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Selecting a major is one of the most consequential decisions a student will make in college. Though major selection is often conceived of as a discrete choice made at a particular point in time, many students change their majors at least once during college. This article examines the process of changing majors as a key education transition. Drawing from 38 interviews with college students at a public university in the USA who changed their declared major, this study explores the ways they make meaning of transitions between fields of study. Specifically, I ask: How do students describe their experiences navigating the process of switching college majors? Six themes emerged in relation to three phases of transition: endings, neutral zones, and new beginnings. These themes provide new understandings of students' meaning making about their experiences moving between majors. In doing so, this study (1) demonstrates the value of studying major change as an important educational transition and (2) sheds light on the potential for employing theories of transition to understand non-normative and non-linear transitions in higher education. Implications for higher education research and practice are discussed.

Background: The Latarjet procedure was developed for the treatment of anterior shoulder instability in young, high-demand patients with attritional glenoid bone loss, whose risk of redislocation following primary dislocation may exceed 90%. Coracoid graft osteolysis and prominent screws are commonly observed in late computed tomography (CT) scans of patients who re-present following the procedure, but the clinical relevance of osteolysis in the overall Latarjet cohort is undetermined. We aimed to evaluate clinical and radiological outcomes in patients who underwent the Latarjet procedure, and to determine if severe coracoid graft osteolysis compromised clinical outcomes. Methods: This was a retrospective analysis of patients who underwent the open Latarjet procedure. Patients were invited via an e-questionnaire that contained a Western Ontario Shoulder Instability Index (WOSI), and queried about redislocation and reoperation since index surgery. Preoperative glenoid bone loss was calculated on CT using the best-fit circle method. Osteolysis was graded (0, screw head buried in graft; 1, screw head exposed; 2, threads exposed; 3, complete resorption/severe osteolysis) at the level of the proximal and distal screws respectively, on axial CT scans performed ≥ 12 months postoperatively. Results: Between 2011 and 2022, a single surgeon performed 442 Latarjet procedures. One hundred fifty eight patients responded to the questionnaire at median (interquartile range [IQR]) 44 (27-70) months postoperatively, among whom the median (IQR) WOSI score was 352 (142-666) points (0 = best, 2100 = worst). Recurrent anterior instability occurred in 3/158 (2%) patients. One patient required reoperation for this indication. Among patients who had CT scans ≥ 12 months postoperatively (median [IQR] 40 [29-69] months), 1 patient developed severe osteolysis around both screws (WOSI = 90), 17/62 (27%) patients developed severe osteolysis around 1 screw, all of which were proximal (median [IQR] WOSI = 235 [135-644]), and 44/62 (71%) patients did not develop severe osteolysis around either screw (median [IQR] WOSI = 487 [177-815]). There were no statistically significant differences in WOSI scores between groups based on the presence of severe osteolysis. Conclusion: The Latarjet is reliable procedure that has a low rate of redislocation and reoperation. Severe coracoid graft osteolysis occurs with time, and always affects the proximal graft first. The presence of severe osteolysis did not compromise clinical outcomes.

Abstract This cross-sectional study investigated differences in the plasma metabolome in two groups of adults that were of similar age but varied markedly in body composition and dietary and physical activity patterns. Study participants included 52 adults in the lifestyle group (LIFE) (28 males, 24 females) and 52 in the control group (CON) (27 males, 25 females). The results using an extensive untargeted ultra high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) metabolomics analysis with 10,535 metabolite peaks identified 486 important metabolites (variable influence on projections scores of VIP ≥ 1) and 16 significantly enriched metabolic pathways that differentiated LIFE and CON groups. A novel metabolite signature of positive lifestyle habits emerged from this analysis highlighted by lower plasma levels of numerous bile acids, an amino acid profile characterized by higher histidine and lower glutamic acid, glutamine, β-alanine, phenylalanine, tyrosine, and proline, an elevated vitamin D status, higher levels of beneficial fatty acids and gut microbiome catabolism metabolites from plant substrates, and reduced levels of N-glycan degradation metabolites and environmental contaminants. This study established that the plasma metabolome is strongly associated with body composition and lifestyle habits. The robust lifestyle metabolite signature identified in this study is consistent with an improved life expectancy and a reduced risk for chronic disease.

Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation-many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.

Abstract National parks and other protected areas are important for preserving landscapes and biodiversity worldwide. An essential component of the mission of the United States (U.S.) National Park Service (NPS) requires understanding and maintaining accurate inventories of species on protected lands. We describe a new, national-scale synthesis of amphibian species occurrence in the NPS system. Many park units have a list of amphibian species observed within their borders compiled from various sources and available publicly through the NPSpecies platform. However, many of the observations in NPSpecies remain unverified and the lists are often outdated. We updated the amphibian dataset for each park unit by collating old and new park-level records and had them verified by regional experts. The new dataset contains occurrence records for 292 of the 424 NPS units and includes updated taxonomy, international and state conservation rankings, hyperlinks to a supporting reference for each record, specific notes, and related fields which can be used to better understand and manage amphibian biodiversity within a single park or group of parks.

Abstract Coarse graining techniques play an essential role in accelerating molecular simulations of systems with large length and time scales. Theoretically grounded bottom-up models are appealing due to their thermodynamic consistency with the underlying all-atom models. In this direction, machine learning approaches hold great promise to fitting complex many-body data. However, training models may require collection of large amounts of expensive data. Moreover, quantifying trained model accuracy is challenging, especially in cases of non-trivial free energy configurations, where training data may be sparse. We demonstrate a path towards uncertainty-aware models of coarse grained free energy surfaces. Specifically, we show that principled Bayesian model uncertainty allows for efficient data collection through an on-the-fly active learning framework and opens the possibility of adaptive transfer of models across different chemical systems. Uncertainties also characterize models’ accuracy of free energy predictions, even when training is performed only on forces. This work helps pave the way towards efficient autonomous training of reliable and uncertainty aware many-body machine learned coarse grain models.

Abstract Catastrophic state changes often occur in ecosystems as consequences of shifts in the dominant life forms, such as in the case of sportfish introduction into naturally fishless mountain lakes. While the pronounced ecological displacement of native communities by these novel predators (i.e., weak resistance) is well documented, few studies have also examined the dynamics of their recovery rates (i.e., “engineering resilience”) following stressor removal. We addressed this knowledge gap by quantifying the taxonomic and species trait‐based ordination trajectories of crustacean zooplankton communities in stocked alpine lakes, which differed in how they were restored to a natural fishless state over a period of six decades. Resilience and resistance trajectories differed in each lake as the ecological importance of trait‐based species recolonization potential (e.g., asexual vs. sexual reproduction) replaced that of tolerance of size‐selective predation by fish (e.g., body size, pigmentation, motility). As a result, re‐establishment of large‐bodied zooplankton following the elimination of fish restored annual secondary production. In contrast, a more gradual unidirectional ordination trajectory toward smaller zooplankton body size and a decline in total zooplankton biomass occurred in a nearby alpine lake containing a protected native bull trout population. Although recovery trajectories returned via routes that differed from those of earlier resistance trajectories (i.e., hysteresis), we discovered that full taxonomic and functional recovery was realized in all the restored fishless lakes within three decades, regardless of the approach used to achieve ecosystem restoration.

BackgroundGermline variants in fumarate hydratase (FH) are associated with autosomal dominant (AD) hereditary leiomyomatosis and renal cell cancer (HLRCC) and autosomal recessive (AR) fumarase deficiency (FMRD). The prevalence and cancer penetrance across different FH variants remain unclear.MethodsA database containing 120,061 records from individuals undergoing cancer germline testing was obtained. FH variants were classified into 3 categories: AD HLRCC variants, AR FMRD variants, and variants of unknown significance (VUSs). Individuals with variants from these categories were compared with those with negative genetic testing.ResultsFH variants were detected in 1.3% of individuals (AD HLRCC, 0.3%; AR FMRD, 0.4%; VUS, 0.6%). The rate of AD HLRCC variants discovered among reportedly asymptomatic individuals without a clear indication for HLRCC testing was 1 in 2668 (0.04%). In comparison with those with negative genetic testing, the renal cell carcinoma (RCC) prevalence was elevated with AD HLRCC variants (17.0% vs 4.5%; P

Contribution: A roadmap is provided for building a quantum engineering education program to satisfy U.S. national and international workforce needs. Background: The rapidly growing quantum information science and engineering (QISE) industry will require both quantum-aware and quantum-proficient engineers at the bachelor's level. Research Question: What is the best way to provide a flexible framework that can be tailored for the full academic ecosystem? Methodology: A workshop of 480 QISE researchers from across academia, government, industry, and national laboratories was convened to draw on best practices; representative authors developed this roadmap. Findings: 1) For quantum-aware engineers, design of a first quantum engineering course, accessible to all STEM students, is described; 2) for the education and training of quantum-proficient engineers, both a quantum engineering minor accessible to all STEM majors, and a quantum track directly integrated into individual engineering majors are detailed, requiring only three to four newly developed courses complementing existing STEM classes; 3) a conceptual QISE course for implementation at any postsecondary institution, including community colleges and military schools, is delineated; 4) QISE presents extraordinary opportunities to work toward rectifying issues of inclusivity and equity that continue to be pervasive within engineering. A plan to do so is presented, as well as how quantum engineering education offers an excellent set of education research opportunities; and 5) a hands-on training plan on quantum hardware is outlined, a key component of any quantum engineering program, with a variety of technologies, including optics, atoms and ions, cryogenic and solid-state technologies, nanofabrication, and control and readout electronics.

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

Abstract Interventions of the host–pathogen dynamics provide strong tests of relationships, yet they are still rarely applied across multiple populations. After American bullfrogs (Rana catesbeiana) invaded a wildlife refuge where federally threatened Chiricahua leopard frogs (R. chiricahuensis) were reintroduced 12 years prior, managers launched a landscape‐scale eradication effort to help ensure continued recovery of the native species. We used a before‐after‐control‐impact design and environmental DNA sampling of 19 eradication sites and 18 control sites between fall 2016 and winter 2020–2021 to measure community‐level responses to bullfrog eradication, including for two pathogens. Dynamic occupancy models revealed successful eradication from 94% of treatment sites. Native amphibians did not respond to bullfrog eradication, but the pathogens amphibian chytrid fungus (Batrachochytrium dendrobatidis) and ranaviruses were coextirpated with bullfrogs. Our spatially replicated experimental approach provides strong evidence that management of invasive species can simultaneously reduce predation and disease risk for imperiled species.

Research documents persistent gender inequality in the educational experiences of second-generation immigrant (SGI) students whose parents immigrated to the United States. This qualitative study draws from 27 in-depth interviews to explore the experiences of SGI women as they navigate the senior-year transition in conversation with their parents. Findings show how beliefs regarding gender inform the contours of parental expectations for soon-to-be graduates. SGI women confronted a series of gendered expectations for (a) family life and marriage, (b) future careers and further education, and (c) geographic mobility. These dynamics became especially salient for women participants with brothers who were not subjected to the same expectations. SGI women described these expectations as manifestations of gendered double standards. Findings have implications for how higher education can address gender inequality and support SGI women in the senior-year transition.

Abstract The advent of energy-specific collimation in pencil beam scanning (PBS) proton therapy has led to an improved lateral dose conformity for a variety of treatment sites, resulting in better healthy tissue sparing. Arc PBS delivery has also been proposed to enhance high-dose conformity about the intended target, reduce skin toxicity, and improve plan robustness. The goal of this work was to determine if the combination of proton arc and energy-specific collimation can generate better dose distributions as a logical next step to maximize the dosimetric advantages of proton therapy. Plans were optimized using a novel DyNamically collimated proton Arc (DNA) genetic optimization algorithm that was designed specifically for the application of proton arc therapy. A treatment planning comparison study was performed by generating an uncollimated two-field intensity modulated proton therapy and partial arc treatments and then replanning these treatments using energy-specific collimation as delivered by a dynamic collimation system, which is a novel collimation technology for PBS. As such, we refer to this novel treatment paradigm as Dynamically Collimated Proton Arc Therapy (DC-PAT). Arc deliveries achieved a superior target conformity and improved organ at risk (OAR) sparing relative to their two-field counterparts at the cost of an increase to the low-dose, high-volume region of the healthy brain. The incorporation of DC-PAT using the DNA optimizer was shown to further improve the tumor dose conformity. When compared to the uncollimated proton arc treatments, the mean dose to the 10mm of surrounding healthy tissue was reduced by 11.4% with the addition of collimation without meaningfully affecting the maximum skin dose (less than 1% change) relative to a multi-field treatment. In this case study, DC-PAT could better spare specific OARs while maintaining better target coverage compared to uncollimated proton arc treatments. While this work presents a proof-of-concept integration of two emerging technologies, the results are promising and suggest that the addition of these two techniques can lead to superior treatment plans warranting further development.

Summary: Cellular metabolism is tightly regulated by growth factor signaling, which promotes metabolic rewiring to support growth and proliferation. While growth factor-induced transcriptional and post-translational modes of metabolic regulation have been well defined, whether post-transcriptional mechanisms impacting mRNA stability regulate this process is less clear. Here, we present the ZFP36/L1/L2 family of RNA-binding proteins and mRNA decay factors as key drivers of metabolic regulation downstream of acute growth factor signaling. We quantitatively catalog metabolic enzyme and nutrient transporter mRNAs directly bound by ZFP36 following growth factor stimulation—many of which encode rate-limiting steps in metabolic pathways. Further, we show that ZFP36 directly promotes the mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity, and provide evidence of a ZFP36/Eno2 axis during VEGF-stimulated developmental retinal angiogenesis. Thus, ZFP36-mediated mRNA decay serves as an important mode of metabolic regulation downstream of growth factor signaling within dynamic cell and tissue states.

The salamander chytrid fungus (Batrachochytrium salamandrivorans [Bsal]) is causing massive mortality of salamanders in Europe. The potential for spread via international trade into North America and the high diversity of salamanders has catalyzed concern about Bsal in the U.S. Surveillance programs for invading pathogens must initially meet challenges that include low rates of occurrence on the landscape, low prevalence at a site, and imperfect detection of the diagnostic tests. We implemented a large-scale survey to determine if Bsal was present in North America designed to target taxa and localities where Bsal was determined highest risk to be present based on species susceptibility and geography. Our analysis included a Bayesian model to estimate the probability of occurrence of Bsal given our prior knowledge of the occurrence and prevalence of the pathogen. We failed to detect Bsal in any of 11,189 samples from 594 sites in 223 counties within 35 U.S. states and one site in Mexico. Our modeling indicates that Bsal is highly unlikely to occur within wild amphibians in the U.S. and suggests that the best proactive response is to continue mitigation efforts against the introduction and establishment of the disease and to develop plans to reduce impacts should Bsal establish.

The c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To meet this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters, glycolytic enzymes, and represses the expression of thioredoxin interacting protein (TXNIP), which is a potent negative regulator of glucose uptake. A Mychigh/TXNIPlow gene signature is clinically significant as it correlates with poor clinical prognosis in triple-negative breast cancer (TNBC) but not in other subtypes of breast cancer, suggesting a functional relationship between Myc and TXNIP. To better understand how TXNIP contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Myc's intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the nutrient and progrowth signals that control TXNIP expression.

ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

Drug resistance continues to be a significant problem in cancer therapy, leading to relapse and associated mortality. Although substantial progress has been made in understanding drug resistance, significant knowledge gaps remain concerning the molecular underpinnings that drive drug resistance and which processes are unique to certain drug classes. The NCI-60 cell line panel program has evaluated the activity of numerous anticancer agents against many common cancer cell line models and represents a highly valuable resource to study intrinsic drug resistance. Furthermore, great efforts have been undertaken to collect high-quality omics datasets to characterize these cell lines. The current study takes these two sources of data—drug response and omics profiles—and uses a multi-omics investigation to uncover molecular networks that differentiate cancer cells that are sensitive or resistant to antifolates, which is a commonly used class of anticancer drugs. Results from a combination of univariate and multivariate analyses showed numerous metabolic processes that differentiate sensitive and resistant cells, including differences in glycolysis and gluconeogenesis, arginine and proline metabolism, beta-alanine metabolism, purine metabolism, and pyrimidine metabolism. Further analysis using multivariate and integrated pathway analysis indicated purine metabolism as the major metabolic process separating cancer cells sensitive or resistant to antifolates. Additional pathways differentiating sensitive and resistant cells included autophagy-related processes (e.g., phagosome, lysosome, autophagy, mitophagy) and adhesion/cytoskeleton-related pathways (e.g., focal adhesion, regulation of actin cytoskeleton, tight junction). Volcano plot analysis and the receiver operating characteristic (ROC) curves of top selected variables differentiating Q1 and Q4 revealed the importance of genes involved in the regulation of the cytoskeleton and extracellular matrix (ECM). These results provide novel insights toward mechanisms of intrinsic antifolate resistance as it relates to interactions between nucleotide metabolism, autophagy, and the cytoskeleton. These processes should be evaluated in future studies to potentially derive novel therapeutic strategies and personalized treatment approaches to improve antifolate response.

This study aimed to elucidate the molecular determinants influencing the response of cancer cells to alkylating agents, a major class of chemotherapeutic drugs used in cancer treatment. The study utilized data from the National Cancer Institute (NCI)-60 cell line screening program and employed a comprehensive multi-omics approach integrating transcriptomic, proteomic, metabolomic, and SNP data. Through integrated pathway analysis, the study identified key metabolic pathways, such as cysteine and methionine metabolism, starch and sucrose metabolism, pyrimidine metabolism, and purine metabolism, that differentiate drug-sensitive and drug-resistant cancer cells. The analysis also revealed potential druggable targets within these pathways. Furthermore, copy number variant (CNV) analysis, derived from SNP data, between sensitive and resistant cells identified notable differences in genes associated with metabolic changes (WWOX, CNTN5, DDAH1, PGR), protein trafficking (ARL17B, VAT1L), and miRNAs (MIR1302-2, MIR3163, MIR1244-3, MIR1302-9). The findings of this study provide a holistic view of the molecular landscape and dysregulated pathways underlying the response of cancer cells to alkylating agents. The insights gained from this research can contribute to the development of more effective therapeutic strategies and personalized treatment approaches, ultimately improving patient outcomes in cancer treatment.