome, and how HDL might serve as a platform for binding proteins with specific functional properties.

Expert commentary: It is clear that HDL has a diverse protein cargo and that its functions extend well beyond its classic role in lipid transport and reverse cholesterol transport. MS/MS analysis has demonstrated that HDL might contain >80 different proteins. Key challenges are demonstrating that these proteins truly associate with HDL, are functionally important, and that MS-based HDL proteomics can reproducibly detect biomarkers in translational studies of disease risk.     

Towards rationally designed biomanufacturing of therapeutic extracellular vesicles: impact of the bioproduction microenvironment

Extracellular vesicles (EVs), including exosomes, microvesicles, and others, have emerged as potential therapeutics for a variety of applications. Pre-clinical reports of EV efficacy in treatment of non-healing wounds, myocardial infarction, osteoarthritis, traumatic brain injury, spinal cord injury, and many other injuries and diseases demonstrate the versatility of this nascent therapeutic modality. EVs have also been demonstrated to be effective in humans, and clinical trials are underway to further explore their potential. However, for EVs to become a new class of clinical therapeutics, issues related to translation must be addressed. For example, approaches originally developed for cell biomanufacturing, such as hollow fiber bioreactor culture, have been adapted for EV production, but limited knowledge of how the cell culture microenvironment specifically impacts EVs restricts the possibility for rational design and optimization of EV production and potency. In this review, we discuss current knowledge of this issue and delineate potential focus areas for future research towards enabling translation and widespread application of EV-based therapeutics.     

Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold

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William E. Vidaver (1921–2017): an innovator,enthusiastic scientist,inspiring teacher and a wonderful friend

William (Bill) E. Vidaver (February 2, 1921–August 31, 2017), who did his Ph.D. with Laurence (Larry) R. Blinks at Stanford (1964) and a postdoc with C. Stacy French (1965), taught and did research at Simon Fraser University (SFU) for almost 30 years. Here he published over 80 papers in photosynthesis-related areas co-authored by his graduate students, postdocs, visiting professors and SFU colleagues. He developed a unique high-pressure cuvette for the study of oxygen exchange and studied high-pressure effects in photosynthesis. Ulrich (Uli) Schreiber, as a postdoctoral fellow from Germany, introduced measurements on chlorophyll (Chl) a fluorescence to Bill’s lab, leading to the discovery of reversible inhibition of excitation energy transfer between photosynthetic pigments and of a pivotal role of O₂ in the oxidation of the electron transport chain between Photosystem II (PS II) and PS I. Bill’s and Uli’s work led to a patent of a portable chlorophyll fluorometer, the first available commercially, which was later modified to measure whole plantlets. The latter was used in pioneering measurement of the health of forest and crop plants undergoing in vitro clonal micropropagation. With several other researchers (including Doug Bruce, the late Radovan Popovic, and Sarah Swenson), he localized the quenching site of O₂ and showed a dampening effect on measurements of the four-step process of O₂ production by endogenous oxygen uptake. Bill is remembered as a hard-working but fun-loving person with a keen mind and strong sense of social justice.     

Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways

Autism spectrum disorder (ASD) is a group of complex, neurological disorders that affect early cognitive, social, and verbal development. Our understanding of ASD has vastly improved with advances in genomic sequencing technology and genetic models that have identified >800 loci with variants that increase susceptibility to ASD. Although these findings have confirmed its high heritability, the underlying mechanisms by which these genes produce the ASD phenotypes have not been defined. Current efforts have begun to “functionalize” many of these variants and envisage how these susceptibility factors converge at key biochemical and biophysical pathways. In this review, we discuss recent work on intracellular calcium signaling in ASD, including our own work, which begins to suggest it as a compelling candidate mechanism in the pathophysiology of autism and a potential therapeutic target. We consider how known variants in the calcium signaling genomic architecture of ASD may exert their deleterious effects along pathways particularly involving organelle dysfunction including the endoplasmic reticulum (ER), a major calcium store, and the mitochondria, a major calcium ion buffer, and theorize how many of these pathways intersect.     

Unexpected spatial stability of water chemistry in headwater stream networks

Understanding how water and solutes enter and propagate through freshwater landscapes in the Anthropocene is critical to protecting and restoring aquatic ecosystems and ensuring human water security. However, high hydrochemical variability in headwater streams, where most carbon and nutrients enter river networks, has hindered effective modelling and management. We developed an analytical framework informed by landscape ecology and catchment hydrology to quantify spatiotemporal variability across scales, which we tested in 56 headwater catchments, sampled periodically over 12 years in western France. Unexpectedly, temporal variability in dissolved carbon, nutrients and major ions was preserved moving downstream and spatial patterns of water chemistry were stable on annual to decadal timescales, partly because of synchronous variation in solute concentrations. These findings suggest that while concentration and flux cannot be extrapolated among subcatchments, periodic sampling of headwaters provides valuable information about solute sources and subcatchment resilience to disturbance.     

Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11) and association with a unique bimodal expressivity phenotype.

Retinitis pigmentosa (RP) is the name given to a heterogeneous group of retinal degenerations mapping to at least 16 loci. The autosomal dominant form (ARP), accounting for approximately 25% of cases, can be caused by mutations in two genes, rhodopsin and peripherin/RDS, and by at least six other loci identified by linkage analysis. The RP11 locus for adRP has previously been mapped to chromosome 19q13.4 in a large English family. This linkage has been independently confirmed in a Japanese family, and we now report three additional unrelated linked U.K. families, suggesting that this is a major locus for RP. Linkage analysis in the U.K. families refines the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibit incomplete penetrance; some obligate gene carriers remain asymptomatic throughout their lives, whereas symptomatic individuals experience night blindness and visual field loss in their teens and are generally registered as blind by their 30s. This "bimodal expressivity" contrasts with the variable-expressivity RP mapping to chromosome 7p (RP9) in another family, which has implications for diagnosis and counseling of RP11 families. These results may also imply that a proportion of sporadic RP, previously assumed to be recessive, might result from mutations at this locus.     

Irreversible inhibition of human natural killer cell natural cytotoxicity by modification of the extracellular membrane by the adenine nucleotide analog 5′-p-(fluorosulfonyl)benzoyl adenosine

Extracellular adenine nucleotides are inhibitors of the human natural killer cell line NK3.3 natural cytotoxicity activity. Natural cytotoxicity was inhibited approximately 26% by 1 mM ATP and 21% by 1 mM ADP. 5′-Adenylyl imidodiphosphate, a nonhydrolyzable ATP analog, inhibited natural cytotoxicity by 41% at a concentration of 1 mM and > 97% at a concentration of 10 mM. In contrast, AMP was not inhibitory. Adenosine was a weak inhibitor of natural cytotoxicity and may represent an alternate regulatory pathway. Removal of the nucleotides resulted in the restoration of control levels of natural cytotoxicity activity. The affinity label 5′-p-(fluorosulfonyl)benzoyladenosine (5′-FSBA) is a synthetic analog of ATP or ADP containing an electrophilic fluorosulfonyl group capable of covalently modifying proteins at adenine di- and triphosphate nucleotide-binding sites. Natural cytotoxicity was irreversibly inhibited by modification of the extracellular membrane of NK3.3 cells by 5′-FSBA. This inhibition was concentration dependent with an I₅₀ ∼ 100 μM and complete inhibition at 1 mM. Modification of NK3.3 by 5′-FSBA did not affect the formation of effector—target cell conjugates; however, granule release was inhibited. This targets the site of inhibition by 5′-FSBA modification to a pathway preceding granule release. Irreversible, covalent modification of surface adenine nucleotide-binding proteins by 5′-FSBA provides a probe to study the role of specific adenine nucleotide-binding proteins in the extracellular regulation of natural killer cytolytic activity by adenine nucleotides.     

Sex determination in Miocene catarrhine primates

Canines of fossil hominoids and primitive catarrhines from several early, middle, and late Miocene sites were analyzed according to the shape indices described in Kelley (1995) and compared to those of males and females of extant great apes. In bivariate plots of the fossil canines utilizing the indices, 90% of the upper canines and 85% of the lower canines fell within or just outside the exclusively male or exclusively female territories delimited by the extant great apes. The remainder fell in the male-female overlap zones. Sex assignments based on these distributions were nearly 100% concordant with classifications according to canine height, suggesting a high degree of accuracy. There were various taxon-specific shifts in bivariate space among fossil genera, reflecting subtle differences in canine shape between taxa within the overall pattern of similarity to extant great apes as a whole. In many cases these shifts are matched by particular extant-ape species and subspecies, while other fossil taxa have no exact analogue for canine shape among the extant great apes. However, the pattern of spatial segregation of canines identified as either male or female at each of the sites largely mirrors that of males and females within the extant-ape sample, indicating that Miocene catarrhines shared with extant great apes a common pattern of shape differences between male and female canines, regardless of taxonspecific morphologies. These observations demonstrate that the canines of fossil catarrhines can be sexed with a high degree of confidence based solely on intrinsic features of shape. This will permit more reliable characterizations of morphological sexual dimorphism among fossil species. It is also argued that canine shape is a more reliable indicator of sex in fossil taxa than are canine/molar size ratios. © 1995 Wiley-Liss, Inc.