Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity.

A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity, while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code.

Application of Sublimation in the Synthesis and Crystal Growth of Organosulfones.

The solvent-free elimination of sulfinic acid and aromatization of 1,6-trans-substituted bis(arylsulfone) trienes is reported. It is shown that sublimation can be used as a 'green' method to combine the thermal transformation of six trienes and the crystal growth of the resulting 4-(phenylsulfonyl)biphenyls. When the sublimation conditions are carefully controlled, high quality single crystals of the 4-(phenylsulfonyl)biphenyls are obtained. Theoretical modelling of the reaction using the simplified triene Ph-(CH)6-SO2H showed that the cyclization is energetically feasible and that the complete conversion is possible during the timescale of the sublimation. At temperatures slightly higher than the optimum sublimation temperature two of the trienes transformed into 1,4-cyclohexadienes that did not eliminate phenylsulfinic acid. A reaction mechanism involving a 1,3-hydrogen shift induced by free PhS• radicals is proposed for the formation of the 1,4-cyclohexadienes.

Neonatal epidermolysis bullosa: a clinical practice guideline.

DEBRA International is undertaking a long-term initiative to develop clinical practice guidelines (CPGs) for epidermolysis bullosa (EB), to -improve the clinical care of people living with EB. Current neonatal care is based on evidence, clinical expertise and trial and error, with collaboration between the EB specialist team, parent or carer and patient, and is dependent on the neonate's individual presentation and type of EB. Early intervention based on research and clinical practice is needed to establish a foundation of knowledge to guide international practitioners to create and improve standards of care and to be able to work effectively with those newly diagnosed with EB. This CPG was created by an international panel with expertise working with persons with EB. The CPG focuses on neonatal care using a systematic review methodology covering four key areas: (i) diagnosis and parental psychosocial support; (ii) hospital management: medical monitoring, wound care and pain; (iii) feeding and nutrition; and (iv) discharge planning and EB education. These four areas highlight the importance of a multidisciplinary team approach, to provide a patient-specific holistic care model that incorporates the needs and wishes of the parents and carers. The Hospital Implementation Tool included promotes transfer of theory to clinical practice.

Stimulus characteristics of a novel air-based multiple stimulus aesthesiometer.

PURPOSE: To identify the stimulus airflow characteristics and confirm the consistency of a novel air jet-based aesthesiometer capable of producing and applying multiple stimuli separated either by time and/or by space. METHODS: A novel aesthesiometer (Dolphin Aesthesiometer) was designed around a micro-blower under software management. Two nozzle attachments assisted in airflow control (flexible tube 1.6 mm diameter; brass tube 0.5 mm diameter). Four studies that tested the characteristics of the airflow and stimulus consistency were completed: (i) airflow pattern/trajectory, (ii) airflow surface dispersion, (iii) force of airflow across a range of stimulus strengths and (iv) thermal effects on the ocular surface. RESULTS: Stimulus characteristic studies revealed: (i) airflow is coherent within the expected test distance range for the instrument, and spread rate is constant irrespective of stimulus strength; (ii) airflow dispersion occurs upon encountering a surface and dispersion increases with increasing airflow rate; (iii) a consistent and small force (10-4 N) is applied by the airflow and (iv) repeatable thermal effects occur in relation to the airflow, and the mode of stimulation of the Dolphin aesthesiometer is predominantly thermal in nature. CONCLUSIONS: These studies confirm the repeatability and consistency of the novel instrument. The device is suitable for measuring corneal sensitivity. The availability of additional air jets allows the application of multiple stimuli to facilitate corneal summation investigations.

Training simulated participants for role portrayal and feedback practices in communication skills training: A BEME scoping review: BEME Guide No. 86.

