Assessing the feasibility of digital keypress statistics to detect seizures and capture cognitive impairment in patients with epilepsy: A pilot study.

BACKGROUND: Efficient, non-invasive monitoring may provide a more accurate and comprehensive understanding of seizure frequency and the development of some comorbidities in people with epilepsy. Novel keyboard technology measuring digital keypress statistics has demonstrated its practical value for neurodegenerative diseases including Parkinson's Disease and Dementia. Smartphones integrated into daily life may serve as a low-burden longitudinal monitoring system for patients with epilepsy. OBJECTIVE: This study aimed to assess the feasibility of keyboard statistics as an objective measure of seizure frequency for patients with epilepsy, in addition to tracking differences between cognitively normal and cognitively impaired patients. METHODS: Six adult patients admitted to the Epilepsy Monitoring Unit (EMU) at Mayo Clinic in Rochester, Minnesota were studied. The keyboard was installed on the patient's smartphone. In the EMU, typing statistics were correlated to electroencephalogram (EEG) confirmed seizures. After discharge, participants continued using their keyboards and kept a seizure log. We also analyzed the key press/release times and usage of participants' keyboards for adherence. RESULTS: Keyboard sessions during and after seizures assessed for key press/release differences versus baseline showed no statistically significant difference (p = 0.44). Using one-way ANOVA, cognitive impairment's potential impact on keyboard statistics was explored in patients who had neuropsychological testing (N = 3). Significant differences were found between patients with and without cognitive impairment (p < 0.001). No significant difference was noted between patients with mild intellectual disability and normal cognitive function (p = 0.55).

When population growth intensifies intergroup competition, female colobus monkeys free-ride less.

Intergroup aggression often results in the production of public goods, such as a safe and stable social environment and a home range containing the resources required to survive and reproduce. We investigate temporal variation in intergroup aggression in a growing population of colobus monkeys (Colobus vellerosus) to ask a novel question: "Who stepped-up to produce these public goods when doing so became more difficult?". Both whole-group encounters and male incursions occurred more frequently as the population grew. Males and females were both more likely to participate in whole-group encounters when monopolizable food resources were available, indicating both sexes engaged in food defence. However, only females increasingly did so as the population grew, suggesting that it was females who increasingly produced the public good of home range defence as intergroup competition intensified. Females were also more active in male incursions at high population densities, suggesting they increasingly produced the public good of a safe and stable social environment. This is not to say that males were chronic free-riders when it came to maintaining public goods. Males consistently participated in the majority of intergroup interactions throughout the study period, indicating they may have lacked the capacity to invest more time and effort.

A complementary metaproteomic approach to interrogate microbiome cultivated from clinical colon biopsies.

The human gut microbiome plays a vital role in preserving individual health and is intricately involved in essential functions. Imbalances or dysbiosis within the microbiome can significantly impact human health and are associated with many diseases. Several metaproteomics platforms are currently available to study microbial proteins within complex microbial communities. In this study, we attempted to develop an integrated pipeline to provide deeper insights into both the taxonomic and functional aspects of the cultivated human gut microbiomes derived from clinical colon biopsies. We combined a rapid peptide search by MSFragger against the Unified Human Gastrointestinal Protein database and the taxonomic and functional analyses with Unipept Desktop and MetaLab-MAG. Across seven samples, we identified and matched nearly 36,000 unique peptides to approximately 300 species and 11 phyla. Unipept Desktop provided gene ontology, InterPro entries, and enzyme commission number annotations, facilitating the identification of relevant metabolic pathways. MetaLab-MAG contributed functional annotations through Clusters of Orthologous Genes and Non-supervised Orthologous Groups categories. These results unveiled functional similarities and differences among the samples. This integrated pipeline holds the potential to provide deeper insights into the taxonomy and functions of the human gut microbiome for interrogating the intricate connections between microbiome balance and diseases.

Ultrasonic vocalization emission is altered following neonatal hypoxic-ischemic brain injury in mice.

Neonatal hypoxic-ischemic (HI) brain injury leads to cognitive impairments including social communication disabilities. Current treatments do not sufficiently target these impairments, therefore new tools are needed to examine social communication in models for neonatal brain injury. Ultrasonic vocalizations (USVs) during early life show potential as a measurement for social development and reflect landmark developmental stages in neonatal mice. However, changes in USV emission early after HI injury have not been found yet. Our current study examines USV patterns and classes in the first 3 days after HI injury. C57Bl/6 mice were subjected to HI on postnatal day (P)9 and USVs were recorded between P10 and P12. Audio files were analyzed using the VocalMat automated tool. HI-injured mice emitted less USVs, for shorter durations, and at a higher frequency compared to control (sham-operated) littermates. The HI-induced alterations in USVs were most distinct at P10 and in the frequency range of 50-75kHz. At P10 HI-injured mouse pups also produced different ratios of USV class types compared to control littermates. Moreover, alterations in the duration and frequency were specific to certain USV classes in HI animals compared to controls. Injury in the striatum and hippocampus contributed most to alterations in USV communication after HI. Overall, neonatal HI injury leads to USV alterations in newborn mice which could be used as a tool to study early HI-related social communication deficits.

Two high-quality Prototheca zopfii genomes provide new insights into their evolution as obligate algal heterotrophs and their pathogenicity.

The majority of the nearly 10,000 described species of green algae are photoautotrophs; however, some species have lost their ability to photosynthesize and become obligate heterotrophs that rely on parasitism for survival. Two high-quality genomes of the heterotrophic algae Prototheca zopfii Pz20 and Pz23 were obtained using short- and long-read genomic as well as transcriptomic data. The genome sizes were 31.2 Mb and 31.3 Mb, respectively, and contig N50 values of 1.99 Mb and 1.26 Mb. Although P. zopfii maintained its plastid genome, the transition to heterotrophy led to a reduction in both plastid and nuclear genome size, including the loss of photosynthesis-related genes from both the nuclear and plastid genomes and the elimination of genes encoding for carotenoid oxygenase and pheophorbide an oxygenase. The loss of genes, including basic leucine-zipper (bZIP) transcription factors, flavin adenine dinucleotide-linked oxidase, and helicase, could have played a role in the transmission of autotrophy to heterotrophs and in the processes of abiotic stress resistance and pathogenicity. A total of 66 (1.37%) and 73 (1.49%) genes were identified as potential horizontal gene transfer events in the two P. zopfii genomes, respectively. Genes for malate synthase and isocitrate lyase, which are horizontally transferred from bacteria, may play a pivotal role in carbon and nitrogen metabolism as well as the pathogenicity of Prototheca and non-photosynthetic organisms. The two high-quality P. zopfii genomes provide new insights into their evolution as obligate heterotrophs and pathogenicity. IMPORTANCE: The genus Prototheca, characterized by its heterotrophic nature and pathogenicity, serves as an exemplary model for investigating pathobiology. The limited understanding of the protothecosis infectious disease is attributed to the lack of genomic resources. Using HiFi long-read sequencing, both nuclear and plastid genomes were generated for two strains of P. zopfii. The findings revealed a concurrent reduction in both plastid and nuclear genome size, accompanied by the loss of genes associated with photosynthesis, carotenoid oxygenase, basic leucine-zipper (bZIP) transcription factors, and others. The analysis of horizontal gene transfer revealed the presence of 1.37% and 1.49% bacterial genes, including malate synthase and isocitrate lyase, which play crucial roles in carbon and nitrogen metabolism, as well as pathogenicity and obligate heterotrophy. The two high-quality P. zopfii genomes represent valuable resources for investigating their adaptation and evolution as obligate heterotrophs, as well as for developing future prevention and treatment strategies against protothecosis.

The application of PTR-MS and non-targeted analysis to characterize VOCs emitted from a plastic recycling facility fire.

BACKGROUND: On April 11th, 2023, the My Way Trading (MWT) recycling facility in Richmond, Indiana caught fire, mandating the evacuation of local residents and necessitating the U.S. Environmental Protection Agency (EPA) to conduct air monitoring. The EPA detected elevated levels of plastic combustion-related air pollutants, including hydrogen cyanide and benzene. OBJECTIVE: We aimed to identify these and other volatile organic compounds (VOCs) present as well as to identify the potential hazard of each compound for various human health effects. METHODS: To identify the VOCs, we conducted air monitoring at sites within and bordering the evacuation zone using proton transfer reaction mass spectrometry (PTR-MS) and non-targeted analysis (NTA). To facilitate risk assessment of the emitted VOCs, we used the EPA Hazard Comparison Dashboard. RESULTS: We identified 46 VOCs, within and outside the evacuation zone, with average detection levels above local background levels measured in Middletown, OH. Levels of hydrogen cyanide and 4 other VOCs were at least 1.8-fold higher near the incidence site in comparison to background levels and displayed unique temporal and spatial patterns. The 46 VOCs identified had the highest hazardous potential for eye and skin irritation, with approximately 45% and 39%, respectively, of the VOCs classified as high and very high hazards for these endpoints. Notably, all detected VOC levels were below the hazard thresholds set for single VOC exposures; however, hazard thresholds for exposure to VOC mixtures are currently unclear. IMPACT: This study serves as a proof-of-concept that PTR-MS coupled with NTA can facilitate rapid identification and hazard assessment of VOCs emitted following anthropogenic disasters. Furthermore, it demonstrates that this approach may augment future disaster responses to quantify additional VOCs present in complex combustion mixtures.

Evaluating a New Digital App-Based Program for Heart Health: Feasibility and Acceptability Pilot Study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the United States, affecting a significant proportion of adults. Digital health lifestyle change programs have emerged as a promising method of CVD prevention, offering benefits such as on-demand support, lower cost, and increased scalability. Prior research has shown the effectiveness of digital health interventions in reducing negative CVD outcomes. This pilot study focuses on the Lark Heart Health program, a fully digital artificial intelligence (AI)-powered smartphone app, providing synchronous CVD risk counseling, educational content, and personalized coaching. OBJECTIVE: This pilot study evaluated the feasibility and acceptability of a fully digital AI-powered lifestyle change program called Lark Heart Health. Primary analyses assessed (1) participant satisfaction, (2) engagement with the program, and (3) the submission of health screeners. Secondary analyses were conducted to evaluate weight loss outcomes, given that a major focus of the Heart Health program is weight management. METHODS: This study enrolled 509 participants in the 90-day real-world single-arm pilot study of the Heart Health app. Participants engaged with the app by participating in coaching conversations, logging meals, tracking weight, and completing educational lessons. The study outcomes included participant satisfaction, app engagement, the completion of screeners, and weight loss. RESULTS: On average, Heart Health study participants were aged 60.9 (SD 10.3; range 40-75) years, with average BMI indicating class I obesity. Of the 509 participants, 489 (96.1%) stayed enrolled until the end of the study (dropout rate: 3.9%). Study retention, based on providing a weight measurement during month 3, was 80% (407/509; 95% CI 76.2%-83.4%). Participant satisfaction scores indicated high satisfaction with the overall app experience, with an average score of ≥4 out of 5 for all satisfaction indicators. Participants also showed high engagement with the app, with 83.4% (408/489; 95% CI 80.1%-86.7%) of the sample engaging in ≥5 coaching conversations in month 3. The results indicated that participants were successfully able to submit health screeners within the app, with 90% (440/489; 95% CI 87%-92.5%) submitting all 3 screeners measured in the study. Finally, secondary analyses showed that participants lost weight during the program, with analyses showing an average weight nadir of 3.8% (SD 2.9%; 95% CI 3.5%-4.1%). CONCLUSIONS: The study results indicate that participants in this study were satisfied with their experience using the Heart Health app, highly engaged with the app features, and willing and able to complete health screening surveys in the app. These acceptability and feasibility results provide a key first step in the process of evidence generation for a new AI-powered digital program for heart health. Future work can expand these results to test outcomes with a commercial version of the Heart Health app in a diverse real-world sample.

Manganese exposure from spring and well waters in the Shenandoah Valley: interplay of aquifer lithology, soil composition, and redox conditions.

Manganese (Mn) is of particular concern in groundwater, as low-level chronic exposure to aqueous Mn concentrations in drinking water can result in a variety of health and neurodevelopmental effects. Much of the global population relies on drinking water sourced from karst aquifers. Thus, we seek to assess the relative risk of Mn contamination in karst by investigating the Shenandoah Valley, VA region, as it is underlain by both karst and non-karst aquifers and much of the population relies on water wells and spring water. Water and soil samples were collected throughout the Shenandoah Valley, to supplement pre-existing well water and spring data from the National Water Information System and the Virginia Household Water Quality Program, totaling 1815 wells and 119 springs. Soils were analyzed using X-ray fluorescence and Mn K-Edge X-ray absorption near-edge structure spectroscopy. Factors such as soil type, soil geochemistry, and aquifer lithology were linked with each location to determine if correlations exist with aqueous Mn concentrations. Analyzing the distribution of Mn in drinking water sources suggests that water wells and springs within karst aquifers are preferable with respect to chronic Mn exposure, with < 4.9% of wells and springs in dolostone and limestone aquifers exceeding 100 ppb Mn, while sandstone and shale aquifers have a heightened risk, with > 20% of wells exceeding 100 ppb Mn. The geochemistry of associated soils and spatial relationships to various hydrologic and geologic features indicates that water interactions with aquifer lithology and soils contribute to aqueous Mn concentrations. Relationships between aqueous Mn in spring waters and Mn in soils indicate that increasing aqueous Mn is correlated with decreasing soil Mn(IV). These results point to redox conditions exerting a dominant control on Mn in this region.

Soft Synthetic Cells with Mobile Membrane Ligands for Ex Vivo Expansion of Therapy-Relevant T Cell Phenotypes.

The expansion of T cells ex vivo is crucial for effective immunotherapy but currently limited by a lack of expansion approaches that closely mimic in vivo T cell activation. Taking inspiration from bottom-up synthetic biology, a new synthetic cell technology is introduced based on dispersed liquid-liquid phase-separated droplet-supported lipid bilayers (dsLBs) with tunable biochemical and biophysical characteristics, as artificial antigen presenting cells (aAPCs) for ex vivo T cell expansion. These findings obtained with the dsLB technology reveal three key insights: first, introducing laterally mobile stimulatory ligands on soft aAPCs promotes expansion of IL-4/IL-10 secreting regulatory CD8+ T cells, with a PD-1 negative phenotype, less prone to immune suppression. Second, it is demonstrated that lateral ligand mobility can mask differential T cell activation observed on substrates of varying stiffness. Third, dsLBs are applied to reveal a mechanosensitive component in bispecific Her2/CD3 T cell engager-mediated T cell activation. Based on these three insights, lateral ligand mobility, alongside receptor- and mechanosignaling, is proposed to be considered as a third crucial dimension for the design of ex vivo T cell expansion technologies.

The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression.

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

Do Physicians Have a Duty to Support Secondary Use of Clinical Data in Biomedical Research? An Inquiry into the Professional Ethics of Physicians.

Secondary use of clinical data in research or learning activities (SeConts) has the potential to improve patient care and biomedical knowledge. Given this potential, the ethical question arises whether physicians have a professional duty to support SeConts. To investigate this question, we analyze prominent international declarations on physicians' professional ethics to determine whether they include duties that can be considered as good reasons for a physicians' professional duty to support SeConts. Next, we examine these documents to identify professional duties that might conflict with a potential duty of physicians to support SeConts.

CXCL10 is a crucial chemoattractant for efficient intranasal delivery of mesenchymal stem cells to the neonatal hypoxic-ischemic brain.

BACKGROUND: Hypoxic-Ischemic Encephalopathy (HIE) is a leading cause of mortality and morbidity in newborns. Recent research has shown promise in using intranasal mesenchymal stem cell (MSC) therapy if administered within 10 days after Hypoxia-Ischemia (HI) in neonatal mice. MSCs migrate from the nasal cavity to the cerebral lesion in response to chemotactic cues. Which exact chemokines are crucial for MSC guidance to the HI lesion is currently not fully understood. This study investigates the role of CXCL10 in MSC migration towards the HI-injured brain. METHODS: HI was induced in male and female 9-day-old C57BL/6 mice followed by intranasal MSC treatment at day 10 or 17 post-HI. CXCL10 protein levels, PKH26-labeled MSCs and lesion size were assessed by ELISA, immunofluorescent imaging and MAP2 staining respectively. At day 17 post-HI, when CXCL10 levels were reduced, intracranial CXCL10 injection and intranasal PKH26-labeled MSC administration were combined to assess CXCL10-guided MSC migration. MSC treatment efficacy was evaluated after 18 days, measuring lesion size, motor outcome (cylinder rearing task), glial scarring (GFAP staining) and neuronal density (NeuN staining) around the lesion. Expression of the receptor for CXCL10, i.e. CXCR3, on MSCs was confirmed by qPCR and Western Blot. Moreover, CXCL10-guided MSC migration was assessed through an in vitro transwell migration assay. RESULTS: Intranasal MSC treatment at day 17 post-HI did not reduce lesion size in contrast to earlier treatment timepoints. Cerebral CXCL10 levels were significantly decreased at 17 days versus 10 days post-HI and correlated with reduced MSC migration towards the brain. In vitro experiments demonstrated that CXCR3 receptor inhibition prevented CXCL10-guided migration of MSCs. Intracranial CXCL10 injection at day 17 post-HI significantly increased the number of MSCs reaching the lesion which was accompanied by repair of the HI lesion as measured by reduced lesion size and glial scarring, and an increased number of neurons around the lesion. CONCLUSIONS: This study underscores the crucial role of the chemoattractant CXCL10 in guiding MSCs to the HI lesion after intranasal administration. Strategies to enhance CXCR3-mediated migration of MSCs may improve the efficacy of MSC therapy or extend its regenerative therapeutic window.

Signature of Altered Retinal Microstructures and Electrophysiology in Schizophrenia Spectrum Disorders Is Associated With Disease Severity and Polygenic Risk.

BACKGROUND: Optical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk. METHODS: Optical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter. RESULTS: The sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude. CONCLUSIONS: This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden.

Prioritization and Resource Allocation in the Context of the COVID-19 Pandemic: Recommendations for Colorectal and Pancreatic Cancer in Germany.

In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by (1) the urgency relevant to avoid or reduce harm, (2) the likelihood of success of the diagnostic or therapeutic measure advised, and (3) the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin, and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for (1) diagnostic procedures, (2) surgical procedures for cancer, and (3) systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.

Design and characterization of BSA-mycophenolic acid nanocomplexes: Antiviral activity exploration.

The interactions between bovine serum albumin (BSA) and mycophenolic acid (MPA) were investigated in silico through molecular docking and in vitro, using fluorescence spectroscopy. Dynamic light scattering and scanning electron microscopy were used to figure out the structure of MPA-Complex (MPA-C). The binding affinity between MPA and BSA was determined, yielding a Kd value of (12.0 ± 0.7) µM, and establishing a distance of 17 Å between the BSA and MPA molecules. The presence of MPA prompted protein aggregation, leading to the formation of MPA-C. The cytotoxicity of MPA-C and its ability to fight Junín virus (JUNV) were tested in A549 and Vero cell lines. It was found that treating infected cells with MPA-C decreased the JUNV yield and was more effective than free MPA in both cell line models for prolonged time treatments. Our results represent the first report of the antiviral activity of this type of BSA-MPA complex against JUNV, as assessed in cell culture model systems. MPA-C shows promise as a candidate for drug formulation against human pathogenic arenaviruses.

Chromosome-level reference genome and resequencing of 322 accessions reveal evolution, genomic imprint and key agronomic traits in adzuki bean.

Adzuki bean (Vigna angularis) is an important legume crop cultivated in over 30 countries worldwide. We developed a high-quality chromosome-level reference genome of adzuki bean cultivar Jingnong6 by combining PacBio Sequel long-read sequencing with short-read and Hi-C technologies. The assembled genome covers 97.8% of the adzuki bean genome with a contig N50 of approximately 16 Mb and a total of 32 738 protein-coding genes. We also generated a comprehensive genome variation map of adzuki bean by whole-genome resequencing (WGRS) of 322 diverse adzuki beans accessions including both wild and cultivated. Furthermore, we have conducted comparative genomics and a genome-wide association study (GWAS) on key agricultural traits to investigate the evolution and domestication. GWAS identified several candidate genes, including VaCycA3;1, VaHB15, VaANR1 and VaBm, that exhibited significant associations with domestication traits. Furthermore, we conducted functional analyses on the roles of VaANR1 and VaBm in regulating seed coat colour. We provided evidence for the highest genetic diversity of wild adzuki (Vigna angularis var. nipponensis) in China with the presence of the most original wild adzuki bean, and the occurrence of domestication process facilitating transition from wild to cultigen. The present study elucidates the genetic basis of adzuki bean domestication traits and provides crucial genomic resources to support future breeding efforts in adzuki bean.

Cohort profile: BioMD-Y (biopsychosocial factors of major depression in youth) - a biobank study on the molecular genetics and environmental factors of depression in children and adolescents in Munich.

