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In many Arctic regions, marine coastlines change rapidly in our currently warming climate. In contrast, coastal rock cliffs on Svalbard are considered to be relatively stable. Long-term trends of coastal-retreat rates for rock cliffs on Svalbard remain unknown, but quantifying them could improve our understanding of coastal dynamics in the Canadian Arctic Archipelago. This study presents coastal-retreat rates for rock cliffs along several kilometres of Brøggerhalvøya, Svalbard. The analysis relies on high-resolution orthoimages from 1970, 1990, 2010, and 2021. The data are corroborated by high-precision dGNSS (differential Global Navigation Satellite System) measurements obtained along selected segments of the coastline. Our analysis reveals statistically significant acceleration in coastal-retreat rates across Brøggerhalvøya between 2010 and 2021. The northeast-facing coastline features fairly stable conditions, with retreat rates of 0.04 ± 0.06 m a−1 (1970–1990; calculated retreat rate ± the corresponding measurement uncertainty), 0.04 ± 0.04 m a−1 (1990–2010), and 0.06 ± 0.08 m a−1 (2010–2021). Along the southwest-facing coastline, higher retreat rates of 0.26 ± 0.06 m a−1 (1970–1990), 0.24 ± 0.04 m a−1 (1990–2010), and 0.30 ± 0.08 m a−1 (2010–2021) were calculated. For the most recent decade, this corresponds to an increase of 50 % for the northeast-facing coastline and an increase of 25 % for the southwest-facing coastline. Furthermore, for the northeast-facing coastline, the proportion of the coastline affected by erosion increased from 47 % (1970–1990) to 65 % (2010–2021), while it stayed consistently above 90 % for the southwest-facing coastline. The recent acceleration in retreat rates coincides with increasing storminess and retreating sea ice, factors that can enhance coastal erosion.

Abstract Eccentric upper‐body exercise performed 24 h prior to high‐altitude decompression has previously been shown to aggravate venous gas emboli (VGE) load. Yet, it is unclear whether increasing the muscle mass recruited (i.e., upper vs. whole‐body) during eccentric exercise would exacerbate the decompression strain. Accordingly, this study aimed to investigate whether the total muscle mass recruited during eccentric exercise influences the decompression strain. Eleven male participants were exposed to a simulated altitude of 24,000 ft for 90 min on three separate occasions. Twenty‐four hours before each exposure, participants performed one of the following protocols: (i) eccentric whole‐body exercise (ECCw; squats and arm‐cycling exercise), (ii) eccentric upper‐body exercise (ECCu; arm‐cycling), or (iii) no exercise (control). Delayed onset muscle soreness (DOMS) and isometric strength were evaluated before and after each exercise intervention. VGE load was evaluated at rest and after knee‐ and arm‐flex provocations using the 6‐graded Eftedal–Brubakk scale. Knee extensor (−20 ± 14%, P = 0.001) but not elbow flexor (−12 ± 18%, P = 0.152) isometric strength was reduced 24 h after ECCw. ECCu reduced elbow flexor isometric strength at 24 h post‐exercise (−18 ± 10%, P

Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.

Abstract This study aimed to investigate the effect of eccentric exercise on exercise‐induced muscle damage (EIMD) and inflammation on high‐altitude‐induced venous gas emboli (VGE). Subjects were exposed to an altitude of 24,000 ft. for 90 min, with either prior eccentric exercise (ECC) or no exercise (Control) 24 h before. Blood samples were collected at baseline (T0), before (T1), and after (T2) altitude exposures. VGE load was evaluated using the Eftedal‐Brubakk (ΕΒ) scale. Creatine kinase (CK) and myoglobin were used to assess muscle damage, while interleukin‐6 (IL‐6), tumor necrosis factor alpha (TNF‐α), C‐reactive protein (CRP), and fibrinogen were used to evaluate inflammation. ECC showed higher EB‐scores during altitude exposures [median(range), 3(0–5)] than Control [1(0–4), p = 0.019]. Increases in myoglobin (+35%, p = 0.012), CK (+130%, p

Despite the high density of brown bears (Ursus arctos piscator) on the Kamchatka peninsula their genetic variation has not been studied by STR analysis. Our aim was, therefore, to provide population data from the Kamchatka brown bear population applying a validated DNA profiling system. Twelve dinucleotide STRs commonly used in Western-European (WE) populations and four additional ones (G10C, G10J, G10O, G10X), were included. Template input ≥ 0.2 ng was successfully amplified. Measurements of precision, stutter and heterozygous balance showed that markers could be reliably genotyped applying the thresholds used for genotyping WE brown bears. However, locus G10X revealed an ancient allele-specific polymorphism that led to suboptimal amplification of all 174 bp alleles (Kamchatka and WE). Allele frequency estimates and forensic genetic parameters were obtained from 115 individuals successfully identified by genotyping 434 hair samples. All markers met the Hardy-Weinberg and linkage equilibrium expectations, and the power of discrimination ranged from 0.667 to 0.962. The total average probability of identity from the 15 STRs was 1.4 ×10−14 (FST = 0.05) while the total average probability of sibling identity was 6.0 ×10−6. Relationship tests revealed several parent-cub and full sibling pairs demonstrating that the marker set would be valuable for the study of family structures. The population data is the first of its kind from the Kamchatka brown bear population. Population pairwise FST`s revealed moderate genetic differentiation that mirrored the geographic distances to WE populations. The DNA profiling system, providing individual-specific profiles from non-invasive samples, will be useful for future monitoring and conservation purposes

The soft X-ray photoelectron momentum microscopy (PMM) experimental station at the UVSOR Synchrotron Facility has been recently upgraded by additionally guiding vacuum ultraviolet (VUV) light in a normal-incidence configuration. PMM offers a very powerful tool for comprehensive electronic structure analyses in real and momentum spaces. In this work, a VUV beam with variable polarization in the normal-incidence geometry was obtained at the same sample position as the soft X-ray beam from BL6U by branching the VUV beamline BL7U. The valence electronic structure of the Au(111) surface was measured using horizontal and vertical linearly polarized (s-polarized) light excitations from BL7U in addition to horizontal linearly polarized (p-polarized) light excitations from BL6U. Such highly symmetric photoemission geometry with normal incidence offers direct access to atomic orbital information via photon polarization-dependent transition-matrix-element analysis.

Abstract Background The COVID-19 pandemic and other life events may trigger worries and psychological distress. These impacts may lead to unhealthy behaviors, such as tobacco smoking, but the degree of such associations is unclear. The current three-wave longitudinal study examines changes in tobacco smoking in Norway between 2020 and 2022 and their associations with psychological distress as well as health- and economy-related worries. Methods Data were collected in April 2020 (baseline), January 2021, and January 2022 in Bergen, Norway, from an online longitudinal population-based survey. Smoking tobacco (the outcome variable) was dichotomized based on the responses to the question of whether participants smoked cigarettes or not. Tobacco smoking and its associations with psychological distress were assessed among 24,914 participants (response rate 36%) in a mixed model regression presented with coefficients and 95% confidence intervals (CI), adjusting for COVID-19-related worries, home office/study, occupational situation, age, gender, education, having children below 18 years living at home, living alone, and alcohol consumption. Results A total of 10% of the study sample were current smokers at baseline. At baseline, smoking tobacco was associated with high levels of psychological distress (absolute difference 13%, 95% CI 10%; 15%), advanced age (50−59 years: 11%, CI 10%; 13%), and hazardous alcohol use (4%, CI 3%; 5%) compared to their counterparts. Higher education (-5%, CI -6%; -4%), working from home (-4%, CI -5%; -4%), and higher physical activity levels (-4%, CI -5%; -3%) were associated with non-smoking. The prevalence of smoking among individuals experiencing severe psychological distress decreased slightly over time (-2% per year, CI -3%; -1%). Conclusions Smoking was associated with severe psychological distress, advanced age, and hazardous alcohol use at baseline; non-smoking was associated with high education, working from home, and high physical activity. Nevertheless, the smoking rate among individuals experiencing severe psychological distress slightly decreased over the course of the COVID-19 pandemic.

Abstract Background The order Lepidoptera has an abundance of species, including both agriculturally beneficial and detrimental insects. Molecular data has been used to investigate the phylogenetic relationships of major subdivisions in Lepidoptera, which has enhanced our understanding of the evolutionary relationships at the family and superfamily levels. However, the phylogenetic placement of many superfamilies and/or families in this order is still unknown. In this study, we determine the systematic status of the family Argyresthiidae within Lepidoptera and explore its phylogenetic affinities and implications for the evolution of the order. We describe the first mitochondrial (mt) genome from a member of Argyresthiidae, the apple fruit moth Argyresthia conjugella. The insect is an important pest on apples in Fennoscandia, as it switches hosts when the main host fails to produce crops. Results The mt genome of A. conjugella contains 16,044 bp and encodes all 37 genes commonly found in insect mt genomes, including 13 protein-coding genes (PCGs), two ribosomal RNAs, 22 transfer RNAs, and a large control region (1101 bp). The nucleotide composition was extremely AT-rich (82%). All detected PCGs (13) began with an ATN codon and terminated with a TAA stop codon, except the start codon in cox1 is ATT. All 22 tRNAs had cloverleaf secondary structures, except trnS1, where one of the dihydrouridine (DHU) arms is missing, reflecting potential differences in gene expression. When compared to the mt genomes of 507 other Lepidoptera representing 18 superfamilies and 42 families, phylogenomic analyses found that A. conjugella had the closest relationship with the Plutellidae family (Yponomeutoidea-super family). We also detected a sister relationship between Yponomeutoidea and the superfamily Tineidae. Conclusions Our results underline the potential importance of mt genomes in comparative genomic analyses of Lepidoptera species and provide valuable evolutionary insight across the tree of Lepidoptera species.

Abstract Foam formation is a massive challenge in submerged aerated bioprocesses, e.g., in beer fermentation. While the use of antifoam may easily overcome foaming at laboratory scale, it is often an unattractive solution since the challenge remains in future upscaling, as reduced mass transfer and extra steps in product purification and analytics result in increased costs. Interestingly, the number of studies tackling this challenge is relatively low, although literature suggests a range of alternatives, from avoiding foaming to means of controlling or even using foaming as an in situ product removal. Here we give an overview of the topic in five subsections. (1) We argue that a sound understanding of the molecular origin of foaming can facilitate solutions for overcoming the challenge while introducing some long-known challenges (i.e., in beer fermentation). We then review in (2) the apparent avoidance of foam formation before we in (3) summarize possibilities to reduce and control foam after its formation. Subsequently, in (4), we discuss possible solutions that take advantage of foam formation, for example, via foam fractionation for in situ product removal. Finally, in (5), we provide an overview of microbial strain engineering approaches to cope with some aspects of foaming in fermentations. With this review, we would like to sensitize and inform the interested reader while offering an overview of the current literature for the expert, particularly with regard to the foam special issue in Discover Chemical Engineering.

The abundance and diversity of antimicrobial-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs) in agricultural landscapes may be important for the spread of antimicrobial resistance (AMR) in the environment. The aim of this study was to apply screening methods for ARB and ARGs to investigate the impact of farming on the prevalence of AMR in a country with low antibiotic usage. We have analyzed samples (n = 644) from soil and wild terrestrial animals and plants (slugs, snails, mice, shrews, earthworms, and red clover) collected over two years in agricultural fields accompanied by nearby control areas with low human activity. All samples were investigated for the occurrence of 35 different ARGs using high-throughput quantitative PCR (HT-qPCR) on a newly developed DNA array. In addition, samples from the first year (n = 415) were investigated with a culture-based approach combined with whole-genome sequencing (WGS) to identify antimicrobial-resistant E. coli (AREC). ARGs were detected in 59.5% of all samples (2019 + 2020). AREC, which was only investigated in the 2019 samples, was identified in 1.9% of these. Samples collected in the autumn showed more ARGs and AREC than spring samples, and this was more pronounced for organic fields than for conventional fields. Control areas with low human activity showed lower levels of ARGs and a lack of AREC. The use of livestock manure was correlated with a higher level of ARG load than other farming practices. None of the soil samples contained antibiotics, and no association was found between AMR and the levels of metals or pesticides. High qualitative similarity between HT-qPCR and WGS, together with the positive controls to the validation of our 35 ARG assays, show that the microfluid DNA array may be an efficient screening tool on environmental samples. In conclusion, even in a country with a very low consumption of antimicrobials by production animals, our results support the hypothesis of these animals being a source of AREC and ARGs in agricultural environments, primarily through the use of manure.

It is not well investigated whether exposure to specific drug classes is associated with COVID-19. We investigated the risk of SARS-CoV-2 infection and severe COVID-19 among healthcare workers according to prescription drug use. We conducted an observational study among Danish healthcare workers. SARS-CoV-2 positivity was defined as a positive PCR/ELISA test throughout 2020 and severe COVID-19 as any above 48-hour hospitalization within 14 days after infection. Patient characteristics came from online surveys while data on SARS-CoV-2, drugs and hospitalizations came from Danish Health Registers. Infected individuals were matched with uninfected controls based on age, sex, and chronic diseases. Drug exposure was defined as any prescription redemption in the past six and one month(s) before infection for each drug class. Models assessing the risk of infection (conditional logistic regression) and severe COVID-19 (logistic regressions) versus drug usage were adjusted for BMI, smoking, alcohol, education, region, and patient contact when possible. We matched 5,710 SARS-CoV-2-infected cases with 57,021 controls. The odds of infection were reduced by calcium channel blocker (adjusted odds ratio (aOR) 0.81, 95% Confidence Interval (CI): 0.66-1.00) and vasoprotective drug (aOR 0.77, CI: 0.62-0.95) usage during the six months before infection compared to no usage. Exposure to antibacterials in the past month increased the odds of infection (aOR 1.27, CI: 1.09-1.48). Among infected participants, the odds of severe COVID-19 were higher with usage of almost any investigated drug, especially, diuretics (crude odds radio (OR) 4.82, CI:2.15-10.83), obstructive airway disease drugs (OR 4.49, CI: 2.49-8.08), and antibacterials (OR 2.74 CI:1.62-4.61). In conclusion, antibacterials were associated with more SARS-CoV-2 infections and calcium channel blockers with less. Once infected, users of prescription drugs had higher odds of developing severe COVID-19. These findings suggest a need for studies to clarify interactions between specific drug groups, behaviour, known risk factors, and disease susceptibility/severity.

BackgroundOvarian cancer is a challenging disease to diagnose and treat effectively with five-year survival rates below 50%. Previous patient experience research in high-income countries highlighted common challenges and opportunities to improve survival and quality of life for women affected by ovarian cancer. However, no comparable data exist for low-and middle-income countries, where 70% of women with the disease live. This study aims to address this evidence gap.MethodsThis is an observational multi-country study set in low- and middle-income countries. We aim to recruit over 2000 women diagnosed with ovarian cancer across multiple hospitals in 24 countries in Asia, Africa and South America. Country sample sizes have been calculated (n = 70-96 participants /country), taking account of varying national five-year disease prevalence rates. Women within five years of their diagnosis, who are in contact with participating hospitals, are invited to take part in the study. A questionnaire has been adapted from a tool previously used in high-income countries. It comprises 57 multiple choice and two open-ended questions designed to collect information on demographics, women's knowledge of ovarian cancer, route to diagnosis, access to treatments, surgery and genetic testing, support needs, the impact of the disease on women and their families, and their priorities for action. The questionnaire has been designed in English, translated into local languages and tested according to local ethics requirements. Questionnaires will be administered by a trained member of the clinical team.ConclusionThis study will inform further research, advocacy, and action in low- and middle-income countries based on tailored approaches to the national, regional and global challenges and opportunities. In addition, participating countries can choose to repeat the study to track progress and the protocol can be adapted for other countries and other diseases.

Abstract Background Thyrotoxic periodic paralysis (TPP) is a rare condition characterized by muscle paralysis, thyrotoxicosis, and hypokalemia. It presents with paralysis of both proximal and distal musculature in upper and lower limbs and may affect respiratory musculature and the cardiac conduction system. Early diagnosis is essential, as the condition is potentially reversible by oral or intravenous potassium treatment, leading to rapid resolution without lasting weakness. Overlooking the diagnosis may result in respiratory failure and cardiac arrhythmias including QT prolongation, Torsades de points, and ventricular arrhythmias. Case presentation A 19-year-old Caucasian man was admitted acutely with paralysis in upper and lower limbs and tachycardia. Over several months, he had experienced anxiousness, sweating more than usual, had daily palpitations, shortness of breath on exertion, and loose stools, and had lost 21 kg over the last year. Initial blood gas showed very low potassium of 1.4 mM, and blood tests showed decreased Thyroid-stimulating hormone (TSH)

Summary: Mechanical forces provide critical biological signals to cells during healthy and aberrant organ development as well as during disease processes in adults. Within the cardiopulmonary system, mechanical forces, such as shear, compressive, and tensile forces, act across various length scales, and dysregulated forces are often a leading cause of disease initiation and progression such as in bronchopulmonary dysplasia and cardiomyopathies. Engineered in vitro models have supported studies of mechanical forces in a number of tissue and disease-specific contexts, thus enabling new mechanistic insights into cardiopulmonary development and disease. This review first provides fundamental examples where mechanical forces operate at multiple length scales to ensure precise lung and heart function. Next, we survey recent engineering platforms and tools that have provided new means to probe and modulate mechanical forces across in vitro and in vivo settings. Finally, the potential for interdisciplinary collaborations to inform novel therapeutic approaches for a number of cardiopulmonary diseases are discussed.

Synthesis of chemically modified hyaluronic acid (HA) polymers has enabled the fabrication of hydrogels, such as norbornene-modified HA (NorHA) hydrogels that can provide tunable mechanical properties. However, current protocols for the synthesis of NorHA polymers rely on the use of dimethyl sulfoxide (DMSO), a solvent that is cost-intensive and requires extensive dialysis to be removed. To address this limitation, we developed an organic solvent-free NorHA synthesis protocol based on the triazine derivative 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) which enables control over the degree of substituted norbornene groups and hydrogel mechanical properties. Our study further demonstrates the incorporation of enzymatically degradable crosslinkers to fabricate NorHA hydrogels as an in vitro platform to tune cell spreading and nascent protein deposition towards their use in tissue engineering and regenerative medicine.

Rock glaciers are geomorphological expressions of permafrost. Close to sea level in northernmost Norway, in the subarctic Nordkinn peninsula, we have observed several rock glaciers that appear to be active now or were active in the recent past. Active rock glaciers at this elevation have never before been described in Fennoscandia, and they are outside the climatic limits of present-day permafrost according to models. In this study, we have investigated whether or not these rock glaciers are active under the current climate situation. We made detailed geomorphological maps of three rock glacier areas in Nordkinn and investigated the regional ground dynamics using synthetic aperture radar interferometry (InSAR). One of the rock glaciers, namely the Ivarsfjorden rock glacier, was investigated in more detail by combining observations of vertical and horizontal changes from optical images acquired by airborne and terrestrial sensors and terrestrial laser scans (TLSs). The subsurface of the same rock glacier was investigated using a combination of electrical resistivity tomography (ERT) and refraction seismic tomography (RST). We also measured ground surface temperatures between 2016 and 2020, complemented by investigations using an infrared thermal camera, and a multi-decadal climatic analysis. We mapped the rock glaciers in the innermost parts of Store and Lille Skogfjorden as relict, while the more active ones are in the mouths of both fjords, fed by active talus in the upper slopes. Several of the rock glaciers cross over both the Younger Dryas shoreline (25 m a.s.l.) and the Early to Mid-Holocene shoreline at 13 m a.s.l. Both InSAR and optical remote sensing observations reveal low yearly movement rates (centimetres to millimetres per year). The ERT and RST suggest that there is no longer permafrost and ground ice in the rock glacier, while temperature observations on the front slope indicate freezing conditions also in summer. Based on the in situ temperature measurements and the interpolated regional temperature data, we show that the mean annual air temperature (MAAT) of the region has risen by 2 ∘C since the late 19th century to about 1.5 ∘C in the last decade. MAATs below 0 ∘C 100–150 years ago suggest that new rock glacier lobes may have formed at the end of the Little Ice Age (LIA). These combined results indicate that the Nordkinn rock glaciers are transitioning from active to relict stages. The study shows that transitional rock glaciers are still affected by creep, rock falls, snow avalanches, etc., and are not entirely dynamically dead features. Our contrasting results concerning permafrost presence and rock glacier activity show the importance of a multi-methodological approach when investigating slope processes in the edge zones of permafrost influence.

