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This article presents the development of the Equity, Diversity, Inclusivity, and Accessibility (EDIA) Cross-Cutting Theme Project within the Team Primary Care (TPC) initiative, aimed at addressing systemic inequities through innovative educational strategies. Grounded in the social accountability of health professions framework, this project aims to equip primary care teams with the knowledge, skills, and attitudes necessary to promote health equity. The EDIA Integrated Educational Experience (IEE) model includes a self-assessment tool, digital learning space, and national mentorship network, providing a comprehensive approach for primary care teams to promote health equity. The IEE model utilizes a layered micro, meso, and macro approach to support cultural transformation within highly complex healthcare environments. Key lessons learned involve trust- and relationship-building processes to help dismantle historical silos and encourage open dialogue. Future efforts focus on implementation, ensuring adaptability, scalability, and sustainability, positioning the model as a catalyst for equitable primary care delivery., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: There is a link between inflammatory bowel disease (IBD) and poor sleep quality that is presumed to be multifactorial. The purpose of this study was to identify factors that impact sleep quality in this group including clinical disease activity, depression, anxiety, quality of life, and disordered social media use through questionnaires., Methods: This prospective study analyzed sleep quality in adolescent patients ages 13 to 18 with a diagnosis of IBD using objective data from wrist actigraphy and subjective report from the Pittsburgh Sleep Quality Index (PSQI). Additional screeners including the Short Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index, Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module, Generalized Anxiety Disorder 7-item screener, Patient Health Questionnaire depression screener, and Social Media Disorder scale were also collected., Results: Twenty-three subjects enrolled and 16 completed questionnaires. 62.5 % of participants were in clinical remission and the remaining 37.5 % had mild to severe clinical IBD activity. Poor subjective sleep quality was associated with a shorter duration of sleep time and an increased clinical disease activity score. Patients in clinical remission slept for a longer duration than those with mild IBD activity., Conclusions: This study did not identify a significant relationship between sleep quality and psychosocial factors in the adolescent population with IBD, though their influence cannot be discounted. There was a connection between the presence of disease activity and shorter sleep duration. Similarly, PSQI scores correlated with sleep time but not sleep quality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In the marine environment, seaweeds (i.e. marine macroalgae) provide a wide range of ecological services and economic benefits. Like land plants, seaweeds do not provide these services in isolation, rather they rely on their associated microbial communities, which together with the host form the seaweed holobiont. However, there is a poor understanding of the mechanisms shaping these complex seaweed-microbe interactions, and of the evolutionary processes underlying these interactions. Here, we identify the current research challenges and opportunities in the field of seaweed holobiont biology. We argue that identifying the key microbial partners, knowing how they are recruited, and understanding their specific function and their relevance across all seaweed life history stages are among the knowledge gaps that are particularly important to address, especially in the context of the environmental challenges threatening seaweeds. We further discuss future approaches to study seaweed holobionts, and how we can apply the holobiont concept to natural or engineered seaweed ecosystems., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Plants and algae play a crucial role in the earth's ecosystems. Through photosynthesis they convert light energy into chemical energy, capture CO2 and produce oxygen and energy-rich organic compounds. Photosynthetic organisms are primary producers and synthesize the essential omega 3 and omega 6 fatty acids. They have also unique and highly diverse complex lipids, such as glycolipids, phospholipids, triglycerides, sphingolipids and phytosterols, with nutritional and health benefits. Plant and algal lipids are useful in food, feed, nutraceutical, cosmeceutical and pharmaceutical industries but also for green chemistry and bioenergy. The analysis of plant and algal lipidomes represents a significant challenge due to the intricate and diverse nature of their composition, as well as their plasticity under changing environmental conditions. Optimization of analytical tools is crucial for an in-depth exploration of the lipidome of plants and algae. This review highlights how lipidomics analytical tools can be used to establish a complete mapping of plant and algal lipidomes. Acquiring this knowledge will pave the way for the use of plants and algae as sources of tailored lipids for both industrial and environmental applications. This aligns with the main challenges for society, upholding the natural resources of our planet and respecting their limits., (Copyright © 2024. Published by Elsevier Ltd.)

Semantic memory representations are generally well maintained in aging, whereas semantic control is thought to be more affected. To explain this phenomenon, this study tested the predictions of the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), focusing on task demands in aging as a possible framework. The CRUNCH effect would manifest itself in semantic tasks through a compensatory increase in neural activation in semantic control network regions but only up to a certain threshold of task demands. This study compares 39 younger (20-35 years old) with 39 older participants (60-75 years old) in a triad-based semantic judgment task performed in an fMRI scanner while manipulating task demand levels (low versus high) through semantic distance. In line with the CRUNCH predictions, differences in neurofunctional activation and behavioral performance (accuracy and response times) were expected in younger versus older participants in the low- versus high-demand conditions, which should be manifested in semantic control Regions of Interest (ROIs). Our older participants had intact behavioral performance, as proposed in the literature for semantic memory tasks (maintained accuracy and slower response times (RTs)). Age-invariant behavioral performance in the older group compared to the younger one is necessary to test the CRUNCH predictions. The older adults were also characterized by high cognitive reserve, as our neuropsychological tests showed. Our behavioral results confirmed that our task successfully manipulated task demands: error rates, RTs and perceived difficulty increased with increasing task demands in both age groups. We did not find an interaction between age group and task demand, or a statistically significant difference in activation between the low- and high-demand conditions for either RTs or accuracy. As for brain activation, we did not find the expected age group by task demand interaction, or a significant main effect of task demand. Overall, our results are compatible with some neural activation in the semantic network and the semantic control network, largely in frontotemporoparietal regions. ROI analyses demonstrated significant effects (but no interactions) of task demand in the left and right inferior frontal gyrus, the left posterior middle temporal gyrus, the posterior inferior temporal gyrus and the prefrontal gyrus. Overall, our test did not confirm the CRUNCH predictions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Haitas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Schistosomiasis affects approximately 230 million people worldwide. There is an increased incidence of schistosomiasis cases in France acquired from outside the country. This increases the risk of schistosomiasis outbreaks as observed in Corsica. Clinicians from non-endemic regions are not accustomed to diagnosing and managing this pathology. The objective of this study is to provide a better description of the clinical and paraclinical characteristics and disease evolution of affected children., Methods: Through the French Pediatric Nephrology Society and the Pediatric Infectious Pathology Group, we contacted all French pediatric centers that may have treated children with urinary schistosomiasis between 2013 and 2019. Age, sex, comorbidities, and clinical, biological, and radiological data (at discovery and follow-up) were collected retrospectively., Results: A total of 122 patients from 10 different centers were included. The median age was 14 years and the sex ratio M/F was 4:1. Hematuria was present in 82% of the patients while urinary tract abnormality was found in 36% of them. Fourteen patients (11%) displayed complicated forms of urinary schistosomiasis including 10 patients with chronic kidney disease. A total of 110 patients received treatment with praziquantel, which was well-tolerated and led to clinical resolution of symptoms in 98% of cases., Conclusion: Patients with schistosomiasis present frequent kidney, urinary, or genital involvement. Systematic screening of patients returning from endemic areas is therefore recommended, especially since treatment with antiparasitic drugs is effective and well-tolerated. Enhancing medical knowledge of this pathology among all practitioners is essential to improve care and outcomes., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Control of dog-mediated rabies relies on raising awareness, access to post-exposure prophylaxis (PEP) and mass dog vaccination. To assess rabies awareness in Moramanga district, Madagascar, where rabies is endemic, two complementary quantitative and qualitative approaches were carried out in 2018. In the quantitative approach, a standardized questionnaire was administered to 334 randomized participants living in 170 households located less than 5 km from the anti-rabies treatment center (ARTC) located in Moramanga city (thereafter called the central area), and in 164 households located more than 15 km away from the ARTC in two rural communes (thereafter called the remote area). Logistic regression models were fitted to identify factors influencing knowledge and practice scores. The qualitative approach consisted in semi-structured interviews conducted with 28 bite victims who had consulted the ARTC, three owners of biting dogs, three ARTC staff and two local authorities. Overall, 15.6% (52/334) of households owned at least one dog. The dog-to-human ratio was 1:17.6. The central area had a significantly higher dog bite incidence (0.53 per 100 person-years, 95% CI: 0.31-0.85) compared to the remote area (0.22 per 100 person-years, 95% CI: 0.09-0.43) (p = 0.03). The care pathway following a bite depended on wound severity, how the dog was perceived and its owner's willingness to cover costs. Rabies vaccination coverage in dogs in the remote area was extremely low (2.4%). Respondents knew that vaccination prevented animal rabies but owners considered that their own dogs were harmless and cited access and cost of vaccine as main barriers. Most respondents were not aware of the existence of the ARTC (85.3%), did not know the importance of timely access to PEP (92.2%) or that biting dogs should be isolated (89.5%) and monitored. Good knowledge scores were significantly associated with having a higher socio-economic status (OR = 2.08, CI = 1.33-3.26) and living in central area (OR = 1.91, CI = 1.22-3.00). Good practice scores were significantly associated with living in central area (OR = 4.78, CI = 2.98-7.77) and being aware of the ARTC's existence (OR = 2.29, CI = 1.14-4.80). In Madagascar, knowledge on rabies was disparate with important gaps on PEP and animal management. Awareness campaigns should inform communities (i) on the importance of seeking PEP as soon as possible after an exposure, whatever the severity of the wound and the type of biting dog who caused it, and (ii) on the existence and location of ARTCs where free-of-charge PEP is available. They should also encourage owners to isolate and monitor the health of biting dogs. Above all, awareness and dog vaccination campaigns should be designed so as to reach the more vulnerable remote rural populations as knowledge, good practices and vaccination coverage were lower in these areas. They should also target households with a lower socio-economic status. If awareness campaigns are likely to succeed in improving access to ARTCs in Madagascar, their impact on prompting dog owners to vaccinate their own dogs seems more uncertain given the financial and access barriers. Therefore, to reach the 70% dog vaccination coverage goal targeted in rabies elimination programs, awareness campaigns must be combined with free-of-charge mass dog vaccination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Leblanc et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brown macroalgae are colonized by diverse microorganisms influencing the physiology of their host. However, cell-cell interactions within the surface microbiome (epimicrobiome) are largely unexplored, despite the significance of specific chemical mediators in maintaining host-microbiome homeostasis. In this study, by combining liquid chromatography coupled to mass spectrometry (LC-MS) analysis and bioassays, we demonstrated that the widely diverse fungal epimicrobiota of the brown alga Saccharina latissima can affect quorum sensing (QS), a type of cell-cell interaction, as well as bacterial biofilm formation. We also showed the ability of the bacterial epimicrobiota to form and inhibit biofilm growth, as well as to activate or inhibit QS pathways. Overall, we demonstrate that QS and anti-QS compounds produced by the epimicrobiota are key metabolites in these brown algal epimicrobiota communities and highlight the importance of exploring this epimicrobiome for the discovery of new bioactive compounds, including potentially anti-QS molecules with antifouling properties., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Objective: To assess the effectiveness of accelerated transcranial magnetic stimulation (TMS) for treatment-resistant depression (TRD) in a tertiary referral center in Quebec, Canada, focusing on a real-world clinical setting., Methods: We reviewed the data of 247 TRD patients treated between January 2012 and May 2022 who received accelerated TMS. Participants were adults diagnosed with unipolar or bipolar depression, resistant to at least two antidepressant trials, and assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS)., Results: Significant symptom reduction was found in the completer sample (N = 147), with 46.3 % of patients meeting post-treatment response criteria and 36.1 % achieving remission. Baseline severity of depression, age, and the number of antidepressant trials were key predictors of treatment outcomes. Patients who did not complete treatment had generally more severe depressive and anxious symptoms and greater treatment resistance. No significant differences in response rates were observed across different TMS coils., Conclusion: The study demonstrated the effectiveness and tolerability of accelerated TMS for TRD in a real-world clinical setting., Competing Interests: Declaration of Competing Interest The authors of the manuscript hereby declare that they have no competing interests to disclose in relation to the research, authorship, and publication of this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Metabolic pathway drift has been formulated as a general principle to help in the interpretation of comparative analyses between biosynthesis pathways. Indeed, such analyses often indicate substantial differences, even in widespread pathways that are sometimes believed to be conserved. Here, our purpose is to check how much this interpretation fits to empirical data gathered in the field of plant and algal biosynthesis pathways. After examining several examples representative of the diversity of lipid biosynthesis pathways, we explain why it is important to compare closely related species to gain a better understanding of this phenomenon. Furthermore, this comparative approach brings us to the question of how much biotic interactions are responsible for shaping this metabolic plasticity. We end up introducing some model systems that may be promising for further exploration of this question., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zonnequin, Belcour, Delage, Siegel, Blanquart, Leblanc and Markov.)

Legacy radioactive waste can be defined as the radioactive waste produced during the infancy of the civil nuclear industry's development in the mid-20th Century, a time when, unfortunately, waste storage and treatment were not well planned. The marine environment is one of the environmental compartments worth studying in this regard because of legacy waste in specific locations of the seabed. Comprising nearly 70% of the earth's service, the oceans are the largest and indeed the final destination for contaminated fresh waters. For this reason, long-term studies of the accumulation biochemical mechanisms of metallic radionuclides in the marine ecosystem are required. In this context the brown algal compartment may be ecologically relevant because of forming large and dense algal beds in coastal areas and potential important biomass for contamination. This report presents the first step in the investigation of uranium (U, an element used in the nuclear cycle) bioaccumulation in the brown alga Ascophyllum nodosum using a multi-scale spectroscopic and imaging approach. Contamination of A. nodosum specimens in closed aquaria at 13 °C was performed with a defined quantity of U(VI) (10 -5 M). The living algal uptake was quantified by ICP-MS and a localization study in the various algal compartments was carried out by combining electronic microscopy imaging (SEM), X-ray Absorption spectroscopy (XAS) and micro X-ray Florescence (μ-XRF). Data indicate that the brown alga is able to concentrate U(VI) by an active bioaccumulation mechanism, reaching an equilibrium state after 200 h of daily contamination. A comparison between living organisms and dry biomass confirms a stress-response process in the former, with an average bioaccumulation factor (BAF) of 10 ± 2 for living specimens (90% lower compared to dry biomass, 142 ± 5). Also, these results open new perspectives for a potential use of A. nodosum dry biomass as uranium biosorbent. The different partial BAFs (bioaccumulation factors) range from 3 (for thallus) to 49 (for receptacles) leading to a compartmentalization of uranium within the seaweed. This reveals a higher accumulation capacity in the receptacles, the algal reproductive parts. SEM images highlight the different tissue distributions among the compartments with a superficial absorption in the thallus and lateral branches and several hotspots in the oospheres of the female individuals. A preliminary speciation XAS analysis identified a distinct U speciation in the gametes-containing receptacles as a pseudo-autunite phosphate phase. Similarly, XAS measurements on the lateral branches (XANES) were not conclusive with regards to the occurrence of an alginate-U complex in these tissues. Nonetheless, the hypothesis that alginate may play a role in the speciation of U in the algal thallus tissues is still under consideration., (© 2024. The Author(s).)

Background: The value of formative objective structured clinical examinations (OSCEs) during the pre-clinical years of medical education remains unclear. We aimed to assess the effectiveness of a formative OSCE program for medical students in their pre-clinical years on subsequent performance in summative OSCE., Methods: We conducted a non-randomized controlled prospective pilot study that included all medical students from the last year of the pre-clinical cycle of the Université Paris-Cité Medical School, France, in 2021. The intervention group received the formative OSCE program, which consisted of four OSCE sessions, followed by debriefing and feedback, whereas the control group received the standard teaching program. The main objective of this formative OSCE program was to develop skills in taking a structured medical history and communication. All participants took a final summative OSCE. The primary endpoint was the summative OSCE mark in each group. A questionnaire was also administered to the intervention-group students to collect their feedback. A qualitative analysis, using a convenience sample, was conducted by gathering data pertaining to the process through on-site participative observation of the formative OSCE program., Results: Twenty students were included in the intervention group; 776 in the control group. We observed a significant improvement with each successive formative OSCE session in communication skills and in taking a structured medical history (p<0.0001 for both skills). Students from the intervention group performed better in a summative OSCE that assessed the structuring of a medical history (median mark 16/20, IQR [15; 17] versus 14/20, [13; 16], respectively, p = 0.012). Adjusted analyses gave similar results. The students from the intervention group reported a feeling of improved competence and a reduced level of stress at the time of the evaluation, supported by the qualitative data showing the benefits of the formative sessions., Conclusion: Our findings suggest that an early formative OSCE program is suitable for the pre-clinical years of medical education and is associated with improved student performance in domains targeted by the program., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ouldali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the marine environment, distance signaling based on water-borne cues occurs during interactions between macroalgae and herbivores. In the brown alga Laminaria digitata from North-Atlantic Brittany, oligoalginates elicitation or grazing was shown to induce chemical and transcriptomic regulations, as well as emission of a wide range of volatile aldehydes, but their biological roles as potential defense or warning signals in response to herbivores remain unknown. In this context, bioassays using the limpet Patella pellucida and L. digitata were carried out for determining the effects of algal transient incubation with 4-hydroxyhexenal (4-HHE), 4-hydroxynonenal (4-HNE) and dodecadienal on algal consumption by grazers. Simultaneously, we have developed metabolomic and transcriptomic approaches to study algal molecular responses after treatments of L. digitata with these chemical compounds. The results indicated that, unlike the treatment of the plantlets with 4-HNE or dodecadienal, treatment with 4-HHE decreases algal consumption by herbivores at 100 ng.ml -1 . Moreover, we showed that algal metabolome was significantly modified according to the type of aldehydes, and more specifically the metabolite pathways linked to fatty acid degradation. RNAseq analysis further showed that 4-HHE at 100 ng.ml -1 can activate the regulation of genes related to oxylipin signaling pathways and specific responses, compared to oligoalginates elicitation. As kelp beds constitute complex ecosystems consisting of habitat and food source for marine herbivores, the algal perception of specific aldehydes leading to targeted molecular regulations could have an important biological role on kelps/grazers interactions., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD., Competing Interests: TP receives compensation for consulting work from Damona Pharmaceutical Inc., a biotech company developing GABAergic molecules for the treatment of cognitive dysfunctions in depression. ES is co-founder, CEO and CSO of Damona Pharmaceutical Inc. DB receives research support from CIHR, NIH, Brain Canada, and the Temerty Family through the CAMH Foundation. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and has been the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. DB also received in-kind equipment support from Magventure for 3 investigator-initiated studies. DB received medication supplies for an investigator-initiated trial from Indivior. DB has participated in one Scientific Advisory Board Meeting for Janssen and one meeting for Welcony Inc. DV holds the Labatt Family Professorship in Depression Biology, a University Named Professorship at the University of Toronto. She receives research support from CIHR, NIH, the Centre for Addiction and Mental Health (CAMH), University Hospital Network (UHN) and the Department of Psychiatry at the University of Toronto. DV declares no biomedical interests or conflicts. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dharavath, Pina-Leblanc, Tang, Sloan, Nikolova, Pangarov, Ruocco, Shield, Voineskos, Blumberger, Boileau, Bozinoff, Gerretsen, Vieira, Melamed, Sibille, Quilty and Prevot.)

Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1 LSH / HELLS ), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1 Dnmt1 , but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Equitable appointments of departmental leaders in medical schools have lagged behind other Equity, Diversity, and Inclusion (EDI) advancements. The purpose of this research was to 1) analyze how policy documents communicate changing ideas of EDI, employment equity, and departmental leadership; and 2) investigate department heads' (DH) perspectives on EDI policies and practices., Methods: We conducted a critical discourse analysis to examine underlying assumptions shaping EDI and departmental leadership in one Canadian medical school. We created and analyzed a textual archive of EDI documents ( n = 17, 107 pages) and in-depth interviews with past ( n = 6) and current ( n = 12) DH (830 minutes; 177 pages)., Results: Documents framed EDI as: a legal requirement; an aspiration; and historical reparation. In interviews, participants framed EDI as: affirmative action; relationships; numerical representation; and relinquishing privilege. We noted inconsistent definitions of equity-deserving groups., Conclusions: Change is slowly happening, with emerging awareness of white privilege, allyship, co-conspiracy, and the minority tax. However, there is more urgent work to be done. This work requires an intersectional lens. Centering the voices, and taking cues from equity-deserving leaders and scholars will help ensure that EDI pathways, such as those used to cultivate department leaders, are more inclusive, effective, and aligned with intentions., Competing Interests: The authors disclose no conflicts of interest that could impact their conduct or reporting of this study., (© 2023 Cameron, LeBlanc, Mahalik, O’Hearn, Simpson; licensee Synergies Partners.)

Transformation via Agrobacterium tumefaciens is the predominant method used to introduce exogenous DNA into plant genomes 1,2 . Transfer DNA (T-DNA) originating from Agrobacterium can be integrated as a single copy or in complex concatenated forms 3,4 , but the mechanisms affecting final T-DNA structure remain unknown. Here we demonstrate that inclusion of retrotransposon (RT)-derived sequences in T-DNA can increase T-DNA copy number by more than 50-fold in Arabidopsis thaliana. These additional T-DNA copies are organized into large concatemers, an effect primarily induced by the long terminal repeats (LTRs) of RTs that can be replicated using non-LTR DNA repeats. We found that T-DNA concatenation is dependent on the activity of the DNA repair proteins MRE11, RAD17 and ATR. Finally, we show that T-DNA concatenation can be used to increase the frequency of targeted mutagenesis and gene targeting. Overall, this work uncovers molecular determinants that modulate T-DNA copy number in Arabidopsis and demonstrates the utility of inducing T-DNA concatenation for plant gene editing., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Comparative analysis of genome-scale metabolic networks (GSMNs) may yield important information on the biology, evolution, and adaptation of species. However, it is impeded by the high heterogeneity of the quality and completeness of structural and functional genome annotations, which may bias the results of such comparisons. To address this issue, we developed AuCoMe, a pipeline to automatically reconstruct homogeneous GSMNs from a heterogeneous set of annotated genomes without discarding available manual annotations. We tested AuCoMe with three data sets, one bacterial, one fungal, and one algal, and showed that it successfully reduces technical biases while capturing the metabolic specificities of each organism. Our results also point out shared and divergent metabolic traits among evolutionarily distant algae, underlining the potential of AuCoMe to accelerate the broad exploration of metabolic evolution across the tree of life., (© 2023 Belcour et al.; Published by Cold Spring Harbor Laboratory Press.)

Background and Objective: Rare diseases place a significant burden on patients, families, the healthcare system, and society. Evidence on the socioeconomic burden of rare disease is limited and mostly reflects diseases where treatments are available. We developed a framework encompassing recommended cost elements for studies of the socioeconomic burden of rare diseases., Methods: A scoping review, conducted in five databases (Cochrane Library, EconLit, Embase, MEDLINE, and APA PsycINFO), identified English language publications from 2000 to 2021 presenting frameworks developed for determining, measuring or valuing costs for rare or chronic diseases. Cost elements were extracted and used to develop a literature-informed framework. Structured feedback was gathered from experts in rare diseases, health economics/health services, and policy research to revise the framework., Results: Of 2990 records identified, eight papers were included and informed our preliminary framework; three focused on rare disease and five on chronic disease. Following expert input, we developed a framework consisting of nine cost categories (inpatient, outpatient, community, healthcare products/goods, productivity/education, travel/accommodation, government benefits, family impacts, and other), with several cost elements within each category. Our framework includes unique costs, added from the expert feedback, including genetic testing to inform treatment, use of private laboratories or out-of-country testing, family involvement in foundations and organizations, and advocacy costs for special access programs., Conclusions: Our work is the first to identify a comprehensive list of cost elements for rare disease for use by researchers and policy makers to fully capture socioeconomic burden. Use of the framework will increase the quality and comparability of future studies. Future work should focus on measuring and valuing these costs through onset, diagnosis, and post-diagnosis., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Falls are common among the elderly, and can have serious consequences: fracture, hospitalization, loss of independence, institutionalization and death. However, falls are not inevitable, and they can be prevented. The "autonomy prevention" kit (Equilibr'Age workshops, occupational therapy advice) has helped to reduce the number of falls and improve people's quality of life. The program will now be rolled out to a wider public., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objectives: This call to action seeks to improve emergency care in Canada for equity-deserving communities, enabled by equitable representation among emergency physicians nationally. Specifically, this work describes current resident selection processes and makes recommendations to enhance the equity, diversity, and inclusion (EDI) of resident physician selection in Canadian emergency medicine (EM) residency programs., Methods: A diverse panel of EM residency program directors, attending and resident physicians, medical students, and community representatives met monthly from September 2021 to May 2022 via videoconference to coordinate a scoping literature review, two surveys, and structured interviews. This work informed the development of recommendations for incorporating EDI into Canadian EM resident physician selection. At the 2022 Canadian Association of Emergency Physicians (CAEP) Academic Symposium, these recommendations were presented to symposium attendees composed of national EM community leaders, members, and learners. Attendees were divided into small working groups to discuss the recommendations and address three conversation-facilitating questions., Results: Symposium feedback informed a final set of eight recommendations to promote EDI practices during the resident selection process that address recruitment, retention, mitigating inequities and biases, and education. Each recommendation is accompanied by specific, actionable sub-items to guide programs toward a more equitable selection process. The small working groups also described perceived barriers to the implementation of these recommendations and outlined strategies for success that are incorporated into the recommendations., Conclusion: We call on Canadian EM training programs to implement these eight recommendations to strengthen EDI practices in EM resident physician selection and, in doing so, help to improve the care that patients from equity-deserving groups receive in Canada's emergency departments (EDs)., (© 2023. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Context: Studies comparing initial therapy for multisystem inflammatory syndrome in children (MIS-C) provided conflicting results., Objective: To compare outcomes in MIS-C patients treated with intravenous immunoglobulin (IVIG), glucocorticoids, or the combination thereof., Data Sources: Medline, Embase, CENTRAL and WOS, from January 2020 to February 2022., Study Selection: Randomized or observational comparative studies including MIS-C patients <21 years., Data Extraction: Two reviewers independently selected studies and obtained individual participant data. The main outcome was cardiovascular dysfunction (CD), defined as left ventricular ejection fraction < 55% or vasopressor requirement ≥ day 2 of initial therapy, analyzed with a propensity score-matched analysis., Results: Of 2635 studies identified, 3 nonrandomized cohorts were included. The meta-analysis included 958 children. IVIG plus glucocorticoids group as compared with IVIG alone had improved CD (odds ratio [OR] 0.62 [0.42-0.91]). Glucocorticoids alone group as compared with IVIG alone did not have improved CD (OR 0.57 [0.31-1.05]). Glucocorticoids alone group as compared with IVIG plus glucocorticoids did not have improved CD (OR 0.67 [0.24-1.86]). Secondary analyses found better outcomes associated with IVIG plus glucocorticoids compared with glucocorticoids alone (fever ≥ day 2, need for secondary therapies) and better outcomes associated with glucocorticoids alone compared with IVIG alone (left ventricular ejection fraction < 55% ≥ day 2)., Limitations: Nonrandomized nature of included studies., Conclusions: In a meta-analysis of MIS-C patients, IVIG plus glucocorticoids was associated with improved CD compared with IVIG alone. Glucocorticoids alone was not associated with improved CD compared with IVIG alone or IVIG plus glucocorticoids.

Wide bandgap semiconductors such as gallium oxide (Ga 2 O 3 ) have attracted much attention for their use in next-generation high-power electronics. Although single-crystal Ga 2 O 3 substrates can be routinely grown from melt along various orientations, the influence of such orientations has been seldom reported. Further, making rectifying p-n diodes from Ga 2 O 3 has been difficult due to lack of p-type doping. In this study, we fabricated and optimized 2D/3D vertical diodes on β-Ga 2 O 3 by varying the following three factors: substrate planar orientation, choice of 2D material and metal contacts. The quality of our devices was validated using high-temperature dependent measurements, atomic-force microscopy (AFM) techniques and technology computer-aided design (TCAD) simulations. Our findings suggest that 2D/3D β-Ga 2 O 3 vertical heterojunctions are optimized by substrate planar orientation (-201), combined with 2D WS 2 exfoliated layers and Ti contacts, and show record rectification ratios (>10 6 ) concurrently with ON-Current density (>10 3 A cm -2 ) for application in power rectifiers.

Acanthamoeba species, Naegleria fowleri , and Balamuthia mandrillaris are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.0. Herein, we report the activity of the compounds against the trophozoite stage of each of the three amoebae, ranging from nanomolar to low micromolar potency. The most potent compounds that were identified from this screening effort were: 2d ( A. castellanii EC 50 : 0.92 ± 0.3 μM; and N. fowleri EC 50 : 0.43 ± 0.13 μM), 1c and 2b ( N. fowleri EC 50 s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b ( B. mandrillaris EC 50 s: 1.0 ± 0.12 μM, and 1.4 ± 0.17 μM, respectively). With several of these pharmacophores already possessing blood-brain barrier (BBB) permeability properties, or are predicted to penetrate the BBB, these hits present novel starting points for optimization as future treatments for pFLA-caused diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ferrins, Buskes, Kapteyn, Engels, Enos, Lu, Klug, Singh, Quotadamo, Bachovchin, Tear, Spaulding, Forbes, Bag, Rivers, LeBlanc, Burchfield, Armand, Diaz-Gonzalez, Ceballos-Perez, García-Hernández, Pérez-Moreno, Bosch-Navarrete, Ruiz-Pérez, Gamarro, González-Pacanowska, Navarro, Mensa-Wilmot, Pollastri, Kyle and Rice.)

Background: Motorized lengthening nails are the treatment standard for bone lengthening of the lower limbs. However, bony changes namely osteolysis and periosteal hypertrophy have been described after certain type of magnetically driven lengthening nails. The aim of this study was to estimate the proportion rate of radiological bone abnormalities of Fitbone TAA femoral or tibial lengthening nails with a minimum follow-up time of 1 year., Hypothesis: The bone surrounding the telescopic junction of Fitbone lengthening nails does not exhibit osteolysis or periosteal reactions. The bone surrounding the locking screws exhibits cortical hypertrophy., Patients and Methods: Single-centre retrospective case series of patients treated with a Fitbone nails with a minimum follow-up of 1 year after implantation. Standard orthogonal radiographs were obtained postoperatively, weekly during the distraction phase, and then monthly for 6 months, and before removal of the equipment. We looked for bone abnormalities at the telescoping junction of the nail and at the locking screws before removal., Results: In total, 101 patients (58 males, 43 females) with a mean age of 21 years (range: 11.8-53.5) had 128 (101 femoral and 27 tibial) limb lengthening nails implanted between 2010 and 2021. The mean follow-up period was 925 days (range: 371-3587). The mean lengthening was 4.7cm (range: 1.5-8.0). No bones exhibited focal osteolysis or periosteal reactions at the telescopic junction of the lengthening nail. Cortical hypertrophy at the locking screws was observed in significantly more Fitbone nails than previously reported, i.e., 101/128 (79%)., Discussion: Neither focal osteolysis, nor periosteal reactions were observed at the bone surrounding the telescopic junction of 128 Fitbone lengthening nails. Cortical hypertrophy around the single diaphyseal locking screw was observed in 101/128 (79%) of the cases. These absences of osteolytic changes after long term observation are reassuring for both surgeons and patients alike., Level of Evidence: IV., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The vast coastline provides Canada with a flourishing seafood industry including bivalve shellfish production. To sustain a healthy bivalve molluscan shellfish production, the Canadian Shellfish Sanitation Program was established to monitor the health of shellfish harvesting habitats, and fecal coliform bacteria data have been collected at nearly 15,000 marine sample sites across six coastal provinces in Canada since 1979. We applied Functional Principal Component Analysis and subsequent correlation analyses to find annual variation patterns of bacteria levels at sites in each province. The overall magnitude and the seasonality of fecal contamination were modelled by functional principal component one and two, respectively. The amplitude was related to human and warm-blooded animal activities; the seasonality was strongly correlated with river discharge driven by precipitation and snow melt in British Columbia, but such correlation in provinces along the Atlantic coast could not be properly evaluated due to lack of data during winter., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

The carbazole CBL0137 ( 1 ) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei . To advance 1 as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices ( 5j , 5t , 5v , 5w , 5y , 8d , 13i , and 22e ). Based on the overall compound profiles, compounds 5v and 5w were selected for assessment in a mouse model of HAT; while 5v demonstrated a lead-like profile for HAT drug development, 5w showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.

Purpose: The COVID-19 pandemic presented new barriers and exacerbated existing inequities for physician scholars. While COVID-19's impact on academic productivity among women has received attention, the pandemic may have posed additional challenges for scholars from a wider range of equity-deserving groups, including those who hold multiple equity-deserving identities. To examine this concern, the authors conducted a scoping review of the literature through an intersectionality lens., Method: The authors searched peer-reviewed literature published March 1, 2020, to December 16, 2021, in Ovid MEDLINE, Ovid Embase, and PubMed. The authors excluded studies not written in English and/or outside of academic medicine. From included studies, they extracted data regarding descriptions of how COVID-19 impacted academic productivity of equity-deserving physician scholars, analyses on the pandemic's reported impact on productivity of physician scholars from equity-deserving groups, and strategies provided to reduce the impact of the COVID-19 pandemic on academic productivity of physician scholars from equity-deserving groups., Results: Of 11,587 unique articles, 44 met inclusion criteria, including 15 nonempirical studies and 29 empirical studies (22 bibliometrics studies, 6 surveys, and 1 qualitative study). All included articles focused on the gendered impact of the pandemic on academic productivity. The majority of their recommendations focused on how to alleviate the burden of the pandemic on women, particularly those in the early stages of their career and/or with children, without consideration of scholars who hold multiple and intersecting identities from a wider range of equity-deserving groups., Conclusions: Findings indicate a lack of published literature on the pandemic's impact on physician scholars from equity-deserving groups, including a lack of consideration of physician scholars who experience multiple forms of discrimination. Well-intentioned measures by academic institutions to reduce the impact on scholars may inadvertently risk reproducing and sustaining inequities that equity-deserving scholars faced during the pandemic., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of American Medical Colleges.)

Iodine-129 is present in controlled liquid radioactive waste routinely released in seawater by the ORANO nuclear fuel reprocessing plant in La Hague (Normandy, France). Brown algae are known for their exceptional ability to concentrate iodine from seawater. They also potentially emit volatile iodine compounds in response to various stresses, such as during emersion at low tide. For these reasons, brown seaweed is routinely collected for radioactivity monitoring in the marine environment (Fucus serratus and Laminaria digitata). Despite the high concentration ratio, the exact mechanism of iodine uptake is still unclear. Chemical imaging by laser desorption/ionization mass spectrometry provided evidence that iodine is stored by kelps as I - . In this study we investigate in vivo iodine uptake in kelps (L. digitata) with an emphasis on seawater iodine chemical speciation. Our results showed that kelp plantlets were able to take up iodine in the forms of both IO 3 - and I - . We also observed transient net efflux of I - back to seawater but no IO 3 - efflux. Since the seaweed stores I - but takes up both IO 3 - and I - , IO 3 - was likely to be converted into I - at some point in the plantlet. One major outcome of our experiments was the direct observation of the kelp-based biogenic conversion of seawater IO 3 - into I - . On the basis of both IO 3 - and I - uptakes by the seaweed, we propose new steps in the possible iodine concentration mechanism used by brown algae., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Haloacid dehalogenases are potentially involved in bioremediation of contaminated environments and few have been biochemically characterized from marine organisms. The l-2-haloacid dehalogenase (l-2-HAD) from the marine Bacteroidetes Zobellia galactanivorans Dsij T (ZgHAD) has been shown to catalyze the dehalogenation of C2 and C3 short-chain l-2-haloalkanoic acids. To better understand its catalytic properties, its enzymatic stability, active site, and 3D structure were analyzed. ZgHAD demonstrates high stability to solvents and a conserved catalytic activity when heated up to 60°C, its melting temperature being at 65°C. The X-ray structure of the recombinant enzyme was solved by molecular replacement. The enzyme folds as a homodimer and its active site is very similar to DehRhb, the other known l-2-HAD from a marine Rhodobacteraceae. Marked differences are present in the putative substrate entrance sites of the two enzymes. The H179 amino acid potentially involved in the activation of a catalytic water molecule was confirmed as catalytic amino acid through the production of two inactive site-directed mutants. The crystal packing of 13 dimers in the asymmetric unit of an active-site mutant, ZgHAD-H179N, reveals domain movements of the monomeric subunits relative to each other. The involvement of a catalytic His/Glu dyad and substrate binding amino acids was further confirmed by computational docking. All together our results give new insights into the catalytic mechanism of the group of marine l-2-HAD., (© 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS G12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRAS G12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRAS G12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

Competing Interests: Les auteurs déclarent ne pas avoir de liens d’intérêts.

