Novel Quinolizine AIE System: Visualization of Molecular Motion and Elaborate Tailoring for Biological Application

Molecular motions are ubiquitous in nature and they immutably play intrinsic roles in all actions. However, exploring appropriate models to decipher molecular motions is an extremely important but very challenging task for researchers. Considering aggregation-induced emission (AIE) luminogens possess their unique merits to visualize molecular motions, it is particularly fascinating to construct new AIE systems as model to study molecular motion. Herein, a novel quinolizine (QLZ) AIE system was constructed based on the restriction intramolecular vibration mechanism. It was demonstrated that QLZ could act as an ideal model to visualize single-molecule motion and macroscopic molecular motion via fluorescence change. Additionally, further elaborate tailoring of this impressive core achieved highly efficient reactive oxygen species production and realized fluorescence imaging-guided photodynamic therapy applications, which confirms the great application potential of this new AIE-active QLZ core. Therefore, this work not only provides an ideal model to visualize molecular motion but also opens a new way for the application of AIEgens.

Potential implications of angiotensin-converting enzyme 2 blockades on neuroinflammation in SARS-CoV-2 infection

Background: Angiotensin-converting enzyme 2 (ACE2) has been reported as a portal for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Consequently, scientific strategies to combat coronavirus disease of 2019 (COVID-19) were targeted to arrest SARS-CoV-2 invasion by blocking ACE2. While blocking ACE2 appears a beneficial approach to treat COVID-19, clinical concerns have been raised primarily due to the various intrinsic roles of ACE2 in neurological functions. Selective reports indicate that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) upregulate ACE2 levels. ACE2 metabolizes angiotensin II and several peptides, including apelin-13, neurotensin, kinetensin, dynorphin, [des-Arg9] bradykinin, and [Lys-des-Arg9]-bradykinin, which may elicit neuroprotective effects. Since ARBs and ACEIs upregulate ACE2, it may be hypothesized that patients with hypertension receiving ARBs and ACEIs may have higher expression of ACE2 and thus be at a greater risk of severe disease from the SARS-CoV-2 infections. However, recent clinical reports indicate the beneficial role of ARBs/ACEIs in reducing COVID-19 severity. Together, this warrants a further study of the effects of ACE2 blockades in hypertensive patients medicated with ARBs/ACEIs, and their consequential impact on neuronal health. However, the associations between their blockade and any neuroinflammation also warrant further research. Objective: This review collates mechanistic insights into the dichotomous roles of ACE2 in SARS-CoV-2 invasion and neurometabolic functions and the possible impact of ACE2 blockade on neuroinflammation. Conclusion: It has been concluded that ACE2 blockade imposes neuroinflammation.

Lessons Learned in Allergy and Immunology Training: A Survey Analysis

Background: There is currently little Canadian data to assess how well traditional time-based residency training programs have prepared residents for careers in Clinical Immunology and Allergy (CIA). This study aims to identify the perceived preparedness of residents in various areas of practice upon the completion of a Canadian CIA residency training program. Methods: In the summer of 2020, an electronic survey was sent to 2018 and 2019 graduates of Canadian CIA training programs by the Canadian Society of Allergy and Clinical Immunology (CSACI). Results: Former residents felt well prepared in most Medical Expert areas. Residents felt less prepared for the intrinsic roles of Leader, Communicator, Collaborator, Health Advocate, Scholar, and Professional. The majority of the intrinsic competencies were learned through mentorship and on the job after finishing training. Conclusions: Upon completion of training, Canadian CIA residents felt well prepared for many competencies, particularly in Medical Expert areas. Training programs may wish to focus on various intrinsic competencies in order to better prepare residents for transition to practice. Academic half-day was not identified as a primary learning centre for intrinsic competencies, suggesting that new teaching strategies may be required.

