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Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism. [ABSTRACT FROM AUTHOR]

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development. Editor's summary: Muscle-specific kinase (MuSK) is required for the formation and maintenance of neuromuscular junctions, the synaptic connections between motor neurons and muscle fibers. Impairments in MuSK signaling cause certain forms of neuromuscular disease such as congenital myasthenic syndrome and myasthenia gravis. Here, Vanhauwaert et al. present the development of ARGX-119, an agonist antibody for MuSK. ARGX-119 activated MuSK in vitro across different species, including humans, and showed no off-target binding. ARGX-119 was safe in healthy mice and rescued motor function, prolonged survival, and reversed disease relapse in a mouse model of congenital myasthenia. These data support further development of ARGX-119 for neuromuscular diseases. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Automated sensors have potential to standardize and expand the monitoring of insects across the globe. As one of the most scalable and fastest developing sensor technologies, we describe a framework for automated, image-based monitoring of nocturnal insects—from sensor development and field deployment to workflows for data processing and publishing. Sensors comprise a light to attract insects, a camera for collecting images and a computer for scheduling, data storage and processing. Metadata is important to describe sampling schedules that balance the capture of relevant ecological information against power and data storage limitations. Large data volumes of images from automated systems necessitate scalable and effective data processing. We describe computer vision approaches for the detection, tracking and classification of insects, including models built from existing aggregations of labelled insect images. Data from automated camera systems necessitate approaches that account for inherent biases. We advocate models that explicitly correct for bias in species occurrence or abundance estimates resulting from the imperfect detection of species or individuals present during sampling occasions. We propose ten priorities towards a step-change in automated monitoring of nocturnal insects, a vital task in the face of rapid biodiversity loss from global threats. This article is part of the theme issue 'Towards a toolkit for global insect biodiversity monitoring'. [ABSTRACT FROM AUTHOR]

Muscle‐specific kinase myasthenia gravis (MuSK MG) is caused by autoantibodies against MuSK in the neuromuscular junction (NMJ). MuSK MG patients have fluctuating, fatigable skeletal muscle weakness, in particular of bulbar muscles. Severity differs greatly between patients, in spite of comparable autoantibody levels. One explanation for inter‐patient and inter‐muscle variability in sensitivity might be variations in compensatory muscle responses. Previously, we developed a passive transfer mouse model for MuSK MG. In preliminary ex vivo experiments, we observed that muscle contraction of some mice, in particular those with milder myasthenia, had become partially insensitive to inhibition by μ‐Conotoxin‐GIIIB, a blocker of skeletal muscle NaV1.4 voltage‐gated sodium channels. We hypothesised that changes in NaV channel expression profile, possibly co‐expression of (μ‐Conotoxin‐GIIIB insensitive) NaV1.5 type channels, might lower the muscle fibre's firing threshold and facilitate neuromuscular synaptic transmission. To test this hypothesis, we here performed passive transfer in immuno‐compromised mice, using 'high', 'intermediate' and 'low' dosing regimens of purified MuSK MG patient IgG4. We compared myasthenia levels, μ‐Conotoxin‐GIIIB resistance and muscle fibre action potential characteristics and firing thresholds. High‐ and intermediate‐dosed mice showed clear, progressive myasthenia, not seen in low‐dosed animals. However, diaphragm NMJ electrophysiology demonstrated almost equal myasthenic severities amongst all regimens. Nonetheless, low‐dosed mouse diaphragms showed a much higher degree of μ‐Conotoxin‐GIIIB resistance. This was not explained by upregulation of Scn5a (the NaV1.5 gene), lowered muscle fibre firing thresholds or histologically detectable upregulated NaV1.5 channels. It remains to be established which factors are responsible for the observed μ‐Conotoxin‐GIIIB insensitivity and whether the NaV repertoire change is compensatory beneficial or a bystander effect. [ABSTRACT FROM AUTHOR]

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]

Objective: This article describes the development and psychometric evaluation of the Manic Thought Inventory (MTI), a patient-driven self-report inventory to assess the presence of typical (hypo)manic cognitions. Methods: The initial item pool was generated by patients with bipolar disorder (BD) type I and assessed for suitability by five psychiatrists specialized in treating BD. Study 1 describes the item analysis and exploratory factor structure of the MTI in a sample of 251 patients with BD type I. In study 2, the factor structure was validated with confirmatory factor analysis, and convergent and divergent validity were assessed in an independent sample of 201 patients with BD type I. Results: Study 1 resulted in a 50-item version of the MTI measuring one underlying factor. Study 2 confirmed the essentially unidimensional underlying construct in a 47-item version of the MTI. Internal consistency of the 47-item version of the MTI was excellent (α = 0.97). The MTI showed moderate to large positive correlations with other measures related to mania. It was not correlated with measures of depression. Conclusion: The MTI showed good psychometric properties and can be useful in research and clinical practice. Patients could use the MTI to select items that they recognize as being characteristic of their (hypo)manic episodes. By monitoring and challenging these items, the MTI could augment current psychological interventions for BD. [ABSTRACT FROM AUTHOR]

Background: Mindfulness-based cognitive therapy (MBCT) seems a promising intervention for bipolar disorder (BD), but there is a lack of randomised controlled trials (RCT) investigating this. The purpose of this multicentre, evaluator blinded RCT was to investigate the added value of MBCT to treatment as usual (TAU) in BD up to 15 months follow-up (NCT03507647). Methods: A total of 144 participants with BD type I and II were randomised to MBCT + TAU (n = 72) and TAU (n = 72). Primary outcome was current depressive symptoms. Secondary outcomes were current (hypo)manic and anxiety symptoms, recurrence rates, rumination, dampening of positive affect, functional impairment, mindfulness skills, self-compassion, and positive mental health. Potential moderators of treatment outcome were examined. Results: MBCT + TAU was not more efficacious than TAU in reducing current depressive symptoms at post-treatment (95% CI [−7.0 to 1.8], p = 0.303, d = 0.24) or follow-up (95% CI [−2.2 to 6.3], p = 0.037, d = 0.13). At post-treatment, MBCT + TAU was more effective than TAU in improving mindfulness skills. At follow-up, TAU was more effective than MBCT + TAU in reducing trait anxiety and improving mindfulness skills and positive mental health. Exploratory analysis revealed that participants with higher depressive symptoms and functional impairment at baseline benefitted more from MBCT + TAU than TAU. Conclusions: In these participants with highly recurrent BD, MBCT may be a treatment option in addition to TAU for those who suffer from moderate to severe levels of depression and functional impairment. Trial registration: ClinicalTrials.gov, NCT03507647. Registered the 25 April 2018, https://www.clinicaltrials.gov/ct2/show/NCT01126827. [ABSTRACT FROM AUTHOR]

Discontinuing antidepressant medication (ADM) can be challenging for patients and clinicians. In the current study we investigated if Mindfulness-Based Cognitive Therapy (MBCT) added to supported protocolized discontinuation (SPD) is more effective than SPD alone to help patients discontinue ADM. This study describes a prospective, cluster-randomized controlled trial (completed). From 151 invited primary care practices in the Netherlands, 36 (24%) were willing to participate and randomly allocated to SPD+MBCT (k = 20) or SPD (k = 16). Adults using ADM > 9 months were invited by GPs to discuss tapering, followed by either MBCT+SPD, or SPD alone. Exclusion criteria included current psychiatric treatment; substance use disorder; non-psychiatric indication for ADM; attended MBCT within past 5 years; cognitive barriers. From the approximately 3000 invited patients, 276 responded, 119 participated in the interventions and 92 completed all assessments. All patients were offered a decision aid and a personalized tapering schedule (with GP). MBCT consisted of eight group sessions of 2.5 hours and one full day of practice. SPD was optional and consisted of consultations with a mental health assistant. Patients were assessed at baseline and 6, 9 and 12 months follow-up, non-blinded. In line with our protocol, primary outcome was full discontinuation of ADM within 6 months. Secondary outcomes were depression, anxiety, withdrawal symptoms, rumination, well-being, mindfulness skills, and self-compassion. Patients allocated to SPD + MBCT (n = 73) were not significantly more successful in discontinuing (44%) than those allocated to SPD (n = 46; 33%), OR 1.60, 95% CI 0.73 to 3.49, p =.24, number needed to treat = 9. Only 20/73 allocated to MBCT (27%) completed MBCT. No serious adverse events were reported. In conclusion, we were unable to demonstrate a significant benefit of adding MBCT to SPD to support discontinuation in general practice. Actual participation in patient-tailored interventions was low, both for practices and for patients. (Trial registration: ClinicalTrials.gov PRS ID: NCT03361514 registered December 2017) [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we investigated the safety and usefulness of treatment of dog patients with spontaneous bladder cancer with the CVx1 vaccine. The vaccine is directed against a specific protein, named extracellular vimentin, excreted by the tumor vasculature. Twenty dogs diagnosed at the veterinary clinic with bladder cancer were treated with the CVx1 vaccine in combination with the non-steroidal anti-inflammatory drug (NSAID) meloxicam. All dogs responded to the treatment and developed an immune response towards the tumor vasculature. After treatment with the CVx1 vaccine plus meloxicam, the survival was almost doubled (374 days) compared to the historical control group (196 days) treated with the chemotherapy carboplatin in combination with the NSAID piroxicam. Treatment with the CVx1 vaccine combined with meloxicam was safe and well tolerated. Our results justify further development of the CVx1 vaccine for the treatment of human patients in the clinic. It was recently shown that targeting extracellular vimentin (eVim) is safe and effective in preclinical models. Here, we report the safety and efficacy in client-owned dogs with spontaneous bladder cancer of CVx1, an iBoost technology-based vaccine targeting eVim in combination with COX-2 inhibition. This was a single-arm prospective phase 1/2 study with CVx1 in 20 client-owned dogs with spontaneous UC which involved four subcutaneous vaccinations with CVx1 at 2-week intervals for induction of antibody titers, followed by maintenance vaccinations at 2-month intervals. Additionally, daily cyclooxygenase (COX)-2 inhibition with meloxicam was given. The response was assessed by antibody titers, physical condition, abdominal ultrasound and thorax X-ray. The primary endpoints were the development of antibody titers, as well as overall survival compared to a historical control group receiving carboplatin and COX-2 inhibition with piroxicam. Kaplan–Meier survival analysis was performed. All dogs developed antibodies against eVim. Titers were adequately maintained for the duration of this study. A median overall survival of 374 days was observed, which was 196 days for the historical control group (p < 0.01). Short-term grade 1–2 toxicity at the injection site and some related systemic symptoms peri-vaccination were observed. No toxicity was observed related to the induced antibody response. A limitation of this study is the single-arm prospective setting. CVx1 plus meloxicam consistently induced efficient antibody titers, was well tolerated and showed prolonged survival. The results obtained merit further development for human clinical care. [ABSTRACT FROM AUTHOR]

Introduction: Both elevated cortisol and hippocampal volume have been linked to an increased risk for the development of Alzheimer's disease (AD). This longitudinal study assessed the effects of plasma cortisol on hippocampal atrophy and clinical progression rates in patients with mild cognitive impairment (MCI). Methods: Patients with amnestic MCI (n = 304) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on availability of baseline plasma cortisol and hippocampal volume measures, assessed at baseline and during follow‐ups. We investigated associations between plasma cortisol, hippocampal volume, and risk of clinical progression to AD over a study period of up to 100 months (mean follow‐up time 36.8 months) using linear mixed models, Cox proportional hazards models, and Kaplan‐Meier estimators. Results: Plasma cortisol predicted greater hippocampal atrophy, such that participants with higher cortisol showed faster decline in hippocampal volume over time (interaction: β = ‐0.15, p = 0.004). Small hippocampal volume predicted a higher risk of clinical progression to AD (haard ratio [HR] = 2.15; confidence in terval [CI], 1.64–2.80; p < 0.001). A similar effect was not found for cortisol (HR = 1.206; CI, 0.82–1.37; p = 0.670) and there was no statistical evidence for an interaction between hippocampal volume and cortisol on clinical progression (HR = 0.81; CI, 0.57–0.17; p = 0.260). Discussion: Our findings suggest that higher cortisol predicts higher hippocampal atrophy, which in turn is a risk factor for progression to AD. Regulation of the hypothalamic‐pituitary‐adrenal axis through stress‐reducing lifestyle interventions might be a protective factor against hippocampal degeneration at the prodromal stage of AD. [ABSTRACT FROM AUTHOR]

Background: Many patients with Inflammatory Bowel Diseases (IBD) suffer from psychological distress, fatigue and sleep disturbances, which are associated with reduced quality of life (QoL) and increased societal costs. Only limited psychosocial treatment options are available. As Mindfulness-Based Cognitive Therapy (MBCT) has demonstrated to improve psychological distress, QoL and sleep in other populations, MBCT might also be effective in patients with IBD. Methods: The MindIBD study is a prospective, multicentre, randomised controlled trial comparing MBCT plus Treatment As Usual (TAU) versus TAU alone in a targeted number of 136 IBD patients in remission, aged 16 years and older with at least mild psychological distress (Hospital Anxiety and Depression Scale (HADS) total score ≥ 11). Primary outcome is reduction of psychological distress post-intervention, measured by the HADS. In addition, the effect of MBCT on sleep quality (including actigraphy and electroencephalography recordings), fatigue, disease activity, perceived disease control, QoL and positive mental health will be examined. Assessments will be conducted at baseline and at 3, 6, 9 and 12 months follow-up. Cost-effectiveness will be determined and a process evaluation will be conducted. Discussion: This study will provide valuable insight into the clinical effect of MBCT on psychological distress, sleep quality, fatigue and QoL in IBD patients and into the cost-effectiveness. If effective, MBCT can be a valuable addition to the available psychosocial interventions for patients with IBD. Moreover, findings from this study may also be applicable in patients with other chronic conditions. Trial registration: ClinicalTrials.gov: NCT04646785, registered on 30/11/2020. [ABSTRACT FROM AUTHOR]

Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise. [ABSTRACT FROM AUTHOR]

Purpose: Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions. Experimental design: Tissues of renal cell carcinoma (RCC) patients treated with VEGF pathway-targeted drugs and control tissues were subject to RNAseq and immunohistochemical profiling of the leukocyte infiltrate. Analysis of adhesion molecule regulation in cultured endothelial cells, in a preclinical model and in human tissues was performed and correlated to leukocyte infiltration. Results: It is shown that treatment of RCC patients with the drugs sunitinib or bevacizumab overcomes tumor endothelial cell anergy. This treatment resulted in an augmented inflammatory state of the tumor, characterized by enhanced infiltration of all major leukocyte subsets, including T cells, regulatory T cells, macrophages of both M1- and M2-like phenotypes and activated dendritic cells. In vitro, exposure of angiogenic endothelial cells to anti-angiogenic drugs normalized ICAM-1 expression. In addition, a panel of tyrosine kinase inhibitors was shown to increase transendothelial migration of both non-adherent and monocytic leukocytes. In primary tumors of RCC patients, ICAM-1 expression was found to be significantly increased in both the sunitinib and bevacizumab-treated groups. Genomic analysis confirmed the correlation between increased immune cell infiltration and ICAM-1 expression upon VEGF-targeted treatment. Conclusion: The results support the emerging concept that anti-angiogenic therapy can boost immunity and show how immunotherapy approaches can benefit from combination with anti-angiogenic compounds. [ABSTRACT FROM AUTHOR]

Myb-like SWIRM and MPN domains 1 (MYSM1) is a chromatin binding protein with deubiquitinase (DUB) catalytic activity. Rare MYSM1 mutations in human patients result in an inherited bone marrow failure syndrome, highlighting the biomedical significance of MYSM1 in the hematopoietic system. We and others characterized Mysm1-knockout mice as a model of this disorder and established that MYSM1 regulates hematopoietic function and leukocyte development in such models through different mechanisms. It is, however, unknown whether the DUB catalytic activity of MYSM1 is universally required for its many functions and for the maintenance of hematopoiesis in vivo. To test this, here we generated a new mouse strain carrying a Mysm1D660N point mutation (Mysm1DN) and demonstrated that the mutation renders MYSM1 protein catalytically inactive. We characterized Mysm1DN/DN and Mysm1fl/DN CreERT2 mice, against appropriate controls, for constitutive and inducible loss of MYSM1 catalytic function. We report a profound similarity in the developmental, hematopoietic, and immune phenotypes resulting from the loss of MYSM1 catalytic function and the full loss of MYSM1 protein. Overall, our work for the first time establishes the critical role of MYSM1 DUB catalytic activity in vivo in hematopoiesis, leukocyte development, and other aspects of mammalian physiology. [ABSTRACT FROM AUTHOR]

