Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators

Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level provides a starting point for improved therapeutic intervention. SNPs in the innate immune receptor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syndrome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show that these polymorphisms cluster into two primary locations: the ATP/Mg²⁺-binding site and helical domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods.     

Molecular cytogenetics of Androctonus scorpions: an oasis of calm in the turbulent karyotype evolution of the diverse family Buthidae

After years of qualitative and subjective study, quantitative colour science is now enabling rapid measurement, analysis and comparison of colour traits. However, it has not been determined how many replicates one needs to accurately quantify a species' colours for studies aimed at broad cross‐species trait comparison. We address this major methodological knowledge gap. We first quantified and assessed the variance in colour within and between species. Reflectance spectra of flowers from ten plant species and plumage of 20 bird species were measured using a spectrometer, and reflectance (i.e. brightness) and tetrahedral colour‐space coordinates were calculated. analysis of variance (ANOVA) analyses indicate that there is far more variation in the colours of birds and flowers between species (> 77%) than within species. A Mean Absolute Deviation from the Mean test was applied to indicate the sampling replication required for each species. Tetrahedral coordinates were sampled precisely with only one individual per species. Greater replication was needed to sample reflectance with the desired precision, particularly for darker coloured species. Our findings will allow researchers to allocate their sampling effort in a way that maximises the precision of their colour data collection. The fact that only a few replicates per species are necessary will greatly facilitate broad cross‐species comparisons of colour in the future. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 114 , 69–81.     

Immune responses accelerate ageing: proof-of-principle in an insect model

The pathology of many of the world's most important infectious diseases is caused by the immune response. Additionally age-related disease is often attributed to inflammatory responses. Consequently a reduction in infections and hence inflammation early in life has been hypothesized to explain the rise in lifespan in industrialized societies. Here we demonstrate experimentally for the first time that eliciting an immune response early in life accelerates ageing. We use the beetle Tenebrio molitor as an inflammation model. We provide a proof of principle for the effects of early infection on morbidity late in life and demonstrate a long-lasting cost of immunopathology. Along with presenting a proof-of-principle study, we discuss a mechanism for the apparently counter-adaptive persistence of immunopathology in natural populations. If immunopathology from early immune response only becomes costly later in life, natural selection on reducing self-harm would be relaxed, which could explain the presence of immune self-harm in nature.     

Carbon and life cycle implications of thermal recovery from the organic fractions of municipal waste

Purpose

The aim of this research was to determine the optimum way of recovering energy from the biodegradable fractions of municipal waste. A part-life cycle study was carried out on the following wastes: paper, food waste, garden waste, wood, non-recyclable mixed municipal waste and refuse-derived fuel. The energy recovery processes considered were incineration, gasification, combustion in dedicated plant, anaerobic digestion and combustion in a cement kiln.

Methods

The life cycle assessment (LCA) was carried out using WRATE, an LCA tool designed specifically for waste management studies. Additional information on waste composition, waste collection and the performance of the energy recovery processes was obtained from a number of UK-based sources. The results take account of the energy displaced by the waste to energy processes and also the benefits obtained by the associated recycling of digestates, metals and aggregates as appropriate.

Results and discussion

For all the waste types considered the maximum benefits in terms of climate change and non-renewable resource depletion would be achieved by using the waste in a cement kiln as a substitute fuel for coal. When considering the impacts in terms of human toxicity, aquatic ecotoxicity, acidification and eutrophication, direct combustion with energy recovery was the best option. The results were found to be highly sensitive to the efficiency of the energy recovery process and the conventional fuel displaced by the recovered energy.

Conclusions and recommendations

This study has demonstrated that LCA can be used to determine the benefits and burdens associated with recovering energy from municipal waste fractions. However, the findings were restricted by the lack of reliable data on the performance of waste gasification and anaerobic digestion systems and on the burdens arising from collecting the wastes. It is recommended that further work is carried out to address these data gaps.     

