Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M-including H3.2K27M-mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships

Implementing an electronic sideband offset lock for precision spectroscopy in radium

We demonstrate laser frequency stabilization with at least 6 GHz of offset tunability using an in-phase/quadrature (IQ) modulator to generate electronic sidebands (ESB) on a titanium sapphire laser at 714 nm and we apply this technique to the precision spectroscopy of $^{226}$Ra, and $^{225}$Ra. By locking the laser to a single resonance of a high finesse optical cavity and adjusting the lock offset, we determine the frequency difference between the magneto-optical trap (MOT) transitions in the two isotopes to be $2630.0\pm0.3$ MHz, a factor of 29 more precise than the previously available data. Using the known value of the hyperfine splitting of the $^{3}P_{1}$ level, we calculate the isotope shift for the $^{1}S_{0}$ to $^{3}P_{1}$ transition to be $2267.0\pm2.2$ MHz, which is a factor of 8 more precise than the best available value. Our technique could be applied to countless other atomic systems to provide unprecedented precision in isotope shift spectroscopy and other relative frequency comparisons

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors

A large-scale study of a poultry trading network in Bangladesh: implications for control and surveillance of avian influenza viruses

Since its first report in 2007, avian influenza (AI) has been endemic in Bangladesh. While live poultry marketing is widespread throughout the country and known to influence AI dissemination and persistence, trading patterns have not been described. The aim of this study is to assess poultry trading practices and features of the poultry trading networks which could promote AI spread, and their potential implications for disease control and surveillance. Data on poultry trading practices was collected from 849 poultry traders during a cross-sectional survey in 138 live bird markets (LBMs) across 17 different districts of Bangladesh. The quantity and origins of traded poultry were assessed for each poultry type in surveyed LBMs. The network of contacts between farms and LBMs resulting from commercial movements of live poultry was constructed to assess its connectivity and to identify the key premises influencing it

Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAF

Targeted cancer therapies have revolutionized treatment but their efficacies are limited by the development of resistance driven by clonal evolution within tumors. We developed CAPTURE , a single-cell barcoding approach to comprehensively trace clonal dynamics and capture live lineage-coupled resistant cells for in-depth multi-omics analysis and functional exploration. We demonstrate that heterogeneous clones, either preexisting or emerging from drug-tolerant persister cells, dominated resistance to vemurafenib in BRA

A Survey of Dog Owners in Remote Northern Australian Indigenous Communities to Inform Rabies Incursion Planning

Australia is underprepared for a rabies incursion due to a lack of information about how a rabies outbreak would spread within the susceptible canine populations and which control strategies would be best to control it. The aim of this study was to collect information to parameterize a recently developed dog rabies spread model as well as use this information to gauge how the community would accept potential control strategies. Such information–together with model outputs–would be used to inform decision makers on the best control strategies and improve Australia’s preparedness against a canine rabies incursion. The parameters this study focussed on were detection time, vaccination rates and dog-culling and dog movement restriction compliance. A cross-sectional survey of 31 dog-owners, using a questionnaire, was undertaken in the five communities of the Northern Peninsular Area (NPA) in northern Australia regarding community dog movements, veterinary visits, reporting systems, perceptions of sick dogs and potential human behaviours during hypothetical rabies outbreaks. It highlighted the significant shortfalls in veterinary care that would need to be vastly improved during an outbreak, who educational programs should be targeted towards and which dog movements should be restricted. The results indicate that men were significantly more likely than women to allow their dogs to roam and to move their dogs. The current low vaccination rate of 12% highlighted the limited veterinary services that would need to be substantially increased to achieve effective rabies control. Participation in mass vaccination was accepted by 100% of the respondents. There was lower acceptance for other possible rabies control strategies with 10–20% of the respondents stating a resistance to both a mass culling program and a ban on dog movements. Consequently, movement bans and mass dog culling would have limited effectiveness as a control strategy in the NPA community. More than half of the respondents said that they would report their sick dogs within a week. This would lead to a much more optimistic rabies detection time than observed in other regions with recent dog rabies outbreaks. Findings from this study can be used to parameterize a recently developed dog rabies spread model as well as to develop informed policies for managing a future rabies incursion, thus improving Australia’s preparedness against a canine rabies incursion. Author Summary Australia is underprepared for a rabies incursion due to limited information about how a rabies outbreak would behave and which control strategies would be best to control it. A disease spread model of rabies has been developed to help policy-makers decide on the best response to a rabies incursion. However, data to inform this model are lacking. Therefore, the aim of this study was to gather information to parameterize the existing rabies spread model and to gauge how the community would accept potential control strategies. A survey of dog-owners, using a questionnaire, was undertaken in five remote, indigenous communities in northern Australia. We found that compared to women, men were more likely to allow their dogs to roam and to move their dogs. The current vaccination rates in these dog populations are low due to limited veterinary services. This would make delivery of vaccine in the event of a rabies incursion potentially challenging. However, compliance of dog owners with mass vaccination campaigns would be high. However, compliance with movement control of dogs might be problematic, as would the mass culling of dogs, although, rabies detection following an incursion could optimistically occur within a week

