Renal peroxiredoxin 6 interacts with anion exchanger 1 and plays a novel role in pH homeostasis.

Peroxiredoxin 6 (PRDX6) is one of the six members of the PRDX family, which have peroxidase and antioxidant activity. PRDX6 is unique, containing only one conserved cysteine residue (C47) rather than the two found in other PRDXs. A yeast two-hybrid screen found PRDX6 to be a potential binding partner of the C-terminal tail of anion exchanger 1 (AE1), a Cl(-)/HCO(3)(-) exchanger basolaterally expressed in renal α-intercalated cells. PRDX6 immunostaining in human kidney was both cytoplasmic and peripheral and colocalized with AE1. Analysis of native protein showed that it was largely monomeric, whereas expressed tagged protein was more dimeric. Two methionine oxidation sites were identified. In vitro and ex vivo pull-downs and immunoprecipitation assays confirmed interaction with AE1, but mutation of the conserved cysteine resulted in loss of interaction. Prdx6 knockout mice had a baseline acidosis with a major respiratory component and greater AE1 expression than wild-type animals. After an oral acid challenge, PRDX6 expression increased in wild-type mice, with preservation of AE1. However, AE1 expression was significantly decreased in knockout animals. Kidneys from acidified mice showed widespread proximal tubular vacuolation in wild-type but not knockout animals. Knockdown of PRDX6 by siRNA in mammalian cells reduced both total and cell membrane AE1 levels. Thus, PRDX6-AE1 interaction contributes to the maintenance of AE1 during cellular stress such as during metabolic acidosis.Human kidney sections were prepared by Suzy Haward, Addenbrooke's Human Research Tissue Bank, which is supported by the Cambridge Biomedical Research Centre. We thank Dr. Aron Fisher (Institute for Environmental Science, University of Pennsylvania) for the kind gift of Prdx6−/− mice and reagents, Carsten Wagner (Zurich) for antisera, Jane Clarke (University of Cambridge) for modified pRSET-A vector, and Kamburapola Jayawardena for mass spectrometry (CIMR). This work was funded by the Wellcome Trust (award 088489/Z/09/Z to FEKF and Strategic award 100140/Z/12/Z to the Cambridge Institute for Medical Research), and the Jack Kent Cooke Foundation (scholarship to SLS).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ki.2015.27

Bulk localized transport states in infinite and finite quasicrystals via magnetic aperiodicity

Robust edge transport can occur when charged particles in crystalline lattices interact with an applied external magnetic field. Such systems have a spectrum composed of bands of bulk states and in-gap edge states. For quasicrystalline systems, we still expect to observe the basic characteristics of bulk states and current-carrying edge states. We show that, for quasicrystals in magnetic fields, there is an additional third option - bulk localized transport (BLT) states. BLT states share the in-gap nature of the well-known edge states and can support transport, but they are fully contained within the bulk of the system, with no support along the edge. Thus, transport is possible along the edge and within distinct regions of the bulk. We consider both finite-size and infinite-size systems, using rigorous error controlled computational techniques that are not prone to finite-size effects. BLT states are preserved for infinite-size systems, in stark contrast to edge states. This allows us to observe transport in infinite-size systems, without any perturbations, defects, or boundaries being introduced. We confirm the in-gap topological nature of BLT states for finite- and infinite-size systems by computing the Bott index and local Chern marker (common topological measures). BLT states form due to magnetic aperiodicity, arising from the interplay of lengthscales between the magnetic field and the quasiperiodic lattice. BLT could have interesting applications similar to those of edge states, but now taking advantage of the larger bulk of the lattice. The infinite-size techniques introduced here, especially the calculation of topological measures, could also be widely applied to other crystalline, quasicrystalline, and disordered models

Causal categories: relativistically interacting processes

A symmetric monoidal category naturally arises as the mathematical structure that organizes physical systems, processes, and composition thereof, both sequentially and in parallel. This structure admits a purely graphical calculus. This paper is concerned with the encoding of a fixed causal structure within a symmetric monoidal category: causal dependencies will correspond to topological connectedness in the graphical language. We show that correlations, either classical or quantum, force terminality of the tensor unit. We also show that well-definedness of the concept of a global state forces the monoidal product to be only partially defined, which in turn results in a relativistic covariance theorem. Except for these assumptions, at no stage do we assume anything more than purely compositional symmetric-monoidal categorical structure. We cast these two structural results in terms of a mathematical entity, which we call a `causal category'. We provide methods of constructing causal categories, and we study the consequences of these methods for the general framework of categorical quantum mechanics.Comment: 43 pages, lots of figure

The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies.

BACKGROUND: In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment. DESIGN: We reviewed 277 biopsies from the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository, enumerating 9,379 glomeruli by means of whole slide imaging. Glomerular number and the percentage of globally sclerotic glomeruli are values routinely recorded in the official renal biopsy pathology report from the 25 participating centers. Two general trends in reporting were noted: total number per biopsy or average number per level/section. Both of these approaches were assessed for their accuracy in comparison to the analogous numbers of annotated glomeruli on WSI. RESULTS: The number of glomeruli annotated was consistently higher than those reported (p CONCLUSIONS: Although glass slides were not available for direct comparison to whole slide image annotation, this study indicates that routine manual light microscopy assessment of number of glomeruli is inaccurate, and the magnitude of this error is proportional to the total number of glomeruli

Scanning electron diffraction tomography of strain

Abstract: Strain engineering is used to obtain desirable materials properties in a range of modern technologies. Direct nanoscale measurement of the three-dimensional strain tensor field within these materials has however been limited by a lack of suitable experimental techniques and data analysis tools. Scanning electron diffraction has emerged as a powerful tool for obtaining two-dimensional maps of strain components perpendicular to the incident electron beam direction. Extension of this method to recover the full three-dimensional strain tensor field has been restricted though by the absence of a formal framework for tensor tomography using such data. Here, we show that it is possible to reconstruct the full non-symmetric strain tensor field as the solution to an ill-posed tensor tomography inverse problem. We then demonstrate the properties of this tomography problem both analytically and computationally, highlighting why incorporating precession to perform scanning precession electron diffraction (SPED) may be important. We establish a general framework for non-symmetric tensor tomography and demonstrate computationally its applicability for achieving strain tomography with SPED data

The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies

In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment

'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

A distinct bacterial dysbiosis associated skin inflammation in ovine footrot

Ovine footrot is a highly prevalent bacterial disease caused by Dichelobacter nodosus and characterised by the separation of the hoof horn from the underlying skin. The role of innate immune molecules and other bacterial communities in the development of footrot lesions remains unclear. This study shows a significant association between the high expression of IL1β and high D. nodosus load in footrot samples. Investigation of the microbial population identified distinct bacterial populations in the different disease stages and also depending on the level of inflammation. Treponema (34%), Mycoplasma (29%) and Porphyromonas (15%) were the most abundant genera associated with high levels of inflammation in footrot. In contrast, Acinetobacter (25%), Corynebacteria (17%) and Flavobacterium (17%) were the most abundant genera associated with high levels of inflammation in healthy feet. This demonstrates for the first time there is a distinct microbial community associated with footrot and high cytokine expression

Classification and function of small open reading frames

Small open reading frames (smORFs) of 100 codons or fewer are usually - if arbitrarily - excluded from proteome annotations. Despite this, the genomes of many metazoans, including humans, contain millions of smORFs, some of which fulfil key physiological functions. Recently, the transcriptome of Drosophila melanogaster was shown to contain thousands of smORFs of different classes that actively undergo translation, which produces peptides of mostly unknown function. Here, we present a comprehensive analysis of smORFs in flies, mice and humans. We propose the existence of several functional classes of smORFs, ranging from inert DNA sequences to transcribed and translated cis-regulators of translation and peptides with a propensity to function as regulators of membrane-associated proteins, or as components of ancient protein complexes in the cytoplasm. We suggest that the different smORF classes could represent steps in gene, peptide and protein evolution. Our analysis introduces a distinction between different peptide-coding classes of smORFs in animal genomes, and highlights the role of model organisms for the study of small peptide biology in the context of development, physiology and human disease

The AAA-ATPase VPS4 Regulates Extracellular Secretion and Lysosomal Targeting of α-Synuclein

Many neurodegenerative diseases share a common pathological feature: the deposition of amyloid-like fibrils composed of misfolded proteins. Emerging evidence suggests that these proteins may spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. Here, we demonstrated that α-synuclein (αSYN), a principal culprit for Lewy pathology in Parkinson's disease (PD), was present in endosomal compartments and detectably secreted into the extracellular milieu. Unlike prion protein, extracellular αSYN was mainly recovered in the supernatant fraction rather than in exosome-containing pellets from the neuronal culture medium and cerebrospinal fluid. Surprisingly, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of αSYN but facilitated αSYN secretion. The hypersecretion of αSYN in VPS4-defective cells was efficiently restored by the functional disruption of recycling endosome regulator Rab11a. Furthermore, both brainstem and cortical Lewy bodies in PD were found to be immunoreactive for VPS4. Thus, VPS4, a master regulator of MVB sorting, may serve as a determinant of lysosomal targeting or extracellular secretion of αSYN and thereby contribute to the intercellular propagation of Lewy pathology in PD