Identification of Cellular Infiltrates during Early Stages of Brain Inflammation with Magnetic Resonance Microscopy

A comprehensive view of brain inflammation during the pathogenesis of autoimmune encephalomyelitis can be achieved with the aid of high resolution non-invasive imaging techniques such as microscopic magnetic resonance imaging (μMRI). In this study we demonstrate the benefits of cryogenically-cooled RF coils to produce μMRI in vivo, with sufficient detail to reveal brain pathology in the experimental autoimmune encephalomyelitis (EAE) model. We could visualize inflammatory infiltrates in detail within various regions of the brain, already at an early phase of EAE. Importantly, this pathology could be seen clearly even without the use of contrast agents, and showed excellent correspondence with conventional histology. The cryogenically-cooled coil enabled the acquisition of high resolution images within short scan times: an important practical consideration in conducting animal experiments. The detail of the cellular infiltrates visualized by in vivo μMRI allows the opportunity to follow neuroinflammatory processes even during the early stages of disease progression. Thus μMRI will not only complement conventional histological examination but will also enable longitudinal studies on the kinetics and dynamics of immune cell infiltration

Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy

Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5–4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML–IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML

Offspring Hormones Reflect the Maternal Prenatal Social Environment: Potential for Foetal Programming?

Females of many species adaptively program their offspring to predictable environmental conditions, a process that is often mediated by hormones. Laboratory studies have shown, for instance, that social density affects levels of maternal cortisol and testosterone, leading to fitness-relevant changes in offspring physiology and behaviour. However, the effects of social density remain poorly understood in natural populations due to the difficulty of disentangling confounding influences such as climatic variation and food availability. Colonially breeding marine mammals offer a unique opportunity to study maternal effects in response to variable colony densities under similar ecological conditions. We therefore quantified maternal and offspring hormone levels in 84 Antarctic fur seals (Arctocephalus gazella) from two closely neighbouring colonies of contrasting density. Hair samples were used as they integrate hormone levels over several weeks or months and therefore represent in utero conditions during foetal development. We found significantly higher levels of cortisol and testosterone (both P < 0.001) in mothers from the high density colony, reflecting a more stressful and competitive environment. In addition, offspring testosterone showed a significant positive correlation with maternal cortisol (P < 0.05). Although further work is needed to elucidate the potential consequences for offspring fitness, these findings raise the intriguing possibility that adaptive foetal programming might occur in fur seals in response to the maternal social environment. They also lend support to the idea that hormonally mediated maternal effects may depend more strongly on the maternal regulation of androgen rather than cortisol levels

(Photo-)crosslinkable gelatin derivatives for biofabrication applications

Over the recent decades gelatin has proven to be very suitable as an extracellular matrix mimic for bio-fabrication and tissue engineering applications. However, gelatin is prone to dissolution at typical cell culture conditions and is therefore often chemically modified to introduce (photo-)crosslinkable functionalities. These modifications allow to tune the material properties of gelatin, making it suitable for a wide range of biofabrication techniques both as a bioink and as a biomaterial ink (component). The present review provides a non-exhaustive overview of the different reported gelatin modification strategies to yield crosslinkable materials that can be used to form hydrogels suitable for biofabrication applications. The different crosslinking chemistries are discussed and classified according to their mechanism including chain-growth and step-growth polymerization. The step-growth polymerization mechanisms are further classified based on the specific chemistry including different (photo-)click chemistries and reversible systems. The benefits and drawbacks of each chemistry are also briefly discussed. Furthermore, focus is placed on different biofabrication strategies using either inkjet, deposition or light-based additive manufacturing techniques, and the applications of the obtained 3D constructs

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Proteomic Analysis of Pure Human Airway Gland Mucus Reveals a Large Component of Protective Proteins

<div><p>Airway submucosal glands contribute to innate immunity and protect the lungs by secreting mucus, which is required for mucociliary clearance and which also contains antimicrobial, anti-inflammatory, anti-proteolytic and anti-oxidant proteins. We stimulated glands in tracheal trimmings from three lung donors and collected droplets of uncontaminated mucus as they formed at the gland orifices under an oil layer. We analyzed the mucus using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Analysis identified 5486 peptides and 441 proteins from across the 3 samples (269–319 proteins per subject). We focused on 269 proteins common to at least 2 0f 3 subjects, of which 102 (38%) had protective or innate immunity functions. While many of these have long been known to play such roles, for many others their cellular protective functions have only recently been appreciated in addition to their well-studied biologic functions (e.g. annexins, apolipoproteins, gelsolin, hemoglobin, histones, keratins, and lumican). A minority of the identified proteins are known to be secreted via conventional exocytosis, suggesting that glandular secretion occurs via multiple mechanisms. Two of the observed protective proteins, major vault protein and prohibitin, have not been observed in fluid from human epithelial cultures or in fluid from nasal or bronchoalveolar lavage. Further proteomic analysis of pure gland mucus may help clarify how healthy airways maintain a sterile environment.</p></div

Protein families with protective functions found in gland mucus.

<p>At least one member of these families of proteins with protective functions was found in 2–3 samples of human mucus, with (n) indicating the total number of family members found in human gland mucus. MW is shown as kDa. The full list of 102 protective proteins is found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116756#pone.0116756.s003" target="_blank">S3 Table</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116756#pone.0116756.s004" target="_blank">S4 Table</a>. Abbreviations: GBP, Galectin binding protein; DMBT-1, Deleted in malignant brain tumors 1 protein; HSC 71, Heat shock cognate 71 kDa protein; LE inhibitor, Leukocyte elastase inhibitor; PS-A2, pulmonary surfactant A2; 40S RP, 40S ribosomal proteins; and SA A-1, Serum amyloid A-1. Accession # is from the UniProt database <a href="http://www.uniprot.org/uniprot/" target="_blank">http://www.uniprot.org/uniprot/</a>.</p><p>Protein families with protective functions found in gland mucus.</p

Proteins identified in human tracheal submucosal gland mucus by LC-MS/MS.

<p><b>(A)</b> A modified Venn diagram of showing distribution of proteins among three healthy human (HN) donors. Across the 3 donors, 5486 peptides and 441 proteins were identified. Of these, 61% (269 proteins, the shaded area) and 35% (154 proteins) were found in 2–3 and all 3 HN gland mucus samples, respectively. <b>(B)</b> Among these 269 proteins, 102 (38%) were categorized as proteins with “anti”-activities: antimicrobial, antiinflammatory, antiproteolytic and antioxidant. Other biological activities include: biological regulation, metabolic/multi-organismal/developmental processes, binding activity, and establishment of localization.</p

A comparative analysis of anti-proteins of 4 airway secretions.

<p>The data represent a summary of our comparative analysis of 35 common protective HN anti-proteins in the present study to 3 other airway fluids. Abbreviations: SMG, airway submucosal gland mucus; BALF, bronchial alveolar lavage fluid; HTBE, apical fluid of primary human tracheobronchial epithelial cell culture; and NLF, nasal lavage fluid. The data from other airway fluids are referenced in the text.</p><p>A comparative analysis of anti-proteins of 4 airway secretions.</p