Phylodynamic analysis of an emergent Mycobacterium bovis outbreak in an area with no previously known wildlife infections

1. Understanding how an emergent pathogen successfully establishes itself and persists in a previously unaffected population is a crucial problem in disease ecology, with important implications for disease management. In multi-host pathogen systems this problem is particularly difficult, as the importance of each host species to transmission is often poorly characterised, and the disease epidemiology is complex. Opportunities to observe and analyse such emergent scenarios are few. 2. Here, we exploit a unique dataset combining densely-collected data on the epidemiological and evolutionary characteristics of an outbreak of Mycobacterium bovis (the causative agent of bovine tuberculosis, bTB) in a population of cattle and badgers in an area considered low-risk for bTB, with no previous record of either persistent infection in cattle, or of any infection in wildlife. We analyse the outbreak dynamics using a combination of mathematical modelling, Bayesian evolutionary analyses, and machine learning. 3. Comparison to M. bovis whole-genome sequences from Northern Ireland confirmed this to be a single introduction of the pathogen from the latter region, with evolutionary analysis supporting an introduction directly into the local cattle population six years prior to its first discovery in badgers. 4. Once introduced, the evidence supports M. bovis epidemiological dynamics passing through two phases, the first dominated by cattle-to-cattle transmission before becoming established in the local badger population. 5. Synthesis and applications. The raw data object of this analysis were used to support decisions regarding the control of a M. bovis emergent outbreak, of considerable concern because of the geographical distance from previously known high-risk areas. Our further analyses, estimating the time of introduction (and therefore the likely magnitude of any hidden outbreak) and the rates of cross-species transmission, provided valuable confirmation that the extent and focus of the imposed controls were appropriate. Not only these findings strengthen the call for genomic surveillance, but they also pave the path for future outbreaks control, providing insights for more rapid and decisive evidence-based decision-making. As the methods we used and developed are agnostic to the disease itself, they are also valuable for other slowly transmitting pathogens

Developing independent investigators for clinical research relevant for Africa

Sustainable research capacity building requires training individuals at multiple levels within a supportive institutional infrastructure to develop a critical mass of independent researchers. At many African medical institutions, a PhD is important for academic promotion and is, therefore, an important focal area for capacity building programs. We examine the training at the Infectious Diseases Institute (IDI) as a model for in-country training based on systems capacity building and attention to the academic environment. PhD training in Africa should provide a strong research foundation for individuals to perform independent, original research and to mentor others. Training the next generation of researchers within excellent indigenous academic centers of excellence with strong institutional infrastructure will empower trainees to ask regionally relevant research questions that will benefit Africans

The SAMI Galaxy Survey: revisiting galaxy classification through high-order stellar kinematics

Recent cosmological hydrodynamical simulations suggest that integral field spectroscopy can connect the high-order stellar kinematic moments h3 (~skewness) and h4 (~kurtosis) in galaxies to their cosmological assembly history. Here, we assess these results by measuring the stellar kinematics on a sample of 315 galaxies, without a morphological selection, using two-dimensional integral field data from the SAMI Galaxy Survey. Proxies for the spin parameter (${\lambda }_{{R}_{{\rm{e}}}}$) and ellipticity (${\epsilon }_{{\rm{e}}}$) are used to separate fast and slow rotators; there exists a good correspondence to regular and non-regular rotators, respectively, as also seen in earlier studies. We confirm that regular rotators show a strong h3 versus $V/\sigma$ anti-correlation, whereas quasi-regular and non-regular rotators show a more vertical relation in h3 and $V/\sigma$. Motivated by recent cosmological simulations, we develop an alternative approach to kinematically classify galaxies from their individual h3 versus $V/\sigma$ signatures. Within the SAMI Galaxy Survey, we identify five classes of high-order stellar kinematic signatures using Gaussian mixture models. Class 1 corresponds to slow rotators, whereas Classes 2–5 correspond to fast rotators. We find that galaxies with similar {\lambda }_{{R}_{{\rm{e}}}}\mbox{--}{\epsilon }_{{\rm{e}}} values can show distinctly different {h}_{3}\mbox{--}V/\sigma signatures. Class 5 objects are previously unidentified fast rotators that show a weak h3 versus $V/\sigma$ anti-correlation. From simulations, these objects are predicted to be disk-less galaxies formed by gas-poor mergers. From morphological examination, however, there is evidence for large stellar disks. Instead, Class 5 objects are more likely disturbed galaxies, have counter-rotating bulges, or bars in edge-on galaxies. Finally, we interpret the strong anti-correlation in h3 versus $V/\sigma$ as evidence for disks in most fast rotators, suggesting a dearth of gas-poor mergers among fast rotators

The SAMI Galaxy Survey : spatially resolving the main sequence of star formation

We present the ∼800 star formation rate maps for the Sydney-AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey based on H α emission maps, corrected for dust attenuation via the Balmer decrement, that are included in the SAMI Public Data Release 1. We mask out spaxels contaminated by non-stellar emission using the [O iii]/H β, [N ii]/H α, [S ii]/H α, and [O i]/H α line ratios. Using these maps, we examine the global and resolved star-forming main sequences of SAMI galaxies as a function of morphology, environmental density, and stellar mass. Galaxies further below the star-forming main sequence are more likely to have flatter star formation profiles. Early-type galaxies split into two populations with similar stellar masses and central stellar mass surface densities. The main-sequence population has centrally concentrated star formation similar to late-type galaxies, while galaxies >3σ below the main sequence show significantly reduced star formation most strikingly in the nuclear regions. The split populations support a two-step quenching mechanism, wherein halo mass first cuts off the gas supply and remaining gas continues to form stars until the local stellar mass surface density can stabilize the reduced remaining fuel against further star formation. Across all morphologies, galaxies in denser environments show a decreased specific star formation rate from the outside in, supporting an environmental cause for quenching, such as ram-pressure stripping or galaxy interactions.Publisher PDFPeer reviewe

HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC

Wildlife collisions with aircraft: A missing component of land-use planning for airports

Projecting risks posed to aviation safety by wildlife populations is often overlooked in airport land-use planning. However, the growing dependency on civil aviation for global commerce can require increases in capacity at airports which affect land use, wildlife populations, and perspectives on aviation safety. Our objectives were to (1) review legislation that affects airports and surrounding communities relative to managing and reducing wildlife hazards to aviation; (2) identify information gaps and future research needs relative to regulated land uses on and near airports, and the effects on wildlife populations; and (3) demonstrate how information regarding wildlife responses to land-use practices can be incorporated into wildlife-strike risk assessments.We show that guidelines for land-use practices on and near airports with regard to wildlife hazards to aviation can be vague, conflicting, and scientifically ill-supported. We discuss research needs with regard to management of storm water runoff; wildlife use of agricultural crops and tillage regimens relative to revenue and safety; the role of an airport in the landscape matrix with regard to its effects on wildlife species richness and abundance; and spatial and temporal requirements of wildlife species that use airports, relative to implementing current and novel management techniques. We also encourage the development and maintenance of data sets that will allow realistic assessment of wildlife-strike risk relative to current airport conditions and anticipated changes to capacity. Land uses at airports influence wildlife populations, and understanding and incorporating these effects into planning will reduce risks posed to both aviation safety and wildlife species

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio