MHC-linked and un-linked class I genes in the wallaby

Background: MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions. However, there is a fundamental difference between the organization of class I genes in mammals and non-mammals. Non-mammals have a single classical gene responsible for antigen presentation, which is linked to the antigen processing genes, including TAP. This organization allows co-evolution of advantageous class Ia/ TAP haplotypes. In contrast, mammals have multiple classical genes within the MHC, which are separated from the antigen processing genes by class III genes. It has been hypothesized that separation of classical class I genes from antigen processing genes in mammals allowed them to duplicate. We investigated this hypothesis by characterizing the class I genes of the tammar wallaby, a model marsupial that has a novel MHC organization, with class I genes located within the MHC and 10 other chromosomal locations. Results: Sequence analysis of 14 BACs containing 15 class I genes revealed that nine class I genes, including one to three classical class I, are not linked to the MHC but are scattered throughout the genome. Kangaroo Endogenous Retroviruses (KERVs) were identified flanking the MHC un-linked class I. The wallaby MHC contains four non-classical class I, interspersed with antigen processing genes. Clear orthologs of non-classical class I are conserved in distant marsupial lineages. Conclusion: We demonstrate that classical class I genes are not linked to antigen processing genes in the wallaby and provide evidence that retroviral elements were involved in their movement. The presence of retroviral elements most likely facilitated the formation of recombination hotspots and subsequent diversification of class I genes. The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens. The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function

The tammar wallaby major histocompatibility complex shows evidence of past genomic instability

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The major histocompatibility complex (MHC) is a group of genes with a variety of roles in the innate and adaptive immune responses. MHC genes form a genetically linked cluster in eutherian mammals, an organization that is thought to confer functional and evolutionary advantages to the immune system. The tammar wallaby (Macropus eugenii), an Australian marsupial, provides a unique model for understanding MHC gene evolution, as many of its antigen presenting genes are not linked to the MHC, but are scattered around the genome. Results Here we describe the 'core' tammar wallaby MHC region on chromosome 2q by ordering and sequencing 33 BAC clones, covering over 4.5 MB and containing 129 genes. When compared to the MHC region of the South American opossum, eutherian mammals and non-mammals, the wallaby MHC has a novel gene organization. The wallaby has undergone an expansion of MHC class II genes, which are separated into two clusters by the class III genes. The antigen processing genes have undergone duplication, resulting in two copies of TAP1 and three copies of TAP2. Notably, Kangaroo Endogenous Retroviral Elements are present within the region and may have contributed to the genomic instability. Conclusions The wallaby MHC has been extensively remodeled since the American and Australian marsupials last shared a common ancestor. The instability is characterized by the movement of antigen presenting genes away from the core MHC, most likely via the presence and activity of retroviral elements. We propose that the movement of class II genes away from the ancestral class II region has allowed this gene family to expand and diversify in the wallaby. The duplication of TAP genes in the wallaby MHC makes this species a unique model organism for studying the relationship between MHC gene organization and function.Peer Reviewe

Evaluation of two lyophilized molecular assays to rapidly detect foot-and-mouth disease virus directly from clinical samples in field settings

Accurate, timely diagnosis is essential for the control, monitoring and eradication of foot‐and‐mouth disease (FMD). Clinical samples from suspect cases are normally tested at reference laboratories. However, transport of samples to these centralized facilities can be a lengthy process that can impose delays on critical decision making. These concerns have motivated work to evaluate simple‐to‐use technologies, including molecular‐based diagnostic platforms, that can be deployed closer to suspect cases of FMD. In this context, FMD virus (FMDV)‐specific reverse transcription loop‐mediated isothermal amplification (RT‐LAMP) and real‐time RT‐PCR (rRT‐PCR) assays, compatible with simple sample preparation methods and in situ visualization, have been developed which share equivalent analytical sensitivity with laboratory‐based rRT‐PCR. However, the lack of robust ‘ready‐to‐use kits’ that utilize stabilized reagents limits the deployment of these tests into field settings. To address this gap, this study describes the performance of lyophilized rRT‐PCR and RT‐LAMP assays to detect FMDV. Both of these assays are compatible with the use of fluorescence to monitor amplification in real‐time, and for the RT‐LAMP assays end point detection could also be achieved using molecular lateral flow devices. Lyophilization of reagents did not adversely affect the performance of the assays. Importantly, when these assays were deployed into challenging laboratory and field settings within East Africa they proved to be reliable in their ability to detect FMDV in a range of clinical samples from acutely infected as well as convalescent cattle. These data support the use of highly sensitive molecular assays into field settings for simple and rapid detection of FMDV

The OMERACT emerging leaders program: The good, the bad, and the future

The Journal of Rheumatology Copyright © 2019. All rights reserved. Objective. To describe the experience of the first OMERACT Emerging Leaders Program (ELP). Methods. A Delphi process identified positive aspects, areas for improvement, and future directions. Core items were defined as essential if they received ≥ 70% ratings. Results. Participants valued relatable/accessible mentors (100%), including an OMERACT Executive mentor (100%), and a support network of peers (90%). Key items for future development were funding support (100%) and developing knowledge about OMERACT processes (90%) and politics (80%). Conclusion. The ELP has the potential to provide targeted training for early career researchers to develop relevant skills for future leadership roles within OMERACT

Plantar plate pathology is associated with erosive disease in the painful forefoot of patients with rheumatoid arthritis

Background: Disease-related foot pathology is recognised to have a significant impact on mobility and functional capacity in the majority of patients with rheumatoid arthritis (RA). The forefoot is widely affected and the metatarsophalangeal (MTP) joints are the most common site of symptoms. The plantar plates are the fibrocartilaginous distal attachments of the plantar fascia inserting into the five proximal phalanges. Together with the transverse metatarsal ligament they prevent splaying of the forefoot and subluxation of the MTP joints. Damage to the plantar plates is a plausible mechanism therefore, through which the forefoot presentation, commonly described as ‘walking on pebbles’, may develop in patients with RA. The aims of this study were to investigate the relationship between plantar plate pathology and clinical, biomechanical and plain radiography findings in the painful forefoot of patients with RA. Secondly, to compare plantar plate pathology at the symptomatic lesser (2nd-5th) MTP joints in patients with RA, with a group of healthy age and gender matched control subjects without foot pain. Methods: In 41 patients with RA and ten control subjects the forefoot was imaged using 3T MRI. Intermediate weighted fat-suppressed sagittal and short axis sequences were acquired through the lesser MTP joints. Images were read prospectively by two radiologists and consensus reached. Plantar plate pathology in patients with RA was compared with control subjects. Multivariable multilevel modelling was used to assess the association between plantar plate pathology and the clinical, biomechanical and plain radiography findings. Results: There were significant differences between control subjects and patients with RA in the presence of plantar plate pathology at the lesser MTP joints. No substantive or statistically significant associations were found between plantar plate pathology and clinical and biomechanical findings. The presence of plantar plate pathology was independently associated with an increase in the odds of erosion (OR = 52.50 [8.38–326.97], p < 0.001). Conclusion: The distribution of plantar plate pathology at the lesser MTP joints in healthy control subjects differs to that seen in patients with RA who have the consequence of inflammatory disease in the forefoot. Longitudinal follow-up is required to determine the mechanism and presentation of plantar plate pathology in the painful forefoot of patients with RA

Measurement of the recoil polarization in the p (\vec e, e' \vec p) pi^0 reaction at the \Delta(1232) resonance

The recoil proton polarization has been measured in the p (\vec e,e'\vec p) pi^0 reaction in parallel kinematics around W = 1232 MeV, Q^2 = 0.121 (GeV/c)^2 and epsilon = 0.718 using the polarized c.w. electron beam of the Mainz Microtron. Due to the spin precession in a magnetic spectrometer, all three proton polarization components P_x/P_e = (-11.4 \pm 1.3 \pm 1.4) %, P_y = (-43.1 \pm 1.3 \pm 2.2) %, and P_z/P_e = (56.2 \pm 1.5 \pm 2.6) % could be measured simultaneously. The Coulomb quadrupole to magnetic dipole ratio CMR = (-6.4\pm 0.7_{stat}\pm 0.8_{syst}) % was determined from P_x in the framework of the Mainz Unitary Isobar Model. The consistency among the reduced polarizations and the extraction of the ratio of longitudinal to transverse response is discussed.Comment: 5 pages LaTeX, 1 table, 2 eps figure

Anatomical location of erosions at the metatarsophalangeal joints in patients with rheumatoid arthritis

Objective: The aim of this study was to identify the anatomical location of erosions at the MTP joints in patients with RA using high-resolution 3T MRI. Methods: In 24 patients with RA, the more symptomatic forefoot was imaged using 3T MRI. T1-weighted, intermediate-weighted and T2-weighted fat-suppressed sequences were acquired through the MTP joints, together with three-dimensional volumetric interpolated breath-hold examination (3D VIBE) and T1-weighted fat-suppressed post-gadolinium contrast sequences. Images were scored for bone erosion in the distal and proximal part of the MTP joints using the RA MRI scoring (RAMRIS) system. The base of the proximal phalanx and the head of the metatarsal were divided into quadrants to determine the location of erosions (octants) in the dorsal-medial, dorsal-lateral, plantar-medial and plantar-lateral regions. Results: Seventeen females and seven males with a mean age of 55.5 years and disease duration of 10.6 years (range 0.6-36) were included. Eighteen patients were RF positive, the mean 44-joint DAS for CRP and ESR (DAS44CRP and DAS44ESR) were 2.5 (s.d. 0.8) and 2.6 (s.d. 0.9), respectively. In this cohort of patients with RA, irrespective of MTP joint location, octants located in the proximal part (metatarsal) of the joint and the plantar aspect of the joint were more eroded. Conclusion: This is the first study to report the anatomical location of erosions at the MTP joints in patients with RA. We noted that erosions were more commonly seen on the plantar aspect of the metatarsal head in RA, supporting the hypothesis of a relationship between biomechanical demands and bone changes in the forefoot

The P_33(1232) resonance contribution into the amplitudes M_{1+}^{3/2},E_{1+}^{3/2},S_{1+}^{3/2} from an analysis of the p(e,e'p)\pi^0 data at Q^2 = 2.8, 3.2, and 4 (GeV/c)^2 within dispersion relation approach

Within the fixed-t dispersion relation approach we have analysed the TJNAF and DESY data on the exclusive p(e,e'p)\pi^0 reaction in order to find the P_{33}(1232) resonance contribution into the multipole amplitudes M_{1+}^{3/2},E_{1+}^{3/2},S_{1+}^{3/2}. As an input for the resonance and nonresonance contributions into these amplitudes the earlier obtained solutions of the integral equations which follow from dispersion relations are used. The obtained values of the ratio E2/M1 for the \gamma^* N \to P_{33}(1232) transition are: 0.039\pm 0.029, 0.121\pm 0.032, 0.04\pm 0.031 for Q^2= 2.8, 3.2, and 4 (GeV/c)^2, respectively. The comparison with the data at low Q^2 shows that there is no evidence for the presence of the visible pQCD contribution into the transition \gamma N \to P_{33}(1232) at Q^2=3-4 GeV^2. The ratio S_{1+}^{3/2}/M_{1+}^{3/2} for the resonance parts of multipoles is: -0.049\pm 0.029, -0.099\pm 0.041, -0.085\pm 0.021 for Q^2= 2.8, 3.2, and 4 (GeV/c)^2, respectively. Our results for the transverse form factor G_T(Q^2) of the \gamma^* N \to P_{33}(1232) transition are lower than the values obtained from the inclusive data. With increasing Q^2, Q^4G_T(Q^2) decreases, so there is no evidence for the presence of the pQCD contribution here too

Plantar forefoot pressures in psoriatic arthritis-related dactylitis: an exploratory study

Dactylitis is a common feature of psoriatic arthritis (PsA); local physical trauma has been identified as a possible contributing factor. The aim of this study was to explore differences in forefoot plantar pressures in patients with PsA with and without dactylitis and compare to healthy controls. Thirty-six participants were recruited into three groups: group A PsA plus a history of dactylitis; group B PsA, no dactylitis; group C control participants. Forefoot plantar pressures were measured barefoot and in-shoe at the left second and fourth toes and corresponding metatarsophalangeal joints. Temporal and spatial parameters were measured and data from the foot impact scale for rheumatoid arthritis (FIS-RA), EQ5D and health assessment questionnaire (HAQ) were collected. Pressure time integral peak plantar pressure, and contact time barefoot and in-shoe were not significantly different between groups. Temporal and spatial parameters reported no significant differences between groups. ANOVA analysis and subsequent post hoc testing using Games-Howell test yielded significance in FIS-RA scores between both PsA groups versus controls, A p ≤ 0.0001 and PsA group B p < 0.0001 in the FIS-RA impairment and footwear domain, PsA group A p < 0.03 and PsA group B p ≤ 0.05 in the FIS-RA activity and participation domain compared to controls. This is the first exploratory study to investigate forefoot plantar pressures in patients with and without historical dactylitis in PsA. FIS-RA scores indicate PsA patients have significant limitations compared to controls, although a history of dactylitis does not appear to worsen patient reported outcomes

Gomesin peptides prevent proliferation and lead to the cell death of devil facial tumour disease cells.

The Tasmanian devil faces extinction due to devil facial tumour disease (DFTD), a highly transmittable clonal form of cancer without available treatment. In this study, we report the cell-autonomous antiproliferative and cytotoxic activities exhibited by the spider peptide gomesin (AgGom) and gomesin-like homologue (HiGom) in DFTD cells. Mechanistically, both peptides caused a significant reduction at G0/G1 phase, in correlation with an augmented expression of the cell cycle inhibitory proteins p53, p27, p21, necrosis, exacerbated generation of reactive oxygen species and diminished mitochondrial membrane potential, all hallmarks of cellular stress. The screening of a novel panel of AgGom-analogues revealed that, unlike changes in the hydrophobicity and electrostatic surface, the cytotoxic potential of the gomesin analogues in DFTD cells lies on specific arginine substitutions in the eight and nine positions and alanine replacement in three, five and 12 positions. In conclusion, the evidence supports gomesin as a potential antiproliferative compound against DFTD disease