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Summary: Poor immunogenicity of critical epitopes can hamper vaccine efficacy. To boost immune recognition of non- or low-immunogenic antigens, we developed a vaccine platform based on the conjugation of a target protein to a chimeric designer peptide (CDP) of bacterial origin. Here, we exploited this immune Boost (iBoost) technology to enhance the immune response against the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. Despite its fundamental role during viral infection, RBD is only moderately immunogenic. Immunization studies in mice showed that the conjugation of CDP to RBD induced superior immune responses compared to RBD alone. CDP-RBD elicited cross-reactive antibodies against the variants of concern Delta and Omicron. Furthermore, hamsters vaccinated with CDP-RBD developed potent neutralizing antibody responses and were fully protected from lung lesion formation upon challenge with SARS-CoV-2. In sum, we show that the iBoost conjugate vaccine technology provides a valuable tool for both quantitatively and qualitatively enhancing anti-viral immunity.

Trabjerg et al. show that the activity of carnitine palmitoyl transferase 1 (CPT1) and lipid metabolism are associated with the disease progression of the SOD1 G93A mouse model mimicking a motor neuron disease Amyotrophic lateral sclerosis (ALS). This study suggests CPT1 as a potential therapeutic target in treating ALS.

Organ-specific autoimmunity is often characterized by autoantibodies targeting proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized by predominant autoantibodies of the IgG4 subclass (IgG4-autoimmune diseases; IgG4-AID). This group includes pemphigus vulgaris, thrombotic thrombocytopenic purpura, subtypes of autoimmune encephalitis, inflammatory neuropathies, myasthenia gravis and membranous nephropathy. Although the associated autoantibodies target specific antigens in different organs and thus cause diverse syndromes and diseases, they share surprising similarities in genetic predisposition, disease mechanisms, clinical course and response to therapies. IgG4-AID appear to be distinct from another group of rare immune diseases associated with IgG4, which are the IgG4-related diseases (IgG4-RLD), such as IgG4-related which have distinct clinical and serological properties and are not characterized by antigen-specific IgG4. Importantly, IgG4-AID differ significantly from diseases associated with IgG1 autoantibodies targeting the same organ. This may be due to the unique functional characteristics of IgG4 autoantibodies (e.g. anti-inflammatory and functionally monovalent) that affect how the antibodies cause disease, and the differential response to immunotherapies of the IgG4 producing B cells/plasmablasts. These clinical and pathophysiological clues give important insight in the immunopathogenesis of IgG4-AID. Understanding IgG4 immunobiology is a key step towards the development of novel, IgG4 specific treatments. In this review we therefore summarize current knowledge on IgG4 regulation, the relevance of class switching in the context of health and disease, describe the cellular mechanisms involved in IgG4 production and provide an overview of treatment responses in IgG4-AID.

The transcription factor SREBP is a well-studied and major regulator of sterol and fatty acid metabolism. Here, the authors used haploid genetic screens to identify the Golgi-resident protein SPRING as a new modulator of SREBP by regulating the level of functional SREBP cleavage-activating protein (SCAP).

A variety of strategies are used to combine multi-echo functional magnetic resonance imaging (fMRI) data, yet recent literature lacks a systematic comparison of the available options. Here we compare six different approaches derived from multi-echo data and evaluate their influences on BOLD sensitivity for offline and in particular real-time use cases: a single-echo time series (based on Echo 2), the real-time T2*-mapped time series (T2*FIT) and four combined time series (T2*-weighted, tSNR-weighted, TE-weighted, and a new combination scheme termed T2*FIT-weighted). We compare the influences of these six multi-echo derived time series on BOLD sensitivity using a healthy participant dataset (N = 28) with four task-based fMRI runs and two resting state runs. We show that the T2*FIT-weighted combination yields the largest increase in temporal signal-to-noise ratio across task and resting state runs. We demonstrate additionally for all tasks that the T2*FIT time series consistently yields the largest offline effect size measures and real-time region-of-interest based functional contrasts and temporal contrast-to-noise ratios. These improvements show the promising utility of multi-echo fMRI for studies employing real-time paradigms, while further work is advised to mitigate the decreased tSNR of the T2*FIT time series. We recommend the use and continued exploration of T2*FIT for offline task-based and real-time region-based fMRI analysis. Supporting information includes: a data repository (https://dataverse.nl/dataverse/rt-me-fmri), an interactive web-based application to explore the data (https://rt-me-fmri.herokuapp.com/), and further materials and code for reproducibility (https://github.com/jsheunis/rt-me-fMRI).

A multi-echo fMRI dataset (N=28 healthy participants) with four task-based and two resting state runs was collected, curated and made available to the community. Its main purpose is to advance the development of methods for real-time multi-echo functional magnetic resonance imaging (rt-me-fMRI) analysis with applications in neurofeedback, real-time quality control, and adaptive paradigms, although the variety of experimental task paradigms supports a multitude of use cases. Tasks include finger tapping, emotional face and shape matching, imagined finger tapping and imagined emotion processing. This work provides a detailed description of the full dataset; methods to collect, prepare, standardize and preprocess it; quality control measures; and data validation measures. A web-based application is provided as a supplementary tool with which to interactively explore, visualize and understand the data and its derivative measures: https://rt-me-fmri.herokuapp.com/. The dataset itself can be accessed via a data use agreement on DataverseNL at https://dataverse.nl/dataverse/rt-me-fmri. Supporting information and code for reproducibility can be accessed at https://github.com/jsheunis/rt-me-fMRI.

Objective: Aim of this study was to assess the cost‐effectiveness and cost‐utility of mindfulness‐based cognitive therapy (MBCT) and treatment as usual (TAU) compared to TAU alone in adults with Bipolar disorder (BD). Methods: An economic evaluation with a time horizon of 15 months was conducted from a societal perspective. Outcomes were expressed in costs per quality adjusted life years (QALYs) and costs per responder using the inventory of depressive symptomatology clinician rating score. Results: People with BD (N = 144) were included in this study. From a societal perspective, the difference of total costs between MBCT + TAU and TAU was €615, with lower costs in the MBCT + TAU group. Only healthcare costs differed significantly between the two groups. A small difference in QALYs in favor of MBCT + TAU was found combined with lower costs (−€836; baseline adjusted) for MBCT + TAU compared to TAU, resulting in a dominant incremental cost‐utility ratio. The probability that the MBCT + TAU was cost‐effective was 65%. All sensitivity analyses attested to the robustness of the base case analyses. Conclusion: Concludingly, MBCT + TAU seems to be cost‐effective compared to TAU alone, indicated by a small or neglectable difference in effect, in favor of MBCT + TAU, while resulting in lower costs. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual‐level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual‐level treatment response (ITR) score which represents individual‐level benefit of high‐dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating–Sum of Boxes (CDR‐SB;P = 0.034). The observed CDR‐SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. Highlights: Emerging trials have shown a population‐level benefit from amyloid beta (Aβ) removal in slowing cognitive decline in early Alzheimer's disease (AD).This work demonstrates significant heterogeneity of individual‐level treatment effect of aducanumab in early AD.The greatest clinical responders to Aβ removal therapy have a pattern of more severe neurodegenerative process. [ABSTRACT FROM AUTHOR]

Abstract Background Antidepressant use continues to rise, mainly explained by an increase in the proportion of patients receiving long term treatment. Although treatment guidelines recommend discontinuation after sustained remission, discontinuing antidepressants appears to be challenging for both patients and general practitioners (GPs). Mindfulness-Based Cognitive Therapy (MBCT) is an effective intervention that reduces the risk of relapse in recurrent depression and might facilitate discontinuation by teaching patients to cope with withdrawal symptoms and fear of relapse. The current study aims to investigate the effectiveness of the combination of Supported Protocolized Discontinuation (SPD) and MBCT in comparison with SPD alone in successful discontinuation of long-term use of antidepressants in primary care. Methods This study involves a cluster-randomized controlled trial conducted in primary care patients with long-term use antidepressants with baseline and 6, 9 and 12 months follow-up assessments. Patients choosing to discontinue their medication will be offered a combination of SPD and MBCT or SPD alone. Our primary outcome will be full discontinuation of antidepressant medication (= 0 mg) within 6 months after baseline assessment. Secondary outcome measures will be the severity of withdrawal symptoms, symptoms of depression and anxiety, psychological well-being, quality of life and medical and societal costs. Discussion In theory, stopping antidepressant medication seems straightforward. In practice however, patients and their GPs appear reluctant to initiate and accomplish this process. Both patients and professionals are in need of appropriate tools and information to better support the process of discontinuing antidepressant medication. Trial registration ClinicalTrials.gov PRS ID: NCT03361514 retrospectively registered October 2017.

Abstract Background Despite multiple pharmacological interventions, many people with bipolar disorder (BD) experience substantial residual mood symptoms, even in the absence of severe mood episodes, which have a negative impact on the course of illness and quality of life. Limited data are available on how to optimize treatment for BD, especially for those who suffer from persistent and residual depressive symptoms. Preliminary evidence suggests Mindfulness-Based Cognitive Therapy (MBCT) as a psychological treatment option for BD. This study aims to investigate whether adding MBCT to treatment as usual (TAU) will result in symptomatic and functional improvements in adults with BD compared to TAU alone. Methods/design This study is a prospective, evaluator blinded, multicenter, randomized controlled trial of MBCT + TAU and TAU alone in 160 adults with bipolar type I and type II. Assessments will be conducted at baseline (T0), mid-treatment (Tmid), and at 3 (T1), 6 (T2), 9 (T3), 12 (T4), and 15 (T5) months follow-up. Primary outcome is post-treatment severity of depressive symptoms (Inventory of Depressive Symptomatology- Clinician administered). Secondary outcomes are severity of (hypo) manic symptoms, anxiety, relapse rates, overall functioning, positive mental health, and cost-effectiveness. As possible mediators will be assessed rumination of negative affect, dampening and rumination of positive affect, mindfulness skills, and self-compassion. Discussion This study will provide valuable insight into the (cost-)effectiveness of MBCT on clinician- and self-rated symptoms of BD, relapse rates, positive mental health, and overall functioning. Trial registration NCT03507647. Registered 25th of April 2018.

It is difficult to identify cancer driver genes in cancers, for instance BRCA1 mutated breast cancer, that are characterised by large scale genomic alterations. Here, the authors develop genetically engineered mouse models of BRCA1-deficient breast cancer that allow highthroughput in vivo perturbation of candidate driver genes, validating drivers Myc, Met, Pten and Rb1, and identifying MCL1 as a collaborating driver whose targeting can impact efficacy of PARP inhibition.

Extracellular vimentin is a specific marker of the tumor vasculature, where it is secreted by tumor endothelial cells. Vaccination with a conjugate vaccine targeting extracellular vimentin was previously shown to induce a potent humoral immune response and tumor growth inhibition in mice. These data were obtained by vaccination using the toxic Freund’s adjuvant (FA) and are therefore not directly translatable into the clinic. In the present study, we aimed to investigate the potential of the biodegradable Montanide ISA 720 adjuvant. We tested Montanide either alone (MN) or supplemented with CpG 1826 (MN-C). Both adjuvant compositions, as well as FA, resulted in a significant tumor growth inhibition and decreased vessel density in the B16F10 melanoma tumor model. Vaccination of mice with either FA or MN-C resulted in an equally potent humoral immune response towards vimentin, while the antibody titers obtained with MN alone were significantly lower compared to FA. Vaccination coincided with the infiltration of immune cells. The highest number of intratumoral immune cells was seen in tumors from the MN-C group. Therefore, we conclude that Montanide ISA 720 supplemented with CpG allows efficient vaccination against extracellular vimentin, which is a prerequisite for the transfer of the vaccine into the clinic.

Summary: Digital technology is having a major impact on many areas of society, and there is equal opportunity for impact on science. This is particularly true in the environmental sciences as we seek to understand the complexities of the natural environment under climate change. This perspective presents the outcomes of a summit in this area, a unique cross-disciplinary gathering bringing together environmental scientists, data scientists, computer scientists, social scientists, and representatives of the creative arts. The key output of this workshop is an agreed vision in the form of a framework and associated roadmap, captured in the Windermere Accord. This accord envisions a new kind of environmental science underpinned by unprecedented amounts of data, with technological advances leading to breakthroughs in taming uncertainty and complexity, and also supporting openness, transparency, and reproducibility in science. The perspective also includes a call to build an international community working in this important area. The Bigger Picture: Digital technology is having a major impact on many areas of society, and there is equal opportunity for impact on science in addressing grand scientific challenges. This is particularly true in the environmental sciences as we seek to understand the complexities of the natural environment under climate change. This perspective reports on the outcomes from a summit in this area, attended by 42 researchers selected as leading experts operating at the interface between digital technology and the environmental sciences. The key output of this workshop was the Windermere Accord, a collective statement around what is required to achieve a transformative effect through digital technology based around four key pillars of investigation, namely using technology to tame uncertainty; growing advocates and champions to enable, empower, and influence; embracing a new open and transparent style of science; and enabling integration and sophisticated treatment of feedbacks in complex environmental systems. These pillars all feed into the decision-making processes and are supported by a growing community. Looking forward, the accord also identified a pathway with particular emphasis on building an international, cross-disciplinary community to address the key challenges and achieve the real opportunities around digital technology and the environment.

We introduce a new and time-efficient memory-encoding paradigm for functional magnetic resonance imaging (fMRI). This paradigm is optimized for mapping multiple contrasts using a mixed design, using auditory (environmental/vocal) and visual (scene/face) stimuli. We demonstrate that the paradigm evokes robust neuronal activity in typical sensory and memory networks. We were able to detect auditory and visual sensory-specific encoding activities in auditory and visual cortices. Also, we detected stimulus-selective activation in environmental-, voice-, scene-, and face-selective brain regions (parahippocampal place and fusiform face area). A subsequent recognition task allowed the detection of sensory-specific encoding success activity (ESA) in both auditory and visual cortices, as well as sensory-unspecific positive ESA in the hippocampus. Further, sensory-unspecific negative ESA was observed in the precuneus. Among others, the parallel mixed design enabled sustained and transient activity comparison in contrast to rest blocks. Sustained and transient activations showed great overlap in most sensory brain regions, whereas several regions, typically associated with the default-mode network, showed transient rather than sustained deactivation. We also show that the use of a parallel mixed model had relatively little influence on positive or negative ESA. Together, these results demonstrate a feasible, versatile, and brief memory-encoding task, which includes multiple sensory stimuli to guarantee a comprehensive measurement. This task is especially suitable for large-scale clinical or population studies, which aim to test task-evoked sensory-specific and sensory-unspecific memory-encoding performance as well as broad sensory activity across the life span within a very limited time frame.