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Case report on severe myelin oligodendrocyte glycoprotein antibody-associated disease relapse after ectopic pregnancy and laparoscopic medical abortion: relevance of peripheral inflammation for demyelinating disease activity.
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare neurological condition. Tubal ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Regular pregnancy has a disease-modifying effect on MOGAD, with an increased relapse rate postpartum. Still, there are neither case reports nor cohort studies on abortions and ectopic pregnancy as a disease-modifying event for MOGAD. MATERIALS AND METHODS: This is a case report on a severe MOGAD relapse after ectopic pregnancy and laparoscopic abortion. DISCUSSION: For the first time we described that elevated interleukin-1 (IL-1), which was found in cerebrospinal fluid in the current case may be pathogenetically related to ectopic pregnancy. Rituximab (anti-CD20 treatment), downregulated IL-1 and TNF-alfa inflammatory pathways thus is an appropriate drug of choice to treat relapse. Cytokines secreted during ectopic pregnancy could play a disease-modifying role in multiple sclerosis and Guillian-Barré syndrome. CONCLUSION: The first case report of a MOGAD severe relapse after ectopic pregnancy and laparoscopic abortion which resolved with rituximab treatment.
Control of replication and gene expression by ADP-ribosylation of DNA in Mycobacterium tuberculosis.
Mycobacterium tuberculosis maintains long-term infections characterised by the need to regulate growth and adapt to contrasting in vivo environments. Here we show that M. tuberculosis complex bacteria utilise reversible ADP-ribosylation of single-stranded DNA as a mechanism to coordinate stationary phase growth with transcriptional adaptation. The DNA modification is controlled by DarT, an ADP-ribosyltransferase, which adds ADP-ribose to thymidine, and DarG, which enzymatically removes this base modification. Using darG-knockdown M. bovis BCG, we map the first DNA ADP-ribosylome from any organism. We show that inhibition of replication by DarT is reversible and accompanied by extensive ADP-ribosylation at the origin of replication (OriC). In addition, we observe ADP-ribosylation across the genome and demonstrate that ADP-ribose-thymidine alters the transcriptional activity of M. tuberculosis RNA polymerase. Furthermore, we demonstrate that during stationary phase, DarT-dependent ADP-ribosylation of M. tuberculosis DNA is required to optimally induce expression of the Zur regulon, including the ESX-3 secretion system and multiple alternative ribosome proteins. Thus, ADP-ribosylation of DNA can provide a mechanistic link through every aspect of DNA biology from replication to transcription to translation.
ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis
RNA binding proteins (RBP) of the ZFP36 family limit the differentiation and effector functions of CD4 and CD8 T cells, but little is known of their expression or function in regulatory T (Treg) cells. By using Treg cell-restricted deletion of Zfp36 family members we identify the role of Zfp36l1 and Zfp36l2 in Treg cells to maintain immune homeostasis. Mice with Treg cells deficient in these RBP display an inflammatory phenotype with an expansion in the numbers of type-2 conventional dendritic cells, T effector cells, T follicular helper and germinal center B cells and elevated serum cytokines and immunoglobulins. In the absence of Zfp36l1 and Zfp36l2, the pool of cycling CTLA-4 in naïve Treg cells is reduced, Treg cells are less sensitive to IL-2 and IL-7 but are more sensitive to IFNγ. In mice lacking both RBP in Treg cells, the deletion of a single allele of Ifng is sufficient to ameliorate the pathology. Our results indicate that ZFP36L1 and ZFP36L2 regulate the availability of IFNγ and are required for the maintenance of Treg cell stability. Thus, ZFP36L1 and ZFP36L2 regulate multiple pathways that enable Treg cells to enforce immune homeostasis.
RELIGION AND THE SUSCEPTIBILITY TO FALSE BELIEFS
Religion has played a particularly important role in human evolution. It is the one trait that categorically distinguishes us from other animals. Yet it is about belief in a world that does not exist - the spirit world. I shall argue that it arises through two very ancient psychological predispositions. A tendency for the magical to have priority when we cannot see an obvious explanation and a strong tendency to be attracted to charismatic leaders. The first is a derivative of our advanced mentalising capacities, which allow us to imagine worlds that do not exist. The second is seems to be associated with the fact that networks that evolve leaders work more efficiently. Both of these played a central role in our evolution as a species.
Low-Rank Conjugate Gradient-Net for Accelerated Cardiac MR Imaging
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide. Both diagnosis and prognosis of these diseases benefit from high-quality imaging, which cardiac magnetic resonance imaging provides. CMR imaging requires lengthy acquisition times and multiple breath-holds for a complete exam, which can lead to patient discomfort and frequently results in image artifacts. In this work, we present a Low-rank tensor U-Net method (LowRank-CGNet) that rapidly reconstructs highly undersampled data with a variety of anatomy, contrast, and undersampling artifacts. The model uses conjugate gradient data consistency to solve for the spatial and temporal bases and employs a U-Net to further regularize the basis vectors. Currently, model performance is superior to a standard U-Net, but inferior to conventional compressed sensing methods. In the future, we aim to further improve model performance by increasing the U-Net size, extending the training duration, and dynamically updating the tensor rank for different anatomies.
The profile of gastrointestinal dysfunction in prodromal to late-stage Parkinson's disease.
Gastrointestinal dysfunction (GID) may play a key role in Parkinson's disease (PD) but its relationship with disease progression remains unclear. We recruited 404 PD cases, 37 iRBD (isolated REM Sleep Behaviour Disorder) and 105 controls. Participants completed the Gastrointestinal Dysfunction Scale for PD (GIDS-PD) and standardised disease severity assessments. Whole gut transit time (WGTT) was measured by ingestion of blue dye and recorded time to blue stools appearance ('Blue Poop Challenge') in a subset of PD cases. Gastrointestinal symptoms were more common and prevalent in iRBD and PD versus controls, and WGTT was significantly higher in PD versus controls. After adjustment for confounding factors, disease stage was not a significant predictor of GIDS-PD Constipation or Bowel Irritability scores. Longitudinal assessment of GIDS-PD scores and WGTT confirmed stability over a 4 year period. Bowel dysfunction may be a phenotypic feature in a subset of Parkinson's with implications for patient stratification and management.
GPCR signaling via cAMP nanodomains.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, mediating essential physiological responses through diverse intracellular signaling pathways. When coupled to Gs or Gi proteins, GPCR modulates the synthesis of 3'-5'-cyclic adenosine monophosphate (cAMP), which governs a wide array of processes, ranging from cellular growth and survival to metabolic regulation. Studies have highlighted that cAMP is not uniformly distributed within cells but instead is compartmentalized into highly localized nanodomains. These nanodomains, mostly regulated by phosphodiesterases (PDEs), play a critical role in enabling signal precision and functional effects that are specific to individual stimuli. GPCRs can initiate distinct cAMP responses based on their localization within the cell, with evidence showing that both receptors resident at the plasma membrane and intracellular receptors-including endosomal, Golgi, and nuclear GPCRs-elicit unique cAMP signaling profiles. This review examines the mechanisms underlying GPCR signaling through cAMP nanodomains. We focus on the role of PDE-mediated cAMP degradation in shaping local cAMP signals, the emerging views on mechanisms that may contribute to signal compartmentalization, and the role of intracellular membrane compartments. By exploring these aspects, we aim to highlight the complexity of GPCR signaling networks and illustrate some of the implications for the regulation of cellular function.
Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.
We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.
Machine learning-based prediction of anxiety disorders using blood metabolite and social trait data from the UK Biobank
Anxiety disorders are the most prevalent type of mental health disorders and are characterised by excessive fear and worry. Despite affecting one in four individuals within their lifetime, there remains a gap in our understanding regarding the underlying pathophysiology of anxiety disorders, which limits the development of novel treatment options. Exploring blood-based biomarkers of anxiety disorder offers the potential to predict the risk of clinically significant anxiety in the general population, increase our understanding of anxiety pathophysiology, and to reveal options for preventative treatment. Here, using psychosocial variables in combination with blood and urine biomarkers, reported in the UK Biobank, we sought to predict future anxiety onset. Machine learning accurately predicted (ROC AUC: ∼0.83) ICD-10-coded anxiety diagnoses up to 5 years (mean 3.5 years) after blood sampling, against lifetime anxiety-free controls. Analysis of the blood biochemistry measures indicated that anxious individuals were more anaemic and exhibited higher levels of markers of systemic inflammation than controls. However, blood biomarkers alone were not predictive of resilience or susceptibility to anxiety disorders in a subset of individuals rigorously matched for a wide range of psychosocial covariates (ROC AUC: ∼0.50). Overall, we demonstrate that the integration of biological and psychosocial risk factors is an effective tool to screen for and predict anxiety disorder onset in the general population.
Contributed Talks I: The role of fixational drift in the Vernier task.
We develop a simple one-dimensional continuum model of the Vernier discrimination task to study the impact of Gaussian blur, fixational drift, receptor noise, and retinal adaptation on an ideal observer's Vernier performance. Two rectangular stimuli with a prescribed width and relative offset are subjected to a Gaussian blur. Fixational drift shifts the resulting signal with time. The perceived signal is the weighted average over the history of local stimulation encoded by an adaptation kernel. We model this kernel as a difference of two exponentials, introducing two timescales describing initial integration and eventual recovery of a receptor. Ultimately, Gaussian white noise is added to capture random receptor fluctuations. Based on the Bayesian estimation of location and relative offset of both stimuli, we can study Vernier performance through numerical simulation as well as through analytical approximation for different eye movements. Analyzing diffusive motion in particular, we extract the diffusion constant that optimizes stimulus localization for long observation times. This optimal diffusion constant is inversely proportional to an average of the two timescales describing adaptation and proportional to the square of the larger of stimulus size or blurring width, giving rise to two separate regimes. We generalize our analysis to optimize discrimination and extend the class of eye motions considered beyond purely diffusive drift, e.g. with the inclusion of persistence.
