Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Genetic Diversity and Ecological Niche Modelling of Wild Barley:Refugia, Large-Scale Post-LGM Range Expansion and Limited Mid-Future Climate Threats?

Describing genetic diversity in wild barley (Hordeum vulgare ssp. spontaneum) in geographic and environmental space in the context of current, past and potential future climates is important for conservation and for breeding the domesticated crop (Hordeum vulgare ssp. vulgare). Spatial genetic diversity in wild barley was revealed by both nuclear- (2,505 SNP, 24 nSSR) and chloroplast-derived (5 cpSSR) markers in 256 widely-sampled geo-referenced accessions. Results were compared with MaxEnt-modelled geographic distributions under current, past (Last Glacial Maximum, LGM) and mid-term future (anthropogenic scenario A2, the 2080s) climates. Comparisons suggest large-scale post-LGM range expansion in Central Asia and relatively small, but statistically significant, reductions in range-wide genetic diversity under future climate. Our analyses support the utility of ecological niche modelling for locating genetic diversity hotspots and determine priority geographic areas for wild barley conservation under anthropogenic climate change. Similar research on other cereal crop progenitors could play an important role in tailoring conservation and crop improvement strategies to support future human food security

Population genomics of marine zooplankton

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here for personal use, not for redistribution. The definitive version was published in Bucklin, Ann et al. "Population Genomics of Marine Zooplankton." Population Genomics: Marine Organisms. Ed. Om P. Rajora and Marjorie Oleksiak. Springer, 2018. doi:10.1007/13836_2017_9.The exceptionally large population size and cosmopolitan biogeographic distribution that distinguish many – but not all – marine zooplankton species generate similarly exceptional patterns of population genetic and genomic diversity and structure. The phylogenetic diversity of zooplankton has slowed the application of population genomic approaches, due to lack of genomic resources for closelyrelated species and diversity of genomic architecture, including highly-replicated genomes of many crustaceans. Use of numerous genomic markers, especially single nucleotide polymorphisms (SNPs), is transforming our ability to analyze population genetics and connectivity of marine zooplankton, and providing new understanding and different answers than earlier analyses, which typically used mitochondrial DNA and microsatellite markers. Population genomic approaches have confirmed that, despite high dispersal potential, many zooplankton species exhibit genetic structuring among geographic populations, especially at large ocean-basin scales, and have revealed patterns and pathways of population connectivity that do not always track ocean circulation. Genomic and transcriptomic resources are critically needed to allow further examination of micro-evolution and local adaptation, including identification of genes that show evidence of selection. These new tools will also enable further examination of the significance of small-scale genetic heterogeneity of marine zooplankton, to discriminate genetic “noise” in large and patchy populations from local adaptation to environmental conditions and change.Support was provided by the US National Science Foundation to AB and RJO (PLR-1044982) and to RJO (MCB-1613856); support to IS and MC was provided by Nord University (Norway)

Biomarkers of cardiovascular risk across phenotypes of osteoarthritis.

BACKGROUND: The objective of this study was to explore the associations between ultrasonographic and radiographic joint scores and levels of arterial CVD risk markers in patients with osteoarthritis (OA). Secondly, to compare the levels of arterial CVD risk markers between OA phenotypes and controls. METHOD: The "Musculoskeletal pain in Ullensaker" Study (MUST) invited residents of Ullensaker municipality with self-reported OA to a medical examination. OA was defined according to the American College of Rheumatology (ACR) criteria and phenotyped based on joint distribution. Joints of the hands, hips and knees were examined by ultrasonography and conventional radiography, and scored for osteosteophytes. Hands were also scored for inflammation by grey scale (GS) synovitis and power Doppler (PD) signal. Control populations were a cohort of inhabitants of Oslo (OCP), and for external validation, a UK community-based register (UKPC).Pulse pressure augmentation index (AIx) and pulse wave velocity (PWV) were measured using the Sphygmocor apparatus (Atcor®). Ankel-brachial index (ABI) was estimated in a subset of patients. In separate adjusted regression models we explored the associations between ultrasonography and radiograph joint scores and AIx, PWV and ABI. CVD risk markers were also compared between phenotypes of OA and controls in adjusted analyses. RESULTS: Three hundred and sixty six persons with OA were included (mean age (range); 63.0 (42.0-75.0)), (females (%); 264 (72)). Of these, 155 (42.3%) had isolated hand OA, 111 (30.3%) had isolated lower limb OA and 100 (27.3%) had generalized OA. 108 persons were included in the OCP and 963 persons in the UKPC; (mean age (range); OCP: 57.2 (40.4-70.4), UKPC: 63.9 (40.0-75.0), females (%); OCP: 47 (43.5), UKPC: 543 (56.4%). Hand osteophytes were associated with AIx while GS and PD scores were not related to CVD risk markers. All OA phenotypes had higher levels of AIx compared to OCP in adjusted analyses. External validation against UKPC confirmed these findings. CONCLUSIONS: Hand osteophytes might be related to higher risk of CVD. People with OA had higher augmented central pressure compared to controls.Words 330

Biomarkers of cardiovascular risk across phenotypes of osteoarthritis

Abstract: Background: The objective of this study was to explore the associations between ultrasonographic and radiographic joint scores and levels of arterial CVD risk markers in patients with osteoarthritis (OA). Secondly, to compare the levels of arterial CVD risk markers between OA phenotypes and controls. Method: The “Musculoskeletal pain in Ullensaker” Study (MUST) invited residents of Ullensaker municipality with self-reported OA to a medical examination. OA was defined according to the American College of Rheumatology (ACR) criteria and phenotyped based on joint distribution. Joints of the hands, hips and knees were examined by ultrasonography and conventional radiography, and scored for osteosteophytes. Hands were also scored for inflammation by grey scale (GS) synovitis and power Doppler (PD) signal. Control populations were a cohort of inhabitants of Oslo (OCP), and for external validation, a UK community-based register (UKPC). Pulse pressure augmentation index (AIx) and pulse wave velocity (PWV) were measured using the Sphygmocor apparatus (Atcor®). Ankel-brachial index (ABI) was estimated in a subset of patients. In separate adjusted regression models we explored the associations between ultrasonography and radiograph joint scores and AIx, PWV and ABI. CVD risk markers were also compared between phenotypes of OA and controls in adjusted analyses. Results: Three hundred and sixty six persons with OA were included (mean age (range); 63.0 (42.0–75.0)), (females (%); 264 (72)). Of these, 155 (42.3%) had isolated hand OA, 111 (30.3%) had isolated lower limb OA and 100 (27.3%) had generalized OA. 108 persons were included in the OCP and 963 persons in the UKPC; (mean age (range); OCP: 57.2 (40.4–70.4), UKPC: 63.9 (40.0–75.0), females (%); OCP: 47 (43.5), UKPC: 543 (56.4%). Hand osteophytes were associated with AIx while GS and PD scores were not related to CVD risk markers. All OA phenotypes had higher levels of AIx compared to OCP in adjusted analyses. External validation against UKPC confirmed these findings. Conclusions: Hand osteophytes might be related to higher risk of CVD. People with OA had higher augmented central pressure compared to controls. Words 330

Complete Chloroplast Genome Sequences of Important Oilseed Crop Sesamum indicum L

Sesamum indicum is an important crop plant species for yielding oil. The complete chloroplast (cp) genome of S. indicum (GenBank acc no. JN637766) is 153,324 bp in length, and has a pair of inverted repeat (IR) regions consisting of 25,141 bp each. The lengths of the large single copy (LSC) and the small single copy (SSC) regions are 85,170 bp and 17,872 bp, respectively. Comparative cp DNA sequence analyses of S. indicum with other cp genomes reveal that the genome structure, gene order, gene and intron contents, AT contents, codon usage, and transcription units are similar to the typical angiosperm cp genomes. Nucleotide diversity of the IR region between Sesamum and three other cp genomes is much lower than that of the LSC and SSC regions in both the coding region and noncoding region. As a summary, the regional constraints strongly affect the sequence evolution of the cp genomes, while the functional constraints weakly affect the sequence evolution of cp genomes. Five short inversions associated with short palindromic sequences that form step-loop structures were observed in the chloroplast genome of S. indicum. Twenty-eight different simple sequence repeat loci have been detected in the chloroplast genome of S. indicum. Almost all of the SSR loci were composed of A or T, so this may also contribute to the A-T richness of the cp genome of S. indicum. Seven large repeated loci in the chloroplast genome of S. indicum were also identified and these loci are useful to developing S. indicum-specific cp genome vectors. The complete cp DNA sequences of S. indicum reported in this paper are prerequisite to modifying this important oilseed crop by cp genetic engineering techniques

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1β, IL-6, TNF-α, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by the TLR7/8-L R848 (20–30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides. To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24 h followed by addition of CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation

A Tri-Oceanic Perspective: DNA Barcoding Reveals Geographic Structure and Cryptic Diversity in Canadian Polychaetes

Although polychaetes are one of the dominant taxa in marine communities, their distributions and taxonomic diversity are poorly understood. Recent studies have shown that many species thought to have broad distributions are actually a complex of allied species. In Canada, 12% of polychaete species are thought to occur in Atlantic, Arctic, and Pacific Oceans, but the extent of gene flow among their populations has not been tested.Sequence variation in a segment of the mitochondrial cytochrome c oxidase I (COI) gene was employed to compare morphological versus molecular diversity estimates, to examine gene flow among populations of widespread species, and to explore connectivity patterns among Canada's three oceans. Analysis of 1876 specimens, representing 333 provisional species, revealed 40 times more sequence divergence between than within species (16.5% versus 0.38%). Genetic data suggest that one quarter of previously recognized species actually include two or more divergent lineages, indicating that richness in this region is currently underestimated. Few species with a tri-oceanic distribution showed genetic cohesion. Instead, large genetic breaks occur between Pacific and Atlantic-Arctic lineages, suggesting their long-term separation. High connectivity among Arctic and Atlantic regions and low connectivity with the Pacific further supports the conclusion that Canadian polychaetes are partitioned into two distinct faunas.Results of this study confirm that COI sequences are an effective tool for species identification in polychaetes, and suggest that DNA barcoding will aid the recognition of species overlooked by the current taxonomic system. The consistent geographic structuring within presumed widespread species suggests that historical range fragmentation during the Pleistocene ultimately increased Canadian polychaete diversity and that the coastal British Columbia fauna played a minor role in Arctic recolonization following deglaciation. This study highlights the value of DNA barcoding for providing rapid insights into species distributions and biogeographic patterns in understudied groups