Background: The objective of this study was to test a novel household-based approach to improve late-season influenza vaccine uptake during the 2020-2021 season, using Epic's MyChart patient portal messages and/or interactive voice response telephone calls., Methods: This study was a non-blinded, quality improvement program using a block randomized design conducted among patients from Reliant Medical Group clinics residing in a traditional household (≥2 individuals clinically active in the Reliant system living at the same address). Households were randomized 1:1:1 into intervention arms: non-tailored communication (messaging based on CDC's seasonal influenza vaccination campaign), tailored communication (comprehensive communication including reinforcement of the importance of influenza vaccination for high-risk individuals), and standard-of-care control. Influenza vaccination during the program was captured via medical records, and the odds of vaccination among communication arms versus the control arm were assessed. A survey assessing influenza vaccination drivers was administered using MyChart., Results: Influenza vaccination increased by 3.3% during the program period, and no significant differences in vaccination were observed in intervention arms relative to the control arm. Study operationalization faced substantial challenges related to the concurrent COVID-19 pandemic. Compared with vaccinated survey respondents, unvaccinated respondents less frequently reported receiving a recommendation for influenza vaccination from their healthcare provider (15.8% vs. 42.3%, p &lt; 0.001) or awareness that vaccination could protect themselves and higher risk contacts (82.3% vs. 92.6%, p &lt; 0.001)., Conclusions: No significant effects of the interventions were observed. Survey results highlighted the importance of healthcare provider recommendations and the need for increased education around the benefits of vaccination., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Purpose: Podiatrists are generally defined as professionals with high-level skills in the prevention and management of local foot conditions that are not systemic diseases. Across countries, different academic trainings are implemented due to the specific context and practice of podiatric medicine. It is thus essential to support country-specific podiatry education for the development of highly skilled podiatrists. Therefore, we report the development of a podiatric medicine competency framework to support training in Canada., Participants and Methods: A Delphi process was conducted by 12 stakeholders (including 8 podiatry experts) from the University of Québec at Trois-Rivières which is the only university offering the degree of Doctor of Podiatric Medicine (DPM) in Canada. The developed framework is (1) based on the seven key roles of the Canadian medical education directives of specialists (CanMEDs) and, (2) closely aligned with the requirement of the College of Podiatrists of Québec which sets the standards of entry to practice in Québec., Results: The developed framework represents the state of the development process and the consensus of the podiatry experts. It reflects the expected profile of the institution's DPM graduates based on seven key roles (podiatry expert, communicator, collaborator, health advocate, leader and manager, scholar, and professional). This developed framework is an arborescence of complex skills defined in tangible indicators that characterize each expected part of a core competency. Twenty-four core competencies have been determined and divided into 84 enabling competencies and 288 observable indicators., Conclusion: This competency framework has been designed to support high-quality education and to develop podiatry. Next steps include: (1) validation of this framework by external experts, (2) development of rigorous evaluation methods and, (3) concrete actions for its implementation and assessment. This framework would help to define the scope of practice and capabilities of podiatric medicine, both in Canada and internationally., Competing Interests: All authors are affiliated to the Université du Québec à Trois-Rivières. The authors report no conflicts of interest in this work. VB, podiatrist was part of the panel of experts within the Delphi. This project was financially supported by Université du Québec à Trois-Rivières., (© 2022 Blanchette et al.)

Despite the broad array of roles for epigenetic mechanisms on regulating diverse processes in eukaryotes, no experimental system is currently available in plants for the direct assessment of histone function. In this work, we present the development of a genetic strategy in Arabidopsis (Arabidopsis thaliana) whereby modified histone H4 transgenes can completely replace the expression of endogenous histone H4 genes. Accordingly, we established a collection of plants expressing different H4 point mutants targeting residues that may be post-translationally modified in vivo. To demonstrate its utility, we screened this new H4 mutant collection to uncover substitutions in H4 that alter flowering time. We identified different mutations in the H4 tail (H4R17A) and the H4 globular domain (H4R36A, H4R39K, H4R39A, and H4K44A) that strongly accelerate the floral transition. Furthermore, we identified a conserved regulatory relationship between H4R17 and the ISWI chromatin remodeling complex in plants: As with other biological systems, H4R17 regulates nucleosome spacing via ISWI. Overall, this work provides a large set of H4 mutants to the plant epigenetics community that can be used to systematically assess histone H4 function in Arabidopsis and a roadmap to replicate this strategy for studying other histone proteins in plants., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The edge-to-edge connected metal-semiconductor junction (MSJ) for two-dimensional (2D) transistors has the potential to reduce the contact length while improving the performance of the devices. However, typical 2D materials are thermally and chemically unstable, which impedes the reproducible achievement of high-quality edge contacts. Here we present a scalable synthetic strategy to fabricate low-resistance edge contacts to atomic transistors using a thermally stable 2D metal, PtTe 2 . The use of PtTe 2 as an epitaxial template enables the lateral growth of monolayer MoS 2 to achieve a PtTe 2 -MoS 2 MSJ with the thinnest possible, seamless atomic interface. The synthesized lateral heterojunction enables the reduced dimensions of Schottky barriers and enhanced carrier injection compared to counterparts composed of a vertical 3D metal contact. Furthermore, facile position-selected growth of PtTe 2 -MoS 2 MSJ arrays using conventional lithography can facilitate the design of device layouts with high processability, while providing low contact resistivity and ultrashort transfer length on wafer scales., (© 2022. The Author(s).)

We present a numerical study of exciton-polariton (polariton) condensation in a staggered polariton graphene showing a gapped s band. The condensation occurs at the kinetically favorable negative mass extrema (K and K^{'} valleys) of the valence band. Considering attractive polariton-polariton interaction allows us to generate a spatially extended condensate. The symmetry breaking occurring during the condensate buildup leads to the formation of valley-polarized domains. This process can either be spontaneous, following the Kibble-Zurek scenario, or triggered, leading to a controlled spatial distribution of valley-polarized domains. The selection of a single valley breaks time-reversal symmetry, and the walls separating domains exhibit a reconfigurable topologically protected chiral current. This current emerges as a result of the interplay between the nontrivial valley topology and the condensation-induced symmetry breaking.

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors., Significance: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397., (©2022 The Authors; Published by the American Association for Cancer Research.)