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1.
Am J Occup Ther ; 77(3)2023 May 01.
Article in English | MEDLINE | ID: mdl-37272904

ABSTRACT

There is an increasing need to diversify the profession of occupational therapy. To do this, we need to examine the pathway to becoming an occupational therapy practitioner in our education programs. Programs must go beyond a focus on diversity and place an equal emphasis on equity and inclusion. Underrepresented minority students report increased racial bias and a high occurrence of microaggressions in higher education programs, including occupational therapy. These microaggressions are often not addressed and can lead to increased stress, insecurity, and marginalization, as well as decreased retention rates. It is imperative that faculty examine the equity and inclusivity of their programs, and they should be supported in addressing their own implicit bias. Faculty, students, and staff should be equipped to address microaggressions as they occur. This article identifies examples of microaggressions and suggests strategies to address implicit bias and microaggressions in occupational therapy programs.


Subject(s)
Microaggression , Occupational Therapy , Humans , Students , Faculty
2.
BMC Nurs ; 21(1): 295, 2022 Nov 02.
Article in English | MEDLINE | ID: mdl-36324181

ABSTRACT

BACKGROUND: The hospital ethical climate affects the quality of nursing care. A positive ethical climate is likely to reduce the proportion of those who consider leaving the profession, so it is necessary to develop tools which will enable assessment and analysis of the hospital ethical climate. The aim of this study was to examine selected psychometric properties of the Polish version of the Hospital Ethical Climate Survey, assess the hospital ethical climate perceived by nurses and midwives from Polish hospitals, and to determine its correlations with job-related variables. METHODS: A cross-sectional study among 558 nurses and midwives working in hospitals in Poland. RESULTS: The 21-item model showed acceptable model fitness between the hypothetical model of ethical climate and the data in the study. Five items with low factor loadings were removed from the study. The internal consistency was satisfactory (0.93). The mean score for the overall hospital ethical climate was 3.62. The highest mean score of hospital ethical climate in the present study was found in the "peers" subscale and the lowest in the "physicians" subscale. A positive correlation was found between overall hospital ethical climate and respondents' satisfaction with work, salary, and working time. The hospital ethical climate was associated with problems found in nurses and midwives' work, such as: limited time for direct face-to-face care, the lack of equipment and resources to provide high-quality health care, strained relations with hospital managers and other health care professionals, limitations to one's own competences or those of other medical professionals, moral dilemmas related to patient care, the low prestige of nurses'/midwives' work, physical and mental burden, and the risk of making a mistake. CONCLUSION: The Polish 21-item version of the Hospital Ethical Climate Survey is a reliable tool. Correlations revealed that relationships with managers and physicians, and working conditions should be improved in order for the hospital ethical climate to improve.

3.
Am J Occup Ther ; 75(4)2021 Jul 01.
Article in English | MEDLINE | ID: mdl-34780616

ABSTRACT

IMPORTANCE: Sexuality is an important part of the human experience. However, little is known about the experience of sexuality from the perspective of adults with intellectual and developmental disabilities (IDD). OBJECTIVE: To review evidence about the lived experience of sexuality among adults with IDD to inform future research and practice. DATA SOURCES: We located articles using search terms summarized into three categories: intellectual disability, sexual activity, and feelings/opinions. Articles were indexed in the following electronic databases: CINAHL, Scopus, PubMed, and PsycINFO. Study Selection and Data Collection: Arksey and O'Malley's methodology was used to review scientific literature published between 2008 and 2018. The studies were in English, were located in peer-reviewed journals, and described the experience of sexuality from the perspective of people with IDD or observations of expressed sexuality. FINDINGS: Seventeen articles met inclusion criteria. Four main themes emerged: intimate relationships, oppressed sexual activity, knowledge, and identity. Findings indicate that sexuality is a part of the lives of many adults with IDD, regardless of their engagement in sexual activity. CONCLUSIONS AND RELEVANCE: Barriers to expression of sexuality exist for people with IDD. Some of these barriers are internal, although many are external. The results provide support for addressing sexuality among adults with IDD. What This Article Adds: This review provides evidence to support occupational therapy practitioners in including sexuality as a part of their holistic view of clients and as an area for advocacy.


Subject(s)
Intellectual Disability , Occupational Therapy , Adult , Child , Developmental Disabilities , Humans , Sexual Behavior , Sexuality
4.
Prev Sci ; 21(4): 467-476, 2020 05.
Article in English | MEDLINE | ID: mdl-31883063

ABSTRACT

An early adopter of public preschool (i.e., pre-kindergarten, "pre-k"), evidence from Baltimore City, Maryland, can provide insight for those working to improve access to early education opportunities. We followed a cohort of children entering kindergarten in Baltimore City Public Schools during the 2007-2008 year through the 2010-2011 academic year. Students were grouped by pre-k experience: public pre-k (n = 2828), Head Start (n = 839), Head Start plus public pre-k (n = 247), private pre-k (n = 993), or informal care (n = 975). After adjusting for individual- and school-level characteristics, students from the Head Start plus public pre-k group were the most likely to enter kindergarten with the foundational skills and behaviors needed to be successful (vs. all groups, P ≤ .001). Students in informal care were the least likely to enter kindergarten with this skillset (vs. all pre-k groups P ≤ .001). Children from informal care were also significantly more likely than all other groups to be chronically absent in kindergarten (P ≤ .001). By third grade, children from informal care were least likely to be reading on grade level and most likely to have been retained a grade (vs. all pre-k groups P ≤ .001). Children from disadvantaged populations who were not enrolled in pre-k faced significant difficulties keeping up with their peers throughout elementary school; interventions to improve their transition to school and increase their likelihood of academic success are warranted. Universal preschool is likely to improve education outcomes for children in urban areas.


Subject(s)
Academic Success , Students , Baltimore , Child, Preschool , Early Intervention, Educational , Educational Measurement/methods , Humans , Program Evaluation , Regression Analysis , Schools
5.
Biochemistry ; 54(26): 4097-111, 2015 Jul 07.
Article in English | MEDLINE | ID: mdl-26062005

ABSTRACT

N-Glycans are modified as part of a quality control mechanism during glycoprotein folding in the endoplasmic reticulum (ER). Glucosidase II (GII) plays a critical role by generating monoglucosylated glycans that are recognized by lectin chaperones, calnexin and calreticulin. To understand how the hydrolytic activity of GIIα is enhanced by the mannose 6-phosphate receptor (MPR) homology domain (MRH domain) of its ß subunit, we now report a 1.6 Å resolution crystal structure of the MRH domain of GIIß bound to mannose. A comparison of ligand-bound and unbound structures reveals no major difference in their overall fold, but rather a repositioning of side chains throughout the binding pocket, including Y372. Mutation of Y372 inhibits GII activity, demonstrating an important role for Y372 in regulating GII activity. Comparison of the MRH domains of GIIß, MPRs, and the ER lectin OS-9 identified conserved residues that are critical for the structural integrity and architecture of the carbohydrate binding pocket. As shown by nuclear magnetic resonance spectroscopy, mutations of the primary binding pocket residues and adjacent W409, all of which inhibit the activity of GII both in vitro and in vivo, do not cause a significant change in the overall fold of the GIIß MRH domain but impact locally the stability of the binding pocket. W409 does not directly contact mannose; rather, its indole ring is stabilized by binding into a hydrophobic pocket of an adjacent crystallographic neighbor. This suggests that W409 interacts with a hydrophobic region of the GIIß or GIIα subunit to modulate its effect on GII activity.


Subject(s)
Lectins/metabolism , Mannose/metabolism , Schizosaccharomyces/enzymology , alpha-Glucosidases/chemistry , alpha-Glucosidases/metabolism , Amino Acid Sequence , Animals , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Sequence Data , Point Mutation , Protein Structure, Tertiary , Protein Subunits/chemistry , Protein Subunits/genetics , Protein Subunits/metabolism , Receptor, IGF Type 2/metabolism , Schizosaccharomyces/chemistry , Schizosaccharomyces/genetics , Schizosaccharomyces/metabolism , Sequence Alignment , alpha-Glucosidases/genetics
6.
Glycobiology ; 25(6): 591-606, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25573276

ABSTRACT

The 300 kDa cation-independent mannose 6-phosphate receptor (CI-MPR) plays an essential role in lysosome biogenesis by targeting ∼ 60 different phosphomannosyl-containing acid hydrolases to the lysosome. This type I membrane glycoprotein has a large extracellular region comprised of 15 homologous domains. Two mannose 6-phosphate (M6P) binding sites have been mapped to domains 3 and 9, whereas domain 5 binds preferentially to the phosphodiester, M6P-N-acetylglucosamine (GlcNAc). A structure-based sequence alignment predicts that the C-terminal domain 15 contains three out of the four conserved residues identified as essential for carbohydrate recognition by domains 3, 5 and 9 of the CI-MPR, but lacks two cysteine residues that are predicted to form a disulfide bond. To determine whether domain 15 of the CI-MPR has lectin activity and to probe its carbohydrate-binding specificity, truncated forms of the CI-MPR were tested for binding to acid hydrolases with defined N-glycans in surface plasmon resonance analyses, and used to interrogate a phosphorylated glycan microarray. The results show that a construct encoding domains 14-15 binds both M6P and M6P-GlcNAc with similar affinity (Kd = 13 and 17 µM, respectively). Site-directed mutagenesis studies demonstrate the essential role of the conserved Tyr residue in domain 15 for phosphomannosyl binding. A structural model of domain 15 was generated that predicted an Arg residue to be in the binding pocket and mutagenesis studies confirmed its important role in carbohydrate binding. Together, these results show that the CI-MPR contains a fourth carbohydrate-recognition site capable of binding both phosphomonoesters and phosphodiesters.


Subject(s)
Mannosephosphates/metabolism , Receptor, IGF Type 2/chemistry , Receptor, IGF Type 2/metabolism , Animals , Binding Sites , Cations , Cattle , Hydrolases/metabolism , Microarray Analysis , Models, Molecular , Surface Plasmon Resonance
7.
Protein Expr Purif ; 111: 91-7, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25863146

ABSTRACT

The cation-independent mannose 6-phosphate receptor (CI-MPR) is a multifunctional protein that interacts with diverse ligands and plays central roles in autophagy, development, and tumor suppression. By delivering newly synthesized phosphomannosyl-containing acid hydrolases from the Golgi to endosomal compartments, CI-MPR is an essential component in the generation of lysosomes that are critical for the maintenance of cellular homeostasis. The ability of CI-MPR to interact with ∼60 different acid hydrolases is facilitated by its large extracellular region, with four out of its 15 domains binding phosphomannosyl residues. Although the glycan specificity of CI-MPR has been elucidated, the molecular basis of carbohydrate binding has not been determined for two out of these four carbohydrate recognition domains (CRD). Here we report expression of CI-MPR's CRD located in domain 5 that preferentially binds phosphodiester-containing glycans. Domain 5 of CI-MPR was expressed in Escherichia coli BL21 (DE3) cells as a fusion protein containing an N-terminal histidine tag and the small ubiquitin-like modifier (SUMO) protein. The His6-SUMO-CRD construct was recovered from inclusion bodies, refolded in buffer to facilitate disulfide bond formation, and subjected to Ni-NTA affinity chromatography and size exclusion chromatography. Surface plasmon resonance analyses demonstrated that the purified protein was active and bound phosphorylated glycans. Characterization by NMR spectroscopy revealed high quality (1)H-(15)N HSQC spectra. Additionally, crystallization conditions were identified and a crystallographic data set of the CRD was collected to 1.8Šresolution. Together, these studies demonstrate the feasibility of producing CI-MPR's CRD suitable for three-dimensional structure determination by NMR spectroscopic and X-ray crystallographic approaches.


Subject(s)
Escherichia coli/metabolism , Gene Expression , Receptor, IGF Type 2 , Binding Sites , Crystallography, X-Ray , Escherichia coli/genetics , Humans , Nuclear Magnetic Resonance, Biomolecular , Receptor, IGF Type 2/biosynthesis , Receptor, IGF Type 2/chemistry , Receptor, IGF Type 2/genetics , Receptor, IGF Type 2/isolation & purification , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics
8.
Nurs Ethics ; 22(5): 517-32, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25316460

ABSTRACT

BACKGROUND: The exploration of the ethical climate in the care settings for older people is highlighted in the literature, and it has been associated with various aspects of clinical practice and nurses' jobs. However, ethical climate is seldom studied in the older people care context. Valid, reliable, feasible measures are needed for the measurement of ethical climate. OBJECTIVES: This study aimed to test the reliability, validity, and sensitivity of the Hospital Ethical Climate Survey in healthcare settings for older people. DESIGN: A non-experimental cross-sectional study design was employed, and a survey using questionnaires, including the Hospital Ethical Climate Survey was used for data collection. Data were analyzed using descriptive statistics, inferential statistics, and multivariable methods. PARTICIPANTS AND RESEARCH CONTEXT: Survey data were collected from a sample of nurses working in the care settings for older people in Finland (N = 1513, n = 874, response rate = 58%) in 2011. ETHICAL CONSIDERATIONS: This study was conducted according to good scientific inquiry guidelines, and ethical approval was obtained from the university ethics committee. RESULTS: The mean score for the Hospital Ethical Climate Survey total was 3.85 (standard deviation = 0.56). Cronbach's alpha was 0.92. Principal component analysis provided evidence for factorial validity. LISREL provided evidence for construct validity based on goodness-of-fit statistics. Pearson's correlations of 0.68-0.90 were found between the sub-scales and the Hospital Ethical Climate Survey. DISCUSSION: The Hospital Ethical Climate Survey was found able to reveal discrimination across care settings and proved to be a valid and reliable tool for measuring ethical climate in care settings for older people and sensitive enough to reveal variations across various clinical settings. CONCLUSION: The Finnish version of the Hospital Ethical Climate Survey, used mainly in the hospital settings previously, proved to be a valid instrument to be used in the care settings for older people. Further studies are due to analyze the factor structure and some items of the Hospital Ethical Climate Survey.


Subject(s)
Ethics, Institutional , Geriatric Nursing/ethics , Health Care Surveys , Adolescent , Adult , Aged , Attitude of Health Personnel , Cross-Sectional Studies , Female , Finland , Hospital Units/ethics , Hospital Units/organization & administration , Humans , Male , Middle Aged , Nursing Staff, Hospital/psychology , Nursing Staff, Hospital/statistics & numerical data , Organizational Culture , Reproducibility of Results , Young Adult
9.
J Biol Chem ; 288(23): 16460-16475, 2013 Jun 07.
Article in English | MEDLINE | ID: mdl-23609449

ABSTRACT

Here we report for the first time the three-dimensional structure of a mannose 6-phosphate receptor homology (MRH) domain present in a protein with enzymatic activity, glucosidase II (GII). GII is involved in glycoprotein folding in the endoplasmic reticulum. GII removes the two innermost glucose residues from the Glc3Man9GlcNAc2 transferred to nascent proteins and the glucose added by UDP-Glc:glycoprotein glucosyltransferase. GII is composed of a catalytic GIIα subunit and a regulatory GIIß subunit. GIIß participates in the endoplasmic reticulum localization of GIIα and mediates in vivo enhancement of N-glycan trimming by GII through its C-terminal MRH domain. We determined the structure of a functional GIIß MRH domain by NMR spectroscopy. It adopts a ß-barrel fold similar to that of other MRH domains, but its binding pocket is the most shallow known to date as it accommodates a single mannose residue. In addition, we identified a conserved residue outside the binding pocket (Trp-409) present in GIIß but not in other MRHs that influences GII glucose trimming activity.


Subject(s)
Endoplasmic Reticulum , Glycoproteins , Protein Folding , Schizosaccharomyces pombe Proteins , Schizosaccharomyces/enzymology , alpha-Glucosidases , Crystallography, X-Ray , Endoplasmic Reticulum/chemistry , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/metabolism , Glycoproteins/chemistry , Glycoproteins/genetics , Glycoproteins/metabolism , Mannose/chemistry , Mannose/genetics , Mannose/metabolism , Protein Structure, Secondary , Protein Structure, Tertiary , Schizosaccharomyces/genetics , Schizosaccharomyces pombe Proteins/chemistry , Schizosaccharomyces pombe Proteins/genetics , Schizosaccharomyces pombe Proteins/metabolism , alpha-Glucosidases/chemistry , alpha-Glucosidases/genetics , alpha-Glucosidases/metabolism
10.
Proc Natl Acad Sci U S A ; 107(28): 12493-8, 2010 Jul 13.
Article in English | MEDLINE | ID: mdl-20615935

