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Despite the well‐known association of Epstein–Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV‐infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV‐infected B cells induce T‐cell functions relevant for EAE progression. In the current study, we examined the ex vivo cross‐talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi‐) autologous EBV‐infected B‐lymphoblastoid cell lines (B‐LCLs). Results presented here demonstrate that infection with EBV B95‐8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co‐stimulation to T cells. At the cellular level, we observed that MNC co‐culture with B‐LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B‐LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL‐23R and CCR6, which coincided with enhanced IL‐17A production. These results highlight the profound impact that EBV‐infected B‐LCL cells can have on second and third co‐stimulatory signals involved in (autoreactive) T‐cell activation. Multiple sclerosis: Understanding how a virus evades immune responses Research on marmoset white blood cells is helping to elaborate the link between a herpes virus and multiple sclerosis (MS). Yolanda Kap of the Biomedical Primate Research Centre, Rijswijk, The Netherlands and colleagues examined the mechanisms behind a poorly understood but well supported association between MS and Epstein‐Barr virus (EBV). This common virus causes infectious mononucleosis, among other diseases. They examined signalling between T cells and EBV‐infected B cells derived from marmosets with an induced autoimmune inflammation of the brain and spinal cord that resembles MS in humans. The results show EBV‐infected B cells may escape immune defences by causing alterations in T cells and by affecting their activation. EBV infection of B cells increased the expression of nearly 3,000 genes and decreased the expression of more than 2,500 others.

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson’s disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson’s disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.

Mycelium and mycelium-biomass composites are emerging as new sustainable materials with useful flame-retardant potentials. Here we report a detailed characterisation of the thermal degradation and fire properties of fungal mycelium and mycelium-biomass composites. Measurements and analyses are carried out on key parameters such as decomposition temperatures, residual char, and gases evolved during pyrolysis. Pyrolysis flow combustion calorimetry (PCFC) evaluations reveal that the corresponding combustion propensity of mycelium is significantly lower compared to poly(methyl methacrylate) (PMMA) and polylactic acid (PLA), indicating that they are noticeably less prone to ignition and flaming combustion, and therefore safer to use. The hyphal diameters of mycelium decrease following pyrolysis. Cone calorimetry testing results show that the presence of mycelium has a positive influence on the fire reaction properties of wheat grains. This improvement is attributable to the relatively higher charring tendency of mycelium compared to wheat grain, which reduces the heat release rate (HRR) by acting as a thermal insulator and by limiting the supply of combustible gases to the flame front. The mycelium growth time has been found to yield no significant improvements in the fire properties of mycelium-wheat grain composites.

Anopheles stephensi is the most menacing malaria vector to watch for in newly urbanising parts of the world. Its fitness is reported to be a direct consequence of the vector adapting to laying eggs in over-head water tanks with street-side water puddles polluted by oil and sewage. Large frequent inversions in the genome of malaria vectors are implicated in adaptation. We report the genome assembly of a strain of An. stephensi of the type-form, collected from a construction site from Chennai (IndCh) in 2016. The genome reported here with a L50 of 4, completes the trilogy of high-resolution genomes of strains with respect to a 16.5 Mbp 2R b genotype in An. stephensi known to be associated with adaptation to environmental heterogeneity. Unlike the reported genomes of two other strains, STE2 (2R+ b /2R b ) and UCI (2R b /2R b ), IndCh is found to be homozygous for the standard form (2R+ b /2R+ b ). Comparative genome analysis revealed base-level details of the breakpoints and allowed extraction of 22,650 segregating SNPs for typing this inversion in populations. Whole genome sequencing of 82 individual mosquitoes from diverse geographical locations reveal that one third of both wild and laboratory populations maintain the heterozygous genotype of 2R b . The large number of SNPs can be tailored to 1740 exonic SNPs enabling genotyping directly from transcriptome sequencing. The genome trilogy approach accelerated the study of fine structure and typing of an important inversion in An. stephensi , putting the genome resources for this understudied species on par with the extensively studied malaria vector, Anopheles gambiae . We argue that the IndCh genome is relevant for field translation work compared to those reported earlier by showing that individuals from diverse geographical locations cluster with IndCh, pointing to significant convergence resulting from travel and commerce between cities, perhaps, contributing to the survival of the fittest strain.

Polycystic ovary syndrome (PCOS) is indeed one of the most common gynecological endocrine disorders, affecting a significant number of females in their reproductive age. While the exact cause of PCOS is not fully understood, several factors are believed to contribute to its onset. The relationship between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation is complex and not fully understood. While there is evidence to suggest an association between PCOS and inflammation, the exact cause and causal nature of this relationship are still under investigation. Several inflammatory markers, including IL-6 (interleukin-6), TNF-[alpha] (tumor necrosis factor-alpha), IL-17 (interleukin-17), CRP (C-reactive protein), NLR (neutrophil-to-lymphocyte ratio), and PLR (platelet-to-lymphocyte ratio), have been studied about PCOS. These markers are substances produced by the immune system in response to inflammation. Increased levels of IL-17, IL-1, and IL-8 were correlated with PCO. CRP to albumin ratio can be employed as a precise bio-marker for PCOS. The neutrophil-to-lymphocyte ratio (NLR) indicates poor cardiovascular health and metabolic syndrome (MS) and can be considered a negative regulator for FSH which indirectly stimulates testosterone production. Platelet/lymphocyte ratio (PLR) and mean platelet volume (MPV) are also recently found to be associated with PCOS. The literature explaining the underlying mechanisms with specific inflammatory markers and how inflammation relates to PCOS will be highlighted in this review article. It will also discuss the roles of inflammation and the association of different inflammatory markers in the pathogenesis of PCOS, which may usher in a new era in the treatment approach for PCOS.

Inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice to treat inflammatory disorders, with three PDE4 inhibitors currently in clinical use as therapeutics for psoriasis, psoriatic arthritis, atopic dermatitis and chronic obstructive pulmonary disease. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. It was shown that PDE8A plays a major role in controlling T cell and breast cancer cell motility, including adhesion to endothelial cells under physiological shear stress and chemotaxis. This is a unique function of PDE8 not shared by PDE4, another cAMP specific PDE, employed, as noted, as an anti-inflammatory therapeutic. Additionally, a regulatory role was shown for the PDE8A-rapidly accelerated fibrosarcoma (Raf)-1 kinase signaling complex in myelin antigen reactive CD4 + effector T cell adhesion and locomotion by a mechanism differing from that of PDE4. The PDE8A-Raf-1 kinase signaling complex affects T cell motility, at least in part, via regulating the LFA-1 integrin mediated adhesion to ICAM-1. The findings that PDE8A and its isoforms are expressed at higher levels in naive and myelin oligodendrocyte glycoprotein (MOG) 35 – 55 activated effector T (Teff) cells compared to regulatory T (Treg) cells and that PDE8 inhibition specifically affects MOG 35 – 55 activated Teff cell adhesion, indicates that PDE8A could represent a new beneficial target expressed in pathogenic Teff cells in CNS inflammation. The implications of this work for targeting PDE8 in inflammation will be discussed in this review.

After decades of development, inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice for the treatment of inflammatory disorders, with three PDE4 inhibitors being in clinical use as therapeutics for psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease and atopic dermatitis. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. We have previously demonstrated a role for the PDE8A-Raf-1 kinase complex in the regulation of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) activated CD4+ effector T cell adhesion and locomotion by a mechanism that differs from PDE4 activity. In this study, we explored the in vivo treatment of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) induced in mice immunized with MOG using the PDE8-selective inhibitor PF-04957325. For treatment in vivo, mice with EAE were either subcutaneously (s.c.) injected three times daily (10 mg/kg/dose), or were implanted subcutaneously with Alzet mini-osmotic pumps to deliver the PDE8 inhibitor (15.5 mg/kg/day). The mice were scored daily for clinical signs of paresis and paralysis which were characteristic of EAE. We observed the suppression of the clinical signs of EAE and a reduction of inflammatory lesion formation in the CNS by histopathological analysis through the determination of the numbers of mononuclear cells isolated from the spinal cord of mice with EAE. The PDE8 inhibitor treatment reduces the accumulation of both encephalitogenic Th1 and Th17 T cells in the CNS. Our study demonstrates the efficacy of targeting PDE8 as a treatment of autoimmune inflammation in vivo by reducing the inflammatory lesion load.

The Radar for Europa Assessment and Sounding: Ocean to Near-surface (REASON) is a dual-frequency ice-penetrating radar (9 and 60 MHz) onboard the Europa Clipper mission. REASON is designed to probe Europa from exosphere to subsurface ocean, contributing the third dimension to observations of this enigmatic world. The hypotheses REASON will test are that (1) the ice shell of Europa hosts liquid water, (2) the ice shell overlies an ocean and is subject to tidal flexing, and (3) the exosphere, near-surface, ice shell, and ocean participate in material exchange essential to the habitability of this moon. REASON will investigate processes governing this material exchange by characterizing the distribution of putative non-ice material (e.g., brines, salts) in the subsurface, searching for an ice–ocean interface, characterizing the ice shell’s global structure, and constraining the amplitude of Europa’s radial tidal deformations. REASON will accomplish these science objectives using a combination of radar measurement techniques including altimetry , reflectometry , sounding , interferometry , plasma characterization , and ranging . Building on a rich heritage from Earth, the moon, and Mars, REASON will be the first ice-penetrating radar to explore the outer solar system. Because these radars are untested for the icy worlds in the outer solar system, a novel approach to measurement quality assessment was developed to represent uncertainties in key properties of Europa that affect REASON performance and ensure robustness across a range of plausible parameters suggested for the icy moon. REASON will shed light on a never-before-seen dimension of Europa and – in concert with other instruments on Europa Clipper – help to investigate whether Europa is a habitable world.

Nanoparticles show great promise as a platform for developing vaccines for the prevention of infectious disease. We have been investigating a method whereby nanocapsules can be formulated from protein, such that the final capsules contain only the cross-linked protein itself. Such nanocapsules are made using a silica templating system and can be customised in terms of size and porosity. Here we compare the construction and characteristics of nanocapsules from four different proteins: one a model protein (ovalbumin) and three from infectious disease pathogens, namely the influenza virus, Helicobacter pylori and HIV. Two of the nanocapsules were assessed further. We confirm that nanocapsules constructed from the urease A subunit of H. pylori can reduce subsequent infection in a vaccinated mouse model. Further, we show that capsules constructed from the HIV gp120 protein can be taken up by dendritic cells in tissue culture and can be recognised by antibodies raised against the virus. These results point to the utility of this method in constructing protein-only nanocapsules from proteins of varying sizes and isoelectric points.

Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs. regulatory T (Treg) cells and controls CD4(+) Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4(+) Teff cell populations in vivo. Using magnetic bead separation to purify leukocyte populations from the lung draining hilar lymph node (HLN) in a mouse model of ovalbumin-induced allergic airway disease (AAD), we found by Western immunoblot and quantitative (q)RT-PCR that PDE8A protein and gene expression are enhanced in the CD4(+) T cell fraction over the course of the acute inflammatory disease and recede at the late tolerant non-inflammatory stage. To evaluate PDE8A as a potential drug target, we compared the selective and combined effects of the recently characterized highly potent PDE8-selective inhibitor PF-04957325 with the PDE4-selective inhibitor piclamilast (PICL). As previously shown, PF-04957325 suppresses T cell adhesion to endothelial cells. In contrast, we found that PICL alone increased firm T cell adhesion to endothelial cells by ~20% and significantly abrogated the inhibitory effect of PF-04957325 on T cell adhesion by over 50% when cells were co-exposed to PICL and PF-04957325. Despite its robust effect on T cell adhesion, PF-04957325 was over two orders of magnitude less efficient than PICL in suppressing polyclonal Teff cell proliferation, and showed no effect on cytokine gene expression in these cells. More importantly, PDE8 inhibition did not suppress proliferation and cytokine production of myelin-antigen reactive proinflammatory Teff cells in vivo and in vitro. Thus, targeting PDE8 through PF-04957325 selectively regulates Teff cell interactions with endothelial cells without marked immunosuppression of proliferation, while PDE4 inhibition has partially opposing effects. Collectively, our data identify PF-04957325 as a novel function-specific tool for the suppression of Teff cell adhesion and indicate that PDE4 and PDE8 play unique and non-redundant roles in the control of Teff cell functions.