A Healthcare-Academic Practice Partnership Program to Promote Student Nurse Readiness for Work.

Highly skilled new graduate nurses must be better prepared to face the clinical and professional challenges in today's healthcare environment. Compounding these challenges are the growing resignations of clinical faculty and experienced clinical nurses. Innovative programs are needed to bridge the knowledge-practice gap with opportunities to create pipelines to aid the future nursing workforce. A multihospital health system partnered with a local college of nursing to develop a Nursing Student Pipeline Program, which allows nursing students to perform select nursing tasks as employees of the health system. Fifty-six students have been hired to participate in the pilot program. Of the students eligible for hire and who completed the program, 24 are current employees with the healthcare system. Students, preceptors, and managers report the benefits of this program, including that participating in the program supports increasing readiness for practice upon graduation.

Social Determinants of Health in Graduate Nursing Simulation Education: An Integrative Review.

BACKGROUND: This integrative review examined how simulation is being used to teach graduate nursing students about the social determinants of health (SDH). METHODS: The literature search focused on studies that included a sample of graduate nursing students who participated in an SDH simulation-based education (SBE). The timeframe used was 2013 to 2023 as this is when SBE emerged in graduate nursing education. Databases searched included Academic Search Complete, Cumulative Index to Nursing and Allied Health Literature, PubMed, and Web of Science. RESULTS: Nine studies included a sample of graduate nursing students and were included in this review. Published studies ranged from 2013 to 2023. CONCLUSION: The findings of this review highlight the need for graduate nursing faculty to design, implement, and evaluate transformative SDH-specific SBE that prepares students to understand their role as social justice advocates for health equity.

Addressing the Mental Health of Nursing Students During the Pandemic: The Evaluation of a Needs Assessment by a College of Nursing Mental Health Task Force.

BACKGROUND: A Mental Health Task Force (MHTF) was developed in a large public college of nursing in the Southeastern United States to address the urgent mental health needs expressed by growing numbers of nursing students related to the coronavirus disease 2019 (COVID-19). AIMS: The purpose of this study was to report on a needs assessment conducted by the MHTF. METHODS: The needs assessment study design was a 16-item cross-sectional online survey and four "Town Hall" focus groups with nursing students, faculty, and staff (n = 1-8 participants per group). Survey data were analyzed using descriptive statistics and free-text questions from the survey and focus groups were analyzed using a qualitative descriptive approach. RESULTS: Undergraduate and graduate students (n = 115) ranging in age from 17 to 50 years completed the survey; 95% female, 94% full-time, 56% employed, 77% White, and 81% in the Bachelor of Science in Nursing program. Eleven students participated in the focus groups. The analysis of the free-text survey questions identified the students' perceived needs. Mental health care was the most frequently requested, followed by faculty check-ins, stress management, and peer support. CONCLUSIONS: The administration of the survey provided an opportunity for students to communicate concerns and make requests. To address the ongoing effects of the COVID-19 pandemic on nursing students, multi-modal needs assessments should be conducted periodically to identify priority mental health needs.

Correction: Medication Adherence Reminder System for Virtual Home Assistants: Mixed Methods Evaluation Study.

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Tipping Point: Integrating Social Determinants of Health Concepts in a College of Nursing.

BACKGROUND: State health rankings, national nursing education reform, and increasing awareness of social injustices propelled a college of nursing to transform its strategic plan, infrastructure, and curriculum. The prevalence of social determinants of health (SDOH) in South Carolina indicates a need for the state's health workforce to understand the impact of SDOH and recognize strategies to address and ameliorate SDOH. With the paradigmatic integration of diversity, equity, and inclusion in nursing education, there is a need for programmatic and curricular integration of SDOH to increase awareness, foster understanding, and transform perspectives among nursing faculty, staff, and students. METHOD: Institutional changes were made to improve inclusive excellence, and the evolutionary process is described. RESULTS: SDOH-rich resources and experiential learning have been integrated across a college of nursing. CONCLUSION: This journey is ongoing and essential for preparing nurses to advance patient advocacy, health equity, and social justice for diverse populations. [J Nurs Educ. 2021;60(12):703-706.].

Medication Adherence Reminder System for Virtual Home Assistants: Mixed Methods Evaluation Study.

BACKGROUND: Medication nonadherence is a global public health challenge that results in suboptimal health outcomes and increases health care costs. Forgetting to take medicines is one of the most common reasons for unintentional medication nonadherence. Research findings indicate that voice-activated virtual home assistants, such as Amazon Echo and Google Home devices, may be useful in promoting medication adherence. OBJECTIVE: This study aims to create a medication adherence app (skill), MedBuddy, for Amazon Echo devices and measure the use, usability, and usefulness of this medication-taking reminder skill. METHODS: A single-group, mixed methods, cohort feasibility study was conducted with women who took oral contraceptives (N=25). Participants were undergraduate students (age: mean 21.8 years, SD 6.2) at an urban university in the Southeast United States. Participants were given an Amazon Echo Dot with MedBuddy-a new medication reminder skill for Echo devices created by our team-attached to their study account, which they used for 60 days. Participants self-reported their baseline and poststudy medication adherence. MedBuddy use was objectively evaluated by tracking participants' interactions with MedBuddy through Amazon Alexa. The usability and usefulness of MedBuddy were evaluated through a poststudy interview in which participants responded to both quantitative and qualitative questions. RESULTS: Participants' interactions with MedBuddy, as tracked through Amazon Alexa, only occurred on half of the study days (mean 50.97, SD 29.5). At study end, participants reported missing their medication less in the past 1 and 6 months compared with baseline (χ21=0.9 and χ21=0.4, respectively; McNemar test: P<.001 for both). However, there was no significant difference in participants' reported adherence to consistently taking medication within the same 2-hour time frame every day in the past 1 or 6 months at the end of the study compared with baseline (χ21=3.5 and χ21=0.4, respectively; McNemar test: P=.63 and P=.07, respectively). Overall feedback about usability was positive, and participants provided constructive feedback about the skill's features that could be improved. Participants' evaluation of MedBuddy's usefulness was overwhelmingly positive-most (15/23, 65%) said that they would continue using MedBuddy as a medication reminder if provided with the opportunity and that they would recommend it to others. MedBuddy features that participants enjoyed were an external prompt separate from their phone, the ability to hear the reminder prompt from a separate room, multiple reminders, and verbal responses to prompts. CONCLUSIONS: The findings of this feasibility study indicate that the MedBuddy medication reminder skill may be useful in promoting medication adherence. However, the skill could benefit from further usability enhancements.

Relationships Among Nursing Deans' Leadership Styles and Faculty Job Satisfaction Levels.

BACKGROUND: Although there is an abundance of empirical evidence on principals' leadership practices and teacher satisfaction in K-12 settings, a paucity of publications explore nursing faculty job satisfaction as influenced by leadership styles of academic deans. This research examined leadership styles of nursing deans to determine whether they correlate with nursing faculty job satisfaction at public U.S. universities with high research activity. METHOD: A descriptive, correlational study was conducted with electronic self-administered questionnaires. The sample was recruited from 24 universities; 303 questionnaires were returned. RESULTS: Faculty perceived that nursing deans displayed transformational leadership style more frequently. Nursing faculty were moderately satisfied in their jobs, and they were more satisfied with nursing deans who practiced attributed idealized influence. CONCLUSION: Three types of leadership behaviors explained significant variance in faculty job satisfaction, indicating the need for training and development focused on effective leadership behaviors. [J Nurs Educ. 2020;59(2):68-75.].

Membrane interactions of the globular domain and the hypervariable region of KRAS4b define its unique diffusion behavior.

The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable region side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here, we characterize RAS in live human and mouse cells using single-molecule-tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein's globular domain. To understand the altered mobility of an oncogenic KRAS4b, we used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism.

Discovery of thioether-bridged cyclic pentapeptides binding to Grb2-SH2 domain with high affinity.

Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor-bound protein 2 (Grb 2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferate agents due to its potential to shut down the Ras activation pathway. In this study, a series of phosphotyrosine containing cyclic pentapeptides were designed and synthesized based upon the phage library derived cyclopeptide, G1TE. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low micromolar range binding affinity, such as cyclic peptide 15 with an K(d)=0.359microM, which is providing a novel template for the development of Grb2-SH2 domain antagonists as potential therapeutics for certain cancers.

Identification of Shc Src homology 2 domain-binding peptoid-peptide hybrids.

A fluorescence anisotropy (FA) competition-based Shc Src homology 2 (SH2) domain-binding was established using the high affinity fluorescein isothiocyanate (FITC) containing peptide, FITC-NH-(CH2)4-CO-pY-Q-G-L-S-amide (8; Kd = 0.35 microM). Examination of a series of open-chain bis-alkenylamide containing peptides, prepared as ring-closing metathesis precursors, showed that the highest affinities were obtained by replacement of the original Gly residue with N alpha-substituted Gly (NSG) "peptoid" residues. This provided peptoid-peptide hybrids of the form "Ac-pY-Q-[NSG]-L-amide." Depending on the NSG substituent, certain of these hybrids exhibited up to 40-fold higher Shc SH2 domain-binding affinity than the parent Gly-containing peptide (IC50 = 248 microM) (for example, for N-homoallyl analogue 50, IC50 = 6 microM). To our knowledge, this work represents the first successful example of the application of peptoid-peptide hybrids in the design of SH2 domain-binding antagonists. These results could provide a foundation for further structural optimization of Shc SH2 domain-binding peptide mimetics.

Selectivity and mechanism of action of a growth factor receptor-bound protein 2 SRC homology 2 domain binding antagonist.

We have shown previously that a potent synthetic antagonist of growth factor receptor-bound protein 2 (Grb2) Src homology 2 (SH2) domain binding (1) blocks growth factor stimulated motility, invasion, and angiogenesis in cultured cell models, as well as tumor metastasis in animals. To characterize the selectivity of 1 for the SH2 domain of Grb2 over other proteins containing similar structural binding motifs, we synthesized a biotinylated derivative (3) that retained high affinity Grb2 SH2 domain binding and potent biological activity. To investigate the selectivity of 1 and 3 for Grb2, the biotinylated antagonist 3 was used to immobilize target proteins from cell extracts for subsequent identification by mass spectrometry. Non-specific binding was identified in parallel using a biotinylated analogue that lacked a single critical binding determinant. The mechanism of action of the antagonist was further characterized by immunoprecipitation, immunoblotting, and light microscopy. This approach to defining protein binding antagonist selectivity and molecular basis of action should be widely applicable in drug development.

Structural examination of ring-closing metathesis-derived 15-member macrocycles as Grb2 SH2 domain-binding tetrapeptide mimetics.

Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains together with vinyl- and allyl-functionality appended to the beta-methylene of amino-terminal phosphotyrosyl (pTyr) mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containing analogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure may facilitate the development of therapeutically relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this study may also find application to peptide mimetics directed at other biological targets.

Measuring the binding stoichiometry of HIV-1 Gag to very-low-density oligonucleotide surfaces using surface plasmon resonance spectroscopy.

The interaction of the HIV Gag polyprotein with nucleic acid is a critical step in the assembly of viral particles. The Gag polyprotein is composed of the matrix (MA), capsid (CA), and nucleocapsid (NC) domains. The NC domain is required for nucleic acid interactions, and the CA domain is required for Gag-Gag interactions. Previously, we have investigated the binding of the NC protein to d(TG)(n) oligonucleotides using surface plasmon resonance (SPR) spectroscopy. We found a single NC protein is able to bind to more than one immobilized oligonucleotide, provided that the oligonucleotides are close enough together. As NC is believed to be the nucleic acid binding domain of Gag, we might expect Gag to show the same complex behavior. We wished to analyze the stoichiometry of Gag binding to oligonucleotides without this complication due to tertiary complex formation. We have therefore analyzed Gag binding to extremely low oligonucleotide density on SPR chips. Such low densities of oligonucleotides are difficult to accurately quantitate. We have determined by Fourier transform ion cyclotron (FTICR) mass spectrometry that four molecules of NC bind to d(TG)(10) (a 20-base oligonucleotide). We developed a method of calibrating low-density surfaces using NC calibration injections. Knowing the maximal response and the stoichiometry of binding, we can precisely determine the amount of oligonucleotide immobilized at these very-low-density surfaces (<1 Response Unit). Using this approach, we have measured the binding of Gag to d(TG)(10). Gag binds to a 20-mer with a stoichiometry of greater than 4. This suggests that once Gag is bound to the immobilized oligonucleotide, additional Gag molecules can bind to this complex.

Examination of acylated 4-aminopiperidine-4-carboxylic acid residues in the phosphotyrosyl+1 position of Grb2 SH2 domain-binding tripeptides.

A 4-aminopiperidine-4-carboxylic acid residue was placed in the pTyr+1 position of a Grb2 SH2 domain-binding peptide to form a general platform, which was then acylated with a variety of groups to yield a library of compounds designed to explore potential binding interactions, with protein features lying below the betaD strand. The highest affinities were obtained using phenylethyl carbamate and phenylbutyrylamide functionalities.

Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis.

A family of previously reported ring-closing metathesis (RCM)-derived macrocycles that exhibit potent Grb2 SH2 domain-binding affinity is characterized by stereoselectively-introduced upper ring junctions that bear bicyclic aryl substituents. However, the synthetic complexity of these macrocycles presents a potential limit to their therapeutic application. Therefore, the current study was undertaken to simplify these macrocycles through the use of achiral 4-pentenylamides as ring-forming components. A series of macrocycles (5a-f) was prepared bearing both open and cyclic constructs at the upper ring junction. The Grb2 SH2 domain-binding affinities of these macrocycles varied, with higher affinities being obtained with cyclo-substituents. The most potent analogue (5d) contained a cyclohexyl group and exhibited Grb2 SH2 domain-binding affinity (K(D) = 1.3 nM) that was nearly equal to the parent macrocycle (2), which bore a stereoselectively-introduced naphthylmethyl substituent at the upper ring junction (K(D) = 0.9 nM). The results of this study advance design considerations that should facilitate the development of Grb2 SH2 domain-binding antagonists.

Structure-based design of potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics.

Development of Grb2-SH2 domain antagonists is considered to be an effective and non-cytotoxic strategy to develop new antiproliferative agents because of their potential to shut down the Ras signaling pathway. We developed a concise route for the efficient synthesis of G1TE analogs on solid phase. Using this route, a series of cyclic peptides that do not rely on phosphotyrosine or its mimics were designed and synthesized based upon the phage library-derived cyclopeptide, G1TE. Considering that Gly7 plays prominent roles for G1TE binding to the Grb2-SH2 domain, we introduced different amino acids in the 7th position. The D-Ala7-containing peptide 3 demonstrates improved binding affinity by adopting favorable conformation for protein binding. This can be rationalized by molecular modeling. The optimization at the Leu2 position was also studied, and the resulting cyclopeptides exhibited remarkably improved binding affinity. Based upon these global modifications, a highly potent peptide ligand 9 was discovered with a Kd = 17 nM, evaluated by Biacore binding assay. This new analog is one of the most potent non-phosphorus-containing Grb2-SH2 antagonists reported to date. This potent peptidomimetic provides a new template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer.