ABSTRACT

Mannose 6-phosphate (Man-6-P)-dependent trafficking is vital for normal development. The biogenesis of lysosomes, a major cellular site of protein, carbohydrate, and lipid catabolism, depends on the 300-kDa cation-independent Man-6-P receptor (CI-MPR) that transports newly synthesized acid hydrolases from the Golgi. The CI-MPR recognizes lysosomal enzymes bearing the Man-6-P modification, which arises by the addition of GlcNAc-1-phosphate to mannose residues and subsequent removal of GlcNAc by the uncovering enzyme (UCE). The CI-MPR also recognizes lysosomal enzymes that elude UCE maturation and instead display the Man-P-GlcNAc phosphodiester. This ability of the CI-MPR to target phosphodiester-containing enzymes ensures lysosomal delivery when UCE activity is deficient. The extracellular region of the CI-MPR is comprised of 15 repetitive domains and contains three distinct Man-6-P binding sites located in domains 3, 5, and 9, with only domain 5 exhibiting a marked preference for phosphodiester-containing lysosomal enzymes. To determine how the CI-MPR recognizes phosphodiesters, the structure of domain 5 was determined by NMR spectroscopy. Although domain 5 contains only three of the four disulfide bonds found in the other seven domains whose structures have been determined to date, it adopts the same fold consisting of a flattened beta-barrel. Structure determination of domain 5 bound to N-acetylglucosaminyl 6-phosphomethylmannoside, along with mutagenesis studies, revealed the residues involved in diester recognition, including Y679. These results show the mechanism by which the CI-MPR recognizes Man-P-GlcNAc-containing ligands and provides new avenues to investigate the role of phosphodiester-containing lysosomal enzymes in the biogenesis of lysosomes.


Subject(s)
Lysosomes/enzymology , Receptor, IGF Type 2/chemistry , Receptor, IGF Type 2/metabolism , Acetylglucosamine/analogs & derivatives , Binding Sites , Carbohydrates , Cations/chemistry , Cations/metabolism , Golgi Apparatus/metabolism , Humans , Hydrolases/metabolism , Ligands , Lysosomes/metabolism , Mannosephosphates , Phosphoric Diester Hydrolases , Receptors, Somatomedin/metabolism
11.
J Public Health Manag Pract ; 19(4): 341-7, 2013.
Article in English | MEDLINE | ID: mdl-23480897

ABSTRACT

OBJECTIVE: This study compares pre- and posttest Leadership Practices Inventory (LPI-Self) scores for public health leaders who completed the Regional Institute for Health and Environmental Leadership (RIHEL) training program at least 2 years earlier; it seeks to identify factors contributing to changes in practices and overall leadership development for public health and environment leaders. PARTICIPANTS/SETTING: Sixty-seven alumni who completed the yearlong RIHEL program between 1999 and 2002 participated through mailed surveys and phone interviews. MAIN OUTCOME MEASURES: The Leadership Practices Inventory, an alumni leadership development survey, and interviews provided evidence for positive change in leadership practices. RESULTS: Alumni experienced significant increases in pre- to post-LPI scores, collaborative leadership practices, and communication skills consistent with those taught in the RIHEL program. Women presented higher Encourage the Heart scores than men. Years of public health service negatively correlated with Total Change scores of LPI. The RIHEL program as a training intervention was credited significantly with changes in leadership practices for alumni studied. Nine influencing factors were identified for leadership development and are embedded in a Leadership Development Influence Model. These include self-awareness, a leadership development framework, and skills important in multiple leadership situations. Confidence was both an encouraging factor and a resulting factor to the increased exemplary leadership practices. CONCLUSION: Leadership development in public health must include multiple factors to create consistent increases in exemplary leadership practices. While the study focused on the leadership development process itself, RIHEL training was reported as having a positive, significant impact overall in participant leadership development. This study adds research data as a foundation for training content areas of focus. Studies to further test the Leadership Development Influence Model will allow public health training programs to pinpoint training where it can make a difference to improve leadership development in the public health sector.


Subject(s)
Leadership , Public Health Administration , Cooperative Behavior , Data Collection , Female , Humans , Interviews as Topic , Male , Middle Aged , Public Health Administration/education , Public Health Administration/standards , Surveys and Questionnaires , Workforce
12.
bioRxiv ; 2023 Nov 05.
Article in English | MEDLINE | ID: mdl-37961276

ABSTRACT

This study explores the intricacies of dopamine receptor-ligand interactions, focusing on the D1R and D5R subtypes. Using molecular modeling techniques, we investigate the binding of the pan-agonist rotigotine, revealing a universal binding mode at the orthosteric binding pocket (OBP). Additionally, we analyze the stability of antagonist-receptor complexes with SKF83566 and SCH23390. By examining the impact of specific mutations on ligand-receptor interactions through computational simulations and thermostability assays, we gain insights into binding stability. Our research also delves into the structural and energetic aspects of antagonist binding to D1R and D5R in their inactive states. These findings enhance our understanding of dopamine receptor pharmacology and hold promise for drug development in central nervous system disorders, opening doors to future research and innovation in this field.

13.
Home Healthc Now ; 41(2): 105-111, 2023.
Article in English | MEDLINE | ID: mdl-36867484

ABSTRACT

This article is the fifth in a series, Supporting Family Caregivers in the 4Ms of an Age-Friendly Health System, published in collaboration with the AARP Public Policy Institute as part of the ongoing Supporting Family Caregivers: No Longer Home Alone series. The 4Ms of an Age-Friendly Health System (What Matters, Medication, Mentation, and Mobility) is an evidence-based framework for assessing and acting on critical issues in the care of older adults across settings and transitions of care. Engaging the health care team, including older adults and their family caregivers, with the 4Ms framework can help to ensure that every older adult gets the best care possible, is not harmed by health care, and is satisfied with the care they receive. The articles in this series present considerations for implementing the 4Ms framework in the inpatient hospital setting and incorporating family caregivers in doing so. Resources for both nurses and family caregivers, including a series of accompanying videos developed by AARP and the Rush Center for Excellence in Aging and funded by The John A. Hartford Foundation, are also provided. Nurses should read the articles first, so they understand how best to help family caregivers. Then they can refer caregivers to the informational tear sheet-Information for Family Caregivers-and instructional videos, encouraging them to ask questions. For additional information, see Resources for Nurses. Cite this article as: Olson,L.M., et al. Promote Safe Mobility. Am J Nurs 2022; 122(7): 46-52.


Subject(s)
Activities of Daily Living , Caregivers , Humans , Aged , Aging , Patient Care Team , Public Policy
14.
J Nurs Meas ; 31(2): 148-162, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37277157

ABSTRACT

Background and Purpose: Adapting cross-culturally the Hospital Ethical Climate Survey to Brazilian nurses. Methods: A methodological study comprising translation, back translation, multidisciplinary committee, expert panel, pilot test and validation of the instrument. The validation was carried out with 269 nurses of a university hospital in the South of Brazil. Results: In the validation step, the quadratic weighted Kappa test-retest and the correlation coefficient ranged from 0.15 to 0.74. All factor loadings were higher than 0.4, ranging from 0.445 to 0.859. The Portuguese version of the instrument had a 0.93 Cronbach's alpha and the confirmatory analysis demonstrated the model's suitability with five factors and 26 items validated. Conclusions: The version of the instrument adapted to Brazilian Portuguese was considered valid and reliable in this sample.


Subject(s)
Cross-Cultural Comparison , Translations , Humans , Brazil , Reproducibility of Results , Surveys and Questionnaires , Hospitals, University
15.
J Med Chem ; 66(21): 14544-14563, 2023 11 09.
Article in English | MEDLINE | ID: mdl-37857371

ABSTRACT

Enterovirus D68 (EV-D68) virus is a nonpolio enterovirus that typically causes respiratory illness and, in severe cases, can lead to paralysis and death in children. There is currently no vaccine or antiviral for EV-D68. We previously discovered the viral 2A protease (2Apro) as a viable antiviral drug target and identified telaprevir as a 2Apro inhibitor. 2Apro is a viral cysteine protease that cleaves the viral VP1-2A polyprotein junction. In this study, we report the X-ray crystal structures of EV-D68 2Apro, wild-type, and the C107A mutant and the structure-based lead optimization of telaprevir. Guided by the X-ray crystal structure, we predicted the binding pose of telaprevir in 2Apro using molecular dynamics simulations. We then utilized this model to inform structure-based optimization of the telaprevir's reactive warhead and P1-P4 substitutions. These efforts led to the discovery of 2Apro inhibitors with improved antiviral activity than telaprevir. These compounds represent promising lead compounds for further development as EV-D68 antivirals.


Subject(s)
Enterovirus D, Human , Enterovirus Infections , Enterovirus , Child , Humans , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
16.
Biochim Biophys Acta ; 1810(9): 815-26, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21723917

ABSTRACT

BACKGROUND: The mannose 6-phosphate receptor homology (MRH) domain-containing family of proteins, which include recycling receptors (mannose 6-phosphate receptors, MPRs), resident endoplasmic reticulum (ER) proteins (glucosidase II ß-subunit, XTP3-B, OS-9), and a Golgi glycosyltransferase (GlcNAc-phosphotransferase γ-subunit), are characterized by the presence of one or more MRH domains. Many MRH domains act as lectins and bind specific phosphorylated (MPRs) or non-phosphorylated (glucosidase II ß-subunit, XTP3-B and OS-9) high mannose-type N-glycans. The MPRs are the only proteins known to bind mannose 6-phosphate (Man-6-P) residues via their MRH domains. SCOPE OF REVIEW: Recent biochemical and structural studies that have provided valuable insight into the glycan specificity and mechanisms of carbohydrate recognition by this diverse group of MRH domain-containing proteins are highlighted. MAJOR CONCLUSIONS: Currently, three-dimensional structures are known for ten MRH domains, revealing the conservation of a similar fold. OS-9 and the MPRs use the same four residues (Gln, Arg, Glu, and Tyr) to bind mannose. GENERAL SIGNIFICANCE: The MRH domain-containing proteins play key roles in the secretory pathway: glucosidase II, XTP3-B, and OS-9 are involved in the recognition of nascent glycoproteins, whereas the MPRs play an essential role in lysosome biogenesis by targeting Man-6-P-containing lysosomal enzymes to the lysosome.


Subject(s)
Receptor, IGF Type 2/chemistry , Secretory Pathway/physiology , Amino Acid Sequence , Animals , Humans , Lectins/chemistry , Lectins/metabolism , Lysosomes/enzymology , Lysosomes/physiology , Mannosephosphates/metabolism , Models, Molecular , Neoplasm Proteins/chemistry , Polysaccharides/metabolism , Protein Structure, Tertiary , Receptor, IGF Type 2/metabolism , Sequence Alignment , Substrate Specificity
17.
Glycobiology ; 22(7): 983-96, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22369936

ABSTRACT

The 300-kDa cation-independent mannose 6-phosphate receptor (CI-MPR) plays an essential role in the biogenesis of lysosomes by delivering newly synthesized lysosomal enzymes from the trans Golgi network to the endosomal system. The CI-MPR is expressed in most eukaryotes, with Saccharomyces cerevisiae and Caenorhabditis elegans being notable exceptions. Although the repertoire of glycans recognized by the bovine receptor has been studied extensively, little is known concerning the ligand-binding properties of the CI-MPR from non-mammalian species. To assess the evolutionary conservation of the CI-MPR, surface plasmon resonance analyses using lysosomal enzymes with defined N-glycans were carried out to probe the glycan-binding specificity of the Danio rerio CI-MPR. The results demonstrate that the D. rerio CI-MPR harbors three glycan-binding sites that, like the bovine CI-MPR, map to domains 3, 5 and 9 of its 15-domain-containing extracytoplasmic region. Analyses on a phosphorylated glycan microarray further demonstrated the unique binding properties of each of the three sites and showed that, similar to the bovine CI-MPR, only domain 5 of the D. rerio CI-MPR is capable of recognizing Man-P-GlcNAc-containing glycans.


Subject(s)
Polysaccharides/chemistry , Receptor, IGF Type 2/biosynthesis , Zebrafish Proteins/biosynthesis , Amino Acid Sequence , Animals , Binding Sites , Binding, Competitive , Carbohydrate Conformation , Carbohydrate Sequence , Cells, Cultured , Cellulases/chemistry , Conserved Sequence , Evolution, Molecular , Humans , Immobilized Proteins/chemistry , Molecular Sequence Data , Protein Array Analysis , Protein Binding , Protein Structure, Tertiary , Receptor, IGF Type 2/chemistry , Receptor, IGF Type 2/isolation & purification , Sugar Phosphates/chemistry , Surface Plasmon Resonance , Vertebrates , Zebrafish , Zebrafish Proteins/chemistry , Zebrafish Proteins/isolation & purification , alpha-Glucosidases/chemistry
18.
Health Promot Pract ; 13(6): 755-62, 2012 Nov.
Article in English | MEDLINE | ID: mdl-21478370

ABSTRACT

As the Latino population in the United States experiences rapid growth, the well-being of Latino adolescents is a growing concern because of their high rates of mental health problems. Latino adolescents have higher rates of mental health problems than their peers, including depressive symptoms, suicide attempts, and violence. Sophisticated, realistic health promotion efforts are needed to reduce these risk behaviors and enhance protective factors. Parents and schools can be key protective factors, or assets, in adolescents' lives. This article details the steps undertaken to develop Project Wings Home Visits, a collaborative school-based, community-linked mental health promotion intervention for Latino adolescents and their families. Core to the intervention is the use of a community health worker model to provide home-based outreach and education to parents of Latino adolescents. The intervention was developed using a community-based participatory research approach that involved the cooperation of a community health care system, a public high school, and a university. Our process demonstrates the benefits, strengths, and challenges of using community-based participatory research in creating and implementing health promotion interventions.


Subject(s)
Adolescent Behavior/ethnology , Community Mental Health Services/organization & administration , Health Promotion/organization & administration , Hispanic or Latino/psychology , Mental Disorders/ethnology , Adolescent , Adolescent Behavior/psychology , Community Mental Health Services/methods , Community-Based Participatory Research , Health Promotion/methods , House Calls , Humans , Mental Disorders/prevention & control , Minnesota , Parents/education
19.
Am J Nurs ; 122(7): 46-52, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35736603

ABSTRACT

This article is the fifth in a series, Supporting Family Caregivers in the 4Ms of an Age-Friendly Health System, published in collaboration with the AARP Public Policy Institute as part of the ongoing Supporting Family Caregivers: No Longer Home Alone series. The 4Ms of an Age-Friendly Health System (What Matters, Medication, Mentation, and Mobility) is an evidence-based framework for assessing and acting on critical issues in the care of older adults across settings and transitions of care. Engaging the health care team, including older adults and their family caregivers, with the 4Ms framework can help to ensure that every older adult gets the best care possible, is not harmed by health care, and is satisfied with the care they receive. The articles in this series present considerations for implementing the 4Ms framework in the inpatient hospital setting and incorporating family caregivers in doing so. Resources for both nurses and family caregivers, including a series of accompanying videos developed by AARP and the Rush Center for Excellence in Aging and funded by The John A. Hartford Foundation, are also provided. Nurses should read the articles first, so they understand how best to help family caregivers. Then they can refer caregivers to the informational tear sheet-Information for Family Caregivers-and instructional videos, encouraging them to ask questions. For additional information, see Resources for Nurses.


Subject(s)
Caregivers , Aged , Humans
20.
Arthroplast Today ; 15: 24-28, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35368850

ABSTRACT

Background: Before surgery, skin is prepped with antiseptics to reduce risk of surgical site infections. An incise drape can be used as an additional modality to immobilize any remaining bacteria. Good adhesion of this drape is critical for infection prevention. Methods: This is a randomized controlled study using a human volunteer knee model (n = 30) to evaluate the adhesion performance of an incise drape comparing 2 skin preparations. A new investigational 2% chlorhexidine gluconate/70% isopropyl alcohol skin prep (prep A) was compared with an existing skin prep containing the same active agents (prep B). Two samples of an iodine-impregnated incise drape were placed on each knee after prepping. Knees were flexed in dry conditions, under a saline-soaked gauze, and after saline lavage. The frequency of drape lift was recorded after each challenge. Results: After dry flex, 4 of 60 samples (6.7%) had lifted on prep A and 0 on prep B (P = .125). After wet flex, 20 of 60 samples (33%) had lifted on prep A, whereas 42 of 60 samples (70%) had lifted on prep B (P < .0001). After lavage, 23 of 60 samples (38%) had lifted on prep A, whereas 48 of 60 samples (80%) had lifted on prep B (P < .0001). Both preps were well tolerated with minimal erythema and no edema, rash, dryness, or denudation observed. No adverse events were reported. Conclusions: Prep A resulted in reduced frequency of incise drape lift from skin under wet conditions in this model compared with prep B.

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