Ambicultural blending between Eastern and Western paradigms : fresh perspectives for international management research

East and Southeast Asian worldviews are distinctly different from those of the West. Westerners and Asians construct their environments differently, not least because they construct the notion of \u27self\u27 very differently. This paper describes and exemplifies distinctions in cognitive and linguistic styles between the East and the West and outlines the implications of these styles for environmental perspectives and research paradigms. Examples from Thailand illustrate the philosophical roots and practical implications of an indigenous Eastern perspective for local business interactions. We explore the privilege afforded in Western, Cartesian paradigms in (Asian) management research and stimulate debate on the benefits of promoting alternative Asian indigenous perspectives for both management research and management practice. We support the idea that Asian management discourse needs more self-confidence and deserves a more prominent place in international research, not least because international management research will greatly benefit from freshly \u27blended\u27 perspectives that incorporate Eastern and Western perspectives

Achieving Surgical, Obstetric, Trauma, and Anesthesia (SOTA) care for all in South Asia

South Asia is a demographically crucial, economically aspiring, and socio-culturally diverse region in the world. The region contributes to a large burden of surgically-treatable disease conditions. A large number of people in South Asia cannot access safe and affordable surgical, obstetric, trauma, and anesthesia (SOTA) care when in need. Yet, attention to the region in Global Surgery and Global Health is limited. Here, we assess the status of SOTA care in South Asia. We summarize the evidence on SOTA care indicators and planning. Region-wide, as well as country-specific challenges are highlighted. We also discuss potential directions—initiatives and innovations—toward addressing these challenges. Local partnerships, sustained research and advocacy efforts, and politics can be aligned with evidence-based policymaking and health planning to achieve equitable SOTA care access in the South Asian region under the South Asian Association for Regional Cooperation (SAARC)

The vaccination of 35,000 dogs in 20 working days using combined static point and door-to-door methods in Blantyre, Malawi

An estimated 60,000 people die of rabies annually. The vast majority of cases of human rabies develop following a bite from an infected dog. Rabies can be controlled in both human and canine populations through widespread vaccination of dogs. Rabies is particularly problematic in Malawi, costing the country an estimated 13 million USD and 484 human deaths annually, with an increasing paediatric incidence in Blantyre City. Consequently, the aim of this study was to vaccinate a minimum of 75% of all the dogs within Blantyre city during a one month period. Blantyre's 25 administrative wards were divided into 204 working zones. For initial planning, a mean human:dog ratio from the literature enabled estimation of dog population size and dog surveys were then performed in 29 working zones in order to assess dog distribution by land type. Vaccination was conducted at static point stations at weekends, at a total of 44 sites, with each operating for an average of 1.3 days. On Monday to Wednesday, door-to-door vaccination sessions were undertaken in the areas surrounding the preceding static point stations. 23,442 dogs were vaccinated at static point stations and 11,774 dogs were vaccinated during door-to-door vaccinations. At the end of the 20 day vaccination programme, an assessment of vaccination coverage through door-to-door surveys found that of 10,919 dogs observed, 8,661 were vaccinated resulting in a vaccination coverage of 79.3% (95%CI 78.6-80.1%). The estimated human:dog ratio for Blantyre city was 18.1:1. Mobile technology facilitated the collection of data as well as efficient direction and coordination of vaccination teams in near real time. This study demonstrates the feasibility of vaccinating large numbers of dogs at a high vaccination coverage, over a short time period in a large African city

Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo

In past years, much attention has focused on the gene networks that regulate early developmental processes, but less attention has been paid to how multiple networks and processes are temporally coordinated. Recently the discovery of the transcriptional activator Zelda (Zld), which binds to CAGGTAG and related sequences present in the enhancers of many early-activated genes in Drosophila, hinted at a mechanism for how batteries of genes could be simultaneously activated. Here we use genome-wide binding and expression assays to identify Zld target genes in the early embryo with the goal of unraveling the gene circuitry regulated by Zld. We found that Zld binds to genes involved in early developmental processes such as cellularization, sex determination, neurogenesis, and pattern formation. In the absence of Zld, many target genes failed to be activated, while others, particularly the patterning genes, exhibited delayed transcriptional activation, some of which also showed weak and/or sporadic expression. These effects disrupted the normal sequence of patterning-gene interactions and resulted in highly altered spatial expression patterns, demonstrating the significance of a timing mechanism in early development. In addition, we observed prevalent overlap between Zld-bound regions and genomic “hotspot” regions, which are bound by many developmental transcription factors, especially the patterning factors. This, along with the finding that the most over-represented motif in hotspots, CAGGTA, is the Zld binding site, implicates Zld in promoting hotspot formation. We propose that Zld promotes timely and robust transcriptional activation of early-gene networks so that developmental events are coordinated and cell fates are established properly in the cellular blastoderm embryo