Probing light vector mediators with coherent scattering at future facilities

Future experiments dedicated to the detection of Coherent Elastic Neutrino-Nucleus Scattering may be powerful tools in probing light new physics. In this paper we study the sensitivity on light Z' mediators of two proposed experiments: a directional low pressure Time Projection Chamber detector, nu BDX-DRIFT, that will utilize neutrinos produced at the Long Baseline Neutrino Facility, and several possible experiments to be installed at the European Spallation Source. We compare the results obtained with existing limits from fixed-target, accelerator, solar neutrino and reactor experiments. Furthermore, we show that these experiments have the potential to test unexplored regions that, in some case, could explain the anomalous magnetic moment of the muon or peculiar spectral features in the cosmic neutrino spectrum observed by IceCube

Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype

Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or -independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance

Resistance-based probabilistic design by order statistics for an oil and gas deep-water well casing string affected by wear during kick load

Deep-water wells for oil and gas extraction make structural components, such as casing and tubing, work in extremely harsh environmental conditions that accelerate component degradation and increase failure probability. Therefore, it is important to properly design casing strings under these operative circumstances (Baraldi et al., 2012)

The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint

Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species.Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling.Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors

contribution of bronchial biopsies in the evaluation of pathogenesis and progression of copd

This review summarizes and discusses the lung pathology of COPD patients emphasising on inflammatory cell phenotypes and mechanisms which prevail in different clinical conditions. In bronchial biopsies a series of events takes place during the progression of the disease from mild to severe. T-lymphocytes, particularly CD8+ cells and macrophages are the prevalent inflammatory cells in the lungs of healthy smokers and patients with mild/moderate COPD. This T-cell activation seems to be sustained by CD4+, CD8+ cells and macrophages expressing transcription factors and Tc1 cytokines such as NF-kB, STAT4 and IFNγ. In contrast, severe disease is characterized by lymphocytes producing greater amounts of TGF-ß1 and by an increase of nitrotyrosine immunoreactivity and activated neutrophils, macrophages and MPO+ cells. However, the mechanisms involved in neutrophilic migration and adhesion are currently under investigation. Recent data has shown that in severe COPD there is an impaired neutrophil capability to respond to chemotactic stimuli, as well as an increased collagen adhesion of neutrophils due to the up-regulation of CD44 and CD11b receptors. This data together, may account for the increased neutrophilia observed in the severe disease states of COPD. In this context, insights obtained from the tissutal analysis of bronchial biopsies represent an irreplaceable route to further progresses in to the pathogenesis of this disease

ColibriES: A Milliwatts RISC-V Based Embedded System Leveraging Neuromorphic and Neural Networks Hardware Accelerators for Low-Latency Closed-loop Control Applications

End-to-end event-based computation has the potential to push the envelope in latency and energy efficiency for edge AI applications. Unfortunately, event-based sensors (e.g., DVS cameras) and neuromorphic spike-based processors (e.g., Loihi) have been designed in a decoupled fashion, thereby missing major streamlining opportunities. This paper presents ColibriES, the first-ever neuromorphic hardware embedded system platform with dedicated event-sensor interfaces and full processing pipelines. ColibriES includes event and frame interfaces and data processing, aiming at efficient and long-life embedded systems in edge scenarios. ColibriES is based on the Kraken system-on-chip and contains a heterogeneous parallel ultra-low power (PULP) processor, frame-based and event-based camera interfaces, and two hardware accelerators for the computation of both event-based spiking neural networks and frame-based ternary convolutional neural networks. This paper explores and accurately evaluates the performance of event data processing on the example of gesture recognition on ColibriES, as the first step of full-system evaluation. In our experiments, we demonstrate a chip energy consumption of 7.7 \si{\milli\joule} and latency of 164.5 \si{\milli\second} of each inference with the DVS Gesture event data set as an example for closed-loop data processing, showcasing the potential of ColibriES for battery-powered applications such as wearable devices and UAVs that require low-latency closed-loop control

ColibriUAV: An Ultra-Fast, Energy-Efficient Neuromorphic Edge Processing UAV-Platform with Event-Based and Frame-Based Cameras

The interest in dynamic vision sensor (DVS)-powered unmanned aerial vehicles (UAV) is raising, especially due to the microsecond-level reaction time of the bio-inspired event sensor, which increases robustness and reduces latency of the perception tasks compared to a RGB camera. This work presents ColibriUAV, a UAV platform with both frame-based and event-based cameras interfaces for efficient perception and near-sensor processing. The proposed platform is designed around Kraken, a novel low-power RISC-V System on Chip with two hardware accelerators targeting spiking neural networks and deep ternary neural networks.Kraken is capable of efficiently processing both event data from a DVS camera and frame data from an RGB camera. A key feature of Kraken is its integrated, dedicated interface with a DVS camera. This paper benchmarks the end-to-end latency and power efficiency of the neuromorphic and event-based UAV subsystem, demonstrating state-of-the-art event data with a throughput of 7200 frames of events per second and a power consumption of 10.7 \si{\milli\watt}, which is over 6.6 times faster and a hundred times less power-consuming than the widely-used data reading approach through the USB interface. The overall sensing and processing power consumption is below 50 mW, achieving latency in the milliseconds range, making the platform suitable for low-latency autonomous nano-drones as well

Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH‑regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen‑activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen‑activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH‑regulated transcription factor. Phosphorylation occurred at multiple residues in the C‑terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14‑3‑3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy