Investigating the expression and role of chloride ion channels in diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive type of glial brain tumour found in the pons region of the brainstem. DIPG accounts for about 10% of childhood central nervous system tumours and the prognosis for these children is poor. Resistance to radiation, the only current available therapy for DIPG, is one of the biggest challenges. This resistance could be due to the plasticity of DIPG cells, allowing them to rapidly adapt in response to different conditions. Preliminary RNA sequencing analyses of patient tumours identified the expression of ion channel genes including the GABA family. It is known that ion channels regulate tumour plasticity in other cancers and as such we aimed to investigate and characterise the role of ion channels in DIPG. This study aimed to validate the mRNA and protein expression of the GABA-A receptors associated with ligand-gated chloride channels, in DIPG patient-derived cell lines. The results of the study validated mRNA expression of the GABA-A receptor subunits using semi-quantitative and quantitative RT-PCR. Protein expression of three of the most highly expressed subunits (GABRA2, GABRA4, and GABRA5) was also demonstrated using western blotting and immunocytochemistry. Furthermore, a drug screen and titration showed that some GABA-A receptor modulators significantly inhibited proliferation of DIPG cells. This work confirmed that GABA-A subunits are expressed in DIPG cells and that blocking these ion channels inhibits DIPG cell proliferation. These findings form the foundation for future studies that will investigate GABA-A receptor drugs as potential treatments for DIPG using preclinical models

Virtual Reality Applications for Higher Educations: A Market Analysis

Benefits and applications of virtual reality (VR) in higher education have seen much interest both from research and industry. While several immersive VR applications for higher education have been described, a structured analysis of such applications on the market does not exist. We use design elements from research for applying VR in higher education to analyze available VR apps. The analyzed VR applications were acquired from pertinent online stores to capture the market’s state. We analyze the current picture of the available apps by categorizing them based on design elements and learning content. The aims are to map what types of apps are available, to study what expected types cannot (yet) be found, to compare the current state of the literature and the educational VR app market, as well as to scrutinize the most frequently used design elements for VR in education

Probing spacetime and accretion model for the Galactic Center: Comparison of Kerr and dilaton black hole shadows

In the vicinity of black holes, the influence of strong gravity, plasma physics, and emission processes govern the behavior of the system. Since observations such as those carried out by the EHT are not yet able to unambiguously constrain models for astrophysical and gravitational properties, it is imperative to explore the accretion models, particle distribution function, and description of the spacetime geometry. Our current understanding of these properties is often based on the assumption that the spacetime is well-described by by the Kerr solution to general relativity, combined with basic emission and accretion models. We explore alternative models for each property performing general relativistic magnetohydrodynamic and radiative transfer simulations. By choosing a Kerr solution to general relativity and a dilaton solution to Einstein-Maxwell-dilaton-axion gravity as exemplary black hole background spacetimes, we aim to investigate the influence of accretion and emission models on the ability to distinguish black holes in two theories of gravity. We carry out three-dimensional general relativistic magnetohydrodynamics simulations of both black holes, matched at their innermost stable circular orbit, in two distinct accretion scenarios. Using general-relativistic radiative transfer calculations, we model the thermal synchrotron emission and in the next step apply a non-thermal electron distribution function, exploring representative parameters to compare with multiwavelength observations. We further consider Kerr and dilaton black holes matched at their unstable circular photon orbits, as well as their event horizons. From multiwavelength emission and spectral index analysis, we find that accretion model and spacetime have only a small impact on the spectra compared to the choice of emission model

Interaction between a hotspot and a fracture zone: The crustal structure of Walvis Ridge at 6° E

Highlights • Late stage volcanism covers old oceanic crust north of the Florianopolis Fracture Zone. • No influence of fracture zone on formation of Walvis Ridge at 6° E. • Walvis Ridge at 6° E erupted in deep water environment. Abstract The Walvis Ridge is one of the major hotspot trails in the South Atlantic and a classical example for volcanic island chains. Two models compete about the origin of the ridge: It is either the result of a deep mantle plume or active fracture zones above mantle inhomogeneities. Among other things crustal information is needed to constrain the models. Here, we provide such constraint with a 480 km long P-wave velocity model of the deep crustal structure of the eastern Walvis Ridge at 6° E. According to our data the Walvis Ridge stretches across the Florianopolis Fracture Zone into the Angola Basin. Here, we observe a basement high and thick basaltic layers covering the oceanic crust and the fracture zone. We found two crustal roots along the profile: one is located beneath the ridge crest, the other one beneath the northern basement high in the Angola Basin. The crustal thickness reaches 18 km and 12 km and the lower crustal velocities are 7.2 km/s and 7.4 km/s, respectively. The bathymetric expression of the ridge along the profile is less pronounced than closer to shore, which is mainly attributable to the absence of a thick layer of volcanic debris, rather than to reduced crustal thickness below the basement surface. Therefore, this part of the ridge was never or only briefly subaerially exposed. The crustal structure suggests that the ridge and the fracture zone formed independently of each other. The oceanic crust north of the fracture zone, which is buried underneath the basalt layer, is younger than the reconstructed age of hotspot volcanism of the Walvis Ridge. We interpret these structures north of the fracture zone to be at least partly a product of late stage volcanism

South Atlantic opening: A plume-induced breakup?

Upwelling hot mantle plumes are thought to disintegrate continental lithosphere and are considered to be drivers of active continental breakup. The formation of the Walvis Ridge during the opening of the South Atlantic is related to a putative plume-induced breakup. We investigated the crustal structure of the Walvis Ridge (southeast Atlantic Ocean) at its intersection with the continental margin and searched for anomalies related to the possible plume head. The overall structure we identify suggests that no broad plume head existed during opening of the South Atlantic and anomalous mantle melting occurred only locally. We therefore question the importance of a plume head as a driver of continental breakup and further speculate that the hotspot was present before the rifting, leaving a track of kimberlites in the African craton

A nonmitochondrial hydrogen production in Naegleria gruberi

Naegleria gruberi is a free-living heterotrophic aerobic amoeba well known for its ability to transform from an amoeba to a flagellate form. The genome of N. gruberi has been recently published, and in silico predictions demonstrated that Naegleria has the capacity for both aerobic respiration and anaerobic biochemistry to produce molecular hydrogen in its mitochondria. This finding was considered to have fundamental implications on the evolution of mitochondrial metabolism and of the last eukaryotic common ancestor. However, no actual experimental data have been shown to support this hypothesis. For this reason, we have decided to investigate the anaerobic metabolism of the mitochondrion of N. gruberi. Using in vivo biochemical assays, we have demonstrated that N. gruberi has indeed a functional [FeFe]-hydrogenase, an enzyme that is attributed to anaerobic organisms. Surprisingly, in contrast to the published predictions, we have demonstrated that hydrogenase is localized exclusively in the cytosol, while no hydrogenase activity was associated with mitochondria of the organism. In addition, cytosolic localization displayed for HydE, a marker component of hydrogenase maturases. Naegleria gruberi, an obligate aerobic organism and one of the earliest eukaryotes, is producing hydrogen, a function that raises questions on the purpose of this pathway for the lifestyle of the organism and potentially on the evolution of eukaryotes

Tokenizer Choice For LLM Training: Negligible or Crucial?

The recent success of LLMs has been predominantly driven by curating the training dataset composition, scaling of model architectures and dataset sizes and advancements in pretraining objectives, leaving tokenizer influence as a blind spot. Shedding light on this underexplored area, we conduct a comprehensive study on the influence of tokenizer choice on LLM downstream performance by training 24 mono- and multilingual LLMs at a 2.6B parameter scale, ablating different tokenizer algorithms and parameterizations. Our studies highlight that the tokenizer choice can significantly impact the model's downstream performance, training and inference costs. In particular, we find that the common tokenizer evaluation metrics fertility and parity are not always predictive of model downstream performance, rendering these metrics a questionable proxy for the model's downstream performance. Furthermore, we show that multilingual tokenizers trained on the five most frequent European languages require vocabulary size increases of factor three in comparison to English. While English-only tokenizers have been applied to the training of multi-lingual LLMs, we find that this approach results in a severe downstream performance degradation and additional training costs of up to 68%, due to an inefficient tokenization vocabulary

Anti-Diarrheal Mechanism of the Traditional Remedy Uzara via Reduction of Active Chloride Secretion

BACKGROUND AND PURPOSE: The root extract of the African Uzara plant is used in traditional medicine as anti-diarrheal drug. It is known to act via inhibition of intestinal motility, but malabsorptive or antisecretory mechanisms are unknown yet. EXPERIMENTAL APPROACH: HT-29/B6 cells and human colonic biopsies were studied in Ussing experiments in vitro. Uzara was tested on basal as well as on forskolin- or cholera toxin-induced Cl(-) secretion by measuring short-circuit current (I(SC)) and tracer fluxes of (22)Na(+) and (36)Cl(-). Para- and transcellular resistances were determined by two-path impedance spectroscopy. Enzymatic activity of the Na(+)/K(+)-ATPase and intracellular cAMP levels (ELISA) were measured. KEY RESULTS: In HT-29/B6 cells, Uzara inhibited forskolin- as well as cholera toxin-induced I(SC) within 60 minutes indicating reduced active chloride secretion. Similar results were obtained in human colonic biopsies pre-stimulated with forskolin. In HT-29/B6, the effect of Uzara on the forskolin-induced I(SC) was time- and dose-dependent. Analyses of the cellular mechanisms of this Uzara effect revealed inhibition of the Na(+)/K(+)-ATPase, a decrease in forskolin-induced cAMP production and a decrease in paracellular resistance. Tracer flux experiments indicate that the dominant effect is the inhibition of the Na(+)/K(+)-ATPase. CONCLUSION AND IMPLICATIONS: Uzara exerts anti-diarrheal effects via inhibition of active chloride secretion. This inhibition is mainly due to an inhibition of the Na(+)/K(+)-ATPase and to a lesser extent to a decrease in intracellular cAMP responses and paracellular resistance. The results imply that Uzara is suitable for treating acute secretory diarrhea