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The Meteosat Third Generation (MTG) Lightning Imager (LI) is the first geostationary optical lightning detector imaging Europe, Africa, and a large fraction of the Atlantic Ocean. Launched on board of the MTG-I1 satellite on 13 December 2022, LI will perform the detection from space of optical pulses produced by lightning. Optical pulses at cloud tops are produced by the photons emitted by lightning electric discharges within or below clouds that reach cloud tops after multiple scattering. The LI senses this cloud-top light within a 1.9 nm wide band centred on 777 nm, with a 4.5 km resolution at sub-satellite point, and 1 kHz acquisition frequency. The LI instrument consists of four cameras (optical channels), covering a total of 84% of visible disk with continuous lightning data. The field of view of the LI fully covers Europe and Africa. In addition, the eastern and southern parts of the Atlantic Ocean, eastern part of South America and north western part of the Indian Ocean are also covered. The operationally disseminated LI data (expected in early 2024) will consist of point data and accumulated data. The most important point data products for severe storm monitoring and tracking are the lightning groups (LGR) and lightning flashes (LFL), containing the times, latitudes, longitudes and optical radiance information of observed lightning groups and flashes. The lightning group product is similar to strokes/pulses produced by ground-based lightning location systems while the LI flash product is similar to flashes produced by ground-based systems. In addition to point data, three accumulated data products, Accumulated Flashes (AF), Accumulated Flash Area (AFA) and Accumulated Flash Radiance (AFR) will be disseminated. All accumulated products provide users with information about the full accumulated spatial extent of the observed optical pulses. This is achieved by integrating over 30 sec pixels-based lightning detections composing the Level 2 flashes (also available in LFL as point data). This type of data will allow users to monitor features like long horizontal lightning channels in the stratiform regions of Mesoscale Convective Systems. Finally, all accumulated products are provided to users on the Flexible Combined Imager (FCI) 2 km grid, making it easy to combine LI and FCI products for more advanced severe weather monitoring products. The presentation will give a brief overview of the LI System to introduce examples of LI data complemented by some early Commissioning results.

An understanding of drug resistance and the development of novel strategies to sensitize highly resistant cancers rely on the availability of suitable preclinical models that can accurately predict patient responses. One of the disadvantages of existing preclinical models is the inability to contextually preserve the human tumor microenvironment (TME) and accurately represent intratumoral heterogeneity, thus limiting the clinical translation of data. By contrast, by representing the culture of live fragments of human tumors, the patient-derived explant (PDE) platform allows drug responses to be examined in a three-dimensional (3D) context that mirrors the pathological and architectural features of the original tumors as closely as possible. Previous reports with PDEs have documented the ability of the platform to distinguish chemosensitive from chemoresistant tumors, and it has been shown that this segregation is predictive of patient responses to the same chemotherapies. Simultaneously, PDEs allow the opportunity to interrogate molecular, genetic, and histological features of tumors that predict drug responses, thereby identifying biomarkers for patient stratification as well as novel interventional approaches to sensitize resistant tumors. This paper reports PDE methodology in detail, from collection of patient samples through to endpoint analysis. It provides a detailed description of explant derivation and culture methods, highlighting bespoke conditions for particular tumors, where appropriate. For endpoint analysis, there is a focus on multiplexed immunofluorescence and multispectral imaging for the spatial profiling of key biomarkers within both tumoral and stromal regions. By combining these methods, it is possible to generate quantitative and qualitative drug response data that can be related to various clinicopathological parameters and thus potentially be used for biomarker identification.

The transcription factor p63 belongs to the p53-family and is a master regulator of proliferative potential, lineage specification, and differentiation in epithelia during development and tissue homeostasis. In cancer, p63 contribution is isoform-specific, with both oncogenic and tumour suppressive roles attributed, for ΔNp63 and TAp63, respectively. Recently, p53 and TAp73, in line with other tumour suppressor genes, have emerged as important regulators of energy metabolism and metabolic reprogramming in cancer. To date, p63 contributions in controlling energy metabolism have been partially investigated; given the extensive interaction of the p53 family members, these studies have potential implications in tumour cells for metabolic reprogramming. Here, we review the role of p63 isoforms, TAp63 and ΔNp63, in controlling cell metabolism, focusing on their specific metabolic target genes and their physiological/functional context of action.

The inhibition of PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, breaking tumour-induced immune tolerance and restoring anti-tumour immunity. Bioinformatics and protein expression studies have shown that PIK3CD/PI3Kδ is also highly expressed in certain solid malignancies. IOA-244 is a novel, highly selective PI3Kδ inhibitor, with the unique property of being ATP non-competitive. In addition to the effects of PI3Kδ inhibition on the balance of CD8+ T cells and T regulatory cells in the tumour microenvironment, we have recently demonstrated that IOA-244 effectively controls the growth of tumour cells with high levels of PI3Kδ in vivo in T-cell deficient hosts. Analysis of TCGA datasets shows that certain solid tumours express high levels of PIK3CD transcript, comparable to that of diffuse large B cell lymphoma. Of these indications, cutaneous and uveal melanoma are amongst the highest expressers. To support the clinical development of IOA-244, we demonstrate that patient-derived melanoma cells with a high expression of PIK3CD are susceptible to treatment with IOA-244 in a mouse patient-derived xenograft model. Furthermore, in vitro explant studies using clinical biopsy material demonstrates that PI3Kδ expression can be detected in tumour tissue and that IOA-244 has an anti-proliferative function when added to these samples. Based on these and other supporting data, IOA-244 has received clinical trial approval in Europe and phase I clinical testing is underway in solid tumours with an anticipated high Treg:CD8 ratio and/or high protein expression of PI3Kδ. Citation Format: Amy R. MacQueen, Giuditta Viticchie, Karolina Niewola, Francesca Finotello, Ian Powley, Pritom Shah, Lars van der Veen, Michael Lahn, Zoe Johnson. A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 666.

The c-Met receptor, also known as the HGF receptor, is one of the most studied tyrosine kinase receptors, yet its biological functions and activation mechanisms are still not fully understood. c-Met has been implicated in embryonic development and organogenesis, in tissue remodelling homeostasis and repair and in cancer metastasis. These functions are indicative of the many cellular processes in which the receptor plays a role, including cell motility, scattering, survival and proliferation. In the context of malignancy, sustained activation of c-Met leads to a signalling cascade involving a multitude of kinases that initiate an invasive and metastatic program. Many proteins can affect the activation of c-Met, including a variety of other cell surface and membrane-spanning molecules or receptors. Some cell surface molecules share structural homology with the c-Met extracellular domain and can activate c-Met via clustering through this domain (e.g., plexins), whereas other receptor tyrosine kinases can enhance c-Met activation and signalling through intracellular signalling cascades (e.g., EGFR). In this review, we provide an overview of c-Met interactions and crosstalk with partner molecules and the functional consequences of these interactions on c-Met activation and downstream signalling, c-Met intracellular localization/recycling and c-Met degradation.

A differentiation-promoting micro-RNA regulates actin cable dynamics, intercellular adhesion, and cell migration in human and mouse epidermis., During keratinocyte differentiation and stratification, cells undergo extensive remodeling of their actin cytoskeleton, which is important to control cell mobility and to coordinate and stabilize adhesive structures necessary for functional epithelia. Limited knowledge exists on how the actin cytoskeleton is remodeled in epithelial stratification and whether cell shape is a key determinant to trigger terminal differentiation. In this paper, using human keratinocytes and mouse epidermis as models, we implicate miR-24 in actin adhesion dynamics and demonstrate that miR-24 directly controls actin cable formation and cell mobility. miR-24 overexpression in proliferating cells was sufficient to trigger keratinocyte differentiation both in vitro and in vivo and directly repressed cytoskeletal modulators (PAK4, Tks5, and ArhGAP19). Silencing of these targets recapitulated the effects of miR-24 overexpression. Our results uncover a new regulatory pathway involving a differentiation-promoting microribonucleic acid that regulates actin adhesion dynamics in human and mouse epidermis.

Sodium 2-propenyl thiosulfate, a water-soluble organo-sulfane sulfur compound isolated from garlic, induces apoptosis in a number of cancer cells. The molecular mechanism of action of sodium 2-propenyl thiosulfate has not been completely clarified. In this work we investigated, by in vivo and in vitro experiments, the effects of this compound on the expression and activity of rhodanese. Rhodanese is a protein belonging to a family of enzymes widely present in all phyla and reputed to play a number of distinct biological roles, such as cyanide detoxification, regeneration of iron–sulfur clusters and metabolism of sulfur sulfane compounds. The cytotoxic effects of sodium 2-propenyl thiosulfate on HuT 78 cells were evaluated by flow cytometry and DNA fragmentation and by monitoring the progressive formation of mobile lipids by NMR spectroscopy. Sodium 2-propenyl thiosulfate was also found to induce inhibition of the sulfurtransferase activity in tumor cells. Interestingly, in vitro experiments using fluorescence spectroscopy, kinetic studies and MS analysis showed that sodium 2-propenyl thiosulfate was able to bind the sulfur-free form of the rhodanese, inhibiting its thiosulfate:cyanide-sulfurtransferase activity by thiolation of the catalytic cysteine. The activity of the enzyme was restored by thioredoxin in a concentration-dependent and time-dependent manner. Our results suggest an important involvement of the essential thioredoxin–thioredoxin reductase system in cancer cell cytotoxicity by organo-sulfane sulfur compounds and highlight the correlation between apoptosis induced by these compounds and the damage to the mitochondrial enzymes involved in the repair of the Fe–S cluster and in the detoxification system.

A large area ring-imaging Cherenkov detector has been designed to provide clean hadron identification capability in the momentum range from 3 GeV/c up to 8 GeV/c for the CLAS12 experiments at the upgraded 12 GeV continuous electron beam accelerator facility of Jefferson Laboratory. The adopted solution foresees a novel hybrid optics design based on aerogel radiator, composite mirrors and high-packed and high-segmented photon detectors. Cherenkov light will either be imaged directly (forward tracks) or after two mirror reflections (large angle tracks). We report here the results of the tests of a large scale prototype of the RICH detector performed with the hadron beam of the CERN T9 experimental hall for the direct detection configuration. The tests demonstrated that the proposed design provides the required pion-to-kaon rejection factor of 1:500 in the whole momentum range., Comment: 15 pages, 23 figures, to appear on EPJA

ADvanced Astronomy for HELIophysics (ADAHELI) is a Small Mission to study the structure and fast dynamics of the low solar atmosphere, performing Visible-NIR monochromatic and broad-band observations. The mission will achieve millimeter full disk observations as well. The ADAHELI Team has succesfully completed, in December 2008, the Phase A study awarded by the Italian Space Agency (ASI). The Interferometer for SOlar Dynamics (ISODY), on board the ADAHELI satellite, comprises a Gregorian telescope and its focal plane suite. The advanced design focal plane suite uses fast CMOS cameras for investigating photospheric and chromospheric fast dynamics and structure. ISODY is equipped with a pioneering focal plane suite composed of a spectral channel, based upon a tandem of Fabry-Perot interferometers operating in the visible-NIR spectral region, a broad band channel for high resolution imaging, and a correlation tracker used as an image stabilization system. ADAHELI's mission profile has been tailored to limit the spacecraft's radial velocity in the Sunward direction, to not exceed ±4 km/s, during 95% of the yearly orbit, to allow a continuous use of the on-board interferometer.

There is a long-standing debate why the Mn i 5394.7 Å line in the solar irradiance spectrum brightens more at higher activity than other photospheric lines. The claim that this is caused by spectral interlocking to chromospheric emission in the Mg ii h&k lines is disputed. In this paper we settle this issue, using classical one-dimensional modeling for demonstration and modern three-dimensional MHD simulation for verification and analysis. The unusual sensitivity of the Mn i 5394.7 Å line to solar activity is due to its excessive hyperfine structure. This overrides the thermal and granular Doppler smearing through which the other, narrower, photospheric lines lose such sensitivity.We take the nearby Fe i 5395.2 Å line as example of the latter, and analyze the formation of both lines in detail to demonstrate and explain the granular Doppler brightening which affects all narrow photospheric lines. Neither the chromosphere nor Mg ii h&k emission play a role, nor is it correct to describe the activity sensitivity of Mn i 5394.7 Å in terms of plage models with outward increasing temperature contrast. The Mni 5394.7 Å line represents a proxy diagnostic of strong-field magnetic concentrations in the deep solar photosphere comparable to the G band and the blue wing of Hα, but not a better one than these. The Mn i lines are more promising as diagnostics of weak fields in high-resolution Stokes polarimetry.

There is a long-standing debate why the Mn i 5394.7 Å line in the solar irradiance spectrum brightens more at higher activity than other photospheric lines. The claim that this is caused by spectral interlocking to chromospheric emission in the Mg ii h&k lines is disputed. In this paper we settle this issue, using classical one-dimensional modeling for demonstration and modern three-dimensional MHD simulation for verification and analysis. The unusual sensitivity of the Mn i 5394.7 Å line to solar activity is due to its excessive hyperfine structure. This overrides the thermal and granular Doppler smearing through which the other, narrower, photospheric lines lose such sensitivity.We take the nearby Fe i 5395.2 Å line as example of the latter, and analyze the formation of both lines in detail to demonstrate and explain the granular Doppler brightening which affects all narrow photospheric lines. Neither the chromosphere nor Mg ii h&k emission play a role, nor is it correct to describe the activity sensitivity of Mn i 5394.7 Å in terms of plage models with outward increasing temperature contrast. The Mni 5394.7 Å line represents a proxy diagnostic of strong-field magnetic concentrations in the deep solar photosphere comparable to the G band and the blue wing of Hα, but not a better one than these. The Mn i lines are more promising as diagnostics of weak fields in high-resolution Stokes polarimetry.

Sodium 2-propenyl thiosulfate, a water-soluble organo-sulfane sulfur compound isolated from garlic, induces apoptosis in a number of cancer cells. The molecular mechanism of action of sodium 2-propenyl thiosulfate has not been completely clarified. In this work we investigated, by in vivo and in vitro experiments, the effects of this compound on the expression and activity of rhodanese. Rhodanese is a protein belonging to a family of enzymes widely present in all phyla and reputed to play a number of distinct biological roles, such as cyanide detoxification, regeneration of iron-sulfur clusters and metabolism of sulfur sulfane compounds. The cytotoxic effects of sodium 2-propenyl thiosulfate on HuT 78 cells were evaluated by flow cytometry and DNA fragmentation and by monitoring the progressive formation of mobile lipids by NMR spectroscopy. Sodium 2-propenyl thiosulfate was also found to induce inhibition of the sulfurtransferase activity in tumor cells. Interestingly, in vitro experiments using fluorescence spectroscopy, kinetic studies and MS analysis showed that sodium 2-propenyl thiosulfate was able to bind the sulfur-free form of the rhodanese, inhibiting its thiosulfate:cyanide-sulfurtransferase activity by thiolation of the catalytic cysteine. The activity of the enzyme was restored by thioredoxin in a concentration-dependent and time-dependent manner. Our results suggest an important involvement of the essential thioredoxin-thioredoxin reductase system in cancer cell cytotoxicity by organo-sulfane sulfur compounds and highlight the correlation between apoptosis induced by these compounds and the damage to the mitochondrial enzymes involved in the repair of the Fe-S cluster and in the detoxification system.

Keratinocyte proliferation and migration are crucial steps for the rapid closure of the epidermis during wound healing, but the molecular mechanisms involved in this cellular response remain to be completely elucidated. Here, by in situ hybridization we characterize the expression pattern of miR-203 after the induction of wound in mouse epidermis, showing that its expression is downregulated in the highly proliferating keratinocytes of the ‘migrating tongue', whereas it is strongly expressed in the differentiating cells of the skin outside the wound. Furthermore, subcutaneous injections of antagomiR-203 in new born mice dorsal skin strengthened, in vivo, the inverse correlation between miR-203 expression and two new target mRNAs: RAN and RAPH1. Our data suggest that miR-203, by controlling the expression of target proteins that are responsible for both keratinocyte proliferation and migration, exerts a specific role in wound re-epithelialization and epidermal homeostasis re-establishment of injured skin.

Prostate cancers show a slow progression from a local lesion (primary tumor) to a metastatic and hormone-resistant phenotype. After an initial step of hyperplasia, in a high percentage of cases a neoplastic transformation event occurs that, less frequently, is followed by epithelial to mesenchymal transition and invasion of healthy tissues (usually bones). MicroRNA-203 (miR-203) is a tumor suppressor microRNA often silenced in different malignancies. Here, we show that miR-203 is downregulated in clinical primary prostatic tumors compared to normal prostate tissue, and in metastatic prostate cancer cell lines compared to normal epithelial prostatic cells. Overexpression of miR-203 in brain or bone metastatic prostate cell lines (DU145 and PC3) is sufficient to induce a mesenchymal to epithelial transition with inhibition of cell proliferation, migration and invasiveness. We have identified CKAP2, LASP1, BIRC5, WASF1, ASAP1 and RUNX2 as new miR-203 direct target mRNAs involved in these events. Therefore, miR-203 could be a potentially new prognostic marker and therapeutic target in metastatic prostate cancer.