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The recent development of high-throughput workflows in genomics and transcriptomics revealed that efficient annotation of such results is essential for researchers to draw conclusions from obtained results. Although some tools are available, their functionality is limited. Here, we present AGouTI-a universal tool for flexible annotation of any genomic or transcriptomic coordinates using known genomic features deposited in different publicly available databases in the form of GTF or GFF files. In contrast to currently available tools, AGouTI is designed to provide a flexible selection of genomic features overlapping or adjacent to annotated intervals and can be used on custom column-based text files obtained from different data analysis pipelines. Although providing many unique options, AGouTI is straightforward in installation and usage, enabling effortless integration into existing data analysis workflows.

We report on a portable dielectrophoresis manipulation platform, for the positioning and immobilization of small dielectric objects, such as cells or microbes, using a circular array of up to six symmetrically arranged and independently controllable micro-electrodes. The system’s micro-controller-instructed electronic drivers can be operated in three distinct modes. We demonstrate the system’s function by actuating bacterial cells to specific locations and orientations within a region of interest. Using a deep learning approach, we map voltage phase combinations of the six electrodes to geometrical trap position locations, thereby facilitating smooth trajectory planning.

Loss-of-function genetic tools are widely applied for validating therapeutic targets, but their utility remains limited by incomplete on- and uncontrolled off-target effects. We describe artificial RNA interference (ARTi) based on synthetic, ultra-potent, off-target-free shRNAs that enable efficient and inducible suppression of any gene upon introduction of a synthetic target sequence into non-coding transcript regions. ARTi establishes a scalable loss-of-function tool with full control over on- and off-target effects.

Abstract The effect of electron‐beam patterning on the water uptake and ionic conductivity of Nafion films using a combination of X‐ray photoelectron spectroscopy, quartz crystal microbalance studies, neutron reflectometry, and impedance spectroscopy is reported. The aim is to further characterize the nanoscale patterned Nafion structures recently used as a key element in novel ion‐to‐electron transducers by Gluschke et al. To enable this, the electron beam patterning process is developed for large areas, achieving patterning speeds approaching 1 cm2 h−1, and patterned areas as large as 7 cm2 for the neutron reflectometry studies. It is ultimately shown that electron‐beam patterning affects both the water uptake and the ionic conductivity, depending on film thickness. Type‐II adsorption isotherm behavior is seen for all films. For thick films (≈230 nm), a strong reduction in water uptake with electron‐beam patterning is found. In contrast, for thin films (≈30 nm), electron‐beam patterning enhances water uptake. Notably, for either thickness, the reduction in ionic conductivity arising from electron‐beam patterning is kept to less than an order of magnitude. Mechanisms are proposed for the observed behavior based on the known complex morphology of Nafion films to motivate future studies of electron‐beam processed Nafion.

Precancerous cells in the oral cavity may appear as oral potentially malignant disorders, but they may also present as dysplasia without visual manifestation in tumor-adjacent tissue. As it is currently not possible to prevent the malignant transformation of these oral precancers, new treatments are urgently awaited. Here, we generated precancer culture models using a previously established method for the generation of oral keratinocyte cultures and incorporated CRISPR/Cas9 editing. The generated cell lines were used to investigate the efficacy of a set of small molecule inhibitors. Tumor-adjacent mucosa and oral leukoplakia biopsies were cultured and genetically characterized. Mutations were introduced in CDKN2A and TP53 using CRISPR/Cas9 and combined with the ectopic activation of telomerase to generate cell lines with prolonged proliferation. The method was tested in normal oral keratinocytes and tumor-adjacent biopsies and subsequently applied to a large set of oral leukoplakia biopsies. Finally, a subset of the immortalized cell lines was used to assess the efficacy of a set of small molecule inhibitors. Culturing and genomic engineering was highly efficient for normal and tumor-adjacent oral keratinocytes, but success rates in oral leukoplakia were remarkably low. Knock-out of CDKN2A in combination with either the activation of telomerase or knock-out of TP53 seemed a prerequisite for immortalization. Prolonged culturing was accompanied by additional genetic aberrations in these cultures. The generated cell lines were more sensitive than normal keratinocytes to small molecule inhibitors of previously identified targets. In conclusion, while very effective for normal keratinocytes and tumor-adjacent biopsies, the success rate of oral leukoplakia cell culturing methods was very low. Genomic engineering enabled the prolonged culturing of OL-derived keratinocytes but was associated with acquired genetic changes. Further studies are required to assess to what extent the immortalized cultures faithfully represent characteristics of the cells in vivo.

This work presents anodically electrodeposited copper (Cu)/chitosan gel as a novel precursor for synthesizing a Cu/carbon nanocomposite through laser-induced carbonization. Metal/carbon nanocomposites offering advantageous properties compared to their individual counterparts stand out in various applications, particularly in those involving electrochemical phenomena. However, their synthesis often suffers from complicated and time-consuming synthesis procedures. Here, we integrate anodic electrodeposition and laser-induced carbonization to yield a rapid, simple, and inexpensive procedure for synthesizing metal/carbon nanocomposite. A precursor composite involving Cu-coordinated chitosan film is achieved through anodic electrodeposition on a copper anode. Irradiation by an infrared laser with optimized parameters results in the thermochemical decomposition of the Cu/chitosan composite, rapidly forming a nanocomposite material featuring highly graphitized and porous carbon materials. Elemental mapping confirms the formation of the nanocomposite, although no crystalline phases of copper are observed during X-ray diffraction. This can be attributed to the rapid nature of the laser-carbonization process. The nanocomposite material is further demonstrated for electrochemical sensing of hydrogen peroxide (H2O2), exhibiting a sensitivity of 2.65 mM−1 for concentrations ranging from 0.01 mM to 0.1 mM H2O2, and 0.01 ± 0.01 mM−1 for concentrations from 0.1 to 10 mM H2O2. These sensitivities are comparable to other non-enzymatic H2O2 biosensors. The finding of this work signifies a rapid and facile method for synthesizing metal/carbon nanocomposites with strong implications for the field of biosensors.

Abstract Background Timely identification of deteriorating COVID-19 patients is needed to guide changes in clinical management and admission to intensive care units (ICUs). There is significant concern that widely used Early warning scores (EWSs) underestimate illness severity in COVID-19 patients and therefore, we developed an early warning model specifically for COVID-19 patients. Methods We retrospectively collected electronic medical record data to extract predictors and used these to fit a random forest model. To simulate the situation in which the model would have been developed after the first and implemented during the second COVID-19 ‘wave’ in the Netherlands, we performed a temporal validation by splitting all included patients into groups admitted before and after August 1, 2020. Furthermore, we propose a method for dynamic model updating to retain model performance over time. We evaluated model discrimination and calibration, performed a decision curve analysis, and quantified the importance of predictors using SHapley Additive exPlanations values. Results We included 3514 COVID-19 patient admissions from six Dutch hospitals between February 2020 and May 2021, and included a total of 18 predictors for model fitting. The model showed a higher discriminative performance in terms of partial area under the receiver operating characteristic curve (0.82 [0.80–0.84]) compared to the National early warning score (0.72 [0.69–0.74]) and the Modified early warning score (0.67 [0.65–0.69]), a greater net benefit over a range of clinically relevant model thresholds, and relatively good calibration (intercept = 0.03 [− 0.09 to 0.14], slope = 0.79 [0.73–0.86]). Conclusions This study shows the potential benefit of moving from early warning models for the general inpatient population to models for specific patient groups. Further (independent) validation of the model is needed.

Abstract Background Miniscrew-Assisted Rapid Palatal Expansion (MARPE) is a non-surgical orthodontic treatment for transverse maxillary deficiency. This study aimed to investigate the Oral Health-related Quality of Life (OHRQoL) and pain perception of patients undergoing MARPE treatment. Methods 42 consecutive patients (9 men, 33 women) from the age of 16 onwards (mean: 27.4 ± 9.3 years; range 17.1–55.7 years) who received a MARPE treatment were included. OHRQoL was assessed with the short form of the Oral Health Impact Profile (OHIP-14) questionnaire. Patients filled out the questionnaire at baseline (T0) and weekly during the expansion phase (P1) and in the post-expansion phase (P2). Pain intensity was assessed with a Visual Analogue Scale (VAS) questionnaire and filled out daily during expansion, along with a question on the intake of analgesics. The mean weekly and total OHIP-score and OHIP-score per domain were calculated at T0, P1 and P2, as well as mean weekly and total VAS-scores for average pain, maximum pain and analgesics intake during P1. Kruskal–Wallis tests were used to test for differences in OHIP between T0, P1 and P2. The level of significance was set at 0.05. Results The mean OHIP-score was 10.86 ± 9.71 at T0 and increased to 17.18 ± 10.43 during P1 (p

Prenatal exposure to endocrine disrupting chemicals can interfere with development, and has been associated with social-cognitive functioning and adverse health outcomes later in life. Exposure-associated changes of DNA methylation (DNAm) patterns have been suggested as a possible mediator of this relationship. This study investigated whether prenatal low-dose exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) is associated with altered DNAm patterns across the genome in a Western urban-industrial population. In 142 mother-infant pairs from the Duisburg Birth Cohort Study, PCBs and PCDD/Fs levels were quantified from maternal blood during late pregnancy and associated with DNAm levels in cord blood using the Illumina EPIC beadchip. The epigenome-wide association studies (EWAS) identified 32 significantly differentially methylated positions (DMPs) and eight differentially methylated regions (DMRs) associated with six congeners of PCB and PCDD in females or males (FDRs < 0.05). DMPs and DMRs mapped to genes involved in neurodevelopment, gene regulation, and immune functioning. Weighted gene correlation network analysis (WGCNA) showed 31 co-methylated modules (FDRs < 0.05) associated with one congener of PCDF levels in females. Results of both analytical strategies indicate that prenatal exposure to PCBs and PCDD/Fs is associated with altered DNAm of genes involved in neurodevelopment, gene expression and immune functioning. DNAm and gene expression levels of several of these genes were previously associated with EDC exposure in rodent models. Follow-up studies will clarify whether these epigenetic changes might contribute to the origin for adverse mental and health outcomes.

Abstract Human salivary histatin 1 (Hst1) exhibits a series of cell-activating properties, such as promoting cell spreading, migration, and metabolic activity. We recently have shown that fluorescently labeled Hst1 (F-Hst1) targets and activates mitochondria, presenting an important molecular mechanism. However, its regulating signaling pathways remain to be elucidated. We investigated the influence of specific inhibitors of G protein-coupled receptors (GPCR), endocytosis pathways, extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, p38 signaling, mitochondrial respiration and Na+/K+-ATPase activity on the uptake, mitochondria-targeting and -activating properties of F-Hst1. We performed a siRNA knockdown (KD) to assess the effect of Sigma-2 receptor (S2R) /Transmembrane Protein 97 (TMEM97)—a recently identified target protein of Hst1. We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1. Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1. The inhibitors of GPCR, ERK1/2, phagocytosis, and clathrin-mediated endocytosis (CME) as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake, which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity. Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1. We further showed the intracellular trafficking and targeting process of F-Hst1, in which early endosome plays an important role. Overall, phagocytosis, CME, GPCR, ERK signaling, and S2R/TMEM97 are involved in the internalization of Hst1, while only CME and S2R/TMEM97 are critical for its subcellular targeting. The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.

Abstract Background Beta-lactam antimicrobial concentrations are frequently suboptimal in critically ill patients. Population pharmacokinetic (PopPK) modeling is the golden standard to predict drug concentrations. However, currently available PopPK models often lack predictive accuracy, making them less suited to guide dosing regimen adaptations. Furthermore, many currently developed models for clinical applications often lack uncertainty quantification. We, therefore, aimed to develop machine learning (ML) models for the prediction of piperacillin plasma concentrations while also providing uncertainty quantification with the aim of clinical practice. Methods Blood samples for piperacillin analysis were prospectively collected from critically ill patients receiving continuous infusion of piperacillin/tazobactam. Interpretable ML models for the prediction of piperacillin concentrations were designed using CatBoost and Gaussian processes. Distribution-based Uncertainty Quantification was added to the CatBoost model using a proposed Quantile Ensemble method, useable for any model optimizing a quantile function. These models are subsequently evaluated using the distribution coverage error, a proposed interpretable uncertainty quantification calibration metric. Development and internal evaluation of the ML models were performed on the Ghent University Hospital database (752 piperacillin concentrations from 282 patients). Ensuing, ML models were compared with a published PopPK model on a database from the University Medical Centre of Groningen where a different dosing regimen is used (46 piperacillin concentrations from 15 patients.). Results The best performing model was the Catboost model with an RMSE and $$R^2$$ R 2 of 31.94–0.64 and 33.53–0.60 for internal evaluation with and without previous concentration. Furthermore, the results prove the added value of the proposed Quantile Ensemble model in providing clinically useful individualized uncertainty predictions and show the limits of homoscedastic methods like Gaussian Processes in clinical applications. Conclusions Our results show that ML models can consistently estimate piperacillin concentrations with acceptable and high predictive accuracy when identical dosing regimens as in the training data are used while providing highly relevant uncertainty predictions. However, generalization capabilities to other dosing schemes are limited. Notwithstanding, incorporating ML models in therapeutic drug monitoring programs seems definitely promising and the current work provides a basis for validating the model in clinical practice.

Abstract Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation (p A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

The past decade has witnessed a proliferation of big team science (BTS), endeavours where a comparatively large number of researchers pool their intellectual and/or material resources in pursuit of a common goal. Despite this burgeoning interest, there exists little guidance on how to create, manage and participate in these collaborations. In this paper, we integrate insights from a multi-disciplinary set of BTS initiatives to provide a how-to guide for BTS. We first discuss initial considerations for launching a BTS project, such as building the team, identifying leadership, governance, tools and open science approaches. We then turn to issues related to running and completing a BTS project, such as study design, ethical approvals and issues related to data collection, management and analysis. Finally, we address topics that present special challenges for BTS, including authorship decisions, collaborative writing and team decision-making.

IntroductionThere is a large interindividual variability in cognitive functioning with increasing age due to biological and lifestyle factors. One of the most important lifestyle factors is the level of physical fitness (PF). The link between PF and brain activity is widely accepted but the specificity of cognitive functions affected by physical fitness across the adult lifespan is less understood. The present study aims to clarify whether PF is basically related to cognition and general intelligence in healthy adults, and whether higher levels of PF are associated with better performance in the same or different cognitive functions at different ages.MethodsA sample of 490 participants (20–70 years) was analyzed to examine this relationship. Later, the sample was split half into the young to middle-aged group (YM; 20–45 years; n = 254), and the middleaged to older group (MO; 46–70 years; n = 236). PF was measured by a quotient of maximum power in a bicycle ergometry test PWC-130 divided by body weight (W/kg), which was supported by a self-reported level of PF. Cognitive performance was evaluated by standardized neuropsychological test batteries.ResultsRegression models showed a relationship between PF and general intelligence (g-factor) and its subcomponents extracted using structural equation modeling (SEM) in the entire sample. This association was moderated by age, which also moderated some specific cognitive domains such as attention, logical reasoning, and interference processing. After splitting the sample into two age groups, a significant relationship was found between cognitive status, as assessed by the Mini Mental State Examination (MMSE), and PF in both age groups. However, apart from cognitive failures in daily life (CFQ), no other association between PF and specific cognitive functions was found in the YM group. In contrast, several positive associations were observed in the MO group, such as with selective attention, verbal memory, working memory, logical reasoning, and interference processing.DiscussionThese findings show that middle-aged to older adults benefit more from PF than younger to middle-aged adults. The results are discussed in terms of the neurobiological mechanisms underlying the cognitive effects of PF across the lifespan.Clinical trial registration:https://clinicaltrials.gov/ct2/show/NCT05155397, identifier NCT05155397.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain. Characterizing cellular diversity is necessary to understand the function of different cell types in the brain. This Consensus View provides a guide to the cellular and spatial approaches used in cell type surveys by the BRAIN Initiative Cell Census Network (BICCN), as well as information on accessing and using the BICCN data and its extensive resources.

BackgroundAnti-GAD65 autoantibodies (GAD65-Abs) may occur in patients with epilepsy and other neurological disorders, but the clinical significance is not clear-cut. Whereas high levels of GAD65-Abs are considered pathogenic in neuropsychiatric disorders, low or moderate levels are only considered as mere bystanders in, e.g., diabetes mellitus type 1 (DM1). The value of cell-based assays (CBA) and immunohistochemistry (IHC) for GAD65-Abs detection has not been clearly evaluated in this context.ObjectiveTo re-evaluate the assumption that high levels of GAD65-Abs are related to neuropsychiatric disorders and lower levels only to DM1 and to compare ELISA results with CBA and IHC to determine the additional value of these tests.Methods111 sera previously assessed for GAD65-Abs by ELISA in routine clinical practice were studied. Clinical indications for testing were, e.g., suspected autoimmune encephalitis or epilepsy (neuropsychiatric cohort; n = 71, 7 cases were initially tested positive for GAD65-Abs by ELISA), and DM1 or latent autoimmune diabetes in adults (DM1/LADA cohort (n = 40, all were initially tested positive)). Sera were re-tested for GAD65-Abs by ELISA, CBA, and IHC. Also, we examined the possible presence of GAD67-Abs by CBA and of other neuronal autoantibodies by IHC. Samples that showed IHC patterns different from GAD65 were further tested by selected CBAs.ResultsELISA retested GAD65-Abs level in patients with neuropsychiatric diseases was higher than in patients with DM1/LADA (only retested positive samples were compared; 6 vs. 38; median 47,092 U/mL vs. 581 U/mL; p = 0.02). GAD-Abs showed positive both by CBA and IHC only if antibody levels were above 10,000 U/mL, without a difference in prevalence between the studied cohorts. We found other neuronal antibodies in one patient with epilepsy (mGluR1-Abs, GAD-Abs negative), and in a patient with encephalitis, and two patients with LADA.ConclusionGAD65-Abs levels are significantly higher in patients with neuropsychiatric disease than in patients with DM1/LADA, however, positivity in CBA and IHC only correlates with high levels of GAD65-Abs, and not with the underlying diseases.

BackgroundAs employees age, their physical and mental abilities decline and work ability decreases, enhancing the risk for long-term sick leave or even premature retirement. However, the relative impact of biological and environmental determinants on work ability with increasing age is poorly understood in terms of their complexity. ObjectivePrevious research has shown relationships between work ability and job and individual resources, as well as specific demographic and lifestyle-related variables. However, other potentially important predictors of work ability remain unexplored, such as personality traits and biological determinants, including cardiovascular, metabolic, immunological, and cognitive abilities or psychosocial factors. Our aim was to systematically evaluate a wide range of factors to extract the most crucial predictors of low and high work ability across the working life span. MethodsAs part of the Dortmund Vital Study, 494 participants from different occupational sectors, aged between 20 and 69 years, completed the Work Ability Index (WAI) assessing employee’s mental and physical resources. A total of 30 sociodemographic variables were grouped into 4 categories (social relationships, nutrition and stimulants, education and lifestyle, and work related), and 80 biological and environmental variables were grouped into 8 domains (anthropometric, cardiovascular, metabolic, immunologic, personality, cognitive, stress related, and quality of life) and have been related to the WAI. ResultsUsing the analyses, we extracted important sociodemographic factors influencing work ability, such as education, social activities, or sleep quality, and identified age-dependent and age-independent determinants of work ability. Regression models explained up to 52% of the WAI variance. Negative predictors of work ability were chronological and immunological age, immunological inefficiency, BMI, neuroticism, psychosocial stress, emotional exhaustion, demands from work, daily cognitive failures, subclinical depression, and burnout symptoms. Positive predictors were maximum heart rate during ergometry, normal blood pressure, hemoglobin and monocyte concentration, weekly physical activity, commitment to the company, pressure to succeed, and good quality of life. ConclusionsThe identified biological and environmental risk factors allowed us to evaluate work ability in its complexity. Policy makers, employers, and occupational safety and health personnel should consider the modifiable risk factors we identified to promote healthy aging at work through focused physical, dietary, cognitive, and stress-reduced preventive programs, in addition to well-balanced working conditions. This may also increase the quality of life, commitment to the job, and motivation to succeed, which are important factors to maintain or even enhance work ability in the aging workforce and to prevent early retirement. Trial RegistrationClinicalTrials.gov NCT05155397; https://clinicaltrials.gov/ct2/show/NCT05155397 International Registered Report Identifier (IRRID)RR2-10.2196/32352

Abstract This work establishes carbon nanofibre-mediated patterning of metal oxide nanostructures, through the combination of electrospinning and vapor-phase transport growth. Electrospinning of a suitable precursor with subsequent carbonization results in the patterning of catalyst gold nanoparticles embedded within carbon nanofibres. During vapor-phase transport growth, these nanofibres allow preferential growth of one-dimensional metal oxide nanostructures, which grow radially outward from the nanofibril axis, yielding a hairy caterpillar-like morphology. The synthesis of metal oxide caterpillars is demonstrated using zinc oxide, indium oxide, and tin oxide. Source and substrate temperatures play the most crucial role in determining the morphology of the metal oxide caterpillars, whereas the distribution of the nanofibres also has a significant impact on the overall morphology. Introducing the current methodology with near-field electrospinning further facilitates user-defined custom patterning of metal oxide caterpillar-like structures.

Digital services such as repositories and science gateways have become key resources for the neuroscience community, but users often have a hard time orienting themselves in the service landscape to find the best fit for their particular needs. INCF has developed a set of recommendations and associated criteria for choosing or setting up and running a repository or scientific gateway, intended for the neuroscience community, with a FAIR neuroscience perspective.

We present the James Clerk Maxwell Telescope (JCMT) 850 μ m Legacy Release, containing uniformly reduced, coadded tiles, and catalogs of detected emission, for the 850 μ m data from all Submillimetre Common User Bolometer Array 2 (SCUBA-2) observations taken between 2011 February 2 and 2020 August 1. This release provides the fastest and easiest way to identify uniformly determined 850 μ m detections and calibrated fluxes for any position observed by the JCMT. The coadded observations include 11,722 hr of observing time and cover 1516 square degrees of the sky, with detections of contiguous areas of emission at better than 5 σ covering 2.46 square degrees of area. Within these regions 21,059 individual local maxima were detected. Fifteen tiles contain regions with a noise level better than 0.0025 mJy arcsec ^−2 . The data are gridded onto HEALPix tiles of ≈1° a side, using the HEALPix projection with pixels of size ≈3.″22. The coadds have been calibrated into units of mJy arcsec ^−2 using the standard date-varying SCUBA-2 flux-conversion factor (FCF) from Mairs et al. (2021). We then examined the accuracy of this calibration for our data set by calculating self-derived FCF values for our two most-used standard sources, finding a result within the expected errors but with a larger standard deviation of 9%. The coadds and catalogs can be searched and retrieved via the Canadian Astronomy Data Centre (project code: JCMT-LR). Combined catalogs of all detected regions and of all local maxima can be downloaded from the Canadian Advanced Network for Astronomy Research Data Publication Service (doi: http://doi.org/10.11570/23.0013 ), along with masks showing the full area observed in this release and the full area of detected emission.

This paper presents methodologies and equipment for SI-traceable inline measurements of water content (a critical quality parameter) in solid biofuels. Inline measurement systems for water content are commonly used at CHP plants, providing continuous real-time data. However, the accuracy of these systems is in most cases unsatisfactory, mainly because the systems are not calibrated representatively for the relevant material, and until now, calibrations traceable to the SI system have not been available. To provide reliable and accurate inline water content data, new procedures and equipment for calibrating measurement systems were developed. Two reference methods for the determination of water content were developed; one measures the airflow and dewpoint of desorbed water in the air passing a test sample, while the other uses a P2O₅-sensor. Additionally, a transfer standard based on a cavity resonance sensor was developed for fast onsite calibration of the inline sensor at the power plant. This new instrument allows for quick and accurate measurements. The transfer standard is made metrologically traceable to the primary measurement standards. The entire system was demonstrated by calibrating an inline microwave-based (MW) sensor at the CHP plant of VERDO in Randers, Denmark. Thus, a complete metrological traceability chain was established from an industrial to a primary standard.

While several studies have shown associations between hearing disorders and congenital toxoplasmosis, the present study investigated the impact of chronic, latent Toxoplasma gondii (T. gondii) infection on hearing loss. We used a regression analysis to explore whether latent T. gondii infection modulates changes in hearing thresholds over an age range from 20 to 70 years. We analyzed audiometric data of 162 T. gondii IgG-positive and 430 T. gondii-negative participants, collected in the Dortmund Vital Study (DVS, ClinicalTrials.gov Identifier: NCT05155397), a prospective study on healthy cognitive aging. The regression analysis indicated that latent toxoplasmosis was associated with an accelerated development in hearing loss over the observed age range. Hearing loss was less frequent in IgG-positive than in IgG-negative participants up to the age of about 40 for a low (0.125–1 kHz)-frequency range. For high (2–8 kHz) frequencies, this pattern reversed for ages above 65 years. We discuss these findings on hearing function in the context of a recently proposed model, suggesting that latent toxoplasmosis can differentially affect brain functions across a lifespan.

Background: Systemic sclerosis (SSc) patients face an elevated risk of cardiovascular disease (CVD), even when classic cardiovascular risk factors are considered. Plasma dephosphorylated-uncarboxylated Matrix Gla-protein (dp-ucMGP), an inactive form of MGP, is associated with increased CVD risk. Smooth muscle cells, implicated in SSc’s development, are the primary dp-ucMGP producers. This study assessed dp-ucMGP levels and initial CVD events in early-diagnosed SSc patients, investigating its potential as a CVD and all-cause mortality predictor over time. Methods: In a cohort of 87 SSc patients (excluding those with pre-existing CVD or on dialysis), baseline dp-ucMGP levels were measured, along with cardiovascular risk factors. Validation involved assessing dp-ucMGP in a subset of treatment-naive SSc patients. Results: A significantly elevated median dp-ucMGP level of 634 pmol/L (IQR 301) compared with healthy controls (dp-ucMGP < 393 pmol/L; p < 0.001) was observed. Validation in a treatment-naive SSc patient subset yielded similar results (median 589 pmol/L; IQR 370). During a median 10.5-year follow-up among 78 SSc patients, 33.3% experienced their first CVD event, independent of traditional risk factors. Elevated dp-ucMGP levels (>634 pmol/L) correlated with a higher risk of CVD and/or death (log-rank test: p < 0.01). Conclusions: In summary, dp-ucMGP emerges as a novel biomarker in SSc patients, with elevated levels indicating an increased risk of CVD and/or mortality in this population.

Cyclic five-membered disulfides (1,2-dithiolanes) have been reported either as nonspecific redox motifs, or as highly specific cellular probes for thioredoxin reductase (TrxR). Here the authors show that 1,2-dithiolane probes are nonspecifically reduced by a range of thiol reductants and are not sensitive to TrxR modulation, thus they are unsuitable as cellular probes for TrxR.

Brain atlases are widely used in neuroscience as resources for conducting experimental studies, and for integrating, analyzing, and reporting data from animal models. A variety of atlases are available, and it may be challenging to find the optimal atlas for a given purpose and to perform efficient atlas-based data analyses. Comparing findings reported using different atlases is also not trivial, and represents a barrier to reproducible science. With this perspective article, we provide a guide to how mouse and rat brain atlases can be used for analyzing and reporting data in accordance with the FAIR principles that advocate for data to be findable, accessible, interoperable, and re-usable. We first introduce how atlases can be interpreted and used for navigating to brain locations, before discussing how they can be used for different analytic purposes, including spatial registration and data visualization. We provide guidance on how neuroscientists can compare data mapped to different atlases and ensure transparent reporting of findings. Finally, we summarize key considerations when choosing an atlas and give an outlook on the relevance of increased uptake of atlas-based tools and workflows for FAIR data sharing.

In vitro to in vivo extrapolation represents a critical challenge in toxicology. In this paper we explore extrapolation strategies for acetaminophen (APAP) based on mechanistic models, comparing classical (CL) homogeneous compartment pharmacodynamic (PD) models and a spatial-temporal (ST), multiscale digital twin model resolving liver microarchitecture at cellular resolution. The models integrate consensus detoxification reactions in each individual hepatocyte. We study the consequences of the two model types on the extrapolation and show in which cases these models perform better than the classical extrapolation strategy that is based either on the maximal drug concentration (Cmax) or the area under the pharmacokinetic curve (AUC) of the drug blood concentration. We find that an CL-model based on a well-mixed blood compartment is sufficient to correctly predict the in vivo toxicity from in vitro data. However, the ST-model that integrates more experimental information requires a change of at least one parameter to obtain the same prediction, indicating that spatial compartmentalization may indeed be an important factor.

Mouse models are frequently used to study chronic liver diseases (CLDs). To assess their translational relevance, we quantified the similarity of commonly used mouse models to human CLDs based on transcriptome data. Gene‐expression data from 372 patients were compared with data from acute and chronic mouse models consisting of 227 mice, and additionally to nine published gene sets of chronic mouse models. Genes consistently altered in humans and mice were mapped to liver cell types based on single‐cell RNA‐sequencing data and validated by immunostaining. Considering the top differentially expressed genes, the similarity between humans and mice varied among the mouse models and depended on the period of damage induction. The highest recall (0.4) and precision (0.33) were observed for the model with 12‐months damage induction by CCl4 and by a Western diet, respectively. Genes consistently up‐regulated between the chronic CCl4 model and human CLDs were enriched in inflammatory and developmental processes, and mostly mapped to cholangiocytes, macrophages, and endothelial and mesenchymal cells. Down‐regulated genes were enriched in metabolic processes and mapped to hepatocytes. Immunostaining confirmed the regulation of selected genes and their cell type specificity. Genes that were up‐regulated in both acute and chronic models showed higher recall and precision with respect to human CLDs than exclusively acute or chronic genes. Conclusion: Similarly regulated genes in human and mouse CLDs were identified. Despite major interspecies differences, mouse models detected 40% of the genes significantly altered in human CLD. The translational relevance of individual genes can be assessed at https://saezlab.shinyapps.io/liverdiseaseatlas/.

Abstract Background Supraclavicular block (SCB) with long-acting local anaesthetic is commonly used for surgical repair of distal radial fractures (DRF). Studies have shown a risk for rebound pain when the block fades. This randomised single-centre study aimed to compare pain and opioid consumption the first three days post-surgery between SCB-mepivacaine vs. SCB-ropivacaine, with general anaesthesia (GA) as control. Methods Patients (n = 90) with ASA physical status 1–3 were prospectively randomised to receive; SCB with mepivacine 1%, 25–30 ml (n = 30), SCB with ropivacaine 0.5%, 25–30 ml (n = 30) or GA (n = 30) with propofol/fentanyl/sevoflurane. Study objectives compared postoperative pain with Numeric Rating Scale (NRS) and sum postoperative Opioid Equivalent Consumption (OEC) during the first 3 days post-surgery between study-groups. Results The three groups showed significant differences in postoperative pain-profile. Mean NRS at 24 h was significantly lower for the SCB-mepivacaine group (p = 0.018). Further both median NRS and median OEC day 0 to 3 were significanly lower in the SCB-mepivacaine group as compared to the SCB-ropivacaine group during the first three days after surgery; pain NRS 1 (IQR 0.3–3.3) and 2.7 (IQR 1.3–4.2) (p = 0.017) and OEC 30 mg (IQR 10–80) and 85 mg (IQR 45–125) (p = 0.004), respectively. The GA-group was in between both in pain NRS and median sum OEC. Unplanned healthcare contacts were highest among SCB-ropivacaine patients (39.3%) vs. SCB-mepivacaine patients (0%) and GA-patients (3.4%). Conclusions The potential benefit of longer duration of analgesia, associated to a long-acting local anaesthetic agent, during the early postoperative course must be put in perspective of potential worse pain progression following block resolution. Trial registration NCT03749174 (clinicaltrials.gov, Nov 21, 2018, retrospectively registered).

Summary: Partial liver removal is an important therapy option for liver cancer. In most patients within a few weeks, the liver is able to fully regenerate. In some patients, however, regeneration fails with often severe consequences. To better understand the control mechanisms of liver regeneration, experiments in mice were performed, guiding the creation of a spatiotemporal 3D model of the regenerating liver. The model represents cells and blood vessels within an entire liver lobe, a macroscopic liver subunit. The model could reproduce the experimental data only if a biomechanical growth control (BGC)-mechanism, inhibiting cell cycle entrance at high compression, was taken into account and predicted that BGC may act as a short-range growth inhibitor minimizing the number of proliferating neighbor cells of a proliferating cell, generating a checkerboard-like proliferation pattern. Model-predicted cell proliferation patterns in pigs and mice were found experimentally. The results underpin the importance of biomechanical aspects in liver growth control.

Effectively addressing public health crises like the COVID-19 pandemic requires persuading the mass public to change their behavior in significant ways. Many efforts to encourage behavior change-such as public service announcements, social media posts, and billboards-involve short, persuasive appeals, yet the effectiveness of these messages is unclear. Early in the COVID-19 pandemic, we tested whether short messages could increase intentions to comply with public health guidelines. To identify promising messages, we conducted two pretests (n = 1,596) in which participants rated the persuasiveness of 56 unique messages: 31 based on the persuasion and social influence literatures and 25 drawn from a pool of crowdsourced messages generated by online respondents. The four top-rated messages emphasized: (1) civic responsibility to reciprocate the sacrifices of health care workers, (2) caring for the elderly and vulnerable, (3) a specific, sympathetic victim, and (4) limited health care system capacity. We then conducted three well-powered, pre-registered experiments (total n = 3,719) testing whether these four top-rated messages, and a standard public health message based on language from the CDC, increased intentions to comply with public health guidelines, such as masking in public spaces. In Study 1, we found the four messages and the standard public health message significantly outperformed a null control. In Studies 2 and 3, we compared the effects of persuasive messages to the standard public health message, finding that none consistently out-performed the standard message. This is in line with other research showing minimal persuasive effects of short messages after the very early stages of the pandemic. Across our studies, we found that (1) short messages can increase intentions to comply with public health guidelines, but (2) short messages featuring persuasive techniques from the social science literature did not substantially outperform standard public health messages.

BackgroundHigh frequency jet ventilation (HFJV) can be used to minimise sub-diaphragmal organ displacements. Treated patients are in a supine position, under general anaesthesia and fully muscle relaxed. These are factors that are known to contribute to the formation of atelectasis. The HFJV-catheter is inserted freely inside the endotracheal tube and the system is therefore open to atmospheric pressure.AimThe aim of this study was to assess the formation of atelectasis over time during HFJV in patients undergoing liver tumour ablation under general anaesthesia.MethodIn this observational study twenty-five patients were studied. Repeated computed tomography (CT) scans were taken at the start of HFJV and every 15 minutes thereafter up until 45 minutes. From the CT images, four lung compartments were defined: hyperinflated, normoinflated, poorly inflated and atelectatic areas. The extension of each lung compartment was expressed as a percentage of the total lung area.ResultAtelectasis at 30 minutes, 7.9% (SD 3.5, p = 0.002) and at 45 minutes 8,1% (SD 5.2, p = 0.024), was significantly higher compared to baseline 5.6% (SD 2.5). The amount of normoinflated lung volumes were unchanged over the period studied. Only a few minor perioperative respiratory adverse events were noted.ConclusionAtelectasis during HFJV in stereotactic liver tumour ablation increased over the first 45 minutes but tended to stabilise with no impact on normoinflated lung volume. Using HFJV during stereotactic liver ablation is safe regarding formation of atelectasis.

Mercury (Hg) release from contaminated legacy sites is a large contributor to riverine ecosystems and can represent a significant local and regional environmental issue even long after the initial site contamination. Understanding processes of in-stream species transformation is therefore important to assess the fate and bioavailability of the released Hg. In this study, we investigated in-stream Hg transformation processes with analyses of Hg binding forms and Hg stable isotopes. Stream sediments were collected downstream of a former kyanization facility (Black Forest, SW Germany), where highly soluble Hg(II)-chloride (HgCl2) was used as an anti-fouling agent to treat timber. Exfiltration of partly anoxic, contaminated groundwater with Hg concentrations of up to 700 μg L−1 into the adjacent Gutach stream is the main source of Hg to sediments. Total Hg concentrations in the stream bottom sediments (

Abstract Climate change has dramatic impacts on ecological systems, affecting a range of ecological factors including phenology, species abundance, diversity, and distribution. The breadth of climate change impacts on ecological systems leads to the occurrence of fingerprints of climate change. However, climate fingerprints are usually identified across broad geographical scales and are potentially influenced by publication biases. In this study, we used natural history collections spanning over 250 years, to quantify a range of ecological responses to climate change, including phenology, abundance, diversity, and distributions, across a range of taxa, including vertebrates, invertebrates, plants, and fungi, within a single region, Central Norway. We tested the hypotheses that ecological responses to climate change are apparent and coherent at a regional scale, that longer time series show stronger trends over time and in relation to temperature, and that ecological responses change in trajectory at the same time as shifts in temperature. We identified a clear regional coherence in climate signal, with decreasing abundances of limnic zooplankton (on average by 7691 individuals m−3 °C−1) and boreal forest breeding birds (on average by 1.94 territories km−2 °C−1), and earlier plant flowering phenology (on average 2 days °C−1) for every degree of temperature increase. In contrast, regional‐scale species distributions and species diversity were largely stable. Surprisingly, the effect size of ecological response did not increase with study duration, and shifts in responses did not occur at the same time as shifts in temperature. This may be as the long‐term studies include both periods of warming and temperature stability, and that ecological responses lag behind warming. Our findings demonstrate a regional climate fingerprint across a long timescale. We contend that natural history collections provide a unique window on a broad spectrum of ecological responses at timescales beyond most ecological monitoring programs. Natural history collections are thus an essential source for long‐term ecological research.

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease in Western countries. It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including liver diseases, are linked with brain dysfunctions. Therefore, this study aims to unravel the effect of MASLD on brain histology, cognitive functions, and neurotransmitters. For this purpose, mice fed for 48 weeks on standard (SD) or Western diet (WD) were evaluated by behavioral tests, followed by sacrifice and analysis of the liver-brain axis including histopathology, immunohistochemistry, and biochemical analyses. Histological analysis of the liver showed features of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the WD-fed mice including lipid droplet accumulation, inflammation, and fibrosis. This was accompanied by an elevation of transaminase and alkaline phosphatase activities, increase in inflammatory cytokine and bile acid concentrations, as well as altered amino acid concentrations in the blood. Interestingly, compromised blood capillary morphology coupled with astrogliosis and microgliosis were observed in brain hippocampus of the WD mice, indicating neuroinflammation or a disrupted neurovascular unit. Moreover, attention was impaired in WD-fed mice along with the observations of impaired motor activity and balance, enhanced anxiety, and stereotyped head-twitch response (HTR) behaviors. Analysis of neurotransmitters and modulators including dopamine, serotonin, GABA, glutamate, and acetylcholine showed region-specific dysregulation in the brain of the WD-fed mice. In conclusion, the induction of MASH in mice is accompanied by the alteration of cellular morphology and neurotransmitter expression in the brain, associated with compromised cognitive functions.

