Loss of ATRX in Chondrocytes Has Minimal Effects on Skeletal Development

BACKGROUND:Mutations in the human ATRX gene cause developmental defects, including skeletal deformities and dwarfism. ATRX encodes a chromatin remodeling protein, however the role of ATRX in skeletal development is currently unknown. METHODOLOGY/PRINCIPAL FINDINGS:We induced Atrx deletion in mouse cartilage using the Cre-loxP system, with Cre expression driven by the collagen II (Col2a1) promoter. Growth rate, body size and weight, and long bone length did not differ in Atrx(Col2cre) mice compared to control littermates. Histological analyses of the growth plate did not reveal any differences between control and mutant mice. Expression patterns of Sox9, a transcription factor required for cartilage morphogenesis, and p57, a marker of cell cycle arrest and hypertrophic chondrocyte differentiation, was unaffected. However, loss of ATRX in cartilage led to a delay in the ossification of the hips in some mice. We also observed hindlimb polydactily in one out of 61 mutants. CONCLUSIONS/SIGNIFICANCE:These findings indicate that ATRX is not directly required for development or growth of cartilage in the mouse, suggesting that the short stature in ATR-X patients is caused by defects in cartilage-extrinsic mechanisms

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease

Genomic Signatures of Strain Selection and Enhancement in Bacillus atrophaeus var. globigii, a Historical Biowarfare Simulant

(BG) as a simulant for biological warfare (BW) agents, knowledge of its genome composition is limited. Furthermore, the ability to differentiate signatures of deliberate adaptation and selection from natural variation is lacking for most bacterial agents. We characterized a lineage of BGwith a long history of use as a simulant for BW operations, focusing on classical bacteriological markers, metabolic profiling and whole-genome shotgun sequencing (WGS). on the nucleotide level. WGS of variants revealed that several strains were mixed but highly related populations and uncovered a progressive accumulation of mutations among the “military” isolates. Metabolic profiling and microscopic examination of bacterial cultures revealed enhanced growth of “military” isolates on lactate-containing media, and showed that the “military” strains exhibited a hypersporulating phenotype.Our analysis revealed the genomic and phenotypic signatures of strain adaptation and deliberate selection for traits that were desirable in a simulant organism. Together, these results demonstrate the power of whole-genome and modern systems-level approaches to characterize microbial lineages to develop and validate forensic markers for strain discrimination and reveal signatures of deliberate adaptation

Comparative Genomics of 2009 Seasonal Plague (Yersinia pestis) in New Mexico

Plague disease caused by the Gram-negative bacterium Yersinia pestis routinely affects animals and occasionally humans, in the western United States. The strains native to the North American continent are thought to be derived from a single introduction in the late 19th century. The degree to which these isolates have diverged genetically since their introduction is not clear, and new genomic markers to assay the diversity of North American plague are highly desired. To assay genetic diversity of plague isolates within confined geographic areas, draft genome sequences were generated by 454 pyrosequencing from nine environmental and clinical plague isolates. In silico assemblies of Variable Number Tandem Repeat (VNTR) loci were compared to laboratory-generated profiles for seven markers. High-confidence SNPs and small Insertion/Deletions (Indels) were compared to previously sequenced Y. pestis isolates. The resulting panel of mutations allowed clustering of the strains and tracing of the most likely evolutionary trajectory of the plague strains. The sequences also allowed the identification of new putative SNPs that differentiate the 2009 isolates from previously sequenced plague strains and from each other. In addition, new insertion points for the abundant insertion sequences (IS) of Y. pestis are present that allow additional discrimination of strains; several of these new insertions potentially inactivate genes implicated in virulence. These sequences enable whole-genome phylogenetic analysis and allow the unbiased comparison of closely related isolates of a genetically monomorphic pathogen

Signalling and the Evolution of Cooperative Foraging in Dynamic Environments

Understanding cooperation in animal social groups remains a significant challenge for evolutionary theory. Observed behaviours that benefit others but incur some cost appear incompatible with classical notions of natural selection; however, these behaviours may be explained by concepts such as inclusive fitness, reciprocity, intra-specific mutualism or manipulation. In this work, we examine a seemingly altruistic behaviour, the active recruitment of conspecifics to a food resource through signalling. Here collective, cooperative behaviour may provide highly nonlinear benefits to individuals, since group functionality has the potential to be far greater than the sum of the component parts, for example by enabling the effective tracking of a dynamic resource. We show that due to this effect, signalling to others is an evolutionarily stable strategy under certain environmental conditions, even when there is a cost associated to this behaviour. While exploitation is possible, in the limiting case of a sparse, ephemeral but locally abundant nutrient source, a given environmental profile will support a fixed number of signalling individuals. Through a quantitative analysis, this effective carrying capacity for cooperation is related to the characteristic length and time scales of the resource field

Testing the relative sensitivity of 102 ecological variables as indicators of woodland condition in the New Forest, UK.

Forests globally are facing an increasing number of threats from modified disturbance regimes, novel stressors and changing environmental conditions. This has ultimately resulted in declines in the ecological condition of many forest and woodland ecosystems, leading to widespread tree mortality and stand dieback. Effective indicators of overall woodland ecological condition are therefore needed for environmental monitoring and to support management responses. To test the effectiveness of different variables that could potentially be used as indicators of woodland condition, 102 variables that describe woodland structure, composition, functioning, edaphic conditions and disturbance regimes were assessed along 12 replicate gradients of beech stand dieback. Results indicated that 35 variables differed significantly between at least two stages of the dieback gradient, indicating their sensitivity to stand dieback. Seven of these indicators related to woodland species composition, two to functional processes, 20 to structural features, four to edaphic conditions, and two to disturbance regimes. These results demonstrate that effective indicators can potentially be identified for each of the ecological categories. Effective composition indicators included species richness of ectomycorrhizal fungi, ground flora and epiphytic lichens; functional indicators were soil respiration rate and net nitrification rate; edaphic conditions included soil Na:Ca ratio, exchangeable sodium, total carbon, Ca:Al ratio; structural indicators included canopy openness, litter cover, sward height, and volume of deadwood, and for disturbance the indicator was Equus dung density. Other measures, such as shrub cover and species richness of carabid beetles and spiders, were not found to vary significantly along the dieback gradients, and were therefore not identified as effective indicators. These results demonstrate the value of gradient analysis for evaluating indicators of woodland condition, but also highlight the need for multi-site studies to identify indicators with widescale applicability

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe