Chp8, a diguanylate cyclase from Pseudomonas syringae pv tomato DC3000 suppresses the PAMP flagellin, increases EPS and promotes plant immune evasion.

The bacterial plant pathogen Pseudomonas syringae causes disease in a wide range of plants. The associated decrease in crop yields results in economic losses and threatens global food security. Competition exists between the plant immune system and the pathogen, the basic principles of which can be applied to animal infection pathways. P. syringae uses a type III secretion system (T3SS) to deliver virulence factors into the plant that promote survival of the bacterium. The P. syringae T3SS is a product of the hypersensitive response and pathogenicity (hrp) and hypersensitive response and conserved (hrc) gene cluster, which is strictly controlled by the codependent enhancer-binding proteins HrpR and HrpS. Through a combination of bacterial gene regulation and phenotypic studies, plant infection assays, and plant hormone quantifications, we now report that Chp8 (i) is embedded in the Hrp regulon and expressed in response to plant signals and HrpRS, (ii) is a functional diguanylate cyclase, (iii) decreases the expression of the major pathogen-associated molecular pattern (PAMP) flagellin and increases extracellular polysaccharides (EPS), and (iv) impacts the salicylic acid/jasmonic acid hormonal immune response and disease progression. We propose that Chp8 expression dampens PAMP-triggered immunity during early plant infection.

Glycine betaine-mediated protection of peas (Pisum sativum L.) during blanching and frozen storage

We used glycine betaine (5–20% w/v) for blanching green peas (100°C, 60 s), and their subsequent freezing and storage (–20°C, 90 days). Blanching after the addition of glycine betaine at ≥10% (w/v) followed by a 90 day storage period which resulted in the most desirable outcome: higher vitamin C levels, a superior green color, enhanced organoleptic quality and texture, and improved retention of peroxidase and lipoxygenase activity relative to control peas (no glycine betaine added). Microscopic characterizations of control and treated peas revealed that glycine betaine acts as a cryoprotectant which maintains cellular integrity. Glycine betaine (10% w/v) could be used commercially for production of frozen peas with better quality attributes.

Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

Aging in personal and social immunity: do immune traits senesce at the same rate?

How much should an individual invest in immunity as it grows older? Immunity is costly and its value is likely to change across an organism's lifespan. A limited number of studies have focused on how personal immune investment changes with age in insects, but we do not know how social immunity, immune responses that protect kin, changes across lifespan, or how resources are divided between these two arms of the immune response. In this study, both personal and social immune functions are considered in the burying beetle, Nicrophorus vespilloides. We show that personal immune function declines (phenoloxidase levels) or is maintained (defensin expression) across lifespan in nonbreeding beetles but is maintained (phenoloxidase levels) or even upregulated (defensin expression) in breeding individuals. In contrast, social immunity increases in breeding burying beetles up to middle age, before decreasing in old age. Social immunity is not affected by a wounding challenge across lifespan, whereas personal immunity, through PO, is upregulated following wounding to a similar extent across lifespan. Personal immune function may be prioritized in younger individuals in order to ensure survival until reproductive maturity. If not breeding, this may then drop off in later life as state declines. As burying beetles are ephemeral breeders, breeding opportunities in later life may be rare. When allowed to breed, beetles may therefore invest heavily in "staying alive" in order to complete what could potentially be their final reproductive opportunity. As parental care is important for the survival and growth of offspring in this genus, staying alive to provide care behaviors will clearly have fitness payoffs. This study shows that all immune traits do not senesce at the same rate. In fact, the patterns observed depend upon the immune traits measured and the breeding status of the individual.

Alterations in Circulating Immune Cells in Neovascular Age-Related Macular Degeneration

Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible blindness in developed countries. Recent advances have highlighted the essential role of inflammation in the development of the disease. In addition to local retinal chronic inflammatory response, systemic immune alterations have also been observed in AMD patients. In this study we investigated the association between the frequency of circulating leukocyte populations and the prevalence as well as clinical presentations of nAMD. Leukocyte subsets of 103 nAMD patients (most of them were receiving anti-VEGF therapy prior to enrolment) and 26 controls were analysed by flow cytometry by relative cell size, granularity and surface markers. Circulating CD11b(+) cells and CD16(hi)HLA-DR(-) neutrophils were significantly increased (P = 0.015 and 0.009 respectively) in nAMD when compared to controls. The percentage of circulating CD4(+) T-cells was reduced in nAMD patients without subretinal fibrosis (P = 0.026) compared to patients with subretinal fibrosis. There was no correlation between the percentage of circulating leukocytes and the responsiveness to anti-VEGF therapy in nAMD patients. Our results suggest that higher levels of circulating CD11b(+) cells and neutrophils are associated with nAMD and that reduced levels of CD4(+) T-cells are associated with the absence of subretinal fibrosis in nAMD.

Refugees and Human Rights: The Future of International Protection in the UK

The global refugee crisis is raising profound questions for the future of international protection. This article, based on a talk given as part of Refugee Week 2015, offers reflections on the current debate. The need to internationalise the conversation is underlined. Although no one state can resolve the problems of the world, it is precisely in the response to the plight of the forcibly displaced that commitments to human rights and refugee protection are tested in practical terms. This article argues that the UK’s approach remains inadequate and problematic.

Exploring inequities in child welfare and child protection services: Explaining the ‘inverse intervention law’

Attempts to record, understand and respond to variations in child welfare and protection reporting, service patterns and outcomes are international, numerous and longstanding. Reframing such variations as an issue of inequity between children and between families opens the way to a new approach to explaining the profound difference in intervention rates between and within countries and administrative districts. Recent accounts of variation have frequently been based on the idea that there is a binary division between bias and risk (or need). Here we propose seeing supply (bias) and demand (risk) factors as two aspects of a single system, both framed, in part, by social structures. A recent finding from a study of intervention rates in England, the 'inverse intervention law', is used to illustrate the complex ways in which a range of factors interact to produce intervention rates. In turn, this analysis raises profound moral, policy, practice and research questions about current child welfare and child protection services.

A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer

Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or 'BRCAness', is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies.We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways.

Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

The Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) recently published four consensus molecular subtypes (CMS’s) representing the underlying biology in CRC. The Microsatellite Instable (MSI) immune group, CMS1, has a favorable prognosis in early stage disease, but paradoxically has the worst prognosis following relapse, suggesting the presence of factors enabling neoplastic cells to circumvent this immune response. To identify the genes influencing subsequent poor prognosis in CMS1, we analyzed this subtype, centered on risk of relapse.
In a cohort of early stage colon cancer (n=460), we examined, in silico, changes in gene expression within the CMS1 subtype and demonstrated for the first time the favorable prognostic value of chemokine-like factor (CKLF) gene expression in the adjuvant disease setting [HR=0.18, CI=0.04-0.89]. In addition, using transcription profiles originating from cell sorted CRC tumors, we delineated the source of CKLF transcription within the colorectal tumor microenvironment to the leukocyte component of these tumors. Further to this, we confirmed that CKLF gene expression is confined to distinct immune subsets in whole blood samples and primary cell lines, highlighting CKLF as a potential immune cell-derived factor promoting tumor immune-surveillance of nascent neoplastic cells, particularly in CMS1 tumors. Building on the recently reported CRCSC data, we provide compelling evidence that leukocyte-infiltrate derived CKLF expression is a candidate biomarker of favorable prognosis, specifically in MSI-immune stage II/III disease.