Structural magnetic resonance imaging in amyotrophic lateral sclerosis: cortical morphometry, diffusion properties and lesion detection as potential biomarkers for the state and progression of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the motor system of the central nervous system. The aim of this thesis is to evaluate the potential of structural magnetic resonance imaging (MRI) biomarkers of the brain grey matter (GM) and white matter (WM) for the state and progression of ALS. The thesis has been conducted on behalf of a treatment program on a named patient basis at the University Hospital of Regensburg. 31 patients with written informed consent are compared to a control sample of 34 age-matched healthy participants. Routine MRI scans have been conducted approximately every 3 months and include T1-weighted imaging, diffusion weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) sequences at 1.5 Tesla. The subprojects of the thesis investigate precentral and postcentral cortical thinning (study 1), spread of alterations of fractional anisotropy (FA) across different WM types (study 2), and FLAIR lesion detection (study 3) in the same ALS cohort. Candidate MRI biomarkers are associated with neurophysiological and clinical biomarkers. Statistical analysis includes both cross-sectional and longitudinal analyses. Special focus is set on the individual patient. Cortical thinning is more pronounced in the precentral cortex than in the postcentral cortex. Combinatory biomarker use reveals evident differences in temporal dynamics of cortical thickness, clinical and neurophysiological biomarkers over time. Reduction of FA is consistently detected in the corticospinal tract (CST) and extra motor WM and most pronounced in the brainstem. Spread of FA alterations resembles both dying-forward and dying-back disease propagation and is not linked to patients’ clinical or demographic characteristics. WM lesions as detected by FLAIR hyperintensity are more frequent in ALS patients than in controls, most pronounced in the CST, and associated with an inferior survival. Together, the findings of this thesis suggest that MRI biomarkers may contribute to the diagnosis, prognosis and understanding of ALS disease and disease courses on an individual scope

IAP Studie 2022 − Der Mensch in der Arbeitswelt 4.0 : Lernen in der Arbeitswelt 4.0

Weitere Informationen und ein Factsheet verfügbar unter: https://www.zhaw.ch/de/psychologie/institute/iap/iap-studie/#c193677Die IAP Studie 2022 stellt das Lernen in den Mittelpunkt und befasst sich damit, wie sich Lernen in der Arbeitswelt 4.0 verändert und welche Lernansätze die aktuellen Bedürfnisse der Organisationen und deren Mitarbeitenden am besten adressieren. Die Studie geht den Fragen nach: Wann, wo und wie wir heute sowie in Zukunft lernen? Welche Voraussetzungen sind für das Lernen in Organisationen hilfreich? Welche Rolle nehmen dabei das HR, Personalentwicklung und die Führung ein? Die IAP Studie 2022 umfasst eine quantitative Online-Umfrage und qualitative, strukturierte Interviews mit Führungspersonen und Fachpersonen aus HR und Personalentwicklung aus Unternehmen in der Schweiz

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis

This document is the Accepted Manuscript version of the following article: Riessland et al., 'Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis', The American Journal of Human Genetics, Vol. 100 (2): 297-315, first published online 26 January 2017. The final, published version is available online at doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.005 © 2017 American Society of Human Genetics.Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.Peer reviewedFinal Accepted Versio

Fiber Mediated Receptor Masking in Non-Infected Bystander Cells Restricts Adenovirus Cell Killing Effect but Promotes Adenovirus Host Co-Existence

The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Visual-vestibular processing in the human Sylvian fissure

Unlike other sensory systems, the cortical organization of the human vestibular system is not well established. A central role is assumed for the region of the posterior Sylvian fissure, close to the posterior insula. At this site, activation during vestibular stimulation has been observed in previous imaging studies and labeled as the parieto-insular vestibular cortex area (PIVC). However, vestibular responses are found in other parts of the Sylvian fissure as well, including a region that is referred to as the posterior insular cortex (PIC). The anatomical and functional relationship between PIC and PIVC is still poorly understood, because both areas have never been compared in the same participants. Therefore, to better understand the apparently more complex organization of vestibular cortex in the Sylvian fissure, we employed caloric and visual object motion stimuli during functional magnetic resonance imaging and compared location and function of PIVC and PIC in the same participants. Both regions responded to caloric vestibular stimulation, but only the activation pattern in right PIVC reliably represented the direction of the caloric stimulus. Conversely, activity in PIVC was suppressed during stimulation with visual object motion, whereas PIC showed activation. Area PIC is located at a more posterior site in the Sylvian fissure than PIVC. Our results suggest that PIVC and PIC should be considered separate areas in the vestibular Sylvian network, both in terms of location and function

Initiation of Dopaminergic Differentiation of Nurr1^- Mesencephalic Precursor Cells Depends on Activation of Multiple Mitogen-Activated Protein Kinase Pathways

Interleukin-1 (IL-1) plays a pivotal role in terminal dopaminergic differentiation of midbrain-derived neural precursor cells already committed to the mesencephalic dopaminergic phenotype (named mdNPCs for mesencephalic dopaminergic neural precursor cells). Here we characterized the molecular events in long-term expanded rat nuclear receptor related-1^- (Nurr1^-) mdNPCs in response to IL-1β during their terminal dopaminergic specification. We showed that IL-1β induced a rapid induction of mRNA of dopaminergic key fate-determining transcription factors, such as Nurr1 and Pitx3, and a subsequent increase of tyrosine hydroxylase protein as an early marker for dopaminergic neurons in vitro. These effects of IL-1β were specific for mdNPCs and were not observed in striatal neural precursor cells (NPCs). Surprisingly, IL-1β did not activate the NF-κB pathway or the transcription factor activating protein 1 (AP-1), but inhibition of nuclear translocation of NF-κB by SN50 facilitated IL-1β-induced Nurr1 expression and dopaminergic differentiation of mdNPCs. Incubation of mdNPCs with IL-1β led to a rapid phosphorylation of ERK1/2 and p38 mitogen-activated protein (MAP) kinases within 1 to 3 hours, whereas Jun kinase was not phosphorylated in response to IL-1β. Consistently, inhibition of the ERK1/2 pathway or p38 MAP kinase blocked Nurr1 upregulation and further dopaminergic specification of mdNPCs, but not differentiation into MAP2ab^+ neurons. IL-1 receptor antagonist did not block early dopaminergic differentiation events, suggesting that the effects of IL-1β are not mediated through activation of IL-1 receptor type I. Our results indicate that induction of terminal dopaminergic specification of Nurr1^- mdNPCs by IL-1β depends on activation of the ERK1/2 and p38 MAP kinase pathway

Is the near-spherical shape the "new black" for smoke?

We examine the capability of near-sphericalshaped particles to reproduce the triple-wavelength particle linear depolarization ratio (PLDR) and lidar ratio (LR) values measured over Europe for stratospheric smoke originating from Canadian wildfires. The smoke layers were detected both in the troposphere and the stratosphere, though in the latter case the particles presented PLDR values of almost 18% at 532 nm as well as a strong spectral dependence from the UV to the near-IR wavelength. Although recent simulation studies of rather complicated smoke particle morphologies have shown that heavily coated smoke aggregates can produce large PLDR, herein we propose a much simpler model of compact near-spherical smoke particles. This assumption allows for the reproduction of the observed intensive optical properties of stratospheric smoke, as well as their spectral dependence. We further examine whether an extension of the current Aerosol Robotic Network (AERONET) scattering model to include the near-spherical shapes could be of benefit to the AERONET retrieval for stratospheric smoke cases associated with enhanced PLDR. Results of our study illustrate the fact that triple-wavelength PLDR and LR lidar measurements can provide us with additional insight when it comes to particle characterization. © 2020 Author(s)