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Cartilaginous fishes (chondrichthyans: chimeras and elasmobranchs -sharks, skates, and rays) hold a key phylogenetic position to explore the origin and diversifications of jawed vertebrates. Here, we report and integrate reference genomic, transcriptomic, and morphological data in the small-spotted catshark Scyliorhinus canicula to shed light on the evolution of sensory organs. We first characterize general aspects of the catshark genome, confirming the high conservation of genome organization across cartilaginous fishes, and investigate population genomic signatures. Taking advantage of a dense sampling of transcriptomic data, we also identify gene signatures for all major organs, including chondrichthyan specializations, and evaluate expression diversifications between paralogs within major gene families involved in sensory functions. Finally, we combine these data with 3D synchrotron imaging and in situ gene expression analyses to explore chondrichthyan-specific traits and more general evolutionary trends of sensory systems. This approach brings to light, among others, novel markers of the ampullae of Lorenzini electrosensory cells, a duplication hotspot for crystallin genes conserved in jawed vertebrates, and a new metazoan clade of the transient-receptor potential (TRP) family. These resources and results, obtained in an experimentally tractable chondrichthyan model, open new avenues to integrate multiomics analyses for the study of elasmobranchs and jawed vertebrates. [ABSTRACT FROM AUTHOR]

Globally, road fatalities affect wildlife populations and ecosystems, leading to ecological imbalances, economic losses, and safety hazards for both animals and humans. However, the emotional toll on humans is less well understood. This research explores tourists' responses to roadkill, using emotional geography as the overarching framework, and focusing on the island state of Tasmania in Australia. Tasmania is known for its diverse and abundant native wildlife, as well as the unfortunate distinction of having Australia's highest rate of wildlife fatalities caused by vehicle collisions, commonly referred to as roadkill. A mixed‐method questionnaire asked respondents to share emotions, and we then considered their relationships to socio‐demographic attributes. Around 97% of respondents encountered roadkill during their stays, and 63% encountered live animals on or near the road. Tourists identified sadness as the most felt emotion when confronted with the consequences of wildlife–vehicle collisions. Anger and disgust were also experienced, primarily because of the unpleasant sight of roadkill and the realisation that animals suffered. Women reported being more negatively affected than men. Tourists who had visited to see wildlife were more affected than those who had not. Analysis leads to the conclusion that unplanned, sporadic, unexpected, and confronting encounters with dead animals detract from the tourism experience for most, especially encounters with wildlife was anticipated as a positive experience on tour. Such findings have wider implications for those working in the tourism industry in mainland Australia, Canada, and South Africa, where roadkill is also problematic. [ABSTRACT FROM AUTHOR]

Objective: Describe the demographic data and clinical phenotype of cranial palsy induced by immune checkpoint inhibitors (CNP-ICI). Methods: A systematic literature review of the literature was performed in Pubmed, Web of Science, and Embase, including 68 articles and 136 patients (PROSPERO no. CRD42024517262). Results: Out of the 1205 articles screened, 68 articles were included after fulfilling the inclusion criteria, for a total of 136 patients. All articles were case reports and case series. In the cohort studied, 52% of patients were treated with anti PD-1/PDL-1 therapies, 14% with anti CTLA-4 therapies, and 34% with a combination of anti CTLA-4 and anti PD-1/PDL-1 therapies. The facial nerve was the most affected cranial nerve, involved in 38% of cases, followed by the optic nerve (35%), the cochleovestibular nerve (12%), and the abducens nerve (10%). The median time from the initial immune checkpoint inhibitor (ICI) injection to the onset CNP-ICI was 10 weeks (IQR 4–20). Magnetic resonance imaging demonstrated contrast enhancement or abnormal signal of the affected nerve in 43% of cases. Cerebrospinal fluid analysis indicated lymphocytic pleocytosis in 59% of cases. At the onset of immune-related adverse events, 89% of patients discontinued immunotherapy, and 92% received treatment for CNP-ICI. Treatment regimens included corticosteroids in 86% of cases, intravenous immunoglobulin in 21%, and plasma exchange in 5.1%. Among the whole population, 33% achieved recovery, 52% showed clinical improvement, 16% remained stable, and 3% experienced worsening of their condition. Rechallenge with immunotherapy was significantly associated with the emergence of new immune-related Adverse Events (irAEs). Conclusion: ICI therapy may lead to cranial nerve involvement, particularly affecting the facial nerve, typically presenting around 10 weeks after treatment initiation. While corticosteroid therapy often resulted in patient improvement, rechallenging with ICIs were associated with new irAEs. [ABSTRACT FROM AUTHOR]

Simple Summary: Wildlife–vehicle collisions continue to threaten Tasmanian wildlife and cause animal welfare issues. As Tasmanian residents often consider roadkill as part of the landscape, tourists' attitudes and behaviour could provide new insights when seeking solutions. Using a self-reporting questionnaire, we found that most tourists view wildlife–vehicle collisions as a serious issue, and humans must take responsibility for minimising the problem. Even though residents seem hardened to roadkill, they appear to play an important role in communicating the issue to tourists. Tourists express a willingness to adopt mitigation strategies, such as altering travelling speed or travelling times. However, this research reveals that the importance of safely removing carcasses and checking on the victims and their surviving young is not fully understood. Tourists indicated that they do not know what to do or whom to contact when confronted with injured, surviving, or deceased wildlife. We suggest that the tourism industry, alongside other stakeholders, can play a significant role in raising awareness and education, as well as inform campaigns tailored to Tasmanian residents. The surge in wildlife–vehicle collision research has not yet translated into a substantial decrease in animal fatalities. In line with the prevailing view, we suspect that drivers' behaviour may be the most crucial element. We address a research gap in drivers' attitudes towards and behaviour in response to wildlife–vehicle collisions from a tourist perspective. We designed a questionnaire to examine tourists' attitudes and behaviour in relation to wildlife–vehicle collisions while driving in Tasmania. We found that the respondents' sociodemographic attributes had minimal effect on their practical responses to roadkill. Tourists consider wildlife–vehicle collisions a serious problem for both biodiversity loss and animal welfare reasons, and their willingness to change their behaviour was high. However, many respondents did not stop to check for surviving pouch young. This inaction resulted either from overlooking the importance of pouch checking or a lack of knowledge on what action needed to be taken. There may also be a lack of understanding that roadkill left on the road leads to secondary roadkill incidents. Even though tourist behaviour does not automatically represent residents' behaviour, these findings will help to improve and tailor educational approaches to rectify the driver awareness/behaviour gap for both tourists and residents. [ABSTRACT FROM AUTHOR]

Atypical Chemokine Receptor 3 (ACKR3) belongs to the G protein-coupled receptor family but it does not signal through G proteins. The structural properties that govern the functional selectivity and the conformational dynamics of ACKR3 activation are poorly understood. Here, we combined hydrogen/deuterium exchange mass spectrometry, site-directed mutagenesis, and molecular dynamics simulations to examine the binding mode and mechanism of action of ACKR3 ligands of different efficacies. Our results show that activation or inhibition of ACKR3 is governed by intracellular conformational changes of helix 6, intracellular loop 2, and helix 7, while the DRY motif becomes protected during both processes. Moreover, we identified the binding sites and the allosteric modulation of ACKR3 upon β-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small ligands, the binding mode of β-arrestin 1, the activation dynamics, and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins. [ABSTRACT FROM AUTHOR]

Alternative splicing significantly enhances the diversity of the G protein-coupled receptor (GPCR) family, including the histamine H3 receptor (H3R). This post-transcriptional modification generates multiple H3R isoforms with potentially distinct pharmacological and physiological profiles. H3R is primarily involved in the presynaptic inhibition of neurotransmitter release in the central nervous system. Despite the approval of pitolisant for narcolepsy (Wakix®) and daytime sleepiness in adults with obstructive sleep apnea (Ozawade®) and ongoing clinical trials for other H3R antagonists/inverse agonists, the functional significance of the numerous H3R isoforms remains largely enigmatic. Recent publicly available RNA sequencing data have confirmed the expression of multiple H3R isoforms in the brain, with some isoforms exhibiting unique tissue-specific distribution patterns hinting at isoform-specific functions and interactions within neural circuits. In this review, we discuss the complexity of H3R isoforms with a focus on their potential roles in central nervous system (CNS) function. Comparative analysis across species highlights evolutionary conservation and divergence in H3R splicing, suggesting species-specific regulatory mechanisms. Understanding the functionality of H3R isoforms is crucial for the development of targeted therapeutics. This knowledge will inform the design of more precise pharmacological interventions, potentially enhancing therapeutic efficacy and reducing adverse effects in the treatment of neurological and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Fishing-down-marine-food-webs has resulted in alarming declines of various species worldwide. Benthic rays are one examples of such overexploited species. On tidal flats, these rays are highly abundant and play an ecologically important role. They use tidal flats as refuge, feeding and resting grounds, during which they bury into the sediment, which results in sediment bioturbation. Changes in bioturbation intensity, following ray removal, may affect the biogeomorphology of tidal flats with possible cascading effects on the macrozoobenthic community. However, it is poorly understood how these indirect effects could influence ecosystem function. We therefore studied the geomorphic impact of benthic rays (specifically the pearl whipray/stingray Fontitrygon margaritella) on the tropical tidal flats of the Bijagós Archipelago, Guinea-Bissau, on a landscape scale. We investigated 1) bioturbation rates by rays using drone and ground surveys, 2) the spatial distribution of ray pits on multiple tidal flats, 3) the impact of rays on sediment properties and macrozoobenthos by experimental exclusion (15 months). Benthic rays bioturbated 3.7 ± 0.35% of the tidal flat's sediment surface per day over one single 24-h period, which equals a complete top-sediment-surface turnover every 27 days. The spatial distribution of ray pits was affected by tidal flat geomorphology since pits decayed faster at areas exposed to strong hydrodynamic forces. Predator exclusion altered sediment properties, leading to changes in sedimentation (− 17%) and erosion (− 43%) rates. In addition, macrozoobenthic species composition changed, marked by an increase in Capitellidae worms and a greater biomass of Malacostraca over time. These changes indicated substantial effects of ray bioturbation on the biotic and geomorphic landscape of tidal flats. Overall, we conclude that changing abundances of benthic rays can have clear landscape-wide geomorphological effects on intertidal ecosystems. These indirect consequences of fisheries should be incorporated in integrative management plans to preserve tidal flats and connected ecosystems. [ABSTRACT FROM AUTHOR]

NanoLuc-mediated bioluminescence resonance energy transfer (NanoBRET) has gained popularity for its ability to homogenously measure ligand binding to G protein-coupled receptors (GPCRs), including the subfamily of chemokine receptors. These receptors, such as ACKR3, CXCR4, CXCR3, play a crucial role in the regulation of the immune system, are associated with inflammatory diseases and cancer, and are seen as promising drug targets. The aim of this study was to optimize NanoBRET-based ligand binding to NLuc-ACKR3 and NLuc-CXCR4 using different fluorescently labeled chemokine CXCL12 analogs and their use in a multiplex NanoBRET binding assay of two chemokine receptors at the same time. The four fluorescent CXCL12 analogs (CXCL12-AZD488, -AZD546, -AZD594, -AZD647) showed high-affinity saturable binding to both NLuc-ACKR3 and NLuc-CXCR4, with relatively low levels of non-specific binding. Additionally, the binding of all AZDye-labeled CXCL12s to Nluc receptors was inhibited by pharmacologically relevant unlabeled chemokines and small molecules. The NanoBRET binding assay for CXCL10-AZD488 binding to Nluc-CXCR3 was also successfully established and successfully employed for the simultaneous measurement of the binding of unlabeled small molecules to NLuc-CXCR3 and NLuc-CXCR4. In conclusion, multiplexing the NanoBRET-based competition binding assay is a promising tool for testing unlabeled (small) molecules against multiple GPCRs simultaneously. [ABSTRACT FROM AUTHOR]

The modulation of biological processes with light-sensitive chemical probes promises precise temporal and spatial control. Yet, the design and synthesis of suitable probes is a challenge for medicinal chemists. This article introduces a photocaging strategy designed to modulate the pharmacology of histamine H3 receptors (H3R) and H4 receptors (H4R). Employing the photoremovable group BODIPY as the caging entity for two agonist scaffolds—immepip and 4-methylhistamine—for H3R and H4R, respectively, we synthesized two BODIPY-caged compounds, 5 (VUF25657) and 6 (VUF25678), demonstrating 10–100-fold reduction in affinity for their respective receptors. Notably, the caged H3R agonist, VUF25657, exhibits approximately a 100-fold reduction in functional activity. The photo-uncaging of VUF25657 at 560 nm resulted in the release of immepip, thereby restoring binding affinity and potency in functional assays. This approach presents a promising method to achieve optical control of H3R receptor pharmacology. [ABSTRACT FROM AUTHOR]

The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.The histamine H4 receptor (H4R) plays key roles in immune cell function. Here, the authors report structures of H4R-Gi complex with various ligands bound, revealing distinct ligand binding modes and a basis for rational design of novel antihistamines targeting H4R. [ABSTRACT FROM AUTHOR]

The Arabidopsis thaliana DREB2A transcription factor interacts with the negative regulator RCD1 and the ACID domain of subunit 25 of the transcriptional co-regulator mediator (Med25) to integrate stress signals for gene expression, with elusive molecular interplay. Using biophysical and structural analyses together with high-throughput screening, we reveal a bivalent binding switch in DREB2A containing an ACID-binding motif (ABS) and the known RCD1-binding motif (RIM). The RIM is lacking in a stress-induced DREB2A splice variant with retained transcriptional activity. ABS and RIM bind to separate sites on Med25-ACID, and NMR analyses show a structurally heterogeneous complex deriving from a DREB2A-ABS proline residue populating cis- and trans-isomers with remote impact on the RIM. The cis-isomer stabilizes an α-helix, while the trans-isomer may introduce energetic frustration facilitating rapid exchange between activators and repressors. Thus, DREB2A uses a post-transcriptionally and post-translationally modulated switch for transcriptional regulation.Transcription factor DREB2A interacts with Med25 to regulate stress responses. Here, the authors show that DREB2A uses splicing and proline-isomerization for this regulation and that proline cis-trans switching introduces structural frustration facilitating regulator exchange. [ABSTRACT FROM AUTHOR]

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Copyright of Pedagogiek is the property of Amsterdam University Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

What does the increased reliance on digital communication technologies by migrants, refugees, asylum seekers, migrant communities, governments and researchers reveal about the benefits, limits and politics of everyday mobile and immobile experiences during the pandemic? This introduction to the special issue on cultures of (im)mobile entanglements addresses this inquiry, alongside ten articles covering themes of governance and surveillance, agency and negotiated subjectivities, translocal and transnational solidarity, as well as doing research in pandemic times. Critically engaging with both mobility and immobility in the intersecting field of mobilities and migration research, the special issue centres a multidimensional and multi-scalar perspective on the deep interlinking of various modes of mobilities and stasis in and beyond spatial and temporal conditions mediated by politically and culturally structured digitalization. It endeavours to create a vantage point to critically examine the mobility–immobility continuum as informed by power relations, hierarchies and inequalities in a networked and global society. [ABSTRACT FROM AUTHOR]

This article analyses the communication activities of Filmstichting West Indië, which in the late 1940s and early 1950s produced 12 documentary propaganda films about Dutch colonial Suriname, and the resistance against these reductive representations in zines of the Surinamese migrant organization Vereniging Ons Suriname. We draw on hence unstudied archival material to dissect the role of media operations, as persuasive, strategic media productions, in constructing and challenging differential relations between colonizers and colonial subjects, and symbolically negotiating how different territories and bodies relate to each other. A visual and textual analysis of the cases unpacks historical struggles over the regimes of (post)colonial (im)mobilities, as they are produced and articulated within regimes of representation. We ultimately argue that, in order to understand the historical constitution of mobility regimes (and, in order to be able to critique them), we need to study the co-production of mobility regimes within regimes of mediated representation. [ABSTRACT FROM AUTHOR]

Many therapies in clinical trials are based on single drug-single target relationships. To further extend this concept to multi-target approaches using multi-targeted drugs, we developed a machine learning pipeline to unravel the target landscape of kinase inhibitors. This pipeline, which we call 3D-KINEssence, uses a new type of protein fingerprints (3D FP) based on the structure of kinases generated through a 3D convolutional neural network (3D-CNN). These 3D-CNN kinase fingerprints were matched to molecular Morgan fingerprints to predict the targets of each respective kinase inhibitor based on available bioactivity data. The performance of the pipeline was evaluated on two test sets: a sparse drug-target set where each drug is matched in most cases to a single target and also on a densely-covered drug-target set where each drug is matched to most if not all targets. This latter set is more challenging to train, given its non-exclusive character. Our model's root-mean-square error (RMSE) based on the two datasets was 0.68 and 0.8, respectively. These results indicate that 3D FP can predict the target landscape of kinase inhibitors at around 0.8 log units of bioactivity. Our strategy can be utilized in proteochemometric or chemogenomic workflows by consolidating the target landscape of kinase inhibitors. Author summary: In this publication we have set up a new method to predict the targets kinase inhibitors. This information is important since it allows to understand how the inhibition of multiple targets by an inhibitor translates to its potency. For this, we have used a convolutional neural networks (CNN) strategy that is commonly used to classify images with common but also different elements, for instance to recognize classes (predicting which animal is shown) or subtle changes (predicting which emotions are shown on a face). In this case we have used CNN models to detect patterns in 3-dimensional information from kinase structures and matched this to the bioactivity of their respective inhibitors. We show that our method has a similar performance as benchmark methods in the field. However, since recognized patterns can be made explicit, our method could help to make the underlying artificial intelligence method explainable. In the future this could lead to more optimal matching of multi-target drugs to diseases that have multiple vulnerabilities. [ABSTRACT FROM AUTHOR]

Objective: Although the COVID-19 pandemic has affected mental health, understanding who has been affected most and why is incomplete. We sought to understand changes in mental health in the context of transmission numbers and pandemic (social) restrictions and whether changes in mental health varied among population groups. Methods: We analyzed data from 92 062 people (aged ≥16 years and able to read Dutch) who participated in the Corona Behavioral Unit cohort study at the National Institute for Public Health and the Environment, the Netherlands, from April 17, 2020, through January 25, 2022. Participants self-reported mental well-being through multiple rounds of surveys. We used a multivariable linear mixed-effects model to analyze loneliness, general mental health, and life satisfaction. Results: As strictness of pandemic prevention measures and social restrictions increased, people's feelings of loneliness increased and mental health and life satisfaction decreased. As restrictions were relaxed, loneliness decreased and general mental health improved. Younger people (aged 16-24 y) versus older people (aged ≥40 y), people with low (vs high) education levels, and people living alone (vs living together) were more likely to have negative well-being outcomes. We observed that trajectories over time differed considerably only by age, with participants aged 16-24 years affected substantially more than participants aged ≥40 years by pandemic social restrictions. These patterns were consistent across multiple waves of SARS-CoV-2 infection. Conclusions: Our findings suggest that the social restrictions imposed by the Dutch government during the study period were associated with reduced mental well-being, especially among younger people. However, people appeared resilient as they recovered during periods when restrictions were relaxed. Monitoring and supporting well-being, in particular to reduce loneliness, may help younger people during periods of intense social restrictions. [ABSTRACT FROM AUTHOR]

Brain oedema is a life-threatening complication of various neurological conditions. Understanding molecular mechanisms of brain volume regulation is critical for therapy development. Unique insight comes from monogenic diseases characterized by chronic brain oedema, of which megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. Variants in MLC1 or GLIALCAM , encoding proteins involved in astrocyte volume regulation, are the main causes of MLC. In some patients, the genetic cause remains unknown. We performed genetic studies to identify novel gene variants in MLC patients, diagnosed by clinical and MRI features, without MLC1 or GLIALCAM variants. We determined subcellular localization of the related novel proteins in cells and in human brain tissue. We investigated functional consequences of the newly identified variants on volume regulation pathways using cell volume measurements, biochemical analysis and electrophysiology. We identified a novel homozygous variant in AQP4 , encoding the water channel aquaporin-4, in two siblings, and two de novo heterozygous variants in GPRC5B , encoding the orphan G protein-coupled receptor GPRC5B, in three unrelated patients. The AQP4 variant disrupts membrane localization and thereby channel function. GPRC5B, like MLC1, GlialCAM and aquaporin-4, is expressed in astrocyte endfeet in human brain. Cell volume regulation is disrupted in GPRC5B patient-derived lymphoblasts. GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation. In conclusion, we identify aquaporin-4 and GPRC5B as old and new players in genetic brain oedema. Our findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema. [ABSTRACT FROM AUTHOR]

This 'cohort profile' aims to provide a description of the study design, methodology, and baseline characteristics of the participants in the Corona Behavioral Unit cohort. This cohort was established in response to the COVID-19 pandemic by the Dutch National Institute for Public Health and the Environment (RIVM) and the regional public health services. The aim was to investigate adherence of and support for COVID-19 prevention measures, psychosocial determinants of COVID-19 behaviors, well-being, COVID-19 vaccination, and media use. The cohort also examined specific motivations and beliefs, such as for vaccination, which were collected through either closed-ended items or open text responses. In April 2020, 89,943 participants aged 16 years and older were recruited from existing nation-wide panels. Between May 2020 and September 2022, 99,676 additional participants were recruited through online social media platforms and mailing lists of higher education organizations. Participants who consented were initially invited every three weeks (5 rounds), then every six weeks (13 rounds), and since the summer of 2022 every 12 weeks (3 rounds). To date, 66% of participants were female, 30% were 39 years and younger, and 54% completed two or more questionnaires, with an average of 9.2 (SD = 5.7) questionnaires. The Corona Behavioral Unit COVID-19 cohort has published detailed insights into longitudinal patterns of COVID-19 related behaviors, support of COVID-19 preventive measures, as well as peoples' mental wellbeing in relation to the stringency of these measures. The results have informed COVID-19 policy making and pandemic communication in the Netherlands throughout the COVID-19 pandemic. The cohort data will continuously be used to examine COVID-19 related outcomes for scientific analyses, as well as to inform future pandemic preparedness plans. [ABSTRACT FROM AUTHOR]

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC50 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC50 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC50 > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies. [ABSTRACT FROM AUTHOR]

Intertidal habitats (i.e. marine habitats that are (partially) exposed during low tide) have traditionally been studied from a shorebird‐centred perspective. We show that these habitats are accessible and important to marine predators such as elasmobranchs (i.e. sharks and rays). Our synthesis shows that at least 43 shark and 45 ray species, of which 54.5% are currently threatened, use intertidal habitats. Elasmobranchs use intertidal habitats mostly for feeding and as refugia, but also for parturition and thermoregulation. However, the motivation of intertidal habitat use remains unclear due to limitations to observe elasmobranch behaviour in these dynamic habitats. We argue that elasmobranch predators can play an important role in intertidal food webs by feeding on shared resources during high tide (i.e. 'high‐tide predators'), which are accessible and also consumed by terrestrial or avian predators during low tide (i.e. 'low‐tide predators'). In addition, elasmobranchs are able to change the bio‐geomorphology of intertidal habitats by increasing habitat heterogeneity due to feeding activities and may also alter resource availability for other consumers. We discuss how the ecological role of elasmobranchs in intertidal habitats is being affected by the continued overexploitation of these species, and conversely, how the global loss of intertidal areas poses an additional threat to an already vulnerable taxonomic group. We conclude that studies on intertidal ecology should include both low‐tide (e.g. shorebirds) and high‐tide (e.g. elasmobranchs) predatory guilds and their ecological interactions. The global loss of elasmobranch predatory species and intertidal habitat provides additional compelling arguments for the conservation of these areas. [ABSTRACT FROM AUTHOR]

Background Primary immunodeficiencies (PIDs) in adults are mainly revealed by recurrent and/or severe bacterial infections. The objective of this study was to evaluate a systematic research strategy of PIDs in adults with unexplained bacterial infections, with a special focus on specific polysaccharide antibody deficiency (SPAD). Methods In this prospective multicenter study, inclusion criteria were recurrent benign upper and lower respiratory tract infections (RTIs) for at least two years (group 1), at least one upper or lower RTI requiring hospitalization (group 2), and/or at least one invasive infection documented with encapsulated bacteria (group 3). Main exclusion criteria were all local and general conditions that could explain infections. If no PID diagnosis was made, response to polysaccharide antigens was assessed using a pneumococcal polysaccharide vaccine. Results From March 2015 to March 2020, 118 patients were included (37 males, median age of 41 years): 73, 17, and 28 in groups 1, 2, and 3, respectively. Forty-seven PIDs were diagnosed, giving an estimated frequency of 39.8% (95% confidence interval [CI] [30.4, 48.8]). SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%), and was made in 23, 5, and 9 patients from groups 1 to 3, respectively. All SPAD patients received conjugate vaccines and, according to their infectious history, were on surveillance or treated with preventive antibiotics (n = 6) and/or with immunoglobulins replacement therapy (n = 10), the latter being dramatically efficient in all cases. Conclusions Considering its high prevalence among adults with unexplained recurrent and/or severe bacterial infections, SPAD should be screened in those patients. Clinical Trials Registration NCT02972281. [ABSTRACT FROM AUTHOR]

Avian pathogenic Escherichia coli (APEC) can cause colibacillosis in poultry, characterised by localised or systemic infections. Colibacillosis is considered one of the leading causes of economic losses in the poultry industry due to reduced performance, increased mortality, treatment costs and carcass condemnations. A live attenuated Escherichia coli O78 aroA gene mutant is widely used to prevent disease. However, no effective strategies to differentiate the vaccine strain from field strains are available, hampering follow-up of vaccination campaigns. In the current study, we report a PCR-based method to simultaneously detect the vaccine strain by targeting the vaccine-specific mutation in the aroA gene, as well as the wild type E. coli strains by targeting the xanQ gene. The specificity of this PCR was evaluated using 123 E. coli isolates, form which 5 WT aroA auxotrophic strains (WT strains with a natural aroA deficiency), as well as 7 non-Escherichia isolates. The PCR showed 100% sensitivity of the xanQ primers for E. coli detection and 100% sensitivity of the ΔaroA primers for the vaccine strain. In order to allow quantification of the vaccine strain in complex samples containing many different E. coli strains and other related organisms, such as chicken faeces, a probe-based duplex qPCR was developed. The limit of detection (LOD) of this duplex qPCR method was 8.4*103 copies/g faeces. The specificity of the duplex qPCR was confirmed by determining both the vaccine strain levels, and the total E. coli load in intestinal digesta from both vaccinated and non-vaccinated birds. E. coli could be detected in both vaccinated and non-vaccinated birds. The duplex qPCR was specific for the vaccine strain as this strain was detected in all vaccinated birds, whereas no signal was detected in non-vaccinated birds. The duplex qPCR is helpful in monitoring colonization and shedding of the vaccine strain. [ABSTRACT FROM AUTHOR]

Estimates regarding the prevalence of chronic wounds in the Netherlands vary from 350 000 to 500 000. The cross-sectional multicenter study presented here provides evidence for the incidence and prevalence of wounds and chronic wounds. The primary aim of the present study was to provide evidence for incidence and prevalence of (chronic) wounds outside the hospital. The secondary aim was to optimize the organization for chronic wounds care within our region. From January 2017 until January 2018, information was prospectively collected of patients with new onset of wounds in 2 general practitioner practices to which 19 100 patients are enrolled. For the patients with new onset of wounds the "fast track protocol" was used and outcomes including etiology and wound healing were measured. This protocol included a structured treatment protocol and predetermined triage moments. The Alrijne Wound Centre database 2014 was used as a control group (469 records). The incidence of new onset of wounds was 364/19 100 (1.9%). The prevalence of wounds was 405/19 100 (2.1%). The prevalence of chronic wounds, that is, wounds that did not show a sufficient healing rate after 4 to 6 weeks, was 78/19 100 (0.4%). Time to referral to a wound physician (the triage moment) was 5 weeks versus 19 weeks in 2014 (P <.001). Unnecessary referrals to the hospital was reduced by 17.4% (P =.007). In conclusion, the prevalence of the chronic wounds was 4 per 1000 patients. The use of the "fast track" protocol optimizes wound care, wounds heal faster, and unnecessary referrals decrease significantly. [ABSTRACT FROM AUTHOR]

Environmental tolerance curves, representing absolute fitness against the environment, are an empirical assessment of the fundamental niche, and emerge from the phenotypic plasticity of underlying phenotypic traits. Dynamic plastic responses of these traits can lead to acclimation effects, whereby recent past environments impact current fitness. Theory predicts that higher levels of phenotypic plasticity should evolve in environments that fluctuate more predictably, but there have been few experimental tests of these predictions. Specifically, we still lack experimental evidence for the evolution of acclimation effects in response to environmental predictability. Here, we exposed 25 genetically diverse populations of the halotolerant microalgae Dunaliella salina to different constant salinities, or to randomly fluctuating salinities, for over 200 generations. The fluctuating treatments differed in their autocorrelation, which determines the similarity of subsequent values, and thus environmental predictability. We then measured acclimated tolerance surfaces, mapping population growth rate against past (acclimation) and current (assay) environments. We found that experimental mean and variance in salinity caused the evolution of niche position (optimal salinity) and breadth, with respect to not only current but also past (acclimation) salinity. We also detected weak but significant evidence for evolutionary changes in response to environmental predictability, with higher predictability leading notably to lower optimal salinities and stronger acclimation effect of past environment on current fitness. We further showed that these responses are related to the evolution of plasticity for intracellular glycerol, the major osmoregulatory mechanism in this species. However, the direction of plasticity evolution did not match simple theoretical predictions. Our results underline the need for a more explicit consideration of the dynamics of environmental tolerance and its underlying plastic traits to reach a better understanding of ecology and evolution in fluctuating environments. [ABSTRACT FROM AUTHOR]

This editorial introduces the thematic issue titled Inclusive Media Literacy Education for Diverse Societies. We start by introducing our aims for developing a more open and inviting approach to media education. We argue for a media education that acknowledges a variety of voices, and that provides skills and recognition for everyone, irrespective of their social class, status, gender identification, sexuality, race, ability, and other variables. The articles in this issue address the role of media literacy education in relation to questions of in- and exclusion, social justice, voice, and listening. The issue covers a variety of critical, non-Western perspectives needed to challenge dominant regimes of representation. The editorial is enriched by the artist Neetje's illustrations of the workshop that preceded the publication of this thematic issue. [ABSTRACT FROM AUTHOR]

Conformational biosensors to monitor the activation state of G protein-coupled receptors are a useful addition to the molecular pharmacology assay toolbox to characterize ligand efficacy at the level of receptor proteins instead of downstream signaling. We recently reported the initial characterization of a NanoBRET-based conformational histamine H3 receptor (H3R) biosensor that allowed the detection of both (partial) agonism and inverse agonism on living cells in a microplate reader assay format upon stimulation with H3R ligands. In the current study, we have further characterized this H3R biosensor on intact cells by monitoring the effect of consecutive ligand injections in time and evaluating its compatibility with photopharmacological ligands that contain a light-sensitive azobenzene moiety for photo-switching. In addition, we have validated the H3R biosensor in membrane preparations and found that observed potency values better correlated with binding affinity values that were measured in radioligand competition binding assays on membranes. Hence, the H3R conformational biosensor in membranes might be a ready-to-use, high-throughput alternative for radioligand binding assays that in addition can also detect ligand efficacies with comparable values as the intact cell assay. [ABSTRACT FROM AUTHOR]

This special issue explores the role that digital technology plays in the lives of migrants. It does so by paying close attention to governmental and supranational organizations as well as to subjective and affective dimensions of the everyday. Digital migration practices emerge as complex negotiations in the digital media sphere between infrastructural bias and agential opportunities, contesting racial practices as well as enabling digitally mediated bonds of solidarity and intimacy. The issue offers nuanced critical perspectives ranging from surveillance capitalism, extractive humanitarianism, datafication, and border regimes to choreographies of care and intimacy in transnational settings, among other aspects. Renowned international scholars reflect on these issues from different vantage points. The closing forum section provides state-of-the-art commentaries on digital diaspora, affect and belonging, voice and visibility in the digital media sphere, queer migrant interventions in non-academic settings, and datafication and media infrastructures in "deep time." [ABSTRACT FROM AUTHOR]

While infrastructures of media and of migration currently converge in specific ways, in this commentary, we consider how these infrastructures always reflect distinctive moments in media history, as well as in migration history. An archaeological approach to infrastructure posits that media infrastructures do not spring into action fully formed, and neither is there ever a moment when they would be fully formed. We propose the perspective of deep time of infrastructures as a way of opening up unresolved questions about what critical researchers can and should do with historically-informed inquiry of media technologies across migration contexts. We specifically operationalize the deep time of media and migration infrastructures by addressing the three dimensions of: (1) materialities; (2) practices; and (3) imaginaries. [ABSTRACT FROM AUTHOR]

In bony vertebrates, skeletal mineralization relies on the secretory calcium-binding phosphoproteins (Scpp) family whose members are acidic extracellular proteins posttranslationally regulated by the Fam20°C kinase. As scpp genes are absent from the elephant shark genome, they are currently thought to be specific to bony fishes (osteichthyans). Here, we report a scpp gene present in elasmobranchs (sharks and rays) that evolved from local tandem duplication of sparc-L 5′ exons and show that both genes experienced recent gene conversion in sharks. The elasmobranch scpp is remarkably similar to the osteichthyan scpp members as they share syntenic and gene structure features, code for a conserved signal peptide, tyrosine-rich and aspartate/glutamate-rich regions, and harbor putative Fam20°C phosphorylation sites. In addition, the catshark scpp is coexpressed with sparc-L and fam20°C in tooth and scale ameloblasts, similarly to some osteichthyan scpp genes. Despite these strong similarities, molecular clock and phylogenetic data demonstrate that the elasmobranch scpp gene originated independently from the osteichthyan scpp gene family. Our study reveals convergent events at the sparc-L locus in the two sister clades of jawed vertebrates, leading to parallel diversification of the skeletal biomineralization toolkit. The molecular evolution of sparc-L and its coexpression with fam20°C in catshark ameloblasts provides a unifying genetic basis that suggests that all convergent scpp duplicates inherited similar features from their sparc-L precursor. This conclusion supports a single origin for the hypermineralized outer odontode layer as produced by an ancestral developmental process performed by Sparc-L, implying the homology of the enamel and enameloid tissues in all vertebrates. [ABSTRACT FROM AUTHOR]

The histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) and plays a key role in allergic reactions upon activation by histamine which is locally released from mast cells and basophils. Consequently, H1R is a well-established therapeutic target for antihistamines that relieve allergy symptoms. H1R signals via heterotrimeric Gq proteins and is phosphorylated by GPCR kinase (GRK) subtypes 2, 5, and 6, consequently facilitating the subsequent recruitment of β-arrestin1 and/or 2. Stimulation of a GPCR with structurally different agonists can result in preferential engagement of one or more of these intracellular signaling molecules. To evaluate this so-called biased agonism for H1R, bioluminescence resonance energy transfer (BRET)-based biosensors were applied to measure H1R signaling through heterotrimeric Gq proteins, second messengers (inositol 1,4,5-triphosphate and Ca2+), and receptor-protein interactions (GRKs and β-arrestins) in response to histamine, 2-phenylhistamines, and histaprodifens in a similar cellular background. Although differences in efficacy were observed for these agonists between some functional readouts as compared to reference agonist histamine, subsequent data analysis using an operational model of agonism revealed only signaling bias of the agonist Br-phHA-HA in recruiting β-arrestin2 to H1R over Gq biosensor activation. [ABSTRACT FROM AUTHOR]

This article addresses the smartphone as a complicated technology of forced migration: a device that accompanies those who move, but which also records and catalogues digital traces within life contexts of conflict, uprooting, migration and resettlement. We conceptualise smartphones as personal digital archives: migrants' curation of their own stories on their own portable devices. Personal digital archives, we argue, reflect the migrant gaze and constitute mobile subaltern subjects' record of forced migration. Inductively learning from fieldwork conducted across five sites over 5 years, we analyse how the personal digital archive records and reflects the mediation of migration in its three dimensions: symbolic, affective and material. By focussing on personal digital archives, we recentre the authority of migrants as witnessing subjects of their own life stories. Their archives as autonomous migrant records provide a powerful basis to reflect upon and potentially contest mainstream western journalism cultures, which too often reduce migration to a spectacle and the migrant to a dehistoricised figure with little agency or voice. [ABSTRACT FROM AUTHOR]

The pearl whipray Fontitrygon margaritella (Compagno & Roberts, 1984) is a common elasmobranch in coastal western African waters. However, knowledge on their life-history and trophic ecology remains limited. Therefore, we aimed to determine the growth, maturity and diet of F. margaritella from the Bijagós Archipelago in Guinea-Bissau. Growth was modelled with: von Bertalanffy, Gompertz and logistic functions. Model selection revealed no model significantly outperformed another. The sampled age ranged from less than 1 to 7 years (1.8 ± 1.9 cm, mean ± standard deviation) and size (disc width) ranged from 12.2 to 30.6 cm (18.7 ± 5.2 cm). Size-at-maturity was estimated at 20.3 cm (95% CI [18.8-21.8 cm]) for males and 24.3 cm for females (95% CI [21.9-26.5 cm]), corresponding ages of 2.2 and 3.9 years. The diet differed significantly among young-of-the-year (YOY), juveniles and adults (p = 0.001). Diet of all life stages consisted mainly of crustaceans (27.4%, 28.5%, 33.3%) and polychaetes (12.5%, 26.7%, 20.3%), for YOY, juveniles and adults respectively. This study shows that F. margaritella is relatively fastgrowing, matures early and experiences ontogenetic diet shifts. These results contribute to status assessments and conservation efforts of F. margaritella and closely related species. [ABSTRACT FROM AUTHOR]

Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis. PrRP binds with high affinity to G-protein coupled receptor 10 (GPR10) and with lesser activity towards the neuropeptide FF receptor type 2 (NPFF2R). The present study aimed to develop long-acting PrRP31 analogues with potent anti-obesity efficacy. A comprehensive series of C18 lipidated PrRP31 analogues was characterized in vitro and analogues with various GPR10 and NPFF2R activity profiles were profiled for bioavailability and metabolic effects following subcutaneous administration in diet-induced obese (DIO) mice. PrRP31 analogues acylated with a C18 lipid chain carrying a terminal acid (C18 diacid) were potent GPR10-selective agonists and weight-neutral in DIO mice. In contrast, acylation with aliphatic C18 lipid chain (C18) resulted in dual GPR10-NPFF2R co-agonists that suppressed food intake and promoted a robust weight loss in DIO mice, which was sustained for at least one week after last dosing. Rapid in vivo degradation of C18 PrRP31 analogues gave rise to circulating lipidated PrRP metabolites maintaining dual GPR10-NPFF2R agonist profile and long-acting anti-obesity efficacy in DIO mice. Combined GPR10 and NPFF2R activation may therefore be a critical mechanism for obtaining robust anti-obesity efficacy of PrRP31 analogues. [ABSTRACT FROM AUTHOR]

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) (p = 0.017) for progression during follow-up. Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS. [ABSTRACT FROM AUTHOR]

While cartilage is an ancient tissue found both in protostomes and deuterostomes, its mineralization evolved more recently, within the vertebrate lineage. SPARC , SPARC-L , and the SCPP members (Secretory Calcium-binding PhosphoProtein genes which evolved from SPARC-L) are major players of dentine and bone mineralization, but their involvement in the emergence of the vertebrate mineralized cartilage remains unclear. We performed in situ hybridization on mineralizing cartilaginous skeletal elements of the frog Xenopus tropicalis (Xt) and the shark Scyliorhinus canicula (Sc) to examine the expression of SPARC (present in both species), SPARC-L (present in Sc only) and the SCPP members (present in Xt only). We show that while mineralizing cartilage expresses SPARC (but not SPARC-L) in Sc , it expresses the SCPP genes (but not SPARC) in Xt , and propose two possible evolutionary scenarios to explain these opposite expression patterns. In spite of these genetic divergences, our data draw the attention on an overlooked and evolutionarily conserved peripheral cartilage subdomain expressing SPARC or the SCPP genes and exhibiting a high propensity to mineralize. [ABSTRACT FROM AUTHOR]

Contemporary migration infrastructures commonly reflect imaginaries of technological solutionism. Fantasies of efficient ordering, administrating and limiting of refugee bodies in space and time through migration infrastructures are distinctive, but not novel as they draw on long historical lineages. Drawing on archival records, we present a case-study on post-World-War-II refugee encampments. By highlighting the deeply historical role of media in migration governance, i.e. the act of mediation through technological infrastructuring, we seek to bring together the fields of migration studies and media studies. We argue that this cross-fertilization helps to historically untangle power dimensions, inherent workings, as well as human experiences imbued in the tech-based management of migration 'crises'. Uncovering historical underpinnings of digitalized asylum regimes through the prism of media infrastructures, and socio-technical imaginaries surrounding them, points at continuities and genealogies of containing and managing people in time and space, reaching into technologies of colonial and fascist projects. We thus seek to explore the assumptions that drive the build-up of migration and media infrastructures: How are migrants, camps, media and their infrastructural interrelations imagined? Which cultural horizons are reflected in technologies, which functions are imagined for whom, and how are utilitarian ideas about humanitarianism and migration control embedded? [ABSTRACT FROM AUTHOR]

Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIa) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance ?-hydroxybutyrate (GHB) bind selectively to CaMKIIα. By means of a 2.2-Å x-ray crystal structure of ligand-bound CaMKIIα hub, we reveal the molecular details of the binding site deep within the hub. Furthermore, we show that binding of GHB and related analogs to this site promotes concentration-dependent increases in hub thermal stability believed to alter holoenzyme functionality. Selectively under states of pathological CaMKIIα activation, hub ligands provide a significant and sustained neuroprotection, which is both time and dose dependent. This is demonstrated in neurons exposed to excitotoxicity and in a mouse model of cerebral ischemia with the selective GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid). Together, our results indicate a hitherto unknown mechanism for neuroprotection by a highly specific and unforeseen interaction between the CaMKIIα hub domain and small molecule brain-penetrant GHB analogs. This establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia in particular. [ABSTRACT FROM AUTHOR]

Delineating human cardiac pathologies and their basic molecular mechanisms relies on research conducted in model organisms. Yet translating findings from preclinical models to humans present a significant challenge, in part due to differences in cardiac protein expression between humans and model organisms. Proteins immediately determine cellular function, yet their large-scale investigation in hearts has lagged behind those of genes and transcripts. Here, we set out to bridge this knowledge gap: By analyzing protein profiles in humans and commonly used model organisms across cardiac chambers, we determine their commonalities and regional differences. We analyzed cardiac tissue from each chamber of human, pig, horse, rat, mouse, and zebrafish in biological replicates. Using mass spectrometry–based proteomics workflows, we measured and evaluated the abundance of approximately 7,000 proteins in each species. The resulting knowledgebase of cardiac protein signatures is accessible through an online database: atlas.cardiacproteomics.com. Our combined analysis allows for quantitative evaluation of protein abundances across cardiac chambers, as well as comparisons of cardiac protein profiles across model organisms. Up to a quarter of proteins with differential abundances between atria and ventricles showed opposite chamber-specific enrichment between species; these included numerous proteins implicated in cardiac disease. The generated proteomics resource facilitates translational prospects of cardiac studies from model organisms to humans by comparisons of disease-linked protein networks across species. This study provides protein abundance profiles for thousands of proteins across cardiac chambers for humans and five commonly used model organisms. This quantitative proteomics dataset represents the most comprehensive such resource to date, and can be queried via a web browser to identify the most appropriate model organism for future studies. [ABSTRACT FROM AUTHOR]

Matrix Gla protein (Mgp) and bone Gla protein (Bgp) are vitamin-K dependent proteins that bind calcium in their γ-carboxylated versions in mammals. They are recognized as positive (Bgp) or negative (Mgp and Bgp) regulators of biomineralization in a number of tissues, including skeletal tissues of bony vertebrates. The Mgp/Bgp gene family is poorly known in cartilaginous fishes, which precludes the understanding of the evolution of the biomineralization toolkit at the emergence of jawed vertebrates. Here we took advantage of recently released genomic and transcriptomic data in cartilaginous fishes and described the genomic loci and gene expression patterns of the Mgp/Bgp gene family. We identified three genes, Mgp1, Mgp2, and Bgp, in cartilaginous fishes instead of the single previously reported Mgp gene. We describe their genomic loci, resulting in a dynamic evolutionary scenario for this gene family including several events of local (tandem) duplications, but also of translocation events, along jawed vertebrate evolution. We describe the expression patterns of Mgp1 , Mgp2 , and Bgp in embryonic stages covering organogenesis in the small-spotted catshark Scyliorhinus canicula and present a comparative analysis with Mgp/Bgp family members previously described in bony vertebrates, highlighting ancestral features such as early embryonic, soft tissues, and neuronal expressions, but also derived features of cartilaginous fishes such as expression in fin supporting fibers. Our results support an ancestral function of Mgp in skeletal mineralization and a later derived function of Bgp in skeletal development that may be related to the divergence of bony vertebrates. [ABSTRACT FROM AUTHOR]

Summary: Immunogenicity risk assessment is a critical element in protein drug development. Currently, the risk assessment is most often performed using MHC‐associated peptide proteomics (MAPPs) and/or T‐cell activation assays. However, this is a highly costly procedure that encompasses limited sensitivity imposed by sample sizes, the MHC repertoire of the tested donor cohort and the experimental procedures applied. Recent work has suggested that these techniques could be complemented by accurate, high‐throughput and cost‐effective prediction of in silico models. However, this work covered a very limited set of therapeutic proteins and eluted ligand (EL) data. Here, we resolved these limitations by showcasing, in a broader setting, the versatility of in silico models for assessment of protein drug immunogenicity. A method for prediction of MHC class II antigen presentation was developed on the hereto largest available mass spectrometry (MS) HLA‐DR EL data set. Using independent test sets, the performance of the method for prediction of HLA‐DR antigen presentation hotspots was benchmarked. In particular, the method was showcased on a set of protein sequences including four therapeutic proteins and demonstrated to accurately predict the experimental MS hotspot regions at a significantly lower false‐positive rate compared with other methods. This gain in performance was particularly pronounced when compared to the NetMHCIIpan‐3.2 method trained on binding affinity data. These results suggest that in silico methods trained on MS HLA EL data can effectively and accurately be used to complement MAPPs assays for the risk assessment of protein drugs. [ABSTRACT FROM AUTHOR]