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Abstract Background Children with affective dysregulation (AD) show an excessive reactivity to emotionally positive or negative stimuli, typically manifesting in chronic irritability, severe temper tantrums, and sudden mood swings. AD shows a large overlap with externalizing and internalizing disorders. Given its transdiagnostic nature, AD cannot be reliably and validly captured only by diagnostic categories such as disruptive mood dysregulation disorder (DMDD). Therefore, this study aimed to evaluate two semi-structured clinical interviews—one for parents and one for children. Methods Both interviews were developed based on existing measures that capture particular aspects of AD. We analyzed internal consistencies and interrater agreement to evaluate their reliability. Furthermore, we analyzed factor loadings in an exploratory factor analysis, differences in interview scores between children with and without co-occurring internalizing and externalizing disorders, and associations with other measures of AD and of AD-related constructs. The evaluation was performed in a screened community sample of children aged 8–12 years (n = 445). Interrater reliability was additionally analyzed in an outpatient sample of children aged 8–12 years (n = 27). Results Overall, internal consistency was acceptable to good. In both samples, we found moderate to excellent interrater reliability on a dimensional level. Interrater agreement for the dichotomous diagnosis DMDD was substantial to perfect. In the exploratory factor analysis, almost all factor loadings were acceptable. Children with a diagnosis of disruptive disorder, attention-deficit/hyperactivity disorder, or any disorder (disruptive disorder, attention-deficit/hyperactivity disorder, and depressive disorder) showed higher scores on the DADYS interviews than children without these disorders. The correlation analyses revealed the strongest associations with other measures of AD and measures of AD-specific functional impairment. Moreover, we found moderate to very large associations with internalizing and externalizing symptoms and moderate to large associations with emotion regulation strategies and health-related quality of life. Conclusions The analyses of internal consistency and interrater agreement support the reliability of both clinical interviews. Furthermore, exploratory factor analysis, discriminant analyses, and correlation analyses support the interviews’ factorial, discriminant, concurrent, convergent, and divergent validity. The interviews might thus contribute to the reliable and valid identification of children with AD and the assessment of treatment responses. Trial registration ADOPT Online: German Clinical Trials Register (DRKS) DRKS00014963. Registered 27 June 2018.

Abstract Heart failure remains a leading cause of mortality. Therapeutic intervention for heart failure would benefit from targeted delivery to the damaged heart tissue. Here, we applied in vivo peptide phage display coupled with high-throughput Next-Generation Sequencing (NGS) and identified peptides specifically targeting damaged cardiac tissue. We established a bioinformatics pipeline for the identification of cardiac targeting peptides. Hit peptides demonstrated preferential uptake by human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and immortalized mouse HL1 cardiomyocytes, without substantial uptake in human liver HepG2 cells. These novel peptides hold promise for use in targeted drug delivery and regenerative strategies and open new avenues in cardiovascular research and clinical practice.

Abstract A key player of excitable cells in the heart and brain is the L-type calcium channel CaV1.3. In the heart, it is required for voltage-dependent Ca2+-signaling, i.e., for controlling and modulating atrial cardiomyocyte excitation-contraction coupling. The clustering of CaV1.3 in functionally relevant channel multimers has not been addressed due to a lack of stoichiometric labeling combined with high-resolution imaging. Here, we developed a HaloTag-labeling strategy to visualize and quantify CaV1.3 clusters using STED nanoscopy to address the questions of cluster size and intra-cluster channel density. Channel clusters were identified in the plasma membrane of transfected live HEK293 cells as well as in giant plasma membrane vesicles derived from these cells that were spread on modified glass support to obtain supported plasma membrane bilayers (SPMBs). A small fraction of the channel clusters was colocalized with early and recycling endosomes at the membranes. STED nanoscopy in conjunction with live-cell and SPMB imaging enabled us to quantify CaV1.3 cluster sizes and their molecular density revealing significantly lower channel densities than expected for dense channel packing. CaV1.3 channel cluster size and molecular density were increased in SPMBs after treatment of the cells with the sympathomimetic compound isoprenaline, suggesting a regulated channel cluster condensation mechanism.

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common autosomal dominant muscle disorders, yet no cure or amelioration exists. The clinical presentation is diverse, making it difficult to identify the actual driving pathomechanism among many downstream events. To unravel this complexity, we performed a meta-analysis of 13 original omics datasets (in total 171 FSHD and 129 control samples). Our approach confirmed previous findings about the disease pathology and specified them further. We confirmed increased expression of former proposed DUX4 biomarkers, and furthermore impairment of the respiratory chain. Notably, the meta-analysis provides insights about so far not reported pathways, including misregulation of neuromuscular junction protein encoding genes, downregulation of the spliceosome, and extensive alterations of nuclear envelope protein expression. Finally, we developed a publicly available shiny app to provide a platform for researchers who want to search our analysis for genes of interest in the future.

Abstract Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.

Evaluating uncertainties of geological features on fluid temperature and pressure changes in a reservoir plays a crucial role in the safe and sustainable operation of high-temperature aquifer thermal energy storage (HT-ATES). This study introduces a new automated surface fitting function in the Python API (application programming interface) of Gmsh (v4.11) to simulate the impacts of structural barriers and variations of the reservoir geometries on thermohydraulic behaviour in heat storage applications. These structural features cannot always be detected by geophysical exploration but can be present due to geological complexities. A Python workflow is developed to implement an automated mesh generation routine for various geological scenarios. This way, complex geological models and their inherent uncertainties are transferred into reservoir simulations. The developed meshing workflow is applied to two case studies: (1) Greater Geneva Basin with the Upper Jurassic (“Malm”) limestone reservoir and (2) the 5° eastward-tilted DeepStor sandstone reservoir in the Upper Rhine Graben with a uniform thickness of 10 m. In the Greater Geneva Basin example, the top and bottom surfaces of the reservoir are randomly varied by ± 10 and ± 15 m, generating a total variation of up to 25 % from the initially assumed 100 m reservoir thickness. The injected heat plume in this limestone reservoir is independent of the reservoir geometry variation, indicating the limited propagation of the induced thermal signal. In the DeepStor reservoir, a vertical sub-seismic fault juxtaposing the permeable sandstone layers against low permeable clay-marl units is added to the base case model. The fault is located in distances varying from 4 to 118 m to the well to quantify the possible thermohydraulic response within the model. The variation in the distance between the fault and the well resulted in an insignificant change in the thermal recovery (∼ 1.5 %) but up to a ∼ 10.0 % pressure increase for the (shortest) distance of 4 m from the injection well. Modelling the pressure and temperature distribution in the 5° tilted reservoir, with a well placed in the centre of the model, reveals that heat tends to accumulate in the updip direction, while pressure increases in the downdip direction.

Background: Physical inactivity is associated with health risks, contributing to various diseases and all-cause mortality. Despite recommendations for regular physical activity (PA), many adults remain inactive, influenced by socioeconomic and environmental factors. Digital interventions, particularly web-based PA programs, offer promising possibilities to promote PA across populations. These programs vary in their effectiveness, reflecting differences in design, user engagement, and behavior change techniques employed. Objective: This study evaluates the effectiveness of the 12-week multimodal web-based TKFitnessCoach. The PA online program is part of the TK-HealthCoach. This study investigates the program's impact on self-reported PA levels, goal attainment, healthrelated quality of life, body weight, and eating behavior, comparing an interactive personalized web-based intervention and non-interactive web-based health information. Methods: In a randomized controlled trial (RCT), participants were allocated to either the intervention group (IG), receiving access to the interactive TK-FitnessCoach, or the control group (CG) that was provided a static website with evidence-based information on PA. The study targeted a German-speaking adult population interested in improving health behavior. Data was assessed at T0 (beginning of the study), T1 (postintervention), T2, 6 months, and T3, 12 months follow-ups, focusing on self-reported PA at T3 and on various secondary outcomes. Results: We achieved equally distributed sociodemographics in both the IG and the CG with a mean age of 42.8 (IG), resp. 43.1 years (CG), and female participants of 76.1 % (IG), resp. 74.7 % (CG). PA at baseline was 277.9 min/week in the IG and 273.3 min/week in the CG. Both, the IG (n = 1153 in the Intention-to-treat (ITT) dataset) and CG (n = 1177 in the ITT dataset) exhibited significant increases in PA over time (IG(T3-T0) = 72.92 min/week; CG(T3-T0) = 74.12 min/week).However, the study did not find significant differences in the effectiveness of the interactive TK-FitnessCoach compared to the non-interactive control in terms of improving PA and related health outcomes. The intensity of using the TK-FitnessCoach was not associated with PA. Conclusions: Both programs were effective in promoting PA among adults, with no significant differences observed between the two RCT groups. This highlights the potential of digital interventions in addressing physical inactivity, suggesting that the effectiveness of such programs may not solely depend on their interactivity but also on the quality and relevance of the information provided. Further research is needed to explore optimization strategies for such interventions, especially for persons with low PA, including user engagement, behavior change techniques, and the integration of objective PA tracking methods. Trial registration: German Clinical Trials Register DRKS00020249; https://drks.de/search/en/trial/DRKS00020249.

Mosquito-borne Zika virus (ZIKV) from sub-Saharan Africa has recently gained attention due to its epidemic potential and its capacity to be highly teratogenic. To improve our knowledge on currently circulating strains of African ZIKV, we conducted protein sequence alignment and identified contemporary West Africa NS1 (NS1CWA) protein as a highly conserved viral protein. Comparison of NS1CWA with the NS1 of the historical African ZIKV strain MR766 (NS1MR766), revealed seven amino acid substitutions. The effects of NS1 mutations on protein expression, virus replication, and innate immune activation were assessed in human cells using recombinant NS1 proteins and a chimeric viral clone MR766 with NS1CWA replacing NS1MR766. Our data indicated higher secretion efficiency of NS1CWA compared to NS1MR766 associated with a change in subcellular distribution. A chimeric MR766 virus with NS1CWA instead of authentic protein displayed a greater viral replication efficiency, leading to more pronounced cell death compared to parental virus. Enhanced viral growth was associated with reduced activation of innate immunity. Our data raise questions of the importance of NS1 protein in the pathogenicity of contemporary ZIKV from sub-Saharan Africa and point to differences within viral strains of African lineage.

Abstract We here explore the potential of the fungal genus Aureobasidium as a prototype for a microbial chassis for industrial biotechnology in the context of a developing circular bioeconomy. The study emphasizes the physiological advantages of Aureobasidium, including its polyextremotolerance, broad substrate spectrum, and diverse product range, making it a promising candidate for cost‐effective and sustainable industrial processes. In the second part, recent advances in genetic tool development, as well as approaches for up‐scaled fermentation, are described. This review adds to the growing body of scientific literature on this remarkable fungus and reveals its potential for future use in the biotechnological industry.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

BackgroundUnderstanding the distinct immunologic responses to SARS-CoV-2 infection among pediatric populations is pivotal in navigating the COVID-19 pandemic and informing future public health strategies. This study aimed to identify factors associated with heightened antibody responses in children and adolescents to identify potential unique immune dynamics in this population.MethodsData collected between July and December 2023 from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a statewide prospective population-based antibody survey among 1-to-19-year-old participants, were analyzed. Each participant had the following data available for analysis: (1) Roche Elecsys® Anti-SARS-CoV-2 Immunoassay for Nucleocapsid protein antibodies (Roche N-test), (2) qualitative and semi-quantitative detection of antibodies to the SARS CoV-2 spike protein receptor binding domain (Roche S-test), and (3) self-reported antigen/PCR COVID-19 test results, vaccination, and health status. Statistical analysis identified associations between participant characteristics and spike antibody quartile group.ResultsThe analytical sample consisted of 411 participants (mean age 12.2 years, 50.6% female). Spike antibody values ranged from a low of 6.3 U/ml in the lowest quartile to a maximum of 203,132.0 U/ml in the highest quartile in the aggregate sample. Older age at test date (OR = 1.22, 95% CI: 1.12, 1.35, p

Summary: Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.

