HER2/HER3/NRG1b Heterocomplex Structure and Assembly

Cell communication is essential for cellular function and relies on the faithful transmission of signals across the plasma membrane through membrane receptors. Receptor kinases constitute an important class of molecular antennas in which the extracellular signal binding module is linked to an intracellular kinase along one polypeptide chain. Perturbations in this finely coordinated system causes aberrant signaling which lead to pathological states such as cancer or developmental disorders. Despite the disease relevance and extensive therapeutic focus, we fundamentally do not understand how receptor kinases transmit a signal across the plasma membrane in the absence of full-length structures. This is particularly true for the Human Epidermal Growth Factor Receptor 2 (HER2), an orphan receptor, and the Human Epidermal Growth Factor Receptor 3 (HER3), a pseudokinase receptor which form a potent pro-oncogenic heterocomplex upon binding to extracellular ligand. Here, we present three novel high-resolution cryo-electron microscopy (cryo-EM) structures of the extracellular domain of the breast cancer receptor, HER2, engaged with its liganded co-receptor, HER3, solved in the context of near full-length receptors. As the first singly-liganded human HER receptor structures, our findings provide a missing link in the HER receptor field, offer the dimerization arm as an allosteric sensor for ligand binding, visualize HER3 in an extended state for the first time, demonstrate how the most frequent oncogenic HER2 variant, HER2 S310F, exploits dimerization arm dynamics to enhance heterodimerization, and unveil previously unknown details on how commonly prescribed biologic agents bind the heterodimer. Our studies on near full-length HER2 and HER3, when isolated alone, surprisingly reveal that HER2 is a homodimer that may adopt an autoinhibited state and HER3, contrary to dogma, homodimerizes in the presence of NRG1b. Taken together, these findings made possible through the lens of full-length receptor biophysics, explain ligand allostery, inform rational drug design, and add nuance to a model of HER2/HER3/NRG1b heterocomplex assembly

The Journey Through No-Man's Land: A Phenomenological Study of NFL Free-Agent Players' Transition Experience from Active NFL Player to Retired NFL Player

The transition from professional sport marks the beginning of what has been found to be a difficult and stressful experience (Park, Lavallee, & Todd, 2013). Exiting a career serves as a major life change that requires one to adjust to numerous changes (Erpic, Wylleman, & Zupancic, 2004). Research has highlighted a number of personal and contextual factors that affect the quality of the transition experience (Knights, Sherry, & Ruddock-Hudson, 2016; Park et al., 2013); however, no studies to date have examined players who are in the midst of the transition. This qualitative, phenomenological study was undertaken to address the research question: What is the lived experience of NFL free-agent players as they transition from an active NFL player to a retired NFL player? In-depth interviews completed with 12 NFL free-agent players found a three-phase process of transitioning, consisting of the initial reaction, “no-man’s land,” and the final realization. Six themes emerged that described the players’ experience: (1) participants identified a trigger event prior to deselection; (2) being deselected was sudden, leaving participants shocked, isolated, and angry; (3) the subsequent period was dynamic, emotionally, cognitively, and behaviorally; (4) players reached a point of realization about their future; (5) the loss of the NFL community was a significant challenge; and (6) four protective factors helped participants. The study offers recommendations related to theory, practice, and future research

CD44 Mediates Bone Marrow Stromal Cell Resistance to T Cell Redirection Therapy

T cell redirection therapeutics such as a bispecific antibodies and chimeric antigen receptor T cells (CAR T) have shown clinical relevance for hematological malignancies with the recent approvals of blinatumomab and tisagenlecleucel. Hematological malignancies, including acute myeloid leukemia (AML), originate in the bone marrow (BM). Dysfunctions in the AML BM are immune-suppressive and contribute to resistance, compared to healthy BM. Previous studies have shown that AML cells are protected against chemotherapeutic and immune-based therapies when they are co-cultured on BM stromal cells. To evaluate the protective effect of BM stromal cells, we utilized a bispecific antibody targeting both CD123 (AML cells) and CD3 (T cells) with AML cells grown in co-culture with BM stromal cells. We observed that the cytotoxic activity of our CD123xCD3 bispecific antibody was inhibited with multiple BM stromal cell types. Inhibition of the CD44 receptor with either a neutralizing antibody or a knock-out (KO) using clustered regularly interspaced short palindromic repeats (CRISPR) technology on both AML and stromal cells restored the activity of our CD123xCD3 bispecific antibody. Combination of anti-CD44 agents with T cell redirection agents may be a rational approach to improve their efficacy and provide deeper responses

How Webinar Experiences Influence Selection of Online Doctoral Programs: A Qualitative Descriptive Study

