Congenital Chest Lesions and Interventions.

Anomalies of the fetal chest require advanced imaging with ultrasound and MR imaging as well as expertise on the part of the interpreting pediatric radiologist. Congenital diaphragmatic hernia and congenital lung malformation are the most frequently seen, and in both conditions, the radiologist should provide both detailed anatomic description and measurement data for prognostication. This article provides a detailed approach to imaging the anatomy, in-depth explanation of available measurements and prognostic value, and keys to identifying candidates for fetal intervention. Less common congenital lung tumors and mediastinal and chest wall masses are also reviewed.

Label-Free Imaging of Inflammation at the Level of Single Cells in the Living Human Eye.

Purpose: Putative microglia were recently detected using adaptive optics ophthalmoscopy in healthy eyes. Here we evaluate the use of nonconfocal adaptive optics scanning light ophthalmoscopy (AOSLO) for quantifying the morphology and motility of presumed microglia and other immune cells in eyes with retinal inflammation from uveitis and healthy eyes. Design: Observational exploratory study. Participants: Twelve participants were imaged, including 8 healthy participants and 4 posterior uveitis patients recruited from the clinic of 1 of the authors (M.H.E.). Methods: The Pittsburgh AOSLO imaging system was used with a custom-designed 7-fiber optical fiber bundle for simultaneous confocal and nonconfocal multioffset detection. The inner retina was imaged at several locations at multiple timepoints in healthy participants and uveitis patients to generate time-lapse images. Main Outcome Measures: Microglia and macrophages were manually segmented from nonconfocal AOSLO images, and their morphological characteristics quantified (including soma size, diameter, and circularity). Cell soma motion was quantified across time for periods of up to 30 minutes and their speeds were calculated by measuring their displacement over time. Results: A spectrum of cell morphologies was detected in healthy eyes from circular amoeboid cells to elongated cells with visible processes, resembling activated and ramified microglia, respectively. Average soma diameter was 16.1 ± 0.9 µm. Cell movement was slow in healthy eyes (0.02 µm/sec on average), but macrophage-like cells moved rapidly in some uveitis patients (up to 3 µm/sec). In an eye with infectious uveitis, many macrophage-like cells were detected; during treatment their quantity and motility decreased as vision improved. Conclusions: In vivo adaptive optics ophthalmoscopy offers promise as a potentially powerful tool for detecting and monitoring inflammation and response to treatment at a cellular level in the living eye. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Applying Implementation Science to Identify Primary Care Providers' Enablers and Barriers to Using Survivorship Care Plans.

Primary care providers (PCPs) have been given the responsibility of managing the follow-up care of low-risk cancer survivors after they are discharged from the oncology center. Survivorship Care Plans (SCPs) were developed to facilitate this transition, but research indicates inconsistencies in how they are implemented. A detailed examination of enablers and barriers that influence their use by PCPs is needed to understand how to improve SCPs and ultimately facilitate cancer survivors' transition to primary care. An interview guide was developed based on the second version of the Theoretical Domains Framework (TDF-2). PCPs participated in semi-structured interviews. Qualitative content analysis was used to develop a codebook to code text into each of the 14 TDF-2 domains. Thematic analysis was also used to generate themes and subthemes. Thirteen PCPs completed the interview and identified the following barriers to SCP use: unfamiliarity with the side effects of cancer treatment (Knowledge), lack of clarity on the roles of different healthcare professionals (Social Professional Role and Identity), follow-up tasks being outside of scope of practice (Social Professional Role and Identity), increased workload, lack of options for psychosocial support for survivors, managing different electronic medical records systems, logistical issues with liaising with oncology (Environmental Context and Resources), and patient factors (Social Influences). PCPs value the information provided in SCPs and found the follow-up guidance provided to be most helpful. However, SCP use could be improved through streamlining methods of communication and collaboration between oncology centres and community-based primary care settings.

A cost-effectiveness analysis of reduced viral transmission with baloxavir marboxil versus oseltamivir or no treatment for seasonal and pandemic influenza management in the United Kingdom.

BACKGROUND: Baloxavir marboxil is an oral, single-dose, cap-dependent endonuclease inhibitor that reduces the duration of influenza symptoms and rapidly stops viral shedding. We developed a susceptible, exposed, infected, recovered (SEIR) model to inform a cost-effectiveness model (CEM) of baloxavir versus oseltamivir or no antiviral treatment in the UK. RESEARCH DESIGN AND METHODS: The SEIR model estimated the attack rates among otherwise healthy and high-risk individuals in seasonal and pandemic settings. The CEM assumed that a proportion of infected patients would receive antiviral treatment. Results were reported at the population level (per 10,000 at risk of infection). RESULTS: The SEIR model estimated greater reductions in infections with baloxavir. In a seasonal setting, baloxavir provided incremental cost-effectiveness ratios (ICERs) of £1884 per quality-adjusted life-year (QALY) gained versus oseltamivir and a dominant cost-effectiveness position versus no antiviral treatment in the total population; ICERs of £2574/QALY versus oseltamivir and £128/QALY versus no antiviral treatment were seen in the high-risk population. Baloxavir was also cost-effective versus oseltamivir or no antiviral treatment and reduced population-level health system occupancy concerns during a pandemic. CONCLUSION: Baloxavir treatment resulted in the fewest influenza cases and was cost-effective versus oseltamivir or no antiviral treatment from a UK National Health Service perspective.

Baloxavir marboxil ('baloxavir') is a prescription medicine for people who become ill with influenza (or 'the flu') that can reduce how long flu symptoms last and the likelihood of complications from the flu that may require going to the hospital. Baloxavir can also reduce the amount and duration of virus shed by infected individuals thus potentially slow or stop the flu from spreading to healthy people. We studied differences in reducing predicted flu infections between baloxavir and another flu treatment, known as oseltamivir, or no flu treatment at all. Treatment with baloxavir resulted in fewer flu infections in the UK population than oseltamivir or no treatment. We then studied how these differences might affect costs between baloxavir and oseltamivir or no treatment at a population level in the UK. Overall, in the majority of scenarios explored in the model, baloxavir was cost-effective as an antiviral treatment for people with the flu in the UK.

Usability of mechanical assistive technologies for performing activities involving the upper extremities in individuals with impairments: a systematic review.

PURPOSE: To conduct a systematic review on the impacts of using mechanical assistive devices on function, performance in activities and participation of persons with upper extremity impairments, and to synthesize the strengths and limitations of these devices. METHOD: Three independent reviewers conducted systematic searches of articles published between 2003 and 2023 in Compendex, Inspec, Embase, PubMed/Medline, IEEE Xplore, and Web of Science, as well as manual searches on the RESNA website for conference papers over the same period. The methodological quality of articles was appraised using the QualSyst tool. RESULTS: From the 34 retained studies, 28 mechanical devices were identified and classified into two categories: (1) mobile arm supports (MASs) designed to perform multiple activities, and (2) devices used to assist with a specific activity of daily living (ADL). Overall, MASs helped users to perform manual activities in elevation and/or against gravity. Specific ADL devices allowed users to perform unique activities requiring fine motor skills such as opening a medicine container. Some of these devices have advantages like portability, adaptability, low cost, and ease of use. Limitations most often reported included interference or mobility restraints. CONCLUSION: This review synthesizes the impacts of mechanical devices on the three domains of the International Classification of Functioning, Disability and Health (ICF) for individuals with upper extremity impairments. Impacts regarding function and performance in activities were more often measured than participation. Future studies should include outcomes related to participation, as taking this aspect into account might favor successful continued use of assistive devices.

Mechanical mobile arm supports can compensate for upper extremity muscle weakness and help users to perform diverse activities against gravity, including self-care, productivity and leisure activities.Mechanical assistive devices designed for specific activities of daily living (ADLs) can increase users' ability to perform activities requiring manual dexterity and fine motor skills, such as eating, handwriting, performing personal care or playing a musical instrument.Portability, adaptability, low cost, and ease of use are most often reported as strengths of specific ADL devices, while interference and mobility restrictions are aspects that still need to be reduced with respect to mechanical mobile arm supports.

Genomic and phenomic predictions help capture low-effect alleles promoting seed germination in oilseed rape in addition to QTL analyses.

KEY MESSAGE: Phenomic prediction implemented on a large diversity set can efficiently predict seed germination, capture low-effect favorable alleles that are not revealed by GWAS and identify promising genetic resources. Oilseed rape faces many challenges, especially at the beginning of its developmental cycle. Achieving rapid and uniform seed germination could help to ensure a successful establishment and therefore enabling the crop to compete with weeds and tolerate stresses during the earliest developmental stages. The polygenic nature of seed germination was highlighted in several studies, and more knowledge is needed about low- to moderate-effect underlying loci in order to enhance seed germination effectively by improving the genetic background and incorporating favorable alleles. A total of 17 QTL were detected for seed germination-related traits, for which the favorable alleles often corresponded to the most frequent alleles in the panel. Genomic and phenomic predictions methods provided moderate-to-high predictive abilities, demonstrating the ability to capture small additive and non-additive effects for seed germination. This study also showed that phenomic prediction estimated phenotypic values closer to phenotypic values than GEBV. Finally, as the predictive ability of phenomic prediction was less influenced by the genetic structure of the panel, it is worth using this prediction method to characterize genetic resources, particularly with a view to design prebreeding populations.

