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Influenza is one of the leading causes of disease-related mortalities worldwide. Several strategies have been implemented during the past decades to hinder the replication cycle of influenza viruses, all of which have resulted in the emergence of resistant virus strains. The most recent example is baloxavir marboxil, where a single mutation in the active site of the target endonuclease domain of the RNA-dependent-RNA polymerase renders the recent FDA approved compound ∼1000-fold less effective. Raltegravir is a first-in-class HIV inhibitor that shows modest activity to the endonuclease. Here, we have used structure-guided approaches to create rationally designed derivative molecules that efficiently engage the endonuclease active site. The design strategy was driven by our previously published structures of endonuclease-substrate complexes, which allowed us to target functionally conserved residues and reduce the likelihood of resistance mutations. We succeeded in developing low nanomolar equipotent inhibitors of both wild-type and baloxavir-resistant endonuclease. We also developed macrocyclic versions of these inhibitors that engage the active site in the same manner as their 'open' counterparts but with reduced affinity. Structural analyses provide clear avenues for how to increase the affinity of these cyclic compounds.

The use of biological hard structures, such as otoliths, is the most common method of aging bony fish (Pannella, 1971; Gauldie and Nelson, 1990; Stevenson and Campana, 1992), dating back [...]

Elementary general music teachers encounter challenging behaviors in the music classroom when teaching students with emotional/behavioral disorders (EBD), which require prevention and response. In this article, I reviewed literature on pedagogical strategies and interventions for students with EBD in the elementary general music classroom. The review is organized as follows: (a) introduction and process, (b) overview of trauma, (c) overview of EBD, (d) principles of trauma-informed care, and (e) summary and recommendations. Through this review, I present current knowledge on best practices for understanding and framing the unique behavioral needs of special learners with EBD through a trauma-informed lens.

Over the past decade Aboriginal and Torres Strait Islander studies and perspectives have been mandated across the Australian national curriculum and all teachers are now required to demonstrate strategies for teaching Aboriginal and Torres Strait Islander students and have a broad knowledge of Aboriginal histories, cultures and languages. This paper describes a project focused on enabling Aboriginal Education Workers (AEWs) to play a critical role in transforming these initiatives into real and sustainable change through authentic, technology-based pedagogy. Indigenous research methodologies and design-based research (DBR) were used to investigate the potential educational roles for AEWs enabled by elearning and new technologies. The project, called "Skilling Up: Improving educational opportunities for AEWs through technology based pedagogy" was funded by the Office of Learning and Teaching. This paper reports on the findings of the study conducted in Western Australia, including pre-study survey results, together with a description of a unit of study to provide opportunities for AEWs to use technologies in their work, and to create authentic digital stories for use in teacher education. The development of design principles for the design of such environments is also discussed.

Barriers to literacy complicate collaboration between English as a Second Language (ESL) teachers, content teachers, and teachers of students who are visually impaired (i.e., those who are blind or have low vision). Each teacher brings knowledge of practice in their field to the table, but where the overlap occurs for students with visual impairments who are English learners is not always clear. Most preparation programs for teachers of students with visual impairments do not prepare teachers to work with English learners. Nor do pre-service ESL teachers learn about teaching students with visual impairments. Disagreements among teachers result in these students not receiving appropriate supports. In this paper, the author outlines barriers facing students with visual impairments who are learning English and shares practices that can help them build literacy skills. The literacy strategies for reading, writing, listening, and speaking that have been highlighted in this article can help teachers of students who are visually impaired, ESL teachers, and content teachers collaborate effectively to meet best the needs of students with visual impairments who are learning English.

Focused ultrasound has experimentally been found to enhance the diffusion of nanoparticles; our aim with this work is to study this effect closer using both experiments and non-equilibrium molecular dynamics. Measurements from single particle tracking of 40 nm polystyrene nanoparticles in an agarose hydrogel with and without focused ultrasound are presented and compared with a previous experimental study using 100 nm polystyrene nanoparticles. In both cases, we observed an increase in the mean square displacement during focused ultrasound treatment. We developed a coarse-grained non-equilibrium molecular dynamics model with an implicit solvent to investigate the increase in the mean square displacement and its frequency and amplitude dependencies. This model consists of polymer fibers and two sizes of nanoparticles, and the effect of the focused ultrasound was modeled as an external oscillating force field. A comparison between the simulation and experimental results shows similar mean square displacement trends, suggesting that the particle velocity is a significant contributor to the observed ultrasound-enhanced mean square displacement. The resulting diffusion coefficients from the model are compared to the diffusion equation for a two-time continuous time random walk. The model is found to have the same frequency dependency. At lower particle velocity amplitude values, the model has a quadratic relation with the particle velocity amplitude as described by the two-time continuous time random walk derived diffusion equation, but at higher amplitudes, the model deviates, and its diffusion coefficient reaches the non-hindered diffusion coefficient. This observation suggests that at higher ultrasound intensities in hydrogels, the non-hindered diffusion coefficient can be used. [ABSTRACT FROM AUTHOR]

The rise in college preparatory coursework across American high schools appears not to affect college enrollment and graduation rates. This study uses the Civil Rights Data Collection to evaluate three stages along the college preparatory pipeline: access to, enrollment in, and mastery of Advanced Placement® and International Baccalaureate® coursework to understand the cumulative academic opportunities shaping students' college readiness. Leaks in the pipeline divert out historically marginalized students. An adaptation of the Herfindahl-Hirschman Index captures the magnitude of these racial and ethnic disparities. Social context explains where school and district resources alleviate disparities to provide more equitable (i.e., proportionally representative) academic opportunities. These findings offer substantive direction to improve equality in students' college readiness opportunities.

To identify the dominant cultural models among parents transmitting faith to their children, we find few methodological guidelines to guide coding and analysis of semi-structured interviews. We thus developed a three-phase procedure for our research team. Phase-one follows Campbell et al. by unitizing on meanings rather than words/pages, including creating decision rules documents, keyword lists, and summary memos. We provide empirical support for the reliability of those procedures and contribute by adding final validity checks into phase one and a new set of second-order coding procedures as phase two and phase three, as suggested by Miles and Huberman, to transform theme analysis into patterned findings. Phase two codes the latent patterns underlying the phase-one thematic codes. Phase three quantifies phase-two codes into matrices. Although time intensive, other researchers can apply these procedures to produce transparent, auditable findings.

The transport of drugs into tumor cells near the center of the tumor is known to be severely hindered due to the high interstitial pressure and poor vascularization. The aim of this work is to investigate the possibility to induce acoustic streaming in a tumor. Two tumor cases (breast and abdomen) are simulated to find the acoustic streaming and temperature rise, while varying the focused ultrasound transducer radius, frequency, and power for a constant duty cycle (1%). In the absence of perfusion, the simulated rise in temperature, despite the low duty cycle, never reaches a steady state and is fitted to a logarithmic equation, enabling predictions of the temperature for long treatment times. Higher frequencies and larger probe radii are found to result in shorter treatment times relative to the temperature rise, at the cost of a smaller treated area. Results from the simulations indicate that it may be possible to achieve reasonable acoustic streaming values in tumor without the temperature exceeding 50 °C. Treatment times for streaming a distance of 50 μm in the breast case are shown to range from less than one and a half hour to 93 h, depending on the probe settings. [ABSTRACT FROM AUTHOR]

Objective: To estimate a causal relationship between mental health staffing and time to initiation of mental health care for new patients. Data Sources and Study Setting: As the largest integrated health care delivery system in the United States, the Veterans Health Administration (VHA) provides a unique setting for isolating the effects of staffing on initiation of mental health care where demand is high and out‐of‐pocket costs are not a relevant confounder. We use data from the Department of Defense and VHA to obtain patient and facility characteristics and health care use. Study Design: To isolate exogenous variation in mental health staffing, we used an instrumental variables approach—two‐stage residual inclusion with a discrete time hazard model. Our outcome is time to initiation of mental health care after separation from active duty (first appointment) and our exposure is mental health staffing (standardized clinic time per 1000 VHA enrollees per pay period). Data Collection/Extraction Methods: Our cohort consists of all Veterans separating from active duty between July 2014 and September 2017, who were enrolled in the VHA, and had at least one diagnosis of post‐traumatic stress disorder, major depressive disorder, and/or substance use disorder in the year prior to separation from active duty (N = 54,209). Principal Findings: An increase of 1 standard deviation in mental health staffing results in a higher likelihood of initiating mental health care (adjusted hazard ratio: 3.17, 95% confidence interval: 2.62, 3.84, p < 0.001). Models stratified by tertile of mental health staffing exhibit decreasing returns to scale. Conclusions: Increases in mental health staffing led to faster initiation of care and are especially beneficial in facilities where staffing is lower, although initiation of care appears capacity‐limited everywhere. [ABSTRACT FROM AUTHOR]

The "Journal of Research in Music Education" ("JRME") is the longest running serial dedicated to music education research, and its articles are widely considered exemplars in the field worldwide. This is a bibliometric study of the sources cited in articles published in the "JRME" from its inception in 1953 to 2015. We extracted 31,679 references from 1,341 the "JRME" articles; rank-ordered those frequently cited journals, articles, and authors; investigated the interdisciplinarity of cited journals; observed the age density of cited sources; and studied the proportional distribution of reference types. Results were then compared across 10-year spans, except for the first, which was 12 years, and discussed in light of known parameters for research in other fields. These analyses have revealed several interesting trends reflecting the evolution and maturation of the journal and music education research.

Signaling by Toll-like receptors (TLRs) on intestinal epithelial cells (IECs) is critical for intestinal homeostasis. To visualize epithelial expression of individual TLRs in vivo, we generated five strains of reporter mice. These mice revealed that TLR expression varied dramatically along the length of the intestine. Indeed, small intestine (SI) IECs expressed low levels of multiple TLRs that were highly expressed by colonic IECs. TLR5 expression was restricted to Paneth cells in the SI epithelium. Intestinal organoid experiments revealed that TLR signaling in Paneth cells or colonic IECs induced a core set of host defense genes, but this set did not include antimicrobial peptides, which instead were induced indirectly by inflammatory cytokines. This comprehensive blueprint of TLR expression and function in IECs reveals unexpected diversity in the responsiveness of IECs to microbial stimuli, and together with the associated reporter strains, provides a resource for further study of innate immunity.