From vision to implementation: Building a national undergraduate paediatric curriculum

Objective There are many challenges in ensuring medical students learn paediatrics. Medical educators must develop and maintain curricula that meet learners’ needs and accreditation requirements. Paediatricians and family physicians, practicing and teaching in busy clinical environments, require Canadian-relevant curricular guidance and resources to teach and assess learners. Students struggle with curricular cohesion, clear expectations, and resources. Recognizing these challenges and acknowledging the need to address them, the Paediatric Undergraduate Program Directors of Canada (PUPDOC) created canuc-paeds, a comprehensive competency-based undergraduate curriculum that teachers and students would actually use. Methods Curriculum development included the following: utilization of best practices in curriculum development, an environmental scan, development of guiding principles, Delphi surveys, in-person meetings, and quality improvement. All Canadian paediatric undergraduate educator leaders and other stakeholders were invited to participate. Results The curriculum, based on the RCPSC CanMEDS Framework, includes 29 clinical presentations, each with key conditions, foundational knowledge objectives, and learning resources. Essential paediatric-specific physical examination and procedural skills that graduating medical students are expected to perform are identified. Objectives specific to Intrinsic Roles of Collaborator, Communicator, Professional, Leader, Health Advocate and Scholar that can be assessed in the field of paediatrics at the undergraduate level are articulated. The national curriculum has been implemented widely at Canadian medical schools. Online, open-access clinical resources have been developed and are being used world-wide. Conclusion This curriculum provides overarching Canadian-specific curricular guidance and resources for students and for the paediatricians and family physicians who are responsible for teaching and assessing undergraduate learners.

Analysis of Supervisors' Feedback to Residents on Communicator, Collaborator, and Professional Roles During Case Discussions

ABSTRACT Background Literature examining the feedback supervisors give to residents during case discussions in the realms of communication, collaboration, and professional roles (intrinsic roles) focuses on analyses of written feedback and self-reporting. Objectives We quantified how much of the supervisors' verbal feedback time targeted residents' intrinsic roles and how well feedback time was aligned with the role targeted by each case. We analyzed the educational goals of this feedback. We assessed whether feedback content differed depending on whether the residents implied or explicitly expressed a need for particular feedback. Methods This was a mixed-methods study conducted from 2017 to 2019. We created scripted cases for radiology and internal medicine residents to present to supervisors, then analyzed the feedback given both qualitatively and quantitatively. The cases were designed to highlight the CanMEDS intrinsic roles of communicator, collaborator, and professional. Results Radiologists (n = 15) spent 22% of case discussions providing feedback on intrinsic roles (48% aligned): 28% when the case targeted the communicator role, 14% for collaborator, and 27% for professional. Internists (n = 15) spent 70% of discussions on intrinsic roles (56% aligned): 66% for communicator, 73% for collaborator, and 72% for professional. Radiologists' goals were to offer advice (66%), reflections (21%), and agreements (7%). Internists offered advice (41%), reflections (40%), and clarifying questions (10%). We saw no consistent effects when residents explicitly requested feedback on an intrinsic role. Conclusions Case discussions represent frequent opportunities for substantial feedback on intrinsic roles, largely aligned with the clinical case. Supervisors predominantly offered monologues of advice and agreements.

Evaluation of a collaborator objective structured clinical examination (COSCE) in postgraduate medical education

Background: Effective intra- and interprofessional collaboration abilities are necessary for safe and effective medical care, however such roles are often informally taught in postgraduate medical education with lack of opportunity for practice and feedback. The Objective Structured Clinical Encounter (OSCE) is a common approach in medical education. Adaptations of the OSCE have been found useful in the assessment of collaborator competencies amongst interprofessional student groups and assessment of intrinsic roles, like collaboration.Objective: The purpose of this study was to evaluate the effectiveness of a Collaborator Objective Structured Clinical Encounter (COSCE) as a method of formative assessment on collaborator competencies for postgraduate trainees. Methods: This study involved a one group, pretest-posttest evaluation conducted in 2018. PGY1 residents completed a Team Skills Scale immediately before and after COSCE participation, completed an evaluation survey to report satisfaction, and were assessed by facilitators and peer assessors using a COSCE rubric.Results: Residents reported significant improvement in their pre (N=35) to post-team skills (N=37) scores and an overall positive level of satisfaction with the COSCE experience (N=37/39, 94.9% response rate). Transfer of care skills (e.g., handover) demonstrated the lowest performance scores across all COSCE stations. Peer assessor (N = 204) and facilitator scores (N = 47) also indicated a moderate level of interrelatedness. Conclusion: A COSCE is a feasible method of formative assessment, fostering reflection and learning, and providing feedback on collaborator skills early in postgraduate medical education. Peer assessment may also hold promise as a formative assessment method on intra- and interprofessional collaboration.

The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment

The Kelch-like ECH-associated protein 1 (KEAP1)—Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) system attracts extensive interest from scientists in basic and clinical cancer research fields, as NRF2 exhibits activity as both an oncogene and tumor suppressor, depending on the context. Especially unique and malignant, NRF2-addicted cancers exhibit high levels of NRF2 expression. Somatic mutations identified in the NRF2 or KEAP1 genes of NRF2-addicted cancers cause the stabilization and accumulation of NRF2. NRF2-addicted cancers hijack the intrinsic roles that NRF2 plays in cytoprotection, including antioxidative and anti-electrophilic responses, as well as metabolic reprogramming, and acquire a marked advantage to survive under severe and limited microenvironments. Therefore, NRF2 inhibitors are expected to have therapeutic effects in patients with NRF2-addicted cancers. In contrast, NRF2 activation in host immune cells exerts significant suppression of cancer cell growth, indicating that NRF2 inducers also have the potential to be therapeutics for cancers. Thus, the KEAP1–NRF2 system makes a broad range of contributions to both cancer development and suppression. These observations thus demonstrate that both NRF2 inhibitors and inducers are useful for the treatment of cancers with high NRF2 activity.

Distinct Molecular Pattern-Induced Calcium Signatures Lead to Different Downstream Transcriptional Regulations via AtSR1/CAMTA3

Plants encrypt the perception of different pathogenic stimuli into specific intracellular calcium (Ca2+) signatures and subsequently decrypt the signatures into appropriate downstream responses through various Ca2+ sensors. Two microbe-associated molecular patterns (MAMPs), bacterial flg22 and fungal chitin, and one damage-associated molecular pattern (DAMP), AtPep1, were used to study the differential Ca2+ signatures in Arabidopsis leaves. The results revealed that flg22, chitin, and AtPep1 induced distinct changes in Ca2+ dynamics in both the cytosol and nucleus. In addition, Flg22 and chitin upregulated the expression of salicylic acid-related genes, ICS1 and EDS1, whereas AtPep1 upregulated the expression of jasmonic acid-related genes, JAZ1 and PDF1.2, in addition to ICS1 and EDS1. These data demonstrated that distinct Ca2+ signatures caused by different molecular patterns in leaf cells lead to specific downstream events. Furthermore, these changes in the expression of defense-related genes were disrupted in a knockout mutant of the AtSR1/CAMTA3 gene, encoding a calmodulin-binding transcription factor, in which a calmodulin-binding domain on AtSR1 was required for deciphering the Ca2+ signatures into downstream transcription events. These observations extend our knowledge regarding unique and intrinsic roles for Ca2+ signaling in launching and fine-tuning plant immune response, which are mediated by the AtSR1/CAMTA3 transcription factor.

The Nuclear Receptor Seven Up Regulates Genes Involved in Immunity and Xenobiotic Response in the Adult Drosophila Female Fat Body

The physiology of organisms depends on inter-organ communication in response to changes in the environment. Nuclear receptors are broadly expressed transcription factors that respond to circulating molecules to control many biological processes, including immunity, detoxification, and reproduction. Although the tissue-intrinsic roles of nuclear receptors in reproduction have been extensively studied, there is increasing evidence that nuclear receptor signaling in peripheral tissues can also influence oogenesis. We previously showed that the Drosophila nuclear receptor Seven up (Svp) is required in the adult fat body to regulate distinct steps of oogenesis; however, the relevant downstream targets of Svp remain unknown. Here, we took an RNA sequencing approach to identify candidate Svp targets specifically in the adult female fat body that might mediate this response. svp knockdown in the adult female fat body significantly downregulated immune genes involved in the first line of pathogen defense, suggesting a role for Svp in stimulating early immunity. In addition, we found that Svp transcriptionally regulates genes involved in each step of the xenobiotic detoxification response. Based on these findings, we propose a testable model in which Svp functions in the adult female fat body to stimulate early defense against pathogens and facilitate detoxification as part of its mechanisms to promote oogenesis.