Modest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal.

Low protein synthesis is a feature of somatic stem cells that promotes regeneration in multiple tissues. Modest increases in protein synthesis impair stem cell function, but the mechanisms by which this occurs are largely unknown. We determine that low protein synthesis within hematopoietic stem cells (HSCs) is associated with elevated proteome quality in vivo. HSCs contain less misfolded and unfolded proteins than myeloid progenitors. Increases in protein synthesis cause HSCs to accumulate misfolded and unfolded proteins. To test how proteome quality affects HSCs, we examine Aarssti/sti mice that harbor a tRNA editing defect that increases amino acid misincorporation. Aarssti/sti mice exhibit reduced HSC numbers, increased proliferation, and diminished serial reconstituting activity. Misfolded proteins overwhelm the proteasome within Aarssti/sti HSCs, which is associated with increased c-Myc abundance. Deletion of one Myc allele partially rescues serial reconstitution defects in Aarssti/sti HSCs. Thus, HSCs are dependent on low protein synthesis to maintain proteostasis, which promotes their self-renewal

Rhenium elemental and isotopic variations at magmatic temperatures

Recent analytical advances in the measurement of rhenium (Re) isotope ratios allow its potential as a palaeoredox and chemical weathering proxy to be explored. However, a successful isotopic proxy must be grounded by an understanding of its composition and behaviour in the solid Earth. Here, we present Re concentrations and Re isotopic (δ187Re) compositions for a well-characterised sequence of lavas from Hekla volcano, Iceland. The concentration of Re varies from 0.02 to 1.4 ng/g, decreasing from basalt to more evolved lavas. We show that the crystallisation and removal of magnetite is responsible for the Re decrease in this system. By contrast, δ187Re values for the same suite of samples show a relatively narrow range (−0.45 to −0.22 ‰), suggesting minimal resolvable Re isotope fractionation between magnetite and the silicate melt. Together with other samples, including mid-ocean ridge basalts, these first igneous data can be used to estimate a baseline for terrestrial materials (δ187Re = −0.33 ± 0.15 ‰, 2 s.d., n = 14), from which low-temperature Re isotope variations in Earth’s surficial environments can be assessed, alongside the global isotope mass balance of Re

A field evaluation of the Hardy TB MODS Kit™ for the rapid phenotypic diagnosis of tuberculosis and multi-drug resistant tuberculosis.

BACKGROUND: Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory. METHODS & FINDINGS: 2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3-99.8%), 98.3% (97.5-98.8%), 95.8% (94.0-97.1%), and 99.7% (99.3-99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9-13) days for conventional MODS and 8.5 (7-11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples). CONCLUSIONS: MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest

[Reliability of Commercial Tests for Hepatitis C Virus].

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Towards a general framework for predicting threat status of data-deficient species from phylogenetic, spatial and environmental information

In taxon-wide assessments of threat status many species remain not included owing to lack of data. Here, we present a novel spatial-phylogenetic statistical framework that uses a small set of readily available or derivable characteristics, including phylogenetically imputed body mass and remotely sensed human encroachment, to provide initial baseline predictions of threat status for data-deficient species. Applied to assessed mammal species worldwide, the approach effectively identifies threatened species and predicts the geographical variation in threat. For the 483 data-deficient species, the models predict highly elevated threat, with 69% ‘at-risk’ species in this set, compared with 22% among assessed species. This results in 331 additional potentially threatened mammals, with elevated conservation importance in rodents, bats and shrews, and countries like Colombia, Sulawesi and the Philippines. These findings demonstrate the future potential for combining phylogenies and remotely sensed data with species distributions to identify species and regions of conservation concern

Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation.

Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signalling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to haematologic defects associated with mitochondrial diseases and ageing