Search

College is a major critical juncture for students in which they learn to author their lives. For students who are pre-service teachers, college provides an opportunity for them to develop their leader identity, a skill critical to their professional success. We posited there is a relationship between leader identity and self-authorship, such that those students with a high level of self-authorship are likely to have a high level of leader identity. To test our hypothesis, we use a cross-sections design surveying a sample of preservice teachers to assess their leader identity and self-authorship. Our survey garnered quantitative and qualitative data. Our analysis revealed traits associated with levels of leader identity and self-authorship. We found a strong positive correlation between the two variables, indicating a potential relationship. We explored the findings in our discussion and implications, recognized our study limitations, and suggested directions for future research.

Teacher recruitment is a pressing need in the United States. Equally important is the recruitment of more racial-minority teachers to help close the teacher-student diversity gap. We surveyed 300 undergraduates at our university regarding their perspectives on teaching careers--what they found attractive and deterring. Results from this survey and three race-alike focus groups were analyzed for racial group differences to inform recruitment strategies. Black, indigenous, and people of color respondents generally found proposed deterrents more dissuading than did White respondents, especially deterrents considered to be racially charged. Personal experiences as a K-12 student emerged as salient, attracting some but deterring others from teaching.

There has been a continuous focus on developing quality physical education (PE) experiences that empower students to understand movement and engage in physical activity. This article describes a pedagogical approach that was developed to assist the PE student in understanding more about their own and others' physical activity capacities. This new instructional approach, which is grounded in scientific methods, is called the Informed Learner in Physical Education (ILPE). The ILPE was developed to provide teachers with a pedagogical approach to facilitate meaningful learning and empower students within PE with the overarching goal of students becoming "informed learners of and about movement and physical activity." Within the ILPE there are four features: (1) Activity Context and Educational Focus, (2) Inquiry Question, (3) Investigation, and (4) Evaluation and Articulation of Findings. These features and teacher considerations are discussed to assist PE teachers in the design and implementation of an ILPE experience.

β-arrestins play a key role in G protein-coupled receptor (GPCR) internalization, trafficking, and signaling. Whether β-arrestins act independently of G protein-mediated signaling has not been fully elucidated. Studies using genome-editing approaches revealed that whereas G proteins are essential for mitogen-activated protein kinase activation by GPCRs., β-arrestins play a more prominent role in signal compartmentalization. However, in the absence of G proteins, GPCRs may not activate β-arrestins, thereby limiting the ability to distinguish G protein from β-arrestin-mediated signaling events. We used β2-adrenergic receptor (β2AR) and its β2AR-C tail mutant expressed in human embryonic kidney 293 cells wildtype or CRISPR-Cas9 gene edited for Gαs, β-arrestin1/2, or GPCR kinases 2/3/5/6 in combination with arrestin conformational sensors to elucidate the interplay between Gαs and β-arrestins in controlling gene expression. We found that Gαs is not required for β2AR and β-arrestin conformational changes, β-arrestin recruitment, and receptor internalization, but that Gαs dictates the GPCR kinase isoforms involved in β-arrestin recruitment. By RNA-Seq analysis, we found that protein kinase A and mitogen-activated protein kinase gene signatures were activated by stimulation of β2AR in wildtype and β-arrestin1/2-KO cells but absent in Gαs-KO cells. These results were validated by re-expressing Gαs in the corresponding KO cells and silencing β-arrestins in wildtype cells. These findings were extended to cellular systems expressing endogenous levels of β2AR. Overall, our results support that Gs is essential for β2AR-promoted protein kinase A and mitogen-activated protein kinase gene expression signatures, whereas β-arrestins initiate signaling events modulating Gαs-driven nuclear transcriptional activity.

