Star-forming cores embedded in a massive cold clump: Fragmentation, collapse and energetic outflows

The fate of massive cold clumps, their internal structure and collapse need to be characterised to understand the initial conditions for the formation of high-mass stars, stellar systems, and the origin of associations and clusters. We explore the onset of star formation in the 75 M_sun SMM1 clump in the region ISOSS J18364-0221 using infrared and (sub-)millimetre observations including interferometry. This contracting clump has fragmented into two compact cores SMM1 North and South of 0.05 pc radius, having masses of 15 and 10 M_sun, and luminosities of 20 and 180 L_sun. SMM1 South harbours a source traced at 24 and 70um, drives an energetic molecular outflow, and appears supersonically turbulent at the core centre. SMM1 North has no infrared counterparts and shows lower levels of turbulence, but also drives an outflow. Both outflows appear collimated and parsec-scale near-infrared features probably trace the outflow-powering jets. We derived mass outflow rates of at least 4E-5 M_sun/yr and outflow timescales of less than 1E4 yr. Our HCN(1-0) modelling for SMM1 South yielded an infall velocity of 0.14 km/s and an estimated mass infall rate of 3E-5 M_sun/yr. Both cores may harbour seeds of intermediate- or high-mass stars. We compare the derived core properties with recent simulations of massive core collapse. They are consistent with the very early stages dominated by accretion luminosity.Comment: Accepted for publication in ApJ, 14 pages, 7 figure

Structural and ultrastructural alterations in human olfactory pathways and possible associations with herpesvirus 6 infection

Publisher Copyright: © 2017 Skuja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Structural and ultrastructural alterations in human olfactory pathways and putative associations with human herpesvirus 6 (HHV-6) infection were studied. The olfactory bulb/tract samples from 20 subjects with an unspecified encephalopathy determined by pathomorphological examination of the brain autopsy, 17 healthy age-matched and 16 younger controls were used. HHV-6 DNA was detected in 60, 29, and 19% of cases in these groups, respectively. In the whole encephalopathy group, significantly more HHV-6 positive neurons and oligodendrocytes were found in the gray matter, whereas, significantly more HHV-6 positive astrocytes, oligodendrocytes, microglia/macrophages and endothelial cells were found in the white matter. Additionally, significantly more HHV-6 positive astrocytes and, in particular, oligodendrocytes were found in the white matter when compared to the gray matter. Furthermore, when only HHV-6 PCR+ encephalopathy cases were studied, we observed similar but stronger associations between HHV-6 positive oligodendrocytes and CD68 positive cells in the white matter. Cellular alterations were additionally evidenced by anti-S100 immunostaining, demonstrating a significantly higher number of S100 positive cells in the gray matter of the whole encephalopathy group when compared to the young controls, and in the white matter when compared to both control groups. In spite the decreased S100 expression in the PCR+ encephalopathy group when compared to PCR- cases and controls, groups demonstrated significantly higher number of S100 positive cells in the white compared to the gray matter. Ultrastructural changes confirming the damage of myelin included irregularity of membranes and ballooning of paranodal loops. This study shows that among the cellular targets of the nervous system, HHV-6 most severely affects oligodendrocytes and the myelin made by them.publishersversionPeer reviewe

Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells

Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration

Varicella zoster virus (VZV) is a highly prevalent human pathogen that establishes latency in neurons of the peripheral nervous system. Primary infection causes varicella whereas reactivation results in zoster, which is often followed by chronic pain in adults. Following infection of epithelial cells in the respiratory tract, VZV spreads within the host by hijacking leukocytes, including T cells, in the tonsils and other regional lymph nodes, and modifying their activity. In spite of its importance in pathogenesis, the mechanism of dissemination remains poorly understood. Here we addressed the influence of VZV on leukocyte migration and found that the purified recombinant soluble ectodomain of VZV glycoprotein C (rSgC) binds chemokines with high affinity. Functional experiments show that VZV rSgC potentiates chemokine activity, enhancing the migration of monocyte and T cell lines and, most importantly, human tonsillar leukocytes at low chemokine concentrations. Binding and potentiation of chemokine activity occurs through the C-terminal part of gC ectodomain, containing predicted immunoglobulin-like domains. The mechanism of action of VZV rSgC requires interaction with the chemokine and signalling through the chemokine receptor. Finally, we show that VZV viral particles enhance chemokine-dependent T cell migration and that gC is partially required for this activity. We propose that VZV gC activity facilitates the recruitment and subsequent infection of leukocytes and thereby enhances VZV systemic dissemination in humans

Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

This is the author accepted manuscript. the final version is available from the American Association for Cancer Research via the DOI in this recordData Availability: All raw data used in this study is publicly available. Previously published CIS gene expression and methylation data is stored on GEO under accession number GSE108124; matched stromal gene expression data is stored under accession number GSE133690. Previously published CIS whole genome sequencing data is available from the European Genome Phenome Archive (https://www.ebi.ac.uk/ega/) under accession number EGAD00001003883. Annotated H&E images of all samples used for lymphocyte quantification were deposited to the Image Data Resource (https://idr.openmicroscopy.org) under accession number idr0082.Code Availability: All code used in our analysis will be made available at http://github.com/ucl446 respiratory/cis_immunology on publication. All software information, and parameters used in our analysis can be found here.Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27-CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426

Massively Parallel Reasoning

this article we do not distinguish between connectionist systems and artificial neural networks. We prefer the term connectionist system as it expresses the fact that we are dealing with a computational model, where most of the knowledge is encoded in the connections between simple computing units. c fl 1998 Kluwer Academic Publishers. Printed in the Netherlands. entwurf.tex; 18/02/1998; 14:09; p.1 2 There is a straightforward relation between propositional logic and symmetric networks. E.g., Pinkas showed that finding a global minimum of a symmetric network corresponds precisely to finding a model for a propositional logic formula and vice versa (Pin91). However, in a symmetric network one unit is updated and eventually flipped at a time as otherwise the network is not guaranteed to converge to a global minimum. This kind of sequential behavior is inadequate for certain propositional logic formulas and we will show in Section 3 how this problem can be solved. The development of connectionist models which go beyond propositional logic has turned out to be extremely difficult, and no such connectionist model is known so far. Besides technical problems like the variable binding problem or the problem of representing potentially infinite structures, the difficulties are ultimately linked to the fact that predicate logic is undecidable. Typically, connectionist models aiming at going beyond propositional logic are structured connectionist networks using local coding (see e.g. (LD89; SA93; Hol93)). To handle the undecidability of predicate logic, however, such networks have to be able to extend their topology during the inference process. Although recruitment learning (Fel82) can potentially cope with such problems, we are unaware of any application of recruitment learning..

A Recursive Neural Network for Reflexive Reasoning

We formally specify a connectionist system for generating the least model of a datalogic program which uses linear time and space. The system is shown to be sound and complete if only unary relation symbols are involved and complete but unsound otherwise. For the latter case a criteria is defined which guarantees correctness. Finally, we compare our system to the forward reasoning version of Shruti

A crucial role for B cells in neuroinvasive scrapie

Although prion proteins are most efficiently propagated through intracerebral inoculation, peripheral administration has caused the diseases kuru, iatrogenic Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) and new-variant CJD. The development of neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system. Here we investigate the identity of these cells by using a panel of immune-deficient mice inoculated with prions intraperitoneally: we found that defects affecting only T lymphocytes had no apparent effect, but that all mutations that disrupted the differentiation and response of B lymphocytes prevented the development of clinical scrapie. As an absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells, a lack of any of these three components may prevent the development of clinical scrapie. However, we found that scrapie developed after peripheral inoculation in mice expressing immunoglobulins that were exclusively of the M subclass and without detectable specificity for the normal form of the prion PrPC, and in mice which had differentiated B cells but no functional follicular dendritic cells. We conclude that differentiated B cells are crucial for neuroinvasion by scrapie, regardless of the specificity of their receptors