Kinesin light chain 1 suppression impairs human embryonic stem cell neural differentiation and amyloid precursor protein metabolism

The etiology of sporadic Alzheimer disease (AD) is largely unknown, although evidence implicates the pathological hallmark molecules amyloid beta (Aβ) and phosphorylated Tau. Work in animal models suggests that altered axonal transport caused by Kinesin-1 dysfunction perturbs levels of both Aβ and phosphorylated Tau in neural tissues, but the relevance of Kinesin-1 dependent functions to the human disease is unknown. To begin to address this issue, we generated human embryonic stem cells (hESC) expressing reduced levels of the kinesin light chain 1 (KLC1) Kinesin-1 subunit to use as a source of human neural cultures. Despite reduction of KLC1, undifferentiated hESC exhibited apparently normal colony morphology and pluripotency marker expression. Differentiated neural cultures derived from KLC1-suppressed hESC contained neural rosettes but further differentiation revealed obvious morphological changes along with reduced levels of microtubule-associated neural proteins, including Tau and less secreted Aβ, supporting the previously established connection between KLC1, Tau and Aβ. Intriguingly, KLC1-suppressed neural precursors (NPs), isolated using a cell surface marker signature known to identify cells that give rise to neurons and glia, unlike control cells, failed to proliferate. We suggest that KLC1 is required for normal human neural differentiation, ensuring proper metabolism of AD-associated molecules APP and Tau and for proliferation of NPs. Because impaired APP metabolism is linked to AD, this human cell culture model system will not only be a useful tool for understanding the role of KLC1 in regulating the production, transport and turnover of APP and Tau in neurons, but also in defining the essential function(s) of KLC1 in NPs and their progeny. This knowledge should have important implications for human neurodevelopmental and neurodegenerative diseases.     

A miRNA signature of prion induced neurodegeneration

MicroRNAs (miRNAs) are small, non-coding RNA molecules which are emerging as key regulators of numerous cellular processes. Compelling evidence links miRNAs to the control of neuronal development and differentiation, however, little is known about their role in neurodegeneration. We used microarrays and RT-PCR to profile miRNA expression changes in the brains of mice infected with mouse-adapted scrapie. We determined 15 miRNAs were de-regulated during the disease processes; miR-342-3p, miR-320, let-7b, miR-328, miR-128, miR-139-5p and miR-146a were over 2.5 fold up-regulated and miR-338-3p and miR-337-3p over 2.5 fold down-regulated. Only one of these miRNAs, miR-128, has previously been shown to be de-regulated in neurodegenerative disease. De-regulation of a unique subset of miRNAs suggests a conserved, disease-specific pattern of differentially expressed miRNAs is associated with prion-induced neurodegeneration. Computational analysis predicted numerous potential gene targets of these miRNAs, including 119 genes previously determined to be also de-regulated in mouse scrapie. We used a co-ordinated approach to integrate miRNA and mRNA profiling, bioinformatic predictions and biochemical validation to determine miRNA regulated processes and genes potentially involved in disease progression. In particular, a correlation between miRNA expression and putative gene targets involved in intracellular protein-degradation pathways and signaling pathways related to cell death, synapse function and neurogenesis was identified.     

Working with nature to improve the environment and profitability of irrigated cotton production at ‘Kilmarnock’, Namoi Valley,New South Wales

Several environmentally positive farming innovations at ‘Kilmarnock’ near Boggabri, New South Wales, have been monitored over time and have revealed a positive impact upon this irrigated cotton farming enterprise's financial sustainability and environmental footprint. This study demonstrates economic benefits from environmental approaches to farm management.     

Differences in tree and shrub establishment due to tree guard type in a temperate upland pasture

Success of establishing native trees in cool temperate environments depends on the ability of seedlings to withstand subzero temperatures and recurrent frosts. This study compared the survival and growth of five tree and shrub species with two guard types at three landscape positions in an upland pasture. Seedlings were planted between December 2013 and March 2014. Half of the seedlings were planted in tall Corflute^® guards (60 cm high), and the remaining seedlings were interplanted in milk cartons (30 cm). Seedling survival and height were measured in November 2014. Hourly temperature readings were recorded between March and November 2014. Seedling height for all species was greater in tall guards than milk cartons at all landscape positions, possibly at least partly due to etiolation. However, seedlings in tall guards survived better than seedlings in milk cartons at mid‐ and upper‐slope positions. Higher temperatures may have benefited seedling performance by prolonging the growing season as average maximum temperature was significantly higher inside tall guards than milk cartons and ambient conditions at all landscape positions. Average daily temperature was significantly higher in tall guards compared to milk cartons and ambient conditions at the upper‐slope site only. There were no significant differences in average minimum temperature between guard types at all landscape positions.     

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including G_sα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of G_sα in the osteoblast lineage. Postnatal removal of G_sα in the osteoblast lineage (P-G_sα^OsxKO mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1–34) (80 μg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-G_sα^OsxKO mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-G_sα^OsxKO mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via G_sα but not phospholipase C via G_q/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of G_sα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond G_sα and G_q/11 act downstream of PTH on osteoblast differentiation.