Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery, spreading efficiently via low-dose fecal-oral transmission. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries but is now emerging as a problem in the developing world, seeming to replace the more diverse Shigella flexneri in areas undergoing economic development and improvements in water quality. Classical approaches have shown that S. sonnei is genetically conserved and clonal. We report here whole-genome sequencing of 132 globally distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and that diversified into several distinct lineages with unique characteristics. Our analysis suggests that the majority of this diversification occurred in Europe and was followed by more recent establishment of local pathogen populations on other continents, predominantly due to the pandemic spread of a single, rapidly evolving, multidrug-resistant lineage.     

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.     

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.     

Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.     

Solvent Extraction Developments in Southern Africa

Introduction Solvent extraction (SX) has been an integral part of the hydrometallurgist’s arsenal in Southern Africa for many decades[1]. In the early 1970s, several SX plants were built to recover uranium, commonly occurring with the gold-bearing minera…     

Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine

The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens. Understanding how pathogen-specific immunity is elicited while avoiding inappropriate responses to the background of innocuous antigens is essential for understanding and treating intestinal infections and inflammatory diseases. The ingestion of protein antigen can induce oral tolerance, which is mediated in part by a subset of intestinal dendritic cells (DCs) that promote the development of regulatory T cells. The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c(+) CD11b(+) MHCII(+) cells) comprised of two predominant subsets: CD103(+) CX(3)CR1(-) DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells, and CD103(-) CX(3)CR1(+) DCs (with features of macrophages), which promote tumour necrosis factor-α (TNF-α) production, colitis, and the development of T(H)17 T cells. However, the mechanisms by which different intestinal LP-DC subsets capture luminal antigens in vivo remains largely unexplored. Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103(+) LP-DCs. The preferential delivery of antigens to DCs with tolerogenic properties implies a key role for this GC function in intestinal immune homeostasis.     

IDH mutation impairs histone demethylation and results in a block to cell differentiation

Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.     

Ungulate herbivory on alpine willow in the Sangre de Cristo Mountains of Colorado

In many areas of the Rocky Mountains, elk ( Cervus elaphus ) migrate from low-elevation mountain valleys during spring to high-elevation subalpine and alpine areas for the summer. Research has focused on the impacts of elk herbivory on winter-range plant communities, particularly on woody species such as willow and aspen; however, little information is available on the effects of elk herbivory on alpine willows. In the Sangre de Cristo Mountains of south central Colorado, select alpine areas appear to receive high levels of summer elk herbivory, while other areas are nearly unbrowsed. In 2005 and 2008, we measured willow height, cover, and utilization on sites that appeared to be used heavily by elk, as well as on sites that appeared to be used lightly, to determine differences between these communities over time. We found less willow cover and shorter willows at sites that received higher levels of browsing compared to those that had lower levels of browsing. Human recreational use was greater at lightly browsed sites than at highly browsed sites. From 2005 to 2008, willow utilization declined, and willow cover and height increased at sites with heavy browsing, likely owing to ownership change of adjacent valley land which led to (1) removal of grazing competition from cattle at valley locations and (2) increased human use in alpine areas, which displaced elk. We discuss the implications of increased human use and climate change on elk use of these alpine habitats. En muchas áreas de las Montañas Rocosas, el ciervo rojo ( Cervus elaphus ) migra durante la primavera de valles montañosos de baja elevación a áreas altas subalpinas y alpinas para el verano. Hasta ahora la investigación se ha enfocado en el impacto de la herbivoría del ciervo rojo sobre las comunidades de plantas en el invierno, particularmente en las especies leñosas como el sauce y el álamo; sin embargo, existe poca información disponible sobre el efecto de la herbivoría del ciervo rojo en los sauces alpinos. En la cordillera Sangre de Cristo al centro-sur de Colorado, ciertas áreas alpinas parecen tener altos niveles de herbivoría de verano por el ciervo rojo, en tanto que otras áreas quedan casi sin ramoneo. En 2005 y 2008 medimos la altura, cobertura y uso de los sauces en sitios en los que parecía haber sido abundante el ramoneo y los comparamos con sitios donde parecía haber sido más ligero, a fin de determinar las diferencias entre estas comunidades en el tiempo. Encontramos menos cobertura y altura de sauces en los sitios que recibían niveles más altos de ramoneo en comparación a los que tenían menos evidencia de ello. El uso humano recreativo era mayor en los sitios de ramoneo ligero que en donde era abundante. De 2005 a 2008, disminuyó el uso y aumentó la cobertura y la altura en sitios de ramoneo abundante, probablemente debido a que un valle adyacente cambió de propietario, lo cual provocó (1) la eliminación de la competencia por el pastoreo en ganado en el valle; y (2) un aumento del uso humano en áreas alpinas, desplazando al ciervo rojo. Discutimos las implicaciones del aumento del uso humano y el cambio climático en el uso por el ciervo rojo de estos hábitats alpinos.     

Effects of Douglas-fir foliage age class on western spruce budworm oviposition choice and larval performance

The western spruce budworm ( Choristoneura occidentalis Freeman) prefers to feed on flushing buds and current-year needles of Douglas-fir ( Pseudotsuga menziesii [Mirb.] Franco). Budworm larvae will not typically consume older age classes of needles unless all current-year foliage is depleted. We tested the following null hypotheses: (1) budworm larvae can feed on foliage with a wide range of qualities (i.e., current 1-, 2-, or 3-year-old needles) without measurable effects on fitness; and (2) budworm adults do not show any oviposition preference linked to the age of the foliage they fed on as larvae. We used both laboratory and field experiments. There was strong evidence to support rejection of hypothesis 1. Budworm larvae had greater survival from the 4th instar to pupal stage when they fed on current-year foliage (43%-52% survival) versus older age classes of foliage (0-25% survival). Pupae from current-year foliage were also heavier than pupae from ≥ 1-year-old foliage. There was weak evidence to support rejecting hypothesis 2; budworm adults that fed had fed on current-year or 3-year-old foliage as larvae preferred to oviposit on current-year foliage. Similar conclusions were drawn from the laboratory and field experiments.