IntroductionThe COVID-19 pandemic and infection control measures caused changes to daily life for most people. Heavy alcohol consumption and physical inactivity are two important behavioral risk factors for noncommunicable diseases worldwide. The COVID-19 pandemic, with its social distancing measures, home office policies, isolation, and quarantine requirements may have an impact on these factors. This three-wave longitudinal study aims to investigate if psychological distress and worries related to health and economy were associated with levels and changes in alcohol consumption and physical activity during the two first years of the COVID-19 pandemic in Norway.MethodsWe used data collected in April 2020, January 2021, and January 2022 from an online longitudinal population-based survey. Alcohol consumption and physical activity status were assessed at all three measuring points via the Alcohol Use Disorder Identification Test (AUDIT-C) and the International Physical Activity Questionnaire (IPAQ-SF). COVID-19-related worries, home office/study, occupational situation, age, gender, children below 18 years living at home, and psychological distress (measured with the Symptom Checklist (SCL-10)) were included as independent variables in the model. A mixed model regression was used and presented with coefficients with 95% confidence intervals (CI).ResultsAnalysis of data from 25,708 participants demonstrates that participants with substantial symptoms of psychological distress more often reported higher alcohol consumption (1.86 units/week, CI 1.48–2.24) and lower levels of physical activity [−1,043 Metabolic Equivalents of Task (METs) per week, CI −1,257;−828] at baseline. Working/studying from home (0.37 units/week, CI 0.24–0.50) and being male (1.57 units/week, CI 1.45–1.69) were associated with higher alcohol consumption. Working/studying from home (−536 METs/week, CI −609;−463), and being older than 70 years (−503 METs/week, CI −650;−355) were related to lower levels of physical activity. The differences in activity levels between those with the highest and lowest levels of psychological distress reduced over time (239 METs/week, CI 67;412), and similarly the differences in alcohol intake reduced over time among those having and not having children

Abstract Background Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. Conclusion Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Epithelial organoids derived from intestinal tissue, called enteroids, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, and drug development. Here, we interrogated the cell signaling environment within the developing human intestine to identify niche cues that may be important for epithelial development and homeostasis. We identified an EGF family member, EPIREGULIN (EREG), which is robustly expressed in the developing human crypt. Enteroids generated from the developing human intestine grown in standard culture conditions, which contain EGF, are dominated by stem and progenitor cells and feature little differentiation and no spatial organization. Our results demonstrate that EREG can replace EGF in vitro, and EREG leads to spatially resolved enteroids that feature budded and proliferative crypt domains and a differentiated villus-like central lumen. Multiomic (transcriptome plus epigenome) profiling of native crypts, EGF-grown enteroids, and EREG-grown enteroids showed that EGF enteroids have an altered chromatin landscape that is dependent on EGF concentration, downregulate the master intestinal transcription factor CDX2, and ectopically express stomach genes, a phenomenon that is reversible. This is in contrast to EREG-grown enteroids, which remain intestine like in culture. Thus, EREG creates a homeostatic intestinal niche in vitro, enabling interrogation of stem cell function, cellular differentiation, and disease modeling.

Sleep is a complex and plastic behavior regulated by multiple brain regions and influenced by numerous internal and external stimuli. Thus, to fully uncover the function(s) of sleep, cellular resolution of sleep-regulating neurons needs to be achieved. Doing so will help to unequivocally assign a role or function to a given neuron or group of neurons in sleep behavior. In the Drosophila brain, neurons projecting to the dorsal fan-shaped body (dFB) have emerged as a key sleep-regulating area. To dissect the contribution of individual dFB neurons to sleep, we undertook an intersectional Split-GAL4 genetic screen focusing on cells contained within the 23E10-GAL4 driver, the most widely used tool to manipulate dFB neurons. In this study, we demonstrate that 23E10-GAL4 expresses in neurons outside the dFB and in the fly equivalent of the spinal cord, the ventral nerve cord (VNC). Furthermore, we show that 2 VNC cholinergic neurons strongly contribute to the sleep-promoting capacity of the 23E10-GAL4 driver under baseline conditions. However, in contrast to other 23E10-GAL4 neurons, silencing these VNC cells does not block sleep homeostasis. Thus, our data demonstrate that the 23E10-GAL4 driver contains at least 2 different types of sleep-regulating neurons controlling distinct aspects of sleep behavior.

Introduction: Biomolecules bind to and transform nanoparticles, mediating their fate in biological systems. Despite over a decade of research into the protein corona, the role of protein modifications in mediating their interaction with nanomaterials remains poorly understood. In this study, we evaluated how glycation of the most abundant blood protein, human serum albumin (HSA), influences the formation of the protein corona on 40 nm silver nanoparticles (AgNPs) and the toxicity of AgNPs to the HepG2 human liver cell line.Methods: The effects of glycation on AgNP-HSA interactions were quantified using circular dichroism spectroscopy to monitor protein structural changes, dynamic light scattering to assess AgNP colloidal stability, zeta potential measurements to measure AgNP surface charge, and UV-vis spectroscopy and capillary electrophoresis (CE) to evaluate protein binding affinity and kinetics. The effect of the protein corona and HSA glycation on the toxicity of AgNPs to HepG2 cells was measured using the WST cell viability assay and AgNP dissolution was measured using linear sweep stripping voltammetry.Results and Discussion: Results from UV-vis and CE analyses suggest that glycation of HSA had little impact on the formation of the AgNP protein corona with protein-AgNP association constants of ≈2x107 M-1 for both HSA and glycated HSA (gHSA). The formation of the protein corona itself (regardless of whether it was formed from HSA or glycated HSA) caused an approximate 2-fold decrease in cell viability compared to the no protein AgNP control. While the toxicity of AgNPs to cells is often attributed to dissolved Ag(I), dissolution studies showed that the protein coated AgNPs underwent less dissolution than the no protein control, suggesting that the protein corona facilitated a nanoparticle-specific mechanism of toxicity. Overall, this study highlights the importance of protein coronas in mediating AgNP interactions with HepG2 cells and the need for future work to discern how protein coronas and protein modifications (like glycation) may alter AgNP reactivity to cellular organisms.

Abstract The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Objective: To retrospectively evaluate the safety and efficacy of percutaneous image-guided mediastinal mass core-needle biopsy. Patients and Methods: Retrospective review of an institutionally maintained biopsy registry identified 337 computed tomography– or ultrasound-guided percutaneous mediastinal mass core needle biopsies between October 2002 and August 2017 in a single quaternary referral center. Mean patient age was 51 (range, 18 to 93) years. Procedural techniques, anticoagulation/antiplatelet therapy, and tumor anatomical characteristics were reviewed. Classification and gradation of complications was based on the Clavien-Dindo system. Diagnostic yield was defined as the ratio of diagnostic biopsy to all biopsies performed. Results: Mean tumor size was 59.2 (range, 10 to 180) mm with 89.9% (n=303) of lesions located in the prevascular (anterior) mediastinum. There was a single major complication (0.3%) of a symptomatic pneumothorax requiring intervention. There were seven (2.1%) minor complications, including three bleeding complications. A transpleural approach was the only variable associated with an increased complication rate (P

Subarctic peatlands underlain by permafrost contain significant amounts of organic carbon. Our ability to quantify the evolution of such permafrost landscapes in numerical models is critical for providing robust predictions of the environmental and climatic changes to come. Yet, the accuracy of large-scale predictions has so far been hampered by small-scale physical processes that create a high spatial variability of thermal surface conditions, affecting the ground thermal regime and thus permafrost degradation patterns. In this regard, a better understanding of the small-scale interplay between microtopography and lateral fluxes of heat, water and snow can be achieved by field monitoring and process-based numerical modeling. Here, we quantify the topographic changes of the Šuoššjávri peat plateau (northern Norway) over a three-year period using drone-based repeat high-resolution photogrammetry. Our results show thermokarst degradation is concentrated on the edges of the plateau, representing 77 % of observed subsidence, while most of the inner plateau surface exhibits no detectable subsidence. Based on detailed investigation of eight zones of the plateau edge, we show that this edge degradation corresponds to an annual volume change of 0.13±0.07 m3 yr−1 per meter of retreating edge (orthogonal to the retreat direction). Using the CryoGrid3 land surface model, we show that these degradation patterns can be reproduced in a modeling framework that implements lateral redistribution of snow, subsurface water and heat, as well as ground subsidence due to melting of excess ice. By performing a sensitivity test for snow depths on the plateau under steady-state climate forcing, we obtain a threshold behavior for the start of edge degradation. Small snow depth variations (from 0 to 30 cm) result in highly different degradation behavior, from stability to fast degradation. For plateau snow depths in the range of field measurements, the simulated annual volume changes are broadly in agreement with the results of the drone survey. As snow depths are clearly correlated with ground surface temperatures, our results indicate that the approach can potentially be used to simulate climate-driven dynamics of edge degradation observed at our study site and other peat plateaus worldwide. Thus, the model approach represents a first step towards simulating climate-driven landscape development through thermokarst in permafrost peatlands.

Background: Use of physical activity in the treatment and follow-up of people receiving opioid substitution therapy is an understudied area of research. Therefore, the objective of this systematic review was to synthesize the currently available research on the role of physical activity in opioid substitution therapy and proper adaptions for the group. Methods: A systematic search was performed on PsycINFO, EMBASE, MEDLINE, CINAHL, and Web of Science until September 2021 (PROSPERO-reg.no: CRD42020109873). The inclusion criteria were studies involving physical activity interventions for opioid substitution patients. Reference lists of relevant studies were screened to identify additional relevant studies. Data extracted were compiled into tables and descriptively presented. Results: The search yielded 2105 unique records. A total of 10 studies were included, whose methodological quality ranged from satisfactory to very good. Study quality was assessed using a 7-/8-point quality score. The agreement between the reviewers, assessed with Cohen’s kappa, was 0.91. Overall, the results suggest that physical activity increases physical fitness of patients in opioid substitution therapy and decreases substance use. The minority of studies in this field are of high quality with sufficient power. Conclusions: The findings of this systematic review suggest beneficial effects of physical activity on physical fitness, substance use, and mental health for patients in opioid substitution therapy. Although the findings are quite consistent across studies, high-quality studies and sufficiently powered clinical trials are needed to confirm and validate the findings and to conclude on the degree of impact.

Abstract Harvest can disrupt wildlife populations by removing adults with naturally high survival. This can reshape sociospatial structure, genetic composition, fitness, and potentially affect evolution. Genetic tools can detect changes in local, fine‐scale genetic structure (FGS) and assess the interplay between harvest‐caused social and FGS in populations. We used data on 1614 brown bears, Ursus arctos, genotyped with 16 microsatellites, to investigate whether harvest intensity (mean low: 0.13 from 1990 to 2005, mean high: 0.28 from 2006 to 2011) caused changes in FGS among matrilines (8 matrilines; 109 females ≥4 years of age), sex‐specific survival and putative dispersal distances, female spatial genetic autocorrelation, matriline persistence, and male mating patterns. Increased harvest decreased FGS of matrilines. Female dispersal distances decreased, and male reproductive success was redistributed more evenly. Adult males had lower survival during high harvest, suggesting that higher male turnover caused this redistribution and helped explain decreased structure among matrilines, despite shorter female dispersal distances. Adult female survival and survival probability of both mother and daughter were lower during high harvest, indicating that matriline persistence was also lower. Our findings indicate a crucial role of regulated harvest in shaping populations, decreasing differences among “groups,” even for solitary‐living species, and potentially altering the evolutionary trajectory of wild populations.

PurposeHypobaric hypoxic habitats are currently being touted as a potential solution to minimise decompression procedures in preparation for extra vehicular activities during future space missions. Since astronauts will live in hypoxic environments for the duration of such missions, the present study sought to elucidate the separate and combined effects of inactivity [simulated with the experimental bed rest (BR) model] and hypoxia on sleep characteristics in women.MethodsTwelve women (Age = 27 ± 3 year) took part in three 10-day interventions, in a repeated measures cross-over counterbalanced design: (1) normobaric normoxic BR (NBR), (2) normobaric hypoxic BR (HBR; simulated altitude of 4,000 m), and (3) normobaric hypoxic ambulatory (HAMB; 4,000 m) confinement, during which sleep was assessed on night 1 and night 10 with polysomnography. In addition, one baseline sleep assessment was performed. This baseline assessment, although lacking a confinement aspect, was included statistically as a fourth comparison (i.e., pseudo normobaric normoxic ambulatory; pNAMB) in the present study.ResultsHypoxia decreased sleep efficiency (p = 0.019), increased N1% sleep (p = 0.030), decreased N3 sleep duration (p = 0.003), and increased apnea hypopnea index (p < 0.001). BR impaired sleep maintenance, efficiency, and architecture [e.g., N2% sleep increased (p = 0.033)]. Specifically, for N3% sleep, the effects of partial pressure of oxygen and activity interacted. Hypoxia decreased N3% sleep both when active (pNAMB vs HAMB; p < 0.001) and inactive (NBR vs HBR; p = 0.021), however, this decrease was attenuated in the inactive state (–3.8%) compared to the active state (–10.2%).ConclusionA 10-day exposure to hypoxia and BR negatively impacted sleep on multiple levels as in macrostructure, microstructure and respiratory functioning. Interestingly, hypoxia appeared to have less adverse effects on sleep macrostructure while the participants were inactive (bed ridden) compared to when ambulatory. Data were missing to some extent (i.e., 20.8%). Therefore, multiple imputation was used, and our results should be considered as exploratory.

Giant panda could have bamboo as their exclusive diet for about 2 million years because of the contribution of numerous enzymes produced by their gut bacteria, for instance laccases. Laccases are blue multi-copper oxidases that catalyze the oxidation of a broad spectrum of phenolic and aromatic compounds with water as the only byproduct. As a “green enzyme,” laccases have potential in industrial applications, for example, when dealing with degradation of recalcitrant biopolymers, such as lignin. In the current study, a bacterial laccase, Lac51, originating from Pseudomonas putida and identified in the gut microbiome of the giant panda’s gut was transiently expressed in the non-food plant Nicotiana benthamiana and characterized. Our results show that recombinant Lac51 exhibits bacterial laccase properties, with optimal pH and temperature at 7–8 and 40°C, respectively, when using syringaldazine as substrate. Moreover, we demonstrate the functional capability of the plant expressed Lac51 to oxidize lignin using selected lignin monomers that serve as substrates of Lac51. In summary, our study demonstrates the potential of green and non-food plants as a viable enzyme production platform for bacterial laccases. This result enriches our understanding of plant-made enzymes, as, to our knowledge, Lac51 is the first functional recombinant laccase produced in plants.

BackgroundChronic pain is a major health challenge to those affected. Blended care with psychomotor physiotherapy (PMP) combined with eHealth self-management might be beneficial. ObjectiveThis study aims to explore how patients with chronic pain experience the combination of PMP and the use of EPIO, an eHealth self-management intervention for chronic pain. MethodsIndividual semistructured interviews were conducted with 5 adult patients with chronic pain (ie, participants) who used EPIO in combination with PMP over a period of 10 to 15 weeks. Interviews explored participants’ experiences using this treatment combination in relation to their pain and analyzed their experiences using systematic text condensation. ResultsParticipants described having benefited from using EPIO in combination with PMP in terms of increased awareness of bodily signals and how pain was related to stress and activity. They also described changes in the relationship to themselves in terms of increased self-acceptance, self-assertion, and hope and their relationship to their pain in terms of seeing pain as less harmful and engaging in more active coping strategies. ConclusionsResults indicate that a blended care approach combining eHealth self-management interventions such as EPIO with PMP may be of value to patients living with chronic pain. Trial RegistrationClinicalTrials.gov NCT03705104; https://clinicaltrials.gov/ct2/show/NCT03705104

Due to the observations of weight loss at high altitude, normobaric hypoxia has been considered as a method of weight loss in obese individuals. With this regard, the aim of the present study was to determine the effect of hypoxia per se on metabolism in men with excess weight. Eight men living with excess weight (125.0 ± 17.7 kg; 30.5 ± 11.1 years, BMI: 37.6 ± 6.2 kg⋅m–2) participated in a randomized cross-over study comprising two 10-day confinements: normobaric (altitude of facility ≃ 940 m) normoxia (NORMOXIA; PIO2 = 133 mmHg), and normobaric hypoxia (HYPOXIA). The PIO2 in the latter was reduced from 105 (simulated altitude of 2,800 m) to 98 mmHg (simulated altitude of 3,400 m over 10 days. Before, and at the end of each confinement, participants completed a meal tolerance test (MTT). Resting energy expenditure (REE), circulating glucose, GLP-1, insulin, catecholamines, ghrelin, peptide-YY (PYY), leptin, gastro-intestinal blood flow, and appetite sensations were measured in fasted and postprandial states. Fasting REE increased after HYPOXIA (+358.0 ± 49.3 kcal⋅day–1, p = 0.03), but not after NORMOXIA (−33.1 ± 17.6 kcal⋅day–1). Postprandial REE was also significantly increased after HYPOXIA (p ≤ 0.05), as was the level of PYY. Furthermore, a tendency for decreased energy intake was concomitant with a significant body weight reduction after HYPOXIA (−0.7 ± 0.2 kg) compared to NORMOXIA (+1.0 ± 0.2 kg). The HYPOXIA trial increased the metabolic requirements, with a tendency toward decreased energy intake concomitant with increased PYY levels supporting the notion of a hypoxia-induced appetite inhibition, that could potentially lead to body weight reduction. The greater postprandial blood-glucose response following hypoxic confinement, suggests the potential development of insulin resistance.

Hematological changes are commonly observed following prolonged exposure to hypoxia and bed rest. Typically, such responses have been reported as means and standard deviations, however, investigation into the responses of individuals is insufficient. Therefore, the present study retrospectively assessed individual variation in the hematological responses to severe inactivity (bed rest) and hypoxia. The data were derived from three-bed rest projects: two 10-d (LunHab project: 8 males; FemHab project: 12 females), and one 21-d (PlanHab project: 11 males). Each project comprised a normoxic bed rest (NBR; PIO2=133mmHg) and hypoxic bed rest (HBR; PIO2=91mmHg) intervention, where the subjects were confined in the Planica facility (Rateče, Slovenia). During the HBR intervention, subjects were exposed to normobaric hypoxia equivalent to an altitude of 4,000m. NBR and HBR interventions were conducted in a random order and separated by a washout period. Blood was drawn prior to (Pre), during, and post bed rest (R1, R2, R4) to analyze the individual variation in the responses of red blood cells (RBC), erythropoietin (EPO), and reticulocytes (Rct) to bed rest and hypoxia. No significant differences were found in the mean ∆(Pre-Post) values of EPO across projects (LunHab, FemHab, and PlanHab; p>0.05), however, female EPO responses to NBR (Range - 17.39, IQR – 12.97 mIU.ml−1) and HBR (Range – 49.00, IQR – 10.91 mIU.ml−1) were larger than males (LunHab NBR Range – 4.60, IQR – 2.03; HBR Range – 7.10, IQR – 2.78; PlanHab NBR Range – 7.23, IQR – 1.37; HBR Range – 9.72, IQR – 4.91 mIU.ml−1). Bed rest duration had no impact on the heterogeneity of EPO, Rct, and RBC responses (10-d v 21-d). The resultant hematological changes that occur during NBR and HBR are not proportional to the acute EPO response. The following cascade of hematological responses to NBR and HBR suggests that the source of variability in the present data is due to mechanisms related to hypoxia as opposed to inactivity alone. Studies investigating hematological changes should structure their study design to explore these mechanistic responses and elucidate the discord between the EPO response and hematological cascade to fully assess heterogeneity.