TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Phylogeny, biogeography and diversification patterns of side-necked turtles (Testudines: Pleurodira)

Pleurodires or side-necked turtles are today restricted to freshwater environments of South America, Africa– Madagascar and Australia, but in the past they were distributed much more broadly, being found also on Eurasia, India and North America, and marine environments. Two hypotheses were proposed to explain this distribution; in the first, vicariance would have shaped the current geographical distribution and, in the second, extinctions constrained a previously widespread distribution. Here, we aim to reconstruct pleurodiran biogeographic history and diversification patterns based on a new phylogenetic hypothesis recovered from the analysis of the largest morphological dataset yet compiled for the lineage, testing which biogeographical process prevailed during its evolutionary history. The resulting topology generally agrees with previous hypotheses of the group and shows that most diversification shifts were related to the exploration of new niches, e.g. littoral or marine radiations. In addition, as other turtles, pleurodires do not seem to have been much affected by either the Cretaceous– Palaeogene or the Eocene–Oligocene mass extinctions. The biogeographic analyses highlight the predominance of both anagenetic and cladogenetic dispersal events and support the importance of transoceanic dispersals as a more common driver of area changes than previously thought, agreeing with previous studies with other non-turtle lineages.Fil: Ferreira, Gabriel S.. Universidade de Sao Paulo; Brasil. Senckenberg Centre For Human Evolution And Palaeoenvironment; Alemania. Universität Tübingen; AlemaniaFil: Bronzati Filho, Mario. Bayerische Staatssammlung für Paläontologie und Geologie; AlemaniaFil: Langer, Max C.. Universidade de Sao Paulo; BrasilFil: Sterli, Juliana. Museo Paleontológico Egidio Feruglio; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Parametric study of EEG sensitivity to phase noise during face processing

<b>Background: </b> The present paper examines the visual processing speed of complex objects, here faces, by mapping the relationship between object physical properties and single-trial brain responses. Measuring visual processing speed is challenging because uncontrolled physical differences that co-vary with object categories might affect brain measurements, thus biasing our speed estimates. Recently, we demonstrated that early event-related potential (ERP) differences between faces and objects are preserved even when images differ only in phase information, and amplitude spectra are equated across image categories. Here, we use a parametric design to study how early ERP to faces are shaped by phase information. Subjects performed a two-alternative force choice discrimination between two faces (Experiment 1) or textures (two control experiments). All stimuli had the same amplitude spectrum and were presented at 11 phase noise levels, varying from 0% to 100% in 10% increments, using a linear phase interpolation technique. Single-trial ERP data from each subject were analysed using a multiple linear regression model. <b>Results: </b> Our results show that sensitivity to phase noise in faces emerges progressively in a short time window between the P1 and the N170 ERP visual components. The sensitivity to phase noise starts at about 120–130 ms after stimulus onset and continues for another 25–40 ms. This result was robust both within and across subjects. A control experiment using pink noise textures, which had the same second-order statistics as the faces used in Experiment 1, demonstrated that the sensitivity to phase noise observed for faces cannot be explained by the presence of global image structure alone. A second control experiment used wavelet textures that were matched to the face stimuli in terms of second- and higher-order image statistics. Results from this experiment suggest that higher-order statistics of faces are necessary but not sufficient to obtain the sensitivity to phase noise function observed in response to faces. <b>Conclusion: </b> Our results constitute the first quantitative assessment of the time course of phase information processing by the human visual brain. We interpret our results in a framework that focuses on image statistics and single-trial analyses

Potentially malignant disorders revisited-The lichenoid lesion/proliferative verrucous leukoplakia conundrum

Background: Clinically identifiable potentially malignant disorders (PMD) precede oral squamous cell carcinoma development. Oral lichenoid lesions (OLL) and proliferative verrucous leukoplakia (PVL) are specific precursor lesions believed to exhibit both treatment resistance and a high risk of malignant transformation (MT). Methods: A retrospective review of 590 PMD patients treated in Northern England by CO2 laser surgery between 1996 and 2014 was carried out. Lesions exhibiting lichenoid or proliferative verrucous features were identified from the patient database and their clinicopathological features and outcome post-treatment determined at the study census date of 31 December 2014. Results: One hundred and 98 patients were identified as follows: 118 OLL and 80 PVL, most frequently leukoplakia at ventrolateral tongue and floor of mouth sites, equally distributed between males and females. Most exhibited dysplasia on incision biopsy (72% OLL; 85% PVL) and were treated by laser excision rather than ablation (88.1% OLL; 86.25% PVL). OLL were more common in younger patients (OLL 57.1 year; PVL 62.25 years; P =.008) and more likely than PVL to present as erythroleukoplakia (OLL 15.3%; PVL 2.5%; P =.003). Whilst no significant difference was seen between OLL and PVL achieving disease-free status (69.5% and 65%, respectively; P =.55), this was less than the overall PMD cohort (74.2%). MT was identified in 2 OLL (1.7%) and 2 PVL (2.5%) during follow-up. Conclusion: One-third of PMD cases showed features of OLL or PVL, probably representing a disease presentation continuum. Post-treatment disease-free status was less common in OLL and PVL, although MT was infrequent

Exclusive neuronal expression of SUCLA2 in the human brain

SUCLA2 encodes the ATP-forming subunit (A-SUCL-) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL- immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming subunit (G-SUCL-) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL- immunoreactivity that was however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex

Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events

Peer reviewedPublisher PD

Installing hydrolytic activity into a completely <i>de novo </i>protein framework

The design of enzyme-like catalysts tests our understanding of sequence-to-structure/function relationships in proteins. Here we install hydrolytic activity predictably into a completely de novo and thermostable α-helical barrel, which comprises seven helices arranged around an accessible channel. We show that the lumen of the barrel accepts 21 mutations to functional polar residues. The resulting variant, which has cysteine–histidine–glutamic acid triads on each helix, hydrolyses p-nitrophenyl acetate with catalytic efficiencies that match the most-efficient redesigned hydrolases based on natural protein scaffolds. This is the first report of a functional catalytic triad engineered into a de novo protein framework. The flexibility of our system also allows the facile incorporation of unnatural side chains to improve activity and probe the catalytic mechanism. Such a predictable and robust construction of truly de novo biocatalysts holds promise for applications in chemical and biochemical synthesis

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3&gt;2.1×10-12¿¿s/eV at 90% C.L

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Particle emission characteristics of a gas turbine with a double annular combustor

The total climate, air quality and health impact of aircraft black carbon (BC) emissions depends on quantity (mass and number concentration), as well as morphology (fractal dimension and surface area) of emitted BC aggregates. This study examines multiple BC emission metrics from a gas turbine with a double annular combustor, CFM56-5B4-2P. As a part of the SAMPLE III.2 campaign, concurrent measurements of particle mobility, particle mass, particle number concentration and mass concentration, as well as collection of transmission electron microscopy (TEM) samples, allowed for characterization of the BC emissions. Mass- and number-based emission indices were strongly influenced by thrust setting during pilot combustion and ranged from <1 to 208 mg/kg-fuel and 3×1012 to 3×1016 particles/kg-fuel, respectively. Mobility measurements indicated that mean diameters ranged from 7-44 nm with a strong dependence on thrust during pilot-only combustion. Using aggregation and sintering theory with empirical effective density relationships, a power law relationship between primary particle diameter and mobility diameter is presented. Mean primary particle diameter ranged from 6-19 nm, however, laser induced incandescence (LII) and mass-mobility calculated primary particle diameters demonstrated opposite trends with thrust setting. Similarly, mass-mobility-calculated aggregate mass specific surface area and LII-measured surface area were not in agreement, indicating both methods need further development and validation before use as quantitative indicators of primary particle diameter and mass-specific surface area.The authors express their gratitude to a number of people and organizations in helping to plan, conduct, finance and provide instruments for this measurement campaign. The 537 European Aviation Safety Agency (EASA) funded the SAMPLE III SC02 campaign (EASA.2010.FC.10, Specific Contract No: SC02). The Federal Office of Civil Aviation, Switzerland (FOCA) was critical in for providing additional financial support and arranging facilities which made this study possible. We also thank the SR Technics test bed staff, including Frithjof Siegerist, for operating the engines and enabling access to the test facility. We thank AVL, Cambustion, Grimm & TSI supplying both instruments and expertise.This is the author accepted manuscript. The final version is available from Taylor & Francis via http://dx.doi.org/10.1080/02786826.2015.107845