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Abstract Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C–H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, we report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. This study demonstrates that this reaction is driven by the generation of long-lived arenium intermediates generated by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients.

Abstract Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine’s effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.

Plasminogen deficiency type 1 (PLGD-1, hypoplasminogenemia) is an ultra-rare, lifelong disease associated with development of fibrinous lesions in multiple organ systems. Depending on lesion location, clinical manifestations of PLGD-1 can result in acute and/or chronic respiratory airway disease which can compromise respiratory function leading to life-threatening events. Early recognition and effective treatment of airway obstruction caused by fibrinous lesions are critical to prevent morbidity due to respiratory compromise. However, physicians may not be familiar with the clinical presentation and management of PLGD-1, causing delays in diagnosis and treatment and potentially contributing to morbidity. Presented here is a case series of one adult and three pediatric patients with severe respiratory complications of PLGD-1 successfully managed by infusions of plasminogen, human-tvmh replacement therapy. Patients’ respiratory symptoms were resolved or greatly improved, and treatment was generally well tolerated. In all patients, baseline plasminogen activity was substantially increased with plasminogen replacement therapy administered initially every one to two days followed by extended interval dosing as symptoms were controlled or resolved. All four described cases support the clinical benefit of replacement therapy with plasminogen, human-tvmh in the resolution of life-threatening respiratory complications associated with PLGD-1. Clinical manifestations in addition to respiratory lesions were also improved or resolved with continued treatment.

BackgroundSocial cognitive impairments are prevalent in schizophrenia spectrum disorder (SSD) and have detrimental effects on functioning. Cognitive remediation (CR) has shown its efficacy in improving social cognitive impairments, although the transfer of these skills to daily life and the personalization of these interventions remain challenging. RC2S (Remédiation Cognitive de la Cognition Sociale dans la Schizophrénie; Cognitive remediation of social cognition in Schizophrenia) is a French CR that combines the learning of strategies and practice using paper-and-pencil exercises and digital relational simulations. This French program was designed as an in-person intervention. ObjectiveThis project aims to culturally adapt the RC2S program, in French-Canadian and North American English and to assess the feasibility, acceptability, safety, and implementation of a remote version in people with SSD. An exploratory objective is to assess the preliminary effect of remote RC2S on goal attainment, social cognition, and psychosocial outcomes. MethodsWe will use a pre-post quasi-experimental design. First, the translation and cultural adaptation in North American English and French-Canadian of RC2S is presented. Then, 20 participants aged ≥18 years with a diagnosis of SSD, presenting with a subjective or an objective impairment in social cognition, will be included to receive RC2S. In addition, 5 therapists will be included as research participants to assess their perspective on RC2S. Participants with SSD will undergo a baseline remote assessment of their social cognition, clinical symptoms, and functioning. They will then start remote RC2S for 24 biweekly individual 1-hour sessions with a therapist. Following the case formulation and goal setting, participants will complete personalized paper-and-pencil exercises to develop strategies and integrative digital relational simulations, during which they will help an avatar navigate through a variety of social contexts and relationships. The last 2 sessions are dedicated to the transfer to daily life. All participants will complete in-session questionnaires assessing therapeutic alliance, motivation, acceptability, feasibility, and implementation. Following RC2S, the participants with SSD will repeat the same assessment as the baseline. Descriptive statistics will be used to summarize the data about acceptability, feasibility, safety, and implementation. To assess the preliminary effect of RC2S, an intention-to-treat approach will be used with linear mixed models for repeated measures with fixed effects of time. ResultsSo far, 45% (9/20) of participants with SSD (mean age 37.9, SD 9.3 years) have completed the project. They received a mean of 20.5 out of 24 (SD 3.5) sessions of RC2S. A total of 5 therapists also completed the project. ConclusionsImproving social cognitive impairments is an important target in SSD to promote functional recovery. Using digital technologies to address these impairments and deliver the intervention is a promising approach to increase the ecological validity of CR and access to the intervention. Trial RegistrationClinicalTrials.gov NCT05017532; https://classic.clinicaltrials.gov/ct2/show/NCT05017532 International Registered Report Identifier (IRRID)DERR1-10.2196/54251

It was previously reported that crocin, a water-soluble carotenoid isolated from the Crocus sativus L. (saffron), has protective effects on cardiac cells and may neutralize and even prevent the formation of excess number of free radicals; however, functional mechanisms of crocin activity have been poorly understood. In the present research, we aimed to study the functional mechanism of crocin in the heart exposed to oxidative stress. Accordingly, oxidative stress was modeled in vitro on human umbilical vein endothelial cells (HUVECs) and in vivo in mice using cellular stressors. The beneficial effects of crocin were investigated at cellular and molecular levels in HUVECs and mice hearts. Results indicated that oral administration of crocin could have protective effects on HUVECs. In addition, it protects cardiac cells and significantly inhibits inflammation via modulating molecular signaling pathways TLR4/PTEN/AKT/mTOR/NF-κB and microRNA (miR-21). Here we show that crocin not only acts as a direct free radical scavenger but also modifies the gene expression profiles of HUVECs and protects mice hearts with anti-inflammatory action under oxidative stress.

Abstract The implication of reduced proteasomal function in neurodegenerative diseases combined with studies showing the protective effects of increasing proteasome activity in animal models highlight the need to understand the capacity for proteasome activation by small molecules. The C-terminal HbYX motif is present on many proteasome binding proteins and functions to tether activators to the 20S core particle. Previous studies have shown that peptides with a HbYX motif can autonomously activate 20S gate-opening to allow protein degradation. In this study, through an iterative process of peptide synthesis, we design a HbYX-like dipeptide mimetic that represents only the fundamental components of the HbYX motif. The mimetic robustly induces gate-opening in archaeal, yeast, and mammalian proteasomes. We identify multiple proteasome α subunit residues in the archaeal proteasome involved in HbYX-dependent activation. When stimulated by the mimetic, the mammalian 20S can degrade unfolded proteins such as tau. Findings using our peptide mimetic suggest the HbYX-dependent mechanism requires cooperative binding in at least two intersubunit pockets of the α ring. Most significantly, our peptide mimetic reverses proteasome impairment by neurodegenerative disease-associated oligomers. Collectively, these results validate HbYX-like molecules as having robust potential to stimulate proteasome function, which are potentially useful for treating neurodegenerative diseases.

The human Dickkopf (DKK) family includes four main secreted proteins, DKK-1, DKK-2, DKK-3, and DKK-4, as well as the DKK-3 related protein soggy (Sgy-1 or DKKL1). These glycoproteins play crucial roles in various biological processes, and especially modulation of the Wnt signaling pathway. DKK-3 is distinct, with its multifaceted roles in development, stem cell differentiation and tissue homeostasis. Intriguingly, DKK-3 appears to have immunomodulatory functions and a complex role in cancer, acting as either a tumor suppressor or an oncogene, depending on the context. DKK-3 is a promising diagnostic and therapeutic target that can be modulated by epigenetic reactivation, gene therapy and DKK-3-blocking agents. However, further research is needed to optimize DKK-3-based therapies. In this review, we comprehensively describe the known functions of DKK-3 and highlight the importance of context in understanding and exploiting its roles in health and disease.

