Sorting Out Pandora’s Box: Discerning the Dynamic Roles of Liver Microenvironment in Oncolytic Virus Therapy for Hepatocellular Carcinoma

Oncolytic viral therapies have recently found their way into clinical application for hepatocellular carcinoma (HCC), a disease with limited treatment options and poor prognosis. Adding to the many intrinsic challenges of in vivo oncolytic viral therapy, is the complex microenvironment of the liver, which imposes unique limitations to the successful delivery and propagation of the virus. The normal liver milieu is characterized by an intricate network of hepatocytes and non-parenchymal cells including Kupffer cells, stellate cells, and sinusoidal endothelial cells, which can secrete antiviral cytokines, provide a platform for non-specific uptake, and form a barrier to efficient viral spread. In addition, NK cells are greatly enriched in the liver, contributing to the innate defense against viruses. The situation is further complicated when HCC arises in the setting of underlying hepatitis virus infection and/or hepatic cirrhosis, which occurs in more than 90% of clinical cases. These conditions pose further inhibitory effects on oncolytic virus therapy due to the presence of chronic inflammation, constitutive cytokine expression, altered hepatic blood flow, and extracellular matrix deposition. In addition, oncolytic viruses can modulate the hepatic microenvironment, resulting in a complex interplay between virus and host. The immune system undoubtedly plays a substantial role in the outcome of oncolytic virus therapy, both as an inhibitor of viral replication, and as a potent mechanism of virus-mediated tumor cell killing. This review will discuss the particular challenges of oncolytic viral therapy for HCC, as well as some potential strategies for modulating the immune system and synergizing with the hepatic microenvironment to improve therapeutic outcome. <br/

Light-Weight Vision Transformer with Parallel Local and Global Self-Attention

While transformer architectures have dominated computer vision in recent years, these models cannot easily be deployed on hardware with limited resources for autonomous driving tasks that require real-time-performance. Their computational complexity and memory requirements limits their use, especially for applications with high-resolution inputs. In our work, we redesign the powerful state-of-the-art Vision Transformer PLG-ViT to a much more compact and efficient architecture that is suitable for such tasks. We identify computationally expensive blocks in the original PLG-ViT architecture and propose several redesigns aimed at reducing the number of parameters and floating-point operations. As a result of our redesign, we are able to reduce PLG-ViT in size by a factor of 5, with a moderate drop in performance. We propose two variants, optimized for the best trade-off between parameter count to runtime as well as parameter count to accuracy. With only 5 million parameters, we achieve 79.5$\%$ top-1 accuracy on the ImageNet-1K classification benchmark. Our networks demonstrate great performance on general vision benchmarks like COCO instance segmentation. In addition, we conduct a series of experiments, demonstrating the potential of our approach in solving various tasks specifically tailored to the challenges of autonomous driving and transportation.Comment: This paper has been accepted at IEEE Intelligent Transportation Systems Conference (ITSC), 202

Sanktionen und eine schwierige Wirtschaftslage: Irans Einlenken im Nuklearkonflikt

Am 24. November 2013 vereinbarten die fünf UN-Vetomächte und Deutschland (P5+1) und Iran in der dritten Genfer Verhandlungsrunde seit der Wahl von Hassan Rohani zum iranischen Präsidenten ein auf sechs Monate festgelegtes Übergangsabkommen zur Beilegung des Nuklearstreits. Angesichts ernsthafter Sorgen um die wirtschaftliche Lage – infolge umfassender internationaler Sanktionen sowie der sozioökonomischen Irrfahrt der Regierung unter Mahmud Ahmadinejad – und der hohen Zustimmungsraten für Präsident Rohani sucht die iranische Führung eine rasche Einigung im Konflikt um das eigene Nuklearprogramm. Der Spielraum des neuen Präsidenten für dringend notwendige wirtschaftspolitische Maßnahmen ist aufgrund der bestehenden Sanktionen deutlich eingeschränkt. Irans Staatsführung hatte die Förderung des Nuklearprogramms zum wesentlichen Bestandteil der eigenen Legitimationsstrategie erklärt. Im Kontext internationaler Sanktionen wurde das Programm als Symbol des nationalen Fortschritts, regionaler Führungsambitionen und des Widerstands gegen die "globale Arroganz" inszeniert. Die Klientelpolitik Ahmadinejads zugunsten städtischer und ländlicher Geringverdiener sowie paramilitärischer Gruppen und die Inkaufnahme umfangreicher Wirtschaftssanktionen als Folge der konfrontativen Nuklearpolitik haben der Wirtschaft und der Gesamtbevölkerung geschadet. Innerhalb der politischen Elite Irans besteht derzeit ein Konsens, das Nuklearprogramm einzuschränken und die ökonomischen und außenpolitischen Fehlentwicklungen zu korrigieren. Der Revolutionsführer Ayatollah Ali Khamenei trägt diesen Konsens mit. Sollte es Rohani gelingen, die Aufhebung der schmerzhaften Erdöl- und Finanzsanktionen zu erreichen und die Wirtschaft des Landes anzukurbeln sowie gleichzeitig das Recht auf eigene Urananreicherung gegenüber den P5+1 durchzusetzen, wird er seine Position behaupten und festigen können

Cell cycle progression or translation control is not essential for vesicular stomatitis virus oncolysis of hepatocellular carcinoma.

The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). Identifying key regulators in diverse transduction pathways that define VSV oncolysis in cancer cells represents a fundamental prerequisite to engineering more effective oncolytic viral vectors and adjusting combination therapies. After having identified defects in the signalling cascade of type I interferon induction, responsible for attenuated antiviral responses in human HCC cell lines, we have now investigated the role of cell proliferation and translation initiation. Cell cycle progression and translation initiation factors eIF4E and eIF2Bepsilon have been recently identified as key regulators of VSV permissiveness in T-lymphocytes and immortalized mouse embryonic fibroblasts, respectively. Here, we show that in HCC, decrease of cell proliferation by cell cycle inhibitors or siRNA-mediated reduction of G(1) cyclin-dependent kinase activities (CDK4) or cyclin D1 protein expression, do not significantly alter viral growth. Additionally, we demonstrate that translation initiation factors eIF4E and eIF2Bepsilon are negligible in sustaining VSV replication in HCC. Taken together, these results indicate that cellular proliferation and the initiation phase of cellular protein synthesis are not essential for successful VSV oncolysis of HCC. Moreover, our observations indicate the importance of cell-type specificity for VSV oncolysis, an important aspect to be considered in virotherapy applications in the future

Effects of recombinant adenovirus-mediated expression of IL-2 and IL-12 in human B lymphoma cells on co-cultured PBMC

BACKGROUND: Modulation of the immune system by genetically modified lymphoma cell vaccines is of potential therapeutic value in the treatment of B cell lymphoma. However, the anti-tumor effect of any single immunogene transfer has so far been limited. Combination treatment of recombinant IL-2 and IL-12 has been reported to be synergistic for inducing anti-tumor responses in solid tumors but the potential of IL-2/IL-12 gene modified B cell lymphoma cells has not been explored yet. METHODS: Using three different human B cell lymphoma cell lines and primary samples from patients with B cell neoplasms, expression levels of the coxsackie B-adenovirus receptor (CAR) and alpha (v) integrins were analyzed by fluorescence-activated cell sorter (FACS). Adenoviral transduction efficiencies were determined by GFP expression analysis and IL-2 and IL-12 cytokine production was quantified by enzyme-linked immunosorbent (ELISA) assays. Proliferative activities of peripheral blood mononuclear cells (PBMC) stimulated with either cytokine derived from supernatants of transduced lymphoma cells were measured by cell proliferation (MTT) assays. An EuTDA cytotoxicity assay was used to compare cytotoxic activities of IL-2 and/or IL-12 stimulated PBMC against unmodified lymphoma cells. RESULTS: We found that B cell lymphoma cell lines could be transduced with much higher efficiency than primary tumor samples, which appeared to correlate with the expression of CAR. Adenoviral-expressed IL-2 and IL-12 similarly led to dose-dependent increases in proliferation rates of PBMC obtained from healthy donors. IL-2 and/or IL-12 transduced lymphoma cells were co-cultured with PBMC, which were assayed for their cytolytic activity against unmodified lymphoma cells. We found that IL-2 stimulated PBMC elicited a significant anti-tumor effect but not the combined effect of IL-2/IL-12 or IL-12 alone. CONCLUSION: This study demonstrates that the generation of recombinant adenovirus modified lymphoma cell vaccines based on lymphoma cell lines expressing IL-2 and IL-12 cytokine genes is technically feasible, induces increases in proliferation rates and cytotoxic activity of co-cultured PBMC, and warrants further development for the treatment of lymphoma patients in the future

High-Throughput Techniques for Measuring the Spin Hall Effect

The spin Hall effect in heavy-metal thin films is routinely used to convert charge currents into transverse spin currents and can be used to exert torque on adjacent ferromagnets. Conversely, the inverse spin Hall effect is frequently used to detect spin currents by charge currents in spintronic devices up to the terahertz frequency range. Numerous techniques to measure the spin Hall effect or its inverse have been introduced, most of which require extensive sample preparation by multistep lithography. To enable rapid screening of materials in terms of charge-to-spin conversion, suitable high-throughput methods for measuring the spin Hall angle are required. Here we compare two lithography-free techniques, terahertz emission spectroscopy and broadband ferromagnetic resonance, with standard harmonic Hall measurements and theoretical predictions using the binary-alloy series AuxPt1−x as a benchmark system. Despite their being highly complementary, we find that all three techniques yield a spin Hall angle with approximately the same x dependence, which is also consistent with first-principles calculations. Quantitative discrepancies are discussed in terms of magnetization orientation and interfacial spin-memory loss

NFDI4BioDiversity - NFDI-Konsortium für Biodiversitäts-, Ökologische und Umweltdaten

NFDI4BioDiversity ist ein Konsortium innerhalb der Nationalen Forschungsdateninfrastruktur (NFDI) mit einem Schwerpunkt auf Services für die Biodiversitätsforschung und Ökologie. Unzählige Studien belegen den Rückgang der Biodiversität auf unserem Planeten. Drängende Fragen in diesem Zusammenhang sind unter anderem welche Auswirkungen der Rückgang der Biodiversität auf die betroffenen Ökosysteme hat und welche (anthropogenen) Einflüsse die Biodiversität reduzieren oder fördern. Um die komplexen Zusammenhänge zu verstehen und daraus Handlungsempfehlungen abzuleiten, werden vielfältige, qualitätsgesicherte und FAIRe[1] Daten benötigt. Diese umfassen das Vorkommen von Pflanzen, Tieren und Mikroorganismen, einschließlich ihrer genotypischen, phänotypischen und funktionalen Vielfalt, sowie deren Zusammenspiel in Populationen und Ökosystemen. In NFDI4BioDiversity haben sich 49 Partner aus Wissenschaft, Behörden und Bürgerwissenschaften zusammengeschlossen, um die Mobilisierung und Publikation vorhandener Daten voranzutreiben, effiziente Workflows zu entwickeln und Tools und Services zur Unterstützung von Analysen bereitzustellen. [1] FAIR: Findable, Accessible, Interoperable, Reusable, aus: Wilkinson, Mark D., et al. „The FAIR Guiding Principles for scientific data management and stewardship”, Scientific Data 3:160018 (March 2016), doi: 10.1038/sdata.2016.1

Systematic Heterogeneity of Fractional Vesicle Pool Sizes and Release Rates of Hippocampal Synapses

AbstractHippocampal neurons in tissue culture develop functional synapses that exhibit considerable variation in synaptic vesicle content (20–350 vesicles). We examined absolute and fractional parameters of synaptic vesicle exocytosis of individual synapses. Their correlation to vesicle content was determined by activity-dependent discharge of FM-styryl dyes. At high frequency stimulation (30 Hz), synapses with large recycling pools released higher amounts of dye, but showed a lower fractional release compared to synapses that contained fewer vesicles. This effect gradually vanished at lower frequencies when stimulation was triggered at 20 Hz and 10 Hz, respectively. Live-cell antibody staining with anti-synaptotagmin-1-cypHer 5, and overexpression of synaptopHluorin as well as photoconversion of FM 1-43 followed by electron microscopy, consolidated the findings obtained with FM-styryl dyes. We found that the readily releasable pool grew with a power function with a coefficient of 2/3, possibly indicating a synaptic volume/surface dependency. This observation could be explained by assigning the rate-limiting factor for vesicle exocytosis at high frequency stimulation to the available active zone surface that is proportionally smaller in synapses with larger volumes

Demonstrating Analog Inference on the BrainScaleS-2 Mobile System

We present the BrainScaleS-2 mobile system as a compact analog inference engine based on the BrainScaleS-2 ASIC and demonstrate its capabilities at classifying a medical electrocardiogram dataset. The analog network core of the ASIC is utilized to perform the multiply-accumulate operations of a convolutional deep neural network. At a system power consumption of 5.6W, we measure a total energy consumption of 192uJ for the ASIC and achieve a classification time of 276us per electrocardiographic patient sample. Patients with atrial fibrillation are correctly identified with a detection rate of (93.7${\pm}$0.7)% at (14.0${\pm}$1.0)% false positives. The system is directly applicable to edge inference applications due to its small size, power envelope, and flexible I/O capabilities. It has enabled the BrainScaleS-2 ASIC to be operated reliably outside a specialized lab setting. In future applications, the system allows for a combination of conventional machine learning layers with online learning in spiking neural networks on a single neuromorphic platform