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Reproducibility of computational research is often challenging despite established guidelines and best practices. Translating these guidelines into practical applications remains difficult. Here, we present ENCORE, an approach to enhance transparency and reproducibility by guiding researchers in how to structure and document a computational project. ENCORE builds on previous efforts in computational reproducibility and integrates all project components into a standardized file system structure. It utilizes pre-defined files as documentation templates, leverages GitHub for software versioning, and includes an HTML-based navigator. ENCORE is designed to be agnostic to the type of computational project, data, programming language, and ICT infrastructure, and does not rely on specific software tools. We also share our group's experience using ENCORE, highlighting that the most significant challenge to the routine adoption of approaches like ours is the lack of incentives to motivate researchers to dedicate sufficient time and effort to ensure reproducibility. Reproducibility of computational research remains challenging. Here, authors present ENCORE, an approach to enhance reproducibility. The most significant challenge to the routine adoption of approaches like ENCORE is the lack of incentives for researchers to dedicate sufficient time and effort to ensure reproducibility. [ABSTRACT FROM AUTHOR]

Genome differential positioning within interphase nuclei remains poorly explored. We extended and validated Tyramide Signal Amplification (TSA)-seq to map genomic regions near nucleoli and pericentric heterochromatin in four human cell lines. Our study confirmed that smaller chromosomes localize closer to nucleoli but further deconvolved this by revealing a preference for chromosome arms below 36-46 Mbp in length. We identified two lamina associated domain subsets through their differential nuclear lamina versus nucleolar positioning in different cell lines which showed distinctive patterns of DNA replication timing and gene expression across all cell lines. Unexpectedly, active, nuclear speckle-associated genomic regions were found near typically repressive nuclear compartments, which is attributable to the close proximity of nuclear speckles and nucleoli in some cell types, and association of centromeres with nuclear speckles in human embryonic stem cells (hESCs). Our study points to a more complex and variable nuclear genome organization than suggested by current models, as revealed by our TSA-seq methodology. In this study, TSA-seq was used to compare the distribution and association of genomic regions with the nuclear lamina, nucleoli and pericentric heterochromatin across four human cell lines. [ABSTRACT FROM AUTHOR]

Tamoxifen is widely used in patients with hormone receptor‐positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z‐endoxifen. The Z‐endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z‐endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z‐endoxifen concentration and tamoxifen treatment outcomes, and identify a Z‐endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed‐effect (NLME) model for tamoxifen and Z‐endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z‐endoxifen. The final parent‐metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co‐medication with CYP2D6 inhibitors, on Z‐endoxifen pharmacokinetics. Future work will use the model to simulate Z‐endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long‐term survival to identify the Z‐endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor‐positive breast cancer. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM(hGBM)models in humanized mice using patientderived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBMtumor engraftment and growth in bonemarrow-liverthymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBMbiologywithin the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM. [ABSTRACT FROM AUTHOR]

Play is thought to serve different purposes at different times during ontogeny. The nature and frequency of play are expected to change accordingly over the developmental trajectory and with socio-ecological context. Orangutans offer the opportunity to disentangle the ontogenetic trajectories of solitary and social play with their extended immature phase, and socio-ecological variation among populations and species. We evaluated the frequency of play in 39 immature individuals across two populations (Pongo pygmaeus wurmbii, at Tuanan, Borneo, and P. abelii at Suaq, Sumatra), age (0–11 years), sex, and social context, using more than 11 500 h of full-day focal observation data. We found independent age trajectories of different play types, with solitary object and solitary locomotor peaking before social play. Social play partners changed during ontogeny, and male immatures were more likely to engage in non-mother social play than females. Overall, social play was more frequent at Suaq than Tuanan, linked to the more frequent availability of partners. Furthermore, per time in association with conspecifics, Tuanan immatures were as likely to engage in social play as their peers at Suaq, suggesting similar intrinsic motivation. Increasing fruit availability correlated with both longer associations and increased social play frequency in the less sociable population of Tuanan, but not at Suaq. Our findings on orangutans support evidence from other species that different play types follow different developmental trajectories, vary with sex, social opportunities, and ecological context. Although drawing functional inferences is challenging, the distinct developmental trajectories reflecting adult sociability and behavioral repertoires may indicate that play serves several, non-mutually exclusive functions during ontogeny. [ABSTRACT FROM AUTHOR]

We examined the effectiveness of a mindfulness-based intervention (MBI) compared to a social-emotional empathy-based intervention (EBI), and a passive control group in promoting compassion among Jewish-Israeli kindergartners. Three middle-class public kindergartens were randomly assigned to the MBI (n = 26;Mage = 5.03), EBI (n = 24;Mage = 5.02), or control groups (n = 24;Mage = 5.16; Ngirls = 40). The interventions lasted 12-weeks. Pre- and post-intervention, children's cognitive compassion was assessed utilizing computerized continuous performance tasks for attention/impulsivity, and structured observations of attention to teacher and on-task behaviors; emotional compassion was measured with structured observations of prosociality, negative affect, social-emotional difficulties, and aggression; intentional and actual compassion was measured using a compassionate responding paradigm. Research Findings: Results showed that MBI participants decreased impulsivity and improved sustained attention, increased attentiveness to the teacher, and reduced social difficulties and aggression – these effects did not appear for either other group. Additionally, the MBI and EBI participants increased prosociality and compassionate behaviors more than the control group, however the magnitude of change from the MBI was significantly larger. The MBI increased cognitive, emotional, intentional, and behavioral skills and understanding that are essential components necessary to engage in compassion. Practice or Policy: MBIs can be effectively led by teachers and integrated into school curriculum to facilitate just and caring educational communities. [ABSTRACT FROM AUTHOR]

The reconstruction of clonal families (CFs) in B-cell receptor (BCR) repertoire analysis is a crucial step to understand the adaptive immune system and how it responds to antigens. The BCR repertoire of an individual is formed throughout life and is diverse due to several factors such as gene recombination and somatic hypermutation. The use of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using next generation sequencing enabled the generation of full BCR repertoires that also include rare CFs. The reconstruction of CFs from AIRR-seq data is challenging and several approaches have been developed to solve this problem. Currently, most methods use the heavy chain (HC) only, as it is more variable than the light chain (LC). CF reconstruction options include the definition of appropriate sequence similarity measures, the use of shared mutations among sequences, and the possibility of reconstruction without preliminary clustering based on V- and J-gene annotation. In this study, we aimed to systematically evaluate different approaches for CF reconstruction and to determine their impact on various outcome measures such as the number of CFs derived, the size of the CFs, and the accuracy of the reconstruction. The methods were compared to each other and to a method that groups sequences based on identical junction sequences and another method that only determines subclones. We found that after accounting for data set variability, in particular sequencing depth and mutation load, the reconstruction approach has an impact on part of the outcome measures, including the number of CFs. Simulations indicate that unique junctions and subclones should not be used as substitutes for CF and that more complex methods do not outperform simpler methods. Also, we conclude that different approaches differ in their ability to correctly reconstruct CFs when not considering the LC and to identify shared CFs. The results showed the effect of different approaches on the reconstruction of CFs and highlighted the importance of choosing an appropriate method. [ABSTRACT FROM AUTHOR]

Counting nematodes is a labor-intensive and time-consuming task, yet it is a pivotal step in various quantitative nematological studies; preparation of initial population densities and final population densities in pot, micro-plot and field trials for different objectives related to management including sampling and location of nematode infestation foci. Nematologists have long battled with the complexities of nematode counting, leading to several research initiatives aimed at automating this process. However, these research endeavors have primarily focused on identifying single-class objects within individual images. To enhance the practicality of this technology, there’s a pressing need for an algorithm that cannot only detect but also classify multiple classes of objects concurrently. This study endeavors to tackle this challenge by developing a user-friendly Graphical User Interface (GUI) that comprises multiple deep learning algorithms, allowing simultaneous recognition and categorization of nematode eggs and second stage juveniles of Meloidogyne spp. In total of 650 images for eggs and 1339 images for juveniles were generated using two distinct imaging systems, resulting in 8655 eggs and 4742 Meloidogyne juveniles annotated using bounding box and segmentation, respectively. The deep-learning models were developed by leveraging the Convolutional Neural Networks (CNNs) machine learning architecture known as YOLOv8x. Our results showed that the models correctly identified eggs as eggs and Meloidogyne juveniles as Meloidogyne juveniles in 94% and 93% of instances, respectively. The model demonstrated higher than 0.70 coefficient correlation between model predictions and observations on unseen images. Our study has showcased the potential utility of these models in practical applications for the future. The GUI is made freely available to the public through the author’s GitHub repository (https://github.com/bresilla/ nematode_counting). While this study currently focuses on one genus, there are plans to expand the GUI’s capabilities to include other economically significant genera of plant parasitic nematodes. Achieving these objectives, including enhancing the models’ accuracy on different imaging systems, may necessitate collaboration among multiple nematology teams and laboratories, rather than being the work of a single entity. With the increasing interest among nematologists in harnessing machine learning, the authors are confident in the potential development of a universal automated nematode counting system accessible to all. This paper aims to serve as a framework and catalyst for initiating global collaboration toward this important goal. [ABSTRACT FROM AUTHOR]

Theoretical and empirical scholars of cultural evolution have traditionally studied social learning strategies, such as conformity, as adaptive strategies to obtain accurate information about the environment, whereas within social psychology there has been a greater focus upon the social consequences of such strategies. Although these two approaches are often used in concert when studying human social learning, we believe the potential social benefits of conformity, and of social learning more broadly, have been overlooked in studies of non‐humans. We review evidence from studies of homophily, imitation, and rapid facial mimicry that suggests that behaving like others affords social benefits to non‐human animals and that behaviour matching may be deployed strategically to increase affiliation. Furthermore, we review studies of conformity in dispersers, and suggest that forgoing personal information or preferences in favour of those of the new group during immigration may be a strategy to facilitate social integration. We therefore propose that the informational and social functions of conformity apply to humans and animals alike. We use this perspective to generate several interesting research questions to inspire work in this field. For example, under what conditions do animals use informational or social conformity and what role does uncertainty play in social learning in immigrant individuals? [ABSTRACT FROM AUTHOR]

Surface facial electromyography (EMG) is commonly used to detect emotions from subtle facial expressions. Although there are established procedures for collecting EMG data and some aspects of their processing, there is little agreement among researchers about the optimal way to process the EMG signal, so that the study-unrelated variability (noise) is removed, and the emotion-related variability is best detected. The aim of the current paper was to establish an optimal processing pipeline for EMG data for identifying emotional expressions in facial muscles. We identified the most common processing steps from existing literature and created 72 processing pipelines that represented all the different processing choices. We applied these pipelines to a previously published dataset from a facial mimicry experiment, where 100 adult participants observed happy and sad facial expressions, whilst the activity of their facial muscles, zygomaticus major and corrugator supercilii, was recorded with EMG. We used a resampling approach and subsets of the original data to investigate the effect and robustness of different processing choices on the performance of a logistic regression model that predicted the mimicked emotion (happy/sad) from the EMG signal. In addition, we used a random forest model to identify the most important processing steps for the sensitivity of the logistic regression model. Three processing steps were found to be most impactful: baseline correction, standardisation within muscles, and standardisation within subjects. The chosen feature of interest and the signal averaging had little influence on the sensitivity to the effect. We recommend an optimal processing pipeline, share our code and data, and provide a step-by-step walkthrough for researchers. [ABSTRACT FROM AUTHOR]

Structural and functional differences in the hippocampus have been related to the episodic memory and social impairments observed in autism spectrum disorder (ASD). In neurotypical individuals, hippocampal–cortical functional connectivity systematically varies between anterior and posterior hippocampus, with changes observed during typical development. It remains unknown whether this specialization of anterior–posterior hippocampal connectivity is disrupted in ASD, and whether age‐related differences in this specialization exist in ASD. We examined connectivity of the anterior and posterior hippocampus in an ASD (N = 139) and non‐autistic comparison group (N = 133) aged 5–21 using resting‐state functional magnetic resonance imaging (MRI) data from the Healthy Brain Network (HBN). Consistent with previous results, we observed lower connectivity between the whole hippocampus and medial prefrontal cortex in ASD. Moreover, preferential connectivity of the posterior relative to the anterior hippocampus for memory‐sensitive regions in posterior parietal cortex was reduced in ASD, demonstrating a weaker anterior–posterior specialization of hippocampal–cortical connectivity. Finally, connectivity between the posterior hippocampus and precuneus negatively correlated with age in the ASD group but remained stable in the comparison group, suggesting an altered developmental specialization. Together, these differences in hippocampal–cortical connectivity may help us understand the neurobiological basis of the memory and social impairments found in ASD. Lay Summary: The brain's hippocampus is an important structure for memory, learning, and social interaction. Research has shown differences in the structure and function of the hippocampus in autism. We investigated the anterior–posterior specialization of the hippocampus; whereby the front and back portions of the hippocampus display unique patterns of coordinated activity with the rest of the brain. This specialization matures during child development and is related to memory performance. Based on previous work, we hypothesized that hippocampal specialization would differ in those diagnosed with autism. Using magnetic resonance imaging, we measured the coordinated activity of the hippocampus with the rest of the brain in autistic and non‐autistic children and young adults. We identified several brain regions displaying different hippocampal specialization between autistic and non‐autistic participants. Many of these regions are known to be involved in memory processes. Interestingly, only the autistic group showed age‐related differences in specialization. This suggests that distinct developmental patterns of hippocampal specialization exist in autistic and non‐autistic children. These findings help us understand how the hippocampus functions differently in autism and may give insight into differences in memory and social behavior. [ABSTRACT FROM AUTHOR]

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Neutropenia is the major dose‐limiting toxicity of irinotecan‐based therapy. The objective of this study was to assess whether inclusion of germline genetic variants into a population pharmacokinetic/pharmacodynamic model can improve prediction of irinotecan‐induced grade 4 neutropenia and identify novel variants of clinical value. A semimechanistic population pharmacokinetic/pharmacodynamic model was used to predict neutrophil response over time in 197 patients receiving irinotecan. Covariate analysis was performed for demographic/clinical factors and 4,781 genetic variants in 84 drug response‐ and toxicity‐related genes to identify covariates associated with neutrophil response. We evaluated the predictive value of the model for grade 4 neutropenia reflecting different clinical scenarios of available data on identified demographic/clinical covariates, baseline and post‐treatment absolute neutrophil counts (ANCs), individual pharmacokinetics, and germline genetic variation. Adding 8 genetic identified covariates (rs10929302 (UGT1A1), rs1042482 (DPYD), rs2859101 (HLA‐DQB3), rs61754806 (NR3C1), rs9266271 (HLA‐B), rs7294 (VKORC1), rs1051713 (ALOX5), and ABCB1 rare variant burden) to a model using only baseline ANCs improved prediction of irinotecan‐induced grade 4 neutropenia from area under the receiver operating characteristic curve (AUC‐ROC) of 50–64% (95% confidence interval (CI), 54–74%). Individual pharmacokinetics further improved the prediction to 74% (95% CI, 64–84%). When weekly ANC was available, the identified covariates and individual pharmacokinetics yielded no additional contribution to the prediction. The model including only ANCs at baseline and at week 1 achieved an AUC‐ROC of 78% (95% CI, 69–88%). Germline DNA genetic variants may contribute to the prediction of irinotecan‐induced grade 4 neutropenia when incorporated into a population pharmacokinetic/pharmacodynamic model. This approach is generalizable to drugs that induce neutropenia and ultimately allows for personalized intervention to enhance patient safety. [ABSTRACT FROM AUTHOR]

Starting December 2019, a novel coronavirus (SARS-CoV-2) spread among humans across the world. From 2020 onward, farmed mink were found susceptible to the virus. In this paper, we describe the Dutch surveillance system and the added surveillance components for early detection of SARS-CoV-2 outbreaks and their results in Dutch mink farms. In the Netherlands, a surveillance system was in place in which mink farmers could submit carcasses for postmortem evaluation and could contact a telephone helpdesk for veterinary advise. Through this system, the first SARS-CoV-2 outbreak in two mink farms was detected in April 2020. Immediately, the Dutch Ministry of Agriculture commissioned a consortium of statutory and research institutes to intensify the surveillance system. The program consisted of both passive surveillance, i.e., mandatory notifications and active surveillance components, i.e., serological screenings and weekly risk-based sampling of dead mink for early detection of new SARS-CoV-2 infections. When one of the surveillance components indicated a suspicion of a possible SARS-CoV-2 infection, follow-up samplings were conducted and at confirmation, all mink were culled. During 2020, 67 out of 124 mink farms that were under surveillance became infected with SARS-CoV-2 (54%). Of these, 31 were detected based on clinical signs (passive surveillance of clinical signs) and 36 were detected through active surveillance. From the mink farms with a new SARS-CoV-2 outbreak that was detected through the surveillance, in 19% of the farms (n = 7), the mink never showed any clinical signs of SARS-CoV-2 and might have been missed by the passive notification system. This study underlines the added value of a surveillance system that can quickly be intensified. The subsequent combination of both passive and active surveillance has shown to be effective in the early detection of emerging pathogens, which is important to minimize the risk of zoonotic spill-over. [ABSTRACT FROM AUTHOR]

Neuromorphic processors promise low-latency and energy-efficient processing by adopting novel brain-inspired design methodologies. Yet, current neuromorphic solutions still struggle to rival conventional deep learning accelerators' performance and area efficiency in practical applications. Event-driven data-flow processing and near/in-memory computing are the two dominant design trends of neuromorphic processors. However, there remain challenges in reducing the overhead of event-driven processing and increasing the mapping efficiency of near/in-memory computing, which directly impacts the performance and area efficiency. In this work, we discuss these challenges and present our exploration of optimizing event-based neural network inference on SENECA, a scalable and flexible neuromorphic architecture. To address the overhead of event-driven processing, we perform comprehensive design space exploration and propose spike-grouping to reduce the total energy and latency. Furthermore, we introduce the event-driven depth-first convolution to increase area efficiency and latency in convolutional neural networks (CNNs) on the neuromorphic processor. We benchmarked our optimized solution on keyword spotting, sensor fusion, digit recognition and high resolution object detection tasks. Compared with other state-of-the-art large-scale neuromorphic processors, our proposed optimizations result in a 6× to 300× improvement in energy efficiency, a 3× to 15× improvement in latency, and a 3× to 100× improvement in area efficiency. Our optimizations for event-based neural networks can be potentially generalized to a wide range of event-based neuromorphic processors. [ABSTRACT FROM AUTHOR]

Obligate intracellular bacteria have remained those for which effective vaccines are unavailable, mostly because protection does not solely rely on an antibody response. Effective antibody-based vaccines, however, have been developed against extracellular bacteria pathogens or toxins. Additionally, obligate intracellular bacteria have evolved many mechanisms to subvert the immune response, making vaccine development complex. Much of what we know about protective immunity for these pathogens has been determined using infection-resolved cases and animal models that mimic disease. These studies have laid the groundwork for antigen discovery, which, combined with recent advances in vaccinology, should allow for the development of safe and efficacious vaccines. Successful vaccines against obligate intracellular bacteria should elicit potent T cell memory responses, in addition to humoral responses. Furthermore, they ought to be designed to specifically induce strong cytotoxic CD8+ T cell responses for protective immunity. This review will describe what we know about the potentially protective immune responses to this group of bacteria. Additionally, we will argue that the novel delivery platforms used during the Sars-CoV-2 pandemic should be excellent candidates to produce protective immunity once antigens are discovered. We will then look more specifically into the vaccine development for Rickettsiaceae, Coxiella burnetti, and Anaplasmataceae from infancy until today. We have not included Chlamydia trachomatis in this review because of the many vaccine related reviews that have been written in recent years. [ABSTRACT FROM AUTHOR]

Plants growing with neighbors compete for light and consequently increase the growth of their vegetative organs to enhance access to sunlight. This response, called shade avoidance syndrome (SAS), involves photoreceptors such as phytochromes as well as phytochrome interacting factors (PIFs), which regulate the expression of growth‐mediating genes. Numerous cell wall‐related genes belong to the putative targets of PIFs, and the importance of cell wall modifications for enabling growth was extensively shown in developmental models such as dark‐grown hypocotyl. However, the contribution of the cell wall in the growth of de‐etiolated seedlings regulated by shade cues remains poorly established. Through analyses of mechanical and biochemical properties of the cell wall coupled with transcriptomic analysis of cell wall‐related genes from previously published data, we provide evidence suggesting that cell wall modifications are important for neighbor proximity‐induced elongation. Further analysis using loss‐of‐function mutants impaired in the synthesis and remodeling of the main cell wall polymers corroborated this. We focused on the cgr2cgr3 double mutant that is defective in methylesterification of homogalacturonan (HG)‐type pectins. By following hypocotyl growth kinetically and spatially and analyzing the mechanical and biochemical properties of cell walls, we found that methylesterification of HG‐type pectins was required to enable global cell wall modifications underlying neighbor proximity‐induced hypocotyl growth. Collectively, our work suggests that plant competition for light induces changes in the expression of numerous cell wall genes to enable modifications in biochemical and mechanical properties of cell walls that contribute to neighbor proximity‐induced growth. [ABSTRACT FROM AUTHOR]

A wide variety of control and surveillance programmes that are designed and implemented based on country-specific conditions exists for infectious cattle diseases that are not regulated. This heterogeneity renders difficult the comparison of probabilities of freedom from infection estimated from collected surveillance data. The objectives of this review were to outline the methodological and epidemiological considerations for the estimation of probabilities of freedom from infection from surveillance information and review state-of-the-art methods estimating the probabilities of freedom from infection from heterogeneous surveillance data. Substantiating freedom from infection consists in quantifying the evidence of absence from the absence of evidence. The quantification usually consists in estimating the probability of observing no positive test result, in a given sample, assuming that the infection is present at a chosen (low) prevalence, called the design prevalence. The usual surveillance outputs are the sensitivity of surveillance and the probability of freedom from infection. A variety of factors influencing the choice of a method are presented; disease prevalence context, performance of the tests used, risk factors of infection, structure of the surveillance programme and frequency of testing. The existing methods for estimating the probability of freedom from infection are scenario trees, Bayesian belief networks, simulation methods, Bayesian prevalence estimation methods and the STOC free model. Scenario trees analysis is the current reference method for proving freedom from infection and is widely used in countries that claim freedom. Bayesian belief networks and simulation methods are considered extensions of scenario trees. They can be applied to more complex surveillance schemes and represent complex infection dynamics. Bayesian prevalence estimation methods and the STOC free model allow freedom from infection estimation at the herdlevel from longitudinal surveillance data, considering risk factor information and the structure of the population. Comparison of surveillance outputs from heterogeneous surveillance programmes for estimating the probability of freedom from infection is a difficult task. This paper is a 'guide towards substantiating freedom from infection' that describes both all assumptionslimitations and available methods that can be applied in different settings. [ABSTRACT FROM AUTHOR]

Introduction: Plant growth is a plastic phenomenon controlled both by endogenous genetic programs and by environmental cues. The embryonic stem, the hypocotyl, is an ideal model system for the quantitative study of growth due to its relatively simple geometry and cellular organization, and to its essentially unidirectional growth pattern. The hypocotyl of Arabidopsis thaliana has been studied particularly well at the molecular-genetic level and at the cellular level, and it is the model of choice for analysis of the shade avoidance syndrome (SAS), a growth reaction that allows plants to compete with neighboring plants for light. During SAS, hypocotyl growth is controlled primarily by the growth hormone auxin, which stimulates cell expansion without the involvement of cell division. Methods: We assessed hypocotyl growth at cellular resolution in Arabidopsis mutants defective in auxin transport and biosynthesis and we designed a mathematical auxin transport model based on known polar and non-polar auxin transporters (ABCB1, ABCB19, and PINs) and on factors that control auxin homeostasis in the hypocotyl. In addition, we introduced into the model biophysical properties of the cell types based on precise cell wall measurements. Results and Discussion: Our model can generate the observed cellular growth patterns based on auxin distribution along the hypocotyl resulting from production in the cotyledons, transport along the hypocotyl, and general turnover of auxin. These principles, which resemble the features of mathematical models of animal morphogen gradients, allow to generate robust shallow auxin gradients as they are expected to exist in tissues that exhibit quantitative auxin-driven tissue growth, as opposed to the sharp auxin maxima generated by patterning mechanisms in plant development. [ABSTRACT FROM AUTHOR]

The article focuses on exploring genetic polymorphisms as potential contributors to severe postoperative pain. Topics include the use of pharmacogenetics in pain therapy to predict individual analgesic response, the impact of genetic variants on opioid metabolism, and the influence of genetic polymorphisms on the effectiveness of analgesics in specific patient populations, such as those with red hair.

The reconstruction of clonal families (CFs) in B-cell receptor (BCR) repertoire analysis is a crucial step to understand the adaptive immune system and how it responds to antigens. The BCR repertoire of an individual is formed throughout life and is diverse due to several factors such as gene recombination and somatic hypermutation. The use of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using next generation sequencing enabled the generation of full BCR repertoires that also include rare CFs. The reconstruction of CFs from AIRR-seq data is challenging and several approaches have been developed to solve this problem. Currently, most methods use the heavy chain (HC) only, as it is more variable than the light chain (LC). CF reconstruction options include the definition of appropriate sequence similarity measures, the use of shared mutations among sequences, and the possibility of reconstruction without preliminary clustering based on V- and J-gene annotation. In this study, we aimed to systematically evaluate different approaches for CF reconstruction and to determine their impact on various outcome measures such as the number of CFs derived, the size of the CFs, and the accuracy of the reconstruction. The methods were compared to each other and to a method that groups sequences based on identical junction sequences and another method that only determines subclones. We found that after accounting for data set variability, in particular sequencing depth and mutation load, the reconstruction approach has an impact on part of the outcome measures, including the number of CFs. Simulations indicate that unique junctions and subclones should not be used as substitutes for CF and that more complex methods do not outperform simpler methods. Also, we conclude that different approaches differ in their ability to correctly reconstruct CFs when not considering the LC and to identify shared CFs. The results showed the effect of different approaches on the reconstruction of CFs and highlighted the importance of choosing an appropriate method. [ABSTRACT FROM AUTHOR]

Objectively as possible using disability and impairment scales. Applying these outcome measures consistently in clinical practice aids in recognizing the effectiveness (or lack thereof) of a treatment and facilitates timely consideration of alternative diagnoses or treatments. This review provides an overview of the current perspectives on the diagnostic process and first-line treatments for managing the disease. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM(hGBM)models in humanized mice using patientderived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBMtumor engraftment and growth in bonemarrow-liverthymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBMbiologywithin the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the T cell receptor (TCRβ) repertoire in peripheral blood and muscle tissues of treatment naïve patients with newly diagnosed idiopathic inflammatory myopathies (IIMs). Methods: High throughput RNA sequencing of the TCRβ chain was performed in peripheral blood and muscle tissue in twenty newly-diagnosed treatment-naïve IIM patients (9 DM, 5 NM/OM, 5 IMNM and 1 ASyS) and healthy controls. Results thereof were correlated with markers of disease activity. Results: Muscle tissue of IIM patients shows more expansion of TCRb clones and decreased diversity when compared to peripheral blood of IIM as well as healthy controls (both p=0.0001). Several expanded TCRb clones in muscle are tissue restricted and cannot be retrieved in peripheral blood. These clones have significantly longer CDR3 regions when compared to clones (also) found in circulation (p=0.0002), while their CDR3 region is more hydrophobic (p<0.01). Network analysis shows that clonal TCRβ signatures are shared between patients. Increased clonal expansion in muscle tissue is significantly correlated with increased CK levels (p=0.03), while it tends to correlate with decreased muscle strength (p=0.08). Conclusion: Network analysis of clones in muscle of IIM patients shows shared clusters of sequences across patients. Muscle-restricted CDR3 TCRβ clones show specific structural features in their T cell receptor. Our results indicate that clonal TCRβ expansion in muscle tissue might be associated with disease activity. Collectively, these findings support a role for specific clonal T cell responses in muscle tissue in the pathogenesis of the IIM subtypes studied. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Escherichia coli (CREC) ST410 has recently emerged as a major global health problem. Here, we report a shift in CREC prevalence in Chinese hospitals between 2017 and 2021 with ST410 becoming the most commonly isolated sequence type. Genomic analysis identifies a hypervirulent CREC ST410 clone, B5/H24RxC, which caused two separate outbreaks in a children's hospital. It may have emerged from the previously characterised B4/H24RxC in 2006 and has been isolated in ten other countries from 2015 to 2021. Compared with B4/H24RxC, B5/H24RxC lacks the blaOXA-181-bearing X3 plasmid, but carries a F-type plasmid containing blaNDM-5. Most of B5/H24RxC also carry a high pathogenicity island and a novel O-antigen gene cluster. We find that B5/H24RxC grew faster in vitro and is more virulent in vivo. The identification of this newly emerged but already globally disseminated hypervirulent CREC clone, highlights the ongoing evolution of ST410 towards increased resistance and virulence. In this work, the authors identified a hypervirulent carbapenem-resistant Escherichia coli ST410 clone which carries a high pathogenicity island and an O-antigen gene cluster. The findings highlight the ongoing evolution of ST410 towards increased resistance and virulence. [ABSTRACT FROM AUTHOR]

Aims: Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole‐blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Methods: Data of pregnant women using a twice‐daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness‐of‐fit plots, visual predictive checks and a bootstrap analysis. Results: A total of 260 whole‐blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. Conclusions: Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole‐blood tacrolimus predose concentrations during pregnancy, increasing the dose is required. [ABSTRACT FROM AUTHOR]

Human scalp hair is an easily available but complex matrix for determination of cortisone and cortisol, and has been shown to reflect long-term glucocorticoid exposure. Hair glucocorticoid analysis has been used to detect hypo- and hypercortisolism. In this study, we describe the development and validation of a LC-MS/MS method for quantification of cortisone and cortisol in human scalp hair, and provide a novel approach for analysis and interpretation of the results. Improved sample preparation using pulverization and solid phase extraction allowed for low sample volumes (10 mg). Baseline chromatographic separation without matrix interference was achieved by reversed phase chromatography and MRM measurement in negative ion mode. Run-to-run time was 8 min. Mixed model analyses were performed to create individual patterns of cortisone and cortisol concentrations. Matrix matched calibration curves showed excellent linearity up to 100 pg (analyte)/mg (hair) for both cortisone and cortisol (R2>0.995). LLOQ was 1.5 and 1.0 pg/mg for cortisone and cortisol, respectively. Matrix effect was negligible for hair color (recoveries 95–105 %). Cortisone and cortisol concentrations decreased from proximal to distal hair segments, following a predictable, but subject-specific pattern, with less individual variation for cortisone than for cortisol. This improved LC-MS/MS method is able to accurately quantify cortisone and cortisol in human hair with minimum matrix interference. This new way of data analysis and interpretation including individual patterns of cortisone and cortisol will be of help with detection of pathological concentrations in both the high – and the low ranges of glucocorticoids. [ABSTRACT FROM AUTHOR]

Soil health assessments that integrate physical, chemical and biological indicators help the evaluation of soil functioning, provide a framework for monitoring soil degradation, guide land management activities and secure the delivery of soil ecosystem services. In this study, we assessed soil health by soil texture class on arable land in Southeast Norway and mid-Norway and between grassland and arable land in mid-Norway. We used descriptive statistics and the Welch t-test with unequal variance and Bonferroni corrections to compare a physical soil indicator (bulk density) and chemical indicators (organic matter, P-AL, K-AL, Ca-AL, Mg-AL, Na-AL and pH). We developed scoring curves from cumulative normal distribution functions on regional soil data for various soil indicators where climate, soil texture class and land use were considered. Our results show that for certain soil texture classes, average soil indicator values differed between pedo-climatic zones on arable land, but for others the difference was not significant. The variability between the pedo-climatic zones for these can be neglected, but for the ones that differ, the variability is important to consider when assessing soil health. Similarly, this was the case when comparing land use (grassland and arable land) for most soil indicators in mid-Norway. This finding illustrates the importance of addressing unique local conditions in soil health assessments. We propose aggregating similar soil texture classes where no differences are apparent when developing scoring curves. The sub-optimal levels of plant available nutrients (P-AL and K-AL) found in the soil in both pedo-climatic zones highlights the importance of suitable threshold values for targeted soil ecosystem services to ensure soil health and sustainable agricultural production. We also recommend prioritizing the most relevant soil ecosystem services to limit the number of soil indicators that need monitoring. [ABSTRACT FROM AUTHOR]

Mimicking another individual functions as a social glue: it smoothens the interaction and fosters affiliation. Here, we investigated whether the intrinsic motivation to affiliate with others, stemming from attachment relationships, modulates individuals' engagement in facial mimicry (FM). Participants (N = 100; MAge = 24.54 years, SDAge = 3.90 years) observed faces with happy, sad, and neutral expressions, while their facial muscle activity was recorded with electromyography. Attachment was measured with the Attachment Styles Questionnaire, which provides a multidimensional profile for preoccupied and dismissing styles. It was proposed that the preoccupied and dismissing styles are characterized by high and low intrinsic affiliation motivation, respectively, and these were hypothesized to manifest in enhanced and diminished FM. Participants showed happy and sad FM, yet attachment styles did not significantly predict FM. Bayes Factor analyses lend evidence favoring the null hypothesis, suggesting that adult attachment do not contribute to FM. [ABSTRACT FROM AUTHOR]

In many group-living species, individuals are required to flexibly modify their communicative behaviour in response to current social challenges. To unravel whether sociality and communication systems co-evolve, research efforts have often targeted the links between social organisation and communicative repertoires. However, it is still unclear which social or interactional factors directly predict communicative complexity. To address this issue, we studied wild and zoo-housed immature orangutans of two species to assess the impact of the socio-ecological setting on the production of non-vocal signal repertoires. Specifically, we compared repertoire size, dyadic repertoire similarity, and number of social goals (i.e. observer's estimate of the signaller's intended interaction outcome) for communicative interactions with mothers versus other conspecifics, controlling for critical individual and environmental factors. In this small sample of immature orangutans, wild-captive contrasts were statistically significant only for other-directed repertoires, but not for mother-directed repertoires, and not for the number of social goals that immatures communicated towards. While the repertoires of individuals living in the same research setting were more similar than those living in contrasting settings, this difference was most pronounced for other-directed repertoires of the less socially tolerant orangutan species. These results suggest that the boosted interactional opportunities in captivity rather than mere differences in environmental affordances or communicative needs drive the wild-captive contrast in orangutan communicative repertoires. Overall, this fine-grained analysis of repertoires further underscores that not only a species' social organisation but also the targeted audience may have a profound impact on communicative behaviour. Significance statement: Navigating a dynamic social environment often requires flexible signal use. While it has repeatedly been shown that the social organisation and structure of species predict the complexity of their communication systems, the mechanisms underlying these relationships are largely unknown. Because targeted studies to assess this issue in great apes are difficult, we take an alternative approach here: we compare the same species living in the wild and in artificial habitats in captivity. This contrast allows a direct test of how repertoires respond to the relevant difference in socio-ecological conditions. Our results show that the diversity of interaction partners (i.e. social opportunities), but not the diversity of social goals (i.e. possible interaction outcomes) or the broader physical opportunities (i.e. safe ground use), predict the size and consistency of wild and captive signalling repertoires. [ABSTRACT FROM AUTHOR]

This article discusses a scientific study of a mummified child from Zagreb Cathedral in Croatia. The study aimed to gain a deeper understanding of the child's life and human physiology through medical and scientific assessment of the remains. The remains were imaged using various techniques, including digital radiographs and CT scans, and isotope analysis was conducted. The findings revealed that the child was between three and five years old at the time of death and that the mummification process likely occurred in the tenth century CE. The study raises questions about why the child was mummified using an old Egyptian technique despite the practice being discontinued in Egypt by the seventh century CE. Further molecular analysis is hoped to provide more insights into these questions. [Extracted from the article]

Previous work indicated that the incidence of travellers' diarrhoea (TD) is higher in soldiers of British origin, when compared to soldiers of Nepalese descent (Gurkhas). We hypothesise that the composition of the gut microbiota may be a contributing factor in the risk of developing TD in soldiers of British origin. This study aimed to characterise the gut microbial composition of Gurkha and non-Gurkha soldiers of the British Army. Recruitment of 38 soldiers (n = 22 Gurkhas, n = 16 non-Gurkhas) and subsequent stool collection, enabled shotgun metagenomic sequencing-based analysis of the gut microbiota. The microbiota of Gurkhas had significantly (P < 0.05) lower diversity, for both Shannon and Simpson diversity indices, using species level markers than the gut microbiota of non-Gurkha soldiers. Non-metric Multidimensional Scaling (NMDS) of the Bray-Curtis distance matrix revealed a significant difference in the composition of the gut microbiota between Gurkhas and non-Gurkha soldiers, at both the species level (P = 0.0178) and the genus level (P = 0.0483). We found three genera and eight species that were significantly enriched in the non-Gurkha group and one genus (Haemophilus) and one species (Haemophilus parainfluenzae) which were enriched in the Gurkha group. The difference in the microbiota composition between Gurkha soldiers and soldiers of British origin may contribute to higher colonization resistance against diarrhoeal pathogens in the former group. Our findings may enable further studies into interventions that modulate the gut microbiota of soldiers to prevent TD during deployment. [ABSTRACT FROM AUTHOR]

Two cases show osimertinib/sotorasib combination could be effective in KRAS G12C-driven osimertinib resistance. [ABSTRACT FROM AUTHOR]

Background: This study explores what pre-service teachers identify as uncertainties within two climate board games and to what aspects of reality they relate these uncertainties, if at all. Should games be suitable resources for teaching topics related to climate change uncertainty, I expect pre-service teachers to (a) identify uncertainties within climate board games, and (b) relate these uncertainties to reality. Intervention: To explore whether and how pre-service teachers identify and relate in-game uncertainties to reality, pre-service teachers played and discussed two climate board games (Another Future and CATAN: Oil Springs Scenario). Methods: A content analysis of pre-service teachers' audio-recorded discussions about the games was conducted. First, a conventional content analysis indicated the uncertainties that they identified. Second, further analysis showed how the pre-service teachers related these uncertainties to reality. Results: This study indicates that pre-service teachers identify various uncertainties from two different board games, including the occurrence/impact of catastrophes and the behaviour of players, who can ruin the game. In most cases, the pre-service teachers link these uncertainties to reality. Pre-service teachers discuss, for example, political dilemmas and interests, climate justice issues, challenges of and adaptation to possible catastrophes, and the significance of environmental activism. Discussion: The research findings are discussed in relation to existing literature on uncertainty in climate change games. Teacher educators and teachers using games for education about climate change uncertainties are recommended to encourage dialogues about these uncertainties, use or take into account context, and consider games as tools for learning to live with climate change uncertainty. [ABSTRACT FROM AUTHOR]

Summary: Background: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate‐polyglutamate (MTX‐PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD). Aim: To investigate the relationship between MTX‐PGs and methotrexate drug survival, efficacy and toxicity Methods: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step‐up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX‐PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation. Results: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 μg/g (IQR 73–480). After the 12‐month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty‐one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX‐PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75–0.99), lower FCP (β −3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 μg/g; OR 1.1, 95% CI 1.0–1.3). Higher MTX‐PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX‐PGs and HBI or hepatotoxicity. Conclusions: Higher MTX‐PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX‐PG3 could be used for TDM if a target concentration can be established. [ABSTRACT FROM AUTHOR]