The purpose of this qualitative descriptive study was to explore how doctoral students describe their pre-enrollment experiences in an interactive technology-based webinar with senior leaders, and how the webinar experiences influenced their selection of an online doctoral program at a Christian university in the southwestern United States. The theoretical foundations were the media richness theory, the social presence theory, Tinto’s theory, and the concept of customer value. The overarching research question was: How do doctoral students describe their pre-enrollment experiences in an interactive technology-based webinar with senior leaders, and how the webinar experiences influenced their selection of an online doctoral program? The sample included online doctoral students who participated in an interactive technology-based webinar with senior university leaders and then enrolled in an online doctoral program. Data collection included semi-structured interviews as well as marketing artifacts and documents that influenced the decision to become an online doctoral student. Data analysis included descriptive statistics and thematic analysis. The findings from this study included factors that contributed to the success of marketing webinars, the interactions and connections with senior leaders, what prospective students found of value within the webinar and academic experience that motivated decision making, and the elements of marketing that influenced students to select the university and an online doctoral program. Future research recommendations are presented and are based on the findings of this study

Policy Expectations and Care-Provider Perceptions for Hospital Emergency Preparedness

Maintaining preparedness for a disaster is a patient and provider safety issue that is often not a priority for hospital planning; however, the inability to implement and evaluate disaster/emergency preparedness programs may render hospitals and the overall healthcare system fragile and dysfunctional amidst such crises. Priorities such as emergency-department overcrowding and lack of funding emerge daily and contribute to the inability of hospitals to respond appropriately to unexpected events. This study was conducted with the aim to assess the correlation between disaster/emergency preparedness and related problems, policy, and politics. A cross-sectional survey design was used to determine whether problems, policy, and politics perceived by Tennessee acute-care hospital nurses predicted the disaster/emergency preparedness of their hospitals. A multiple linear regression model was applied to assess the effects of disaster/emergency problems, policy, and politics on disaster/emergency preparedness. A regression equation was created with respect to problems, policy, and politics predictor variables with age, gender, education, and location used as confounding variables. The results of the study revealed that policy (β = 0.41, p =.01) and politics (β = 0.26, p =.02) were related to disasters/emergencies, and these two significant variables can be used to predict disaster preparedness. In summary, disaster/emergency policy and politics predict preparedness within healthcare settings, including hospitals. These findings are suggestive of the urgent need for social change to require, develop, and implement a statewide hospital and overall standardized healthcare disaster/emergency-preparedness system with surveillance and monitoring for indicators of occurrence

Creative Play for Teaching Empathy to Young Children: an Inner Exploration of an Instructor's Process, a Visual and Narrative Journey

Operating from the hypothesis that much of our prejudice and inequality results from a lack of empathy, my dissertation answers the research question: What reflective insights emerge from an autoethnographic study of creative story-telling and play, in online teaching of elementary grade children? This autoethnographic study, with video component, examines my online teaching and experiences that emphasize playfulness, empathy, diversity and inclusion, in the context of education and for general youth development. Through the use of documentary-style presentation, I offer excerpts of me teaching, an online version of storytelling and play, as learning tools to facilitate the understanding of empathy and shared humanity. I provide a recorded narrative of my reflections that I film, in addition to a prose introduction. The dissertation has three main dimensions: a) Excerpts of recorded online teaching of just me (no children are seen) and portions of already existing footage of interviews, b) Narrative of reflections for class planning, personal and academic discoveries, teaching, and other data comprised of journal entries, personal reflections, poetry, c) Intro, citations of research, literature review, and conclusions. I believe my illustrations will make for unique connections between playfulness and the development of empathy. Keywords: Play, creative play, empathy, education, K-6 education, online teaching, puppets, story, storytelling, hierarchy, discrimination, prejudice, inequality

A Case Study on Sexual Violence in Conflict

Conflict-related sexual violence (CRSV) is a longstanding atrocity that has plagued societies since the earliest documentation of war. Much of the existing research focuses on the reactionary implications and impact on individuals, families, communities, and the larger society. In this case study, the researcher focused on how policy, procedure, and culture influence CRSV. Using the ongoing conflict with Ukraine, Russia, and Crimea, the researcher veered away from the more commonly utilized conflicts in Africa, such as the Democratic Republic of Congo (DRC). This conflict was used to demonstrate that sexual violence is not limited by geographical boundaries, but rather is a global phenomenon that needs further scrutiny of such use in Western societies. In this study, the researcher used Wood’s Typology of Rape (2018) as the theoretical framework to guide how policies and procedures influence CRSV. Wood’s typology provides guidance of rape as policy versus practice, and these delineations were used to identify the policies and procedures that were used in the Ukraine, Russia, Crimea conflict. There was not a theoretical framework to identify cultural influences; however, various cultural constructs from previous studies were identified in this study. Four out of six of the criteria for both policies and procedures were identified in the data and 10 different cultural constructs were found. The findings demonstrate a need for collaboration with key stakeholders, both within the conflict zones and those on the outside making legal and political decisions. The evidence shows that the militarized environment leaves combatants and citizens vulnerable to CRSV and the response is there after the crimes are committed. However, there are policy, procedural, and cultural components that can be used to prevent CRSV from happening in the first place and this study and others can be used to support such efforts

