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The number of studies investigating the effects of ocean acidification on marine organisms and communities increases every year. Results are not easily comparable since the carbonate chemistry and ancillary data are not always reported in similar units and scales and are not calculated using similar sets of constants. To facilitate data comparison, a data compilation hosted by the PANGAEA Data Publisher was initiated in 2008 and is updated on a regular basis (https://doi.org/10.1594/PANGAEA.962556; Ocean Acidification International Coordination Centre (OA-ICC), 2023). By November 2023, a total of 1501 datasets (over 25 million data points) from 1554 papers had been archived. To easily filter and access relevant biological response data from this compilation, a user-friendly portal (https://oa-icc.ipsl.fr, last access: 9 November 2023) was launched in 2018. Here, we present an update of this data compilation since its second description by Yang et al. (2016) and provide an overview of the OA-ICC portal for ocean acidification biological response data, launched in 2018. Most of the study sites from which data have been archived are in the North Atlantic Ocean, North Pacific Ocean, South Pacific Ocean, and Mediterranean Sea, while polar oceans are still relatively poorly represented. Mollusca and Cnidaria are still the best-represented taxonomic groups. The biological processes most reported in the datasets are growth and morphology. Other variables that can potentially be affected by ocean acidification and are often reported include calcification/dissolution, primary production/photosynthesis, and biomass/abundance. The majority of the compiled datasets have considered ocean acidification as a single stressor, but their relative contribution has decreased from 68 % before 2015 to 57 % today, showing a clear tendency towards more data archived from multifactorial studies.

Abstract Background Patients with neurological disorders including stroke use rehabilitation to improve cognitive abilities, to regain motor function and to reduce the risk of further complications. Robotics-assisted tilt table technology has been developed to provide early mobilisation and to automate therapy involving the lower limbs. The aim of this study was to evaluate the feasibility of employing a feedback control system for heart rate (HR) during robotics-assisted tilt table exercise in patients after a stroke. Methods This feasibility study was designed as a case series with 12 patients ( $$n = 12$$ n = 12 ) with no restriction on the time post-stroke or on the degree of post-stroke impairment severity. A robotics-assisted tilt table was augmented with force sensors, a work rate estimation algorithm, and a biofeedback screen that facilitated volitional control of a target work rate. Dynamic models of HR response to changes in target work rate were estimated in system identification tests; nominal models were used to calculate the parameters of feedback controllers designed to give a specified closed-loop bandwidth; and the accuracy of HR control was assessed quantitatively in feedback control tests. Results Feedback control tests were successfully conducted in all 12 patients. Dynamic models of heart rate response to imposed work rate were estimated with a mean root-mean-square (RMS) model error of 2.16 beats per minute (bpm), while highly accurate feedback control of heart rate was achieved with a mean RMS tracking error (RMSE) of 2.00 bpm. Control accuracy, i.e. RMSE, was found to be strongly correlated with the magnitude of heart rate variability (HRV): patients with a low magnitude of HRV had low RMSE, i.e. more accurate HR control performance, and vice versa. Conclusions Feedback control of heart rate during robotics-assisted tilt table exercise was found to be feasible. Future work should investigate robustness aspects of the feedback control system. Modifications to the exercise modality, or alternative modalities, should be explored that allow higher levels of work rate and heart rate intensity to be achieved.

Climate change is a global challenge with multiple far-reaching consequences, including the intensification and increased frequency of many extreme-weather events. In response to this pressing issue, we present ClimaMeter, a platform designed to assess and contextualize extreme-weather events relative to climate change. The platform offers near-real-time insights into the dynamics of extreme events, serving as a resource for researchers and policymakers while also being a science dissemination tool for the general public. ClimaMeter currently analyses heatwaves, cold spells, heavy precipitation, and windstorms. This paper elucidates the methodology, data sources, and analytical techniques on which ClimaMeter relies, providing a comprehensive overview of its scientific foundation. We further present two case studies: the late 2023 French heatwave and the July 2023 Storm Poly. We use two distinct datasets for each case study, namely Multi-Source Weather (MSWX) data, which serve as the reference for our rapid-attribution protocol, and the ERA5 dataset, widely regarded as the leading global climate reanalysis. These examples highlight both the strengths and limitations of ClimaMeter in expounding the link between climate change and the dynamics of extreme-weather events.

Abstract Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Abstract Background Heart rate variability (HRV) may provide objective information about cardiogenic autonomic balance in individuals with spinal cord injury (SCI). The aim of this study was to characterize the diurnal variation of HRV in individuals with SCI at lesion level T6 and above and lesion level below T6. Methods This was a retrospective analysis of a prior cross-sectional study. Individuals with chronic SCI underwent 24 h recording of the time between consecutive R waves (RR interval) to derive parameters of HRV as follows: standard deviation of all normal-to-normal R–R intervals (SDNN) and square root of the mean of the squared differences between successive R–R intervals (RMSSD) (time domain); and high frequency power (HF), low-frequency power (LF), very low frequency power (VLF), ultra-low frequency power (ULF) and total power (TP) (frequency domain). Changes in the magnitude of HRV outcomes over the 24 h period were investigated using a novel multi-component cosinor model constrained to the form of a three-harmonic Fourier series. Results Participants were grouped as lesion level T6 and above (n = 22) or below T6 (n = 36). Most of them were male (n = 40, 69%) and the median age (interquartile range) was 50.5 (28) years. Both groups exhibited similar diurnal patterns in most HRV metrics. The lowest values occurred in the late afternoon (4–6 pm) and gradually increased, peaking around midnight to early morning (1–6 am). Exceptions included RMSSD, which peaked before midnight, and ULF, which showed a double peak pattern that peaked from 11 am to 1 pm and 4–6 am in participants with lesion level at T6 and above. The HRV values in participants with lesion level T6 and above were generally lower than participants with lesion level below T6, except for peak values of RMSSD, HF and LF. Conclusion This study demonstrated substantial diurnal variation of HRV in participants with SCI in both groups of participants. In clinical and research settings, diurnal variations in HRV must be taken into consideration.

Abstract Fecal calprotectin is an established marker of gut inflammation in inflammatory bowel disease (IBD). Elevated levels of fecal calprotectin as well as gut microbial dysbiosis have also been observed in other clinical conditions. However, systemic and multi-omics alterations linked to elevated fecal calprotectin in older individuals remain unclear. This study comprehensively investigated the relationship between fecal calprotectin levels, gut microbiome composition, serum inflammation and targeted metabolomics markers, and relevant lifestyle and medical data in a large sample of older individuals (n = 735; mean age ± SD: 68.7 ± 6.3) from the TREND cohort study. Low (0–50 μg/g; n = 602), moderate (> 50–100 μg/g; n = 64) and high (> 100 μg/g; n = 62) fecal calprotectin groups were stratified. Several pro-inflammatory gut microbial genera were significantly increased and short-chain fatty acid producing genera were decreased in high vs. low calprotectin groups. In serum, IL-17C, CCL19 and the toxic metabolite indoxyl sulfate were increased in high vs. low fecal calprotectin groups. These changes were partially mediated by the gut microbiota. Moreover, the high fecal calprotectin group showed increased BMI and a higher disease prevalence of heart attack and obesity. Our findings contribute to the understanding of fecal calprotectin as a marker of gut dysbiosis and its broader systemic and clinical implications in older individuals.

Abstract The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5’-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.

The objective of this project was to address design gaps in previous programs that address scientific argumentation in middle schools. We adopted gamification mechanics (e.g., stimulus and response and progression) to design a computer-assisted program to better support students' development of scientific argumentation. In this paper, we describe the development of a gamified tool to support the representation of collaborative scientific argumentation for middle school students and describe how a faculty member in the Instructional Technology program and a faculty member and students in the Department of Computer Science collaborated and delivered project work through the Agile methodology. We developed two iterations of the prototype and conducted usability tests of the two iterations of the design with adults and middle school students in the United States. This study presents how the design evolved from the first to the second iteration based on usability testing results. The adult participants (e.g., science pre-service teachers and an in-service teacher) and student participants provided suggestions for further improvement of the second iteration of the prototype.

ADAM17 sheds EGFR/erbB ligands and triggers oncogenic pathways that lead to the progression of solid tumors. We targeted the ADAM17 disintegrin and cysteine rich domain region (D+C) to generate a panel of single-chain antibody fragments (scFvs) that selectively bind to the D or C domains of ADAM17, but not of ADAM10 or ADAM19. From the panel, we selected one scFv, referred to as C12, based on its high binding affinity towards the target, and re-formatted it to a full IgG for further studies. High-resolution cryo-electron microscopy studies documented that the mAb binds to the ADAM17 C-domain that in ADAM proteases, notably ADAM10 and ADAM17, is known to impart substrate-specificity. The C12 mAb significantly inhibited EGFR phosphorylation in cancer cell lines by hindering the cleavage of EGFR ligands tethered to the cell surface. This inhibition provides a mechanism for potential anti-tumor effects, and indeed C12 diminished the viability of a variety of EGFR-expressing cancer cell lines. Cell-based ELISA studies revealed that C12 preferentially bound to activated ADAM17 present on tumor cells, as compared to the autoinhibited ADAM17 that is the predominant form on HEK293 and other non-tumor cells. C12 also exhibited tumor growth inhibition in an ovarian cancer xenograft mouse model. Consistent with its selective tumor cell binding in vitro, radioimmuno PET (positron emission tomography) imaging with 89Zr-DFO-C12 in mouse xenograft models confirmed tumoral accumulation of the C12 mAb.

Objective After infection with SARS-CoV-2, a substantial proportion of patients develop long-lasting sequelae. These sequelae include fatigue (potentially as severe as that seen in ME/CFS cases), cognitive dysfunction, and psychiatric symptoms. Because the pathophysiology of these sequelae remains unclear, existing therapeutic concepts address the symptoms through pacing strategies, cognitive training, and psychological therapy. Methods Here, we present a protocol for a digital multimodal structured intervention addressing common symptoms through three intervention modules: BRAIN, BODY, and SOUL. This intervention includes an assessment conducted via a mobile “post-COVID-19 bus” near the patient's home, as well as the use of wearable devices and mobile applications to support pacing strategies and collection of data, including ecological momentary assessment. Results We will focus on physical component subscore of the SF36 as Quality of Life parameter as the primary outcome parameter for WATCH to take into account the holistic approach that is necessary for care of post-COVID patients Conclusion In the current project, we present a protocol for a holistic and multimodal structured therapeutic concept which is easily accessible, and scalable for post-COVID patients.

IntroductionWith age, sensory, cognitive, and motor abilities decline, and the risk for neurodegenerative disorders increases. These impairments influence the quality of life and increase the need for care, thus putting a high burden on society, the economy, and the healthcare system. Therefore, it is important to identify factors that influence healthy aging, particularly ones that are potentially modifiable through lifestyle choices. However, large-scale studies investigating the influence of multi-modal factors on a global description of healthy aging measured by multiple clinical assessments are sparse.MethodsWe propose a machine learning model that simultaneously predicts multiple cognitive and motor outcome measurements on a personalized level recorded from one learned composite score. This personalized composite score is derived from a large set of multi-modal components from the TREND cohort, including genetic, biofluid, clinical, demographic, and lifestyle factors.ResultsWe found that a model based on a single composite score was able to predict cognitive and motor abilities almost as well as a classical flexible regression model specifically trained for each single clinical score. In contrast to the flexible regression model, our composite score model is able to identify factors that globally influence cognitive and motoric abilities as measured by multiple clinical scores. The model identified several risk and protective factors for healthy aging and recovered physical exercise as a major, modifiable, protective factor.DiscussionWe conclude that our low parametric modeling approach successfully recovered known risk and protective factors of healthy aging on a personalized level while providing an interpretable composite score. We suggest validating this modeling approach in other cohorts.

Physical security is an important aspect of devices for which an adversary can manipulate the physical execution environment. Recently, more and more attention has been directed towards a security model that combines the capabilities of passive and active physical attacks, i.e., an adversary that performs fault-injection and side-channel analysis at the same time. Implementing countermeasures against such a powerful adversary is not only costly but also requires the skillful combination of masking and redundancy to counteract all reciprocal effects. In this work, we propose a new methodology to generate combined-secure circuits. We show how to transform Threshold Implementation (TI)-like constructions to resist any adversary with the capability to tamper with internal gates and probe internal wires. For the resulting protection scheme, we can prove the combined security in a well-established theoretical security model. Since the transformation preserves the advantages of TI-like structures, the resulting circuits prove to be more efficient in the number of required bits of randomness (up to 100%), the latency in clock cycles (up to 40%), and even the area for pipelined designs (up to 40%) than the state of the art for an adversary restricted to manipulating a single gate and probing a single wire.

The development of a new and straightforward chemoselective method for the synthesis of uracil-based structures by combining Suzuki–Miyaura and Sonogashira–Hagihara cross-coupling is reported. The methodology was applied to synthesize a series of novel compounds. The tolerance of the combination of different functional groups was tested. The influence of different functional groups on the physical properties was studied by ultraviolet–visible (UV–vis) and fluorescence spectroscopy, providing new insights into the potential applications of uracil-based structures.

Abstract With disease-modifying treatment for Parkinson’s disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1NMC) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1NMC, longitudinal data of 56 GBA1NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1wildtype) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan–Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1NMC showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1NMC compared to GBA1wildtype, but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan–Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1NMC. Incidence of PD was significantly higher in GBA1NMC. In conclusion, our study extends data on GBA1NMC indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.

Cutaneous melanoma (CM) is a candidate for screening programs because its prognosis is excellent when diagnosed at an early disease stage. Targeted screening of those at high risk for developing CM, a cost-effective alternative to population-wide screening, requires valid procedures to identify the high-risk group. Self-assessment of the number of nevi has been suggested as a component of such procedures, but its validity has not yet been established. We analyzed the level of agreement between self-assessments and examiner assessments of the number of melanocytic nevi in the area between the wrist and the shoulder of both arms based on 4548 study subjects in whom mutually blinded double counting of nevi was performed. Nevus counting followed the IARC protocol. Study subjects received written instructions, photographs, a mirror, and a “nevometer” to support self-assessment of nevi larger than 2 mm. Nevus counts were categorized based on the quintiles of the distribution into five levels, defining a nevus score. Cohen’s weighted kappa coefficient (κ) was estimated to measure the level of agreement. In the total sample, the agreement between self-assessments and examiner assessments was moderate (weighted κ = 0.596). Self-assessed nevus counts were higher than those determined by trained examiners (mean difference: 3.33 nevi). The level of agreement was independent of sociodemographic and cutaneous factors; however, participants’ eye color had a significant impact on the level of agreement. Our findings show that even with comprehensive guidance, only a moderate level of agreement between self-assessed and examiner-assessed nevus counts can be achieved. Self-assessed nevus information does not appear to be reliable enough to be used in individual risk assessment to target screening activities.

Abstract Background The German Rivermead Post-Concussion Symptoms Questionnaire (RPQ) can be used to assess post-concussion symptoms (PCS) after traumatic brain injury (TBI) in adults, adolescents, and children. Methods In this study, we examined the psychometric properties of the German RPQ proxy version (N = 146) for children (8—12 years) after TBI at the item, total and scale score level. Construct validity was analyzed using rank correlations with the proxy-assessed Post-Concussion Symptoms Inventory (PCSI-P), the Patient Health Questionnaire 9 (PHQ-9), and the Generalized Anxiety Disorder Scale 7 (GAD-7). Furthermore, sensitivity testing was performed concerning subjects’ sociodemographic and injury-related characteristics. Differential item functioning (DIF) was analyzed to assess the comparability of RPQ proxy ratings for children with those for adolescents. Results Good internal consistency was demonstrated regarding Cronbach’s α (0.81—0.90) and McDonald’s ω (0.84—0.92). The factorial validity of a three-factor model was superior to the original one-factor model. Proxy ratings of the RPQ total and scale scores were strongly correlated with the PCSI-P (ϱ = 0.50—0.69), as well as moderately to strongly correlated with the PHQ-9 (ϱ = 0.49—0.65) and the GAD-7 (ϱ = 0.44—0.64). The DIF analysis revealed no relevant differences between the child and adolescent proxy versions. Conclusions The German RPQ proxy is a psychometrically reliable and valid instrument for assessing PCS in children after TBI. Therefore, RPQ self- and proxy-ratings can be used to assess PCS in childhood as well as along the lifespan of an individual after TBI.

Abstract Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p

Abstract The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and metabolic syndrome. The sublines BFMI861-S1 and BFMI861-S2 differ in weight despite high genetic similarity and a shared obesity-related locus. This study focused on identifying additional body weight quantitative trait loci (QTLs) by analyzing weekly weight measurements in a male population of the advanced intercross line BFMI861-S1 x BFMI861-S2. QTL analysis, utilizing 200 selectively genotyped mice (GigaMUGA) and 197 males genotyped for top SNPs, revealed a genome-wide significant QTL on Chr 15 (68.46 to 81.40 Mb) for body weight between weeks 9 to 20. Notably, this QTL disappeared (weeks 21 to 23) and reappeared (weeks 24 and 25) coinciding with a diet change. Additionally, a significant body weight QTL on Chr 16 (3.89 to 22.79 Mb) was identified from weeks 6 to 25. Candidate genes, including Gpt, Cbx6, Apol6, Apol8, Sun2 (Chr 15) and Trap1, Rrn3, Mapk1 (Chr 16), were prioritized. This study unveiled two additional body weight QTLs, one of which is novel and responsive to diet changes. These findings illuminate genomic regions influencing weight in BFMI and emphasize the utility of time series data in uncovering novel genetic factors.

One of the most important tools available to limit the spread and impact of infectious diseases is vaccination. It is therefore important to understand what factors determine people's vaccination decisions. To this end, previous behavioural research made use of, (i) controlled but often abstract or hypothetical studies (e.g., vignettes) or, (ii) realistic but typically less flexible studies that make it difficult to understand individual decision processes (e.g., clinical trials). Combining the best of these approaches, we propose integrating real-world Bluetooth contacts via smartphones in several rounds of a game scenario, as a novel methodology to study vaccination decisions and disease spread. In our 12-week proof-of-concept study conducted with N = 494 students, we found that participants strongly responded to some of the information provided to them during or after each decision round, particularly those related to their individual health outcomes. In contrast, information related to others' decisions and outcomes (e.g., the number of vaccinated or infected individuals) appeared to be less important. We discuss the potential of this novel method and point to fruitful areas for future research.

The beneficial effects of feeding probiotic Bacillus subtilis DSM 32315 (BS) and Bacillus velezensis CECT 5940 (BV) to chickens in vivo are well-documented, with potential immune modulation as a key mechanism. In this study, we investigated the direct interactions of chicken peripheral blood mononuclear cells (PBMCs) with BS or BV in vitro through whole transcriptome profiling and cytokine array analysis. Transcriptome profiling revealed 20 significantly differentially expressed genes (DEGs) in response to both Bacillus treatments, with twelve DEGs identified in BS-treated PBMCs and eight in BV-treated PBMCs. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated significant regulation of immune-related pathways by both BS and BV. Notably, BS treatment upregulated genes associated with immune cell surface markers (CD4, CD25, CD28), anti-inflammatory cytokine interleukin-10 (IL-10), and C-C motif chemokine ligand 5 (CCL5), while downregulating the gene encoding pro-inflammatory IL-16. BV treatment similarly affected genes associated with immune cell surface markers, IL-16, and CCL5, with no impact on the gene encoding IL-10. Both treatments induced higher expression of the gene encoding the avian β-defensin 1 (AvBD1). The results of this in vitro study indicate an immunomodulatory effect of BS and BV in chicken PBMCs by regulating genes involved in anti-inflammatory, bacteriostatic, protective, and pro-inflammatory responses. Consequently, BS and BV may serve to augment the immune system’s capacity to defend against infection by modulating immune responses and cytokine expression. Thus, the administration of these probiotics holds promise for reducing reliance on antimicrobials in farming practices.

IntroductionThe taxonomy and phylogeny of the giant honey bees (Apis; subgenus Megapis) remain controversial and unresolved. The species boundaries within the subgenus are unclear, and some species that are recognized on the basis of genetic differences lack supporting morphological characteristics. Two species are now well accepted: Apis dorsata Fabricius, 1793, of tropical regions of Asia, and Apis laboriosa Moore et al., 1871, an inhabitant of the foothills of the Himalayas and neighboring mountain ranges. In addition, researchers have suggested that the two allopatric populations of giant honey bees that inhabit Sulawesi, Indonesia (Apis binghami Cockerell, 1906) and the oceanic Philippine islands (Apis breviligula Maa, 1953), as well as the South Indian form also deserve species status. We evaluated morphological characters of all of these taxa in order to revise the taxonomy of the subgenus.MethodsWe conducted a taxonomic study based on morphological characters of Megapis from throughout Asia. In addition, we created taxonomic keys to workers and drones for the giant honey bee species that we recognize.ResultsOur study confirms that A. laboriosa is a distinct species based on numerous morphological characters. Moreover, A. dorsata of mainland Asia differs from the two island taxa based on coloration, ocellus size, and the spacing of compound eyes and ocelli. We found no evidence that breviligula of the Philippines has a distinctively short tongue. Moreover, we detected only one minor character (the shape of sternum 5) that differed statistically between bees from Sulawesi and the Philippines. We conclude that the bees from these islands represent a single morphological species, A. binghami, with two subspecies, A. b. binghami and A. b. breviligula. A. dorsata from the Andaman Islands are smaller than but conspecific with dorsata of mainland Asia. We found no morphological autapomorphies in the giant honey bees of southern India that are known to differ in mtDNA from A. dorsata from elsewhere in mainland Asia.DiscussionOur morphological examination of Megapis specimens firmly supports three species of giant honey bees: A. laboriosa, A. dorsata, and A. binghami. More detailed examination of specimens is required to reconcile our three morphological species with the five clades that have been identified with genetic analyses.

Objectives A hard lockdown was presumed to lead to delayed diagnosis and treatment of serious diseases, resulting in higher acuity at admission. This should be elaborated based on the estimated acuity of the cases, changes in findings during hospitalisation, age structure and biological sex.Design Retrospective monocentric cross-sectional study.Setting German Neuroradiology Department at a .Participants In 2019, n=1158 patients were admitted in contrast to n=884 during the first hard lockdown in 2020 (11th–13th week).Main outcome measures Three radiologists evaluated the initial case acuity, classified them into three groups (not acute, subacute and acute), and evaluated if there was a relevant clinical deterioration. The data analysis was conducted using non-parametric methods and multivariate regression analysis.Results A 24% decrease in the number of examinations from 2019 to 2020 (p=0.025) was revealed. In women, the case acuity increased by 21% during the lockdown period (p=0.002). A 30% decrease in acute cases in men was observable (in women 5% decrease). Not acute cases decreased in both women and men (47%; 24%), while the subacute cases remained stable in men (0%) and decreased in women (28%). Regression analysis revealed the higher the age, the higher the acuity (p

Abstract Established methods of age estimation are based on correlating defined maturation stages of bony structures with tables representing the observed range of biological ages in the majority of cases. In this retrospective monocentric study in southwestern Germany, common age estimation methodology was assessed in n = 198 subjects at the age of 25 or younger by analyzing the influence of age, quadratic age, biological sex and age-sex interaction on the ossification stages of the medial epiphysis fugue. Three readers (ICC ≥ 0.81 for left/right side) evaluated routine care computed tomography images of the clavicle with a slice thickness of 1 mm. By using least square regression analyses, to determine the real biological age a quadratic function was determined corrected for the age estimated by established methods and sex (R2 = 0.6 each side), reducing the mean absolute error and root mean squared error in the age estimation of women (2.57 and 3.19) and men (2.57 and 3.47) to 1.54 and 1.82 for women, and 1.54 and 2.25 for men. In women, the medial clavicle epiphysis seem to fuse faster, which was particularly observable from approximately 18 years of age. Before that age, the estimation method was relatively close to the ideal correlation between assessed and real age. To conclude, the presented new method enables more precise age estimation in individuals and facilitates the determination and quantification of additional variables, quantifying their influence on the maturation of the medial clavicle epiphysis based on the established ossification stages.

Abstract Background In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. Methods An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. Results 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. Conclusions This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

Abstract Background Two genomes $$\mathbb {A}$$ A and $$\mathbb {B}$$ B over the same set of gene families form a canonical pair when each of them has exactly one gene from each family. Denote by $$n_*$$ n ∗ the number of common families of $$\mathbb {A}$$ A and $$\mathbb {B}$$ B . Different distances of canonical genomes can be derived from a structure called breakpoint graph, which represents the relation between the two given genomes as a collection of cycles of even length and paths. Let $$c_i$$ c i and $$p_j$$ p j be respectively the numbers of cycles of length i and of paths of length j in the breakpoint graph of genomes $$\mathbb {A}$$ A and $$\mathbb {B}$$ B . Then, the breakpoint distance of $$\mathbb {A}$$ A and $$\mathbb {B}$$ B is equal to $$n_*-\left( c_2+\frac{p_0}{2}\right)$$ n ∗ - c 2 + p 0 2 . Similarly, when the considered rearrangements are those modeled by the double-cut-and-join (DCJ) operation, the rearrangement distance of $$\mathbb {A}$$ A and $$\mathbb {B}$$ B is $$n_*-\left( c+\frac{p_e }{2}\right)$$ n ∗ - c + p e 2 , where c is the total number of cycles and $$p_e$$ p e is the total number of paths of even length. Motivation The distance formulation is a basic unit for several other combinatorial problems related to genome evolution and ancestral reconstruction, such as median or double distance. Interestingly, both median and double distance problems can be solved in polynomial time for the breakpoint distance, while they are NP-hard for the rearrangement distance. One way of exploring the complexity space between these two extremes is to consider a $$\sigma _k$$ σ k distance, defined to be $$n_*-\left( c_2+c_4+\ldots +c_k+\frac{p_0+p_2+\ldots +p_{k-2}}{2}\right)$$ n ∗ - c 2 + c 4 + … + c k + p 0 + p 2 + … + p k - 2 2 , and increasingly investigate the complexities of median and double distance for the $$\sigma _4$$ σ 4 distance, then the $$\sigma _6$$ σ 6 distance, and so on. Results While for the median much effort was done in our and in other research groups but no progress was obtained even for the $$\sigma _4$$ σ 4 distance, for solving the double distance under $$\sigma _4$$ σ 4 and $$\sigma _6$$ σ 6 distances we could devise linear time algorithms, which we present here.

Abstract The cleaning of aged silk fibers poses a common challenge in the conservation of textiles, since traditional cleaning techniques often yield unsatisfactory results or even harm objects. In this regard, cleaning objects with laser radiation is a promising addition to the range of available methods. Due to it being contactless, even brittle and touch-sensitive objects with disfiguring or harmful soiling could potentially be cleaned and therefore made accessible for research and presentation. Examples of treatment have sometimes shown spectacular results. Still there is some skepticism concerning the safety of this treatment for textile materials, which has been strengthened through previous 532 nm wavelength nanosecond laser cleaning studies on silk fibers. Taking these published results into account, the range of examined laser parameters has been extended in this study, from 532 nm nanosecond laser to 1064 nm nanosecond and even 800 nm femtosecond laser, reevaluating the effect of this treatment on the fibers. The physicochemical processes taking place on the silk fibers when cleaning with lasers are complex and still not fully understood. The aim of this project was therefore to bring more clarification about potential effects of those processes on the condition of silk samples treated with a set of different parameters for wavelength, pulse duration, energy density and number of pulses per spot. It also looks at the influence of the presence of soiling on the results. The analysis of potential effects was then carried out using statistical methods and advanced analytics. Scanning electron microscopy, Fourier-transform infrared spectroscopy and colorimetry technology provided the required insights to better assess the effects. Results show that laser cleaning of silk fibers, like most other conventional cleaning techniques, is not completely without risk, but knowing what the possible effects are helps making decisions on whether the benefits of the technique used justify these risks.

Abstract Seed amplification assays have been implemented in Parkinson’s disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens. While the assays’ qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson’s disease with positive CSF alpha-synuclein seeding status. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p ≤ 0.001, respectively). Results remained similar in separate subgroup analyses of patients with and without GBA mutation. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline.

In England, a new model of apprenticeship was initiated in whose stated intention was to 'put employers in the driving seat'. Regulation of the new model was focused on the mandatory 20% of apprentices' work time allocated to off-the-job training offered by colleges and other training providers. Based on case studies of employers and training providers across a range of industry sectors, this paper brings together data from two projects researching the on-the-job and off-the-job training elements of the new model. Three contrasting modes of apprenticeship emerged: developing apprentices to become experts in an industry-wide community of practice; apprenticeship as staff development; and apprenticeship as income stream. These resulted from different forms of employer-provider collaboration, enabled through a marketized landscape of training providers, and flexibility in regulations that requires very little of employers. Utilising Fuller and Unwin's work on expansive and restrictive environments, we found that that the new model supports a range of apprenticeships some being excellent but also others that are not worthy of the me. The paper concludes that quality apprenticeships tended to be in traditional industries and relied on strong partnerships between employers and training providers that worked against the grain of competitive market relations.

Emerging from the development of single-energy Computed Tomography (CT) and Dual-Energy Computed Tomography, Multi-Energy Computed Tomography (MECT) is a promising tool allowing advanced material and tissue decomposition and thereby enabling the use of multiple contrast materials in preclinical research.The scope of this work was to evaluate whether a usual preclinical micro-CT system is applicable for the decomposition of different materials using MECT together with a matrix-inversion method and how different changes of the measurement-environment affect the results.A matrix-inversion based algorithm to differentiate up to five materials (iodine, iron, barium, gadolinium, residual material) by applying four different acceleration voltages/energy levels was established. We carried out simulations using different ratios and concentrations (given in fractions of volume units, VU) of the four different materials (plus residual material) at different noise-levels for 30 keV, 40 keV, 50 keV, 60 keV, 80 keV and 100 keV (monochromatic). Our simulation results were then confirmed by using region of interest-based measurements in a phantom-study at corresponding acceleration voltages. Therefore, different mixtures of contrast materials were scanned using a micro-CT. Voxel wise evaluation of the phantom imaging data was conducted to confirm its usability for future imaging applications and to estimate the influence of varying noise-levels, scattering, artifacts and concentrations.The analysis of our simulations showed the smallest deviation of 0.01 (0.003–0.15) VU between given and calculated concentrations of the different contrast materials when using an energy-combination of 30 keV, 40 keV, 50 keV and 100 keV for MECT. Subsequent MECT phantom measurements, however, revealed a combination of acceleration voltages of 30 kV, 40 kV, 60 kV and 100 kV as most effective for performing material decomposition with a deviation of 0.28 (0–1.07) mg/ml. The feasibility of our voxelwise analyses using the proposed algorithm was then confirmed by the generation of phantom parameter-maps that matched the known contrast material concentrations. The results were mostly influenced by the noise-level and the concentrations used in the phantoms.MECT using a standard micro-CT combined with a matrix inversion method is feasible at four different imaging energies and allows the differentiation of mixtures of up to four contrast materials plus an additional residual material.