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Guest blog by Dr Kathrin Meyer, Secretary General of the International Holocaust Remembrance Alliance, and Dr Karel Berkhoff, Co-Director at the European Holocaust Research Infrastructure

The Pilot Lab Exascale Earth System Modelling (PL-ExaESM) is a “Helmholtz-Inkubator Information & Data Science” project and explores specific concepts to enable exascale readiness of Earth System models and associated work flows in Earth System science. PL-ExaESM provides a new platform for scientists of the Helmholtz Association to develop scientific and technological concepts for future generation Earth System models and data analysis systems.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible disease-modifying gene. The complex interplay between the EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated and includes a putative pro-apoptotic activity of the unbound receptor compared to ephrin-bound receptor. We recently reported that astrocytes from patients with ALS induce cell death in co-cultured MNs. Here we found that first-generation synthetic EphA4 agonistic agent 123C4, effectively protected MNs when co-cultured with reactive astrocytes from patients with ALS from multiple subgroups (sALS and mutant SOD1). Newer generation and more potent EphA4 agonistic agents 150D4, 150E8, and 150E7 provided effective protection at a lower therapeutic dose. Combined, the data suggest that the development of EphA4 agonistic agents provides potentially a promising therapeutic strategy for patients with ALS.

Guest blog by Dr Kathrin Meyer, Secretary General of the International Holocaust Remembrance Alliance, and Dr Karel Berkhoff, Co-Director at the European Holocaust Research Infrastructure

In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Together with preliminary in vivo pharmacology studies, the data form a strong foundation for the translation of these agents for the treatment of ALS and potentially other human diseases.

In human-robot collaborative interaction scenarios, nonverbal communication plays an important role. Both, signals sent by a human collaborator need to be identified and interpreted by the robotic system, and the signals sent by the robot need to be identified and interpreted by the human. In this paper, we focus on the latter. We implemented on an industrial robot in a VR environment nonverbal behavior signalling the user that it is now their turn to proceed with a pick-and-place task. The signals were presented in four different test conditions: no signal, robot arm gesture, light signal, combination of robot arm gesture and light signal. Test conditions were presented to the participants in two rounds. The qualitative analysis was conducted with focus on (i) potential signals in human behaviour indicating why some participants immediately took over from the robot whereas others needed more time to explore, (ii) human reactions after the nonverbal signal of the robot, and (iii) whether participants showed different behaviours in the different test conditions. We could not identify potential signals why some participants were immediately successful and others not. There was a bandwidth of behaviors after the robot stopped working, e.g. participants rearranged the objects, looked at the robot or the object, or gestured the robot to proceed. We found evidence that robot deictic gestures were helpful for the human to correctly interpret what to do next. Moreover, there was a strong tendency that humans interpreted the light signal projected on the robot's gripper as a request to give the object in focus to the robot. Whereas a robot's pointing gesture at the object was a strong trigger for the humans to look at the object., Comment: 6 pages, 5 figures, 2 tables, HRI21 Workshop on "Exploring Applications for Autonomous Non-Verbal Human-Robot Interactions" March 8 2021

With increased applications of collaborative robots (cobots) in industrial workplaces, behavioural effects of human-cobot interactions need to be further investigated. This is of particular importance as nonverbal behaviours of collaboration partners in human-robot teams significantly influence the experience of the human interaction partners and the success of the collaborative task. During the Ars Electronica 2020 Festival for Art, Technology and Society (Linz, Austria), we invited visitors to exploratively interact with an industrial robot, exhibiting restricted interaction capabilities: extending and retracting its arm, depending on the movements of the volunteer. The movements of the arm were pre-programmed and telecontrolled for safety reasons (which was not obvious to the participants). We recorded video data of these interactions and investigated general nonverbal behaviours of the humans interacting with the robot, as well as nonverbal behaviours of people in the audience. Our results showed that people were more interested in exploring the robot's action and perception capabilities than just reproducing the interaction game as introduced by the instructors. We also found that the majority of participants interacting with the robot approached it up to a distance which would be perceived as threatening or intimidating, if it were a human interaction partner. Regarding bystanders, we found examples where people made movements as if trying out variants of the current participant's behaviour., Comment: 5 pager, 2 pictures, HRI21 Workshop on "Exploring Applications for Autonomous Non-Verbal Human-Robot Interactions" March 8 2021

Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration, paralysis, and death. Accurate disease modeling, identifying disease mechanisms, and developing therapeutics is urgently needed. We previously reported motor neuron toxicity through postmortem ALS spinal cord-derived astrocytes. However, these cells can only be harvested after death, and their expansion is limited. We now report a rapid, highly reproducible method to convert adult human fibroblasts from living ALS patients to induced neuronal progenitor cells and subsequent differentiation into astrocytes (i-astrocytes). Non-cell autonomous toxicity to motor neurons is found following coculture of i-astrocytes from familial ALS patients with mutation in superoxide dismutase or hexanucleotide expansion in C9orf72 (ORF 72 on chromosome 9) the two most frequent causes of ALS. Remarkably, i-astrocytes from sporadic ALS patients are as toxic as those with causative mutations, suggesting a common mechanism. Easy production and expansion of i-astrocytes now enables rapid disease modeling and high-throughput drug screening to alleviate astrocyte-derived toxicity.

In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilization of exon 7 and the production of functional protein. It has been hypothesized that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here, we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germline transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease

Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.

"From virtual abstraction to appropriated archival images and experiments with narrative structure, this international group of artists moves beyond creating easily consumed and didactic depictions. Together their works raise questions, asking how we can find new ways to say ‘no’ and form suggestions for alternatives, both politically and aesthetically." -- Publisher's website.

"From virtual abstraction to appropriated archival images and experiments with narrative structure, this international group of artists moves beyond creating easily consumed and didactic depictions. Together their works raise questions, asking how we can find new ways to say ‘no’ and form suggestions for alternatives, both politically and aesthetically." -- Publisher's website.

Hemochromatosis type 2 gene (HFE2) is highly expressed in skeletal muscle and liver hepatocytes. Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and enhances the BMP-induced hepcidin expression. Hepcidin is a central iron regulatory hormone predominantly secreted from hepatocytes. HJV also binds neogenin, a membrane protein widely expressed in many tissues. Neogenin is required for the processing and release of HJV from cells. The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a human hepatoma cell line. Knockdown of endogenous neogenin markedly suppresses HJV release, but has no evident effect on HJV trafficking to the plasma membrane. Addition of a soluble neogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the cell surface. At the plasma membrane it undergoes endocytosis in a dynamin-independent but cholesterol-dependent manner. The additional findings that HJV release is coupled to lysosomal degradation of neogenin, that HJV undergoes endocytosis, and that cholesterol depletion by filipin blocks both HJV endocytosis and HJV release, suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface.

Hemochromatosis type 2 gene (HFE2) is highly expressed in skeletal muscle and liver hepatocytes. Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and enhances the BMP-induced hepcidin expression. Hepcidin is a central iron regulatory hormone predominantly secreted from hepatocytes. HJV also binds neogenin, a membrane protein widely expressed in many tissues. Neogenin is required for the processing and release of HJV from cells. The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a human hepatoma cell line. Knockdown of endogenous neogenin markedly suppresses HJV release, but has no evident effect on HJV trafficking to the plasma membrane. Addition of a soluble neogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the cell surface. At the plasma membrane it undergoes endocytosis in a dynamin-independent but cholesterol-dependent manner. The additional findings that HJV release is coupled to lysosomal degradation of neogenin, that HJV undergoes endocytosis, and that cholesterol depletion by filipin blocks both HJV endocytosis and HJV release, suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface.

In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilization of exon 7 and the production of functional protein. It has been hypothesized that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here, we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germline transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease