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CA extern Overexpression of the dihydrolipoamide S-succinyltransferase (DLST) is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and specifically with the oxidative phosphorylation (OXPHOS) pathway. Inhibitors of OXPHOS were previously suggested as a potential therapeutic strategy for a subset of patients with high-risk neuroblastoma. Here, we tested if cell lines with DLST amplifications or high mRNA levels were associated with sensitivity to 250 drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset by comparing them to cell lines without these changes. DLST-altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells. Moreover, several protein kinase inhibitors were identified to be efficient in cell lines with DLST amplifications or high mRNA levels, suggesting a vulnerability of DLST-altered cell lines for drugs targeting the ERK/MAPK pathway. Furthermore, increased DLST expression in cell lines with driver mutations in KRAS supported this relationship. We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of DLST amplifications or high mRNA levels. The new drug candidates proposed here could serve in experimental testing on drug efficacy in knock-in cell lines and DLST-activated tumors.

Coupled laboratory-numerical experiments of Rayleigh-B\'enard convection (RBC) in liquid gallium subject to a vertical magnetic field are presented. The experiments are carried out in two cylindrical containers with diameter-to-height aspect ratio $\Gamma = 1.0$ and $2.0$ at varying thermal forcing (Rayleigh numbers $10^5 \lesssim Ra \lesssim 10^8$) and magnetic field strength (Chandrasekhar numbers $0\lesssim Ch \lesssim 3\times 10^5$). Laboratory measurements and numerical simulations confirm that magnetoconvection in our finite cylindrical tanks onsets via non-drifting wall-attached modes, in good agreement with asymptotic predictions for a semi-infinite domain. With increasing supercriticality, the experimental and numerical thermal measurements and the numerical velocity data reveal transitions between wall mode states with different azimuthal mode numbers and between wall-dominated convection to wall and interior multimodality. These transitions are also reflected in the heat transfer data, which combined with previous studies, connect onset to supercritical turbulent behaviors in liquid metal magnetoconvection over a large parameter space. The gross heat transfer behaviors between magnetoconvection and rotating convection in liquid metals are compared and discussed., Comment: 19 pages (including 4 pages of appendix), 8 figures

We study the topology and the temporal dynamics of turbulent Rayleigh-Benard convection in a liquid metal with a Prandtl number of 0.03 located inside a box with a square base area and an aspect ratio of five. Experiments and numerical simulations are focused on the moderate Rayleigh number range, where a new cellular flow regime has been reported by a previous study (Akashi et al., Phys. Rev. Fluids, vol.4, 2019, 033501). This flow structure shows symmetries with respect to the vertical planes crossing at the center of the container. The dynamic behaviour is dominated by strong three-dimensional oscillations with a period length that corresponds to the turnover time. Our analysis reveals that the flow structure in the aspect ratio five box corresponds in key features to the jump rope vortex structure, which has recently been discovered in an aspect ratio two cylinder (Vogt et al., Proc. Natl Acad. Sci. USA, vol.115, 2018, 12674-12679). While in the cylinder a single jump rope vortex occurs, the coexistence of four recirculating swirls is detected in this study. %Their cycling movement is restrained by the limited height of the fluid layer in the aspect ratio five box. Their approach to the lid or the bottom of the convection box causes a temporal deceleration of both the horizontal velocity at the respective boundary and the vertical velocity in the bulk, which in turn is reflected in Nusselt number oscillations. The cellular flow regime shows remarkable similarities to properties commonly attributed to turbulent superstructures

The large-scale circulation (LSC) is the most fundamental turbulent coherent flow structure in Rayleigh-Bénard convection. Further, LSCs provide the foundation upon which superstructures, the largest observable features in convective systems, are formed. In confined cylindrical geometries with diameter-to-height aspect ratios of , LSC dynamics are known to be governed by a quasi-two-dimensional, coupled horizontal sloshing and torsional (ST) oscillatory mode. In contrast, in cylinders, a three-dimensional jump rope vortex (JRV) motion dominates the LSC dynamics. Here, we use dynamic mode decomposition (DMD) on direct numerical simulation data of liquid metal to show that both types of modes co-exist in and cylinders but with opposite dynamical importance. Furthermore, with this analysis, we demonstrate that ST oscillations originate from a tilted elliptical mean flow superposed with a symmetric higher-order mode, which is connected to the four rolls in the plane perpendicular to the LSC in tanks.

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before, albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

Additional file 3: Supplementary Material ��� File 3: Instructions for using PTEE.

Additional file 1: Supplementary Material ��� File 1: Displays number of expressed genes as a function of number of samples/individuals per tissue.

Phenotypic intratumoral heterogeneity and temporal transitions between cell differentiation states represent major drivers of tumor fitness in melanoma. Expression of the histone H3K4 demethylase KDM5B/JARID1B follows a highly dynamic equilibrium across melanoma cells. When challenged for example with targeted or cytotoxic drugs, the intrinsically slow-cycling KDM5B high cell state becomes initially enriched, whereas under persistent drug-exposure melanomas decrease KDM5B expression again to re-enter cell proliferation for long-term tumor repopulation. However, the exact role of KDM5B for tumor cell differentiation and fate remained elusive so far. Here, we show that melanoma fitness can be overcome by molecular enforcement of high KDM5B expression levels. KDM5B-up-scaled melanoma cells are transcriptionally reprogramed towards a differentiated melanocytic profile including a slow-cycling state. This effect can be phenocopied by a newly identified chemical compound also leading to decelerated tumor growth. Mechanistically, KDM5B represents a checkpoint for coordinating the differentiation phenotype of melanoma cells via transcriptional reprograming, cell cycle delay, and attenuation of cytokinetic abscission. These findings indicate that tumor plasticity per se , i.e. the necessity of cancer cells to dynamically switch between different cell cycling and differentiation states, represents an important oncologic process that can be chemically overcome.

bioRxiv Preprint

Using trio exome sequencing, we identified de novo heterozygous missense variants in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes the p21-activated kinase, a major driver of neuronal development in humans and other organisms. In normal neurons, PAK1 dimers reside in a trans-inhibited conformation, where each autoinhibitory domain covers the kinase domain of the other monomer. Upon GTPase binding via CDC42 or RAC1, the PAK1 dimers dissociate and become activated. All identified variants are located within or close to the autoinhibitory switch domain that is necessary for trans-inhibition of resting PAK1 dimers. Protein modelling supports a model of reduced ability of regular autoinhibition, suggesting a gain of function mechanism for the identified missense variants. Alleviated dissociation into monomers, autophosphorylation and activation of PAK1 influences the actin dynamics of neurite outgrowth. Based on our clinical and genetic data, as well as the role of PAK1 in brain development, we suggest that gain of function pathogenic de novo missense variants in PAK1 lead to moderate-to-severe intellectual disability, macrocephaly caused by the presence of megalencephaly and ventriculomegaly, (febrile) seizures and autism-like behaviour.

For rapidly rotating turbulent Rayleigh--B��nard convection in a slender cylindrical cell, experiments and direct numerical simulations reveal a boundary zonal flow (BZF) that replaces the classical large-scale circulation. The BZF is located near the vertical side wall and enables enhanced heat transport there. Although the azimuthal velocity of the BZF is cyclonic (in the rotating frame), the temperature is an anticyclonic traveling wave of mode one whose signature is a bimodal temperature distribution near the radial boundary. The BZF width is found to scale like $Ra^{1/4}Ek^{2/3}$ where the Ekman number $Ek$ decreases with increasing rotation rate.

Computational codes for direct numerical simulations of Rayleigh-B��nard (RB) convection are compared in terms of computational cost and quality of the solution. As a benchmark case, RB convection at $Ra=10^8$ and $Pr=1$ in a periodic domain, in cubic and cylindrical containers is considered. A dedicated second-order finite-difference code (AFID/RBflow) and a specialized fourth-order finite-volume code (Goldfish) are compared with a general purpose finite-volume approach (OpenFOAM) and a general purpose spectral-element code (Nek5000). Reassuringly, all codes provide predictions of the average heat transfer that converge to the same values. The computational costs, however, are found to differ considerably. The specialized codes AFID/RBflow and Goldfish are found to excel in efficiency, outperforming the general purpose flow solvers Nek5000 and OpenFOAM by an order of magnitude with an error on the Nusselt number $Nu$ below $5\%$. However, we find that $Nu$ alone is not sufficient to assess the quality of the numerical results: in fact, instantaneous snapshots of the temperature field from a near wall region obtained for deliberately under-resolved simulations using Nek5000 clearly indicate inadequate flow resolution even when $Nu$ is converged. Overall, dedicated special purpose codes for RB convection are found to be more efficient than general purpose codes., 12 pages, 5 figures

Earth's magnetic field is generated by convective motions in its liquid metal core. In this fluid, the heat diffuses significantly more than momentum and thus, the ratio of these two diffusivities, the Prandtl number Pr, is well below unity. The thermally-driven convective flow dynamics of liquid metals are very different from Pr ~ 1 fluids, like water and those used in current dynamo simulations. In order to characterize rapidly rotating thermal convection in low Pr number fluids, we have performed laboratory experiments in an aspect ratio H/D = 1.94 cylinder using liquid gallium (Pr ~0.025) as the working fluid. The Ekman number, E, which characterizes the effect of rotation, varies from E = 5x10^-5 to 5x10^-6 and the Rayleigh number, Ra, which characterizes the buoyancy forcing, varies from Ra ~ 2x10^5 to 1.5x10^7. Using measurements of heat transfer effciency, characterized by the Nusselt number Nu, and point-wise temperature measurements within the fluid, we characterize the different styles of low Pr rotating convective flow. The convection threshold is first overcome in the form of container scale inertial oscillatory modes. At stronger forcing, sidewall-attached modes are identifed for the first time in liquid metal laboratory experiments. These wall modes coexist with the bulk oscillatory modes. At Ra well below the values where steady rotating columnar convection occurs, the bulk flow becomes turbulent. Our results imply that rotating convective flows in liquid metals do not develop in the form of quasi-steady columns, as in Pr ~ 1 fluids, but in the form of oscillatory convective motions. Therefore, the flows that drive thermally-driven dynamo action in low Pr geophysical and astrophysical fluids can differ substantively than those occuring in current-day Pr ~ 1 numerical models. Since oscillatory convection is significantly easier to excite than steady convection, it may be that thermally-driven oscillatory motions will generate dynamo action in planetary settings, well before steady convective flows are even actuated. Furthermore, our experimental results show that relatively low wavenumber, wall-attached modes can be dynamically important in rapidly rotating convection in liquid metals.

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFN 3 secretion by CD8 + T cells is critical for therapy efficacy having anti-proliferative and pro-Apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFN 3 resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFN 3 signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-Tumour IFN 3 activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFN 3. Allelic JAK1/2 losses predisposing to IFN 3 resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-Treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-Tumour IFN 3 activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFN 3 resistance should be considered in therapeutic decision-making. CA Paschen

We consider rotating Rayleigh-B��nard convection of a fluid with a Prandtl number of $Pr = 0.8$ in a cylindrical cell with an aspect ratio $��= 1/2$. Direct numerical simulations were performed for the Rayleigh number range $10^5 \leq Ra \leq 10^9$ and the inverse Rossby number range $0 \leq 1/Ro \leq 20$. We propose a method to capture regime transitions based on the decomposition of the velocity field into toroidal and poloidal parts. We identify four different regimes. First, a buoyancy dominated regime occurring as long as the toroidal energy $e_{tor}$ is not affected by rotation and remains equal to that in the non-rotating case, $e^0_{tor}$. Second, a rotation influenced regime, starting at rotation rates where $e_{tor} > e^0_{tor}$ and ending at a critical inverse Rossby number $1/Ro_{cr}$ that is determined by the balance of the toroidal and poloidal energy, $e_{tor} = e_{pol}$. Third, a rotation dominated regime, where the toroidal energy $e_{tor}$ is larger than both, $e_{pol}$ and $e^0_{tor}$. Fourth, a geostrophic turbulence regime for high rotation rates where the toroidal energy drops below the value of non-rotating convection.

Bohemia, Bd. 38 Nr. 1 (1997)

Bohemia, Bd. 37 Nr. 2 (1996)

Baitoushan is an intraplate stratovolcano, located on the border between China und North Korea (42°N/128°E). The volcanic activity is associated with the continental rift system of the North East Asian mainland. The ea. 1OOO AD eruption of Baitoushan volcano began with a Plinian eruption phase associated with pyroclastic flows. The ejecta contains of juvenile white to grey, highly vesiculated, crystal poor pumices and pumice clasts, whereby ~1 % are light-dark-colored banded pumices. The lithic components are fragments of older basalt and trachyte lava flows of the stratocone and of syenite intrnsions. The explosivity of the emption decreased during the second eruption phase. The proximal agglutinate (hot fallout) and pyroclastic flows consist of dark colored, crystal rich pumices and welded glass shards. Approximately 95 % of the bulk eruption volume was erupted during the first eruption phase, and the ejected volcanic ash within the Plinian eruption column is estimated to have entered the stratosphere. The border between troposphere and stratosphere at 42°N latitude is at a height of ~13 km. The height of the Plinian eruption cloumn is estimated to be ≤ 25 km, based on the distribution of the maximal pumice clasts in the proximal fallout fan (isopleth). The fallout fan covers an area of ≤ 15 x 10s km2, and extended as far as 1000 km to the east. The thickness distribution of the fallout is based on fieldwork in China and North Korea for the proximal and piston core data (literature) from the Sea of Japan for the distal deposits. Based on the relation between fallout thickness and square root of the fallout area, after Fierstein & Nathenson (1992), a tephra volume of 96 ± 19 km3 has been calculated. This tephra volume corresponds to a magma volume (DRE) of 24 km3 ± 5 km3. During the Baitoushan eruption, 94% peralkaline rhyolitic and trachytic comendites, 5% trachytes and 1 % trachyandesites has been erupted. The comendites contain of ~3 vol % phenocrysts: anorthoclase > hedenbergite > fayalite > Fe-Ti-Oxide >> apatite ± quartz. The trachytes contain 10 - 20 vol% phenocrysts: anorthoclase > hedenbergite > fayalite > Fe-Ti-Oxide. The anorthoclase crystals typically showing sieve textured cores, mantled by an idiomorphic rim. The trachyandesites a phenocryst assemblage of plagioclase > olivine (e.g. Fo 78) ≥ augite. The trace element composition of the Baitoushan magmas show decreasing Sr, Ba, Sc, and Eu concentrations from trachyandesite (Sr ≤ 60 ppm) to comendite (Sr ≤ 20 ppm). In contrast to incompatible trace elements (e.g. Zr) showing a strong increase from trachyandesitic (Zr ≤ 500 ppm), trachytic (Zr 500-900 ppm), to comenditic trachyte (Zr 800-1400 ppm) and comenditic rhyolite (Zr 1500-2400 ppm). The comendite magma appears to have been generated by fractional crystallisation from a trachyte magma, as shown by fractionation calculations, based on fractional crystallization models. The postulated trachyte magma is exclusively represented by melt inclusions in phenocrysts of the comendite.The comenditic rhyolite magma is interpreted to have been located at a depth od approximately 4 km. It was underlain by a trachyte magma, generated by fractional crystallization from a basaltic parental magma, resembling the Zr-rich Gaima Plateau basalts. A compositional gap of major- and trace elements of the comenditic rhyolites and the trachyte, cannot be explained by fractionation models. They are interpreted to represent two separate magma batches. The comenditic trachyte was generated by the mixing between the comenditic rhyolite and the trachyte magmas. Mixing of comenditic rhyolite and trachyandesite magmas took place during the ca. 1000 AD eruption (syneruptive) as indicated by mixing textures (banded pumice). The injection of trachyandesite into the top of the compositionally zoned magma column offers a viable mechanism for triggering the massive 1OOO AD eruption. The mass of volatiles emitted to the atmosphere during eruption was estimated, based on the petrologic method after Devine et al. (1984) and Sigurdsson et al. (1985). The average water content in the comenditic matrix glass is 1.5 wt%, and 0.5 wt% in the trachytic matrix glasses. The comenditic melt inclusions contain ~ 5.2 wt% H2O. Melt inclusions in feldspar and quartz present the highest halogen concentrations: Cl between 3060 and 5800 ppm, F between 2630 and 6200 ppm. The comenditic matrix glasses is separated into a halogen-rich group (Cl 4400 ppm and F 3500 ppm) and halogen poor group (Cl 4000 ppm and F 2300 ppm). Only 20 % of all S analyses of the comenditic matrix glasses and melt inclusions lie above the detection limit (≥ 250 ppm S). The difference between pre- (melt inclusions) and post-eruptive (matrix glasses) water content is 3.7 ± 0.6 wt% H20 (SIMS). In view of the fact that the elements Cl, F, and S show heterogeneous distribution in the comenditic melt, the differences between pre- and posteruptive halogen contents are 909 ± 90 ppm Cl, and 1863 ± 280 ppm and 302 ± 40 ppm F. The difference for S has been estimated based on the maximal S content of the melt inclusion and the detection limit, resulting 205 ± 40 ppm S. The mass of volatiles emitted during the Baitoushan eruption has been estimated after the mass balance calcultion from Gerlach et al. (1994). The volatile yield to the atmosphere is 1796 ± 460 megatons H2O, 45 ± 8 megatons chlorine, 42 ± 13 megatons fluorine, and 2 ± 0.6 megatons sulphur. No paleoclimatic records are known for the Baitoushan eruption (historic records or sulfate layers in Greenland ice cores). The magnitude of the ea. 1000 AD Baitoushan eruption, was certainly comparable to Tambora (1815 AD) and Krakatau (1883 AD), which caused temporary climate changes. The ea. 1000 AD eruption of Baitoushan volcano was thus one of the largest eruptions of the last 2000 years and therefore can be expected to have had a substantial, shortlived effect on climate during that time.

The 5th European Postgraduate Fluid Dynamics Conference will continue an annual succession of fluid dynamics-themed conferences, organised and attended by doctoral students across Europe. All previous conferences, EPFDC-2007 (Birmingham), EPFDC-2008 (Keele), EPFDC-2009 (Nottingham), EPFDC-2010 (Paris) have shown to be a success and have proved to be an excellent platform for students to both present their research and network with others. This year the conference, EPFDC 5, will be held in Göttingen, Germany and is jointly hosted by the Institute of Aerodynamics and Flow Technology of the German Aerospace Center and the Max Planck Institute for Dynamics and Self-Organisation. Following the spirit of preceding years, this conference will provide an open-forum for PhD students from all over Europe giving a short talk or presenting a poster. The sessions will be devoted to the broad scope of topics of fluid- and flow-based research including, but not limited to aerodynamics, geophysical flows, turbulence, hydrodynamic stability, multiphase flow and biofluid dynamics. The attendees will get the opportunity to share their ideas and their work in an environment of current and future colleagues. Furthermore four accomplished scholars will give plenary talk from these many diverse areas of fluid dynamics.