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Chemokines are small proteins involved in recruiting leukocytes to sites of inflammation via interactions with specific cell surface receptors. CCL22 is a chemokine known to play a critical role in inflammatory diseases such as atopic dermatitis and asthma; inhibition of this chemokine therefore represents an attractive therapeutic strategy. Herein, we describe the discovery of cyclic d-sulfopeptide inhibitors of CCL22 identified through mirror-image mRNA display with genetic reprogramming. Chemical synthesis of mirror-image d-CCL22 enabled screening of a cyclic peptide library comprised of all l-amino acids, with reprogramming of l-sulfotyrosine to mimic the presence of this post-translational modification on native chemokine receptors. Enriched macrocyclic peptides were prepared in their mirror-image d-form and assessed for binding against native l-CCL22. The most potent ligand, a plasma-stable d-cyclic peptide bearing four d-sulfotyrosine residues, exhibited nanomolar affinity for CCL22, high selectivity over other chemokines, and nanomolar inhibition of CCL22 signaling through CCR4. This work highlights the vast potential of mirror-image mRNA display technology for discovering proteolytically stable d-peptide inhibitors of protein-protein interactions relevant across a range of therapeutic indications.

Introduction: Doctor of Physical Therapy (DPT) education programs have been charged with developing a culturally competent health care workforce to better meet the needs of diverse communities and reduce health inequities. The purpose of this longitudinal, quasi-experimental educational intervention study was to examine the effects of an integrated DPT program curriculum on student cultural competence at a public, midsize, midwestern university., Review of Literature: There is an abundance of research on conceptual models and frameworks for the development of cultural competence within health care education with many studies relying on self-perception to measure outcomes. Using the Model of Interculturalization as a theoretical framework, this study explored the development of cultural competence among DPT students using the Intercultural Development Inventory (IDI)., Subjects: A purposeful convenience sample of DPT students ( n = 177) was used., Methods: The IDI was administered to 3 student cohorts. One cohort had data at 4 different time points, including upon entry into the program (baseline) and at the end of the first, second, and third year. Two cohorts had data for 2 time points. IDI Developmental Orientation (DO) and Orientation Gap (OG) scores were used to measure cultural competence and accuracy of self-perception of cultural competence. Data analysis was performed using descriptive statistics, independent and dependent sample t -tests, and analysis of variances., Results: There were no differences between the cohorts. There were statistically significant improvements in both cultural competence (DO scores) and accuracy of self-perception of cultural competence (OG scores) for 2 cohorts. However, significant change only occurred during year 1. No other differences across time for any of the cohorts were significant., Discussion and Conclusion: Findings can be leveraged and incorporated into recommendations for curricular revision and program reform targeting cultural competence development among DPT students., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Academy of Physical Therapy Education, APTA.)

Drugs are administered at a dosing schedule set by their therapeutic index, and termination of action is achieved by clearance and metabolism of the drug. In some cases, such as anticoagulant drugs or immunotherapeutics, it is important to be able to quickly reverse the drug's action. Here, we report a general strategy to achieve on-demand reversibility by designing a supramolecular drug (a noncovalent assembly of two cooperatively interacting drug fragments held together by transient hybridization of peptide nucleic acid (PNA)) that can be reversed with a PNA antidote that outcompetes the hybridization between the fragments. We demonstrate the approach with thrombin-inhibiting anticoagulants, creating very potent and reversible bivalent direct thrombin inhibitors (K i  = 74 pM). The supramolecular inhibitor effectively inhibited thrombus formation in mice in a needle injury thrombosis model, and this activity could be reversed by administration of the PNA antidote. This design is applicable to therapeutic targets where two binding sites can be identified., (© 2024. The Author(s).)

Although the viral nature of videos that capture violent and racialized policing of Black Americans in the United States can increase awareness, exposure to race-based violence can result in vicarious traumatization, particularly among Black Americans. The relationship between anticipatory traumatic reactions (ATRs) and racial identity attitudes is not clearly addressed in the extant body of literature. The current study addresses this research disparity by first analyzing group mean differences among Black Americans ( N  = 138) who were assigned to audiovisual, written, and imaginal exposure groups. The current study also used a cluster analysis of Black Americans to examine the differences between racial identity attitudes and ATRs following media exposure to undue police violence. Results from the study indicated that no differences in ATRs existed based on types of media exposure. Significant differences across three racial identity clusters existed between ATR in association with attitudes of assimilation, miseducation, self-hatred, anti-dominance, and ethnic-racial salience. Findings from the study suggest that mental health professionals should attend to racial identity attitudes as a relevant factor in how Black American clients experience the psychological impact of media exposure to undue police violence., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

The development of effective antiviral compounds is essential for mitigating the effects of the COVID-19 pandemic. Entry of SARS-CoV-2 virions into host cells is mediated by the interaction between the viral spike (S) protein and membrane-bound angiotensin-converting enzyme 2 (ACE2) on the surface of epithelial cells. Inhibition of this viral protein-host protein interaction is an attractive avenue for the development of antiviral molecules with numerous spike-binding molecules generated to date. Herein, we describe an alternative approach to inhibit the spike-ACE2 interaction by targeting the spike-binding interface of human ACE2 via mRNA display. Two consecutive display selections were performed to direct cyclic peptide ligand binding toward the spike binding interface of ACE2. Through this process, potent cyclic peptide binders of human ACE2 (with affinities in the picomolar to nanomolar range) were identified, two of which neutralized SARS-CoV-2 entry. This work demonstrates the potential of targeting ACE2 for the generation of anti-SARS-CoV-2 therapeutics as well as broad spectrum antivirals for the treatment of SARS-like betacoronavirus infection.

As university faculty must continually grow in their instructional skills and proficiencies with new tools to remain relevant to the educational needs of their students, effective models of professional learning and development are important areas of need and topics for research. However, many outdated professional development models do not create the desired results of technology integration into university teaching. More responsive and innovative models of faculty learning could be the answer. The purpose of the current research study was to explore the impact individualized professional development had on faculty's understanding, experience, and use of a technological tool. A qualitative research design was implemented to analyze data from interviews and surveys. The participants were a convenience sample of six faculty members across five different programs within one university located in the southeastern United States. Data were analyzed using a hybrid coding method and the results revealed that the procedures facilitated implementation of a technological tool within the specific contexts of their courses. Participating faculty appreciated the utility of the provided training and how closely the designed resources mirrored those they would encounter in their instruction of students. Based on study findings and other relevant research, a new model for individualized professional development using a technological tool is proposed which can help to guide future faculty learning., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M pro ) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 M pro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M pro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these M pro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC 50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis ( Mtb ) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro . We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.

The modification of peptides and proteins has emerged as a powerful means to efficiently prepare high value bioconjugates for a range of applications in chemical biology and for the development of next-generation therapeutics. Herein, we report a novel method for the chemoselective late-stage modification of peptides and proteins at cysteine in aqueous buffer with suitably functionalised diaryliodonium salts, furnishing stable thioether-linked synthetic conjugates. The power of this new platform is showcased through the late-stage modification of the affibody zEGFR and the histone protein H2A., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities via the intrinsic pathway of coagulation and the kallikrein-kinin system, respectively. Inhibition of Factor XIIa (FXIIa), an initiator of the contact system, has been demonstrated to lead to thrombo-protection and anti-inflammatory effects in animal models and serves as a potentially safer target for the development of antithrombotics. Herein, we describe the use of the Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology to identify a series of potent and selective cyclic peptide inhibitors of FXIIa. Cyclic peptides were evaluated in vitro , and three lead compounds exhibited significant prolongation of aPTT, a reduction in thrombin generation, and an inhibition of bradykinin formation. We also describe our efforts to identify the critical residues for binding FXIIa through alanine scanning, analogue generation, and via in silico methods to predict the binding mode of our lead cyclic peptide inhibitors.

Almost all eukaryotic proteins receive diverse post-translational modifications (PTMs) that modulate protein activity. Many histone PTMs are well characterized, heavily influence gene regulation, and are often predictors of distinct transcriptional programs. Although our understanding of the histone PTM network has matured, much is yet to be understood about the roles of transcription factor (TF) PTMs, which might well represent a similarly complex and dynamic network of functional regulation. Members of the bromodomain and extra-terminal domain (BET) family of proteins recognize acetyllysine residues and relay the signals encoded by these modifications. Here, we have investigated the acetylation dependence of several functionally relevant BET-TF interactions in vitro using surface plasmon resonance, nuclear magnetic resonance, and X-ray crystallography. We show that motifs known to be acetylated in TFs E2F1 and MyoD1 can interact with all bromodomains of BRD2, BRD3, and BRD4. The interactions are dependent on diacetylation of the motifs and show a preference for the first BET bromodomain. Structural mapping of the interactions confirms a conserved mode of binding for the two TFs to the acetyllysine binding pocket of the BET bromodomains, mimicking that of other already established functionally important histone- and TF-BET interactions. We also examined a motif from the TF RelA that is known to be acetylated but were unable to observe any interaction, regardless of the acetylation state of the sequence. Our findings overall advance our understanding of BET-TF interactions and suggest a physical link between the important diacetylated motifs found in E2F1 and MyoD1 and the BET-family proteins.

The conserved MLR COMPASS-like complexes are histone modifiers that are recruited by a variety of transcription factors to enhancer regions where they act as necessary epigenetic tools for enhancer establishment and function. A critical in vivo target of the Drosophila MLR complex is the bantam miRNA that regulates cell survival and functions in feedback regulation of cellular signaling pathways during development. We determine that loss of Drosophila MLR complex function in developing wing and eye imaginal discs results in growth and patterning defects that are sensitive to bantam levels. Consistent with an essential regulatory role in modulating bantam transcription, the MLR complex binds to tissue-specific bantam enhancers and contributes to fine-tuning expression levels during larval tissue development. In wing imaginal discs, the MLR complex attenuates bantam enhancer activity by negatively regulating expression; whereas, in differentiating eye discs, the complex exerts either positive or negative regulatory activity on bantam transcription depending on cell fate. Furthermore, while the MLR complex is not required to control bantam levels in undifferentiated eye cells anterior to the morphogenetic furrow, it serves to prepare critical enhancer control of bantam transcription for later regulation upon differentiation. Our investigation into the transcriptional regulation of a single target in a developmental context has provided novel insights as to how the MLR complex contributes to the precise timing of gene expression, and how the complex functions to help orchestrate the regulatory output of conserved signaling pathways during animal development., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Our rural orthopaedic service has undergone service restructure during the COVID-19 pandemic in order to sustain hip fracture care. All adult trauma care has been centralised to the Royal Shrewsbury Hospital for assessment and medical input, before transferring those requiring operative intervention to the Robert Jones and Agnes Hunt Orthopaedic Hospital. We aim to review the impact of COVID-19 on hip fracture workload and service changes upon management of hip fractures., Methods: We reviewed our prospectively maintained trust database and National Hip Fracture Database records for the months of March and April between the years 2016 and 2020. Our assessment included fracture pattern (intrascapular vs extracapsular hip fracture), treatment intervention, length of stay and mortality., Results: We treated 288 patients during March and April between 2016 and 2020, with a breakdown of 55, 58, 53, 68, and 54 from 2016 to 2020 respectively. Fracture pattern distribution in the pre-COVID-19 years of 2016 to 2019 was 58% intracapsular and 42% extracapsular. In 2020 (COVID-19 period) the fracture patterns were 65% intracapsular and 35% extracapsular. Our mean length of stay was 13.1 days (SD 8.2) between 2016 to 2019, and 5.0 days (6.3) days in 2020 (p < 0.001). Between 2016 and 2019 we had three deaths in hip fracture patients, and one death in 2020. Hemiarthroplasty and dynamic hip screw fixation have been the mainstay of operative intervention across the five years and this has continued in the COVID-19 period. We have experienced a rise in conservatively managed patients; ten in 2020 compared to 14 over the previous four years., Conclusion: There has not been a reduction in the number of hip fractures during COVID-19 period compared to the same time period over previous years. In our experience, there has been an increase in conservative treatment and decreased length of stay during the COVID -19 period.Cite this article: Bone Joint Open 2020;1-8:500-507., (© 2020 Author(s) et al.)

Targeting chemokine signaling is an attractive avenue for the treatment of inflammatory disorders. Tyrosine sulfation is an important post-translational modification (PTM) that enhances chemokine-receptor binding and is also utilized by a number of pathogenic organisms to improve the binding affinity of immune-suppressive chemokine binding proteins (CKBPs). Here we report the display selection of tyrosine-sulfated cyclic peptides using a reprogrammed genetic code to discover high-affinity ligands for the chemokine CCL11 (eotaxin-1). The selected cyclic sulfopeptides possess high affinity for the target chemokine (as well as one or more of the related family members CCL2, CCL7 and CCL24) and inhibit CCL11 activation of CC chemokine receptor 3 (CCR3). This work demonstrates the utility of exploiting native PTMs as binding motifs for the generation of new leads for medicinal chemistry.

Aim: To explore nurses' perceptions of nurse managers' (NMs') communicative relationships that encourage nurses' decisions to buy-in to organisational initiatives to enhance patients' experiences with care (PEC)., Background: The role of the nurse to patient experience is well established, yet little is known about how the communicative relationship between manager and nurse relates to nurse buy-in to PEC initiatives., Method: An exploratory qualitative descriptive study was conducted with 15 nurses from two inpatient medical-surgical units in a large acute care hospital using semi-structured interviews., Results: Three themes were identified. The communicative relationship was developed and strengthened through the manager's: (a) multimodal approach to communicating and influencing, (b) engaging and supporting staff and (c) promoting staff-led decision-making., Conclusions: Nurses in our study who reported having a strong communicative relationship with their NM perceived that this relationship encouraged their buy-in and engagement in PEC initiatives., Implications for Nursing Management: An assessment of the communication between the frontline NM and his or her team is important for understanding why initiatives to support PEC are or are not yielding desired results., (© 2020 John Wiley & Sons Ltd.)

Objective: The aim of this study was to understand how nurses in a 25-bed critical-access hospital (CAH) led change to become the 1st to achieve Magnet®., Background: Approximately 21% of the US population lives in rural areas served by CAHs. Rural nurse executives are particularly challenged with limited resources., Methods: Staff nurses, nurse managers, interprofessional care providers, the chief nursing officer, and board of directors (n = 27) were interviewed. Observations of hospital units and administrative meetings were done, and hospital reports were analyzed., Results: Nine themes emerged to support a conceptual model of leading change. The CAH spent 3 years of its 6-year journey establishing organizational readiness. Nurses overcame complex challenges by balancing operational support and fostering relationships. The Magnet journey led to significantly improved nurse and patient outcomes. A new organizational culture centered on shared governance, evidence-based practice, and higher education emerged., Conclusions: The journey to Magnet leads to improved nurse, patient, and organization outcomes.

Aim: To report an analysis of the concept of leading change., Background: Nurses have been called to lead change to advance the health of individuals, populations, and systems. Conceptual clarity about leading change in the context of nursing and healthcare systems provides an empirical direction for future research and theory development that can advance the science of leadership studies in nursing., Design: Concept analysis., Data Sources: CINAHL, PubMed, PsycINFO, Psychology and Behavioral Sciences Collection, Health Business Elite and Business Source Premier databases were searched using the terms: leading change, transformation, reform, leadership and change. Literature published in English from 2001 - 2015 in the fields of nursing, medicine, organizational studies, business, education, psychology or sociology were included., Methods: Walker and Avant's method was used to identify descriptions, antecedents, consequences and empirical referents of the concept. Model, related and contrary cases were developed., Results: Five defining attributes of leading change were identified: (a) individual and collective leadership; (b) operational support; (c) fostering relationships; (d) organizational learning; and (e) balance. Antecedents were external or internal driving forces and organizational readiness. The consequences of leading change included improved organizational performance and outcomes and new organizational culture and values., Conclusion: A theoretical definition and conceptual model of leading change were developed. Future studies that use and test the model may contribute to the refinement of a middle-range theory to advance nursing leadership research and education. From this, empirically derived interventions that prepare and enable nurses to lead change to advance health may be realized., (© 2016 John Wiley & Sons Ltd.)

Distal radius fractures are increasingly treated by internal fixation, but there have been relatively few studies relating to functional outcome at 12 months or more. The aim of this study was to ascertain the patient reported function of the wrist at a minimum of 12 months following fixation of a distal radius fracture, the time taken to return to work, and the complication rate. We conducted a retrospective review of 187 consecutive patients treated by a specialist hand and wrist trauma team at a tertiary referral unit over a 5 year period. Mean age was 57.3 years (range 16-93). Median time to surgery was 4 days (interquartile range 2-9). Median follow up was 31 months (interquartile range 23-41 months). The median PRWE score was 3; (range 0-83). There was no difference in outcome in patients who had surgery delayed by greater than 2 weeks (p > 0.05). The median time to return to work was 5 weeks (interquartile range 1-8 weeks). There were 15 complications (8 %) including 3 tendon injuries. We have demonstrated an early return to work in patients who were employed, a low complication rate, and highly favourable functional outcomes at a mean of 30 months postoperatively. We recommend the use of the DVR plate and involvement of a dedicated hand and wrist trauma team for treatment of unstable fractures of the distal radius.

The mixed-lineage leukemia family of histone methyltransferases (MLL1-4, or KMT2A-D) were previously linked to cancer through the founding member, MLL1/KMT2A, which is often involved in translocation-associated gene fusion events in childhood leukemias. However, in recent years, a multitude of tumor exome sequencing studies have revealed that orthologues MLL3/KMT2C and MLL2/KMT2D are mutated in a significant percentage of a large variety of malignancies, particularly solid tumors. These unexpected findings necessitate a deeper inspection into the activities and functional differences between the MLL/KMT2 family members. This review provides an overview of this protein family and its relation to cancers, focusing on the recent links between MLL3/KMT2C and MLL2/4/KMT2D and their potential roles as tumor suppressors in an assortment of cell types., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The Institute of Medicine's Future of Nursing report advocates for full nurse leader representation across multiple settings to address current challenges in our health care system. The purpose of this study was to examine nursing leadership development needs among Kansas registered nurses (RNs)., Methods: Data were collected through an online survey and analyzed using quantitative and qualitative methods., Results: Nearly 1,000 Kansas RNs participated. Most reported holding one or more leadership positions. Prevalent leadership goals were health care organization volunteer administrative roles. The most frequently identified barrier to developing leadership roles was time constraints. Many wanted to develop skills to serve on a board, 20% were interested in personal leadership development, and 19% in policy development., Conclusions: Based on the findings, the Kansas Action Coalition leadership team is developing programs to address the leadership needs of Kansas RNs. By building capacity in advanced leadership roles, RNs will be better prepared serve as full partners and lead efforts to promote the health of Kansans., (Copyright © 2015 Elsevier Inc. All rights reserved.)