BACKGROUND: Providing feedback is a key aspect of simulated participants' (SPs) educational work. In teaching contexts, the ability to provide feedback to learners is central to their role. Suboptimal feedback practices may deny learners the valuable feedback they need to learn and improve. This scoping review systematically maps the evidence related to SPs' role as educators and identifies how SPs prepare for their role and feedback practices. METHODS: The authors conducted a scoping review and included a group of international stakeholders with experience and expertise in SP methodology. Five online databases were systematically searched and ERIC, MedEdPortal and MedEdPublish were hand searched to identify relevant studies. Inclusion/exclusion criteria were developed. Data screening and subsequently data charting were performed in pairs. The results of data charting were thematically analysed including categories relating to the Association of SP Educators (ASPE) Standards of Best Practice (SOBP). RESULTS: From 8179 articles identified for the title and abstract screening, 98 studies were included. Studies reported the benefit of SPs' authentic role portrayal and feedback interactions for learners and on the reported learning outcomes. Data was heterogeneous with a notable lack of consistency in the detail regarding the scenario formats for communication skills training interventions, SP characteristics, and approaches to training for feedback and role portrayal. CONCLUSIONS: The published literature has considerable heterogeneity in reporting how SPs are prepared for role portrayal and feedback interactions. Additionally, our work has identified gaps in the implementation of the ASPE SOBP, which promotes effective SP-learner feedback interactions. Further research is required to identify effective applications of SP methodology to prepare SPs for their role as educators.

A cross-disciplinary approach to learning medical physiology and behavioral skills involving drama students performing as simulated patients.

The early years of physiology education in medical curricula provide unique challenges. As well as inculcating concepts that are seen as difficult, modern curricula require that students learn in context in case-based learning courses. Additionally, regulating bodies stress that the soft skills of compassion, communication, and empathy are embedded throughout curricula. This has driven work in our organization involving drama and final-year medicine students during which they collaborate in realistic simulations of doctor/patient interactions. We adapted this transdisciplinary approach to second-year physiology tutorials. This emphasized the holistic importance of physiology to patient care, while also embedding "human factors" skills from the very earliest stages of the curriculum. After preparing by attending acting classes based on aspects of Konstantin Stanislavski's "System," the authors supervised tutorials in which drama students participated in a "physiology of hypofertility" session for second-year medical students, playing a 34-year-old woman with premature menopause (or their partner). Opinion (from all students) was evaluated by Likert questionnaires (which included open questions). A focus group of drama students was also interviewed, and the conversation was recorded for thematic analysis. Positive Likert scores were recorded for the authenticity of the tutorials, skills development, fostering empathy, and motivating students to improve. All participants evaluated the tutorial as highly enjoyable. These scores are reflected in positive open commentary on the questionnaires and in the focus group interviews. The results suggest that even basic science tutorials give opportunities for interdisciplinary study and enhancement of behavioral skills while gaining enthusiastic student acceptance.NEW & NOTEWORTHY This work details how physiology tutorials for early years medical students are transformed by taking the clinical case off the two-dimensional page and instead having the case scenario acted by drama students. This adds context and authenticity. The benefits are twofold: emphasizing the importance of physiology to the budding clinician and embedding empathy and compassion from the earliest points in a clinician's career.

MUC1 Glycopeptide Vaccine Modified with a GalNAc Glycocluster Targets the Macrophage Galactose C-type Lectin on Dendritic Cells to Elicit an Improved Humoral Response.

Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production.

HUWE1 employs a giant substrate-binding ring to feed and regulate its HECT E3 domain.

HUWE1 is a universal quality-control E3 ligase that marks diverse client proteins for proteasomal degradation. Although the giant HECT enzyme is an essential component of the ubiquitin-proteasome system closely linked with severe human diseases, its molecular mechanism is little understood. Here, we present the crystal structure of Nematocida HUWE1, revealing how a single E3 enzyme has specificity for a multitude of unrelated substrates. The protein adopts a remarkable snake-like structure, where the C-terminal HECT domain heads an extended alpha-solenoid body that coils in on itself and houses various protein-protein interaction modules. Our integrative structural analysis shows that this ring structure is highly dynamic, enabling the flexible HECT domain to reach protein targets presented by the various acceptor sites. Together, our data demonstrate how HUWE1 is regulated by its unique structure, adapting a promiscuous E3 ligase to selectively target unassembled orphan proteins.

Visual Image Annotation for Bowel Obstruction: Repeatability and Agreement with Manual Annotation and Neural Networks.

Bowel obstruction is a common cause of acute abdominal pain. The development of algorithms for automated detection and characterization of bowel obstruction on CT has been limited by the effort required for manual annotation. Visual image annotation with an eye tracking device may mitigate that limitation. The purpose of this study is to assess the agreement between visual and manual annotations for bowel segmentation and diameter measurement, and to assess agreement with convolutional neural networks (CNNs) trained using that data. Sixty CT scans of 50 patients with bowel obstruction from March to June 2022 were retrospectively included and partitioned into training and test data sets. An eye tracking device was used to record 3-dimensional coordinates within the scans, while a radiologist cast their gaze at the centerline of the bowel, and adjusted the size of a superimposed ROI to approximate the diameter of the bowel. For each scan, 59.4 ± 15.1 segments, 847.9 ± 228.1 gaze locations, and 5.8 ± 1.2 m of bowel were recorded. 2d and 3d CNNs were trained using this data to predict bowel segmentation and diameter maps from the CT scans. For comparisons between two repetitions of visual annotation, CNN predictions, and manual annotations, Dice scores for bowel segmentation ranged from 0.69 ± 0.17 to 0.81 ± 0.04 and intraclass correlations [95% CI] for diameter measurement ranged from 0.672 [0.490-0.782] to 0.940 [0.933-0.947]. Thus, visual image annotation is a promising technique for training CNNs to perform bowel segmentation and diameter measurement in CT scans of patients with bowel obstruction.

Interdisciplinary collaborative working on surgical ward rounds: reality or rhetoric? A systematic review.

Daily surgical ward rounds shape the quality of postoperative care and contribute to positive patient outcomes. Despite their importance, strategies to facilitate and promote deliberate interdisciplinary collaboration within surgical ward rounds have not been comprehensively investigated. This paper systematically reviews the literature to identify what is known from existing publications about interdisciplinary working on surgical ward rounds. Pubmed, Embase, CINAHL, Scopus, and Web of Science were searched from database inception until May 2021 for studies involving interdisciplinary surgical ward rounds. Also, journal hand searches were undertaken. All potential abstracts and papers were screened independently by two reviewers to determine inclusion. All included papers were assessed for methodological quality using the accepted quality criteria outlined in the BEME No. 1 guide. A modified Kirkpatrick model was employed to analyze and synthesize the included studies. The search identified 1765 studies. Reviews of 861 abstracts resulted in the retrieval of 124 articles for full-text screening. Thirty-two papers met the inclusion/exclusion criteria. The levels of research evidence were low with 11 papers scoring either grade 4 (results are clear and very likely to be true) or grade 5 (results are unequivocal) in accordance with the BEME No. 1 guide. These 11 studies had three foci (1) full teams managing specific medical conditions through deliberate interdisciplinary collaboration on ward rounds (n = 5); (2) suggestions on the best format for interdisciplinary collaboration on ward rounds (n = 3); and, (3) the roles of specific disciplines in a collaborative surgical round (n = 3). Physicians, intensivists, and pediatricians embrace the benefits of interdisciplinary working to facilitate the improvement of communication, collaboration, and patient safety. Yet, persistent hierarchies within surgical wards act as a barrier often preventing allied health professionals from speaking up, thus perpetuating intra disciplinary siloed behaviors. This barrier contributes to a dearth of research evidence to facilitate interdisciplinary collaborative intentionality in surgical ward rounds and surgical education. Given the high-risk nature of surgery, interdisciplinary collaboration is a critical component for patient safety. Our findings serve as a call to action to address the rhetoric of interdisciplinary collaboration on surgical ward rounds. An evidence-base is required to design, educate for and implement interdisciplinary collaborative opportunities in surgical wards so this critical aspect of patient care becomes a reality.

What is the Sugar Code?

A code is defined by the nature of the symbols, which are used to generate information-storing combinations (e. g. oligo- and polymers). Like nucleic acids and proteins, oligo- and polysaccharides are ubiquitous, and they are a biochemical platform for establishing molecular messages. Of note, the letters of the sugar code system (third alphabet of life) excel in coding capacity by making an unsurpassed versatility for isomer (code word) formation possible by variability in anomery and linkage position of the glycosidic bond, ring size and branching. The enzymatic machinery for glycan biosynthesis (writers) realizes this enormous potential for building a large vocabulary. It includes possibilities for dynamic editing/erasing as known from nucleic acids and proteins. Matching the glycome diversity, a large panel of sugar receptors (lectins) has developed based on more than a dozen folds. Lectins 'read' the glycan-encoded information. Hydrogen/coordination bonding and ionic pairing together with stacking and C-H/π-interactions as well as modes of spatial glycan presentation underlie the selectivity and specificity of glycan-lectin recognition. Modular design of lectins together with glycan display and the nature of the cognate glycoconjugate account for the large number of post-binding events. They give an entry to the glycan vocabulary its functional, often context-dependent meaning(s), hereby building the dictionary of the sugar code.

Laboratory coagulation tests and recombinant porcine factor VIII: A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder caused by development of auto-antibodies to endogenous coagulation factor VIII (FVIII). Recombinant porcine factor VIII (rpFVIII) is currently licensed only for the management of bleeding in patients with AHA. Regular monitoring of rpFVIII is recommended to assess treatment effectiveness. AIM: This guideline from the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) examines the current publications in the area and aims to offer advice for the laboratory monitoring of rpFVIII in patients with AHA. METHODS: A review of the current literature was undertaken followed by critical review by the authors. RESULTS/CONCLUSIONS: A validated one-stage clotting FVIII assay is recommended for the measurement and regular monitoring of rpFVIII. Assessment of cross-reacting rpFVIII inhibitors by one-stage porcine Bethesda assay should be performed as part of the initial diagnosis of AHA or prior to treatment with rpFVIII. Available data show that chromogenic FVIII assays underestimate rpFVIII and this should be considered if measurement of rpFVIII is required in patients receiving Emicizumab.

Targeting osteoarthritis-associated galectins and an induced effector class by a ditopic bifunctional reagent: Impact of its glycan part on binding measured in the tissue context.

Pairing glycans with tissue lectins controls multiple effector pathways in (patho)physiology. A clinically relevant example is the prodegradative activity of galectins-1 and -3 (Gal-1 and -3) in the progression of osteoarthritis (OA) via matrix metalloproteinases (MMPs), especially MMP-13. The design of heterobifunctional inhibitors that can block galectin binding and MMPs both directly and by preventing their galectin-dependent induction selectively offers a perspective to dissect the roles of lectins and proteolytic enzymes. We describe the synthesis of such a reagent with a bivalent galectin ligand connected to an MMP inhibitor and of two tetravalent glycoclusters with a subtle change in headgroup presentation for further elucidation of influence on ligand binding. Testing was performed on clinical material with mixtures of galectins as occurring in vivo, using sections of fixed tissue. Two-colour fluorescence microscopy monitored binding to the cellular glycome after optimization of experimental parameters. In the presence of the inhibitor, galectin binding to OA specimens was significantly reduced. These results open the perspective to examine the inhibitory capacity of custom-made ditopic compounds on binding of lectins in mixtures using sections of clinical material with known impact of galectins and MMPs on disease progression.

Applying Patient and Public Involvement in preclinical research: A co-created scoping review.

BACKGROUND: Patient and Public Involvement (PPI) in research aims to improve the quality, relevance and appropriateness of research. PPI has an established role in clinical research where there is evidence of benefit, and where policymakers and funders place continued emphasis on its inclusion. However, for preclinical research, PPI has not yet achieved the same level of integration. As more researchers, including our team, aim to include PPI in preclinical research, the development of an evidence-based approach is important. Therefore, this scoping review aimed to identify and map studies where PPI has been used in preclinical research and develop principles that can be applied in other projects. METHODS: A scoping review was conducted to search the literature in Medline (PubMed), EMBASE, CINAHL, PsycInfo and Web of Science Core Collection to identify applied examples of preclinical PPI. Two independent reviewers conducted study selection and data extraction separately. Data were extracted relating to PPI in terms of (i) rationale and aims, (ii) approach used, (iii) benefits and challenges, (iv) impact and evaluation and (v) learning opportunities for preclinical PPI. Findings were reviewed collaboratively by PPI contributors and the research team to identify principles that could be applied to other projects. RESULTS: Nine studies were included in the final review with the majority of included studies reporting PPI to improve the relevance of their research, using approaches such as PPI advisory panels and workshops. Researchers report several benefits and challenges, although evidence of formal evaluation is limited. CONCLUSION: Although currently there are few examples of preclinical research studies reporting empirical PPI activity, their findings may support those aiming to use PPI in preclinical research. Through collaborative analysis of the scoping review findings, several principles were developed that may be useful for other preclinical researchers. PATIENT OR PUBLIC CONTRIBUTION: This study was conducted as part of a broader project aiming to develop an evidence base for preclinical PPI that draws on a 5-year preclinical research programme focused on the development of advanced biomaterials for spinal cord repair as a case study. A PPI Advisory Panel comprising seriously injured rugby players, clinicians, preclinical researchers and PPI facilitators collaborated as co-authors on the conceptualization, execution and writing of this review, including refining the findings into the set of principles reported here.

Effectiveness of interventions to support the transition home after acute stroke: a systematic review and meta-analysis.

BACKGROUND: Effective support interventions to manage the transition to home after stroke are still mostly unknown. AIM: The purpose of this systematic review was to investigate the effectiveness of support interventions at transition from organised stroke services to independent living at home. METHODS: The Cochrane Central Register of Controlled Trials, six databases including MEDLINE and Embase, trial registries, grey literature, and Google Scholar were all searched, up to June 2021. We included randomised controlled trials enrolling people with stroke to receive either standard care or any type of support intervention from organised stroke services to home. The primary outcome was functional status. Two authors determined eligibility, extracted data, evaluated risk of bias (ROB2), and verified the evidence (GRADE). Where possible we performed meta-analyses using Risk Ratios (RR) or Mean Differences (MD). RESULTS: We included 17 studies. Support interventions led to important improvements in functional status, as determined by the Barthel Index up, to 3-months (MD 7.87 points, 95%CI:6.84 to 19.16; 620 participants; five studies; I2 = 77%). Results showed modest but significant functional gains in the medium to long-term (6-12 month follow up, MD 2.91 points, 95%CI:0.03 to 5.81; 1207 participants; six studies; I2 = 84%). Certainty of evidence was low. Support interventions may enhance quality of life for up to 3-months (MD 1.3,95% CI:0.84 to 1.76), and reduce depression (SMD -0.1,95% CI:-0.29 to - 0.05) and anxiety (MD -1.18,95% CI:-1.84 to - 0.52) at 6-12 months. Effects on further secondary outcomes are still unclear. CONCLUSIONS: Incorporating support interventions as people who have experienced a stroke transition from hospital to home can improve functional status and other outcomes. Due to study heterogeneity, the essential components of effective transition of care interventions are still unknown. Adoption of core outcome sets in stroke research would allow for greater comparison across studies. Application of a development and evaluation framework engaging stakeholders would increase understanding of priorities for stroke survivors, and inform the key components of an intervention at transition from hospital-to-home. TRIAL REGISTRATION: CRD42021237397 - https://www.crd.york.ac.uk/prospero.

A quality assurance initiative on improving cefazolin perioperative redose compliance.

OBJECTIVE: Compliance with perioperative antibiotic prophylaxis is crucial for preventing surgical site infection. Anesthesiologists can play a significant role in reducing surgical site infections by following clinical practice guidelines for antibiotic prophylaxis and redosing during surgery. A quality assurance initiative was implemented at a tertiary hospital with the goal of improving cefazolin perioperative antibiotic compliance. DESIGN: This was a retrospective observational study. SETTING: Main operating room of a tertiary care teaching hospital in New York, USA. Our main operating room includes 22 operating rooms that incorporates surgeries from general surgery, vascular surgery, neurology, gynecology, urology, orthopedics, ear, nose and throat (ENT) etc. PARTICIPANTS: All cases in the main operating room from March 1, 2018 to March 31, 2021 that received first dose of Cefazolin and in which the duration of surgery was more than 4 hrs. INTERVENTION: A multifaceted intervention was initiated to address low compliance with cefazolin redosing. Multifaceted interventions included the development of a perioperative antibiotic guide for anesthesia providers, automated reminders in anesthesia electronic medical records, grand rounds education, survey and email communications, and regular feedback reports to the anesthesia department. MAIN OUTCOME MEASURES: Cefazolin perioperative redose compliance rate. RESULTS: Rates of redose compliance were examined in three time periods: preintervention, intervention and postintervention. Cefazolin redosing compliance was 58% in the preintervention period and 90% in the postintervention period. There was a significant positive change in the trend of compliance during the intervention period, indicating that the odds of compliance increased by 13% per month in the intervention period compared to the preintervention period (odds ratio = 1.13, P < 0.001). Redose compliance improvements were sustained a year after the postintervention period (an average of 91%). Surgical site infection rates for colon, coronary artery bypass graft and hip surgeries did not show any significant trend during these time periods. CONCLUSION: Multifaceted interventions led to significant and sustained improvements in cefazolin redosing compliance in the main operating room of a tertiary hospital.

Self-regulatory learning theory as a lens on how undergraduate and postgraduate learners respond to feedback: A BEME scoping review: BEME Guide No. 66.

INTRODUCTION: Little is known of processes by which feedback affects learners to influence achievement. This review maps what is known of how learners interact with feedback, to better understand how feedback affects learning strategies, and to explore enhancing and inhibiting factors. METHODS: Pilot searching indicated a wide range of interpretations of feedback and study designs, prompting the use of scoping methodology. Inclusion criteria comprised: (i) learners (undergraduate, postgraduate, continuing education) who regularly receive feedback, and (ii) studies that associated feedback with subsequent learner reaction. The screening was performed independently in duplicate. Data extraction and synthesis occurred via an iterative consensus approach. Self-regulatory learning theory (SRL) was used as the conceptual framework. RESULTS: Of 4253 abstracts reviewed, 232 were included in the final synthesis. Understandings of feedback are diverse; a minority adopt recognised definitions. Distinct learner responses to feedback can be categorized as cognitive, behavioural, affective, and contextual with complex, overlapping interactions. Importantly emotional responses are commonplace; factors mediating them are pivotal in learner recipience. CONCLUSION: Feedback benefits learners most when focussed on learner needs, via engagement in bi-directional dialogue. Learner emotions must be supported, with the construction of positive learner-teacher relationships. A developmental agenda is key to learner's acceptance of feedback and enhancing future learning.

A scoping review: virtual patients for communication skills in medical undergraduates.

