The LuGRE project: a scientific opportunity to study GNSS signals at the Moon

The Lunar GNSS Receiver Experiment (LuGRE) is a joint NASA-Italian Space Agency (ASI) payload on the Firefly Blue Ghost Mission 1 with the goal to demonstrate GNSS-based positioning, navigation, and timing at the Moon. When launched, LuGRE will collect GPS and Galileo measurements in transit between Earth and the Moon, in lunar orbit, and on the lunar surface, and will conduct onboard and ground-based navigation experiments using the collected data. These investigations will be based on the observation of the data collected by a custom development performed by the company Qascom, based on the Qascom QN400-Space GNSS receiver. The receiver is able to provide, PVT solutions, the GNSS raw observables obtained by the real time operation, as well as snapshots of IF digital samples collected by the RF front-end at frequencies L1/E1 and L5/E5. These data will be the input for the different science investigations, that require then the development of proper analysis tools that will be the core of the ground segment during the mission. The current work done by the science team of NASA and ASI, which is supported by a research team at Politecnico di Torino, is planning the data acquisitions during the time windows dedicated to the LuGRE payload in the checkout, transit and surface mission phases

Occurrence of the Blue button Porpita porpita along the Italian Ionian and Tyrrhenian coasts

New individuals of Porpita porpita were detected along the Italian coasts of the Mediterranean Sea. In recent years, due to warming Mediterranean waters, the species has spread even further. This observation opens new horizons for further reports of this species in the Ionian and Tyrrhenian Seas of Italy

Iron-coated Komodo dragon teeth and the complex dental enamel of carnivorous reptiles.

Komodo dragons (Varanus komodoensis) are the largest extant predatory lizards and their ziphodont (serrated, curved and blade-shaped) teeth make them valuable analogues for studying tooth structure, function and comparing with extinct ziphodont taxa, such as theropod dinosaurs. Like other ziphodont reptiles, V. komodoensis teeth possess only a thin coating of enamel that is nevertheless able to cope with the demands of their puncture-pull feeding. Using advanced chemical and structural imaging, we reveal that V. komodoensis teeth possess a unique adaptation for maintaining their cutting edges: orange, iron-enriched coatings on their tooth serrations and tips. Comparisons with other extant varanids and crocodylians revealed that iron sequestration is probably widespread in reptile enamels but it is most striking in V. komodoensis and closely related ziphodont species, suggesting a crucial role in supporting serrated teeth. Unfortunately, fossilization confounds our ability to consistently detect similar iron coatings in fossil teeth, including those of ziphodont dinosaurs. However, unlike V. komodoensis, some theropods possessed specialized enamel along their tooth serrations, resembling the wavy enamel found in herbivorous hadrosaurid dinosaurs. These discoveries illustrate unexpected and disparate specializations for maintaining ziphodont teeth in predatory reptiles

The Effects of Biting and Pulling on the Forces Generated during Feeding in the Komodo Dragon (Varanus komodoensis)

In addition to biting, it has been speculated that the forces resulting from pulling on food items may also contribute to feeding success in carnivorous vertebrates. We present an in vivo analysis of both bite and pulling forces in Varanus komodoensis, the Komodo dragon, to determine how they contribute to feeding behavior. Observations of cranial modeling and behavior suggest that V. komodoensis feeds using bite force supplemented by pulling in the caudal/ventrocaudal direction. We tested these observations using force gauges/transducers to measure biting and pulling forces. Maximum bite force correlates with both body mass and total body length, likely due to increased muscle mass. Individuals showed consistent behaviors when biting, including the typical medial-caudal head rotation. Pull force correlates best with total body length, longer limbs and larger postcranial motions. None of these forces correlated well with head dimensions. When pulling, V. komodoensis use neck and limb movements that are associated with increased caudal and ventral oriented force. Measured bite force in Varanus komodoensis is similar to several previous estimations based on 3D models, but is low for its body mass relative to other vertebrates. Pull force, especially in the ventrocaudal direction, would allow individuals to hunt and deflesh with high success without the need of strong jaw adductors. In future studies, pull forces need to be considered for a complete understanding of vertebrate carnivore feeding dynamics

Molecular basis of targeted therapy in T/NKcell lymphoma/leukemia: A comprehensive genomic and immunohistochemical analysis of a panel of 33 cell lines

T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways. The study identified TP53, NOTCH1 and DNMT3A as the most frequently mutated genes. We also found common alterations in JAK/STAT and epigenetic pathways. Immunohistochemical analysis showed nuclear accumulation of MYC (in 85% of the cases), NFKB (62%), p-STAT (44%) and p-MAPK (30%). This panel of cell lines captures the complexity of T/NK-cell lymphoproliferative processes samples, with the partial exception of AITL cases. Integrated mutational and immunohistochemical analysis shows that mutational changes cannot fully explain the activation of key survival pathways and the resulting phenotypes. The combined integration of mutational/expression changes forms a useful tool with which new compounds may be assayed

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy

Characterization of the Endothelial Cell Cytoskeleton following HLA Class I Ligation

Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood.The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin.Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types as a method for uncovering novel regulators of cytoskeleton changes

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS <sup>SMARCB1-</sup> , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS <sup>SMARCB1-</sup> show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS <sup>Smarcb1-</sup> . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS <sup>SMARCB1-</sup> within the TME

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding