Efficacy of a pre-operative anaemia clinic in patients undergoing elective abdominal cancer surgery.

BACKGROUND: Pre-operative iron deficiency anaemia (IDA) is common in patients undergoing elective major abdominal surgery and is associated with increased risk of perioperative complications. However, widespread implementation of pre-operative anaemia management is lacking. Guidelines recommend investigation of anaemia preferably 4-6 weeks before surgery to allow time for correction. However, this is not always feasible in abdominal cancer surgery with short time to surgery and may be influenced by concomitant chemotherapy. The objective of this study was to assess the efficacy of implementing a pre-operative screening and treatment programme for IDA in elective abdominal cancer surgery patients, with short duration to surgery and concomitant use of chemotherapy. METHODS: All patients scheduled for elective abdominal cancer surgery with IDA were included. Anaemia was defined according to the World Health Organization-criteria and iron deficiency as a transferrin saturation <0.20. The primary outcome was change in haemoglobin (Hb) between iron infusion and surgery in patients receiving pre-operative intravenous iron infusion. RESULTS: Of 178 diagnosed IDA patients 134 (75%) received intravenous iron, 103 pre-operatively (58%) at median day 17 (interquartile range: 9-27) before surgery while 31 (17%) received post-operative intravenous iron treatment. The pre-operative Hb increased 0.89 g/dL (95% CI: 0.64-1.13, p < .001) compared to a decrease of 0.4 g/dL (95% CI: 0.19-0.58, p < .001) in 75 patients not treated pre-operatively. Patients diagnosed with severe anaemia had the largest pre-operative Hb increase. Iron infusion >2 weeks pre-operatively resulted in a greater Hb increment of 1.13 g/dL (95% CI: 0.81-1.45) compared to iron infusion ≤2 weeks before surgery 0.48 g/dL (95% CI: 0.16-0.81). Hb increased by 0.64 g/dL (95% CI 0.19-1.21) in patients receiving chemotherapy ≤31 days prior to surgery. CONCLUSION: In patients scheduled for abdominal cancer surgery, including in patients with concomitant chemotherapy, pre-operative IDA management is feasible and results in a significant pre-operative Hb increase compared to patients not treated. On the day of surgery 25% patients treated pre-operatively were no longer anaemic.

Acute effects of a simulated quick return on subjective sleepiness, mood, and cognitive performance: A laboratory crossover controlled trial.

Sleep loss due to short time off between shifts has been proposed as a mechanism contributing to impaired functioning in occupational settings. This laboratory crossover trial (ClinicalTrials.gov identifier: NCT05162105, N = 66) compared subjective sleepiness, mood, and cognitive performance on a day shift after an evening shift with only 8 h off between shifts (quick return, QR) to a day shift after another day shift with 16 h off between shifts (control). Results indicated higher subjective sleepiness (Karolinska Sleepiness Scale) during the QR condition compared to the control condition (p < 0.001). No significant differences were found on mood (Positive and Negative Affect Schedule) and cognitive performance (Psychomotor Vigilance- and Digit Symbol Substitution Test) between the conditions. Findings of increased subjective sleepiness corroborate previous field studies. This trial is to our knowledge the first to compare mood and cognitive performance after a QR to a longer shift transition using an experimental design. Future research should explore the effects of accumulated sleep loss associated with QRs (e.g. having several QRs within a short time period) on behavioral outcomes.

circHIPK3 nucleates IGF2BP2 and functions as a competing endogenous RNA.

Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2-STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation.

The receiver operating characteristic curve accurately assesses imbalanced datasets.

Many problems in biology require looking for a "needle in a haystack," corresponding to a binary classification where there are a few positives within a much larger set of negatives, which is referred to as a class imbalance. The receiver operating characteristic (ROC) curve and the associated area under the curve (AUC) have been reported as ill-suited to evaluate prediction performance on imbalanced problems where there is more interest in performance on the positive minority class, while the precision-recall (PR) curve is preferable. We show via simulation and a real case study that this is a misinterpretation of the difference between the ROC and PR spaces, showing that the ROC curve is robust to class imbalance, while the PR curve is highly sensitive to class imbalance. Furthermore, we show that class imbalance cannot be easily disentangled from classifier performance measured via PR-AUC.

Molecular properties and diagnostic potential of monoclonal antibodies targeting cytotoxic α-synuclein oligomers.

α-Synuclein (α-syn) accumulates as insoluble amyloid but also forms soluble α-syn oligomers (αSOs), thought to be even more cytotoxic than fibrils. To detect and block the unwanted activities of these αSOs, we have raised 30 monoclonal antibodies (mAbs) against different forms of αSOs, ranging from unmodified αSOs to species stabilized by lipid peroxidation products and polyphenols, αSOs formed by C-terminally truncated α-syn, and multivalent display of α-syn on capsid virus-like particles (cVLPs). While the mAbs generally show a preference for αSOs, they also bind fibrils, but to variable extents. Overall, we observe great diversity in the mAbs' relative affinities for monomers and αSOs, varied requirements for the C-terminal extension of α-syn, and only a modest effect on α-syn fibrillation. Several mAbs show several orders of magnitude preference for αSOs over monomers in in-solution studies, while the commercial antibody MJF14 only bound 10-fold more strongly to αSOs than monomeric α-syn. Gratifyingly, seven mAbs almost completely block αSO permeabilization of membrane vesicles. Five selected mAbs identified α-syn-related pathologies like Lewy bodies (LBs) and Lewy Neurites, as well as Glial Cytoplasmic Inclusions in postmortem brains from people diagnosed for PD, dementia with LBs or multiple system atrophy, although to different extents. Three mAbs were particularly useful for pathological evaluation of postmortem brain human tissue, including early stages of PD. Although there was no straightforward connection between the mAbs' biophysical and immunohistochemical properties, it is encouraging that this comprehensive collection of mAbs able to recognize different aggregated α-syn species in vitro also holds diagnostic potential.

In Silico Tools for Predicting Novel Epitopes.

Identifying antigens within a pathogen is a critical task to develop effective vaccines and diagnostic methods, as well as understanding the evolution and adaptation to host immune responses. Historically, antigenicity was studied with experiments that evaluate the immune response against selected fragments of pathogens. Using this approach, the scientific community has gathered abundant information regarding which pathogenic fragments are immunogenic. The systematic collection of this data has enabled unraveling many of the fundamental rules underlying the properties defining epitopes and immunogenicity, and has resulted in the creation of a large panel of immunologically relevant predictive (in silico) tools. The development and application of such tools have proven to accelerate the identification of novel epitopes within biomedical applications reducing experimental costs. This chapter introduces some basic concepts about MHC presentation, T cell and B cell epitopes, the experimental efforts to determine those, and focuses on state-of-the-art methods for epitope prediction, highlighting their strengths and limitations, and catering instructions for their rational use.

Secukinumab and Dead Sea Climatotherapy Impact Resolved Psoriasis Skin Differently Potentially Affecting Disease Memory.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory.

COVID-19 Vaccination Before Initiating Rituximab Treatment Induces Strong Serological Response in Autoimmune Rheumatic Disease, Reducing Post-Pandemic Concerns About the Impact of Rituximab.

OBJECTIVE: Rituximab (RTX)-treated patients exhibit suboptimal responses to COVID-19 vaccines. However, existing research primarily involves patients already receiving RTX when vaccines were introduced, failing to account for the current landscape where patients are vaccinated before initiating RTX. Our objective was to compare the serological response to COVID-19 vaccines in patients vaccinated before or after RTX initiation. METHODS: We included 254 RTX-treated patients with autoimmune inflammatory rheumatic diseases (AIIRDs) and 113 blood donors (BDs) in a retrospective, observational cohort study. Patients were categorized based on the timing of RTX treatment relative to primary COVID-19 vaccination. Serological vaccine responses were assessed using three immunoassays, and logistic regression analysis was used to identify predictors of serological response. RESULTS: Patients vaccinated before initiating RTX treatment had significantly higher seroconversion rates of SARS-CoV-2 immunoglobulin G (87%) and neutralizing antibodies (91%) compared with those receiving RTX before and after vaccination (n = 132) (61% and 65%, respectively). In the logistic regression analysis, a positive serological response was associated with the number of vaccines administered >9 months after the last RTX treatment. Patients receiving the highest number of vaccines with >9 months after RTX showed a response comparable to that of the BDs. CONCLUSION: Vaccinating before RTX initiation yields a robust serological response in patients with AIIRDs. Furthermore, we highlight the reversibility of antibody impairment after RTX treatment cessation, provided that adequate vaccinations occur within a minimum of 9 months after RTX. Our findings offer essential insights for clinical decision-making regarding COVID-19 vaccination and RTX treatment, alleviating concerns about future RTX use.

Does job control contribute to differences in physician-certified sickness absence across office concepts? A mediation analysis in a nationally representative sample.

OBJECTIVES: Several studies have found higher sickness absence in shared and open workspaces than in private offices, but little is known about why these differences occur. We propose and test job control as a potential mechanism underlying observed differences in the risk of physician-certified sickness absence between private offices and shared and open workspaces. METHODS: We conducted a counterfactual mediation analysis using observational survey data from a nationally representative sample of Norwegian employees merged with prospective data from national registries (N=5512). The registry data included information about whether participants had any physician-certified sickness absence the year following the survey. Models were adjusted for age, sex, education level, occupation group, executive/leadership responsibility, and time spent on office work. RESULTS: We found significantly higher sickness absence risk in conventional [risk ratio (RR) 1.12, 95% confidence interval (CI) 1.01‒1.25] and non-territorial (RR 1.20, 95% 1.04‒1.37) open-plan and non-territorial shared-room offices (RR 1.29, 95% CI 1.13‒1.48) compared to private offices. Natural indirect effects due to job control were statistically significant in all contrasts and accounted for 19-34% of total effects depending on contrast. CONCLUSIONS: Findings were in line with hypothesized relationships and suggest that job control may be a mechanism underlying observed differences in sickness absence across office concepts. Future studies should continue to explore potential mechanisms linking shared and open workspaces to higher sickness absence and other unfavorable outcomes in the workplace, particularly with study designs that provide stronger basis for causal inference.

Next-generation IEDB tools: a platform for epitope prediction and analysis.

The Next-Generation (NG) IEDB Tools website (https://nextgen-tools.iedb.org) provides users with a redesigned interface to many of the algorithms for epitope prediction and analysis that were originally released on the legacy IEDB Tools website. The initial release focuses on consolidation of all tools related to HLA class I epitopes (MHC binding, elution, immunogenicity, and processing), making all of these predictions accessible from a single application and allowing for their simultaneous execution with minimal user inputs. Additionally, the PEPMatch tool for identifying highly similar epitopes in a set of curated proteomes, as well as a tool for epitope clustering, are available on the site. The NG Tools site allows users to build data pipelines by sending the output of one tool as input for the next. Over the next several years, all pre-existing IEDB Tools, and any newly developed tools, will be integrated into this new site. Here we describe the philosophy behind the redesign and demonstrate the utility and productivity enhancements that are enabled by the new interface.

Simulated quick returns in a laboratory context and effects on sleep and pre-sleep arousal between shifts: a crossover controlled trial.

This trial presents a laboratory model investigating the effect of quick returns (QRs, <11 h time off between shifts) on sleep and pre-sleep arousal. Using a crossover design, 63 participants worked a simulated QR condition (8 h time off between consecutive evening- and day shifts) and a day-day (DD) condition (16 h time off between consecutive day shifts). Participants slept at home and sleep was measured using a sleep diary and sleep radar. Compared to the DD condition, the QR condition reduced subjective and objective total sleep time by approximately one hour (both p < .001), reduced time in light- (p < .001), deep- (p = .004), rapid eye movement (REM, p < .001), percentage of REM sleep (p = .023), and subjective sleep quality (p < .001). Remaining sleep parameters and subjective pre-sleep arousal showed no differences between conditions. Results corroborate previous field studies, validating the QR model and indicating causal effects of short rest between shifts on common sleep parameters and sleep architecture.

This trial proposes a laboratory model to investigate the consequences of quick returns (QRs, <11h time off between shifts) on subjective/objective sleep and pre-sleep arousal. QRs reduced total sleep time, light-, deep-, REM sleep, whereas pre-sleep arousal was unaffected. Results emphasise the importance of ensuring sufficient rest time between shifts.Abbreviation: QR: Quick return; DD: Day-day; NREM: Non-rapid eye movement; REM: Rapid eye movement; PSG: Polysomnography; TIB: Time in bed; SOL: Sleep onset latency; WASO: Wake after sleep onset; TST: Total sleep time; EMA: Early morning awakening; PSAS: Pre-Sleep Arousal Scale; MEQ: Morning-Evening Questionnaire; LMM: Linear mixed model; EMM: Estimated marginal mean; SD: Standard deviation; SE: Standard error; d: Cohens' d; h: hours; m: minutes.

Leaders as the targets of workplace bullying - prevalence and outcomes.

PURPOSE: Bullying of leaders is an underexplored topic in organizational research. To fill this knowledge gap, the aims of this study were to determine the prevalence of bullying of leaders and to examine whether holding a formal leadership position influences the relationships between exposure to bullying and the outcomes job satisfaction and depression. METHODS: Data from two separate surveys were employed: (1) A cross-sectional occupation specific sample comprising 678 Norwegian child welfare social workers; (2) A nationally representative probability sample of 1,608 Norwegian employees with two time-points (6 months' time-lag). RESULTS: Analyzing multiple indicators of workplace bullying, holding a formal leadership position had no impact on the initial risk of being bullied. Analyses of prospective data showed that leaders report a somewhat stronger increase in levels of bullying over time compared to non-leaders, although the effect size was small. With exception of a small buffering effect on the cross-sectional association between exposure to bullying behaviors and job satisfaction in the second sample, holding a leadership position had no effect on the strength of the association between bullying and outcomes. CONCLUSION: The findings show that leaders have the same risk of being bullied and are influenced by bullying in roughly the same manner as non-leaders. Organizational measures and interventions against bullying should therefore consider leaders as a risk group in line with other employees.

IMPROVE: a feature model to predict neoepitope immunogenicity through broad-scale validation of T-cell recognition.

Background: Mutation-derived neoantigens are critical targets for tumor rejection in cancer immunotherapy, and better tools for neoepitope identification and prediction are needed to improve neoepitope targeting strategies. Computational tools have enabled the identification of patient-specific neoantigen candidates from sequencing data, but limited data availability has hindered their capacity to predict which of the many neoepitopes will most likely give rise to T cell recognition. Method: To address this, we make use of experimentally validated T cell recognition towards 17,500 neoepitope candidates, with 467 being T cell recognized, across 70 cancer patients undergoing immunotherapy. Results: We evaluated 27 neoepitope characteristics, and created a random forest model, IMPROVE, to predict neoepitope immunogenicity. The presence of hydrophobic and aromatic residues in the peptide binding core were the most important features for predicting neoepitope immunogenicity. Conclusion: Overall, IMPROVE was found to significantly advance the identification of neoepitopes compared to other current methods.

Effects of a work schedule with abated quick returns on insomnia, sleepiness, and work-related fatigue: results from a large-scale cluster randomized controlled trial.

STUDY OBJECTIVES: To investigate the effect of a work schedule with abated quick returns (i.e. > 11 hours between two shifts) on insomnia, daytime sleepiness, and work-related fatigue compared to a shift schedule maintaining the usual number of quick returns. METHODS: A two-armed cluster randomized controlled trial including 66 units was conducted at a university hospital in Norway. Units with healthcare workers on rotating shift schedules were randomly assigned to a shift schedule with abated quick returns (intervention) or to continue with a schedule including quick returns as usual (control) for 6 months. Questionnaires assessed symptoms of insomnia (Bergen Insomnia Scale [BIS]), daytime sleepiness (Epworth Sleepiness Scale [ESS]), and work-related fatigue (Revised Swedish Occupational Fatigue Inventory) at baseline and towards the end of the intervention. Data were analyzed using multilevel linear mixed-effects models, and Cohen's d was used to calculate the effect size between groups. RESULTS: Overall, 1314 healthcare workers (85.2% female) completed the baseline questionnaire (response rate 49.1%), and 552 completed the follow-up questionnaire. The intervention reduced quick returns from an average of 13.2 (SD = 8.7) to 6.7 (SD = 6.0), while the control group's average remained relatively unchanged from 13.2 (SD = 8.7) to 12.0 (SD = 9.3). Results showed a small improvement in symptoms of insomnia (BIS; d = -0.13, p = .022) and daytime sleepiness (ESS; d = -0.14, p = .013) in favor of the intervention. No effects were observed on work-related fatigue. CONCLUSIONS: Reducing the number of quick returns in the work schedule resulted in improvements in insomnia and daytime sleepiness. The findings highlight the importance of sufficient daily rest time in the work schedule of healthcare workers. CLINICAL TRIAL: Health Promoting Work Schedules: The Effect of Abolishing Quick Returns (HeWoS); clinicaltrials.gov/ct2/show/NCT04693182; Registered at ClinicalTrials.gov with the identifier NCT04693182.

Impact of psychosocial work factors on risk of medically certified sick leave due to common mental disorders: a nationwide prospective cohort study of Norwegian home care workers.

BACKGROUND: The Norwegian home care services experience a high level of sick leave, a large proportion of which is due to common mental disorders. A substantial number of such cases can be attributed to psychosocial factors at work, but more knowledge about occupation-specific risk factors is needed to develop targeted preventive measures to reduce sick leave levels. The aim of this study is to identify the most prominent psychosocial work factors influencing the risk of sick leave spells due to common mental disorders. METHODS: Employees from a random sample of 130 Norwegian home care services (N = 1.819) completed a baseline survey on 15 psychosocial work factors. Participants were subsequently followed up for 26 months using registry data on sick leave. The outcome measure was the number of medically certified sick leave spells due to common mental disorders during follow-up in the Norwegian social insurance database. Incidence risk ratios (IRR) and 95% confidence intervals (CIs) were calculated using negative binomial regression with robust standard errors. RESULTS: Emotional dissonance (IRR 1.30, 95% CI 1.05-1.60) and emotional demands (IRR 1.35, 95% CI 1.14-1.58) were associated with an excess risk of sick leave, while control over work pacing (IRR 0.78, 95% CI 0.62-0.98) was associated with a reduced risk. An estimated 30% (95% CI 8.73-48.82) of sick leave cases were attributable to emotional dissonance and 27% (95% CI 4.80-46.33) were attributable to emotional demands. Control over work pacing was estimated to have prevented 20% (95% CI 1.32-37.78) of the sick leave cases. CONCLUSIONS: This study found that emotional dissonance and emotional demands were robust risk factors for sick leave due to common mental disorders, and that control of work pacing constituted a robust protective factor against sick leave.

Enhancing TCR specificity predictions by combined pan- and peptide-specific training, loss-scaling, and sequence similarity integration.

Predicting the interaction between Major Histocompatibility Complex (MHC) class I-presented peptides and T-cell receptors (TCR) holds significant implications for vaccine development, cancer treatment, and autoimmune disease therapies. However, limited paired-chain TCR data, skewed towards well-studied epitopes, hampers the development of pan-specific machine-learning (ML) models. Leveraging a larger peptide-TCR dataset, we explore various alterations to the ML architectures and training strategies to address data imbalance. This leads to an overall improved performance, particularly for peptides with scant TCR data. However, challenges persist for unseen peptides, especially those distant from training examples. We demonstrate that such ML models can be used to detect potential outliers, which when removed from training, leads to augmented performance. Integrating pan-specific and peptide-specific models alongside with similarity-based predictions, further improves the overall performance, especially when a low false positive rate is desirable. In the context of the IMMREP22 benchmark, this modeling framework attained state-of-the-art performance. Moreover, combining these strategies results in acceptable predictive accuracy for peptides characterized with as little as 15 positive TCRs. This observation places great promise on rapidly expanding the peptide covering of the current models for predicting TCR specificity. The NetTCR 2.2 model incorporating these advances is available on GitHub (https://github.com/mnielLab/NetTCR-2.2) and as a web server at https://services.healthtech.dtu.dk/services/NetTCR-2.2/.

The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier.

Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.

DiscoTope-3.0: improved B-cell epitope prediction using inverse folding latent representations.

Accurate computational identification of B-cell epitopes is crucial for the development of vaccines, therapies, and diagnostic tools. However, current structure-based prediction methods face limitations due to the dependency on experimentally solved structures. Here, we introduce DiscoTope-3.0, a markedly improved B-cell epitope prediction tool that innovatively employs inverse folding structure representations and a positive-unlabelled learning strategy, and is adapted for both solved and predicted structures. Our tool demonstrates a considerable improvement in performance over existing methods, accurately predicting linear and conformational epitopes across multiple independent datasets. Most notably, DiscoTope-3.0 maintains high predictive performance across solved, relaxed and predicted structures, alleviating the need for experimental structures and extending the general applicability of accurate B-cell epitope prediction by 3 orders of magnitude. DiscoTope-3.0 is made widely accessible on two web servers, processing over 100 structures per submission, and as a downloadable package. In addition, the servers interface with RCSB and AlphaFoldDB, facilitating large-scale prediction across over 200 million cataloged proteins. DiscoTope-3.0 is available at: https://services.healthtech.dtu.dk/service.php?DiscoTope-3.0.

A giant stem-group chaetognath.

Chaetognaths, with their characteristic grasping spines, are the oldest known pelagic predators, found in the lowest Cambrian (Terreneuvian). Here, we describe a large stem chaetognath, Timorebestia koprii gen. et sp. nov., from the lower Cambrian Sirius Passet Lagerstätte, which exhibits lateral and caudal fins, a distinct head region with long antennae and a jaw apparatus similar to Amiskwia sagittiformis. Amiskwia has previously been interpreted as a total-group chaetognathiferan, as either a stem-chaetognath or gnathostomulid. We show that T. koprii shares a ventral ganglion with chaetognaths to the exclusion of other animal groups, firmly placing these fossils on the chaetognath stem. The large size (up to 30 cm) and gut contents in T. koprii suggest that early chaetognaths occupied a higher trophic position in pelagic food chains than today.

A large-scale study of peptide features defining immunogenicity of cancer neo-epitopes.

Accurate prediction of immunogenicity for neo-epitopes arising from a cancer associated mutation is a crucial step in many bioinformatics pipelines that predict outcome of checkpoint blockade treatments or that aim to design personalised cancer immunotherapies and vaccines. In this study, we performed a comprehensive analysis of peptide features relevant for prediction of immunogenicity using the Cancer Epitope Database and Analysis Resource (CEDAR), a curated database of cancer epitopes with experimentally validated immunogenicity annotations from peer-reviewed publications. The developed model, ICERFIRE (ICore-based Ensemble Random Forest for neo-epitope Immunogenicity pREdiction), extracts the predicted ICORE from the full neo-epitope as input, i.e. the nested peptide with the highest predicted major histocompatibility complex (MHC) binding potential combined with its predicted likelihood of antigen presentation (%Rank). Key additional features integrated into the model include assessment of the BLOSUM mutation score of the neo-epitope, and antigen expression levels of the wild-type counterpart which is often reflecting a neo-epitope's abundance. We demonstrate improved and robust performance of ICERFIRE over existing immunogenicity and epitope prediction models, both in cross-validation and on external validation datasets.