Abstract Background Heparin is used worldwide for 70 years during all non-cardiac arterial procedures (NCAP) to reduce thrombo-embolic complications (TEC). But heparin also increases blood loss causing possible harm for the patient. Heparin has an unpredictable effect in the individual patient. The activated clotting time (ACT) can measure the effect of heparin. Currently, this ACT is not measured during NCAP as the standard of care, contrary to during cardiac interventions, open and endovascular. A RCT will evaluate if ACT-guided heparinization results in less TEC than the current standard: a single bolus of 5000 IU of heparin and no measurements at all. A goal ACT of 200–220 s should be reached during ACT-guided heparinization and this should decrease (mortality caused by) TEC, while not increasing major bleeding complications. This RCT will be executed during open abdominal aortic aneurysm (AAA) surgery, as this is a standardized procedure throughout Europe. Methods Seven hundred fifty patients, who will undergo open AAA repair of an aneurysm originating below the superior mesenteric artery, will be randomised in 2 treatment arms: 5000 IU of heparin and no ACT measurements and no additional doses of heparin, or a protocol of 100 IU/kg bolus of heparin and ACT measurements after 5 min, and then every 30 min. The goal ACT is 200–220 s. If the ACT after 5 min is < 180 s, 60 IU/kg will be administered; if the ACT is between 180 and 200 s, 30 IU/kg. If the ACT is > 220 s, no extra heparin is given, and the ACT is measured after 30 min and then the same protocol is applied. The expected incidence for the combined endpoint of TEC and mortality is 19% for the 5000 IU group and 11% for the ACT-guided group. Discussion The ACTION-1 trial is an international RCT during open AAA surgery, designed to show superiority of ACT-guided heparinization compared to the current standard of a single bolus of 5000 IU of heparin. A significant reduction in TEC and mortality, without more major bleeding complications, must be proven with a relevant economic benefit. Trial registration {2a} NTR NL8421 ClinicalTrials.gov NCT04061798 . Registered on 20 August 2019 EudraCT 2018-003393-27 Trial registration: data set {2b} Data category Information Primary registry and trial identifying number ClinicalTrials.gov : NCT04061798 Date of registration in primary registry 20-08-2019 Secondary identifying numbers NTR: NL8421 EudraCT: 2018-003393-27 Source(s) of monetary or material support ZonMw: The Netherlands Organisation for Health Research and Development Dijklander Ziekenhuis Amsterdam UMC Primary sponsor Dijklander Ziekenhuis Secondary sponsor(s) N/A Contact for public queries A.M. Wiersema, MD, PhD Arno@wiersema.nu 0031-229 208 206 Contact for scientific queries A.M. Wiersema, MD, PhD Arno@wiersema.nu 0031-229 208 206 Public title ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair (ACTION-1) Scientific title ACTION-1: ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair, a Randomised Trial Countries of recruitment The Netherlands. Soon the recruitment will start in Germany Health condition(s) or problem(s) studied Abdominal aortic aneurysm, arterial disease, surgery Intervention(s) ACT-guided heparinization 5000 IU of heparin Key inclusion and exclusion criteria Ages eligible for the study: ≥18 years Sexes eligible for the study: both Accepts healthy volunteers: no Inclusion criteria: Study type Interventional Allocation: randomized Intervention model: parallel assignment Masking: single blind (patient) Primary purpose: treatment Phase IV Date of first enrolment March 2020 Target sample size 750 Recruitment status Recruiting Primary outcome(s) The primary efficacy endpoint is 30-day mortality and in-hospital mortality during the same admission. The primary safety endpoint is the incidence of bleeding complications according to E-CABG classification, grade 1 and higher. Key secondary outcomes Serious complications as depicted in the Suggested Standards for Reports on Aneurysmal disease: all complications requiring re-operation, longer hospital stay, all complications

The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). The canonical pathway topology is characterized by sequential phosphorylation of kinases in the cytoplasm that defines the subcellular localization of YAP and TAZ. However, the molecular mechanisms controlling the nuclear/cytoplasmic shuttling dynamics of both factors under physiological and tissue-damaging conditions are poorly understood. By implementing experimental in vitro data, partial differential equation modeling, as well as automated image analysis, we demonstrate that nuclear phosphorylation contributes to differences between YAP and TAZ localization in the nucleus and cytoplasm. Treatment of hepatocyte-derived cells with hepatotoxic acetaminophen (APAP) induces a biphasic protein phosphorylation eventually leading to nuclear protein enrichment of YAP but not TAZ. APAP-dependent regulation of nuclear/cytoplasmic YAP shuttling is not an unspecific cellular response but relies on the sequential induction of reactive oxygen species (ROS), RAC-alpha serine/threonine-protein kinase (AKT, synonym: protein kinase B), as well as elevated nuclear interaction between YAP and AKT. Mouse experiments confirm this sequence of events illustrated by the expression of ROS-, AKT-, and YAP-specific gene signatures upon APAP administration. In summary, our data illustrate the importance of nuclear processes in the regulation of Hippo pathway activity. YAP and TAZ exhibit different shuttling dynamics, which explains distinct cellular responses of both factors under physiological and tissue-damaging conditions.

BackgroundVaccines can be less immunogenic in people living with HIV (PLWH), but for SARS-CoV-2 vaccinations this is unknown. In this study we set out to investigate, for the vaccines currently approved in the Netherlands, the immunogenicity and reactogenicity of SARS-CoV-2 vaccinations in PLWH.Methods and findingsWe conducted a prospective cohort study to examine the immunogenicity of BNT162b2, mRNA-1273, ChAdOx1-S, and Ad26.COV2.S vaccines in adult PLWH without prior COVID-19, and compared to HIV-negative controls. The primary endpoint was the anti-spike SARS-CoV-2 IgG response after mRNA vaccination. Secondary endpoints included the serological response after vector vaccination, anti-SARS-CoV-2 T-cell response, and reactogenicity. Between 14 February and 7 September 2021, 1,154 PLWH (median age 53 [IQR 44-60] years, 85.5% male) and 440 controls (median age 43 [IQR 33-53] years, 28.6% male) were included in the final analysis. Of the PLWH, 884 received BNT162b2, 100 received mRNA-1273, 150 received ChAdOx1-S, and 20 received Ad26.COV2.S. In the group of PLWH, 99% were on antiretroviral therapy, 97.7% were virally suppressed, and the median CD4+ T-cell count was 710 cells/μL (IQR 520-913). Of the controls, 247 received mRNA-1273, 94 received BNT162b2, 26 received ChAdOx1-S, and 73 received Ad26.COV2.S. After mRNA vaccination, geometric mean antibody concentration was 1,418 BAU/mL in PLWH (95% CI 1322-1523), and after adjustment for age, sex, and vaccine type, HIV status remained associated with a decreased response (0.607, 95% CI 0.508-0.725, p < 0.001). All controls receiving an mRNA vaccine had an adequate response, defined as >300 BAU/mL, whilst in PLWH this response rate was 93.6%. In PLWH vaccinated with mRNA-based vaccines, higher antibody responses were predicted by CD4+ T-cell count 250-500 cells/μL (2.845, 95% CI 1.876-4.314, p < 0.001) or >500 cells/μL (2.936, 95% CI 1.961-4.394, p < 0.001), whilst a viral load > 50 copies/mL was associated with a reduced response (0.454, 95% CI 0.286-0.720, p = 0.001). Increased IFN-γ, CD4+ T-cell, and CD8+ T-cell responses were observed after stimulation with SARS-CoV-2 spike peptides in ELISpot and activation-induced marker assays, comparable to controls. Reactogenicity was generally mild, without vaccine-related serious adverse events. Due to the control of vaccine provision by the Dutch National Institute for Public Health and the Environment, there were some differences between vaccine groups in the age, sex, and CD4+ T-cell counts of recipients.ConclusionsAfter vaccination with BNT162b2 or mRNA-1273, anti-spike SARS-CoV-2 antibody levels were reduced in PLWH compared to HIV-negative controls. To reach and maintain the same serological responses as HIV-negative controls, additional vaccinations are probably required.Trial registrationThe trial was registered in the Netherlands Trial Register (NL9214). https://www.trialregister.nl/trial/9214.

When one thinks about electrodes, especially ones meant for humans, one typically thinks of some kind of metal. Whether on the skin or in the brain, metal electrodes are characteristically expensive, stiff, non-efficient in electron-ion transduction, and prone to toxic metal ion by-products during stimulation. In order to circumvent these disadvantages, electrically-conductive laser-induced graphene (LIG) and mixed electron-ion conducting polymer (poly(3, 4‐ethylenedioxythiophene) polystyrene sulfonate – PEDOT:PSS) was leveraged to create a metal-free electrode combination that allows for an economical, soft, and organic electrode for applications on human skin. Compared to clinical-standard silver – silver chloride (Ag/AgCl) skin electrodes, the metal-free hydrogel electrodes show notable improvement in electrochemical stability and prolonged stable potentials during long-term DC stimulation (0.5–24 h). Recording and stimulation performance on human participants rivals that of Ag/AgCl, thus fortifying the notion that they are an appropriate progression to their noble metal counterparts.

Abstract Determining the mechanisms driving range-wide reductions in Atlantic salmon marine survival is hindered by an insufficient understanding of their oceanic ecology and distribution. We attached 204 pop-up satellite archival tags to post-spawned salmon when they migrated to the ocean from seven European areas and maiden North American salmon captured at sea at West Greenland. Individuals migrated further north and east than previously reported and displayed increased diving activity near oceanographic fronts, emphasizing the importance of these regions as feeding areas. The oceanic distribution differed among individuals and populations, but overlapped more between geographically proximate than distant populations. Dissimilarities in distribution likely contribute to variation in growth and survival within and among populations due to spatio-temporal differences in environmental conditions. Climate-induced changes in oceanographic conditions will alter the location of frontal areas and may have stock-specific effects on Atlantic salmon population dynamics, likely having the largest impacts on southern populations.

Vibrational energy transfer (VET) is essential for protein function as it is responsible for efficient energy dissipation in reaction sites and is linked to pathways of allosteric communication. Here authors equipped a tryptophan zipper with a VET injector and a VET sensor for femtosecond pump probe experiments to map the VET.

Abstract Background The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. Methods This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3–4 days for bacterial sepsis patients. Results We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p

There are currently no drugs available to treat SARS-CoV-2 infection. A promising alternative treatment for COVID-19 patients is convalescent plasma. Here, Gharbharan et al. collect covalescent plasma and report no overall clinical benefit for 86 patients hospitalized for COVID-19 and treated with 300 mL convalescent plasma.

In the original publication [...]

Abstract A novel approach for automated high throughput NMR spectroscopy with improved mass-sensitivity is accomplished by integrating microfluidic technologies and micro-NMR resonators. A flow system is utilized to transport a sample of interest from outside the NMR magnet through the NMR detector, circumventing the relatively vast dead volume in the supplying tube by loading a series of individual sample plugs separated by an immiscible fluid. This dual-phase flow demands a real-time robust sensing system to track the sample position and velocities and synchronize the NMR acquisition. In this contribution, we describe an NMR probe head that possesses a microfluidic system featuring: (i) a micro saddle coil for NMR spectroscopy and (ii) a pair of interdigitated capacitive sensors flanking the NMR detector for continuous position and velocity monitoring of the plugs with respect to the NMR detector. The system was successfully tested for automating flow-based measurement in a 500 MHz NMR system, enabling high resolution spectroscopy and NMR sensitivity of 2.18 nmol s1/2 with the flow sensors in operation. The flow sensors featured sensitivity to an absolute difference of 0.2 in relative permittivity, enabling distinction between most common solvents. It was demonstrated that a fully automated NMR measurement of nine individual 120 μL samples could be done within 3.6 min or effectively 15.3 s per sample.

Abstract The low frequency plateau in the frequency response of an untuned micro-resonator permits broadband radio-frequency reception, albeit at the expense of optimal signal-to-noise ratio for a particular nucleus. In this contribution we determine useful figures of merit for broadband micro-coils, and thereby explore the parametric design space towards acceptable simultaneous excitation and reception of a microfluidic sample over a wide frequency band ranging from 13C to 1H, i.e., 125–500 MHz in an 11.74 T magnet. The detector achieves 37% of the performance of a comparably sized, tuned and matched resonator, and a linewidth of 17 ppb using standard magnet shims. The use of broadband detectors circumvents numerous difficulties introduced by multi-resonant RF detector circuits, including sample loading effects on matching, channel isolation, and field distortion.

Objectives Autoimmune antibody profiling plays a prominent role in both classification and prognosis of systemic sclerosis (SSc). In the last years novel autoantibodies have been discovered and have become available in diagnostic assays. However, standardization in autoimmune serology is lacking, which may have a negative impact on the added value of autoantibodies in diagnosis and prognosis of SSc. In this paper we describe the comparison of commercially available diagnostic assays for the detection of SSc-associated autoantibodies and explored the coexistence of multiple SSc-associated autoantibodies within patients. Methods Serum samples of 347 patients from the Nijmegen Systemic Sclerosis Cohort were included in this study. All patients fulfilled the ACR/EULAR 2013 classification criteria for SSc and were classified as DcSSc or LcSSc according to the Leroy and Medsger criteria. All samples were evaluated on standard laboratory diagnostic tests for detection of SSc-specific autoantibodies CENPA and CENPB (ACA), Scl-70 (ATA), RNA Polymerase III (rp11/155) (ARA), and SSc-associated autoantibodies Fibrillarin, Th-To, PM-scl75, PM-Scl100, RNP68/A/C, Ku, NOR90, and PDGFR from suppliers EUROIMMUN, D-tek and Thermo Fisher Scientific. Results We found that 79% of the patients was positive for one or more of the SSc autoantibodies. Overall, a high agreement was observed between the diagnostic methods for the SSC-specific autoantibodies listed in the ACR/EULAR criteria (ATA, ACA, and ARA) (Cohen's kappa 0.53–0.97). However, a lower agreement was found for SSc-associated autoantibodies PM-Scl, and Ku, as well as for the SSc-specific autoantibodies fibrillarin and Th-To. Furthermore, the data revealed that the presence of ATA, ARA and ACA is predominantly mutually exclusive, with only a fraction of the patients testing positive for both ATA and ARA. Conclusion Our data showed high concordance of prevalent SSc-specific autoantibodies between different diagnostic assays. Further standardisation for low prevalent SSc-specific and SSc-associated autoantibodies is needed.

Abstract Nuclear magnetic resonance at low field strength is an insensitive spectroscopic technique, precluding portable applications with small sample volumes, such as needed for biomarker detection in body fluids. Here we report a compact double resonant chip stack system that implements in situ dynamic nuclear polarisation of a 130 nL sample volume, achieving signal enhancements of up to − 60 w.r.t. the thermal equilibrium level at a microwave power level of 0.5 W. This work overcomes instrumental barriers to the use of NMR detection for point-of-care applications.