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Abstract Maple syrup urine disease (MSUD) is a disorder of branched‐chain amino acid metabolism caused by a defect in the branched‐chain α‐ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched‐chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well‐defined disease associations. We report on two families with the same BCKDK variant (c.1115C>G (p.Thr372Arg)). Probands were detected on newborn screening and demonstrated biochemical evidence of MSUD. The variant was identified in reportedly asymptomatic parents and additional family members who had elevated BCAA and alloisoleucine, following an autosomal dominant pattern of inheritance. To better define the functional effect of the variant on the kinase, we completed molecular modeling using sequence‐based (2D), structural‐based (3D), and dynamic‐based (4D) analyses. The BCKDK variant modeling indicated a gain‐of‐function which leads to impaired BCAA catabolism consistent with the biochemical evidence in this cohort. Combining the evidence gained from molecular modeling with the absence of metabolic decompensation in our patients and several adult family members, despite encountering stressors typically problematic in classic MSUD, we suggest that heterozygous gain‐of‐function variants in BCKDK may represent a novel biochemical phenotype of MSUD with a benign clinical course.

Biodiversity conservation can entail socially controversial management interventions such as herbicide applications to eradicate aquatic invasive plants from highly productive native ecosystems. This study used a case example of the successful eradication of Alaska’s first aquatic invasive plant, Elodea spp. from two lakes surrounded by waterfront homes with the objective to measure perceived changes in the use of the lakes by local residents. A household survey was conducted with homeowners before and after the application of herbicides to measure public attitudes and human behavior changes related to the use of herbicide. We found fears and subjective expectations of survey respondents did not match the eventually collected objective scientific data on water quality. Also, we measured a significant negative change in lake-related activities over the duration of the management intervention that is smaller compared to the reduced activity level lake residents anticipated before the application of herbicide. Swimming and the consumption of fish caught in the lakes were the most negatively affected ecosystem services. The study showed the indirect and often hidden effects of management interventions on human risk perceptions that can translate to unintended human behavior changes and a reduction in related ecosystem service use. To account for complex social dimensions of controversial resource management interventions, resource managers require information on broad public value trade-offs and perceived risk beyond that which public meetings can provide. In this context, household surveys before and after resource management interventions can offer insights few other approaches can. The potential for more advanced outreach methods is discussed.

Permafrost-agroecosystems include all cultivation and pastoral activities in areas underlain by permafrost. These systems support local livelihoods and food production and are rarely considered in global agricultural studies but may become more relevant as climate change is increasing opportunities for food production in high latitude and mountainous areas. The exact locations and amount of agricultural production in areas containing permafrost are currently unknown, therefore we provide an overview of countries where both permafrost and agricultural activities are present. We highlight the socioecological diversity and complexities of permafrost-agroecosystems through seven case studies: (1) crop cultivation in Alaska, USA; (2) Indigenous food systems and crop cultivation in the Northwest Territories, Canada; (3) horse and cattle husbandry and Indigenous hay production in the Sakha Republic, Russia; (4) mobile pastoralism and husbandry in Mongolia; (5) yak pastoralism in the Central Himalaya, Nepal; (6) berry picking and reindeer herding in northern Fennoscandia; and (7) reindeer herding in northwest Russia. We discuss regional knowledge gaps associated with permafrost and make recommendations to policy makers and land users for adapting to changing permafrost environments. A better understanding of permafrost-agroecosystems is needed to help sustainably manage and develop these systems considering rapidly changing climate, environments, economies, and industries.

IntroductionVentricular unloading during prolonged bed rest, mechanical circulatory support or microgravity has repeatedly been linked to potentially life-threatening arrhythmias. It is unresolved, whether this arrhythmic phenotype is caused by the reduction in cardiac workload or rather by underlying diseases or external stimuli. We hypothesized that the reduction in cardiac workload alone is sufficient to impair ventricular repolarization and to induce arrhythmias in hearts.MethodsRat hearts were unloaded using the heterotopic heart transplantation. The ECG of unloaded and of control hearts were telemetrically recorded over 56 days resulting in >5 × 106 cardiac cycles in each heart. Long-term electrical remodeling was analyzed using a novel semi-automatic arrhythmia detection algorithm.Results56 days of unloading reduced left ventricular weight by approximately 50%. While unloading did not affect average HRs, it markedly prolonged the QT interval by approximately 66% and induced a median tenfold increase in the incidence of ventricular arrhythmias in comparison to control hearts.ConclusionThe current study provides direct evidence that the previously reported hypertrophic phenotype of repolarization during cardiac unloading translates into an impaired ventricular repolarization and ventricular arrhythmias in vivo. This supports the concept that the reduction in cardiac workload is a causal driver of the development of arrhythmias during ventricular unloading.

TikTok, a social media platform designed for sharing short videos (“microvlogs”), provides an opportunity to learn how nonprofits adapt and implement social media strategies. Similarly, exploring nonprofits’ behavior on TikTok is useful for analyzing the impact that strategy has on the content nonprofits produce and user engagement. Using a mixed-methods design, this study analyzed data from 29 interviews and 575 microvlogs to answer three questions. First, how are nonprofits incorporating microvlogging into their social media strategy? Second, applying the hierarchy of engagement framework, do nonprofits produce social media content aligned with their expressed strategy? Finally, does alignment between strategy and output affect user engagement? The findings indicate that, unlike Facebook and Twitter/X, nonprofits on TikTok harness community-building content to facilitate information sharing and action. Strategy-output alignment significantly increases user engagement, but only for community-building content. Thus, social media strategy may be less important than authenticity on TikTok.

Abstract Background About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells. Methods This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1–5: single dose of 0.5 mg/m2, 1.5 mg/m2, 5 mg/m2, 15 mg/m2, 45 mg/m2; cohort 6: 15 mg/m2 on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow. Results Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m2 FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses. Conclusions FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial. Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254).

Dengue is caused by four genetically distinct viral serotypes, dengue virus (DENV) 1-4. Following transmission by Aedes mosquitoes, DENV can cause a broad spectrum of clinically apparent disease ranging from febrile illness to dengue hemorrhagic fever and dengue shock syndrome. Progress in the understanding of different dengue serotypes and their impacts on specific host-virus interactions has been hampered by the scarcity of tools that adequately reflect their antigenic and genetic diversity. To bridge this gap, we created and characterized infectious clones of DENV1–4 originating from South America, Africa, and Southeast Asia. Analysis of whole viral genome sequences of five DENV isolates from each of the four serotypes confirmed their broad genetic and antigenic diversity. Using a modified circular polymerase extension reaction (CPER), we generated de novo viruses from these isolates. The resultant clones replicated robustly in human and insect cells at levels similar to those of the parental strains. To investigate in vivo properties of these genetically diverse isolates, representative viruses from each DENV serotype were administered to NOD Rag1−/−, IL2rgnull Flk2−/− (NRGF) mice, engrafted with components of a human immune system. All DENV strains tested resulted in viremia in humanized mice and induced cellular and IgM immune responses. Collectively, we describe here a workflow for rapidly generating de novo infectious clones of DENV – and conceivably other RNA viruses. The infectious clones described here are a valuable resource for reverse genetic studies and for characterizing host responses to DENV in vitro and in vivo.

Abstract Background E-learning based laboratory classes can replace or enhance in-classroom laboratories. They typically offer temporal flexibility, self-determined learning speed, repeatability and do not require supervision or face-to-face contact. The aim of this feasibility study was to investigate whether the established in-classroom laboratory class on the baroreceptor reflex (BRR) can be transformed into a new e-learning based asynchronous laboratory class for untrained, non-supervised students without medical equipment. The BRR is a fundamental cardiovascular process which is regularly visualized in physiology during in-classroom laboratories by a student-performed Active Standing Test (AST). During this voluntary provocation of orthostatic stress, the BRR reliably causes a solid rise in heart rate (HR) and a stabilization or even increase in blood pressure (BP). Methods The conventional AST was modified by omission of BP measurements which would require medical devices and was embedded into a framework of interactive digital material allowing independent student performance. With specific adaptions, this instrument was implemented to 1st and 2nd year curricula of human medicine, dental medicine, midwifery and pharmacy. An audience response system was used to collect the students’ data on HR, epidemiology, technical problems, satisfaction and orthostatic symptoms. As primary outcome, we investigated the students’ correct performance of the modified AST regarding textbook conformity of the HR data. Secondary outcomes included technical feasibility, the students’ satisfaction and consistency of HR data within predefined subgroups (e.g., gender, curricula). Descriptive statistics are reported. Results The class was completed by 217 students (mean age: 23 ± 8 [SD], 81% female, 19% male). Mean reported rise of HR during standing was ~ 20 bpm (~ 30%) which is highly concordant to textbooks. Reported feasibility (~ 80% negated any technical issues) and students’ satisfaction (4.4 on 5-point Likert-scale) were high. The HR data were consistent within the subgroups. Conclusion This study demonstrates that the highly relevant BRR can be successfully addressed in an e-learning based asynchronous laboratory class implementing a non-supervised AST restricted to HR measurements embedded in digital material. The robust HR response and the adjustable complexity allow an application to different healthcare-related curricula. This class, therefore, provides a broad audience access to a fundamental concept of cardiovascular physiology.

Abstract There is currently large uncertainty over the impacts of climate change on precipitation trends over the US west coast. Atmospheric rivers (ARs) are a significant source of US west coast precipitation and trends in ARs can provide insight into future precipitation trends. There are already a variety of different methods used to identify ARs, but many are used in contexts that are often difficult to apply to large climate datasets due to their computational cost and requirement of integrated vapor transport as an input variable, which can be expensive to compute in climate models at high temporal frequencies. Using deep learning (DL) to track ARs is a unique approach that can alleviate some of the computational challenges that exist in more traditional methods. However, some questions still remain regarding its flexibility and robustness. This research investigates the consistency of a DL methodology of tracking ARs with more established algorithms to demonstrate its high‐level performance for future studies.

Emerging studies indicate a dangerous trend regarding high levels of stress, depression, and burnout among graduate students across all disciplines. This study focuses on public administration doctoral students specifically and probes this issue further by asking how stress and sources of social and institutional support affect students' perceptions of stress and balance in their lives. To address this, we surveyed students about their experiences navigating and managing stress in their respective doctoral programs and found that four sources of support were critical in decreasing students' stress and perceptions of conflict between their academic and non-academic lives. Our results help to understand the complex experiences of public administration doctoral students and offer insight into how sources of support can help mitigate stress and improve the lives of students. We conclude with recommendations for how doctoral programs can encourage and provide these critical supports and begin to institutionalize student well-being.

The Arctic is undergoing large-scale changes that are likely to accelerate in future decades such as introductions and expansions of invasive species. The Arctic is in a unique position to prevent new introductions and spread of existing invasive species by adopting policies and actions aimed at early detection. Responding to threats from invasive species to minimize impacts to ecosystems, communities, food security, and northern economies will necessitate extensive observations and monitoring, but resource managers often face decisions without having adequate data and resources at hand. Local observing programs such as citizen science and community-based monitoring programs present attractive methods for increasing observing capacity that span contributory and co-created approaches while raising awareness of an issue among stakeholders. While the co-created model has been widely applied and encouraged in the Arctic context, contributory citizen science programs offer an additional tool for addressing observing needs in the Arctic. We showcase three contributory citizen science programs related to freshwater, terrestrial, and marine environments that have supported the objectives of the Alaska Invasive Species Partnership. We discuss criteria for achieving ARIAS priority actions at the participant scale related to participants' motivation and participants' understanding of the value of their contributions, at the programmatic scale, for example promoting accessible, reciprocal, and transparent knowledge exchange, and at the policy and science scale where management action is data driven. The approach is aimed at successful integration of citizen science into Arctic policy making. Finally, we discuss challenges related to broader global data collection and future directions for contributory citizen science within Arctic observing networks. Key words: citizen science; community science; Arctic observing; alien species; monitoring; early detection; evidence-based policy L'Arctique fait l'objet de changements de taille susceptibles de s'accelerer au cours des prochaines decennies, comme l'introduction et l'intensification d'especes envahissantes. L'Arctique se trouve dans la position unique d'empecher les nouvelles introductions et la propagation des especes envahissantes actuelles grace a l'adoption de politiques et de mesures visant a en faire la detection precoce. Reagir aux menaces des especes envahissantes afin de minimiser leurs incidences sur les ecosystemes, les collectivites, la securite alimentaire et les economies nordiques necessitera des activites d'observation et de surveillance d'envergure. Toutefois, les gestionnaires de ressources sont souvent tenus de prendre des decisions sans posseder de donnees et de ressources adequates. Les programmes d'observation locaux, comme les programmes de science citoyenne et les programmes de surveillance communautaire, constituent des methodes interessantes d'augmentation de la capacite d'observation qui comportent des approches contributives et creees en collaboration tout en ayant pour effet de sensibiliser les parties prenantes aux enjeux. Bien que le modele cree en collaboration ait ete applique et encourage a grande echelle dans le contexte de l'Arctique, les programmes de science citoyenne contributive offrent un outil supplementaire pour s'attaquer aux besoins d'observation dans l'Arctique. Nous presentons trois programmes de science citoyenne contributive se rapportant a l'environnement d'eau douce, a l'environnement terrestre et a l'environnement marin, programmes qui s'inscrivent dans les objectifs du partenariat de l'Alaska en matiere d'especes envahissantes (Alaska Invasive Species Partnership). Nous discutons des criteres necessaires a l'atteinte des mesures prioritaires de l'ARIAS a l'echelle du participant, soit en matiere de motivation des participants et de leur comprehension de la valeur de leurs contributions, a l'echelle programmatique, par exemple enfaisant la promotion d'un echange de connaissances accessible, reciproque et transparent, et a l'echelle des politiques et des sciences pour lesquelles les mesures de gestion sont fondees sur les donnees. La demarche vise l'integration reussie de la science citoyenne dans l'elaboration des politiques touchant l'Arctique. Enfin, nous discutons des defis inherents a la collecte generale des donnees globales et a l'orientation future de la science citoyenne contributive au sein des reseaux d'observation de l'Arctique. Mots cles : science citoyenne; science communautaire; observation de l'Arctique; especes etrangeres; surveillance; detection precoce; politique fondee sur des donnees probantes Traduit pour la revue Arctic par Nicole Giguere., INTRODUCTION Native biodiversity of the Arctic provides sustainable resources that support rural and urban cultures, global ecological processes, and economies of the North (Johnson et al., 2007; Courtney et al., [...]

Unraveling the exact nature of nonequilibrium and correlated interactions is paramount for continued progress in many areas of condensed matter science. Such insight is a prerequisite to develop an engineered approach for smart materials with targeted properties designed to address standing needs such as efficient light harvesting, energy storage, or information processing. For this goal, it is critical to unravel the dynamics of the energy conversion processes between carriers in the earliest time scales of the excitation dynamics. We discuss the implementation and benefits of attosecond soft x-ray core-level spectroscopy up to photon energies of 600 eV for measurements in solid-state systems. In particular, we examine how the pairing between coherent spectral coverage and temporal resolution provides a powerful new insight into the quantum dynamic interactions that determine the macroscopic electronic and optical response. We highlight the different building blocks of the methodology and point out the important aspects for its application from condensed matter studies to materials as thin as 25 nm. Furthermore, we discuss the technological developments in the field of tabletop attosecond soft x-ray sources with time-resolved measurements at the near and extended edge simultaneously and investigate the exciting prospective of extending such technique to the study of 2-dimensional materials.

Introduction: Ventricular unloading during prolonged bed rest, mechanical circulatory support or microgravity has repeatedly been linked to potentially life-threatening arrhythmias. It is unresolved, whether this arrhythmic phenotype is caused by the reduction in cardiac workload or rather by underlying diseases or external stimuli. We hypothesized that the reduction in cardiac workload alone is sufficient to impair ventricular repolarization and to induce arrhythmias in hearts. Methods: Rat hearts were unloaded using the heterotopic heart transplantation. The ECG of unloaded and of control hearts were telemetrically recorded over 56 days resulting in >5x106 cardiac cycles in each heart. Long-term electrical remodeling was analyzed using a novel semi-automatic arrhythmia detection algorithm. Results: 56 days of unloading reduced left ventricular weight by approximately 50%. While unloading did not affect average HRs, it markedly prolonged the QT interval by approximately 66% and induced a median tenfold increase in the incidence of ventricular arrhythmias in comparison to control hearts. Conclusion: The current study provides direct evidence that the previously reported hypertrophic phenotype of repolarization during cardiac unloading translates into an impaired ventricular repolarization and ventricular arrhythmias in vivo. This supports the concept that the reduction in cardiac workload is a causal driver of the development of arrhythmias during ventricular unloading. [ABSTRACT FROM AUTHOR]

In the Markham Valley of Papua New Guinea, a Biomass Energy company is currently transforming the landscape by planting thousands of hectares of eucalyptus trees to offer a 'carbon-neutral' way of electricity generation. The company operates in concert with local Wampar landholders, offering jobs, land rents, and business opportunities. This large-scale land transformation from grassland to eucalyptus forests impacts social relations, especially those regulating access to land, and creates more and novel social conflicts within and between kin groups. By presenting four ethnographic portraits, I show how access to and exclusion from land, jobs and monetary benefits are differentially experienced, and how people negotiate these novel effects of 'intimate exclusion' occurring in their midst. There are clear trends towards alienation and exclusion of some people from land to which they formerly had access. Customary claims to usage rights are abrogated except for the primary owners of the land, and sometimes even members of the landholding lineages are deprived of receiving monetary benefits from these enterprises. Access to land, jobs and business opportunities are now governed mainly by social relations with the main decision-makers and proponents of the eucalyptus project. [ABSTRACT FROM AUTHOR]

Identifying, detecting, and localizing extreme weather events is a crucial first step in understanding how they may vary under different climate change scenarios. Pattern recognition tasks such as classification, object detection, and segmentation (i.e., pixel-level classification) have remained challenging problems in the weather and climate sciences. While there exist many empirical heuristics for detecting extreme events, the disparities between the output of these different methods even for a single event are large and often difficult to reconcile. Given the success of deep learning (DL) in tackling similar problems in computer vision, we advocate a DL-based approach. DL, however, works best in the context of supervised learning – when labeled datasets are readily available. Reliable labeled training data for extreme weather and climate events is scarce. We create “ClimateNet” – an open, community-sourced human-expert-labeled curated dataset that captures tropical cyclones (TCs) and atmospheric rivers (ARs) in high-resolution climate model output from a simulation of a recent historical period. We use the curated ClimateNet dataset to train a state-of-the-art DL model for pixel-level identification – i.e., segmentation – of TCs and ARs. We then apply the trained DL model to historical and climate change scenarios simulated by the Community Atmospheric Model (CAM5.1) and show that the DL model accurately segments the data into TCs, ARs, or “the background” at a pixel level. Further, we show how the segmentation results can be used to conduct spatially and temporally precise analytics by quantifying distributions of extreme precipitation conditioned on event types (TC or AR) at regional scales. The key contribution of this work is that it paves the way for DL-based automated, high-fidelity, and highly precise analytics of climate data using a curated expert-labeled dataset – ClimateNet. ClimateNet and the DL-based segmentation method provide several unique capabilities: (i) they can be used to calculate a variety of TC and AR statistics at a fine-grained level; (ii) they can be applied to different climate scenarios and different datasets without tuning as they do not rely on threshold conditions; and (iii) the proposed DL method is suitable for rapidly analyzing large amounts of climate model output. While our study has been conducted for two important extreme weather patterns (TCs and ARs) in simulation datasets, we believe that this methodology can be applied to a much broader class of patterns and applied to observational and reanalysis data products via transfer learning.

Birdwatching is considered one of the fastest growing nature-based tourism sectors in the world. Tourists who identify as birdwatchers tend to be well-educated and wealthy travellers with a specific interest in the places they visit. Birdwatchers can bring economic resources to remote communities diversifying their economies and contribute to biodiversity conservation in areas of bird habitat with global significance. Alaska plays a critical role in understanding the link between bird conservation and bird tourism as it supports the world's largest concentration of shorebirds and is a global breeding hotspot for hundreds of migratory species, including many species of conservation concern for their decline across their ranges. Alaska is also a global destination for birders due to the large congregations of birds that occur during the spring, summer and fall seasons. Despite its global importance, relatively little information exists on the significance of bird tourism in Alaska or on opportunities for community development that align with conservation. This study used ebird data to look at trends in Alaska birdwatching and applied existing information from the Alaska Visitor Statistics Program to estimate visitor expenditures and the impact of that spending on Alaska's regional economies. In 2016, nearly 300,000 birdwatchers visited Alaska and spent $378 million, supporting approximately 4,000 jobs. The study describes bird tourism's contributions to local jobs and income in remote rural and urban economies and discusses opportunities for developing and expanding the nature-based tourism sector. The study points toward the importance of partnering with rural communities and landowners to advance both economic opportunities and biodiversity conservation actions. The need for new data collection addressing niche market development and economic diversification is also discussed.