Background: Minimally invasive surgery is complex and associated with substantial learning curves. Computer-aided anatomy recognition, such as artificial intelligence-based algorithms, may improve anatomical orientation, prevent tissue injury, and improve learning curves. The study objective was to provide a comprehensive overview of current literature on the accuracy of anatomy recognition algorithms in intrathoracic and -abdominal surgery. Methods: This systematic review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Pubmed, Embase, and IEEE Xplore were searched for original studies up until January 2022 on computer-aided anatomy recognition, without requiring intraoperative imaging or calibration equipment. Extracted features included surgical procedure, study population and design, algorithm type, pre-training methods, pre- and post-processing methods, data augmentation, anatomy annotation, training data, testing data, model validation strategy, goal of the algorithm, target anatomical structure, accuracy, and inference time. Results: After full-text screening, 23 out of 7124 articles were included. Included studies showed a wide diversity, with six possible recognition tasks in 15 different surgical procedures, and 14 different accuracy measures used. Risk of bias in the included studies was high, especially regarding patient selection and annotation of the reference standard. Dice and intersection over union (IoU) scores of the algorithms ranged from 0.50 to 0.98 and from 74 to 98%, respectively, for various anatomy recognition tasks. High-accuracy algorithms were typically trained using larger datasets annotated by expert surgeons and focused on less-complex anatomy. Some of the high-accuracy algorithms were developed using pre-training and data augmentation. Conclusions: The accuracy of included anatomy recognition algorithms varied substantially, ranging from moderate to good. Solid comparison between algorithms was complicated by the wide variety of applied methodology, target anatomical structures, and reported accuracy measures. Computer-aided intraoperative anatomy recognition is an upcoming research discipline, but still at its infancy. Larger datasets and methodological guidelines are required to improve accuracy and clinical applicability in future research. Trial registration: PROSPERO registration number: CRD42021264226 [ABSTRACT FROM AUTHOR]

Negative self-referential processing has fruitfully been studied in unipolar depressed patients, but remarkably less in patients with bipolar disorder (BD). This exploratory study examines the relation between task-based self-referential processing and depressive symptoms in BD and their possible importance to the working mechanism of mindfulness-based cognitive therapy (MBCT) for BD. The study population consisted of a subsample of patients with BD (n = 49) participating in an RCT of MBCT for BD, who were assigned to MBCT + TAU (n = 23) or treatment as usual (TAU) (n = 26). Patients performed the self-referential encoding task (SRET), which measures (1) positive and (2) negative attributions to oneself as well as (3) negative self-referential memory bias, before and after MBCT + TAU or TAU. At baseline, all three SRET measures were significantly related to depressive symptoms in patients with BD. Moreover, repeated measures analyses of variance revealed that negative self-referential memory bias diminished over time in the MBCT + TAU group, compared with the TAU group. Given the preliminary nature of our findings, future research should explore the possibly mediating role of reducing negative self-referential memory bias in preventing and treating depressive symptoms in BD through MBCT. [ABSTRACT FROM AUTHOR]

Background: Preliminary evidence suggests that Mindfulness-Based Cognitive Therapy (MBCT) is a promising treatment for bipolar disorder (BD). A proposed working mechanism of MBCT in attenuating depressive symptoms is reducing depressive rumination. The primary aim of this study was to investigate the effect of MBCT on self-reported trait depressive rumination and an experimental state measure of negative intrusive thoughts in BD patients. Exploratively, we investigated the effect of MBCT on positive rumination and positive intrusive thoughts. Methods: The study population consisted of a subsample of bipolar type I or II patients participating in a multicenter randomized controlled trial comparing MBCT + treatment as usual (TAU) (N = 25) to TAU alone (N = 24). Trait depressive rumination (RRS brooding subscale) and intrusive thoughts (breathing focus task (BFT)) were assessed at baseline (full subsample) and post-treatment (MBCT + TAU; n = 15, TAU; n = 15). During the BFT, participants were asked to report negative, positive and neutral intrusive thoughts while focusing on their breathing. Results: Compared to TAU alone, MBCT + TAU resulted in a significant pre- to post-treatment reduction of trait depressive rumination (R2 =.16, F(1, 27) = 5.15, p = 0.031; medium effect size (f2 = 0.19)) and negative intrusive thoughts on the BFT (R2 =.15, F(1, 28) = 4.88, p = 0.036; medium effect size (f2 = 0.17)). MBCT did not significantly change positive rumination or positive intrusive thoughts. Conclusions: MBCT might be a helpful additional intervention to reduce depressive rumination in BD which might reduce risk of depressive relapse or recurrence. Considering the preliminary nature of our findings, future research should replicate our findings and explore whether this reduction in rumination following MBCT indeed mediates a reduction in depressive symptoms and relapse or recurrence in BD. [ABSTRACT FROM AUTHOR]

Galectin-1 (Gal1) is a glycan-binding protein that promotes tumor progression by several distinct mechanisms. Through direct binding to vascular endothelial growth factor (VEGF)-receptor 2, Gal1 is able to induce VEGF-like signaling, which contributes to tumor angiogenesis. Furthermore, several studies have demonstrated an immunosuppressive function of Gal1 through effects on both effector and regulatory T cells. Elevated Gal1 expression and secretion have been shown in many tumor types, and high Gal1 serum levels have been connected to poor prognosis in cancer patients. These findings suggest that therapeutic strategies directed against Gal1 would enable simultaneous targeting of angiogenesis, immune evasion and metastasis. In the current study, we have analyzed the potential of Gal1 as a cancer vaccine target. We show that it is possible to generate high anti-Gal1 antibody levels in mice immunized with a recombinant vaccine protein consisting of bacterial sequences fused to Gal1. Growth of Gal1 expressing melanomas was significantly impaired in the immunized mice compared to the control group. This was associated with improved perfusion of the tumor vasculature, as well as increased infiltration of macrophages and cytotoxic T cells (CTLs). The level of granzyme B, mainly originating from CTLs in our model, was significantly elevated in Gal1 vaccinated mice and correlated with a decrease in tumor burden. We conclude that vaccination against Gal1 is a promising pro-immunogenic approach for cancer therapy that could potentially enhance the effect of other immunotherapeutic strategies due to its ability to promote CTL influx in tumors. [ABSTRACT FROM AUTHOR]

Objective diagnosis and prognosis in major depressive disorder (MDD) remains a challenge due to the absence of biomarkers based on physiological parameters or medical tests. Numerous studies have been conducted to identify functional magnetic resonance imaging‐based biomarkers of depression that either objectively differentiate patients with depression from healthy subjects, predict personalized treatment outcome, or characterize biological subtypes of depression. While there are some findings of consistent functional biomarkers, there is still lack of robust data acquisition and analysis methodology. According to current findings, primarily, the anterior cingulate cortex, prefrontal cortex, and default mode network play a crucial role in MDD. Yet, there are also less consistent results and the involvement of other regions or networks remains ambiguous. We further discuss image acquisition, processing, and analysis limitations that might underlie these inconsistencies. Finally, the current review aims to address and discuss possible remedies and future opportunities that could improve the search for consistent functional imaging biomarkers of depression. Novel acquisition techniques, such as multiband and multiecho imaging, and neural network‐based cleaning approaches can enhance the signal quality in limbic and frontal regions. More comprehensive analyses, such as directed or dynamic functional features or the identification of biological depression subtypes, can improve objective diagnosis or treatment outcome prediction and mitigate the heterogeneity of MDD. Overall, these improvements in functional MRI imaging techniques, processing, and analysis could advance the search for biomarkers and ultimately aid patients with MDD and their treatment course. [ABSTRACT FROM AUTHOR]

Promiscuous activity of the Streptococcus pyogenes DNA nuclease CRISPR-Cas9 can result in destruction of a successfully modified sequence obtained by templated repair of a Cas9-induced DNA double-strand break. To avoid re-cutting, additional target-site-disruptions (TSDs) are often introduced on top of the desired base-pair alteration in order to suppress target recognition. These TSDs may lower the efficiency of introducing the intended mutation and can cause unexpected phenotypes. Alternatively, successfully edited sites can be protected against Cas9 re-cutting activity. This method exploits the finding that Cas9 complexed to trimmed guideRNAs can still tightly bind specific genomic sequences but lacks nuclease activity. We show here that the presence of a guideRNA plus a trimmed guideRNA that matches the successfully mutated sequence, which we call hideRNA, can enhance the recovery of precise single base-pair substitution events tenfold. The benefit of hideRNAs in generating a single point mutation was demonstrated in cell lines using plasmid-based delivery of CRISPR-Cas9 components and in mouse zygotes injected with Cas9/guideRNA plus Cas9/hideRNA ribonucleoprotein complexes. However, hRNA protection sometimes failed, which likely reflects an unfavorable affinity of hRNA/Cas9 versus gRNA/Cas9 for the DNA target site. HideRNAs can easily be implemented into current gene editing protocols and facilitate the recovery of single base-pair substitution. As such, hideRNAs are of great value in gene editing experiments demanding high accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Vaccination against specific proteins in the tumor vasculature has already shown promising results in several preclinical studies. However, the efficacy of vaccination highly depends on the adjuvant used. This study aimed to assess the potential use of the biodegradable adjuvant Montanide ISA 720 in combination with our vaccine against extracellular vimentin, a protein specifically secreted by the tumor vasculature. Compared to the potent but toxic Freund's adjuvant, Montanide showed a comparable immune response and tumor growth inhibition in a preclinical vaccination experiment in mice, especially when supplemented with the immune stimulatory molecule CpG. We also observed that vaccination reduced the blood vessel count and increased the infiltration of immune cells. We conclude that Montanide ISA 720 shows potential to be used as an adjuvant for vaccination against extracellular vimentin for future clinical studies in cancer patients. 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. [ABSTRACT FROM AUTHOR]

Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Antibody targeting of extracellular vimentin shows inhibition of angiogenesis in vitro and in vivo. Effective and safe inhibition of angiogenesis and tumor growth in several preclinical and clinical studies is demonstrated using a vaccination strategy against extracellular vimentin. Targeting vimentin induces a pro-inflammatory condition in the tumor, exemplified by induction of the endothelial adhesion molecule ICAM1, suppression of PD-L1, and altered immune cell profiles. Our findings show that extracellular vimentin contributes to immune suppression and functions as a vascular immune checkpoint molecule. Targeting of extracellular vimentin presents therefore an anti-angiogenic immunotherapy strategy against cancer. The pro-tumorigenic effects of vimentin have been attributed to intracellular functions in tumour cells so far. Here, the authors show that tumour endothelial cells can secrete vimentin as a pro-angiogenic factor and that targeting of vimentin can be used as an immunotherapeutic strategy. [ABSTRACT FROM AUTHOR]

Background: Value Based Health Care (VBHC) is a well-known strategy in most countries, amongst whom the Netherlands, to improve patient-relevant outcomes and reduce healthcare costs. However, a methodology to implement VBHC principles in the full care cycle is lacking. This study describes a stepwise approach to implement and continuously improve patient-relevant outcomes in the total care delivery value chain. Methods: Key principles of VBHC are used to develop a stepwise methodology in which healthcare providers of primary, secondary, and tertiary care collaborate in a physician-driven initiative called the Netherlands Heart Network. The methodology incorporates the Plan-Do-Study-Act cycle to ensure continuous improvement of patient-relevant outcomes. To outline the presented methodology, the medical condition atrial fibrillation is used as a proof of concept. Results: Using the stepwise methodology results in an adequate registration of patient-relevant outcomes and a structured evaluation of adherence to prevailing guidelines. Based on the followed methodology, detailed improvements are defined in order to optimize patient-relevant outcomes. Conclusions: The presented methodology provides a description how to implement VBHC principles in the full cycle of care. Since this methodology is a first concept, future research should apply and assess the stepwise methodology in other fields and for different medical conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Mindfulness‐based cognitive therapy (MBCT) is effective for relapse prevention in major depressive disorder (MDD). It reduces cognitive reactivity (CR) and rumination, and enhances self‐compassion and mindfulness. Although rumination and mindfulness after MBCT are associated with relapse, the association of CR, rumination, self‐compassion, and mindfulness with relapse before initiation of MBCT has never been investigated. Methods: Data were drawn from two randomized controlled trials, including a total of 282 remitted MDD participants (≥3 depressive episodes) who had been using maintenance antidepressant medication (mADM) for at least 6 months before baseline. All participants were offered MBCT while either their mADM was maintained or discontinued after MBCT. CR, rumination, self‐compassion, and mindfulness were assessed at baseline by self‐rated questionnaires and were used in Cox proportional hazards regression models to investigate their association with relapse. Results: CR and mindfulness were associated with relapse, independent of residual symptoms, previous depressive episodes, and mADM‐use. Higher CR and lower mindfulness increased the risk of relapse. Self‐compassion was not associated with relapse. For rumination, a significant interaction with mADM‐use was found. Rumination was associated with relapse in patients who discontinued their mADM, while this effect was absent if patients continued mADM. Conclusions: These results show that CR, rumination, and mindfulness are associated with relapse in remitted MDD‐patients before initiation of MBCT, independent of residual symptoms and previous depressive episodes. This information could improve decisions in treatment planning in remitted individuals with a history of depression. [ABSTRACT FROM AUTHOR]

Tumors can escape immunity through multiple mechanisms, one of which is by enforcing a state of unresponsiveness of the tumor vasculature to inflammatory cytokines. This results in a lack of adhesiveness of angiogenic endothelial cells for immune cells and thus compromised immunity. This type of escape from immunity, called tumor endothelial cell anergy, is the result of exposure to angiogenic growth factors. Angiogenesis is a hallmark not only of cancer but also of embryonic development. It is assumed that angiogenesis-induced suppression of adhesion molecules is a regulatory function to provide an embryo with immune privileged conditions and allow uninterrupted growth and development. It is becoming clear that similar conditions are used by tumors to evade the immune system and ensure progressive growth. Gaining enhanced insight into these immune-privileged conditions is important as endothelial cell anergy can be overcome by angiogenesis inhibitors, an application that is rapidly emerging as a successful strategy to improve immunotherapy. The literature on endothelial adhesion molecule expression and leukocyte-vessel wall interactions during embryonic and fetal development is sparse, but available data allow the hypothesis that tumors, through angiogenesis, enforce an embryonic-like gene expression program in endothelial cells to suppress leukocyte infiltration and compromise antitumor immunity. [ABSTRACT FROM AUTHOR]

Background: Mindfulness-Based Interventions (MBIs) are widely used in clinical and non-clinical populations, but little attention has been given to potential adverse effects (AEs). Aims: This study aimed to gain insight in the prevalence and course of AEs during Mindfulness-Based Cognitive Therapy (MBCT) for patients with bipolar disorder (BD). Method: The current mixed-methods study was conducted as part of a RCT on (cost-) effectiveness of MBCT in 144 patients with BD (Trial registered on 25th of April 2018, ClinicalTrials.gov, NCT03507647). During MBCT, occurrence of AEs was monitored prospectively, systematically, and actively (n = 72). Patients who reported AEs were invited for semi-structured interviews after completing MBCT (n = 29). Interviews were analysed with directed content analysis, using an existing framework by Lindahl et al. Results: AEs were reported by 29 patients, in seven of whom the experiences could not be attributed to MBCT during the interview. AEs were reported most frequently up to week 3 and declined afterwards. Baseline anxiety appeared to be a risk factor for developing AEs. Seven existing domains of AEs were observed: cognitive, perceptual, affective, somatic, conative, sense of self, and social. Influencing factors were subdivided into predisposing, precipitating, perpetuating, and mitigating factors. With hindsight, more than half of patients considered the reported AEs as therapeutic rather than harmful. Conclusions: Although the occurrence of AEs in MBCT for patients with BD is not rare, even in this population with severe mental illness they were not serious or had lasting bad effects. In fact, most of them were seen by the patients as being part of a therapeutic process, although some patients only experienced AEs as negative. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy. [ABSTRACT FROM AUTHOR]

Objectives: Mindfulness-based cognitive therapy (MBCT) has been found effective in reducing depressive symptoms in adults suffering from recurrent depression. However, sustained recovery after MBCT is modest and may require additional, sequential treatment. Basing such additions on known working mechanisms of MBCT, like increases in (self-)compassion, is likely to reap further benefits. Mindfulness-based compassionate living (MBCL) is designed as a follow-up to MBCT and has been shown effective in reducing depressive symptoms. It has a similar format to MBCT: eight weekly group sessions and additional home practice. MBCL has a more explicit focus on cultivating (self-)compassion in response to difficult experiences. Little is known about the potential experiential added value of MBCL after MBCT. The current study aims to fill this gap. Methods: A grounded theory approach was used to analyze in-depth interviews, which were held post-intervention with a purposive sample of patients who participated in a randomized controlled trial of MBCL for recurrent depression. Results: Participants indicated that MBCL particularly had added value in terms of its immediate applicability in situations of deep suffering. Four themes emerged: (1) the container of kindness, (2) exposure to the difficult, (3) empowerment, and (4) common humanity. Conclusion: This study shows that participants experienced an additional value of MBCL over and above MBCT. The results provide insight into the processes underlying the efficacy of MBCL in reducing depressive symptoms and may help address underlying mechanisms of vulnerability in this population as well as tap into mechanisms that enhance resilience. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an acquired autoimmune disorder caused by autoantibodies binding acetylcholine receptors (AChR), muscle‐specific kinase (MuSK), agrin or low‐density lipoprotein receptor‐related protein 4 (Lrp4). These autoantibodies inhibit neuromuscular transmission by blocking the function of these proteins and thereby cause fluctuating skeletal muscle weakness. Several reports suggest that these autoantibodies might also affect the central nervous system (CNS) in MG patients. A comprehensive overview of the timing and localization of the expression of MG‐related antigens in other organs is currently lacking. To investigate the spatio‐temporal expression of MG‐related genes outside skeletal muscle, we used in silico tools to assess public expression databases. Acetylcholine esterase, nicotinic AChR α1 subunit, agrin, collagen Q, downstream of kinase‐7, Lrp4, MuSK and rapsyn were included as MG‐related genes because of their well‐known involvement in either congenital or autoimmune MG. We investigated expression of MG‐related genes in (1) all human tissues using GTEx data, (2) specific brain regions, (3) neurodevelopmental stages, and (4) cell types using datasets from the Allen Institute for Brain Sciences. MG‐related genes show heterogenous spatio‐temporal expression patterns in the human body as well as in the CNS. For each of these genes, several (new) tissues, brain areas and cortical cell types with (relatively) high expression were identified suggesting a potential role for these genes outside skeletal muscle. The possible presence of MG‐related antigens outside skeletal muscle suggests that autoimmune MG, congenital MG or treatments targeting the same proteins may affect MG‐related protein function in other organs. [ABSTRACT FROM AUTHOR]

Detecting early pathological cognitive decline is critical for dementia and aging-related research and clinical diagnostics. Rey's Auditory Verbal Learning Test (AVLT) is commonly used to measure episodic verbal memory. The test requires participants to learn a list of 15 words over several trials. Since multiple testing is often required to detect cognitive decline, but repeating the same test can bias results, we developed 10 German AVLT word lists. We randomly assigned the lists to 4,000 participants (aged 30–94 years) from a population-based cohort to test their comparability, as well as aging effects and sex differences. Nine lists were highly comparable, with only one being slightly more difficult. Recall performance decreased on average by 0.6–1.1 words per trial per decade of age. Perseveration errors decreased with increasing age. Women remembered on average between 0.8 and 1.5 words per trial more than men, regardless of age. Women also outperformed men in the sum of Trials 1–5, learning over trials, retroactive inhibition, and false-positive and interference errors. Proactive inhibition remained stable across age and was unaffected by sex. This German AVLT version presents comparable lists including detailed age and sex references and therefore allows test repetition excluding training effects. These versions are a valuable resource for research and clinical application. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by death of motor neurons. The etiology and pathogenesis remains elusive despite decades of intensive research. Herein, we report that dysregulated metabolism plays a central role in the SOD1 G93A mouse model mimicking ALS. Specifically, we report that the activity of carnitine palmitoyl transferase 1 (CPT1) lipid metabolism is associated with disease progression. Downregulation of CPT1 activity by pharmacological and genetic methods results in amelioration of disease symptoms, inflammation, oxidative stress and mitochondrial function, whereas upregulation by high-fat diet or corticosterone results in a more aggressive disease progression. Finally, we show that downregulating CPT1 shifts the gut microbiota communities towards a protective phenotype in SOD1 G93A mice. These findings reveal that metabolism, and specifically CPT1 lipid metabolism plays a central role in the SOD1 G93A mouse model and shows that CPT1 might be a therapeutic target in ALS. 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. [ABSTRACT FROM AUTHOR]

Background: Home practice is considered a key element in increasing treatment effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) for depression. However, long-term longitudinal research into the associations between home practice and depression outcomes is scarce. The current study examined the prospective associations between the extent of formal home practice and subsequent depression severity during 15 months of follow-up. Methods: Data from two randomized-controlled trials on MBCT for recurrent depression were used (n = 200). Depressive symptoms were assessed at 3-month intervals: 0 (baseline), 3 (posttreatment), 6, 9, 12, and 15 months. Formal home practice frequency was calculated for each 3-month period. Autoregressive latent trajectory (ALT) modelling was applied. Results: Participants practiced formal exercises on 57% (SD = 0.22, range 0–1) of the days during MBCT, equivalent to an average of 4 days per week, which showed a rapid decline after MBCT. The level of depressive symptoms did not change over the full study period. A small positive association was found between formal home practice frequency during each three-month period on subsequent depressive symptoms, but sensitivity analyses did not confirm this. More robust, a small negative association was found between levels of depressive symptoms at each measurement point and formal home practice frequency during the subsequent three-month periods. Conclusions: The hypothesis that more frequent home practice would lead to reductions in depressive symptoms was not confirmed in the current study. Rather, it seems that patients with higher levels of depression may subsequently practice less frequently at home. The interplay between home practice and outcome might not be as straightforward as expected. However, these results are preliminary and should be replicated first before recommendations for clinical practice can be formulated. [ABSTRACT FROM AUTHOR]

Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed "Fab-arm exchange" in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4- mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severemyasthenicmuscleweakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects onMuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders. [ABSTRACT FROM AUTHOR]

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Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Gaining knowledge of dynamic processes of mechanisms underlying mindfulness-based cognitive therapy (MBCT) for recurrent depression could help to improve treatment efficacy. The current study examined the overall course and week-to-week associations of mindfulness and positive/negative affect during MBCT for recurrent depression. Methods: Using data from the MOMENT study, 235 patients with recurrent depression in (partial) remission allocated to MBCT were included. Prior to each MBCT session, self-reports were obtained on mindfulness, positive affect, and negative affect. Results: Autoregressive latent trajectory (ALT) modeling revealed that, across the MBCT course, larger increases in mindfulness were associated with larger increases in positive affect (r =.80, p <.050). Higher general levels of negative affect were associated with smaller increases in mindfulness over time (r = −.26, p <.001). Week-to-week effects showed no reciprocal cross-lagged effects between mindfulness and positive affect or negative affect, except for positive affect at session 2 which was positively associated with mindfulness at session 3 (r =.11, p <.050). Conclusions: The current study supports a positive association in strength of increase between mindfulness and positive affect, while higher general levels of negative affect might be associated with smaller increases of mindfulness during MBCT for recurrent depression. For future research, experience sampling methods (ESMs) are recommended to capture dynamics on a smaller time scale. ALT modeling techniques are advised to be better able to interpret the processes of stability and change during MBCT for recurrent depression. [ABSTRACT FROM AUTHOR]

Reporter proteins have become an indispensable tool in biomedical research. However, exogenous introduction of these reporters into mice poses a risk of rejection by the immune system. Here, we describe the generation, validation and application of a multiple reporter protein tolerant 'Tol' mouse model that constitutively expresses an assembly of shuffled reporter proteins from a single open reading frame. We demonstrate that expression of the Tol transgene results in the deletion of CD8+ T cells specific for a model epitope, and substantially improves engraftment of reporter-gene transduced T cells. The Tol strain provides a valuable mouse model for cell transfer and viral-mediated gene transfer studies, and serves as a methodological example for the generation of poly-tolerant mouse strains. Bresser and Dijkgraaf et al. develop the 'Tol' strain, a genetically modified mouse model that expresses a range of shuffled reporter and modifier proteins from a single open reading frame. This strain is immunologically tolerant to these reporter and modifier proteins, providing a valuable model system for cell transfer studies and virus-mediated gene transfer studies. [ABSTRACT FROM AUTHOR]

Genetically engineered mouse models (GEMMs) of cancer have proven to be of great value for basic and translational research. Although CRISPR‐based gene disruption offers a fast‐track approach for perturbing gene function and circumvents certain limitations of standard GEMM development, it does not provide a flexible platform for recapitulating clinically relevant missense mutations in vivo. To this end, we generated knock‐in mice with Cre‐conditional expression of a cytidine base editor and tested their utility for precise somatic engineering of missense mutations in key cancer drivers. Upon intraductal delivery of sgRNA‐encoding vectors, we could install point mutations with high efficiency in one or multiple endogenous genes in situ and assess the effect of defined allelic variants on mammary tumorigenesis. While the system also produces bystander insertions and deletions that can stochastically be selected for when targeting a tumor suppressor gene, we could effectively recapitulate oncogenic nonsense mutations. We successfully applied this system in a model of triple‐negative breast cancer, providing the proof of concept for extending this flexible somatic base editing platform to other tissues and tumor types. Synopsis: Most human cancers, including breast cancer, are predominantly characterized by missense mutations in driver genes. This study describes a genetically engineered mouse model, in which conditional expression of the BE3 cytidine base editor in the adult mammary gland permits installation of missense or nonsense mutations at one or multiple genomic loci. Introduction of point mutations in endogeneous genes by CRISPR‐Cas9‐mediated base editing allows for assessment of their contribution to mammary tumor formation.Rapid somatic engineering of allelic series of oncogenic missense mutations determines the relative effect size of each genetic perturbation.Biallelic inactivation of endogenous tumor suppressor genes by base editing, although bystander indels are also observed.Simultaneous base editing at multiple genomic loci using arrayed sgRNA vectors. [ABSTRACT FROM AUTHOR]

The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Using haploid genetic screens we identify the SREBP Regulating Gene (SPRING/C12ORF49) as a determinant of the SREBP pathway. SPRING is a glycosylated Golgiresident membrane protein and its ablation in Hap1 cells, Hepa1-6 hepatoma cells, and primary murine hepatocytes reduces SREBP signaling. In mice, Spring deletion is embryonic lethal yet silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, attenuated SREBP signaling in SPRINGKO cells results from reduced SREBP cleavage-activating protein (SCAP) and its mislocalization to the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling and function. Moreover, in line with the role of SREBP in tumor growth, a wide range of tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized modulator of SREBP signaling. [ABSTRACT FROM AUTHOR]