Application of azide-alkyne cycloaddition 'click chemistry' for the synthesis of Grb2 SH2 domain-binding macrocycles.

Copper (I) promoted [3+2] Huisgen cycloaddition of azides with terminal alkynes was used to prepare triazole-containing macrocycles based on the Grb2 SH2 domain-binding motif, 'Pmp-Ac(6)c-Asn', where Pmp and Ac(6)c stand for 4-phosphonomethylphenylalanine and 1-aminocyclohexanecarboxylic acid, respectively. When cycloaddition reactions were conducted at 1mM substrate concentrations, cyclization of monomeric units occurred. At 2mM substrate concentrations the predominant products were macrocyclic dimers. In Grb2 SH2 domain-binding assays the monomeric (S)-Pmp-containing macrocycle exhibited a K(d) value of 0.23microM, while the corresponding dimeric macrocycle was found to have greater than 50-fold higher affinity. The open-chain dimer was also found to have affinity equal to the dimeric macrocycle. This work represents the first application of 'click chemistry' to the synthesis of SH2 domain-binding inhibitors and indicates its potential utility.

Complex interactions of HIV-1 nucleocapsid protein with oligonucleotides.

The HIV-1 nucleocapsid (NC) protein is a small, basic protein containing two retroviral zinc fingers. It is a highly active nucleic acid chaperone; because of this activity, it plays a crucial role in virus replication as a cofactor during reverse transcription, and is probably important in other steps of the replication cycle as well. We previously reported that NC binds with high-affinity to the repeating sequence d(TG)n. We have now analyzed the interaction between NC and d(TG)4 in considerable detail, using surface plasmon resonance (SPR), tryptophan fluorescence quenching (TFQ), fluorescence anisotropy (FA), isothermal titration calorimetry (ITC) and electrospray ionization Fourier transform mass spectrometry (ESI-FTMS). Our results show that the interactions between these two molecules are surprisngly complex: while the K(d) for binding of a single d(TG)4 molecule to NC is only approximately 5 nM in 150 mM NaCl, a single NC molecule is capable of interacting with more than one d(TG)4 molecule, and conversely, more than one NC molecule can bind to a single d(TG)4 molecule. The strengths of these additional binding reactions are quantitated. The implications of this multivalency for the functions of NC in virus replication are discussed.

Design and synthesis of 4-(alpha-hydroxymalonyl)phenylalanine as a new phosphotyrosyl mimetic and its use in growth factor receptor bound 2 src-homology 2 (Grb2 SH2) domain-binding peptides.

A new phosphotyrosyl mimetic 4-(alpha-hydroxymalonyl)phenylalanine and its incorporation into a Grb2 SH2 domain-binding tripeptide are presented. In whole-cell studies using malonyl ethyl ester prodrug derivatives, it was observed that the 4-(alpha-hydroxymalonyl)phenylalanyl-containing peptide exhibited greater efficacy than the nonhydroxylated 4-(malonyl)phenylalanyl-containing congener in blocking the association of Grb2 with activated erbB-2 tyrosine kinase. These results are consistent with de-esterification and at least partial intracellular decarboxylation.

Examination of phosphoryl-mimicking functionalities within a macrocyclic Grb2 SH2 domain-binding platform.

Reported herein are the design, synthesis, and Grb2 SH2 domain-binding affinities of several phosphoryl-mimicking groups displayed within the context of a conformationally constrained macrocyclic platform. With use of surface plasmon resonance techniques, single-digit nanomolar affinities were exhibited by phosphonic acid and malonyl-containing diacidic phosphoryl mimetics (for 4h and 4g, K(D) = 1.47 and 3.62 nM, respectively). Analogues containing monoacidic phosphoryl mimetics provided affinities of K(D) = 16-67 nM. Neutral phosphoryl-mimicking groups did not show appreciable binding.