Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences. An identity-by-descent analysis in a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression, and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome.     

Identification of an emerin–β-catenin complex in the heart important for intercalated disc architecture and β-catenin localisation

How mutations in the protein emerin lead to the cardiomyopathy associated with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is unclear. We identified emerin at the adherens junction of the intercalated disc, where it co-localised with the catenin family of proteins. Emerin bound to wild type β-catenin both in vivo and in vitro. Mutating the GSK3β phosphorylation sites on β-catenin abolished this binding. Wild type but not mutant forms of emerin associated with X-EDMD were able to reduce β-catenin protein levels. Cardiomyocytes from emerin-null mice hearts exhibited erroneous β-catenin distribution and intercalated disc architecture. Treatment of wild type cardiomyocytes with phenylephrine, which inactivates GSK3β, redistributed emerin and β-catenin. Emerin was identified as a direct target of GSK3β activity since exogenous expression of GSK3β reduced emerin levels at the nuclear envelope. We propose that perturbation to or total loss of the emerin–β-catenin complex compromises both intercalated disc function and β-catenin signalling in cardiomyocytes.     

Endospore abundance, microbial growth and necromass turnover in deep sub-seafloor sediment

Two decades of scientific ocean drilling have demonstrated widespread microbial life in deep sub-seafloor sediment, and surprisingly high microbial-cell numbers. Despite the ubiquity of life in the deep biosphere, the large community sizes and the low energy fluxes in this vast buried ecosystem are not yet understood. It is not known whether organisms of the deep biosphere are specifically adapted to extremely low energy fluxes or whether most of the observed cells are in a dormant, spore-like state. Here we apply a new approach--the D:L-amino-acid model--to quantify the distributions and turnover times of living microbial biomass, endospores and microbial necromass, as well as to determine their role in the sub-seafloor carbon budget. The approach combines sensitive analyses of unique bacterial markers (muramic acid and D-amino acids) and the bacterial endospore marker, dipicolinic acid, with racemization dynamics of stereo-isomeric amino acids. Endospores are as abundant as vegetative cells and microbial activity is extremely low, leading to microbial biomass turnover times of hundreds to thousands of years. We infer from model calculations that biomass production is sustained by organic carbon deposited from the surface photosynthetic world millions of years ago and that microbial necromass is recycled over timescales of hundreds of thousands of years.     

Selection of microhabitat by the red-backed vole, Clethrionomys gapperi

Clethrionomys gapperi were captured in microhabitats with greater densities of overall cover than at noncapture or random sites within the study area. Variables describing cover density and distance from free water were selected in a discriminant function analysis to differentiate between vole capture and noncapture sites. Vole capture sites had greater amounts of cover within 4 dm above ground surface and were further from standing water than noncapture sites. The preferential use by C. gapperi of microhabitats with greater densities of cover is in agreement with laboratory and field assessments of habitat use reported in the literature.     

Metagenomic and functional analysis of hindgut microbiota of a wood-feeding higher termite

From the standpoints of both basic research and biotechnology, there is considerable interest in reaching a clearer understanding of the diversity of biological mechanisms employed during lignocellulose degradation. Globally, termites are an extremely successful group of wood-degrading organisms and are therefore important both for their roles in carbon turnover in the environment and as potential sources of biochemical catalysts for efforts aimed at converting wood into biofuels. Only recently have data supported any direct role for the symbiotic bacteria in the gut of the termite in cellulose and xylan hydrolysis. Here we use a metagenomic analysis of the bacterial community resident in the hindgut paunch of a wood-feeding 'higher' Nasutitermes species (which do not contain cellulose-fermenting protozoa) to show the presence of a large, diverse set of bacterial genes for cellulose and xylan hydrolysis. Many of these genes were expressed in vivo or had cellulase activity in vitro, and further analyses implicate spirochete and fibrobacter species in gut lignocellulose degradation. New insights into other important symbiotic functions including H2 metabolism, CO2-reductive acetogenesis and N2 fixation are also provided by this first system-wide gene analysis of a microbial community specialized towards plant lignocellulose degradation. Our results underscore how complex even a 1-microl environment can be.     

Dietary overlap of snow leopard and other carnivores in the Pamirs of Northwestern China

Information about competition between carnivore species for food within high altitude regions is limited.Data collected from the Taxkorgan Nature Reserve,China revealed important interactions between snow leopard(Panthera uncia),grey wolf(Canis lupus),red fox(Vulpes vulpes)and their prey species,including domestic livestock.Sixty-four line transects were conducted in order to identify field signs of habitat occupancy and collect scats for diet analysis.High dietary overlap was observed between all three carnivore species:snow leopard and red fox(Pianka’s index=0.96),red fox and grey wolf(Pianka’s index=0.90),snow leopard and grey wolf(Pianka’s index=0.87).Snow leopard and grey wolf showed significant predation on livestock(36.8%for snow leopard and 29.4%for grey wolf in diet composition).As a pioneering exploration of the endangered snow leopard and its relationship with other species within the alpine ecosystem under livestock grazing pressure,this study contributes a greater understanding of the relationship within carnivore guild in the Pamirs whilst providing implications for conservation planning and project implementation activities in China.     

Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.