IntroductionPeople with schizophrenia often present with Theory of mind (ToM) deficits, and the link between these deficits and clinical symptoms remains to be refined, for instance through the use of more recent assessment methods. The objective of this study was to examine the associations between a psychometrically sound ToM task and the clinical symptoms of schizophrenia as measured with the five dimensions of the Positive and Negative Syndrome Scale (PANSS) namely positive, negative, cognitive/disorganization, depression/anxiety and excitability/hostility, while controlling for non-social cognitive abilities.MethodsSeventy participants with recent-onset schizophrenia spectrum disorders (SSD) were assessed for ToM using the Combined stories task (COST) and for clinical symptoms using the PANSS.ResultsThe results revealed significant correlations between ToM and the positive (r = −0.292, p = 0.015) and cognitive/disorganization (r = −0.480, p < 0.001) dimensions when controlling for non-social cognitive abilities. In contrast, the negative symptoms dimension was only significantly correlated with ToM when non-social cognitive abilities were not controlled for (r = −0.278, p = 0.020).DiscussionVery few prior studies used the five-dimensions of the PANSS to examine the link with ToM and this study is the first to rely on the COST, which includes a non-social control condition. This study highlights the importance of taking non-social cognitive abilities into account when considering the relationship between ToM and symptoms.

Purpose: In this paper, the challenging and thorny issue of assessing graduate attributes (GAs) is addressed. An interdisciplinary team at The University of Alberta -- developed a formative model of assessment centered on students and instructor interaction with course content. Design/methodology/approach: The paper starts by laying the theoretical groundwork on which this novel GA assessment tool is based, that is, competency-based education, assessment theory and GA assessment. It follows with a description of the online assessment tool for GAs that was developed in the course of this project. Findings: The online assessment tool for GAs targets three types of stakeholders: (1) students, who self-assess in terms of GAs, (2) instructors, who use the tool to define the extent to which each GA should be inculcated in their course and (3) administrators, who receive aggregate reports based on the data gathered by the system for high-level analysis and decision-making. Collected data by students and professors advance formative assessment of these transversal skills and assist administration in ensuring the GAs are addressed in academic programs. Graduate attributes assessment program (GAAP) is also a space for students to build a personal portfolio that would be beneficial to highlight their skills for potential employers. Research limitations/implications: This research has strong implications for the universities, since it can help institutions, academics and students achieve better results in their practices. This is done by demonstrating strong links between theory and practice. Although this tool has only been used within the university setting by students, instructors and administrators (for self-, course and teaching and program improvement), it could increase its social and practical impact by involving potential employers and increase our understanding of student employability. Moreover, because the tool collects data on a continuous basis, it lends itself to many possible applications in educational data mining, Practical implications: The GAAP can be used and adapted to various educational contexts. The plugin can be added to any Learning Management System (LMS), and students can have access to their data and results throughout their education. Social implications: The GAAP allows institutions to provide a longitudinal formative assessment of students' graduate attributes acquisition. It provides solid and valid evidence of students' progress in a way that would advance society and citizenship. Originality/value: To date, the GAAP is the first online interactive platform that has been developed to longitudinally assess the acquisition of GAs during a complete academic cycle/cohort. It provides a unique space where students and instructors interact with assessment scales and with concrete data for a complete university experience profile.

Background: YouTube® is the preferred source of junior trainees to prepare for surgeries. However, its educational utility is not yet determined. The objectives of this review are to assess the educational quality of YouTube® videos and to evaluate their quality and utility to complement surgical training. Methods: MEDLINE was searched for relevant articles which were screened by two independent reviewers using strict inclusion and exclusion criteria. Results: Of 261 articles retrieved, 29 were included of which 96.6% reported unsatisfactory educational quality. Scarcity in standardized validated methods to assess the educational utility of YouTube® videos was identified. Video metrics (e.g., likes, views) do not necessarily correlate with the educational value of YouTube® videos. Conclusions: The educational quality of surgical YouTube® videos is inadequate, insufficient and heterogenous primarily due to its public nature. Developing a peer review process would improve the quality of uploaded videos. Moreover, academic entities should promote the development of high-quality content on open access platforms.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method for intraabdominal cavity chemotherapy. It combines the benefits of a minimally invasive approach (low morbidity and easy to repeat) with the pharmacokinetic advantages of intraperitoneal administration and tolerance seems excellent. We would like to report one case of a serious adverse event, acute respiratory distress syndrome, which is likely related to oxaliplatin administration; all signs disappeared within a few days.

Severe cognitive impairments and cognitive distortions are core to schizophrenia-spectrum disorders (SSDs) and are associated with deteriorated social functioning. Despite well-established efficacy of group psychosocial therapies targeting cognitive health in SSDs, dissemination of these programs remains limited. Remote delivery offers a promising strategy for increasing the programs' accessibility. Yet, little research has evaluated group therapies for cognitive health delivered in this way. Thus, we aimed to assess, from participants' and therapists' perspectives, the feasibility, acceptability, as well as levels and process of engagement in a videoconference delivery of group psychosocial therapies for SSD patients' cognitive health. Participants, outpatients, attended Action Based Cognitive Remediation or Metacognitive Training, both adapted for videoconference. Then, participants and therapists completed post-therapy questionnaires. Of the 28 participants attending at least one session, 75% completed more than half of sessions and seven dropped out. Technology did not appear to significantly hinder participation in the programs. All completing participants reported a positive experience with therapy, 67% were not bothered by the distance from the therapist, and 77% trusted that the information shared was kept confidential. Therapist-rated levels of attention M = 7.5/9 (SD = 1.04), participation M = 6.91/9 (SD = 1.32), and social interactions M = 5.31/9 (SD = 1.96) were satisfactory. Nonetheless, participants indicated that they would have appreciated more social interactions with group members. These positive results validate the earliest stage in the implementation process for remote group therapies targeting cognitive health in SSDs. Remote delivery promises to improve access to therapies targeting cognitive health and, ultimately, facilitate functional recovery for SSD patients.

We report the case of a 57-year-old woman who presented with local invasion of the anal canal by mucinous adenocarcinoma, the malignant transformation of a long-term preexisting retrorectal tailgut cyst. This progression is infrequent and justifies preemptive surgical treatment of retrorectal cysts.

“The extraordinary instability of such an “ion” accounts for many of the peculiarities of organic reactions” – Franck C. Whitmore (1932). This statement from Whitmore came in a period where carbocations began to be considered as intermediates in reactions. Ninety years later, pointing at the strong knowledge acquired from the contributions of famous organic chemists, carbocations are very well known reaction intermediates. Among them, destabilized carbocations – carbocations substituted with electron-withdrawing groups – are, however, still predestined to be transient species and sometimes considered as exotic ones. Among them, the CF3-substituted carbocations, frequently suggested to be involved in synthetic transformations but rarely considered as affordable intermediates for synthetic purposes, have long been investigated. This review highlights recent and past reports focusing on their study and potential in modern synthetic transformations.

Background: The COVID-19 pandemic has challenged health care systems. We sought to comprehend the impact of the COVID-19 pandemic on surgical residents’ education and mental well-being across Canada. Methods: An online 51-question survey was distributed to surgical residents across all 17 Canadian post- graduate surgical residency programs. The questionnaire contained questions concerning demographic factors, perceived effects of COVID-19 pandemic on surgical training and residents’ mental health (categorically demonstrating whether it improved, stayed the same, or worsened). Health habits were measured as continuous variables and compared before and during the pandemic. Additionally, participants reported the performance of wellness offices’ response to their needs during this crisis. Results: A total of 122 out of 650 (19%) residents from all surgical specialities anonymously completed the survey. The majority (68%) reported a worsening in their surgical training. 94% of participants favored online teaching as a complementary method to in-person teaching. As to health habits, 38% reported a rise in their alcohol consumption and time spent seated. Only a minority (25%) felt happier and 41% reported experiencing more anxiety in comparison to surgical training pre-COVID-19. Merely 14% reported benefitting from wellness programs. Conclusion: The COVID-19 pandemic had a negative effect on the perceived quality of surgical training, education, and resident mental health. There is an urgent need to reconsider the implemented measures in medical education and urge us to develop better agendas to face the current or future waves.

Background:. Functional recovery after peripheral nerve injury is often suboptimal despite the intrinsic permissive growth environment of the peripheral nervous system. The objective of this systematic review is to explore the use of electrical stimulation (ES) for peripheral nerve regeneration. Methods:. A systematic literature search was conducted from inception to March 2, 2021 to retrieve articles on ES for peripheral nerve regeneration using the PubMed, Ovid MEDLINE, and Embase databases. Primary outcome measures included objective measures of motor and sensory nerve function. Results:. Four randomized control trials, two case reports, and three case series that addressed the aims were identified. The stimulation parameters varied greatly between studies, without an apparent commonality for a given electrical conduit. Outcomes measured included motor (n = 8) and sensory (n = 7) modalities (cold detection, static two-point discrimination, tactile discrimination, and pressure detection), nerve-specific muscle function and bulk, and electromyography (EMG) motor and sensory terminal latency. Different parameters for measurement were utilized and improvement was observed across the studies compared with controls (n = 4) or pre-intervention measurements (n = 5). One randomized control trial reported no benefit of ES and attributed their findings to their stimulation protocol. Complications were documented in three patients only and included wire remnant removal, skin pigmentation, and bone formation. Conclusions:. ES in peripheral nerve regeneration is beneficial in improving and accelerating recovery. A meta-analysis was not performed due to the heterogeneity, but all studies showed positive findings and minor to no complications. These results provide a primer for further development of delivery methods.

Objective:. Despite the success of composite tissue allograft (CTA) such as face and hand transplant at improving recipients’ quality of life, organ donors’ hesitation needs to be better understood. The aim of the study was to assess Canadian organ donors’ willingness to donate their face and hands, and the efficacy of an educational intervention. Methods:. Canadians registered for organ donation were invited to complete an online survey about CTA. An interactive vignette was introduced part way through to clarify transplant-related concepts, with repeat of questions post-vignette exposure to assess attitudes pliability. Results:. A total of 942 participants completed the survey. Fifty-two percent of donors were willing to donate their face after passing, whereas 80% were willing to donate their hands. Reasons to refuse CTA donation included the risk of upsetting their family, having someone look like them, and wanting their body to remain intact. Donors’ willingness to donate their face (38%, P < 0.001) and hands (79%, P = 0.67) decreased following vignette exposure. Comparative analysis of our interventional vignette with a similar study where donors’ donation readiness increased after an educational intervention revealed that our vignette lacked a strong enough emotional component to positively impact donors’ attitude to CTA, and may have exposed participants to alternatives to transplant they were not previously aware of. Conclusions:. Canadian organ donors surveyed were willing to donate their face and hands following death, a willingness reduced after watching our informative vignette. Further qualitative work is required to better understand the educational needs and areas to address to increase donors’ acceptance of CTA.

Background: Canadian medical school curriculums have undergone major restructuring during the COVID-19 pandemic. This study’s goal was to assess the perceived impact of COVID-19 on medical students’ education and wellbeing. Methods: An online survey was distributed to Canadian medical students. Descriptive analyses and ANOVAs were used to assess changes in mental health, health habits and quality of education during the pandemic. Results: 248 medical students from 13 schools across Canada participated in this study. 74% reported a reduction in the quality of their education since COVID-19. 58% of students found online to be inferior to in-person teaching. 65% of students had more time for wellness and leisure activities, about half of the cohort felt more depressed (48%) and lonelier (52%). Student’s overall health habits worsened after the start of the pandemic (F=37.4, p < 0.001). Alcohol drinking, time spent seated, and screen time also increased since the pandemic (p < 0.001). During the pandemic, students with a prior history of depression or anxiety expressed increased depressive symptoms (66% vs. 42%, p =0.003), increased anxiety (69% vs. 41%, p < 0001), worse sleep quality (34% vs. 18%, p = 0.031), and poorer quality of life (55% vs. 65%, p = 0.024) versus those with no prior history. Conclusion: Canadian medical student’s education and wellbeing has been negatively impacted during the pandemic.