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The meters of numerous Bulgarian folk songs and dance pieces are understood to include beats with two categorically different durations, short and long. Commonly performed dance types bear conventional time signatures that index particular sequences of unequal durations, and many Bulgarian musicians know these time signatures. Yet in the case of one popular dance type, elenino horo, performers and published sources express considerable uncertainty and differences of opinion about the durational sequence and time signature. This lack of consensus serves as the starting point for a study of meter in elenino horo as performed on the tŭpan, a large, double-sided drum that is considered the time-keeping instrument in many Bulgarian folk music ensembles. To examine the meter of elenino horo, I put musicians’ statements and my participant observations in dialogue with existing metric theory and quantitative analysis of rhythm in my field recordings. My primary objective is not to settle the debate about elenino horo—though I do take a position about which time signature fits most current performances—but rather to consider what this point of contention suggests about how meters with unequal durations can be structured and how Bulgarian musicians conceptualize meter. I interpret the metric organization of elenino horo in terms of cognitive theory of meter, arguing that the meter of the dance type contradicts current assumptions about constraints on metric structure. I corroborate my perception of durations in the music by analyzing timing in a sample of recordings. In the second part of the article, I turn to musicians’ conceptions of meter in the form of rhythmic templates that many Bulgarian percussionists use instead of time signatures or notation when demonstrating dance types. By examining frequencies of rhythmic patterns and drum strokes in recordings, I show that these templates approximate drummers’ process of generating rhythms in performance, and I identify ways in which commonly used rhythmic patterns communicate meter to listeners and reflect stylistic differences among performers.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Many techniques have been described for reconstruction of the acetabular labrum, but the procedure is known to be technically rigorous leading to lengthy procedure times and traction times. Increasing efficiency of the procedure with respect to graft preparation and delivery remain areas for potential improvement. We describe a simplified procedure for arthroscopic segmental labral reconstruction using peroneus longus allograft and a single working portal to shuttle the graft into the joint via suture anchors placed at the terminal extents of the graft defect. This method allows for efficient preparation, placement and fixation of the graft that can be completed in under 15 minutes.

Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clinical use primarily for the treatment of cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536, a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of additional PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in Plasmodium. A subset of these inhibitors was profiled for their in vitro killing profile, and commonalities between the killing rate and inhibition of nuclear replication were noted. A kinase panel screen identified PfNEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting PfNEK3 may not be the sole target. Genomic analysis of BI-2536-resistant parasites revealed mutations in genes associated with the starvation-induced stress response, suggesting BI-2536 may also inhibit an aminoacyl-tRNA synthetase.

Many techniques have been described for posterior cruciate ligament (PCL) reconstruction, but residual laxity remains an ongoing challenge. Suture or tape augmentation during ligament reconstruction has become a popular option to prevent graft elongation but comes at the expense of additional costs due to implants for augment fixation, and concern for stress shielding of the graft if the augment and graft are not equally tensioned. We introduce a technique for postless tape augmentation during allograft PCL reconstruction that allows for equal tensioning of graft and augment through the use of a sheath and screw construct without the need for additional implants for augment fixation.

Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge of the target. As resistance increases and treatment options at various stages of disease are limited, it is critical to identify multistage drug targets that are readily interrogated in biochemical assays. Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan-life cycle antiparasitic activity showed that all had acquired mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-naïve parasites recapitulated the resistance phenotype, and parasites with conditional knockdowns of cIRS became hypersensitive to two thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A. Our data show that Plasmodium cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.

BackgroundThe benefits of physical activity for cancer survivors are well documented. However, few older cancer survivors are engaged in regular physical activity. Mobile technologies may be an effective method to deliver physical activity promotion programs for older cancer survivors. iCanFit, a mobile-enabled Web-based app, was developed based on formative research and usability testing. This app includes interactive features of physical activity, goal setting and tracking, and receiving personalized visual feedback. ObjectiveThe aim of this study is to pilot test the initial efficacy of iCanFit. MethodsOlder cancer survivors (N=30) were recruited online through our collaborative partnership with a cancer survivor's organization. After the participants completed an online baseline survey, they were asked to use the iCanFit website. Instructional videos on how to use the web app were available on the website. Participants were asked to complete a follow-up survey 2-3 months later. Participants’ physical activity, quality of life, and their experience with iCanFit were measured. ResultsA total of 30 participants completed the baseline survey, and 26 of them (87%, 26/30) also completed a follow-up survey 2-3 months later. The median age of participants was 69 years (range 60-78). Participants’ quality of life and engagement in regular physical activity improved significantly after the use of iCanFit. Participants indicated a general affinity towards the key function “Goals” in iCanFit, which motivated continued activity. They also provided suggestions to further improve the app (eg, adding a reminder functionality, easier or alternative ways of entering activities). ConclusionThe interactive Web-based app iCanFit has demonstrated initial efficacy. Even though our study was limited by a small sample size, convenience sampling, and a short follow-up period, results suggest that using mobile tools to promote physical activity and healthy living among older cancer survivors holds promise. Next steps include refining iCanFit based on users’ feedback and developing versatile functionality to allow easier physical activity goal setting and tracking. We also call for more studies on developing and evaluating mobile and web apps for older cancer survivors.

BackgroundMost older Americans do not exercise regularly and many have chronic conditions. Among an increasing number of fitness mobile and Web apps, few are designed for older adults with chronic conditions despite high ownership rates of mobile tools and Internet access in this population. We designed a mobile-enabled Web app, iCanFit, to promote physical activity in this population. ObjectiveThis study aimed to test the usability and acceptability of iCanFit among older adults in a community setting. MethodsA total of 33 older adults (aged 60 to 82 years) were recruited from communities to test iCanFit. Of these 33, 10 participants completed the usability testing in a computer room of a senior community center. A research assistant timed each Web application task and observed user navigation behavior using usability metrics. The other 23 participants used the website on their own devices at home and provided feedback after 2-3 weeks by completing a user-experience survey assessing ease of use, helpfulness, and satisfaction with iCanFit. ResultsParticipants completed all 15 tasks on the iCanFit site in an average of 31 (SD 6.9) minutes; some tasks required more time or needed assistance. Participants’ comments were addressed to improve the site’s senior friendliness and ease of use. In the user-experience survey, participants reported high levels of usefulness and satisfaction. More than 56% (13/23) of participants indicated they would continue using the program and recommend it to their families or friends. ConclusionsTesting usability and acceptability is a very important step in developing age-appropriate and user-friendly Web apps, especially for older adults. Testing usability and acceptability in a community setting can help reveal users’ experiences and feedback in a real-life setting. Our study suggested that older adults had a high degree of acceptance of iCanFit and could use it easily. The efficacy trial of iCanFit is currently underway.

The COVID-19 pandemic has created many challenges for universities around the world, including how to keep students engaged in their professional development, despite the challenges of remote learning and virtual student services. The goal of this study was to demonstrate the continued importance of Career Professional Development Center (CPDC) support (pre-pandemic to early stages of the pandemic) for business-related internships influencing student professional development engagement (PDE) and anticipated employment upon graduation. PDE encompasses typical CPDC resources (e.g., internship search support; involvement in student professional organizations (SPOs); professional development coaching; and job search assistance). A survey, the Senior Student Satisfaction Survey (SSSS) was deployed prior to graduation to business students. Using the SSSS, two separate samples of graduating business undergraduates at a Mid-Atlantic University in the United States were surveyed, in late Spring 2019 (pre-pandemic) and late Spring 2020 (early pandemic). Pre-pandemic survey results showed that students having at least one internship experience (versus none) were more likely to: join an SPO sooner; attend more SPO meetings/semester; complete their professional development sooner; and anticipate "by graduation" full-time employment. Despite the drop in survey participation due to the pandemic onset, results consistent with this were found with the early pandemic survey. Like other academic-related and campus services in the face of the pandemic, the business school CPDC is adapting to the new remote ways of operating and successfully transitioned their delivery mode to a 100% virtual model to meet the resource challenge of supporting student PDE. It is hoped that the ideas discussed will be useful to a wider audience.

BACKGROUND: Ambient nitrogen dioxide (N[O.sub.2]) and fine particulate matter with aerodynamic diameter [less than or equal to]2.5 [micro]m (P[M.sub.2.5]) threaten public health in the US, and systemic racism has led to modern-day disparities in the distribution and associated health impacts of these pollutants. OBJECTIVES: Many studies on environmental injustices related to ambient air pollution focus only on disparities in pollutant concentrations or provide only an assessment of pollution or health disparities at a snapshot in time. In this study, we compare injustices in N[O.sub.2]- and P[M.sub.2.5]-attributable health burdens, considering N[O.sub.2]-attributable health impacts across the entire US; document changing disparities in these health burdens over time (20102019); and evaluate how more stringent air quality standards would reduce disparities in health impacts associated with these pollutants. METHODS: Through a health impact assessment, we quantified census tract-level variations in health outcomes attributable to N[O.sub.2] and P[M.sub.2.5] using health impact functions that combine demographic data from the US Census Bureau; two spatially resolved pollutant datasets, which fuse satellite data with physical and statistical models; and epidemiologically derived relative risk estimates and incidence rates from the Global Burden of Disease study. RESULTS: Despite overall decreases in the public health damages associated with N[O.sub.2] and P[M.sub.2.5], racial and ethnic relative disparities in N[O.sub.2]-attributable pediatric asthma and P[M.sub.2.5]-attributable premature mortality have widened in the US during the last decade. Racial relative disparities in P[M.sub.2.5] -attributable premature mortality and N[O.sub.2] -attributable pediatric asthma have increased by 16% and 19%, respectively, between 2010 and 2019. Similarly, ethnic relative disparities in P[M.sub.2.5]-attributable premature mortality have increased by 40% and N[O.sub.2]-attributable pediatric asthma by 10%. DISCUSSION: Enacting and attaining more stringent air quality standards for both pollutants could preferentially benefit the most marginalized and minoritized communities by greatly reducing racial and ethnic relative disparities in pollution-attributable health burdens in the US. Our methods provide a semi-observational approach to track changes in disparities in air pollution and associated health burdens across the US. https://doi.org/10.1289/EHP11900, Introduction Ambient nitrogen dioxide (N[O.sub.2]), a marker for the complex mixture of traffic-related pollution, and fine particulate matter with aerodynamic diameter [less than or equal to] 2:5 [micro]m (P[M.sub.2.5]) pose [...]

Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains.

The COVID-19 global pandemic and associated government lockdowns dramatically altered human activity, providing a window into how changes in individual behavior, enacted en masse, impact atmospheric composition. The resulting reductions in anthropogenic activity represent an unprecedented event that yields a glimpse into a future where emissions to the atmosphere are reduced. Furthermore, the abrupt reduction in emissions during the lockdown periods led to clearly observable changes in atmospheric composition, which provide direct insight into feedbacks between the Earth system and human activity. While air pollutants and greenhouse gases share many common anthropogenic sources, there is a sharp difference in the response of their atmospheric concentrations to COVID-19 emissions changes, due in large part to their different lifetimes. Here, we discuss several key takeaways from modeling and observational studies. First, despite dramatic declines in mobility and associated vehicular emissions, the atmospheric growth rates of greenhouse gases were not slowed, in part due to decreased ocean uptake of CO2 and a likely increase in CH4 lifetime from reduced NO x emissions. Second, the response of O3 to decreased NO x emissions showed significant spatial and temporal variability, due to differing chemical regimes around the world. Finally, the overall response of atmospheric composition to emissions changes is heavily modulated by factors including carbon-cycle feedbacks to CH4 and CO2, background pollutant levels, the timing and location of emissions changes, and climate feedbacks on air quality, such as wildfires and the ozone climate penalty.

There is a shift in antimalarial drug discovery from phenotypic screening toward target-based approaches, as more potential drug targets are being validated in Plasmodium species. Given the high attrition rate and high cost of drug discovery, it is important to select the targets most likely to deliver progressible drug candidates. In this paper, we describe the criteria that we consider important for selecting targets for antimalarial drug discovery. We describe the analysis of a number of drug targets in the Malaria Drug Accelerator (MalDA) pipeline, which has allowed us to prioritize targets that are ready to enter the drug discovery process. This selection process has also highlighted where additional data are required to inform target progression or deprioritization of other targets. Finally, we comment on how additional drug targets may be identified.

The RhopH complex is implicated in malaria parasites' ability to invade and create new permeability pathways in host erythrocytes, but its mechanisms remain poorly understood. Here, we enrich the endogenous RhopH complex in a native soluble form, comprising RhopH2, CLAG3.1, and RhopH3, directly from parasite cell lysates and determine its atomic structure using cryo-electron microscopy (cryo-EM), mass spectrometry, and the cryoID program. CLAG3.1 is positioned between RhopH2 and RhopH3, which both share substantial binding interfaces with CLAG3.1 but make minimal contacts with each other. The forces stabilizing individual subunits include 13 intramolecular disulfide bonds. Notably, CLAG3.1 residues 1210 to 1223, previously predicted to constitute a transmembrane helix, are embedded within a helical bundle formed by residues 979 to 1289 near the C terminus of CLAG3.1. Buried in the core of the RhopH complex and largely shielded from solvent, insertion of this putative transmembrane helix into the erythrocyte membrane would likely require a large conformational rearrangement. Given the unusually high disulfide content of the complex, it is possible that such a rearrangement could be initiated by the breakage of allosteric disulfide bonds, potentially triggered by interactions at the erythrocyte membrane. This first direct observation of an exported Plasmodium falciparum transmembrane protein-in a soluble, trafficking state and with atomic details of buried putative membrane-insertion helices-offers insights into the assembly and trafficking of RhopH and other parasite-derived complexes to the erythrocyte membrane. Our study demonstrates the potential the endogenous structural proteomics approach holds for elucidating the molecular mechanisms of hard-to-isolate complexes in their native, functional forms.

The 2018 NASA Health and Air Quality Applied Science Team (HAQAST) Indicators Tiger Team collaboration between NASA-supported scientists and civil society stakeholders aimed to develop satellite-derived global air pollution and climate indicators. This Commentary shares our experience and lessons learned. Together, the team developed methods to track wildfires, dust storms, pollen counts, urban green space, nitrogen dioxide concentrations and asthma burdens, tropospheric ozone concentrations, and urban particulate matter mortality. Participatory knowledge production can lead to more actionable information but requires time, flexibility, and continuous engagement. Ground measurements are still needed for ground truthing, and sustained collaboration over time remains a challenge.

X-ray crystallography often requires non-native constructs involving mutations or truncations, and is challenged by membrane proteins and large multicomponent complexes. We present here a bottom-up endogenous structural proteomics approach whereby near-atomic-resolution cryo electron microscopy (cryoEM) maps are reconstructed ab initio from unidentified protein complexes enriched directly from the endogenous cellular milieu, followed by identification and atomic modeling of the proteins. The proteins in each complex are identified using cryoID, a program we developed to identify proteins in ab initio cryoEM maps. As a proof of principle, we applied this approach to the malaria-causing parasite Plasmodium falciparum, an organism that has resisted conventional structural-biology approaches, to obtain atomic models of multiple protein complexes implicated in intraerythrocytic survival of the parasite. Our approach is broadly applicable for determining structures of undiscovered protein complexes enriched directly from endogenous sources.