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Abstract Animals of the phylum Echinodermata are characterized by a pentaradially symmetric endoskeleton in adults. Echinoids also have endoskeletal spines ranging in length from several millimeters (sand dollars e.g. Mellita quinquiesperforata of the order Clypeasteroida) to 30 cm (the black sea urchin, Diadema antillarum of the order Euechinoidea). Here we integrate an analysis of genetic, structural and molecular properties of spines from the variegated sea urchin, Lytechinus variegatus. Through genetic crosses we learned that white is dominant over red and green colors, and that pigmentation follows classic Mendelian genetics. The abundance of mRNAs encoding flavin mono-oxygenase variancts and polyketide synthase was predictive of the color of the adult and antibodies identified their histological location in the spine cells. By RNA in situ hybridization, candidate genes important for spine biomineralization and pigmentation were mapped onto the spine epithelia, and MicroCT scans of spines from different color morphs concluded that color morphs are entirely due to pigmentation and not to structural variations of the endoskeleton. By confocal microscopy we localized gene expression along and within the spines and learned that genes involved in pigment biosynthesis showed selective distribution along the spine. Spine epidermis is mitotically active and red spherule immunocytes are highly migratory within the spine. Overall the results provide a key foundation for examining the mechanisms of molecular diversity and patterning in the name sake of the phylum Echinodermata.

Abstract Background Visium is a widely-used spatially-resolved transcriptomics assay available from 10x Genomics. Standard Visium capture areas (6.5mm by 6.5mm) limit the survey of larger tissue structures, but combining overlapping images and associated gene expression data allow for more complex study designs. Current software can handle nested or partial image overlaps, but is designed for merging up to two capture areas, and cannot account for some technical scenarios related to capture area alignment. Results We generated Visium data from a postmortem human tissue sample such that two capture areas were partially overlapping and a third one was adjacent. We developed the R/Bioconductor package visiumStitched, which facilitates stitching the images together with Fiji (ImageJ), and constructing SpatialExperiment R objects with the stitched images and gene expression data. visiumStitched constructs an artificial hexagonal array grid which allows seamless downstream analyses such as spatially-aware clustering without discarding data from overlapping spots. Data stitched with visiumStitched can then be interactively visualized with spatialLIBD. Conclusions visiumStitched provides a simple, but flexible framework to handle various multi-capture area study design scenarios. Specifically, it resolves a data processing step without disrupting analysis workflows and without discarding data from overlapping spots. visiumStitched relies on affine transformations by Fiji, which have limitations and are less accurate when aligning against an atlas or other situations. visiumStitched provides an easy-to-use solution which expands possibilities for designing multi-capture area study designs.

Abstract Current delivery practices for insecticide active ingredients are inefficient with only a fraction reaching their intended target. Herein, we developed carbon dot based nanocarriers with molecular baskets (γ-cyclodextrin) that enhance the delivery of active ingredients into insects (southern green stink bugs, Nezara viridula L.) via their tarsal pores. Nezara viridula feeds on leguminous plants worldwide and is a primary pest of soybeans. After two days of exposure, most of the nanocarriers and their active ingredient cargo (>85%) remained on the soybean leaf surface, rendering them available to the insects. The nanocarriers enter stink bugs through their tarsi, enhancing the delivery of a fluorescent chemical cargo by 2.6 times. The insecticide active ingredient nanoformulation (10 ppm) was 25% more effective in controlling the stink bugs than the active ingredient alone. Styletectomy experiments indicated that the improved active ingredient efficacy was due to the nanoformulation entering through the insect tarsal pores, consistent with fluorescent chemical cargo assays. This new nanopesticide approach offers efficient active ingredient delivery and improved integrated pest management for a more sustainable agriculture.

Abstract Background The risk of breast cancer patients for long-term side effects of therapy such as neurotoxicity and cardiotoxicity as well as late effects regarding comorbidities varies from individual to individual. Personalised follow-up care concepts that are tailored to individual needs and the risk of recurrences, side effects and late effects are lacking in routine care in Germany. Methods We describe the methodology of BETTER-CARE, a parallel-arm cluster-randomised controlled trial conducted at 15 intervention and 15 control centres, aiming to recruit 1140 patients, and the results of the pilot phase. The needs- and risk-adapted complex intervention, based on existing development frameworks, includes a multidisciplinary network and digital platforms for symptom and need documentation and just-in-time adaptive interventions. The control group comprises usual care according to clinical guidelines. The primary outcome is health-related quality of life (EORTC QLQ-C30 global health), and secondary outcomes include treatment adherence. Results The 2-month pilot phase comprising 16 patients in one intervention and one control pilot centre demonstrated the feasibility of the BETTER-CARE approach. Discussion BETTER-CARE is a feasible intervention and study concept, investigating individualised needs- and risk-adapted breast cancer follow-up care in Germany. If successful, the approach could be implemented in German routine care. Trial registration German Clinical Trial Register DRKS00028840. Registered on April 2022.

Abstract Introduction Spinal cord stimulation (SCS) represents an established interventional pain therapeutic; however, the SCS effects of SCS waveforms on motor neuron recruitment of the lower limbs of chronic pain patients remain largely unknown. Methods We investigated these effects by performing isometric ankle-dorsal flexions at varying force levels under four SCS conditions: SCS Off (1 week), burst SCS (40 Hz), SCS Off (acute), and tonic SCS (130 Hz). Muscle activity was recorded via high-density surface electromyography (64-electrode grid) on the tibialis anterior muscle. Motor unit action (MUs) potentials were analyzed for recruitment and de-recruitment thresholds, discharge rate, inter-spike interval, and common synaptic input. Results In this prospective study, we included nine patients (five females; four males; mean age 59 years) with chronic pain treated with thoracic (Th7–Th8) epidural spinal stimulation. A total of 97 MUs were found for 15% maximal voluntary torque (MVT) and 83 for 30%MVT, an average of 10.8 ± 3.7 for 15%MVT and 10.4 ± 3.5 for 30%MVT. While a few subject-specific variations were observed, our study suggests that the different SCS frequencies applied do not significantly influence motor unit discharge characteristics in the TA muscle among the participants (p values at 15%MVT were 0.586 (Chi2 = 1.933), 0.737 (Chi2 = 1.267), 0.706 (Chi2 = 1.4) and 0.586 (Chi2 = 1.933), respectively. The p values of the Friedman test at 30%MVT were 0.896 (Chi2 = 0.6), 0.583 (Chi2 = 1.95), 0.896 (Chi2 = 0.6) and 0.256 (Chi2 = 4.05). No significant difference was found for the different stimulation types for the delta (0–5 Hz), alpha (5–12 Hz), and beta (15–30 Hz) bands at both force levels. Conclusions In summary, we did not observe any changes in motor unit oscillatory activity at any low and high bandwidths, indicating that SCS using different waveforms (tonic/burst) does not significantly influence motor neuron recruitment for non-motor individuals with chronic pain.

Abstract Decidualization denotes the process of inflammatory reprogramming of endometrial stromal cells (EnSC) into specialized decidual cells (DC). During this process, EnSC are subjected to endoplasmic reticulum (ER) stress as well as acute cellular senescence. Both processes contribute to the proinflammatory mid-luteal implantation window and their dysregulation has been implicated in reproductive failure. Here, we evaluated the link between ER stress, decidual differentiation and senescence. In-silico analysis identified HSPA5 gene, codifying the ER chaperone BiP, as a potentially critical regulator of cell fate divergence of decidualizing EnSC into anti-inflammatory DC and pro-inflammatory senescent decidual cells (snDC). Knockdown of HSPA5 in primary EnSC resulted both in decreased expression of DC marker genes and attenuated induction of senescence associated β-galactosidase activity, a marker of snDC. Stalling of the decidual reaction upon HSPA5 knockdown was apparent at 8 days of differentiation and was preceded by the upregulation of ER stress associated proteins IRE1α and PERK. Further, HSPA5 knockdown impaired colony-forming unit activity of primary EnSC, indicative of loss of cellular plasticity. Together, our results point to a key role for HSPA5/BiP in decidual transformation of EnSCs and highlight the importance of constraining ER stress levels during this process.

Abstract Kinematic analysis is a central component of movement biomechanics, describing the relative motion of joint segments during different activities, in different subject cohorts, and at different timepoints. Establishing whether two sets of kinematic signals represent fundamentally similar or different underlying motion patterns is especially challenging, given 1) the lack of consensus around reference frame and joint axis definition, and 2) the substantial effect that minimal variations in frame position and orientation are known to have on signal magnitude and characteristics. As such, enormous variability in the reporting of tibiofemoral kinematics has resulted in joint movement patterns that remain controversially discussed. Previously, we demonstrated the ability of the REference FRame Alignment MEthod (REFRAME) to reorientate and reposition differently aligned local segment frames to achieve convergence in signals representing the same underlying motion, thereby offering a novel approach to consistently report joint motion. In this study, for the first time, we apply REFRAME to assess the rotational and translational in vivo tibiofemoral motion of ten healthy subjects during stair descent based on kinematic signals collected using a moving videofluoroscope. Kinematics were analysed before and after different REFRAME implementations, revealing generally neutral ab/adduction behaviour, accompanied by varying degrees of a sinusoidal int/external tibial rotation pattern over the activity cycle. Our data demonstrate that different selected implementations of REFRAME are able to highlight different characteristics of the motion patterns: Minimisation of the translational root-mean-square revealed proximodistal translation patterns with overall neutral progression, while anteroposterior translation showed seemingly different levels of correlation with flexion/extension in different subjects. On the other hand, REFRAME minimisation of translational variances exposed differences in the relative mean displacement between the femoral and tibial origins between subjects, highlighting differences in mean centre of rotation positions. This early application of REFRAME for providing an understanding of tibiofemoral kinematics demonstrates the potential of this novel approach to bring clarity to an otherwise complex representation of highly variable time-series signals, while highlighting the philosophical challenges of clinically interpretating kinematic signals in the first place.

Abstract Background Evidence on long COVID symptom clustering patterns among patients with COVID-19 is limited. We summarized long COVID symptoms in clusters defined by number of symptoms co-occurring together, and we assessed Health-Related Quality of Life (HQRoL), Work Productivity and Activity Impairment (WPAI) outcomes across these clusters over time. We assessed associations between the clusters and BNT162b2 vaccination status. Methods A prospective longitudinal patient-reported outcomes (PRO) study recruited laboratory-confirmed symptomatic COVID-19 patients seeking testing from a national retail pharmacy. Long COVID-19 symptoms were self-reported by participants at 4-week, 3-month and 6-month surveys. Patient classes identified via latent class analysis (LCA) with long COVID-19 symptoms were simplified into clusters based on number of symptoms. HRQoL and WPAI outcomes were collected using EQ-ED-5L and WPAI: GH questionnaires. Mixed models for repeated measures analyses were conducted to examine associations between exposure groups and outcomes. Results The study included 328 participants that were segmented into three groups of long COVID-19 symptoms based on LCA and then simplified by the number of symptoms (Cluster 1 low, 6 symptoms). The number of long COVID-19 symptoms was negatively associated with HRQoL and WPAI, whereby participants with high symptom burden (>6 symptoms) had the lowest HRQoL and WPAI scores assessed by absenteeism, presenteeism, work productivity loss, activity impairment, and hours worked metrics. Compared with those unvaccinated and not up-to-date with COVID-19 vaccination, subjects boosted with BNT162b2 consistently reported less symptom burden during the follow-up, regardless of their symptom-based cluster. Conclusion Three distinct patient clusters based on frequency of long COVID symptoms experienced different HRQoL and WPAI outcomes over 6 months. The cluster with more concomitant symptoms experienced greater burden than the others. Participants up-to-date with BNT162b2 reported lower symptom burden across all clusters and timeframes. Clinical trial registration Clinicaltrials.gov NCT05160636.

Abstract Mozambique is making progress towards elimination of trachoma as a public health problem, but in some districts trachomatous inflammation—follicular (TF) prevalence remains above the 5% elimination threshold despite years of various interventions, including antibiotic mass drug administration. To characterize transmission in four districts, we incorporated testing of ocular infection and serology into routine trachoma impact surveys (TIS) in August 2022. We examined residents aged ≥ 1 year for trachoma and collected information on household water, sanitation, and hygiene. Among children aged 1–9 years, we tested conjunctival swabs for Chlamydia trachomatis nucleic acid and dried blood spots for C. trachomatis antibodies. We modeled age-dependent seroprevalence to estimate seroconversion rate (SCR). We examined 4841 children aged 1–9 years. TF prevalence ranged between 1.1 and 6.0% with three districts below the 5% threshold. PCR-confirmed infection prevalence ranged between 1.1 and 4.8%, and Pgp3 seroprevalence ranged between 8.8 and 24.3%. Pgp3 SCR was 1.9 per 100 children per year in the district with the lowest TF prevalence. Two other districts with TF

Abstract The ultrashort and intense pulses of X-rays produced at X-ray free electron lasers (XFELs) have enabled unique experiments on the atomic level structure and dynamics of matter, with time-resolved studies permitted in the femto- and attosecond regimes. To fully exploit them, it is paramount to obtain a comprehensive understanding of the complex nonlinear interactions that can occur at such extreme X-ray intensities. Herein, we report on the experimental observation of a resonant double-core excitation scheme in N2, where two 1σ core-level electrons are resonantly promoted to unoccupied $$1{\pi }_{g}^{* }$$ 1 π g * molecular orbitals by a single few-femtosecond broad-bandwidth XFEL pulse. The production of these neutral two-site double core hole states is evidenced through their characteristic decay channels, which are observed in good agreement with high-level theoretical calculations. Such multi-core excitation schemes, benefiting from the high interaction cross sections and state- and site-selective nature of resonant X-ray interactions, should be generally accessible in XFEL irradiated molecules, and provide interesting opportunities for chemical analysis and for monitoring ultrafast dynamic processes.

Abstract This study sheds light on the pivotal role of the oncoprotein DEK in B-cell lymphoma. We reveal DEK expression correlates with increased tumor proliferation and inferior overall survival in cases diagnosed with low-grade B-cell lymphoma (LGBCL). We also found significant correlation between DEK expression and copy number alterations in LGBCL tumors, highlighting a novel mechanism of LGBCL pathogenesis that warrants additional exploration. To interrogate the mechanistic role of DEK in B-cell lymphoma, we generated a DEK knockout cell line model, which demonstrated DEK depletion caused reduced proliferation and altered expression of key cell cycle and apoptosis-related proteins, including Bcl-2, Bcl-xL, and p53. Notably, DEK depleted cells showed increased sensitivity to apoptosis-inducing agents, including venetoclax and staurosporine, which underscores the therapeutic potential of targeting DEK in B-cell lymphomas. Overall, our study contributes to a better understanding of DEK’s role as an oncoprotein in B-cell lymphomas, highlighting its potential as both a promising therapeutic target and a novel biomarker for aggressive LGBCL. Further research elucidating the molecular mechanisms underlying DEK-mediated tumorigenesis could pave the way for improved treatment strategies and better clinical outcomes for patients with B-cell lymphoma.

Abstract Background The market for beverages is highly changing within the last years. Increasing consumer awareness towards healthier drinks led to the revival of traditional and the creation of innovative beverages. Various protein-rich legumes were used for milk analogues, which might be also valuable raw materials for refreshing, protein-rich beverages. However, no such applications have been marketed so far, which might be due to unpleasant organoleptic impressions like the legume-typical “beany” aroma. Lactic acid fermentation has already been proven to be a remedy to overcome this hindrance in consumer acceptance. Results In this study, a statistically based approach was used to elucidate the impact of the fermentation parameters temperature, inoculum cell concentration, and methionine addition on the fermentation of lupine- and faba bean-based substrates. A total of 39 models were found and verified. The majority of these models indicate a strong impact of the temperature on the reduction of aldehydes connected to the “beany” impression (e.g., hexanal) and on the production of pleasantly perceived aroma compounds (e.g., β-damascenone). Positively, the addition of methionine had only minor impacts on the negatively associated sulfuric compounds methional, dimethyl sulfide, dimethyl disulfide, and dimethyl trisulfide. Moreover, in further fermentations, the time was added as an additional parameter. It was shown that the strains grew well, strongly acidified the both substrates (pH ≤ 4.0) within 6.5 h, and reached cell counts of > 9 log10 CFU/mL after 24 h. Notably, most of the aldehydes (like hexanal) were reduced within the first 6–7 h, whereas pleasant compounds like β-damascenone reached high concentrations especially in the later fermentation (approx. 24–48 h). Conclusions Out of the fermentation parameters temperature, inoculum cell concentration, and methionine addition, the temperature had the highest influence on the observed aroma and taste active compounds. As the addition of methionine to compensate for the legume-typical deficit did not lead to an adverse effect, fortifying legume-based substrates with methionine should be considered to improve the bioavailability of the legume protein. Aldehydes, which are associated with the “beany” aroma impression, can be removed efficiently in fermentation. However, terminating the process prematurely would lead to an incomplete production of pleasant aroma compounds.

Paludiculture (crop cultivation on wet peatlands) is an effective means to reduce carbon emissions and nutrient losses from formerly drained peatlands. However, methane (CH4) emissions and associated pathways may vary substantially between paludicultures, depending on the cultivated paludicrop. Whereas many studies have investigated diffusive CH4 emissions from paludicrops, large uncertainties exist in relation to the importance of CH4 ebullition, species-specific differences and seasonal dynamics. In this study we aimed to quantify CH4 emissions from stands of three paludicrop species, namely Typha latifolia, Typha angustifolia and Azolla filiculoides. CH4 diffusive fluxes - including plant-mediated emissions - and ebullitive fluxes were studied year-round on a rewetted former agricultural peatland in The Netherlands. Additionally, we tested the effect of irrigation strategy (water table depth) and nutrient loading on CH4 emissions from stands of both Typha species. Diffusive CH4 emissions were lowest from A. filiculoides stands (average 15.4 ± 6.6 mg m-2 d-1), followed by open water (36.4 ± 6.0 mg m-2 d-1). Substantially higher diffusive emissions were measured for both Typha species, with the highest emissions in T. latifolia (187.0 ± 29.4 mg m-2 d-1). Ebullitive fluxes were generally low (< 100 mg m-2 d-1), but the highest ebullitive fluxes occurred in the A. filiculoides stand, contributing 79 % on average to its total CH4 emissions. A water table just below the peat surface substantially reduced Typha CH4 emissions, but also led to lower biomass production, compared to a flooded (+20 cm) water table. Nutrient loading increased biomass production and did not affect diffusive CH4 emissions. Our results underline that species choice substantially affects paludiculture carbon dynamics in the first phase after establishment. Quantifying both diffusive and ebullitive fluxes is of paramount importance in adequately assessing paludiculture CH4 fluxes.

Abstract Binding-activated optical sensors are powerful tools for imaging, diagnostics, and biomolecular sensing. However, biosensor discovery is slow and requires tedious steps in rational design, screening, and characterization. Here we report on a platform that streamlines biosensor discovery and unlocks directed nanosensor evolution through genetically encodable fluorogenic amino acids (FgAAs). Building on the classical knowledge-based semisynthetic approach, we engineer ~15 kDa nanosensors that recognize specific proteins, peptides, and small molecules with up to 100-fold fluorescence increases and subsecond kinetics, allowing real-time and wash-free target sensing and live-cell bioimaging. An optimized genetic code expansion chemistry with FgAAs further enables rapid (~3 h) ribosomal nanosensor discovery via the cell-free translation of hundreds of candidates in parallel and directed nanosensor evolution with improved variant-specific sensitivities (up to ~250-fold) for SARS-CoV-2 antigens. Altogether, this platform could accelerate the discovery of fluorogenic nanosensors and pave the way to modify proteins with other non-standard functionalities for diverse applications.

A 1D imaging soft X-ray spectrometer installed on the small quantum systems (SQS) scientific instrument of the European XFEL is described. It uses movable cylindrical constant-line-spacing gratings in the Rowland configuration for energy dispersion in the vertical plane, and Wolter optics for simultaneous 1D imaging of the source in the horizontal plane. The soft X-ray fluorescence spectro-imaging capability will be exploited in pump–probe measurements and in investigations of propagation effects and other nonlinear phenomena.

Pleural extension of pseudomyxoma peritonei is rare, and treatment demands multidisciplinary care. Perioperative management during cytoreductive surgery and hyperthermic intrathoracic chemotherapy challenges anesthesiology and surgical teams in unique ways. Hemodynamic, arrhythmogenic, ventilatory, fluid balance, acid-base, and nephroprotection issues are important considerations. The use of cytoreductive surgery and hyperthermic intrathoracic chemotherapy for extraperitoneal pseudomyxoma peritonei is an innovative and potentially curative approach. Here, we describe our approach to managing these patients.

In the field of energetic materials, traditional materials with high toxicity or other disadvantages are mostly used. There is an urgent need for trinitrotoluene replacements (TNT), which itself is toxic and its production is problematic due to red wastewater. New materials should be safe to handle, have good performance, and be inexpensive to synthesize. Nitratoalkylazoles are known to have low melting points and good energetic properties compared to TNT. In this paper, seven energetic compounds are synthesized starting from 5-methyltetrazole, 5-hydroxymethyltetrazole and 4,5-bishydroxymethyltriazole. The nitrates are characterized in terms of their physical, chemical, and energetic properties. Of those seven compounds, five are solid, melting between 27 °C and 110 °C, and two are liquid. Methylation and hydroxyalkylation were performed and discussed extensively. The organic nitrate is introduced in the last step so that the synthesis remains safe and scalable. Correlations between the molecular geometry and the melting points are explained. Calculations indicate detonation velocities that are 6%–11% higher than those of TNT. A discussion of the effect of isomerism on the properties leads to surprising insights and should help focus and accelerate research on the replacement of TNT.

The present study aims to elucidate the decomposition mechanism and gas evolution characteristics of a promising energy-rich carbamated microcrystalline cellulose nitrate (M3CN). The molecular structure and morphological characteristics of starting microcrystalline cellulose carbamate (MCCC) and its nitrated derivative were examined using FTIR and SEM techniques. Thermal analysis using TGA and DSC revealed distinct decomposition behaviors for MCCC and M3CN. MCCC exhibited endothermic decomposition linked to the degradation of the cellulosic structure. In contrast, an exothermic decomposition event was observed for M3CN, attributed to the cleavage of energetic groups within the nitrated cellulosic chains. Furthermore, the hyphenated TG-FTIR analysis confirmed that the primary gaseous products emitted during the pyrolysis of M3CN included NO, N2O, NO2, CO2, H2O, CH4, HCHO, HCN, and CHNO. The findings of this study enhance our understanding of the pyrolysis mechanism in cellulose-based energetic materials, providing a significant reference for forthcoming research and explorations in this field.

Abstract Background Adipocytokines play a pivotal role in maintaining adipose tissue homeostasis by regulating cellular metabolism, proliferation, differentiation, and secretory activity. These soluble factors are relevant components for healthy adipose tissue, while their deficiency is closely associated with the development of obesity and related metabolic diseases, e.g., chronic inflammation. In human adipose tissue, inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is expressed in proportion to the development of adipose tissue, i.e., the individual’s BMI. Thus, ITIH5 has been proposed to be an inert marker of human obesity. However, when applied to adipose stem cells in vitro, recombinant (r)ITIH5 protein inhibited proliferation and adipogenesis, suggesting that ITIH5 negatively affects the development of fat mass. We now tested the role of ITIH5 in vivo and compared ITIH5 +/+ wildtype with ITIH5 −/− knockout mice. Results Genetic deletion of ITIH5 significantly increased adipose tissue mass relative to animal bodyweight (p

Abstract Ageing is the accumulation of changes and decline of function of organisms over time. The concept and biomarkers of biological age have been established, notably DNA methylation-based clocks. The emergence of single-cell DNA methylation profiling methods opens the possibility of studying the biological age of individual cells. Here, we generate a large single-cell DNA methylation and transcriptome dataset from mouse peripheral blood samples, spanning a broad range of ages. The number of genes expressed increases with age, but gene-specific changes are small. We next develop scEpiAge, a single-cell DNA methylation age predictor, which can accurately predict age in (very sparse) publicly available datasets, and also in single cells. DNA methylation age distribution is wider than technically expected, indicating epigenetic age heterogeneity and functional differences. Our work provides a foundation for single-cell and sparse data epigenetic age predictors, validates their functionality and highlights epigenetic heterogeneity during ageing.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) continues its significant health and economic impact globally. Despite the success of spike-protein vaccines in preventing severe disease, long-lasting protection against emerging variants and the prevention of breakthrough infections and transmission remain elusive. We generate an intranasal live-attenuated SARS-CoV-2 vaccine, CDO-7N-1, using codon deoptimization. CDO-7N-1 shows highly attenuated replication and minimal or no lung pathology in vivo over multiple passages. It induces robust mucosal and systemic neutralizing antibody and T-cell subset responses, in mice (female K18-hACE2 and male HFH4-hACE2 mice), hamsters, and macaques triggered by a single immunization. Mice and hamsters vaccinated with CDO-7N-1 are protected from challenge with wild-type (WT) SARS-CoV-2 and other variants of concern. Serum from vaccinated animals neutralizes WT SARS-CoV-2, variants of concern (beta and delta), variants of interest (omicron XBB.1.5) and SARS-CoV-1. Antibody responses are sustained and enhanced by repeated immunization or infection with WT SARS-CoV-2. Immunity against all SARS-CoV-2 proteins by CDO-7N-1 should improve efficacy against future SARS-CoV-2 variants.

Abstract Background The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. Methods To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. Results We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. Conclusion The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

Abstract Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Abstract Background Despite advances in total knee arthroplasty, many patients are still unsatisfied with the functional outcome. Multibody simulations enable a more efficient exploration of independent variables compared to experimental studies. However, to what extent numerical models can fully reproduce knee joint kinematics is still unclear. Hence, models must be validated with different test scenarios before being applied to biomechanical questions. Methods In our feasibility study, we analyzed a human knee specimen on a six degree of freedom joint simulator, applying a passive flexion and different laxity tests with sequential states of ligament resection while recording the joint kinematics. Simultaneously, we generated a subject-specific multibody model of the native tibiofemoral joint considering ligaments and contact between articulating cartilage surfaces. Results Our experimental data on the sequential states of ligament resection aligned well with the literature. The model-based knee joint kinematics during passive flexion showed good agreement with the experiment, with root-mean-square errors of less than 1.61 mm for translations and 2.1° for knee joint rotations. During laxity tests, the experiment measured up to 8 mm of anteroposterior laxity, while the numerical model allowed less than 3 mm. Conclusion Although the multibody model showed good agreement to the experimental kinematics during passive flexion, the validation showed that ligament parameters used in this feasibility study are too stiff to replicate experimental laxity tests correctly. Hence, more precise subject-specific ligament parameters have to be identified in the future through model optimization.

In the pursuit of advancing imidazolium-based energetic ionic liquids (EILs), the current study is devoted to the synthesis and characterization of 1,3-dibutyl-imidazolium azide ([BBIm][N3]), as a novel member in this ionic liquids class. The chemical structure of this EIL was rigorously characterized and confirmed using FTIR spectroscopy, 1D, and 2D-NMR analyses. The thermal behavior assessment was conducted through DSC and TGA experiments. DSC analysis revealed an endothermic glass transition at Tg=–61 °C, followed by an exothermic degradation event at Tonset=311 °C. Similarly, TGA thermograms exhibited a one-stage decomposition process resulting in 100% mass loss of the sample. Furthermore, the short-term thermal stability of the azide EIL was investigated by combining the non-isothermal TGA data with the TAS, it-KAS, and VYA/CE isoconversional kinetic approaches. Consequently, the Arrhenius parameters (Ea=154 kJ·mol-1, Log(A/s-1))=11.8) and the most probable reaction model g(α) were determined. The observed high decomposition temperatures and the significantly elevated activation energy affirm the enhanced thermal stability of the modified EIL. These findings revealed that [BBIm][N3] EIL can be a promising candidate for advanced energetic material application.

Abstract Interjurisdictional migrations lead to seasonally changing patterns of exploitation risk, emphasizing the importance of spatially explicit approaches to fishery management. Understanding how risk changes along a migration route supports time-area based fishery management, but quantifying risk can be complicated when multiple fishing methods are geographically segregated and when bycatch species are considered. Further, habitat selection in dynamic environments can influence migration behavior, interacting with other management objectives such as water quality and habitat restoration. As a case study, we examined a novel acoustic telemetry data set for Lake Whitefish in Lake Erie, where they migrate through multiple spatial management units that are variably affected by seasonal hypoxia and host a variety of fisheries. Combining telemetry results with fishery catch and water quality monitoring, we demonstrate three exploitation risk scenarios: (i) high risk due to high residency and high catch, (ii) high risk due to high residency in time-areas with moderate catch, and (iii) low risk due to residency in time-areas with low catch. Interestingly, occupation of low risk refugia was increased by the development of hypoxia in adjacent areas. Consequently, fishery management goals to sustainably manage other target species may be directly and indirectly linked to water quality management goals through Lake Whitefish.

Abstract Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7.

The olive fruit fly, Bactrocera oleae (Rossi) (Diptera: Tephritidae), causes significant damage to olive crops worldwide. However, the factors affecting its survival under water deprivation have not been studied yet. In this study, the water deprivation resistance of male and female olive fruit flies was measured at three ages in virgin and mated adults fed either a full or a restricted diet. The experiments (24 treatments) were conducted under constant laboratory conditions, using insects collected in the wild and reared on olives. Additionally, a baseline experiment was conducted to provide data on the insects’ life expectancy under no-stress conditions. Our findings revealed that males showed much less resistance under water deprivation compared to females. Younger adults endured for longer than older ones, and adults fed a restricted diet endured water deprivation longer than those fed a full diet. Our results suggest that during periods of water scarcity, releasing sterile males is most effective, because the wild male population decreases. Since females of reproductive age are more resistant, this should ensure a higher number of matings with sterile males. These findings can be used to formulate improved pest control strategies that enhance olive product quality while relying less on insecticides.

Abstract Here, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6α, and IRE1α. Notably, dual EZH2/CDK4/6 blockade also reduced 3D-spheroid invasion, partially inhibited tumor growth in ovo, and led to impaired viability of patient-derived organoids. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), EMT-counterregulation (PCDH1) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation.

Abstract The frequency of unprovoked shark bites is increasing worldwide, leading to a growing pressure for mitigation measures to reduce shark-bite risk while maintaining conservation objectives. Personal shark deterrents are a promising and non-lethal strategy that can protect ocean users, but few have been independently and scientifically tested. In Australia, bull (Carcharhinus leucas), tiger (Galeocerdo cuvier), and white sharks (Carcharodon carcharias) are responsible for the highest number of bites and fatalities. We tested the effects of two electric deterrents (Ocean Guardian’s Freedom+ Surf and Freedom7) on the behaviour of these three species. The surf product reduced the probability of bites by 54% across all three species. The diving product had a similar effect on tiger shark bites (69% reduction) but did not reduce the frequency of bites from white sharks (1% increase), likely because the electrodes were placed further away from the bait. Electric deterrents also increased the time for bites to occur, and frequency of reactions and passes for all species tested. Our findings reveal that both Freedom+ Surf and Freedom7 electric deterrents affect shark behaviour and can reduce shark-bite risk for water users, but neither product eliminated the risk of shark bites entirely. The increasing number of studies showing the ability of personal electric deterrents to reduce shark-bite risk highlights personal protection as an effective and important part of the toolbox of shark-bite mitigation measures.

Abstract Background Phase 1 clinical trials involve rigorous safety monitoring to identify any adverse effects of investigational treatments. There is growing evidence that healthy volunteers recruited in these studies may differ with respect to personality traits from the general population. This, in turn, may have a significant impact on the reporting of adverse events, particularly in trials investigating psychoactive treatments, including the psychedelic substances. Main body This analysis stems from our combined experience as investigators in phase 1 clinical trials and conveys an experiential understanding of the impact of psychological heterogeneity on study participation, reporting of adverse events and study outcomes. Conclusion Participant variability due to psychological characteristics is regularly overlooked in phase 1 clinical trials and may significantly impact on reporting of the adverse events. In our opinion, healthy volunteers who present for these studies should not only be defined by the absence of past or current medical and psychiatric illness but also characterised by their psychological attributes.

Abstract Background After settling in the United States (US), immigrants often accumulate obesity and cardiovascular risk factors. As mood is often associated with health behaviors in the US population, mood may be an important mediating factor in immigrant populations. Methods The Healthy Immigrant Community (HIC) study, set in southeast Minnesota, enrolled 475 adult participants in a weight loss intervention designed to reduce cardiovascular risk. Baseline questionnaires assessed mood, nutrition, physical activity, self-efficacy for healthy eating and physical activity, social support, and cohesion. A single-item mood rating of poor or fair was considered “negative”, while ratings of good, very good, or excellent were considered “positive”. Results Hispanic/Latino (n = 268) and Somali (n = 181) adults enrolled in HIC completed baseline measures and were included in this analysis. Participants endorsing negative mood compared to positive mood had lower healthy eating scores (p = 0.02), lower physical activity levels (p = 0.03), lower confidence in eating a healthy diet (p = 0.001), and felt less of a sense of belonging to their community (p = 0.01). Those endorsing negative mood reported receiving less social support to eat healthy (p =

Abstract In response to the COVID-19 pandemic, the American Board of Anesthesiology transitioned from in-person to virtual administration of its APPLIED Examination, assessing more than 3000 candidates for certification purposes remotely in 2021. Four hundred examiners were involved in delivering and scoring Standardized Oral Examinations (SOEs) and Objective Structured Clinical Examinations (OSCEs). More than 80% of candidates started their exams on time and stayed connected throughout the exam without any problems. Only 74 (2.5%) SOE and 45 (1.5%) OSCE candidates required rescheduling due to technical difficulties. Of those who experienced “significant issues”, concerns with OSCE technical stations (interpretation of monitors and interpretation of echocardiograms) were reported most frequently (6% of candidates). In contrast, 23% of examiners “sometimes” lost connectivity during their multiple exam sessions, on a continuum from minor inconvenience to inability to continue. 84% of SOE candidates and 89% of OSCE candidates described “smooth” interactions with examiners and standardized patients/standardized clinicians, respectively. However, only 71% of SOE candidates and 75% of OSCE candidates considered themselves to be able to demonstrate their knowledge and skills without obstacles. When compared with their in-person experiences, approximately 40% of SOE examiners considered virtual evaluation to be more difficult than in-person evaluation and believed the remote format negatively affected their development as an examiner. The virtual format was considered to be less secure by 56% and 40% of SOE and OSCE examiners, respectively. The retirement of exam materials used virtually due to concern for compromise had implications for subsequent exam development. The return to in-person exams in 2022 was prompted by multiple factors, especially concerns regarding standardization and security. The technology is not yet perfect, especially for testing in-person communication skills and displaying dynamic exam materials. Nevertheless, the American Board of Anesthesiology’s experience demonstrated the feasibility of conducting large-scale, high-stakes oral and performance exams in a virtual format and highlighted the adaptability and dedication of candidates, examiners, and administering board staff.

Abstract Topological growth control allows to produce a narrow distribution of outgrown colloidal rods with defined and adjustable length. We use an external magnetic field to assemble paramagnetic colloidal spheres into colloidal rods of a chosen length. The rods reside above a metamorphic hexagonal magnetic pattern. The periodic repetition of specific loops of the orientation of an applied external field renders paramagnetic colloidal particles and their assemblies into active bipeds that walk on the pattern. The metamorphic patterns allow the robust and controlled polymerization of single colloids to bipeds of a desired length. The colloids are exposed to this fixed external control loop that causes multiple simultaneous responses: Small bipeds and single colloidal particles interpret the external magnetic loop as an order to walk toward the active zone, where they assemble and polymerize. Outgrown bipeds interpret the same loop as an order to walk away from the active zone. The topological transition occurs solely for the growing biped and nothing is changed in the environment nor in the magnetic control loop. As in many biological systems the decision of a biped that reached its outgrown length to walk away from the reaction site is made internally, not externally.

Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function is mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include ‘priming’ MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Furthermore, clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.

Abstract Introduction Oral antiviral medications are important tools for preventing severe COVID-19 outcomes. However, their uptake remains low for reasons that are not entirely understood. Our study aimed to assess the association between perceived risk for severe COVID-19 outcomes and oral antiviral use among those who were eligible for treatment based on Centers for Disease Control and Prevention (CDC) guidelines. Methods We surveyed 4034 non-institutionalized US adults in April 2023, and report findings from 934 antiviral-eligible participants with at least one confirmed SARS-CoV-2 infection since December 1, 2021 and no current long COVID symptoms. Survey weights were used to yield nationally representative estimates. The primary exposure of interest was whether participants perceived themselves to be “at high risk for severe COVID-19.” The primary outcome was use of a COVID-19 oral antiviral within 5 days of suspected SARS-CoV-2 infection. Results Only 18.5% of antiviral-eligible adults considered themselves to be at high risk for severe COVID-19 and 16.8% and 15.9% took oral antivirals at any time or within 5 days of SARS-CoV-2 infection, respectively. In contrast, 79.8% were aware of antiviral treatments for COVID-19. Perceived high-risk status was associated with being more likely to be aware (adjusted prevalence ratio [aPR]: 1.11 [95% confidence interval (CI) 1.03–1.20]), to be prescribed (aPR 1.47 [95% CI 1.08–2.01]), and to take oral antivirals at any time (aPR 1.61 [95% CI 1.16–2.24]) or within 5 days of infection (aPR 1.72 [95% CI 1.23–2.40]). Conclusions Despite widespread awareness of the availability of COVID-19 oral antivirals, more than 80% of eligible US adults did not receive them. Our findings suggest that differences between perceived and actual risk for severe COVID-19 (based on current CDC guidelines) may partially explain this low uptake.

Abstract Objective While risk factors for osteoarthritis (OA) are well known, it is not well understood why certain individuals maintain high mobility and joint health throughout their life while others demonstrate OA at older ages. The purpose of this study was to assess which demographic, clinical and MRI quantitative and semi-quantitative factors are associated with preserving healthy knees in older individuals. Methods This study analyzed data from the OA Initiative (OAI) cohort of individuals at the age of 65 years or above. Participants without OA at baseline (BL) (Kellgren-Lawrence (KL) ≤ 1) were followed and classified as incident cases (KL ≥ 2 during follow-up; n = 115) and as non-incident (KL ≤ 1 over 96-month; n = 391). Associations between the predictor-variables sex, age, BMI, race, clinical scoring systems, T2 relaxation times and Whole-Organ Magnetic Resonance Imaging-Score (WORMS) readings at BL and the preservation of healthy knees (KL ≤ 1) during a 96-month follow-up period were assessed using logistic regression models. Results Obesity and presence of pain showed a significant inverse association with maintaining radiographically normal joints in patients aged 65 and above. T2 relaxation times of the lateral femur and tibia as well as the medial femur were also significantly associated with maintaining radiographically normal knee joints. Additionally, absence of lesions of the lateral meniscus and absence of cartilage lesions in the medial and patellofemoral compartments were significantly associated with maintaining healthy knee joints. Conclusion Overall, this study provides protective clinical parameters as well as quantitative and semi-quantitative MR-imaging parameters associated with maintaining radiographically normal knee joints in an older population over 8 years.

Abstract Quantum systems evolve in time in one of two ways: through the Schrödinger equation or wavefunction collapse. So far, deterministic control of quantum many-body systems in the lab has focused on the former, due to the probabilistic nature of measurements. This imposes serious limitations: preparing long-range entangled states, for example, requires extensive circuit depth if restricted to unitary dynamics. In this work, we use mid-circuit measurement and feed-forward to implement deterministic non-unitary dynamics on Quantinuum’s H1 programmable ion-trap quantum computer. Enabled by these capabilities, we demonstrate a constant-depth procedure for creating a toric code ground state in real-time. In addition to reaching high stabilizer fidelities, we create a non-Abelian defect whose presence is confirmed by transmuting anyons via braiding. This work clears the way towards creating complex topological orders in the lab and exploring deterministic non-unitary dynamics via measurement and feed-forward.

Abstract A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.

Abstract Vaccines generally require T lymphocytes for B-cell activation and immunoglobulin class switching in response to peptide or protein antigens. In the absence of T cells, limited IgG class switch takes place, germinal centers are short-lived, and the B cells lack memory. Here, immunization of mice with liposomes containing 15mer peptides and monophosphoryl lipid A (MPLA) as adjuvant, induced T-cell independent (TI) IgG class switch within three days, as well as germinal center formation. The antibody responses were long-lived, strictly dependent on Toll-like receptor 4 (TLR4) signaling, partly dependent on Bruton’s tyrosine kinase (BTK) signal transmission, and independent of signaling through T-cell receptors, MHC class II and inflammasome. The antibody response showed characteristics of both TI type 1 and TI type 2. All IgG subclasses could be boosted months after primary immunization, and the biological function of the secreted antibodies was demonstrated in murine models of allergic anaphylaxis and of bacterial infection. Moreover, antibody responses after immunization with peptide- and MPLA-loaded liposomes could be triggered in neonatal mice and in mice receiving immune-suppressants. This study demonstrates T-cell independent endogenous B-cell memory and recall responses in vivo using a peptide antigen. The stimulation of these antibody responses required a correct and dense assembly and administration of peptide and adjuvant on the surface of liposomes. In the future, TI vaccines may prove beneficial in pathological conditions in which T-cell immunity is compromised through disease or medicines or when rapid, antibody-mediated immune protection is needed.

Abstract Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Abstract Aquaculture is a rapidly growing food production technology, but there are significant concerns related to its environmental impact and adverse social effects. We examine aquaculture outcomes in a three pillars of sustainability framework by analyzing data collected using the Aquaculture Performance Indicators. Using this approach, comparable data has been collected for 57 aquaculture systems worldwide on 88 metrics that measure social, economic, or environmental outcomes. We first examine the relationships among the three pillars of sustainability and then analyze performance in the three pillars by technology and species. The results show that economic, social, and environmental outcomes are, on average, mutually reinforced in global aquaculture systems. However, the analysis also shows significant variation in the degree of sustainability in different aquaculture systems, and weak performance of some production systems in some dimensions provides opportunity for innovative policy measures and investment to further align sustainability objectives.

Abstract Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent’s use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.

Abstract Mental disorders are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders. Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and near-complete genealogies of Denmark and Sweden (n = 17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six mental disorders and 15 cardiometabolic disorders. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with cardiometabolic disorders, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with cardiometabolic disorders was mainly or fully driven by environmental factors. In this work we provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

A direct comparison is made between the effectiveness of Al, Mg, and Be powders as additional fuels in model thermobaric compositions containing 20% fuel, 20% ammonium perchlorate, and 60% RDX (1,3,5-Trinitro-1,3,5-triazacyclohexane) passivated with wax. Experimentally determined calorimetric measurements of the heat of detonation, along with the overpressure histories in an explosion chamber filled with nitrogen, were used to determine the quasi-static pressure (QSP) under anaerobic conditions. Overpressure measurements were also performed in a semi-closed bunker, and all blast wave parameters generated after the detonation of 500 g charges of the tested explosives were determined. Detonation calorimetry results, QSP values, and blast wave parameters (pressure amplitude, specific and total impulses) clearly indicate that Be is much more effective as an additional fuel than either Al or Mg in both anaerobic post-detonation reactions as well as the subsequent aerobic combustion. The heat of detonation of the RDXwax/AP/Be explosive mixture is over 40% and 50% higher than that of the mixture containing aluminum and magnesium instead of beryllium, respectively. Moreover, the TNT equivalent of the Be-containing composition due to the overpressure in the nitrogen-filled explosion chamber is 1.66, while the equivalent calculated using an air shock wave-specific impulse at a distance of 2.5 m is equal to 1.69. The high values of these parameters confirm the high reactivity of beryllium in both the anaerobic and aerobic stages of the thermobaric explosion.

Abstract Bioadhesive materials and patches are promising alternatives to surgical sutures and staples. However, many existing bioadhesives do not meet the functional requirements of current surgical procedures and interventions. Here, we present a translational patch material that exhibits instant adhesion to tissues (2.5-fold stronger than Tisseel, an FDA-approved fibrin glue), ultra-stretchability (stretching to >300% its original length without losing elasticity), compatibility with rapid photo-projection (

Abstract Aims Obesity and epicardial adiposity play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), and both are associated with increased filling pressures and reduced exercise capacity. The haemodynamic basis for these observations remains inaccurately defined. We hypothesize that an abundance of epicardial adipose tissue (EAT) within the pericardial sac is associated with haemodynamic signs of pericardial constraint. Methods and results HFpEF patients who underwent invasive heart catheterization with simultaneous echocardiography were included. Right atrial pressure (RAP), right ventricular end‐diastolic pressure, and pulmonary capillary wedge pressure (PCWP) were invasively measured. The presence of a square root sign on the right ventricular pressure waveform and the RAP/PCWP ratio (surrogate parameters for pericardial constraint) were investigated. EAT thickness alongside the right ventricle was measured on echocardiography. Sixty‐four patients were studied, with a mean age of 73 ± 10 years, 64% women, and a mean body mass index (BMI) of 28.6 ± 5.4 kg/m2. In total, 47 patients (73%) had a square root sign. The presence of a square root sign was associated with higher BMI (29.3 vs. 26.7 kg/m2, P = 0.02), higher EAT (4.0 vs. 3.4 mm, P = 0.03), and higher RAP (9 vs. 6 mmHg, P = 0.04). Women had more EAT than men (4.1 vs. 3.5 mm, P = 0.04), despite a comparable BMI. Women with a square root sign had significantly higher EAT (4.3 vs. 3.3 mm, P = 0.02), a higher mean RAP (9 vs. 5 mmHg, P = 0.02), and a higher RAP/PCWP ratio (0.52 vs. 0.26, P = 0.002). In men, such associations were not seen, although there was no significant interaction between men and women (P > 0.05 for all analyses). Conclusions Obesity and epicardial adiposity are associated with haemodynamic signs of pericardial constraint in patients with HFpEF. The pathophysiological and therapeutic implications of this finding need further study.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Blue (Balaenoptera musculus) and fin (B. physalus) whales are prominent species in the California Current Ecosystem (CCE) using the area for migration and foraging. Blue whales migrate between tropical wintering grounds and higher latitude foraging grounds in the CCE, whereas fin whales may remain there year-round. We used Argos tracks of 182 blue (mean duration: 78 days) and 98 fin (mean duration: 35 days) whales tagged from 1994-2018 along the U.S. West Coast to examine residence time and occupancy in U.S. Navy training and testing areas. Bayesian hierarchical switching state-space model locations calculated from Argos tracks were used to provide residence time and proportion of tracking duration within each Navy area. We also calculated relative occupancy isopleths from the state space models, for both directed and non-directed movement, to assess spatial use of Navy areas. We then used generalized linear mixed models and beta regression to examine relationships between Navy area use and covariates, including six climate indices. Point Mugu Sea Range (PMSR) was the most heavily used Navy area by both species in terms of whale numbers, followed by the Southern California Range Complex (SOCAL). Residence time was longest in PMSR for blue whales and in the Northwest Training and Testing Study Area (NWTT) for fin whales. Blue whale use in PMSR was greater in summer versus autumn and for whales tagged in Southern versus Central California. Proportion of tracking duration decreased in all areas with increasing values of the Oceanic Niño Index (ONI), and in PMSR, with increasing values of the North Pacific Gyre Oscillation. Fin whale residence time was longer in PMSR during summer than winter or spring and decreased with increasing values of Habitat Compression Index and ONI. Proportion of tracking duration for fin whales was greatest in summer in PMSR and in winter in SOCAL and NWTT. Overlap of directed and non-directed movement was greatest in PMSR for both species. This assessment of blue and fin whale residence time and occupancy in Navy areas improves our understanding of potential threats these animals face, not only from military activities in Navy areas, but throughout the CCE.

Background Heart failure (HF) is a chronic disease characterized by high mortality and healthcare expenditures. Digital health solutions, including mobile health applications (apps), offer opportunities to enhance patients’ self-care and quality of life. This qualitative study aimed to explore expectations, experiences, and usage behaviour of HF-patients regarding a self-care app ( DoctorME app). Methods Semi-structured interviews were conducted at 2-3 weeks (initial: n = 38), and 4–6 months (post: n = 45) of app use across four European countries. Most patients were male (initial: 84%; post: 78%), aged 60–69 years (initial and post: 29%), with mild HF symptoms. Interviews were transcribed, pseudonymised, and analysed using qualitative content analysis. Results Five key themes were identified: 1) expectations , 2) perceived usability and benefit, 3) usage behaviour and experiences, 4) self-care, and 5) social influences. Patients expected and valued continuous monitoring of vital signs and weight, early detection of deterioration, and quick feedback. The app was considered user-friendly, with most patients using it as recommended (eight times per month). Those reporting improved self-care attributed it to increased awareness and a sense of security. Patients with established self-care routines did not perceive any additional benefit. Patients’ perceptions on the impact of healthcare professionals’ and relatives opinions on app use were divided. Conclusions User-friendliness, continuous monitoring, rapid feedback, and e-learning modules are crucial for integrating self-care apps into daily HF care. While technical reliability and individualisation may enhance long-term use, most HF patients considered the app as a complement to, not a replacement for, professional healthcare guidance.