This study aimed to systematicically evaluate and quantify the prevalence of weapons in the health care setting. A systematic search of MEDLINE, Embase, Scopus, Web of Science, CINAHL, and EBSCO MegaFILE was performed from inception to January 12, 2024. The primary outcome was the prevalence of weapons in the health care setting on patients and/or visitors. Prevalence was pooled across studies and estimated using a random effects model. Subgroup analyses were done based on types of weapons, characteristics of weapon carriers, weapons screening/detection technology, and screened population characteristics. A total of 14 observational studies were included. All studies were from the United States and were published between 1984 and 2023. Weapons prevalence ranged from 0.4% to 26.3% among populations screened in the included studies. The overall pooled weapons prevalence was 4.0% (95% CI, 2.0%-7.8%). Most weapons were bladed (3.8%; 95% CI, 1.5%-8.9%), followed by other weapons (0.6%; 95% CI, 0.3%-1.3%), and firearms (0.1%; 95% CI, 0.02%-0.5%; P

We explored the challenges with the unplanned change of abruptly shifting to online learning that the COVID-19 pandemic mitigation had on first-year students' perceptions of learning, their connection to the university, and the general college experience. We used a cross-sectional method to gather quantitative and qualitative data using an online survey. More than 200 participating first-year college students indicated concerns with making connections, feeling challenged and unfulfilled with their educational experience, and struggling to adjust to the pandemic-mandated changes. Additionally, we found that students experienced challenges accepting ownership of their learning and navigating ambiguous situations.

Teacher recruitment is a pressing need in the United States. Equally important is the recruitment of more racial-minority teachers to help close the teacher-student diversity gap. We surveyed 300 undergraduates at our university regarding their perspectives on teaching careers--what they found attractive and deterring. Results from this survey and three race-alike focus groups were analyzed for racial group differences to inform recruitment strategies. Black, indigenous, and people of color respondents generally found proposed deterrents more dissuading than did White respondents, especially deterrents considered to be racially charged. Personal experiences as a K-12 student emerged as salient, attracting some but deterring others from teaching., Introduction Enrollments in U.S. teacher preparation programs (TPPs) have declined precipitously in the past several years (Podolsky et al., 2016), threatening the ability of K-12 schools to fill classrooms with [...]

Biofilm-associated infections lead to substantial morbidity. Omadacycline (OMC) is a novel aminomethylcycline with potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis, but data surrounding its use in biofilm-associated infections are lacking. We investigated the activity of OMC alone and in combination with rifampin (RIF) against 20 clinical strains of staphylococci in multiple in vitro biofilm analyses, including an in vitro pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor (CBR) model (simulating human exposures). The observed MICs for OMC demonstrated potent activity against the evaluated strains (0.125 to 1 mg/L), with an increase of MICs generally observed in the presence of biofilm (0.25 to >64 mg/L). Furthermore, RIF was shown to reduce OMC biofilm MICs (bMICs) in 90% of strains, and OMC plus RIF combination in biofilm time-kill analyses (TKAs) exhibited synergistic activity in most of the strains. Within the PK/PD CBR model, OMC monotherapy primarily displayed bacteriostatic activity, while RIF monotherapy generally exhibited initial bacterial eradication, followed by rapid regrowth likely due to the emergence of RIF resistance (RIF bMIC, >64 mg/L). However, the combination of OMC plus RIF produced rapid and sustained bactericidal activity in nearly all the strains (3.76 to 4.03 log10 CFU/cm2 reductions from starting inoculum in strains in which bactericidal activity was reached). Furthermore, OMC was shown to prevent the emergence of RIF resistance. Our data provide preliminary evidence that OMC in combination with RIF could be a viable option for biofilm-associated infections with S. aureus and S. epidermidis. Further research involving OMC in biofilm-associated infections is warranted.

BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF-MEK-EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.

Student motivation has been identified as important in supporting the learning, growth, and development of physical education students. A key construct that is housed within motivation is situational interest. Situational interest is an affective response that has been associated with enhanced levels of student engagement and involvement. The aim of this article is to provide the PE teacher with an understanding of the sources and pedagogical strategies that can assist in supporting the situational interest of students. Specifically, five key sources of situational interest are discussed, as well as teaching and learning approaches that can be applied across a range of PE settings.

College students' interactions with campus leaders is critical to their success, particularly in situations of distress. Yet, little is known about college students' knowledge, perceptions, and identification of campus administrators, faculty members, and staff as leaders and their interactions with these campus leaders. To fill the gap in the literature, we applied a cross-sectional methodology to gather a combination of quantitative and qualitative data using an online survey. We had 60 first-year students participate in our exploratory research by fully completing our survey. We found that students identified their advisors as leaders on campus. We also found most of our participants avoided campus administrators in fear of judgment, intimidation, and feelings of anxiety. Our results have implications for campus leadership, college administrators, student retention, and campus climate. Following our results, we discuss implications for practice and offer additional recommendations for future research.

Head and neck squamous cell carcinoma (HNSCC) ranks sixth in cancer incidence worldwide and has a 5-year survival rate of only 63%. Immunotherapies-principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity-offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first-line treatment of recurrent and metastatic HNSCC; however, less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAE) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.

Many of the fundamental concepts of signal transduction and kinase activity are attributed to the discovery and crystallization of cAMP-dependent protein kinase, or protein kinase A. PKA is one of the best-studied kinases in human biology, with emphasis in biochemistry and biophysics, all the way to metabolism, hormone action, and gene expression regulation. It is surprising, however, that our understanding of PKA's role in disease is largely underappreciated. Although genetic mutations in the PKA holoenzyme are known to cause diseases such as Carney complex, Cushing syndrome, and acrodysostosis, the story largely stops there. With the recent explosion of genomic medicine, we can finally appreciate the broader role of the Gαs-PKA pathway in disease, with contributions from aberrant functioning G proteins and G protein-coupled receptors, as well as multiple alterations in other pathway components and negative regulators. Together, these represent a broad family of diseases we term the Gαs-PKA pathway signalopathies. The Gαs-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the Gαs-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of Gαs-PKA-driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the Gαs-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in Gαs, encoded by GNAS, and mutations that destabilize the PKA holoenzyme. With this review, we hope to incite further study and ultimately the development of new therapeutic strategies in the treatment of a wide range of human diseases. SIGNIFICANCE STATEMENT: Little recognition is given to the causative role of Gαs-PKA pathway dysregulation in disease, with effects ranging from infectious disease, endocrine syndromes, and many cancers, yet these disparate diseases can all be understood by common genetic themes and biochemical signaling connections. By highlighting these common pathogenic mechanisms and bridging multiple disciplines, important progress can be made toward therapeutic advances in treating Gαs-PKA pathway-driven disease.

A major goal of cancer research is to understand how mutations distributed across diverse genes affect common cellular systems, including multiprotein complexes and assemblies. Two challenges—how to comprehensively map such systems and how to identify which are under mutational selection—have hindered this understanding. Accordingly, we created a comprehensive map of cancer protein systems integrating both new and published multi-omic interaction data at multiple scales of analysis. We then developed a unified statistical model that pinpoints 395 specific systems under mutational selection across 13 cancer types. This map, called NeST (Nested Systems in Tumors), incorporates canonical processes and notable discoveries, including a PIK3CA-actomyosin complex that inhibits phosphatidylinositol 3-kinase signaling and recurrent mutations in collagen complexes that promote tumor proliferation. These systems can be used as clinical biomarkers and implicate a total of 548 genes in cancer evolution and progression. This work shows how disparate tumor mutations converge on protein assemblies at different scales.

We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of cancer-enriched interactions reveals a previously unidentified association of the fibroblast growth factor receptor tyrosine kinase 3 with Daple, a guanine-nucleotide exchange factor, resulting in activation of Gαi- and p21-activated protein kinase 1/2 to promote cancer cell migration. Additionally, we observe mutation-enriched interactions between the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase and PIK3CA (the alpha catalytic subunit of phosphatidylinositol 3-kinase) that can inform the response to HER3 inhibition in vivo. We anticipate that the application of this framework will be valuable for translating genetic alterations into a molecular and clinical understanding of the underlying biology of many disease areas.

Abstract Although cholesterol has been hypothesized to promote cancer development through several potential pathways, its role in the risk of developing hormonally driven cancer is controversial. This literature review summarizes evidence from the highest quality studies to examine the consistency and strength of the relationship between serum cholesterol parameters and incidence of hormonally driven cancer. Articles were identified using EMBASE. Longitudinal observational studies published between January 2000 and December 2020 were considered for inclusion. The endpoint of interest was incident prostate, ovary, breast, endometrium, and uterine cancers. In total, 2732 reports were identified and screened; 41 studies were included in the review. No associations were found for ovarian cancer. Most endometrial cancer studies were null. The majority (76.9%) of studies reported no association between cholesterol and prostate cancer. Data on breast cancer were conflicting, associations limited, and effect sizes modest. Our results do not provide evidence for a clear association between cholesterol and different types of incident, hormonally driven reproductive cancers. Future studies should investigate the impact of lipid‐lowering therapy.