Uncertainty mapping and probabilistic tractography using Simulation-based Inference in diffusion MRI: A comparison with classical Bayes.
Simulation-Based Inference (SBI) has recently emerged as a powerful framework for Bayesian inference: Neural networks are trained on simulations from a forward model, and learn to rapidly estimate posterior distributions. We here present an SBI framework for parametric spherical deconvolution of diffusion MRI data of the brain. We demonstrate its utility for estimating white matter fibre orientations, mapping uncertainty of voxel-based estimates and performing probabilistic tractography by spatially propagating fibre orientation uncertainty. We conduct an extensive comparison against established Bayesian methods based on Markov-Chain Monte-Carlo (MCMC) and find that: a) in-silico training can lead to calibrated SBI networks with accurate parameter estimates and uncertainty mapping for both single- and multi-shell diffusion MRI, b) SBI allows amortised inference of the posterior distribution of model parameters given unseen observations, which is orders of magnitude faster than MCMC, c) SBI-based tractography yields reconstructions that have a high level of agreement with their MCMC-based counterparts, equal to or higher than scan-rescan reproducibility of estimates. We further demonstrate how SBI design considerations (such as dealing with noise, defining priors and handling model selection) can affect performance, allowing us to identify optimal practices. Taken together, our results show that SBI provides a powerful alternative to classical Bayesian inference approaches for fast and accurate model estimation and uncertainty mapping in MRI.
Thalamic deep brain stimulation for central poststroke pain syndrome: an international multicenter study.
OBJECTIVE: The effectiveness and optimal stimulation site of deep brain stimulation (DBS) for central poststroke pain (CPSP) remain elusive. The objective of this retrospective international multicenter study was to assess clinical as well as neuroimaging-based predictors of long-term outcomes after DBS for CPSP. METHODS: The authors analyzed patient-based clinical and neuroimaging data of previously published and unpublished cohorts from 6 international DBS centers. DBS leads were reconstructed and normalized. A stimulation map was constructed on the basis of individual stimulation settings and associated outcomes. Furthermore, the authors projected the individual segmented stroke lesions and volumes of tissue activated (VTAs) of the stimulating electrode onto a normalized human connectome to obtain the connectivity profiles of the individual lesions and VTAs. RESULTS: The authors analyzed the data of 54 patients, of whom 15 were excluded from the final analysis due to a lack of imaging data. Among the remaining 39 patients from 6 different cohorts, the authors found 14 (35.9%) responders who were defined by pain relief of at least 50% at 12-month follow-up. Stimulation mapping identified areas in the posterior limb of the internal capsule, the sensorimotor thalamus, and the medial and intralaminar thalamus as effective for pain reduction. Baseline characteristics did not differ between responders and nonresponders. The stimulation sites of the responders showed significantly reduced structural connectivity to the sensory areas of the cerebral cortex compared to nonresponders. CONCLUSIONS: This comprehensive, multicenter analysis corroborates the efficacy of DBS in treating CPSP for a relevant number of patients. The posterior limb of the internal capsule and the sensorimotor thalamus emerged as potential stimulation sweet spots. The difference in structural connectivity between responders and nonresponders may constitute a biomarker of effective stimulation that can help guide surgical planning in future well-designed prospective trials.
1H, 13C and 15N resonance assignments for the acetyltransferase domain of the kinetoplastid kinetochore protein KKT23 from Trypanosoma brucei.
KKT23 is a kinetoplastid-specific kinetochore protein that has a C-terminal GCN5-related histone acetyltransferase domain that acetylates the C-terminal tail of histone H2A. Here, we present the 1H, 13C and 15N resonance assignments for the C-terminal region of KKT23 (KKT23125-348) from Trypanosoma brucei in complex with known cofactors for acetyltransferases, acetyl coenzyme A and coenzyme A. These assignments provide the starting point for detailed investigation of the structure, dynamics and interactions of KKT23 in solution.
Dreaming of Better Treatments: Advances in Drug Development for Sleep Medicine and Chronotherapy.
Throughout history, the development of new sleep medicines has been driven by progress in our understanding of the mechanisms underlying sleep. Ancient civilisations used their understanding of the sedative nature of natural herbs and compounds to induce sleep. The discovery of barbiturates and bromides heralded a new era of synthetic sleep medicine in the 19th century. This was followed by the development of benzodiazepines that were used to inhibit signalling throughout the brain by promoting gamma-amino butyric acid release and thereby produce loss of consciousness. As our understanding of sleep has deepened, newer therapies have more specifically targeted the wake-inducing neurotransmitter orexin with fewer side effects. Given the newly highlighted role of kinases in sleep/wake regulation, we predict that the next breakthroughs in sleep medicine will likely target these kinases. Given the fundamental role that sleep plays in maintaining brain health through processes such as glymphatic clearance, sleep medicine has therapeutic potential beyond just sleep. Recent evidence suggests that sleep disruptions directly contribute to the build-up of pathological neuronal proteins in neurodegenerative disorders. Therefore, sleep medicine could improve prognosis in disorders such as these. Great attention must be paid to the mechanism of action of each sleep medicine, however, as sleep medicines which do not fully mimic sleep could actually worsen disease progression.
Smartphone-based Monitoring and cognition Modification Against Recurrence of Depression (SMARD): An RCT of Memory Bias Modification Training vs. Cognitive Control Training vs. Attention Bias Modification Training in remitted recurrently depressed patients with 1.5 year follow-up.
BACKGROUND: Major Depressive Disorder (MDD) has a 50-80% recurrence rate highlighting the urgent need for more efficient recurrence prevention programs. Currently, recurrences are often identified too late, while existing preventive strategies may not sufficiently address ethio-patho-physiological mechanisms for recurrence. Negative memory bias (the tendency to better remember negative than positive events), negative attention bias (selective attention favoring mood-congruent information), and cognitive control deficits are important factors involved in the onset, maintenance, and recurrence of depressive episodes. METHODS: Here we describe the protocol for the Smartphone-based Monitoring and cognition Modification Against Recurrence of Depression (SMARD) study, aiming to investigate different forms of cognitive training programs administered via smartphones, in order to develop a second-generation recurrence prevention program. In addition, we will gather Experience Sampling Method (ESM) assessments during a 6-day period, and during the follow-up period we will obtain behavioral data on (social) activities with BEHAPP, a smartphone-based Mobile Passive Monitoring application for remote behavioral monitoring to identify behavioral changes indicative of an imminent depressive episode. In a randomized controlled trial, SMARD will compare the effects of a smartphone-based Memory Bias Modification Training (MBT), Cognitive Control Training (CCT), and Attention Bias Modification Training (ABT) versus cognitive domain-specific (active-) sham trainings in 120 remitted MDD-patients with recurrent-MDD. Over the course of three weeks, participants receive multiple daily training sessions. Thereafter, participants will be followed up for 1.5 years with 3-monthly interviews to assess recurrences. DISCUSSION: The SMARD study aims to 1. assess the effects of the cognitive training programs versus their training-specific (active-) sham conditions on changes in memory, cognitive control dysfunction and attention; 2. relate training effects to neural networks previously identified in (recurrence of) MDD (therefore we obtain functional Magnetic Resonance Imaging ((f)MRI) scans before and after the training in a subset of participants); 3. link baseline and change in memory, cognitive control, attention and neural functioning, and ESM data to prospective recurrences; 4. examine whether passive smartphone-use monitoring can be used for prediction of recurrences. TRIAL REGISTRATION: NL-OMON26184 and NL-OMON27513. Registered 12 August 2021-Retrospectively registered, https://onderzoekmetmensen.nl/en/trial/26184 en https://onderzoekmetmensen.nl/en/trial/27513 .
Smelling x as y? On (the impossibility of) multistable perception in the chemical senses.
Multistable percepts are intriguing phenomena whereby an ambiguous sensory input can be perceived in one of several qualitatively different ways. In such cases, people can switch their attention to perceive the stimulus in either way, though they typically cannot maintain both interpretations in awareness simultaneously. The abundance of evidence demonstrating multistable perception in the visual and auditory modalities can be contrasted with the scarcity, if not absence, of studies reporting similar phenomena in the chemical senses (primarily olfaction and gustation), prompting an intriguing question about this apparent qualitative difference between the senses. This paper seeks to address this question by first briefly reviewing multistable perceptual phenomena in vision and audition to underscore their defining features. We then assess the limited body of research that has occasionally linked multistability to the chemical senses. While a few studies suggest loose analogies between olfactory perception and visual or auditory multistability, no compelling evidence exists for such phenomena in taste. We argue that this absence is unlikely to be explained by any single factor. Rather, it appears to stem from a confluence of constraints, including the lack of spatio-temporal structure and intrinsic dimensionality in chemosensory stimuli, as well as their distinct evolutionary functions and cognitive framing. Together, these factors may help to explain why multistable perceptual experiences seem not to emerge in the chemical senses.