PURPOSE: BioMD-Y is a comprehensive biobank study of children and adolescents with major depression (MD) and their healthy peers in Germany, collecting a host of both biological and psychosocial information from the participants and their parents with the aim of exploring genetic and environmental risk and protective factors for MD in children and adolescents. PARTICIPANTS: Children and adolescents aged 8-18 years are recruited to either the clinical case group (MD, diagnosis of MD disorder) or the typically developing control group (absence of any psychiatric condition). FINDINGS TO DATE: To date, four publications on both genetic and environmental risk and resilience factors (including FKBP5, glucocorticoid receptor activation, polygenic risk scores, psychosocial and sociodemographic risk and resilience factors) have been published based on the BioMD-Y sample. FUTURE PLANS: Data collection is currently scheduled to continue into 2026. Research questions will be further addressed using available measures.

Epithelial MAPK signaling directs endothelial NRF2 signaling and IL-8 secretion in a tri-culture model of the alveolar-microvascular interface following diesel exhaust particulate (DEP) exposure.

BACKGROUND: Particulate matter 2.5 (PM2.5) deposition in the lung's alveolar capillary region (ACR) is significantly associated with respiratory disease development, yet the molecular mechanisms are not completely understood. Adverse responses that promote respiratory disease development involve orchestrated, intercellular signaling between multiple cell types within the ACR. We investigated the molecular mechanisms elicited in response to PM2.5 deposition in the ACR, in an in vitro model that enables intercellular communication between multiple resident cell types of the ACR. METHODS: An in vitro, tri-culture model of the ACR, incorporating alveolar-like epithelial cells (NCI-H441), pulmonary fibroblasts (IMR90), and pulmonary microvascular endothelial cells (HULEC) was developed to investigate cell type-specific molecular responses to a PM2.5 exposure in an in-vivo-like model. This tri-culture in vitro model was termed the alveolar capillary region exposure (ACRE) model. Alveolar epithelial cells in the ACRE model were exposed to a suspension of diesel exhaust particulates (DEP) (20 µg/cm2) with an average diameter of 2.5 µm. Alveolar epithelial barrier formation, and transcriptional and protein expression alterations in the directly exposed alveolar epithelial and the underlying endothelial cells were investigated over a 24 h DEP exposure. RESULTS: Alveolar epithelial barrier formation was not perturbed by the 24 h DEP exposure. Despite no alteration in barrier formation, we demonstrate that alveolar epithelial DEP exposure induces transcriptional and protein changes in both the alveolar epithelial cells and the underlying microvascular endothelial cells. Specifically, we show that the underlying microvascular endothelial cells develop redox dysfunction and increase proinflammatory cytokine secretion. Furthermore, we demonstrate that alveolar epithelial MAPK signaling modulates the activation of NRF2 and IL-8 secretion in the underlying microvascular endothelial cells. CONCLUSIONS: Endothelial redox dysfunction and increased proinflammatory cytokine secretion are two common events in respiratory disease development. These findings highlight new, cell-type specific roles of the alveolar epithelium and microvascular endothelium in the ACR in respiratory disease development following PM2.5 exposure. Ultimately, these data expand our current understanding of respiratory disease development following particle exposures and illustrate the utility of multicellular in vitro systems for investigating respiratory tract health.

Viral genome sequencing to decipher in-hospital SARS-CoV-2 transmission events.

The SARS-CoV-2 pandemic has highlighted the need to better define in-hospital transmissions, a need that extends to all other common infectious diseases encountered in clinical settings. To evaluate how whole viral genome sequencing can contribute to deciphering nosocomial SARS-CoV-2 transmission 926 SARS-CoV-2 viral genomes from 622 staff members and patients were collected between February 2020 and January 2021 at a university hospital in Munich, Germany, and analysed along with the place of work, duration of hospital stay, and ward transfers. Bioinformatically defined transmission clusters inferred from viral genome sequencing were compared to those inferred from interview-based contact tracing. An additional dataset collected at the same time at another university hospital in the same city was used to account for multiple independent introductions. Clustering analysis of 619 viral genomes generated 19 clusters ranging from 3 to 31 individuals. Sequencing-based transmission clusters showed little overlap with those based on contact tracing data. The viral genomes were significantly more closely related to each other than comparable genomes collected simultaneously at other hospitals in the same city (n = 829), suggesting nosocomial transmission. Longitudinal sampling from individual patients suggested possible cross-infection events during the hospital stay in 19.2% of individuals (14 of 73 individuals). Clustering analysis of SARS-CoV-2 whole genome sequences can reveal cryptic transmission events missed by classical, interview-based contact tracing, helping to decipher in-hospital transmissions. These results, in line with other studies, advocate for viral genome sequencing as a pathogen transmission surveillance tool in hospitals.