MTP-GO: Graph-Based Probabilistic Multi-Agent Trajectory Prediction with Neural ODEs

Enabling resilient autonomous motion planning requires robust predictions of surrounding road users' future behavior. In response to this need and the associated challenges, we introduce our model titled MTP-GO. The model encodes the scene using temporal graph neural networks to produce the inputs to an underlying motion model. The motion model is implemented using neural ordinary differential equations where the state-transition functions are learned with the rest of the model. Multimodal probabilistic predictions are obtained by combining the concept of mixture density networks and Kalman filtering. The results illustrate the predictive capabilities of the proposed model across various data sets, outperforming several state-of-the-art methods on a number of metrics.Comment: Code: https://github.com/westny/mtp-g

Evaluation of Differentially Constrained Motion Models for Graph-Based Trajectory Prediction

Given their adaptability and encouraging performance, deep-learning models are becoming standard for motion prediction in autonomous driving. However, with great flexibility comes a lack of interpretability and possible violations of physical constraints. Accompanying these data-driven methods with differentially-constrained motion models to provide physically feasible trajectories is a promising future direction. The foundation for this work is a previously introduced graph-neural-network-based model, MTP-GO. The neural network learns to compute the inputs to an underlying motion model to provide physically feasible trajectories. This research investigates the performance of various motion models in combination with numerical solvers for the prediction task. The study shows that simpler models, such as low-order integrator models, are preferred over more complex ones, e.g., kinematic models, to achieve accurate predictions. Further, the numerical solver can have a substantial impact on performance, advising against commonly used first-order methods like Euler forward. Instead, a second-order method like Heun's can significantly improve predictions.Comment: https://github.com/westny/mtp-g

Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial

INTRODUCTION:More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.METHODS:A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.RESULTS:Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred.DISCUSSION:Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS.

A Time Projection Chamber with GEM-Based Readout

For the International Large Detector concept at the planned International Linear Collider, the use of time projection chambers (TPC) with micro-pattern gas detector readout as the main tracking detector is investigated. In this paper, results from a prototype TPC, placed in a 1 T solenoidal field and read out with three independent GEM-based readout modules, are reported. The TPC was exposed to a 6 GeV electron beam at the DESY II synchrotron. The efficiency for reconstructing hits, the measurement of the drift velocity, the space point resolution and the control of field inhomogeneities are presented.Comment: 22 pages, 19 figure

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD

CRISPR interference to evaluate modifiers of C9ORF72-mediated toxicity in FTD

Treatments for neurodegenerative disease, including Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS), remain rather limited, underscoring the need for greater mechanistic insight and disease-relevant models. Our ability to develop novel disease models of genetic risk factors, disease modifiers, and other FTD/ALS-relevant targets is impeded by the significant amount of time and capital required to develop conventional knockout and transgenic mice. To overcome these limitations, we have generated a novel CRISPRi interference (CRISPRi) knockin mouse. CRISPRi uses a catalytically dead form of Cas9, fused to a transcriptional repressor to knockdown protein expression, following the introduction of single guide RNA against the gene of interest. To validate the utility of this model we have selected the TAR DNA binding protein (TDP-43) splicing target, stathmin-2 (STMN2). STMN2 RNA is downregulated in FTD/ALS due to loss of TDP-43 activity and STMN2 loss is suggested to play a role in ALS pathogenesis. The involvement of STMN2 loss of function in FTD has yet to be determined. We find that STMN2 protein levels in familial FTD cases are significantly reduced compared to controls, supporting that STMN2 depletion may be involved in the pathogenesis of FTD. Here, we provide proof-of-concept that we can simultaneously knock down Stmn2 and express the expanded repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene, successfully replicating features of C9-associated pathology. Of interest, depletion of Stmn2 had no effect on expression or deposition of dipeptide repeat proteins (DPRs), but significantly decreased the number of phosphorylated Tdp-43 (pTdp-43) inclusions. We submit that our novel CRISPRi mouse provides a versatile and rapid method to silence gene expression in vivo and propose this model will be useful to understand gene function in isolation or in the context of other neurodegenerative disease models

Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria

Funding Information: The authors thank the individuals who participated in this study and whose contributions made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK Biobank Resource under application numbers 24711 and 24898. Publisher Copyright: © 2023, The Author(s).Urticaria is a skin disorder characterized by outbreaks of raised pruritic wheals. In order to identify sequence variants associated with urticaria, we performed a meta-analysis of genome-wide association studies for urticaria with a total of 40,694 cases and 1,230,001 controls from Iceland, the UK, Finland, and Japan. We also performed transcriptome- and proteome-wide analyses in Iceland and the UK. We found nine sequence variants at nine loci associating with urticaria. The variants are at genes participating in type 2 immune responses and/or mast cell biology (CBLB, FCER1A, GCSAML, STAT6, TPSD1, ZFPM1), the innate immunity (C4), and NF-κB signaling. The most significant association was observed for the splice-donor variant rs56043070[A] (hg38: chr1:247556467) in GCSAML (MAF = 6.6%, OR = 1.24 (95%CI: 1.20–1.28), P-value = 3.6 × 10-44). We assessed the effects of the variants on transcripts, and levels of proteins relevant to urticaria pathophysiology. Our results emphasize the role of type 2 immune response and mast cell activation in the pathogenesis of urticaria. Our findings may point to an IgE-independent urticaria pathway that could help address unmet clinical need.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Förbättrat lärande i utredningsmetodik

Syftet med detta pedagogiska utvecklingsprojekt var att öka förståelsen för hur vi i undervisningen kan stötta studenternas lärande i utredningsmetodik. Efter att inledningsvis studerat litteratur om utredningsmetodik, interv-juades representanter för olika avdelningar på LiU, där studenterna arbe-tar med utredningsprojekt som ligger inom ramen för ovanstående be-skrivning. Intervjuer på 45-90 minuter genomfördes med representanter för sju avdelningar, från tre av LiUs institutioner. En specificering av res-pondenterna finns i bilaga 1. Intervjuerna spelades in med respondenter-nas samtycke. Utifrån intervjuerna valdes en kurs ut som case för djupare studier. Denna kurs följdes under projektets gång genom diskussioner med exami-nator och andra involverade lärare, samt genom enkäter riktade till kurs-deltagarna. Upplevda problem med kursen identifierades, förändringar genomfördes och följdes upp under två kursgenomföranden