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American Occupational Therapy Association fellowship programs are an emerging post-professional educational opportunity aimed at developing practitioners in specialized areas of occupational therapy practice. Mentored practice is a critical and substantial component of fellowship programs; however, the experiences of mentors and fellows have not been well described in the literature. The purpose of this study was to describe the mentored practice experience from the perspectives of the fellow and mentor. This study sought to understand the perceived influence mentored practice may have on the advancement of skills and knowledge in specialty practice areas of occupational therapy. A qualitative exploratory phenomenological design was used to understand the fellowship experience. Four fellows and eight mentors from three American Occupational Therapy Association-accredited fellowship programs at a single institution participated in semi-structured interviews and provided an in-depth understanding of the mentored practice experience. Interview data was coded and analyzed for themes. Key themes emerged related to the mentoring experience, mentoring relationship, and the perceived influence of mentoring on skill and knowledge development. The mentoring experience in fellowship programs was consistently reported as beneficial by both mentors and fellows, particularly in conjunction with fellowship program learning activities. Findings suggested fellows perceive mentoring as having a positive influence on the development of skills and knowledge. Results suggested a need for improved mentor training and support as well as continued exploration of best practices for supporting the unique needs of the post-professional learner, specifically in assessment methods and feedback delivery.

High concentration electrolytes (HCEs) and localized high concentration electrolytes (LHCEs) have emerged as promising candidates to enable higher energy density Li-ion batteries due to their advantageous interfacial properties that result from their unique solvent structures. Using electrophoretic NMR and electrochemical techniques, we characterize and report full transport properties, including the lithium transference numbers (t+) for electrolytes ranging from the conventional ∼1 M to HCE regimes as well as for LHCE systems. We find that compared to conventional electrolytes, t+ increases for HCEs; however the addition of diluents to LHCEs significantly decreases t+. Viscosity effects alone cannot explain this behavior. Using Onsager transport coefficients calculated from our experiments, we demonstrate that there is more positively correlated cation-cation motion in HCEs as well as fast cation-anion ligand exchange consistent with a concerted ion-hopping mechanism. The addition of diluents to LHCEs results in more anticorrelated motion indicating a disruption of concerted cation-hopping leading to low t+ in LHCEs.

UNLABELLED: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201.

Interactions between catalysts and substrates can be highly complex and dynamic, often complicating the development of models to either predict or understand such processes. A dirhodium(II)-catalyzed C-H insertion of donor/donor carbenes into 2-alkoxybenzophenone substrates to form benzodihydrofurans was selected as a model system to explore nonlinear methods to achieve a mechanistic understanding. We found that the application of traditional methods of multivariate linear regression (MLR) correlating DFT-derived descriptors of catalysts and substrates leads to poorly performing models. This inspired the introduction of nonlinear descriptor relationships into modeling by applying the sure independence screening and sparsifying operator (SISSO) algorithm. Based on SISSO-generated descriptors, a high-performing MLR model was identified that predicts external validation points well. Mechanistic interpretation was aided by the deconstruction of feature relationships using chemical space maps, decision trees, and linear descriptors. Substrates were found to have a strong dependence on steric effects for determining their innate cyclization selectivity preferences. Catalyst reactive site features can then be matched to product features to tune or override the resultant diastereoselectivity within the substrate-dictated ranges. This case study presents a method for understanding complex interactions often encountered in catalysis by using nonlinear modeling methods and linear deconvolution by pattern recognition.

Abstract Next-generation sequencing (NGS) has revolutionized genomic research by enabling high-throughput, cost-effective genome and transcriptome sequencing accelerating personalized medicine for complex diseases, including cancer. Whole genome/transcriptome sequencing (WGS/WTS) provides comprehensive insights, while targeted sequencing is more cost-effective and sensitive. In comparison to short-read sequencing, which still dominates the field due to high speed and cost-effectiveness, long-read sequencing can overcome alignment limitations and better discriminate similar sequences from alternative transcripts or repetitive regions. Hybrid sequencing combines the best strengths of different technologies for a more comprehensive view of genomic/transcriptomic variations. Understanding each technology’s strengths and limitations is critical for translating cutting-edge technologies into clinical applications. In this study, we sequenced DNA and RNA libraries of reference samples using various targeted DNA and RNA panels and the whole transcriptome on both short-read and long-read platforms. This study design enables a comprehensive analysis of sequencing technologies, targeting protocols, and library preparation methods. Our expanded profiling landscape establishes a reference point for assessing current sequencing technologies, facilitating informed decision-making in genomic research and precision medicine.

Collaborative writing tasks are common in multilingual university-level writing-intensive classes, but how multilingual language learners (MLLs) are socialized into this group work as a discursive practice is still poorly understood. This case study of adult MLLs in multilingual writing classes at a large public university provides insight into how this socialization can conflict with teaching goals. Membership Categorization Analysis (MCA), a micro-analytic approach, is used to investigate how students inter-subjectively assemble categories of identity in order to articulate their understanding of collaborative writing tasks and how they are obligated to negotiate them. Analysis of classroom talk reveals a conflict between student articulations of how to perform writing tasks when they interact with one another as group members and when they interact individually with instructors. Implications and a possible pedagogical intervention for the framing of collaborative writing tasks are discussed.

Misinformation and disinformation about science have reached alarming levels. Here, we summarize a recent expert report, "Science Education in an Age of Misinformation," that outlines what science education can do to address this problem and, given the urgency, has to do. We highlight the significance of teaching how the social practices of science contribute to establishing a trustworthy consensus and how students should evaluate the credibility of second-hand claims reported in the media or on the internet. We focus on the concepts of epistemic dependence on experts, competent outsiders, credibility, expertise, consensus, deceptive tactics, and science media literacy.

BackgroundNonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD).AimsTo examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM.MethodsThis was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF

Polyelectrolyte solutions (PESs) recently have been proposed as high conductivity, high lithium transference number (t+) electrolytes where the majority of the ionic current is carried by the electrochemically active Li-ion. While PESs are intuitively appealing because anchoring the anion to a polymer backbone selectively slows down anionic motion and therefore increases t+, increasing the anion charge will act as a competing effect, decreasing t+. In this work we directly measure ion mobilities in a model non-aqueous polyelectrolyte solution using electrophoretic Nuclear Magnetic Resonance Spectroscopy (eNMR) to probe these competing effects. While previous studies that rely on ideal assumptions predict that PESs will have higher t+ than monomeric solutions, we demonstrate that below the entanglement limit, both conductivity and t+ decrease with increasing degree of polymerization. For polyanions of 10 or more repeat units, at 0.5 m Li+ we directly observe Li+ move in the "wrong direction" in an electric field, evidence of a negative transference number due to correlated motion through ion clustering. This is the first experimental observation of negative transference in a non-aqueous polyelectrolyte solution. We also demonstrate that t+ increases with increasing Li+ concentration. Using Onsager transport coefficients calculated from experimental data, and insights from previously published molecular dynamics studies we demonstrate that despite selectively slowing anion motion using polyanions, distinct anion-anion correlation through the polymer backbone and cation-anion correlation through ion aggregates reduce the t+ in non-entangled PESs. This leads us to conclude that short-chained polyelectrolyte solutions are not viable high transference number electrolytes. These results emphasize the importance of understanding the effects of ion-correlations when designing new concentrated electrolytes for improved battery performance.

Pronounced voltage hysteresis in Li-excess cathode materials is commonly thought to be associated with oxygen redox. However, these materials often possess overlapping oxygen and transition-metal redox, whose contributions to hysteresis between charge and discharge are challenging to distinguish. In this work, a two-step aqueous redox titration is developed with the aid of mass spectrometry (MS) to quantify oxidized lattice oxygen and Mn3+ /4+ redox in a representative Li-excess cation-disordered rock salt—Li1.2Mn0.4Ti0.4O2 (LMTO). Two MS-countable gas molecules evolve from two separate titrant-analyte reactions, thereby allowing Mn and O redox capacities to be decoupled. The decoupled O and Mn redox coulombic efficiencies are close to 100% for the LMTO cathode, indicating high charge-compensation reversibility. As incremental Mn and O redox capacities are quantitatively decoupled, each redox voltage hysteresis is further evaluated. Overall, LMTO voltage hysteresis arises not only from an intrinsic charge-discharge voltage mismatch related to O redox, but also from asymmetric Mn-redox overvoltages. The results reveal that O and Mn redox both contribute substantially to voltage hysteresis. This work further shows the potential of designing new analytical workflows to experimentally quantify key properties, even in a disordered material having complex local coordination environments.

IntroductionEffects of chronic arterial stiffness on brain aging remain unclear. We, therefore, examined whether long-term trajectories of pulse pressure (PP) predicted brain microstructure, microstructure mediated PP-executive function associations, and APOE genotype modified PP-microstructure associations.MethodsWe examined associations of PP trajectories with brain microstructure measured using restriction spectrum imaging in 146 community-dwelling older adults, whether microstructure mediated PP trajectory-executive function associations, and whether PP-restriction spectrum imaging correlations were modified by APOE-ε4 status.ResultsParticipants with trajectories of high PP had lower restricted isotropic diffusion (RI) compared to those with low PP trajectories and PP-executive function associations were mediated by subcortical and white matter RI. High PP more strongly correlated with lower RI and higher hindered diffusion among APOE-ε4 carriers than non-carriers.DiscussionProlonged elevated PP predicts microstructural abnormalities which may contribute to impaired executive function. APOE-ε4 carriers may be most vulnerable to the adverse effects of PP on brain microstructure.

Fast charging of most commercial lithium-ion batteries is limited due to fear of lithium plating on the graphite anode, which is difficult to detect and poses considerable safety risk. Here we demonstrate the power of simple, accessible and high-throughput cycling techniques to quantify irreversible Li plating spanning data from over 200 cells. We first observe the effects of energy density, charge rate, temperature and state of charge on lithium plating, use the results to refine a mature physics-based electrochemical model and provide an interpretable empirical equation for predicting the plating onset state of charge. We then explore the reversibility of lithium plating and its connection to electrolyte design for preventing irreversible Li accumulation. Finally, we design a method to quantify in situ Li plating for commercially relevant graphite|LiNi0.5Mn0.3Co0.2O2 (NMC) cells and compare with results from the experimentally convenient Li|graphite configuration. The hypotheses and abundant data herein were generated primarily with equipment universal to the battery researcher, encouraging further development of innovative testing methods and data processing that enable rapid battery engineering.

The importance of staying relevant when teaching communication and advertising courses is hardly a new concept nor is the use of modern and evolving technologies to achieve this goal. However, empirically assessing college students' perceptions of online learning when it is a forced choice is an underexplored area. To address this gap and consider the perspectives of diverse student populations, this paper analyzes data collected from a large communication class at a Hispanic serving institution. The purpose of this research is to better understand students' perceptions of teaching technologies, class sizes, benefits and hindrances of online learning, preferred course delivery methods, social adaptations, and perceptions of how their university has handled the transition. Data revealed face-to-face courses were the most desired modality with no race or first-generation (FG) differences; however, gender differences were present. Class size impacted modality preference as well as preference for the inclusion of specific online tools. Additionally, a longitudinal comparison of student data between 2018 and 2020, before and after the onset of the global pandemic, revealed significant differences in student preparedness, faculty interaction, and institutional communication.

Scientific research requires taking risks, as the most cautious approaches are unlikely to lead to the most rapid progress. Yet, much funded scientific research plays it safe and funding agencies bemoan the difficulty of attracting high-risk, high-return research projects. Why don't the incentives for scientific discovery adequately impel researchers toward such projects? Here, we adapt an economic contracting model to explore how the unobservability of risk and effort discourages risky research. The model considers a hidden-action problem, in which the scientific community must reward discoveries in a way that encourages effort and risk-taking while simultaneously protecting researchers' livelihoods against the vicissitudes of scientific chance. Its challenge when doing so is that incentives to motivate effort clash with incentives to motivate risk-taking, because a failed project may be evidence of a risky undertaking but could also be the result of simple sloth. As a result, the incentives needed to encourage effort actively discourage risk-taking. Scientists respond by working on safe projects that generate evidence of effort but that don't move science forward as rapidly as riskier projects would. A social planner who prizes scientific productivity above researchers' well-being could remedy the problem by rewarding major discoveries richly enough to induce high-risk research, but in doing so would expose scientists to a degree of livelihood risk that ultimately leaves them worse off. Because the scientific community is approximately self-governing and constructs its own reward schedule, the incentives that researchers are willing to impose on themselves are inadequate to motivate the scientific risks that would best expedite scientific progress.

Objectives To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study.Design Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined.Setting Children aged 0–18 years from 26 European birth cohorts.Participants 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood.Main outcome measure Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity) at age 6–18 years.Results Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3–5 years was not associated with asthma at age 6–18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results.Conclusions Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood.

ObjectiveTo determine associations of alcohol use with cognitive aging among middle-aged men.Method1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003-2007 to 2016-2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1-4 drinks in past 14 days), light (5-14 drinks), moderate (15-28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors.ResultsPerformance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by -0.21 SD (95% CI -0.35, -0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, -0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association.ConclusionsAlcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Omega-3 intake has been positively associated with healthy brain aging, yet it remains unclear whether high omega-3 intake beginning early in life may optimize its protective effects against brain aging. We examined whether omega-3 intake is associated with brain microstructure over 2 decades later among dementia-free older adults. The 128 participants (62% women; age at magnetic resonance imaging: 76.6 ± 7.9) from the Rancho Bernardo Study of Healthy Aging completed at least 1 dietary assessment between 1984 and 1996 and underwent restriction spectrum imaging (RSI) 22.8 ± 3.1 years later. We evaluated associations between prior omega-3 intake and RSI metrics of gray and white matter (WM) microstructure. Higher prior omega-3 intake was associated with greater restricted diffusion in the superior cortico-striatal fasciculus. A correlation between higher prior omega-3 intake and greater cingulum restricted diffusion was stronger among participants >80 years old. Higher omega-3 intake correlated with greater restricted diffusion in the inferior longitudinal and inferior fronto-occipital fasciculus more strongly for apolipoprotein E (APOE) ε4 carriers than noncarriers. Associations were not modified by adjustment for dietary pattern, health, or lifestyle. High omega-3 intake in midlife may help to maintain WM integrity into older age, particularly in the latest decades of life and among APOE ε4 carriers.

Drawing on transformative experience theory (Pugh, 2011) and in collaboration with high school science teachers, the authors developed an intervention (Seeing Science project) leveraging everyday mobile technology as a tool for integrating in-school and out-of-school experience. Students were instructed to take pictures when they noticed connections to unit content and post these with a caption on a class site. The current study used design-based research methods to revise and evaluate the Seeing Science project over a 2-year period. Revisions to the project were informed by year one data and principles of the Teaching for Transformative Experiences in Science (TTES) instructional model. Data sources included project artifacts, student interviews, and teacher interviews. Revisions to the project resulted in higher quality posts in pre-AP biology classes and greater participation in regular biology classes. Furthermore, an analysis of posts, classroom observations, and student interviews revealed that the project helped some students connect in-school learning to out-of-school experience and undergo transformative experiences. The current study contributes to transformative experience theory by identifying and developing strategies for fostering transformative experiences. These strategies further inform the TTES model and may support depth of learning and career identification.

BACKGROUND: Hearing loss is associated with cognitive decline and increased risk for Alzheimers disease, but the basis of this association is not understood. OBJECTIVE: To determine whether hearing impairment is associated with advanced brain aging or altered microstructure in areas involved with auditory and cognitive processing. METHODS: 130 participants, (mean 76.4±7.3 years; 65% women) of the Rancho Bernardo Study of Healthy Aging had a screening audiogram in 2003-2005 and brain magnetic resonance imaging in 2014-2016. Hearing ability was defined as the average pure tone threshold (PTA) at 500, 1000, 2000, and 4000 Hz in the better-hearing ear. Brain-predicted age difference (Brain-pad) was calculated as the difference between brain-predicted age based on a validated structural imaging biomarker of brain age, and chronological age. Regional diffusion metrics in temporal and frontal cortex regions were obtained from diffusion-weighted MRIs. Linear regression analyses adjusted for age, gender, education, and health-related measures. RESULTS: PTAs were not associated with brain-PAD (β= 0.09; 95% CI: -0.084 to 0.243; p = 0.34). PTAs were associated with reduced restricted diffusion and increased free water diffusion primarily in right hemisphere temporal and frontal areas (restricted diffusion: βs = -0.21 to -0.30; 95% CIs from -0.48 to -0.02; ps

BackgroundAll cancers harbor somatic mutations in their genomes. In principle, mutations affecting between one and fifty base pairs are generally classified as small mutational events. Conversely, large mutational events affect more than fifty base pairs, and, in most cases, they encompass copy-number and structural variants affecting many thousands of base pairs. Prior studies have demonstrated that examining patterns of somatic mutations can be leveraged to provide both biological and clinical insights, thus, resulting in an extensive repertoire of tools for evaluating small mutational events. Recently, classification schemas for examining large-scale mutational events have emerged and shown their utility across the spectrum of human cancers. However, there has been no computationally efficient bioinformatics tool that allows visualizing and exploring these large-scale mutational events.ResultsHere, we present a new version of SigProfilerMatrixGenerator that now delivers integrated capabilities for examining large mutational events. The tool provides support for examining copy-number variants and structural variants under two previously developed classification schemas and it supports data from numerous algorithms and data modalities. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment.ConclusionsThe new version of SigProfilerMatrixGenerator provides the first standardized bioinformatics tool for optimized exploration and visualization of two previously developed classification schemas for copy number and structural variants. The tool is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ .

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.