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Abstract Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs.

The resolution of the incompressible Navier-Stokes equations is tricky, and it is well known that one of the major issue is to approach the space: H1(Ω)∩ H(div 0; Ω) := {v ∈ H1(Ω) : div v = 0}. H 1 (Ω)∩ H ( div 0 ;Ω):= { v ∈ H 1 (Ω): div v = 0 }. $$ \mathbf{H}^1(\Omega) \cap \mathbf{H}(\operatorname{div} 0 ; \Omega):=\left\{\mathbf{v} \in \mathbf{H}^1(\Omega): \operatorname{div} \mathbf{v}=0\right\}. $$ The non-conforming Crouzeix-Raviart finite element are convenient since they induce local mass conservation. Moreover they are such that the stability constant of the Fortin operator is equal to 1. This implies that they can easily handle anisotropic mesh. However spurious velocities may appear and damage the approximation. We propose a scheme here that allows one to reduce the spurious velocities. It is based on a new discretisation for the gradient of pressure based on the symmetric MPFA scheme (finite volume MultiPoint Flux Approximation).

Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment. This review will explore glioma, the gut microbiota, and how their interaction shapes glioma development and therapy responses. Additionally, this review examines the influence of gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan, on glioma development and treatment. It also explores gut microbiome signaling via pattern recognition receptors, and the role of molecular mimicry between microbial and tumor antigens in glioblastoma, and if these interactions affect glioma development and treatment.

As part of the current UK GCSE science curriculum, pupils need to use their understanding of science to answer questions about a series of core experiments. Problem-solving and applying knowledge to new situations is fundamental in enabling students to progress in science; however, many learners struggle to develop these skills. This can lead to inhibited student progress and decreased engagement in science. In response to this, the effect of guided inquiry on student progress and engagement was investigated. Two mixed gender classes of UK high school science students were asked to design and perform an experiment based on one of the core GCSE chemistry experiments--determining the concentration of an acid. By using guided inquiry, all learners showed good progress and a high degree of engagement when researching and designing their method. When using their approach to perform their experiment and process their results, all pupils were able to perform the method they proposed accurately and precisely. Students used their processes of analyzing their results to determine the correct concentration of the acid to two decimal places. This guided inquiry titration lab showed evidence of supporting student learning and provided an opportunity for pupils to use their ideas to solve problems. Student feedback showed that most pupils taking part in this activity (87%) felt this helped their engagement in the course. This activity describes the implementation of guided inquiry to enable students with minimal background knowledge on a topic to take control of their learning, design and execute an experiment and use their results to determine the concentration of an acid, teaching themselves along the way in an effective, engaging manner. This shows that guided inquiry can be used as an effective tool to support progress in a GCSE core practical, and aid engagement in science.

In U.S. deaf education, disablement results from a normative interpretation of disability in the Individuals With Disabilities Education Act. However, Vygotsky's "Fundamentals of Defectology" (1993) allows educators to view current deaf education pedagogical practices through a sociocultural-constructivist lens and reject the current remedial special education model. We explore our experience as teachers of the deaf to analyze the current state of deaf education, synthesizing two core areas of Vygotskian research--sociocultural theory and deaf pedagogy--and applying them within a framework outlining characteristics of accessible educational environments that facilitate deaf children's sociocultural and intellectual development. We also examine how special education laws create barriers to implementing Vygotsky's recommendations, then offer practical, actionable solutions based on our sociocultural-constructivist deaf education synthesis. We close with suggestions for systemic change in deaf education that can provide deaf students with equitable, accessible educational environments.

This research focused on two objectives: (i) investigating the impacts of sediment substitution in the raw meal on the hydration and mechanical-microstructural properties of cement; (ii) assessing the reliability of CEMHYD3D code for modeling the properties of hydrated cement. The experimental results indicated that a maximum rate of sediment up to 7.55% had no impact on the formation of mineralogical phases of clinker, the hydration and mechanical-microstructural development of cement. The degree of hydration and strengths of cement made of sediment substitution were slightly higher than those of reference cement, whereas the critical diameter of pores of both hydrated cements was nearly identical. Comparing the modeling results with the experimental measurements showed good predictions for the degree of hydration, hydration heat as well as strength development. However, the formation of hemi-and mono-carboaluminate phases was not predicted in the model, and the porosity prediction was also limited to the capillary porosity.

SK3 channels are potassium channels found to promote tumor aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing micro RNA (miR)-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and matrix metalloproteinase 9–dependent cell adhesion and invasion. We identified several ether lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether lipids on SK3 activity. The expressions of alkylglycerone phosphate synthase, SK3, and miR were associated in clinical samples emphasizing the clinical consistency of our observations. To our knowledge, this is the first report showing that ether lipids differentially control tumor aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether lipids.

Summary: Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. Methods: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. Findings: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). Interpretation: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. Funding: Funding acknowledgements for each cohort can be found in the Supplementary Note.

The onset of deafblindness profoundly impacts both the individual with this condition and the individual’s family, including siblings. While current studies have primarily focused on the impact felt by parents or spouses, the distinct experiences of siblings have received comparatively less attention. This systematic review addresses the existing research gap regarding the psychological and social consequences experienced by siblings of individuals with deafblindness. A comprehensive search was conducted across multiple electronic databases, including PsycINFO, PsycARTICLES, Dissertations & Theses (on ProQuest), ERIC (Education Resources Information Center), International Bibliography of the Social Sciences (IBSS), Sociological Abstracts, Google Scholar, PubMed, and Cairn Info. Seven studies were identified as meeting the eligibility criteria for inclusion. The review revealed that siblings of individuals with deafblindness face psychological and social challenges, including emotions such as feelings of neglect, resentment, embarrassment, jealousy, and anxiety. Siblings also grapple with communication difficulties, contributing to feelings of exclusion and insecurity. In addition, these siblings take on significant responsibilities within the family and encounter obstacles in forming relationships outside the family. These findings underscore the need of interventions to improve the well-being of siblings of individuals with deafblindness by addressing their psycho-emotional needs and promoting positive social interactions. These findings align with studies conducted on siblings of children with other disabilities. However, additional research is crucial to investigate overlooked dimensions, particularly positive factors like coping mechanisms and resilience, that may influence the mental health and social experiences of these siblings.

Abstract Culture-adapted human mesenchymal stromal cells (hMSCs) are appealing candidates for regenerative medicine applications. However, these cells implanted in lesions as single cells or tissue constructs encounter an ischemic microenvironment responsible for their massive death post-transplantation, a major roadblock to successful clinical therapies. We hereby propose a paradigm shift for enhancing hMSC survival by designing, developing, and testing an enzyme-controlled, nutritive hydrogel with an inbuilt glucose delivery system for the first time. This hydrogel, composed of fibrin, starch (a polymer of glucose), and amyloglucosidase (AMG, an enzyme that hydrolyze glucose from starch), provides physiological glucose levels to fuel hMSCs via glycolysis. hMSCs loaded in these hydrogels and exposed to near anoxia (0.1% pO2) in vitro exhibited improved cell viability and angioinductive functions for up to 14 days. Most importantly, these nutritive hydrogels promoted hMSC viability and paracrine functions when implanted ectopically. Our findings suggest that local glucose delivery via the proposed nutritive hydrogel can be an efficient approach to improve hMSC-based therapeutic efficacy.

Informal caregivers’ own quality of life, health status, and determinants are poorly understood despite their concern for the health of the individuals they assist. To compare the quality of life and the health determinants of older informal caregivers with those of older adults without caregiving responsibilities. An online survey was designed to investigate the quality of life and the health determinants of people aged 65 years and over, with a focus on informal caregivers. In addition to socio-demographic data, the number of informal caregivers was ascertained and the Zarit scale of caregiver burden was applied. Quality of life (SF-12) and health determinants (access to technology and level of physical activity (IPAQ)) were assessed and compared between informal caregivers and non-caregivers. A total of 111 participants were included in the study (70 ± 3.83 years, 71.2% women). The majority of respondents (91.8%) were Belgian. One-third of the respondents identified themselves as informal caregivers and declared themselves as having a severe burden (61.9 ± 15.2/88). Socio-demographic characteristics and access to technology were similar between informal caregivers and non-caregivers (p > 0.05). However, informal caregivers had a lower SF-12 score in the mental score domain (44.3 ± 10.2 vs. 50.7 ± 7.0; p = 0.004) and a lower level of physical activity (434 ± 312 METS/min/week vs. 1126 ± 815 METS/min/week; p = 0.01) than their peers. Informal caregivers reported a lower quality of life and a lower level of physical activity than their peers. Given the recognized importance of physical activity for overall health, this survey highlights the need to promote physical activity among older informal caregivers.

Abstract Glycemic variability remains frequent in patients with type 1 diabetes treated with insulin pumps. Heterogeneous spreads of insulin infused by pump in the subcutaneous (SC) tissue are suspected but were barely studied. We propose a new real-time ex-vivo method built by combining high-precision imaging with simultaneous pressure measurements, to obtain a real-time follow-up of insulin subcutaneous propagation. Human skin explants from post-bariatric surgery are imaged in a micro-computed tomography scanner, with optimised parameters to reach one 3D image every 5 min during 3 h of 1UI/h infusion. Pressure inside the tubing is recorded. A new index of dispersion (IoD) is introduced and computed upon the segmented 3D insulin depot per time-step. Infusions were hypodermal in 58.3% among 24 assays, others being intradermal or extradermal. Several minor bubbles and one occlusion were observed. IoD increases with time for all injections. Inter-assay variability is the smallest for hypodermal infusions. Pressure elevations were observed, synchronised with air bubbles arrivals in the tissue. Results encourage the use of this method to compare infusion parameters such as pump model, basal rate, catheter characteristics, infusion site characteristics or patient phenotype.

Plant architecture is central in determining crop yield. In the short-day species strawberry, a crop vegetatively propagated by daughter-plants produced by stolons, fruit yield is further dependent on the trade-off between sexual reproduction (fruits) and asexual reproduction (daughter-plants). Both are largely dependent on meristem identity, which establishes the development of branches, stolons and inflorescences. Floral initiation and plant architecture are modulated by the balance between two related proteins, FLOWERING LOCUS T (FT) and TERMINAL FLOWER 1 (TFL1). We explored in woodland strawberry the role of the uncharacterised FveFT2 and FveFT3 genes and of the floral repressor FveTFL1 through gene expression analyses, grafting and genetic transformation (overexpression and gene editing). We demonstrate the unusual properties of these genes. FveFT2 is a nonphotoperiodic florigen permitting short-day (SD) flowering and FveTFL1 is the long-hypothesised long-day systemic antiflorigen that contributes, together with FveFT2, to the photoperiodic regulation of flowering. We additionally show that FveFT3 is not a florigen but promotes plant branching when overexpressed, that is likely to be through changing axillary meristem fate, therefore resulting in a 3.5-fold increase in fruit yield at the expense of stolons. We show that our findings can be translated into improvement of cultivated strawberry in which FveFT2 overexpression significantly accelerates flowering.

African swine fever virus represents a significant reemerging threat to livestock populations, as its incidence and geographic distribution have surged over the past decade in Europe, Asia, and Caribbean, resulting in substantial socio-economic burdens and adverse effects on animal health and welfare. In a previous report, we described the protective properties of our newly thermo-attenuated strain (ASFV-989) in pigs against an experimental infection of its parental Georgia 2007/1 virulent strain. In this new study, our objective was to characterize the molecular mechanisms underlying the attenuation of ASFV-989. We first compared the activation of type I interferon pathway in response to ASFV-989 and Georgia 2007/1 infections, employing both in vivo and in vitro models. Expression of IFN-α was significantly increased in porcine alveolar macrophages infected with ASFV-989 while pigs infected with Georgia 2007/1 showed higher IFN-α than those infected by ASFV-989. We also used a medium-throughput transcriptomic approach to study the expression of viral genes by both strains, and identified several patterns of gene expression. Subsequently, we investigated whether proteins encoded by the eight genes deleted in ASFV-989 contribute to the modulation of the type I interferon signaling pathway. Using different strategies, we showed that MGF505-4R interfered with the induction of IFN-α/β pathway, likely through interaction with TRAF3. Altogether, our data reveal key differences between ASFV-989 and Georgia 2007/1 in their ability to control IFN-α/β signaling and provide molecular mechanisms underlying the role of MGF505-4R as a virulence factor.

The blood–brain barrier (BBB) maintains brain homeostasis, regulates influx and efflux transport, and provides protection to the brain tissue. Ultrasound (US) and microbubble (MB)-mediated blood–brain barrier opening is an effective and safe technique for drug delivery in-vitro and in-vivo. However, the exact mechanism underlying this technique is still not fully elucidated. The aim of the study is to explore the contribution of transcytosis in the BBB transient opening using an in-vitro model of BBB. Utilizing a diverse set of techniques, including Ca2+ imaging, electron microscopy, and electrophysiological recordings, our results showed that the combined use of US and MBs triggers membrane deformation within the endothelial cell membrane, a phenomenon primarily observed in the US + MBs group. This deformation facilitates the vesicles transportation of 500 kDa fluorescent Dextran via dynamin-/caveolae-/clathrin- mediated transcytosis pathway. Simultaneously, we observed increase of cytosolic Ca2+ concentration, which is related with increased permeability of the 500 kDa fluorescent Dextran in-vitro. This was found to be associated with the Ca2+-protein kinase C (PKC) signaling pathway. The insights provided by the acoustically-mediated interaction between the microbubbles and the cells delineate potential mechanisms for macromolecular substance permeability.

BackgroundEndotracheal tube fixation in ventilated patients must be appropriate to ensure security during mechanical ventilation and prevent skin lesions. The incidence of endotracheal tube-caused pressure ulcers ranges from 7% to 45%. Various endotracheal tube fixations are used in intensive care units (ICUs) worldwide. By pressure exercised on the skin, these systems could lead to mucosal and skin peri-oral lesions. The main objective of this study is to evaluate the impact of the two fixation systems most commonly used in French ICUs (adhesive elastic band versus fixation cord with PolyVinyl Chloride (PVC) sheath) on the incidence of these peri-oral skin lesions.MethodsThis studyis a multicenter, open-label, controlled, superiority, cluster cross-over randomized trial. 768 patients will be recruited in the 16 ICUs involved. The inclusion of patients will be carried out over two 12-month periods. Each site begins with one of the evaluated fixation systems: elastic adhesive tape or cord associated with a protective sheath. After a 4-month break, each site switches to the other fixation system. The primary outcome is the development of at least one peri-oral lesion during the first ten days of maintaining an orally inserted endotracheal tube. The presence of lesions is assessed by a blinded adjudication committee using photographs taken daily.DiscussionThis study is the first multicenter, randomized trial designed to evaluate the impact of elastic adhesive tape versus fixation cord with PVC sheath on the incidence of peri-oral lesions. The results will provide data which could change and standardize care practices.Trial registrationhttps://www.clinicaltrials.gov. Reference number: NCT04819425.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients’ empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance.

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21.

Abstract Data plots are widely used in science, journalism and politics, since they efficiently allow to depict a large amount of information. Graphicacy, the ability to understand graphs, has thus become a fundamental cultural skill comparable to literacy or numeracy. Here, we introduce a measure of intuitive graphicacy that assesses the perceptual ability to detect a trend in noisy scatterplots (“does this graph go up or down?”). In 3943 educated participants, responses vary as a sigmoid function of the t-value that a statistician would compute to detect a significant trend. We find a minimum level of core intuitive graphicacy even in unschooled participants living in remote Namibian villages (N = 87) and 6-year-old 1st-graders who never read a graph (N = 27). The sigmoid slope that we propose as a proxy of intuitive graphicacy increases with education and tightly correlates with statistical and mathematical knowledge, showing that experience contributes to refining graphical intuitions. Our tool, publicly available online, allows to quickly evaluate and formally quantify a perceptual building block of graphicacy.

Abstract The high mortality rate in nursing homes during the COVID-19 pandemic may be linked to psychological disorders in staff. Hence, we assessed the prevalence and associated factors of probable post-traumatic stress disorder (PTSD), anxiety, depression, and burnout of nursing home staff during the COVID-19 pandemic in a cross-sectional study including 66 randomly selected nursing homes in southern France. 537 of the contacted 3 821 nursing home workers (14.0%) responded between April and October 2021. We collected information on center organization, severity of COVID-19 exposure, and socio-demographic information in an online survey. The prevalence of probable PTSD (PCL-5), anxiety and depressive disorders (Hospital Anxiety Depression Scale) and the sub-scores of burnout syndrome (Maslach Burnout Inventory Human Services Survey for Medical Personnel) were assessed. Probable PTSD was reported in 115/537 responders (21.4% (95% CI [18.0%–24.9%])). After adjustment, low-level exposure to COVID-19 in nursing home residents (AOR, 0.5; 95% CI [0.3–0.9]), fear of managing COVID-19 residents (AOR, 3.5; 95% CI [1.9–6.4]), conflicts with residents (AOR, 2.3; 95% CI, [1.2–4.4]), conflicts with colleagues (AOR, 3.6; 95% CI [1.7–8.6]), cancellation of leave (AOR, 4.8; 95% CI [2.0–11.7]) and temporary worker employment (AOR, 3.4; 95% CI [1.7–6.9]) were associated with higher prevalence of probable PTSD. The prevalence of probable anxiety and depression were 28.8% (95% CI [24.9%–32.7%]) and 10.4% (95% CI [7.8%–13.1%]), respectively. Psychological disorders were observed in nearly one third of nursing home workers during the COVID-19 pandemic. Hence, continuous surveys and preventive measures are needed in this particularly at-risk population.

Abstract Early markers are needed for more effective prevention of Alzheimer’s disease. We previously showed that individuals with Alzheimer’s disease have decreased plasma DYRK1A levels compared to controls. We assessed DYRK1A in the plasma of cognitively healthy elderly volunteers, individuals with either Alzheimer’s disease (AD), tauopathies or Down syndrome (DS), and in lymphoblastoids from individuals with DS. DYRK1A levels were inversely correlated with brain amyloid β burden in asymptomatic elderly individuals and AD patients. Low DYRK1A levels were also detected in patients with tauopathies. Individuals with DS had higher DYRK1A levels than controls, although levels were lower in individuals with DS and with dementia. These data suggest that plasma DYRK1A levels could be used for early detection of at risk individuals of AD and for early detection of AD. We hypothesize that lack of increase of DYRK1A at middle age (40–50 years) could be a warning before the cognitive decline, reflecting increased risk for AD.

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways.

The purpose of this study was to evaluate potential osteoarthritic alterations within the ankle using a surgically-induced chronic lateral ankle instability (CLAI) model. Twelve rats were assigned randomly to either the control (n = 4) or CLAI group (n = 8). Surgery was performed on the right ankle. Osteoarthritis was assessed through in-vivo micro-CT at 8 weeks and a clinical analysis. Macroscopic analysis, high-resolution ex-vivo micro-CT and histological examination were conducted after euthanasia at 12 weeks. Three subgroups (SG) were analyzed. SG1 comprised the operated ankles of the CLAI group (n = 8). SG2 consisted of the non-operated ankles of the CLAI group (n = 8). SG3 included both sides of the control group (n = 8). In-vivo micro-CT revealed no significant differences among the three subgroups when analyzed together (p = 0.42), and when comparing SG1 with SG2 (p = 0.23) and SG3 (p = 0.43) individually. No noticeable clinical differences were observed. After euthanasia, macroscopic analysis employing OARSI score, did not demonstrate significant differences, except between the medial tibia of SG1 and SG3 (p = 0.03), and in the total score comparison between these two subgroups (p = 0.015). Ex-vivo micro-CT did not reveal any differences between the three subgroups regarding bony irregularities and BV/TV measurements (SG1 vs. SG2 vs. SG3: p = 0.72; SG1 vs. SG2: p = 0.80; SG1 vs. SG3: p = 0.72). Finally, there was no difference between the three subgroups regarding OARSI histologic score (p = 0.27). These findings indicate that the current model failed to induce significant osteoarthritis. However, they lay the groundwork for improving the model’s effectiveness and expanding its use in CLAI research, aiming to enhance understanding of this pathology and reduce unnecessary animal sacrifice.

Along with the standard therapies for glioblastoma, patients are commonly prescribed trimethoprim-sulfamethoxazole (TMP-SMX) and dexamethasone for preventing infections and reducing cerebral edema, respectively. Because the gut microbiota impacts the efficacy of cancer therapies, it is important to understand how these medications impact the gut microbiota of patients. Using mice that have been colonized with human microbiota, this study sought to examine how TMP-SMX and dexamethasone affect the gut microbiome. Two lines of humanized microbiota (HuM) Rag1−/− mice, HuM1Rag and HuM2Rag, were treated with either TMP-SMX or dexamethasone via oral gavage once a day for a week. Fecal samples were collected pre-treatment (pre-txt), one week after treatment initiation (1 wk post txt), and three weeks post-treatment (3 wk post txt), and bacterial DNA was analyzed using 16S rRNA-sequencing. The HuM1Rag mice treated with TMP-SMX had significant shifts in alpha diversity, beta diversity, and functional pathways at all time points, whereas in the HuM2Rag mice, it resulted in minimal changes in the microbiome. Likewise, dexamethasone treatment resulted in significant changes in the microbiome of the HuM1Rag mice, whereas the microbiome of the HuM2Rag mice was mostly unaffected. The results of our study show that routine medications used during glioblastoma treatment can perturb gut microbiota, with some microbiome compositions being more sensitive than others, and these treatments could potentially affect the overall efficacy of standard-of-care therapy.

BackgroundSudomotor dysfunction is one of the earliest manifestations of small fiber neuropathy (SFN), reflecting the alteration of sympathetic C fiber innervation of the sweat glands. Among other techniques, such innervation can be assessed by measuring electrochemical skin conductance (ESC) in microsiemens (μS). In this study, ESC was measured at the feet to detect distal SFN. For this objective, the performance of a new device, the Body Scan® (Withings, France), intended for home use, was compared with that of a reference device, the Sudoscan® (Impeto Medical, France), which requires a hospital setting.MethodsIn patients with diabetes with or without neuropathy or non-diabetic patients with lower-limb neuropathy, the diagnostic performance of the Body Scan® measurement was assessed by calculating its sensitivity (Se) and specificity (Sp) to detect at least moderate SFN (Se70 and Sp70), defined by a value of feet ESC ≤ 70 μS and > 50 μS on the Sudoscan® measure, or severe SFN (Se50 and Sp50), defined by a value of feet ESC ≤ 50 μS on the Sudoscan® measure. The agreement between the two devices was assessed with the analysis of Bland–Altman plots, mean absolute error (MAE), and root mean squared error (RMSE) calculations. The repeatability of the measurements was also compared between the two devices.ResultsA total of 147 patients (52% men, mean age 59 years old, 76% diabetic) were included in the analysis. The sensitivity and specificity to detect at least moderate or severe SFN were: Se70 = 0.91 ([0.83, 0.96]), Sp70 = 0.97 ([0.88, 0.99]), Se50 = 0.91 ([0.80, 0.98]), and Sp50 = 0.99 ([0.94, 1]), respectively. The bias and 95% limits of agreement were 1.5 [−5.4, 8.4]. The MAE was 2.9 and the RMSE 3.8. The intra-sample variability was 2.0 for the Body Scan® and 2.3 for the Sudoscan®.ConclusionThe ESC measurements provided by the Body Scan® were in almost perfect agreement with those provided by the reference device, the Sudoscan®, which validates the accuracy of the Body Scan® for the detection of SFN. By enabling simple, rapid, and autonomous use by the patient at home, this new technique will facilitate screening and monitoring of SFN in daily practice.Clinical trial registrationClinicalTrials.gov, identifier NCT05178459.

Abstract To reduce bird collisions on wind turbines, Automatic Detection Systems have been developed to locate approaching birds and trigger turbines to slowdown to 2–3 rotations per minute (rpm). However, it is unknown whether birds can detect this reduced speed and avoid the turbine. We conducted an operant conditioning experiment on domestic doves (Streptopelia roseogrisea) and Harris's hawks (Parabuteo unicinctus) to assess their ability to discriminate between stationary and rotating miniature wind turbines, depending on the rotation speed and the contrast between the white blades and the background (only for doves for the latter). At high contrast, regardless of the speed tested, hawks were able to differentiate between the rotating and stationary turbines, while doves were not able to discriminate the slow‐rotating turbine (3 rpm) from the stationary one. The discrimination threshold increased to 8 rpm for the doves when the contrast was reduced. Our results suggest that the residual wind turbine speed of 2–3 rpm may not be detected by all bird species under all environmental conditions. Increasing the contrast between wind turbines and their environment may improve the detection of low‐speed rotation by some birds, otherwise, complete turbine shutdown should be recommended.

BackgroundPlasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development.MethodsThree hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study).ResultsWe show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score.ConclusionWe find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.

In the next few years, numerous satellites with high-resolution instruments dedicated to the imaging of atmospheric gaseous compounds will be launched, to finely monitor emissions of greenhouse gases and pollutants. Processing the resulting images of plumes from cities and industrial plants to infer the emissions of these sources can be challenging. In particular traditional atmospheric inversion techniques, relying on objective comparisons to simulations with atmospheric chemistry transport models, may poorly fit the observed plume due to modelling errors rather than due to uncertainties in the emissions. The present article discusses how these images can be adequately compared to simulated concentrations to limit the weight of modelling errors due to the meteorology used to analyse the images. For such comparisons, the usual pixel-wise ℒ2 norm may not be suitable, since it does not linearly penalise a displacement between two identical plumes. By definition, such a metric considers a displacement as an accumulation of significant local amplitude discrepancies. This is the so-called double penalty issue. To avoid this issue, we propose three solutions: (i) compensate for position error, due to a displacement, before the local comparison; (ii) use non-local metrics of density distribution comparison; and (iii) use a combination of the first two solutions. All the metrics are evaluated using first a catalogue of analytical plumes and then more realistic plumes simulated with a mesoscale Eulerian atmospheric transport model, with an emphasis on the sensitivity of the metrics to position error and the concentration values within the plumes. As expected, the metrics with the upstream correction are found to be less sensitive to position error in both analytical and realistic conditions. Furthermore, in realistic cases, we evaluate the weight of changes in the norm and the direction of the four-dimensional wind fields in our metric values. This comparison highlights the link between differences in the synoptic-scale winds direction and position error. Hence the contribution of the latter to our new metrics is reduced, thus limiting misinterpretation. Furthermore, the new metrics also avoid the double penalty issue.

Abstract Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer’s disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj = 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.