Changing social contracts in climate-change adaptation

Risks from extreme weather events are mediated through state, civil society and individual action 1 , 2 . We propose evolving social contracts as a primary mechanism by which adaptation to climate change proceeds. We use a natural experiment of policy and social contexts of the UK and Ireland affected by the same meteorological event and resultant flooding in November 2009. We analyse data from policy documents and from household surveys of 356 residents in western Ireland and northwest England. We find significant differences between perceptions of individual responsibility for protection across the jurisdictions and between perceptions of future risk from populations directly affected by flooding events. These explain differences in stated willingness to take individual adaptive actions when state support retrenches. We therefore show that expectations for state protection are critical in mediating impacts and promoting longer-term adaptation. We argue that making social contracts explicit may smooth pathways to effective and legitimate adaptation

Detecting and predicting neutralization of alemtuzumab responses in MS

Objective: To test the hypothesis that anti-drug antibodies against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance. Methods: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding anti-drug antibodies. Alemtuzumab IgG Alexa-Fluor 488 conjugate was used in a competitive-binding cell based assay to detect neutralizing anti-drug antibodies. The assays were used to retrospectively screen, blinded, banked-serum samples from people with multiple sclerosis (n=32) who had received three or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month post-infusion. Results: The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. Anti-drug antibody responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred prior to the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Pre-infusion, anti-drug antibody levels predicted limited, post-infusion lymphocyte depletion. Conclusions: Although anti-drug antibodies to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of, lymphocyte depletion and the anti-drug response may be of practical value in patients requiring additional cycles of alemtuzumab. Anti-drug antibody detection may help to inform on re-treatment or switching to another treatment

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

Use of partial least squares regression to impute SNP genotypes in Italian Cattle breeds

Background The objective of the present study was to test the ability of the partial least squares regression technique to impute genotypes from low density single nucleotide polymorphisms (SNP) panels i.e. 3K or 7K to a high density panel with 50K SNP. No pedigree information was used. Methods Data consisted of 2093 Holstein, 749 Brown Swiss and 479 Simmental bulls genotyped with the Illumina 50K Beadchip. First, a single-breed approach was applied by using only data from Holstein animals. Then, to enlarge the training population, data from the three breeds were combined and a multi-breed analysis was performed. Accuracies of genotypes imputed using the partial least squares regression method were compared with those obtained by using the Beagle software. The impact of genotype imputation on breeding value prediction was evaluated for milk yield, fat content and protein content. Results In the single-breed approach, the accuracy of imputation using partial least squares regression was around 90 and 94% for the 3K and 7K platforms, respectively; corresponding accuracies obtained with Beagle were around 85% and 90%. Moreover, computing time required by the partial least squares regression method was on average around 10 times lower than computing time required by Beagle. Using the partial least squares regression method in the multi-breed resulted in lower imputation accuracies than using single-breed data. The impact of the SNP-genotype imputation on the accuracy of direct genomic breeding values was small. The correlation between estimates of genetic merit obtained by using imputed versus actual genotypes was around 0.96 for the 7K chip. Conclusions Results of the present work suggested that the partial least squares regression imputation method could be useful to impute SNP genotypes when pedigree information is not available

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model.

OBJECTIVE: Despite progress in treating relapsing multiple sclerosis (MS), effective inhibition of nonrelapsing progressive MS is an urgent, unmet, clinical need. Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), provide valuable tools to examine the mechanisms contributing to disease and may be important for developing rational therapeutic approaches for treatment of progressive MS. It has been suggested that myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG35-55 )-induced EAE in nonobese diabetic (NOD) mice resembles secondary progressive MS. The objective was to determine whether the published data merits such claims. METHODS: Induction and monitoring of EAE in NOD mice and literature review. RESULTS: It is evident that the NOD mouse model lacks validity as a progressive MS model as the individual course seems to be an asynchronous, relapsing-remitting neurodegenerative disease, characterized by increasingly poor recovery from relapse. The seemingly progressive course seen in group means of clinical score is an artifact of data handling and interpretation. INTERPRETATION: Although MOG35-55 -induced EAE in NOD mice may provide some clues about approaches to block neurodegeneration associated with the inflammatory penumbra as lesions form, it should not be used to justify trials in people with nonactive, progressive MS. This adds further support to the view that drug studies in animals should universally adopt transparent raw data deposition as part of the publication process, such that claims can adequately be interrogated. This transparency is important if animal-based science is to remain a credible part of translational research in MS.Stichting MS ResearchWellcome TrustMedical Research CouncilNational Multiple Sclerosis Society. Grant Number: RG4132A5/

The developmental impact of prenatal stress, prenatal dexamethasone and postnatal social stress on physiology, behaviour and neuroanatomy of primate offspring: studies in rhesus macaque and common marmoset

RATIONALE: Exposure of the immature mammalian brain to stress factors, including stress levels of glucocorticoids, either prenatally or postnatally, is regarded as a major regulatory factor in short- and long-term brain function and, in human, as a major aetiological factor in neuropsychiatric disorders. Experimental human studies are not feasible and animal studies are required to demonstrate causality and elucidate mechanisms. A number of studies have been conducted and reviewed in rodents but there are relatively few studies in primates. OBJECTIVES: Here we present an overview of our published studies and some original data on the effects of: (1) prenatal stress on hypothalamic-pituitary-adrenal (HPA) re/activity and hippocampus neuroanatomy in juvenile-adolescent rhesus macaques; (2) prenatal dexamethasone (DEX) on HPA activity, behaviour and prefrontal cortex neuroanatomy in infant-adolescent common marmosets; (3) postnatal daily parental separation stress on HPA re/activity, behaviour, sleep and hippocampus and prefrontal cortex neuroanatomy in infant-adolescent common marmoset. RESULTS: Prenatal stress increased basal cortisol levels and reduced neurogenesis in macaque. Prenatal DEX was without effect on HPA activity and reduced social play and skilled motor behaviour in marmoset. Postnatal social stress increased basal cortisol levels, reduced social play, increased awakening and reduced hippocampal glucocorticoid and mineralocorticoid receptor expression in marmoset. CONCLUSIONS: Perinatal stress-related environmental events exert short- and long-term effects on HPA function, behaviour and brain status in rhesus macaque and common marmoset. The mechanisms mediating the enduring effects remain to be elucidated, with candidates including increased basal HPA function and epigenetic programming

Design of a Bovine Low-Density SNP Array Optimized for Imputation

The Illumina BovineLD BeadChip was designed to support imputation to higher density genotypes in dairy and beef breeds by including single-nucleotide polymorphisms (SNPs) that had a high minor allele frequency as well as uniform spacing across the genome except at the ends of the chromosome where densities were increased. The chip also includes SNPs on the Y chromosome and mitochondrial DNA loci that are useful for determining subspecies classification and certain paternal and maternal breed lineages. The total number of SNPs was 6,909. Accuracy of imputation to Illumina BovineSNP50 genotypes using the BovineLD chip was over 97% for most dairy and beef populations. The BovineLD imputations were about 3 percentage points more accurate than those from the Illumina GoldenGate Bovine3K BeadChip across multiple populations. The improvement was greatest when neither parent was genotyped. The minor allele frequencies were similar across taurine beef and dairy breeds as was the proportion of SNPs that were polymorphic. The new BovineLD chip should facilitate low-cost genomic selection in taurine beef and dairy cattle

Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.

BACKGROUND: [corrected] Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments. RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination. CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis