Objectives/Goals: To investigate how distinct KRAS mutations (G12D, G12V, and G12R) drive distinct molecular and phenotypic programs in pancreatic tumorigenesis, linking early lineage and signaling differences to clinical patterns such as stage at diagnosis, nodal status, and survival to ultimately inform allele-specific therapies. Methods/Study Population: We analyzed clinical cohorts (MSK-IMPACT n=1,360; COMPASS n=100) and conducted lineage-tracing studies in mice carrying KRAS-G12D, KRAS-G12V, or KRAS-G12R alleles under inflammatory, genetic, and pharmacologic perturbations. Spatial transcriptomic and proteogenomic profiling of resected PDAC tissues characterized EMT and immune signaling states. Functional studies assessed EGFR–PI3K/AKT–RAC1/VAV1 signaling, including RAC1 inhibition and constitutive AKT activation, to reveal allele-specific susceptibilities. Results/Anticipated Results: KRAS-G12D drove robust lineage plasticity, enhancer remodeling, and early neoplastic progression. KRAS-G12R/V showed limited EMT and increased inflammatory signatures, with impaired EGFR–RAC1/VAV1 activation restricting lineage reversion. Constitutive AKT activation rescued the tumor-initiating defect of KRAS-G12R in vivo, pinpointing a downstream signaling bottleneck, which could be exploited therapeutically. Spatial and transcriptomic profiling of resected human PDAC revealed that KRAS-G12R tumors were more often early-stage, node-negative, and linked to improved survival relative to KRAS-G12D. Discussion/Significance of Impact: Integrating patient and mouse data reveals a mechanistic hierarchy among KRAS alleles that governs lineage fate, signaling reliance, and clinical course, pointing to opportunities for allele-tailored therapeutic strategies in pancreatic cancer.

We report the design and functionality of the Murchison Widefield Array Particle Detector Array (MWA PDA), an array of eight particle scintillation detectors deployed to Inyarrimanha Ilgari Bundara, the Murchison Radio-astronomy Observatory (MRO). The purpose of the instrument is to identify cosmic ray extensive air showers (EAS) occurring over the core of the MWA radio telescope and generate a trigger to allow radio data on the event to be captured and analysed. The system also acts as a pathfinder for a much larger instrument to be deployed in the core of the low-frequency component of the Square Kilometre Array, SKA-Low, by the SKA’s ultra-high-energy particles science working group. Here, we describe the instrument and associated infrastructure, which has been verified to comply with the strict radio-frequency emissions requirements of the MRO, and was deployed in November 2024. We present calibration data, which demonstrates the ability of each detector to identify individual atmospheric muons at the expected rate, and we characterise the temperature dependence of the system. We describe a sample of 35 500 EAS identified using multi-detector coincidence over a 13-d period, and show how the detector data can be used to reconstruct the arrival directions and approximate energies of these events. We conclude that the particle detector array can reliably trigger on and reconstruct EAS contained within the $\sim$$103 \times 90$ m$^2$ core region, arriving within 20$^{\circ}$ of zenith, at primary cosmic ray energies above $\sim$4 PeV. We have also verified that the detector array can generate triggers, allowing the capture of radio data from the MWA correlator for offline analysis.

In 250 men (21·4 (sd 2·9) years; BMI 24·2 (sd 3·0) kg·m–2) commencing arduous military training during winter, we investigated the effect of 12 weeks of vitamin D supplementation on lower body (pelvic girdle, sacrum, coccyx and lower limb) overuse musculoskeletal injury risk in a randomised, placebo-controlled trial. Participants received either simulated sunlight (1·3 × standard erythemal dose in T-shirt and shorts, three times per week for 4 weeks and then once per week for 8 weeks), oral vitamin D3 (1000 IU · d–1 for 4 weeks and then 400 IU · d–1 for 8 weeks) or placebo for each intervention. Serum vitamin D metabolites and bone metabolism biomarkers were measured at baseline, week 5 and week 12. At baseline, 29 % of participants were vitamin D sufficient (25-hydroxyvitamin D ≥ 50 nmol·L–1). Vitamin D supplementation achieved vitamin D sufficiency in 95 % of participants after 4 weeks. During 6 months of training and subsequent 3 years of military service, 100 lower body overuse musculoskeletal injuries were diagnosed by clinicians. Frailty models indicated no difference in injury risk between vitamin D and placebo during military training (HRplacebo:vitamin D = 1·23 (95 % CI 0·57, 2·66), P = 0·597) or military service (HRplacebo:vitamin D = 0·94 (95 % CI 0·60, 1·46), P = 0·782). Both safe simulated sunlight and oral vitamin D3 were effective in achieving and maintaining vitamin D sufficiency in almost all. There was no clear evidence that vitamin D affects the risk of lower body overuse musculoskeletal injury during 6 months of military training or subsequent 3 years of military service.

Pulsed gravity currents are generated by the sequential release of dense material into a lighter ambient. We investigate the dynamics of pulsed gravity currents using physical scale experiments, two-dimensional depth-averaged shallow water equation (SWE) based models and three-dimensional lattice Boltzmann method (LBM) simulations. Integrating these results we show for the first time that short duration pulsed releases generate intrusive layers, which accelerate front propagation relative to an instantaneously released current of the same total volume. Conversely, a long delay time between pulses produces a current that propagates slower than an equivalent instantaneous release. This finding is supported by physical experiments and depth-resolving LBM simulations. The depth-resolving simulations show that intrusions in pulsed flows experience less drag resistance than those generated by instantaneous releases. The depth-averaged model considered in the present study does not accurately capture the intrusive flow dynamics of pulsed currents. However, the limitations of the finite-depth SWE model may be mitigated by extensions to incorporate entrainment and density stratification. The results also motivate further research into the impact of buoyancy Reynolds number and channel slope on the propagation of pulsed currents.

Political science is useful for many things but especially for the suite of research methods that we teach our students that generalize to a wide range of careers. However, that training is often buried deep in the major and is not well integrated into further coursework except perhaps for senior research. In reaction to that model, we started a new program that frontloads quantitative research methods, beginning with data visualization and then modeling following an inquiry model. With their newfound independence, students are able to approach substantive upper-level courses ready to engage the worth of theory by evaluating and updating their empirical tests. This article describes the program and reports on survey results from a 2024 sample of political scientists that reveals broadscale support for the program and its operating assumptions.

Paleontology provides insights into the history of the planet, from the origins of life billions of years ago to the biotic changes of the Recent. The scope of paleontological research is as vast as it is varied, and the field is constantly evolving. In an effort to identify “Big Questions” in paleontology, experts from around the world came together to build a list of priority questions the field can address in the years ahead. The 89 questions presented herein (grouped within 11 themes) represent contributions from nearly 200 international scientists. These questions touch on common themes including biodiversity drivers and patterns, integrating data types across spatiotemporal scales, applying paleontological data to contemporary biodiversity and climate issues, and effectively utilizing innovative methods and technology for new paleontological insights. In addition to these theoretical questions, discussions touch upon structural concerns within the field, advocating for an increased valuation of specimen-based research, protection of natural heritage sites, and the importance of collections infrastructure, along with a stronger emphasis on human diversity, equity, and inclusion. These questions offer a starting point—an initial nucleus of consensus that paleontologists can expand on—for engaging in discussions, securing funding, advocating for museums, and fostering continued growth in shared research directions.

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph–based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly “Question-of-the-Month (QotM) Challenge” series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

The U.S. Department of Agriculture–Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed–crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America’s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency’s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being.

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.

The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.

The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.

Enrichment of the heavy rare earth elements (HREE) in carbonatites is rare as carbonatite petrogenesis favours the light (L)REE. We describe HREE enrichment in fenitized phonolite breccia, focusing on small satellite occurrences 1–2 km from the Songwe Hill carbonatite, Malawi. Within the breccia groundmass, a HREE-bearing mineral assemblage comprises xenotime, zircon, anatase/rutile and minor huttonite/thorite, as well as fluorite and apatite.

A genetic link between HREE mineralization and carbonatite emplacement is indicated by the presence of Sr-bearing carbonate veins, carbonatite xenoliths and extensive fenitization. We propose that the HREE are retained in hydrothermal fluids which are residually derived from a carbonatite after precipitation of LREE minerals. Brecciation provides a focusing conduit for such fluids, enabling HREE transport and xenotime precipitation in the fenite. Continued fluid–rock interaction leads to dissolution of HREE-bearing minerals and further precipitation of xenotime and huttonite/thorite.

