To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and ...compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb. Screening for parallel evolution of Beijing lineage-associated SNPs in other Mtb lineages as a signal of positive selection, we identify an alteration in the ESX-5 type VII-secreted protein EsxW, which could potentially contribute to the enhanced transmission of Beijing lineage Mtb in Vietnamese and other host populations.
Many species around the world have collapsed, yet only some have recovered. A key question is what happens to populations post collapse. Traditionally, marine fish collapses are linked to ...overfishing, poor climate, and recruitment. We test whether the effect on biomass change from these drivers remains the same after a collapse. We used a regression model to analyse the effect of harvesting, recruitment, and climate variability on biomass change before and after a collapse across 54 marine fish populations around the world. The most salient result was the change in fishing effect that became weaker after a collapse. The change in sea temperature and recruitment effects were more variable across systems. The strongest changes were in the pelagic habitats. The resultant change in the sensitivity to external drivers indicates that whilst biomass may be rebuilt, the responses to variables known to affect stocks may have changed after a collapse. Our results show that a general model applied to many stocks provides useful insights, but that not all stocks respond similarly to a collapse calling for stock-specific models. Stocks respond to environmental drivers differently after a collapse, so caution is needed when using pre-collapse knowledge to advise on population dynamics and management.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
An atypically large outbreak of Elizabethkingia anophelis infections occurred in Wisconsin. Here we show that it was caused by a single strain with thirteen characteristic genomic regions. ...Strikingly, the outbreak isolates show an accelerated evolutionary rate and an atypical mutational spectrum. Six phylogenetic sub-clusters with distinctive temporal and geographic dynamics are revealed, and their last common ancestor existed approximately one year before the first recognized human infection. Unlike other E. anophelis, the outbreak strain had a disrupted DNA repair mutY gene caused by insertion of an integrative and conjugative element. This genomic change probably contributed to the high evolutionary rate of the outbreak strain and may have increased its adaptability, as many mutations in protein-coding genes occurred during the outbreak. This unique discovery of an outbreak caused by a naturally occurring mutator bacterial pathogen provides a dramatic example of the potential impact of pathogen evolutionary dynamics on infectious disease epidemiology.
is a growing cause of healthcare-associated infections for which multi-drug resistance is a concern. Its polysaccharide capsule is a major virulence determinant and epidemiological marker. However, ...little is known about capsule epidemiology since serological typing is not widely accessible and many isolates are serologically non-typeable. Molecular typing techniques provide useful insights, but existing methods fail to take full advantage of the information in whole genome sequences. We investigated the diversity of the capsule synthesis loci (K-loci) among 2503
genomes. We incorporated analyses of full-length K-locus nucleotide sequences and also clustered protein-encoding sequences to identify, annotate and compare K-locus structures. We propose a standardized nomenclature for K-loci and present a curated reference database. A total of 134 distinct K-loci were identified, including 31 novel types. Comparative analyses indicated 508 unique protein-encoding gene clusters that appear to reassort via homologous recombination. Extensive intra- and inter-locus nucleotide diversity was detected among the
and
genes, indicating that current molecular typing schemes based on these genes are inadequate. As a solution, we introduce
, a novel software tool that automates the process of identifying K-loci based on full locus information extracted from whole genome sequences (https://github.com/katholt/Kaptive). This work highlights the extensive diversity of
K-loci and the proteins that they encode. The nomenclature, reference database and novel typing method presented here will become essential resources for genomic surveillance and epidemiological investigations of this pathogen.
Other recent studies further highlight the impact of public health programs in accelerating the identification of individuals with hereditary cancers in populations (e.g., Lynch syndrome, hereditary ...breast and ovarian cancer) 6. Even in the genomics age, a simple family health history assessment can enhance the delivery of precision medicine in health care and population settings 8. ...as millions of people have sought direct-to-consumer genetic tests, public health programs can help educate the general public about the promise and limitations of emerging tests in improving health, as well as to track the impact of genomic tests at the population level. In this context, DNA sequencing can increase the precision of diagnosis beyond species to the identification of lineages or variants that may be associated with different degrees of risk and thus prompt different responses in terms of clinical management of the individual patient (e.g. antimicrobial treatment choice) or public health management (e.g. triggering infection control or contact tracing). Genomics is the primary method for monitoring variation in pathogen populations and identifying variants that may be of public health concern due to (i) increased transmissibility; (ii) increased severity; (iii) differences in sensitivity/specificity of current diagnostic tests; and (iv) escape from interventions, such as host immunity (vaccine-induced or natural) or sensitivity to drugs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Growth cones contain mRNAs, translation machinery, and, as we report here, protein degradation machinery. We show that isolated retinal growth cones immediately lose their ability to turn in a ...chemotropic gradient of netrin-1 or Sema3A when translation is inhibited. Translation inhibition also prevents Sema3A-induced collapse, while LPA-induced collapse is not affected. Inhibition of proteasome function blocks responses to netrin-1 and LPA but does not affect Sema3A responses. We further demonstrate in isolated growth cones that netrin-1 and Sema3A activate translation initiation factors and stimulate a marked rise in protein synthesis within minutes, while netrin-1 and LPA elicit similar rises in ubiquitin-protein conjugates. These results suggest that guidance molecules steer axon growth by triggering rapid local changes in protein levels in growth cones.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nascent proteins can be positioned rapidly at precise subcellular locations by local protein synthesis (LPS) to facilitate localized growth responses. Axon arbor architecture, a major determinant of ...synaptic connectivity, is shaped by localized growth responses, but it is unknown whether LPS influences these responses in vivo. Using high-resolution live imaging, we examined the spatiotemporal dynamics of RNA and LPS in retinal axons during arborization in vivo. Endogenous RNA tracking reveals that RNA granules dock at sites of branch emergence and invade stabilized branches. Live translation reporter analysis reveals that de novo β-actin hotspots colocalize with docked RNA granules at the bases and tips of new branches. Inhibition of axonal β-actin mRNA translation disrupts arbor dynamics primarily by reducing new branch emergence and leads to impoverished terminal arbors. The results demonstrate a requirement for LPS in building arbor complexity and suggest a key role for pre-synaptic LPS in assembling neural circuits.
