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Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this superficial simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time.In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction.

BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimers disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

Abstract The integration of extrinsic signaling with cell-intrinsic transcription factors can direct progenitor cells to differentiate into distinct cell fates. In the developing Drosophila eye, differentiation of photoreceptors R1–R7 requires EGFR signaling mediated by the transcription factor Pointed, and our single-cell RNA-Seq analysis shows that the same photoreceptors require the eye-specific transcription factor Glass. We find that ectopic expression of Glass and activation of EGFR signaling synergistically induce neuronal gene expression in the wing disc in a Pointed-dependent manner. Targeted DamID reveals that Glass and Pointed share many binding sites in the genome of developing photoreceptors. Comparison with transcriptomic data shows that Pointed and Glass induce photoreceptor differentiation through intermediate transcription factors, including the redundant homologs Scratch and Scrape, as well as directly activating neuronal effector genes. Our data reveal synergistic activation of a multi-layered transcriptional network as the mechanism by which EGFR signaling induces neuronal identity in Glass-expressing cells.

Abstract The anticipated increase in urban population of 2.5 billion people by 2050 poses significant environmental challenges. While the various environmental impacts of urbanisation have been studied individually, integrated approaches are rare. This study introduces a spatially explicit model to assess urbanization’s effects on ecosystem services (green infrastructure availability, cooling, stormwater retention) and the environmental impact of building construction (material demand, greenhouse gas emissions, land use). Applied to the Netherlands from 2018 to 2050, our results show that integrating green infrastructure development with building construction could increase green areas by up to 5% and stabilize or increase ecosystem service provisioning. Dense building construction with green infrastructure development is generally more beneficial across the Netherlands, reducing resource use and enhancing ecosystem services. Conversely, sparse construction with green infrastructure is more advantageous for newly built areas. These findings offer insights into the environmental consequences of urbanization, guiding sustainable urban planning practices.

Abstract Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this 'superficial' simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time. In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction.

Abstract Background Patient-specific aiming devices (PSAD) may improve precision and accuracy of glenoid component positioning in total shoulder arthroplasty, especially in degenerative glenoids. The aim of this study was to compare precision and accuracy of guide wire positioning into different glenoid models using a PSAD versus a standard guide. Methods Three experienced shoulder surgeons inserted 2.5 mm K-wires into polyurethane cast glenoid models of type Walch A, B and C (in total 180 models). Every surgeon placed guide wires into 10 glenoids of each type with a standard guide by DePuy Synthes in group (I) and with a PSAD in group (II). Deviation from planned version, inclination and entry point was measured, as well as investigation of a possible learning curve. Results Maximal deviation in version in B- and C-glenoids in (I) was 20.3° versus 4.8° in (II) (p

Abstract Background Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimer’s disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. Methods Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. Results Apnea–hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. Conclusion Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

Abstract Metataxonomic studies of ecosystem microbiotas require the simultaneous processing of samples with contrasting physical and biochemical traits. However, there are no published studies of comparisons of different DNA extraction kits to characterize the microbiotas of the main components of terrestrial ecosystems. Here, and to our knowledge for the first time, five DNA extraction kits were used to investigate the composition and diversity of the microbiota of a subset of samples typically studied in terrestrial ecosystems such as bulk soil, rhizosphere soil, invertebrate taxa and mammalian feces. DNA extraction kit was associated with changes in the relative abundance of hundreds of ASVs, in the same samples, resulting in significant differences in alpha and beta diversity estimates of their microbiotas. Importantly, the impact of DNA extraction kit on sample diversity varies according to sample type, with mammalian feces and soil samples showing the most and least consistent diversity estimates across DNA extraction kits, respectively. We show that the MACHEREY–NAGEL NucleoSpin® Soil kit was associated with the highest alpha diversity estimates, providing the highest contribution to the overall sample diversity, as indicated by comparisons with computationally assembled reference communities, and is recommended to be used for any large-scale microbiota study of terrestrial ecosystems.

Background Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC’s Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD. Methods This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak. Results Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p Conclusions Since

BackgroundParaneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans.ObjectivesThese guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included.ResultsChronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients.ConclusionsThese are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

Background Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC’s Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD. Methods This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak. Results Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p

Background Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC’s Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD. Methods This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak. Results Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p Conclusions Since

Background There is a lack of empirical data on design effects (DEFF) for mortality rate for highly clustered data such as with Ebola virus disease (EVD), along with a lack of documentation of methodological limitations and operational utility of mortality estimated from cluster-sampled studies when the DEFF is high. Objectives The objectives of this paper are to report EVD mortality rate and DEFF estimates, and discuss the methodological limitations of cluster surveys when data are highly clustered such as during an EVD outbreak. Methods We analysed the outputs of two independent population-based surveys conducted at the end of the 2014–2016 EVD outbreak in Bo District, Sierra Leone, in urban and rural areas. In each area, 35 clusters of 14 households were selected with probability proportional to population size. We collected information on morbidity, mortality and changes in household composition during the recall period (May 2014 to April 2015). Rates were calculated for all-cause, all-age, under-5 and EVD-specific mortality, respectively, by areas and overall. Crude and adjusted mortality rates were estimated using Poisson regression, accounting for the surveys sample weights and the clustered design. Results Overall 980 households and 6,522 individuals participated in both surveys. A total of 64 deaths were reported, of which 20 were attributed to EVD. The crude and EVD-specific mortality rates were 0.35/10,000 person-days (95%CI: 0.23–0.52) and 0.12/10,000 person-days (95%CI: 0.05–0.32), respectively. The DEFF for EVD mortality was 5.53, and for non-EVD mortality, it was 1.53. DEFF for EVD-specific mortality was 6.18 in the rural area and 0.58 in the urban area. DEFF for non-EVD-specific mortality was 1.87 in the rural area and 0.44 in the urban area. Conclusion Our findings demonstrate a high degree of clustering; this contributed to imprecise mortality estimates, which have limited utility when assessing the impact of disease. We provide DEFF estimates that can inform future cluster surveys and discuss design improvements to mitigate the limitations of surveys for highly clustered data.

Huntington's Disease (HD) is an inheritable neurodegenerative condition caused by an expanded CAG trinucleotide repeat in the HTT gene with a direct correlation between CAG repeats expansion and disease severity with earlier onset-of- disease. Previously we have shown that primary skin fibroblasts from HD patients exhibit unique phenotype disease features, including distinct nuclear morphology and perturbed actin cap linked with cell motility, that are correlated with the HD patient disease severity. Here we provide further evidence that mitochondrial fission-fusion morphology balance dynamics, classified using a custom image-based high-content analysis (HCA) machine learning tool, that improved correlation with HD severity status. This mitochondrial phenotype is supported by appropriate changes in fission-fusion biomarkers (Drp1, MFN1, MFN2, VAT1) levels in the HD patients' fibroblasts. These findings collectively point towards a dysregulation in mitochondrial dynamics, where both fission and fusion processes may be disrupted in HD cells compared to healthy controls. This study shows for the first time a methodology that enables identification of HD phenotype before patient's disease onset (Premanifest). Therefore, we believe that this tool holds a potential for improving precision in HD patient's diagnostics bearing the potential to evaluate alterations in mitochondrial dynamics throughout the progression of HD, offering valuable insights into the molecular mechanisms and drug therapy evaluation underlying biological differences in any disease stage.

Human untargeted metabolomics studies annotate only ~10% of molecular features. We introduce reference-data-driven analysis to match metabolomics tandem mass spectrometry (MS/MS) data against metadata-annotated source data as a pseudo-MS/MS reference library. Applying this approach to food source data, we show that it increases MS/MS spectral usage 5.1-fold over conventional structural MS/MS library matches and allows empirical assessment of dietary patterns from untargeted data.

Many departments in colleges and universities require a capstone course that involves the students conducting a research project. This author has had over 20 years of experience teaching such a capstone course and describes a flexible research method for student research projects -- the vignette study (an experiment embedded in a survey). She also has teams of undergraduate students working in her lab for research credit make progress on a vignette design as one of several research activities. The vignette study can be used for students across many majors, including but not limited to sociology, psychology, criminal justice, nursing, social work, and marketing. Detail is provided on how to teach a capstone course using this flexible research method.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008–2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer’s disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p

Study objectivesFast frequency sleep spindles are reduced in aging and Alzheimer's disease (AD), but the mechanisms and functional relevance of these deficits remain unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD.MethodsFifty-eight cognitively unimpaired, β-amyloid-negative, older adults (mean ± SD; 61.4 ± 6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high-density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13 to

Glycogen storage disease type III (GSDIII) is a hereditary glycogenosis caused by deficiency of the glycogen debranching enzyme (GDE), an enzyme, encoded by Agl, enabling glycogen degradation by catalyzing alpha-1,4-oligosaccharide side chain transfer and alpha-1,6-glucose cleavage. GDE deficiency causes accumulation of phosphorylase-limited dextrin, leading to liver disorder followed by fatal myopathy. Here, we tested the capacity of the new autophagosomal activator GHF-201 to alleviate disease burden by clearing pathogenic glycogen surcharge in the GSDIII mouse model Agl−/−. We used open field, grip strength, and rotarod tests for evaluating GHF-201’s effects on locomotion, a biochemistry panel to quantify hematological biomarkers, indirect calorimetry to quantify in vivo metabolism, transmission electron microscopy to quantify glycogen in muscle, and fibroblast image analysis to determine cellular features affected by GHF-201. GHF-201 was able to improve all locomotion parameters and partially reversed hypoglycemia, hyperlipidemia and liver and muscle malfunction in Agl−/− mice. Treated mice burnt carbohydrates more efficiently and showed significant improvement of aberrant ultrastructural muscle features. In GSDIII patient fibroblasts, GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling. In conclusion, GHF-201 is a viable candidate for treating GSDIII as it recovered a wide range of its pathologies in vivo, in vitro, and ex vivo.

Many concepts in astrophysics research can be difficult for a lay individual to understand or to comprehend their importance. One such example concept is the IceCube Neutrino Observatory, which detects high-energy neutrinos at the South Pole in Antarctica. The observatory uses information from detected neutrinos originating deep in outer space to better understand astrophysical phenomena like black holes or exploding stars. Unfortunately, it is often difficult for the public to understand how these pieces fit together towards creating a more complete understanding of our universe. To promote public understanding of IceCube, an interactive exhibit was created which used large multi-touch screen and Virtual Reality (VR) equipment. The exhibit, placed in a public environment, was evaluated both formally and informally around its effectiveness of providing STEM learning opportunities. The results show that the system not only provided an effective means of conveying content, but also provided a means of sparking the curiosity of users to learn more about the presented subject matter. Further results show that outcomes demonstrated significant differences between subject responses depending upon which of the two deployed devices they used. Findings also provide evidence that retrospective survey designs have the same rigor in data collection as traditional pre-and posttest designs when investigating exhibits. Based on these findings, guidelines are offered for others who aim to deploy similar systems in publicly accessible spaces.