At a maximum Y content of 3100 µg g−1, HREE concentrations in the presented example are not sufficient to constitute ore, but the similar composition and texture of these rocks to other cases of carbonatite-related HREE enrichment suggests that all form via a common mechanism linked to fenitization. Precipitation of HREE minerals only occurs where a pre-existing structure provides a focusing conduit for fenitizing fluids, reducing fluid – country-rock interaction. Enrichment of HREE and Th in fenite breccia serves as an indicator of fluid expulsion from a carbonatite, and may indicate the presence of LREE mineralization within the source carbonatite body at depth.

This article explores the totemic 2020 Queensland state election, at which a two-term government plagued by a deteriorating economy and widely criticised travel restrictions amid the COVID-19 pandemic was returned with an increased majority. The article posits three arguments: that COVID-19 created a new ‘lens’ through which electors evaluated public policy and that allowed voters to frame public health and safety over the more usual measures of economic performance; that Queensland voters drew on their traditional political culture – especially their predilection for strong leadership and state chauvinism – to evaluate the Palaszczuk Labor government’s pandemic management favourably compared with contemporaneous events in Victoria; and that Queensland voters expressed similar confidence in a Labor economic recovery plan that contrasted favourably with the LNP’s economic platform. In sum, this article argues that Queenslanders in 2020 cast a ‘gratitude vote’ for a government they saw as being in control of both public health and economic recovery.

The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.

The distribution of genetic diversity in invasive plant populations can have important management implications. Alligatorweed [Alternanthera philoxeroides (Mart.) Griseb.] was introduced into the United States around 1900 and has since spread throughout much of the southern United States and California. A successful biological control program was initiated in the late 1960s that reduced A. philoxeroides in the southern United States, although control has varied geographically. The degree to which variation among genotypes may be responsible for variation in control efficacy has not been well studied due to a lack of genetic data. We sampled 373 plants from 90 sites across the United States and genotyped all samples at three chloroplast regions to help inform future management efforts. Consistent with clonal spread, there was high differentiation between sites, yet we found six haplotypes and high haplotype diversity (mean h = 0.48) across states, suggesting this plant has been introduced multiple times. Two of the haplotypes correspond to previously described biotypes that differ in their susceptibility to herbicides and herbivory. The geographic distribution of the three common haplotypes varied by latitude and longitude, while the other haplotypes were widespread or localized to one or a few sites. All the haplotypes we screened are hexaploid (6n = 102), which may enhance biological control. Future studies can use these genetic data to determine whether genotypes differ in their invasiveness or respond differently to control measures. Some states, for instance, have mainly a single haplotype that may respond more uniformly to a single control strategy, whereas other states may require a variety of control strategies. These data will also provide the basis for identifying the source regions in South America, which may lead to the discovery of new biological control agents more closely matched to particular genotypes.

We describe 14 yr of public data from the Parkes Pulsar Timing Array (PPTA), an ongoing project that is producing precise measurements of pulse times of arrival from 26 millisecond pulsars using the 64-m Parkes radio telescope with a cadence of approximately 3 weeks in three observing bands. A comprehensive description of the pulsar observing systems employed at the telescope since 2004 is provided, including the calibration methodology and an analysis of the stability of system components. We attempt to provide full accounting of the reduction from the raw measured Stokes parameters to pulse times of arrival to aid third parties in reproducing our results. This conversion is encapsulated in a processing pipeline designed to track provenance. Our data products include pulse times of arrival for each of the pulsars along with an initial set of pulsar parameters and noise models. The calibrated pulse profiles and timing template profiles are also available. These data represent almost 21 000 h of recorded data spanning over 14 yr. After accounting for processes that induce time-correlated noise, 22 of the pulsars have weighted root-mean-square timing residuals of $<\!\!1\,\mu\text{s}$ in at least one radio band. The data should allow end users to quickly undertake their own gravitational wave analyses, for example, without having to understand the intricacies of pulsar polarisation calibration or attain a mastery of radio frequency interference mitigation as is required when analysing raw data files.