•Tracking endogenous RNA shows that RNA docking predicts axon branch emergence in vivo•Axon arbor complexity in vivo depends on local protein synthesis•Axonal β-actin synthesis regulates branching by increased branch initiation•Live imaging reveals de novo synthesis of β-actin hotspots during branch formation
Wong et al. track endogenous RNA granules in single axons in vivo and show that they predict positions of axonal branch formation in the tectum. They also show that perturbation of local protein synthesis in these axons autonomously regulates branch formation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinical resistance against Bedaquiline, the first new anti-tuberculosis compound with a novel mechanism of action in over 40 years, has already been detected in Mycobacterium tuberculosis. As a new ...drug, however, there is currently insufficient clinical data to facilitate reliable and timely identification of genomic determinants of resistance. Here we investigate the structural basis for M. tuberculosis associated bedaquiline resistance in the drug target, AtpE. Together with the 9 previously identified resistance-associated variants in AtpE, 54 non-resistance-associated mutations were identified through comparisons of bedaquiline susceptibility across 23 different mycobacterial species. Computational analysis of the structural and functional consequences of these variants revealed that resistance associated variants were mainly localized at the drug binding site, disrupting key interactions with bedaquiline leading to reduced binding affinity. This was used to train a supervised predictive algorithm, which accurately identified likely resistance mutations (93.3% accuracy). Application of this model to circulating variants present in the Asia-Pacific region suggests that current circulating variants are likely to be susceptible to bedaquiline. We have made this model freely available through a user-friendly web interface called SUSPECT-BDQ, StrUctural Susceptibility PrEdiCTion for bedaquiline (http://biosig.unimelb.edu.au/suspect_bdq/). This tool could be useful for the rapid characterization of novel clinical variants, to help guide the effective use of bedaquiline, and to minimize the spread of clinical resistance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A stronger focus on natural mortality may be required to better understand contemporary changes in fish life histories and behaviour and their responses to anthropogenic drivers. Firstly, natural ...mortality is the selection under which fish evolved in the first place, so a theoretical understanding of effects of natural mortality alone is needed. Secondly, due to trade-offs, most organismal functions can only be achieved at some cost in terms of survival. Several trade-offs might need to be analysed simultaneously with effects on natural mortality being a common currency. Thirdly, there is scattered evidence that natural mortality has been increasing, some would say dramatically, in some fished stocks, which begs explanations. Fourthly, natural mortality most often implies transfer of mass and energy from one species to another, and therefore has foodweb and ecosystem consequences. We therefore analyse a model for evolution of fish life histories and behaviour, where state-dependent energy-allocation and growth strategies are found by optimization. Natural mortality is split into five different components, each specified as the outcome of individual traits and ecological trade-offs: a fixed baseline mortality; size-dependent predation; risk-dependent growth strategy; a fixed mortality when sexually mature; and mortality increasing with reproductive investment. The analysis is repeated with and without fishing. Each component of natural mortality has consequences for optimal life history strategies. Beyond earlier models, we show i) how the two types of reproductive mortality sometimes have similar and sometimes contrasting effects on life history evolution, ii) how ecosystem properties such as food availability and predation levels have stronger effects on optimal strategies than changing other mortality components, and iii) how expected changes in risk-dependent growth strategies are highly variable depending on the type of mortality changed.
► Natural mortality emerges from individual strategies for behaviour and life history. ► Ecological relationships, including anthropogenic change, shape these strategies. ► Fishing will likely select for increased natural mortality as an adaptive response. ► We show sensitivity to several trade-offs between mortality and life history traits.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Tissue mechanics is important for development; however, the spatio-temporal dynamics of in vivo tissue stiffness is still poorly understood. We here developed tiv-AFM, combining time-lapse in vivo ...atomic force microscopy with upright fluorescence imaging of embryonic tissue, to show that during development local tissue stiffness changes significantly within tens of minutes. Within this time frame, a stiffness gradient arose in the developing
brain, and retinal ganglion cell axons turned to follow this gradient. Changes in local tissue stiffness were largely governed by cell proliferation, as perturbation of mitosis diminished both the stiffness gradient and the caudal turn of axons found in control brains. Hence, we identified a close relationship between the dynamics of tissue mechanics and developmental processes, underpinning the importance of time-resolved stiffness measurements.
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