Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2

Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast

Assessing the impact of small amounts of water and iron oxides on adhesion in the wheel/rail interface using High Pressure Torsion testing

A new High Pressure Torsion (HPT) set-up has been developed for assessing the effect of third body materials in the wheel/rail interface in a representative and controlled manner. In this study the technique has been used to investigate the effect of small amounts of water and iron oxides mixtures when subjected to different contact pressures. HPT tests showed reduction in adhesion relative to a dry contact when testing with small amounts of water and/or oxides, however sustained low adhesion (μ<0.05) was not produced. To aid interpretation of the results a model has been developed to explore the behavior encountered when testing with water and iron oxide mixtures. The model relates the shear properties of water and oxide mixtures (with increasing solid content) to a predicted adhesion. The model shows a narrow window of water to oxide fraction is required for reduced adhesion, particularly on rough surfaces, and this correlates with the behavior observed

Transcriptomic and proteomic insight into the effects of a defined European mistletoe extract in Ewing sarcoma cells reveals cellular stress responses

Background The hydrophobic triterpenes, oleanolic and betulinic acid as well as the hydrophilic mistletoe lectins and viscotoxins possess anticancer properties. They do all occur in combination in European mistletoe (Viscum album L.). Commercial Viscum album L. extracts are aqueous, excluding the insoluble triterpenes. We have previously shown that mistletoe lectins and triterpene acids are effective against Ewing sarcoma in vitro, ex vivo and in vivo. Methods We recreated a total mistletoe effect (viscumTT) by combining an aqueous extract (viscum) and a triterpene extract (TT) solubilised with cyclodextrins and analysed the effects of viscumTT and the single extracts on TC-71 Ewing sarcoma cells in vitro by transcriptomic and proteomic profiling. Results Treatment with the extracts strongly impacted Ewing sarcoma cell gene and protein expression. Apoptosis-associated and stress-activated genes were upregulated, proteasomal protein abundance enhanced and ribosomal and spliceosomal proteins downregulated. The mechanism of action of viscum, TT and viscumTT in TC-71 and MHH-ES-1 cells suggests the involvement of the unfolded protein response. While viscum and viscumTT extract treatment indicate response to oxidative stress and activation of stress-mediated MAPK signalling, TT extract treatment suggests the involvement of TLR signalling and autophagy. Conclusions Since the combinatory extract viscumTT exerts highly effective pro-apoptotic effects on Ewing sarcoma cells in vitro, this phytopolychemotherapy could be a promising adjuvant therapeutic option for paediatric patients with Ewing sarcoma

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well

A new approach for modelling mild and severe wear in wheel-rail contacts

This paper presents a new approach for modelling the wear in wheel-rail contacts for a wide range of test and contact conditions (material pairing, load, creep, lubrication etc.) in the mild and severe wear regimes with one set of model coefficients. The approach is based on a detailed analysis of 56 Twin-Disc experiments in combination with existing knowledge from the literature. The model considers the thickness of the damaged layer caused by severe plastic shear deformations in the near-surface layer of wheel or rail and the maximum shear stress in the contact as the main influencing factors responsible for the observed wear behaviour. In this way, a much better prediction quality can be reached for varying test and contact conditions compared to the state of the art energy dissipation or sliding based approaches. The model includes a low number of model coefficients which are independent of test and contact conditions

Wheel-rail creep force model for predicting water induced low adhesion phenomena

A computationally efficient engineering model to predict adhesion in rolling contact in the presence of water is presented which may be implemented in multibody dynamics software or in braking models to study train performance and braking strategies. This model has been developed in a project funded by the Rail Safety and Standards Board (RSSB) and Network Rail. It is referred to as the water-induced low adhesion creep force (WILAC) model. The model covers a wide range of conditions from dry over damp to wet. Special emphasis is put on little amounts of water which can cause low adhesion without any oil or grease. Such conditions may be encountered in humid weather or at the onset of rain. The model is parameterised based on experimental results from a tram wheel test rig. Adhesion values as low as 0.06 are observed at high creep with only wear debris and little water present in the contact. The model results also agree with experimental data from locomotive tests in dry and wet conditions

Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures

Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system

Promoting More Physical Activity and Less Sedentary Behaviour During the COVID-19 Situation – SportStudisMoveYou (SSMY): A Randomized Controlled Trial

Objective: To determine the effect of an innovative, online-based intervention, addressing the possible decline of physical activity (PA) and increase of sedentary behavior (SB) during COVID-19 stay at home restrictions in Switzerland. Methods: This study investigated the effect of a two-week, social cognitive theory based, online-video moderate to vigorous (MV)PA or SB intervention on MVPA and SB behaviour and intention via a 3 group by 2 time point parallel randomized controlled trial during the COVID-19 pandemic. Adults (≥18 yo) were recruited over the internet between April 10th and April 19th 2020 (n = 129; 75.2% female; mean age = 29.0 [SD 11.8] years). Both intervention groups received five videos targeting either SB for the SB group or MVPA for the MVPA group and were compared to an attention control group (fruit and vegetable consumption). It was hypothesized that MVPA time and intention would increase for the MVPA group and the SB group would outperform control on SB behaviour and intention indicators. Results: No significant interactions were found for the MVPA group (n = 41) versus control (n = 40). Only one significant interaction was measured for the SB group (n = 48; intention of active breaks F = (2,114) = 5.84, p = 0.004, ηp2 = 0.09). Although mostly non-significant and small effects, the MVPA group showed results pointing in the hypothesized direction on all PA indicators and the SB on all SB indicators, respectively. Conclusion: Considering this study’s limitations (e.g. small intervention dose), video-based online PA and SB interventions seem promising and feasible. This approach is appropriate for COVID-19 and other stay at home situations

Low aerobic mitochondrial energy metabolism in poorly- or undifferentiated neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Succinate dehydrogenase (SDH) has been associated with carcinogenesis in pheochromocytoma and paraganglioma. In the present study we investigated components of the oxidative phosphorylation system in human neuroblastoma tissue samples.</p> <p>Methods</p> <p>Spectrophotometric measurements, immunohistochemical analysis and Western blot analysis were used to characterize the aerobic mitochondrial energy metabolism in neuroblastomas (NB).</p> <p>Results</p> <p>Compared to mitochondrial citrate synthase, SDH activity was severely reduced in NB (n = 14) versus kidney tissue. However no pathogenic mutations could be identified in any of the four subunits of SDH. Furthermore, no genetic alterations could be identified in the two novel SDH assembly factors SDHAF1 and SDH5. Alterations in genes encoding nfs-1, frataxin and isd-11 that could lead to a diminished SDH activity have not been detected in NB.</p> <p>Conclusion</p> <p>Because downregulation of other complexes of the oxidative phosphorylation system was also observed, a more generalized reduction of mitochondrial respiration seems to be present in neuroblastoma in contrast to the single enzyme defect found in hereditary pheochromocytomas.</p

Towards evidence-based conservation of subterranean ecosystems

Subterranean ecosystems are among the most widespread environments on Earth, yet we still have poor knowledge of their biodiversity. To raise awareness of subterranean ecosystems, the essential services they provide, and their unique conservation challenges, 2021 and 2022 were designated International Years of Caves and Karst. As these ecosystems have traditionally been overlooked in global conservation agendas and multilateral agreements, a quantitative assessment of solution-based approaches to safeguard subterranean biota and associated habitats is timely. This assessment allows researchers and practitioners to understand the progress made and research needs in subterranean ecology and management. We conducted a systematic review of peer-reviewed and grey literature focused on subterranean ecosystems globally (terrestrial, freshwater, and saltwater systems), to quantify the available evidence-base for the effectiveness of conservation interventions. We selected 708 publications from the years 1964 to 2021 that discussed, recommended, or implemented 1,954 conservation interventions in subterranean ecosystems. We noted a steep increase in the number of studies from the 2000s while, surprisingly, the proportion of studies quantifying the impact of conservation interventions has steadily and significantly decreased in recent years. The effectiveness of 31% of conservation interventions has been tested statistically. We further highlight that 64% of the reported research occurred in the Palearctic and Nearctic biogeographic regions. Assessments of the effectiveness of conservation interventions were heavily biased towards indirect measures (monitoring and risk assessment), a limited sample of organisms (mostly arthropods and bats), and more accessible systems (terrestrial caves). Our results indicate that most conservation science in the field of subterranean biology does not apply a rigorous quantitative approach, resulting in sparse evidence for the effectiveness of interventions. This raises the important question of how to make conservation efforts more feasible to implement, cost-effective, and long-lasting. Although there is no single remedy, we propose a suite of potential solutions to focus our efforts better towards increasing statistical testing and stress the importance of standardising study reporting to facilitate meta-analytical exercises. We also provide a database summarising the available literature, which will help to build quantitative knowledge about interventions likely to yield the greatest impacts depending upon the subterranean species and habitats of interest. We view this as a starting point to shift away from the widespread tendency of recommending conservation interventions based on anecdotal and expert-based information rather than scientific evidence, without quantitatively testing their effectiveness.Peer reviewe