Regulation of PPARγ2 Stability and Activity by SHP-1.

The protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) plays an important role in modulating glucose and lipid homeostasis. We previously suggested a potential role of SHP-1 in the regulation of peroxisome proliferator-activated receptor γ2 (PPARγ2) expression and activity but the mechanisms were unexplored. PPARγ2 is the master regulator of adipogenesis, but how its activity is regulated by tyrosine phosphorylation is largely unknown. Here, we found that SHP-1 binds to PPARγ2 primarily via its N-terminal SH2-domain. We confirmed the phosphorylation of PPARγ2 on tyrosine-residue 78 (Y78), which was reduced by SHP-1 in vitro resulting in decreased PPARγ2 stability. Loss of SHP-1 led to elevated, agonist-induced expression of the classical PPARγ2 targets FABP4 and CD36, concomitant with increased lipid content in cells expressing PPARγ2, an effect blunted by abrogation of PPARγ2 phosphorylation. Collectively, we discovered that SHP-1 affects the stability of PPARγ2 through dephosphorylation thereby influencing adipogenesis.

Delicate Analysis of Interacting Proteins and Their Assemblies by Flow Field-Flow Fractionation Techniques.

We study the efficiency of several asymmetrical flow field-flow fractionation (AF4) techniques to investigate self-associating wheat gluten proteins. We compare the use of a denaturing buffer including sodium dodecyl sulfate (SDS) and a mild chaotropic solvent, water/ethanol, as the eluent, on a model gluten sample. Through a thorough analysis of the data obtained from coupled light scattering detectors and with the identification of molecular composition of the eluted protein, we evidence coelution events in several conditions. We show that the focus step used in conventional AF4 with the SDS buffer leads to the formation of aggregates that coelute with monomeric proteins. By contrast, a frit-inlet device enables the fractionation of individual wheat proteins in the SDS buffer. Interestingly conventional AF4, using water/ethanol as eluent, is an effective method for fractionating gluten proteins and their complex dynamic assemblies, which involve weak forces and are composed of both monomeric and polymeric proteins.

Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective.

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Predictors of health-related quality of life in a large cohort of adult patients living with sickle cell disease in France: the DREPAtient study.

Background: Sickle cell disease (SCD) is an inherited autosomal recessive disorder exhibiting a range of symptoms and acute and/or chronic complications that affect the quality of life. This study aimed to assess health-related quality of life (HRQoL) and to identify the associated factors in adult patients with SCD in France. Methods: DREPAtient is a cross-sectional, multicenter study conducted from June 2020 to April 2021 in France and in certain French overseas territories where SCD is highly prevalent. Sociodemographic and clinical data were collected online. HRQoL was assessed by the French version of the 36-Item Short Form Survey (SF-36) questionnaire. HRQoL determinants were identified using multivariable linear regression analysis. Results: In total, 570 participants were included, mostly women (68.9%), with a mean age of 33.3 (±10.7) years. The highest mean score HRQoL was found in the Physical functioning domain (67.5 ± 21.8) and the lowest mean score in the General Health perception domain (37.7 ± 20.3). The mean score of the physical composite (PCS) and mental composite (MCS) of SF-36 summary scores was 40.6 ± 8.9 and 45.3 ± 9.8, respectively. Participants receiving oxygen therapy (ß = -3.20 [95%CI: -5.56; -0.85]), those with a history of femoral osteonecrosis (-3.09 [-4.64; -1.53]), those hospitalized for vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) (-2.58 [-3.93; -1.22]), those with chronic complications (-2.33 [-4.04; -0.62]), female participants (-2.17 [-3.65; -0.69]), those with psychological follow-up (-2.13 [-3.59; -0.67]), older participants (-1.69 [-3.28; -0.09]), and those receiving painkillers (-1.61 [-3.16; -0.06]) reported worse PCS score. By contrast, those who had completed secondary or high school (4.36 [2.41; 6.31]) and those with stable financial situation (2.85 [0.94, 4.76]) reported better PCS scores. Worse MCS scores were reported among participants with psychological follow-up (-2.54 [-4.28; -0.80]) and those hospitalized for VOC/ACS in the last 12 months (-2.38 [-3.99; -0.77]), while those who had relatives' support (5.27 [1.92; 8.62]) and those with stable financial situation (4.95 [2.65; 7.26]) reported better MCS scores. Conclusion: Adults with major SCD reported poor physical and mental HRQoL scores. Hospitalization for VOC/ACS, chronic complications, use of painkillers, perceived financial situation, and support from relatives are important predictors of HRQoL in SCD patients. Interventions to improve HRQoL outcomes SCD should be considered.

The response of Canada's clinical health research ecosystem to the COVID-19 pandemic.

BACKGROUND: The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)-funded studies on COVID-19. METHODS: We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. RESULTS: We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants - 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10-61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6-348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. INTERPRETATION: A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems.

Posttranslational regulation of photosynthetic activity via the TOR kinase in plants.

Chloroplasts are the powerhouse of the plant cell, and their activity must be matched to plant growth to avoid photooxidative damage. We have identified a posttranslational mechanism linking the eukaryotic target of rapamycin (TOR) kinase that promotes growth and the guanosine tetraphosphate (ppGpp) signaling pathway of prokaryotic origins that regulates chloroplast activity and photosynthesis in particular. We find that RelA SpoT homolog 3 (RSH3), a nuclear-encoded enzyme responsible for ppGpp biosynthesis, interacts directly with the TOR complex via a plant-specific amino-terminal region which is phosphorylated in a TOR-dependent manner. Down-regulating TOR activity causes a rapid increase in ppGpp synthesis in RSH3 overexpressors and reduces photosynthetic capacity in an RSH-dependent manner in wild-type plants. The TOR-RSH3 signaling axis therefore regulates the equilibrium between chloroplast activity and plant growth, setting a precedent for the regulation of organellar function by TOR.

An anthropocene-framed transdisciplinary dialog at the chemistry-energy nexus.

At the energy-chemistry nexus, key molecules include carbon dioxide (CO2), hydrogen (H2), methane (CH4), and ammonia (NH3). The position of these four molecules and that of the more general family of synthetic macromolecular polymer blends (found in plastics) were cross-analyzed with the planetary boundary framework, and as part of five scientific policy roadmaps for the energy transition. According to the scenarios considered, the use of some of these molecular substances will be drastically modified in the coming years. Ammonia, which is currently almost exclusively synthesized as feedstock for the fertilizer industry, is envisioned as a future carbon-free energy vector. "Green hydrogen" is central to many projected decarbonized chemical processes. Carbon dioxide is forecast to shift from an unavoidable byproduct to a valuable feedstock for the production of carbon-based compounds. In this context, we believe that interdisciplinary elements from history, economics and anthropology are relevant to any attempted cross-analysis. Distinctive and crucial insights drawn from elements of humanities and social sciences have led us to formulate or re-raise open questions and possible blind-spots in main roadmaps, which were developed to guide, inter alia, chemical research toward the energy transition. We consider that these open questions are not sufficiently addressed in the academic arena around chemical research. Nevertheless, they are relevant to our understanding of the current planetary crisis, and to our capacity to properly assess the potential and limitations of chemical research addressing it. This academic perspective was written to share this understanding with the broader academic community. This work is intended not only as a call for a larger interdisciplinary method, to develop a sounder scientific approach to broader scenarios, but also - and perhaps mostly - as a call for the development of radically transdisciplinary routes of research. As scientists with different backgrounds, specialized in different disciplines and actively involved in contributing to shape solutions by means of our research, we bear ethical responsibility for the consequences of our acts, which often lead to consequences well beyond our discipline. Do our research and the knowledge it produces respond, perpetuate or even aggravate the problems encountered by society?

The effects of artificial intelligence on human resource activities and the roles of the human resource triad: opportunities and challenges.

Introduction: This study analyzes the existing academic literature to identify the effects of artificial intelligence (AI) on human resource (HR) activities, highlighting both opportunities and associated challenges, and on the roles of employees, line managers, and HR professionals, collectively referred to as the HR triad. Methods: We employed the scoping review method to capture and synthesize relevant academic literature in the AI-human resource management (HRM) field, examining 27 years of research (43 peer-reviewed articles are included). Results: Based on the results, we propose an integrative framework that outlines the five primary effects of AI on HR activities: task automation, optimized HR data use, augmentation of human capabilities, work context redesign, and transformation of the social and relational aspects of work. We also detail the opportunities and challenges associated with each of these effects and the changes in the roles of the HR triad. Discussion: This research contributes to the ongoing debate on AI-augmented HRM by discussing the theoretical contributions and managerial implications of our findings, along with avenues for future research. By considering the most recent studies on the topic, this scoping review sheds light on the effects of AI on the roles of the HR triad, enabling these key stakeholders to better prepare for this technological change. The findings can inform future academic research, organizations using or considering the application of AI in HRM, and policymakers. This is particularly timely, given the growing adoption of AI in HRM activities.

Exploring the maternal inheritance transmitted by the oocyte to its progeny.

Fertility is declining worldwide and many couples are turning towards assisted reproductive technologies (ART) to conceive babies. Organisms that propagate via sexual reproduction often come from the fusion between two gametes, an oocyte and a sperm, whose qualities seem to be decreasing in the human species. Interestingly, while the sperm mostly transmits its haploid genome, the oocyte transmits not only its haploid set of chromosomes but also its huge cytoplasm to its progeny. This is what can be defined as the maternal inheritance composed of chromosomes, organelles, lipids, metabolites, proteins and RNAs. To decipher the decline in oocyte quality, it is essential to explore the nature of the maternal inheritance, and therefore study the last stages of murine oogenesis, namely the end of oocyte growth followed by the two meiotic divisions. These divisions are extremely asymmetric in terms of the size of the daughter cells, allowing to preserve the maternal inheritance accumulated during oocyte growth within these huge cells to support early embryo development. Studies performed in Marie-Hélène Verlhac's lab have allowed to discover the unprecedented impact of original acto-myosin based mechanisms in the constitution as well as the preservation of this maternal inheritance and the consequences when these processes go awry.

La fécondité diminue mondialement et de nombreux couples se tournent vers les techniques de procréation médicalement assistée (PMA) pour concevoir des bébés. Les organismes se propageant par reproduction sexuée sont souvent issus de la fusion de deux gamètes, un ovocyte et un spermatozoïde, dont les qualités semblent diminuer dans l'espèce humaine. Si le spermatozoïde transmet principalement son génome haploïde, l'ovocyte transmet à sa progéniture non seulement son lot haploïde de chromosomes, mais aussi son immense cytoplasme. C'est ce que l'on peut définir comme l'héritage maternel, composé de chromosomes, d'organelles, de lipides, de métabolites, de protéines et d'ARNs. Pour comprendre la baisse de qualité des ovocytes, il est essentiel d'explorer la nature de cet héritage maternel, et donc d'étudier les dernières étapes de l'ovogenèse murine, à savoir la fin de la croissance ovocytaire suivie des deux divisions méiotiques. Ces divisions sont extrêmement asymétriques par la taille des cellules filles engendrées, ce qui permet de préserver l'héritage maternel accumulé pendant la croissance de cette énorme cellule, l'ovocyte, pour soutenir le développement précoce de l'embryon. Les études menées dans le laboratoire de Marie-Hélène Verlhac ont permis de découvrir l'impact sans précédent de mécanismes originaux dépendant de l'acto-myosine dans la constitution et la préservation de cet héritage maternel, ainsi que les conséquences des erreurs dans ces processus.

Calcineurin Inhibitor in NEuRoloGically deceased donors to decrease kidney delayed graft function study: study protocol of the CINERGY Pilot randomised controlled trial.

INTRODUCTION: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk. METHODS AND ANALYSIS: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation. ETHICS AND DISSEMINATION: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309). TRIAL REGISTRATION NUMBER: NCT05148715.

APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors.

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion-flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. Here, we identify AETA (Aη), an amyloid-ß precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity by competing with the co-agonist and induces an intracellular conformational modification of GluN1 subunits. This favors non-ionotropic NMDAR signaling leading to enhanced LTD and favors spine shrinkage. Endogenously, AETA production is increased by in vivo chemogenetically induced neuronal activity. Genetic deletion of AETA production alters NMDAR transmission and prevents LTD, phenotypes rescued by acute exogenous AETA application. This genetic deletion also impairs contextual fear memory. Our findings demonstrate AETA-dependent NMDAR activation (ADNA), characterizing AETA as a unique type of endogenous NMDAR modulator that exerts bidirectional control over NMDAR signaling and associated information processing.

Scaling Properties of Gelling Systems in Nonlinear Shear Experiments.

We study model near-critical polymer gelling systems made of gluten protein dispersions stabilized at different distances from the gel point. We impose different shear rates and follow the time evolution of the stress. For sufficiently large shear rates, an intermediate stress overshoot is measured before reaching the steady state. We evidence self-similarity of the stress overshoot as a function of the applied shear rate for samples with various distances from the gel point, which is related to the elastic energy stored by the samples, as for dense systems close to the jamming transition. In concordance with the findings for glassy and jammed systems, we also measure that the stress after flow cessation decreases as a power law with time, with a characteristic relaxation time that depends on the shear rate previously imposed. These features revealed in nonlinear rheology could be the signature of a mesoscopic dynamics, which would depend on the extent of gelation.