BACKGROUND: Communication is an essential competence for medical students. Virtual patients (VP), computerized educational tools where users take the role of doctor, are increasingly used. Despite the wide range of VP utilization, evidence-based practical guidance on supporting development of communication skills for medical students remains unclear. We focused this scoping review on VP affordance for student learning especially important in the current environment of constrained patient access. METHODS: This scoping review followed Arksey & O'Malley's methodology. We tested and used a search strategy involving six databases, resulting in 5,262 citations. Two reviewers independently screened titles, full texts (n= 158) and finally performed data extraction on fifty-five included articles. To support consideration of educational affordance the authors employed a pragmatic framework (derived from activity theory) to map included studies on VP structure, curricular alignment, mediation of VP activity, and socio-cultural context. RESULTS: Findings suggest that not only the VP itself, but also its contextualization and associated curricular activities influence outcomes. The VP was trialled in the highest proportion of papers as a one-off intervention (19 studies), for an average duration of 44.9 minutes (range 10-120min), mainly in senior medical students (n=23), notably the largest group of studies did not have VP activities with explicit curricular integration (47%). There was relatively little repeated practice, low levels of feedback, self-reflection, and assessment. Students viewed VPs overall, citing authenticity and ease of use as important features. Resource implications are often omitted, and costings would facilitate a more complete understanding of implications of VP use. CONCLUSION: Students should be provided with maximal opportunity to draw out the VPs' full potential through repeated practice, without time-constraint and with curricular alignment. Feedback delivery enabling reflection and mastery is also key. The authors recommend educators to explicitly balance computerized authenticity with instructional design integrated within the curriculum.

Crystal Structure of the Carbohydrate Recognition Domain of the Human Macrophage Galactose C-Type Lectin Bound to GalNAc and the Tumor-Associated Tn Antigen.

The human macrophage galactose lectin (MGL) is an endocytic type II transmembrane receptor expressed on immature monocyte-derived dendritic cells and activated macrophages and plays a role in modulating the immune system in response to infections and cancer. MGL contains an extracellular calcium-dependent (C-type) carbohydrate recognition domain (CRD) that specifically binds terminal N-acetylgalactosamine glycan residues such as the Tn and sialyl-Tn antigens found on tumor cells, as well as other N- and O-glycans displayed on certain viruses and parasites. Even though the glycan specificity of MGL is known and several binding glycoproteins have been identified, the molecular basis for substrate recognition has remained elusive due to the lack of high-resolution structures. Here we present crystal structures of the MGL CRD at near endosomal pH and in several complexes, which reveal details of the interactions with the natural ligand, GalNAc, the cancer-associated Tn-Ser antigen, and a synthetic GalNAc mimetic ligand. Like the asialoglycoprotein receptor, additional calcium atoms are present and contribute to stabilization of the MGL CRD fold. The structure provides the molecular basis for preferential binding of N-acetylgalactosamine over galactose and prompted the re-evaluation of the binding modes previously proposed in solution. Saturation transfer difference nuclear magnetic resonance data acquired using the MGL CRD and interpreted using the crystal structure indicate a single binding mode for GalNAc in solution. Models of MGL1 and MGL2, the mouse homologues of MGL, explain how these proteins might recognize LewisX and GalNAc, respectively.

Imitating evolution's tinkering by protein engineering reveals extension of human galectin-7 activity.

Wild-type lectins have distinct types of modular design. As a step to explain the physiological importance of their special status, hypothesis-driven protein engineering is used to generate variants. Concerning adhesion/growth-regulatory galectins, non-covalently associated homodimers are commonly encountered in vertebrates. The homodimeric galectin-7 (Gal-7) is a multifunctional context-dependent modulator. Since the possibility of conversion from the homodimer to hybrids with other galectin domains, i.e. from Gal-1 and Gal-3, has recently been discovered, we designed Gal-7-based constructs, i.e. stable (covalently linked) homo- and heterodimers. They were produced and purified by affinity chromatography, and the sugar-binding activity of each lectin unit proven by calorimetry. Inspection of profiles of binding of labeled galectins to an array-like platform with various cell types, i.e. sections of murine epididymis and jejunum, and impact on neuroblastoma cell proliferation revealed no major difference between natural and artificial (stable) homodimers. When analyzing heterodimers, acquisition of altered properties was seen. Remarkably, binding properties and activity as effector can depend on the order of arrangement of lectin domains (from N- to C-termini) and on the linker length. After dissociation of the homodimer, the Gal-7 domain can build new functionally active hybrids with other partners. This study provides a clear direction for research on defining the full range of Gal-7 functionality and offers the perspective of testing applications for engineered heterodimers.