Manufacturers often blame environmental issues on consumer behaviors. Plastic manufactures provide a classic example, engaging in marketing campaigns attributing responsibility for plastic waste to consumers and deflecting attention from the role of industry. Drawing on attribution theory, we conducted an experiment (n = 113) to test how messaging blaming consumers for plastic waste might influence attitudes, behavioral intentions, and policy support, compared to messaging blaming manufacturers. Compared with the manufacturer-blaming frame, the consumer-blaming frame resulted in less support for regulations increasing consumer accountability for plastic waste. We did not find a significant influence of the message frame on support for regulations holding manufacturers accountable for plastic waste. Based on these results, we suggest that practitioners consider framing messages surrounding plastic waste so as to minimize consumer blame in order to maximize potential support for plastic waste reduction initiatives.

Zika virus (ZIKV) has become a global health problem over the past decade due to the extension of the geographic distribution of the Asian/American genotype. Recent epidemics of Asian/American ZIKV have been associated with developmental disorders in humans. There is mounting evidence that African ZIKV may be associated with increased fetal pathogenicity necessitating to pay a greater attention towards currently circulating viral strains in sub-Saharan Africa. Here, we generated an infectious molecular clone GUINEA-18 of a recently transmitted human ZIKV isolate from West Africa, ZIKV-15555. The available infectious molecular clone MR766MC of historical African ZIKV strain MR766-NIID was used for a molecular clone-based comparative study. Viral clones GUINEA-18 and MR766MC were compared for their ability to replicate in VeroE6, A549 and HCM3 cell lines. There was a lower replication rate for GUINEA-18 associated with weaker cytotoxicity and reduced innate immune system activation compared with MR766MC. Analysis of chimeric viruses between viral clones stressed the importance of NS1 to NS4B proteins, with a particular focus of NS4B on GUINEA-18 replicative properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. GUINEA-18 was greatly efficient in inhibiting stress granule assembly in A549 cells subjected to a physiological stressor, with NS1 to NS4B proteins also being critical in this process. The impact of these GUINEA-18 proteins on viral replicative abilities and host-cell responses to viral infection raises the question of the role of nonstructural proteins in the pathogenicity of currently circulating ZIKV in sub-Saharan Africa.

Usutu virus (USUV) is an emerging flavivirus that is maintained in an enzootic cycle with mosquitoes as vectors and birds as amplifying hosts. In Europe, the virus has caused mass mortality of wild birds, mainly among Common Blackbird (Turdus merula) populations. While mosquitoes are the primary vectors for USUV, Common Blackbirds and other avian species are exposed to other arthropod ectoparasites, such as ticks. It is unknown, however, if ticks can maintain and transmit USUV. We addressed this question using in vitro and in vivo experiments and field collected data. USUV replicated in IRE/CTVM19 Ixodes ricinus tick cells and in injected ticks. Moreover, I. ricinus nymphs acquired the virus via artificial membrane blood-feeding and maintained the virus for at least 70 days. Transstadial transmission of USUV from nymphs to adults was confirmed in 4.9% of the ticks. USUV disseminated from the midgut to the haemocoel, and was transmitted via the saliva of the tick during artificial membrane blood-feeding. We further explored the role of ticks by monitoring USUV in questing ticks and in ticks feeding on wild birds in the Netherlands between 2016 and 2019. In total, 622 wild birds and the Ixodes ticks they carried were tested for USUV RNA. Of these birds, 48 (7.7%) carried USUV-positive ticks. The presence of negative-sense USUV RNA in ticks, as confirmed via small RNA-sequencing, showed active virus replication. In contrast, we did not detect USUV in 15,381 questing ticks collected in 2017 and 2019. We conclude that I. ricinus can be infected with USUV and can transstadially and horizontally transmit USUV. However, in comparison to mosquito-borne transmission, the role of I. ricinus ticks in the epidemiology of USUV is expected to be minor.