Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62

ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based small molecule analogues (SMAs) was synthesised. Four sulfone-containing SMAs termed 11a, 11e, 11i and 12b were found to reduce mouse bone marrow-derived dendritic cell (DC) pathogen-associated molecular pattern (PAMP)-induced pro-inflammatory cytokine production, inhibit NF-κB p65 activation, and suppress LPS-induced up-regulation of CD40 and CD86. Active SMAs also resulted in a DC phenotype that exhibited reduced capacity to prime antigen (Ag)-specific IFN-γ production during co-culture with naïve transgenic TCR DO.11.10 T cells in vitro and reduced their ability, following adoptive transfer, to prime the expansion of Ag-specific T lymphocytes, specifically TH17 cells, in vivo. Consistent with this, mice receiving DCs treated with SMAs exhibited significantly reduced severity of collagen-induced arthritis and this was accompanied by a significant reduction in IL-17+ cells in the draining lymph nodes. Collectively, these studies indicate that drug-like compounds that target DCs can be designed from parasitic worm products and demonstrate the potential for ES-62 SMA-based DC therapy in inflammatory disease

Development of acanthocheilonema viteae in meriones shawi : absence of microfilariae and production of active ES-62

Aims: ES-62 is a well-studied anti-inflammatory molecule secreted by L4-adult stage Acanthocheilonema viteae. We maintain the life cycle of A viteae using Meriones libycus as the definitive host. Here, we investigated whether the full life cycle could be maintained, and functional ES-62 produced, in a related jird species—Meriones shawi. Methods and Results: Adult worms were produced in comparable numbers in the two species, but very few microfilariae (MF) were observed in the M shawi bloodstream. M shawi ES-62 produced ex vivo was functional and protective in a mouse model of arthritis. Myeloid-derived cells from naïve and infected jirds of both species were compared with respect to ROS production and osteoclast generation, and some differences between the two species in both the absence and presence of infection were observed. Conclusions: The life cycle of A viteae cannot be successfully completed in M shawi jirds but L3 stage worms develop to adulthood and produce functional ES-62. Preliminary investigation into jird immune responses suggests that infection can differentially modulate myeloid responses in the two species. However, species-specific reagents are required to understand the complex interplay between A viteae and its host and to explain the lack of circulating MF in infected M shawi jirds

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

Improvements in hygiene and health management have driven significant increases in human lifespan over the last 50 years. Frustratingly however, this extension of lifespan has not been matched by equivalent improvements in late-life health, not least due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, all ageing-associated conditions exacerbated and accelerated by widespread adoption of the high calorie Western diet (HCD). Recently, evidence has begun to emerge that parasitic worm infection might protect against such ageing-associated co-morbidities, as a serendipitous side-effect of their evolution of pro-survival, anti-inflammatory mechanisms. As a novel therapeutic strategy, we have therefore investigated the potential of ES-62, an anti-inflammatory secreted product of the filarial nematode Acanthocheilonema viteae, to improve healthspan (the period of life before diseases of ageing appear) by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We administered ES-62 subcutaneously (at a dose of 1 μg/week) to C57BL/6J mice undergoing HCD-accelerated ageing throughout their lifespan, while subjecting the animals to analysis of 120 immunometabolic responses at various time-points. ES-62 improved a number of inflammatory parameters, but markedly, a range of pathophysiological, metabolic and microbiome parameters of ageing were also successfully targeted. Notably, ES-62-mediated promotion of healthspan in male and female HCD-mice was associated with different mechanisms and reflecting this, machine learning modelling identified sex-specific signatures predictive of ES-62 action against HCD-accelerated ageing. Remarkably, ES-62 substantially increased the median survival of male HCD-mice. This was not the case with female animals and unexpectedly, this difference between the two sexes could not be explained in terms of suppression of the chronic inflammation driving ageing, as ES-62 tended to be more effective in reducing this in female mice. Rather, the difference appeared to be associated with ES-62's additional ability to preferentially promote a healthier gut-metabolic tissue axis in male animals

Deceased Organ Donors With a History of Increased Risk Behavior for the Transmission of Blood-Borne Viral Infection: The UK Experience.

BACKGROUND: Deceased organ donors are routinely screened for behaviors that increase the risk of transmissible blood-borne viral (BBV) infection, but the impact of this information on organ donation and transplant outcome is not well documented. Our aim was to establish the impact of such behavior on organ donation and utilization, as well transplant recipient outcomes. METHODS: We identified all UK deceased organ donors from 2003 to 2015 with a disclosed history of increased risk behavior (IRB) including intravenous drug use (IVDU), imprisonment and increased risk sexual behavior. RESULTS: Of 17 262 potential donors, 659 (3.8%) had IRB for BBV and 285 (1.7%) were seropositive for BBV, of whom half had a history of IRB (mostly IVDU [78.5%]). Of actual donors with IRB, 393 were seronegative for viral markers at time of donation. A history of recent IVDU was associated with fewer potential donors proceeding to become actual organ donors (64% vs 75%, P = 0.007). Donors with IRB provided 1091 organs for transplantation (624 kidneys and 467 other organs). Transplant outcome was similar in recipients of organs from donors with and without IRB. There were 3 cases of unexpected hepatitis C virus transmission, all from an active IVDU donor who was hepatitis C virus seronegative at time of donation, but was found to be viremic on retrospective testing. CONCLUSIONS: Donors with a history of IRB provide a valuable source of organs for transplantation with good transplant outcomes and there is scope for increasing the use of organs from such donors.The National Institute of Health Research, Blood and Transplant Research Unit (NIHR BTRU) on Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership funded this research with NHS Blood and Transplant (NHSBT)

The role of individual protein kinase C isoforms in mouse mast cell function and their targeting by the immunomodulatory parasitic worm product, ES-62

ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, has been shown to modulate the immune system through subversion of signal transduction pathways operating in various immune system cells. With respect to human bone marrow-derived mast cells (BMMCs), ES-62 was previously shown to inhibit FcϵRI-mediated mast cell functional responses such as degranulation and pro-inflammatory cytokine release through a mechanism involving the degradation of PKC-α. At the same time, it was noted that the worm product was able to degrade certain other PKC isoforms but the significance of this was uncertain. In this study, we have employed PKC isoform KO mice to investigate the role of PKC-α, -β -ϵ, and -θ in mouse BMMCs in order to establish their involvement in mast cell-mediated responses and also, if their absence impacts on ES-62’s activity. The data obtained support that in response to antigen cross-linking of IgE bound to FcϵRI, pro-inflammatory cytokine release is controlled in part by a partnership between one conventional and one novel isoform with PKC-α and -θ acting as positive regulators of IL-6 and TNF-α production, while PKC-β and ϵ act as negative regulators of such cytokines. Furthermore, ES-62 appears to target certain other PKC isoforms in addition to PKC-α to inhibit cytokine release and this may enable it to more efficiently inhibit mast cell responses

Ultrasensitive PCR system for HBV DNA detection: Risk stratification for occult hepatitis B virus infection in English blood donors

Occult hepatitis B (HBV) infection (OBI), characterized by low viral loads, accounts for much of the risk of HBV transfusion-transmitted infection. With anticore antibodies (anti-HBc) screening introduced in England, the imperative to identify OBI donors has increased. We aimed to develop an ultra-sensitive PCR system and investigate risk factors for HBV DNA presence in blood donations. Seven extraction methods and three PCR assays were compared. The optimal system was sought to determine HBV DNA presence in anti-HBc-positive donations. Predictors of DNA positivity were subsequently investigated. Extraction from 5 mL of plasma increased sample representation and resulted in HBV DNA detection in low viral load samples (~0.5 IU/mL). Screening of 487 763 donations in 2022 identified two OBI donors and 2042 anti-HBc-positive donors, 412 of the latter with anti-HBs < 100 mIU/mL. Testing of 134 anti-HBc-positive donations utilizing the 5 mL extraction method identified two further HBV DNA-positive donations. Higher anti-HBc titer and anti-HBs negativity were significant predictors of DNA detectability in anti-HBc-positive donations. An ultrasensitive PCR assay identified potentially infectious donations increasing HBV DNA detection in anti-HBc-positive donors from 0.5% to 1.9%. Anti-HBc titers may further complement the risk stratification for DNA positivity in anti-HBc screening and minimize unnecessary donor deferral

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

The CMS Phase-1 pixel detector upgrade

The CMS detector at the CERN LHC features a silicon pixel detector as its innermost subdetector. The original CMS pixel detector has been replaced with an upgraded pixel system (CMS Phase-1 pixel detector) in the extended year-end technical stop of the LHC in 2016/2017. The upgraded CMS pixel detector is designed to cope with the higher instantaneous luminosities that have been achieved by the LHC after the upgrades to the accelerator during the first long shutdown in 2013–2014. Compared to the original pixel detector, the upgraded detector has a better tracking performance and lower mass with four barrel layers and three endcap disks on each side to provide hit coverage up to an absolute value of pseudorapidity of 2.5. This paper describes the design and construction of the CMS Phase-1 pixel detector as well as its performance from commissioning to early operation in collision data-taking.Peer reviewe

Commissioning and performance of the CMS pixel tracker with cosmic ray muons

This is the Pre-print version of the Article. The official published verion of the Paper can be accessed from the link below - Copyright @ 2010 IOPThe pixel detector of the Compact Muon Solenoid experiment consists of three barrel layers and two disks for each endcap. The detector was installed in summer 2008, commissioned with charge injections, and operated in the 3.8 T magnetic field during cosmic ray data taking. This paper reports on the first running experience and presents results on the pixel tracker performance, which are found to be in line with the design specifications of this detector. The transverse impact parameter resolution measured in a sample of high momentum muons is 18 microns.This work is supported by FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTDS (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)