Economic Model Predictive Control of a Chemical Process Using Modified ARX Models

Advanced process control techniques use optimization to increase profit, decrease costs, and minimize the environmental impacts of chemical processes. Current strategies for optimal control use complex non-linear models in an optimization layer and simplified linear models in the control layer. This two-layer approach combined with complex modeling techniques leads to less than optimal control performance due to model mismatch between layers, and prediction that cannot keep up with current market demands. Economic model predictive control (EMPC) is a promising method to optimally control processes in the chemical production industry. EMPC with a linear model identified from input-output data simplifies the prediction of non-linear processes and removes the boundary between optimization and control. However, the inaccuracies of a linear model may degrade the resulting controller design. The purpose of this research is to resolve this drawback by employing multiple linear models to predict outputs, and constrain a non-linear process. A nominal autoregressive model with exogenous inputs (ARX) is designed to capture the trend of process outputs. The nominal linear model is inaccurate, and thus modified ARX models are used to constrain the nominal model by placing dynamic upper and lower bounds on the prediction of the process variable. The nominal process model is then used to calculate the economically optimal trajectory of the process over a specified time-period called the prediction horizon, while the upper and lower bound models constrain the output. The addition of the upper and lower bound models results in significantly more reliable control with respect to operating constraints, therefore enhancing the safety and accuracy of EMPC when used to maximize the economic objective. Process control can be implemented in this way with nearly all commercially available software and hardware, including MATLAB, Siemens PLC, and LabVIEW

An Interpreted Journey of Professional Growth Among Female Baccalaureate Nursing Students: A Hermeneutic Study of Mindfulness Practices

Nursing literature reveals that stress is a leading factor contributing to nursing student attrition, new nurses leaving the profession, and the reduction of positive formation of professional identity during prelicensure education and transition into professional practice, which jeopardizes the growth and replacement needs of the future nursing workforce. Despite extensive quantitative research suggesting mindfulness practices decreases stress and anxiety among college students, nursing students, and nurses, a paucity of qualitative studies exist to inform on the meaning of this experience from the nursing student perspective. Nursing literature also suggests that stress management techniques, cultivating awareness of personal values, and a sense of spirituality cultivate stronger perceptions of professional identity, which is linked to better patient outcomes and is key to job retention. Nursing educators need insight on how mindfulness practices can assist in stress management and the development of optimal professional identity. Using Diekelmann, Allen, and Tanner’s Hermeneutic seven-stage analysis, this study interpreted the meaning of mindfulness practices among nursing students who practiced meditation and/or yoga. All participants in this qualitative study completed a demographic questionnaire and an in-depth interview. Participants included 11 female baccalaureate nursing students from five different BSN programs located in the Mid-Atlantic region. The meaning of mindfulness practices was interpreted as a multidimensional process in the constitutive pattern of professional growth. Four relational themes and four corresponding sub-themes were identified: (1) valued benefits (stress reduction and equanimity), (2) awakening self-love through self-care (self-awareness and self-compassion), (3) emerging self (resilience and presence), and (4) evolving professional identity (holistic person-centered care and patient advocacy). Professional growth was also linked to the Eightfold Path of Buddhist tradition that leads to enlightenment. Professional growth encompassed the age, gender, affective learning, enhanced cognitive reasoning, and the spiritual and self-growth experienced by the participants in this study. These experiences positively impacted professional identity formation and stress management which culminated in the development of moral agency and sound nursing clinical decision-making. Findings from this study offer implications for nursing program administrators and educators to address current and upcoming standards set forth by nursing education organizations by creating academic support programs to promote and ensure student retention, well-being, and safe, quality person-centered care

Impact of Equality and Diversity on Black FBS Head Coaches

This study was conducted using semistructured interviews to investigate the lived career-mobility experiences of six Black FBS head coaches, who had served in that position for at least one season from 2005–2020, through the lens of five tenets of critical race theory, which were also used as study themes: permanence of racism; Whiteness as property; interest convergence; experiential knowledge and counter storytelling; and critique of liberalism. The results were analyzed using open coding to map the coach’s responses to the CRT tenets. Results revealed that the coaches experienced a variety of expected and unexpected psychological stressors such as emotional isolation, limited opportunities to be mentored, pressure to represent their race, and pressure to create other opportunities for Black coaches. Their feelings of desperation and of negative and racial social perceptions may have led to confusion about their long-term professional goals. This study may help sport psychology practitioners gain insights to the challenges this population of coaches’ face when helping them navigate their careers. Future studies could build on this one using qualitative, quantitative, or bifurcated research to investigate hiring practices, leadership, goal setting, and diversity initiatives with athletic directors, university administrators, or White FBS head coaches. This study could also be replicated in 2030, be compared to the 2020 results, and focus on the coping strategies that Black FBS coaches have used to navigate their careers