Oregonin from Alnus incana bark affects DNA methyltransferases expression and mitochondrial DNA copies in mouse embryonic fibroblasts

Oregonin is an open-chain diarylheptanoid isolated from Alnus incana bark that possesses remarkable antioxidant and anti-inflammatory properties, inhibits adipogenesis, and can be used in the prevention of obesity and related metabolic disorders. Here, we aimed to investigate the effects of oregonin on the epigenetic regulation in cells as well as its ability to modulate DNA methylating enzymes expression and mitochondrial DNA (mtDNA) copies. Our results show that oregonin altered the expression of DNA methyltransferases and mtDNA copy numbers in dependency on concentration and specificity of cells genotype. A close correlation between mtDNA copy numbers and mRNA expression of the mtDnmt1 and Dnmt3b was established. Moreover, molecular modeling suggested that oregonin fits the catalytic site of DNMT1 and partially overlaps with binding of the cofactor. These findings further extend the knowledge on oregonin, and elucidate for the first time its potential to affect the key players of the DNA methylation process, namely DNMTs transcripts and mtDNA

A study of super-luminous stars with the Fermi Large Area Telescope

The $\gamma$-ray emission from stars is induced by the interaction of cosmic rays with stellar atmospheres and photon fields. This emission is expected to come in two components: a stellar disk emission, where $\gamma$-rays are mainly produced in atmospheric showers generated by hadronic cosmic rays, and an extended halo emission, where the high density of soft photons in the surroundings of stars create a suitable environment for $\gamma$-ray production via inverse Compton (IC) scattering by cosmic-ray electrons. Besides the Sun, no other disk or halo from single stars has ever been detected in $\gamma$-rays. However, by assuming a cosmic-ray spectrum similar to that observed on Earth, the predicted $\gamma$-ray emission of super-luminous stars, like e.g. Betelgeuse and Rigel, could be high enough to be detected by the Fermi Large Area Telescope (LAT) after its first decade of operations. In this work, we use 12 years of Fermi-LAT observations along with IC models to study 9 super-luminous nearby stars, both individually and via stacking analysis. Our results show no significant $\gamma$-ray emission, but allow us to restrict the stellar $\gamma$-ray fluxes to be on average $<3.3 \times 10^{-11}$ ph cm$^{-2}$ s$^{-1}$ at a 3$\sigma$ confidence level, which translates to an average local density of electrons in the surroundings of our targets to be less than twice of that observed for the Solar System.Comment: 8 pages, 4 figure

Germline and Somatic Pharmacogenomics to Refine Rectal Cancer Patients Selection for Neo-Adjuvant Chemoradiotherapy

Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase,DPYD). The clinical impact of testingDPYD*2A, DPYD*13,c.2846A > Tandc.1236G > A-HapB3before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes areTYMS(Thymidylate Synthase) andMTHFR(Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of aTYMSpolymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, asBRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS(Kirsten Rat Sarcoma viral oncogene homolog), NRAS(Neuroblastoma RAS viral (v-ras) oncogene homolog),PIK3CA(Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well asTP53(Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations inKRASandTP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy

Parameter-free Molecular Super-Structures Quantification in Single-Molecule Localisation Microscopy

Understanding biological function requires the identification and characterization of complex patterns of molecules. Single-molecule localization microscopy (SMLM) can quantitatively measure molecular components and interactions at resolutions far beyond the diffraction limit, but this information is only useful if these patterns can be quantified and interpreted. We provide a new approach for the analysis of SMLM data that develops the concept of structures and super-structures formed by interconnected elements, such as smaller protein clusters. Using a formal framework and a parameter-free algorithm, (super-)structures formed from smaller components are found to be abundant in classes of nuclear proteins, such as heterogeneous nuclear ribonucleoprotein particles (hnRNPs), but are absent from ceramides located in the plasma membrane. We suggest that mesoscopic structures formed by interconnected protein clusters are common within the nucleus and have an important role in the organization and function of the genome. Our algorithm, SuperStructure, can be used to analyze and explore complex SMLM data and extract functionally relevant information

Markerless 3D human pose tracking through multiple cameras and AI: Enabling high accuracy, robustness, and real-time performance

Tracking 3D human motion in real-time is crucial for numerous applications across many fields. Traditional approaches involve attaching artificial fiducial objects or sensors to the body, limiting their usability and comfort-of-use and consequently narrowing their application fields. Recent advances in Artificial Intelligence (AI) have allowed for markerless solutions. However, most of these methods operate in 2D, while those providing 3D solutions compromise accuracy and real-time performance. To address this challenge and unlock the potential of visual pose estimation methods in real-world scenarios, we propose a markerless framework that combines multi-camera views and 2D AI-based pose estimation methods to track 3D human motion. Our approach integrates a Weighted Least Square (WLS) algorithm that computes 3D human motion from multiple 2D pose estimations provided by an AI-driven method. The method is integrated within the Open-VICO framework allowing simulation and real-world execution. Several experiments have been conducted, which have shown high accuracy and real-time performance, demonstrating the high level of readiness for real-world applications and the potential to revolutionize human motion capture.Comment: 19 pages, 7 figure

Actuation and Control of a Steerable Catheter for Mitral Valve Repair

In the field of Structural Heart Diseases, Mitral Regurgitation's incidence is rising because of an aging population worldwide, and it has reached an annual mortality rate near 34%. The procedures of Structural Intervention Cardiology have enlarged the number of treated patients, since their minimally invasive and trans-catheter approach. To provide a forward step-change in this procedure, the aim of this work is to improve the use of the commercially available MitraClip system®, suggesting an innovative robot-assisted platform with autonomous control for the aforementioned system. The presented methodology is constituted of two phases: in the first one, we design, in the Solidworks® environment, 3D print and integrate the mechanical support with electrical motors and micro-controller devoted to catheter's steering. In the second phase, we develop the closed-loop position control to improve the accuracy in the autonomous positioning of the catheter. The described approach was tested to demonstrate its feasibility and dexterity: a position accuracy of 1.1±0.54 mm in following a given optimal trajectory was obtained

Altitudinal training sets of pollen rain – vegetation cover and modelled climate as a tool for the interpretation of paleoecological records

To improve our ability to reconstruct past environments and climate from fossil pollen records, modern proxy calibration studies along climatic and ecological gradients are needed. Here we present the first training set of modern pollen rain, vegetation, climate and terrain parameters developed along a 1700m-high transect in the western Italian Alps. The accurate knowledge on the relationships between these factors is essential for robust and sound reconstructions of past ecosystems based on microscopic plant remains

New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma.

The tyrosine kinase inhibitor (TKI) sorafenib continues to be the anchor drug in the treatment of advanced stage hepatocellular carcinoma (HCC). Other TKIs as well as immune checkpoint inhibitors (ICIs) have also been approved, however the response rates remain poor and heterogeneous among HCC patients, largely due to antitumor drug resistance. Studies aimed at identifying novel biomarkers and developing new strategies to improve the response to current treatment and to overcome drug resistance, are urgently needed. Germline or somatic mutations, neoantigens, and an immunotolerogenic state against constant inflammatory stimuli in the liver, are crucial for the anti-tumor response. A pharmacogenetic approach has been attempted considering germline polymorphisms in genes encoding for proteins involved in drug-targeted pathways. Single gene and comprehensive multi-gene somatic profiling approaches have been adopted in HCC to identify tumor sensitivity scores and immunogenic profiles that can be exploited for new biomarkers and innovative therapeutic approaches. However, the high genomic heterogeneity of tumors and lack of molecularly targeted agents, hamper the discovery of specific molecular markers of resistance to therapy. Adoptive cell therapy with chimeric antigen receptor redirected T (CAR-T) cells targeting specific tumor-associated antigens (TAAs) was proposed recently. The specificity of the chosen TAA, an efficient homing of CAR-T cells to the tumor site, and the ability of CAR-T cells to survive in the tumor microenvironment are central factors in the success of CAR-T therapy. The current review describes the principal systemic treatments for HCC and the molecular evidence regarding potential predictive host and somatic genetic markers, as well as the emerging strategy of liquid biopsy for disease monitoring. Novel immunotherapeutic approaches for HCC treatment, including the use of ICIs and CAR-T, as well as strategies to overcome drug resistance, are discussed

Scaling of a large-scale simulation of synchronous slow-wave and asynchronous awake-like activity of a cortical model with long-range interconnections

Cortical synapse organization supports a range of dynamic states on multiple spatial and temporal scales, from synchronous slow wave activity (SWA), characteristic of deep sleep or anesthesia, to fluctuating, asynchronous activity during wakefulness (AW). Such dynamic diversity poses a challenge for producing efficient large-scale simulations that embody realistic metaphors of short- and long-range synaptic connectivity. In fact, during SWA and AW different spatial extents of the cortical tissue are active in a given timespan and at different firing rates, which implies a wide variety of loads of local computation and communication. A balanced evaluation of simulation performance and robustness should therefore include tests of a variety of cortical dynamic states. Here, we demonstrate performance scaling of our proprietary Distributed and Plastic Spiking Neural Networks (DPSNN) simulation engine in both SWA and AW for bidimensional grids of neural populations, which reflects the modular organization of the cortex. We explored networks up to 192x192 modules, each composed of 1250 integrate-and-fire neurons with spike-frequency adaptation, and exponentially decaying inter-modular synaptic connectivity with varying spatial decay constant. For the largest networks the total number of synapses was over 70 billion. The execution platform included up to 64 dual-socket nodes, each socket mounting 8 Intel Xeon Haswell processor cores @ 2.40GHz clock rates. Network initialization time, memory usage, and execution time showed good scaling performances from 1 to 1024 processes, implemented using the standard Message Passing Interface (MPI) protocol. We achieved simulation speeds of between 2.3x10^9 and 4.1x10^9 synaptic events per second for both cortical states in the explored range of inter-modular interconnections.Comment: 22 pages, 9 figures, 4 table