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Background SARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2. Methods Here, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infection in vivo. Results We demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using an in-vitro model of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects. Conclusions Together, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.

Respiratory viruses remain a significant cause of morbidity and mortality in the human population, underscoring the importance of ongoing basic research into virus–host interactions. However, many critical aspects of infection are difficult, if not impossible, to probe using standard cell lines, 2D culture formats, or even animal models. In vitro systems such as airway epithelial cultures at air–liquid interface, organoids, or ‘on-chip’ technologies allow interrogation in human cells and recapitulate emergent properties of the airway epithelium—the primary target for respiratory virus infection. While some of these models have been used for over thirty years, ongoing advancements in both culture techniques and analytical tools continue to provide new opportunities to investigate airway epithelial biology and viral infection phenotypes in both normal and diseased host backgrounds. Here we review these models and their application to studying respiratory viruses. Furthermore, given the ability of these systems to recapitulate the extracellular microenvironment, we evaluate their potential to serve as a platform for studies specifically addressing viral interactions at the mucosal surface and detail techniques that can be employed to expand our understanding.

IntroductionAutism Spectrum Disorder (ASD) includes a group of developmental disabilities characterized by patterns of delay and deviance in the development of social, communicative, cognitive skills and the presence of repetitive and stereotyped behaviors as well as restricted interests (APA, 2013 DSM 5th ed.).ObjectivesA 22-years old male outpatient affected by Autism Spectrum Disorder (Level 3) and severe ID presented serious challenging behaviors. The patient did not suffer from other psychiatric or neurologic pathologies. The patient did not have constipation or diarrhea or painful symptoms. The patients assumed carbamazepine (modified release) 800 mg/day (blood dosage 6,8 microgram/ml), clonazepam 2,5 mg/ml 15 drops/day, lorazepam 7,5 mg/die.MethodsDue to the onset of challenging behaviors risperidone was introduced. At the dosage of 2 mg/day, the patient reached a discrete control of challenging behaviors. After stopping risperidone because of oculogyric crisis, the patient started to assume valproic acid (chronic formulation) up to 1000 mg/day. After three weeks the patient presented an increase in the blood dosage of ammonium. After the drug stop, the patient began to re-present challenging behaviors. The authors decided to add topiramate at a dosage of 25 mg per day. After three days, the patient began to present nocturnal urinary incontinence. Topiramate was stopped and Gabapentin was introduced in the treatment up to the dosage of 900 mg/day. Lorazepam was gradually tapered off until the intake was terminated, and clonazepam was reduced to 5 drops/day taken at bedtime. The dosage of carbamazepine remained stable.ResultsTable 1.Behavior Problems Inventory subscales scoresPre-treatment (T0)Post-treatment (T1)% ImprovementsBehavior Problems Inventory SubscalesFrequencySeverityFrequencySeverityFrequencySeveritySelf-Injurious Behavior625216,7%0%Stereotyped Behavior4919381622,5%15,8%Aggressive/destructive Behavior3925242038,5%20%ConclusionsAccording to the GABAergic hypothesis of ASD, inhibitory signaling of GABA within and between cortical minicolumns appears to be altered. This alteration would result in information processing with high discrimination between correlated stimuli rather than a generalization of them (Casanova et al. Neuroscientist 2003; 9: 496-507). Gabapentin is a ligand of the auxiliary alpha-2-delta subunit site of voltage-dependent calcium channels and acts as an inhibitor of the channel (Sills Curr Opin Pharmacol 2006; 6 (1):108-13). The altered expression of alpha-2-delta 1 or alpha-2-delta 3 can cause a chronic imbalance between arousal and inhibition that is quite characteristic of ASD (Nelson et al. Neuron 2015;87:684-698). The authors want to speculate on a hypothetical function of gabapentin in remodeling the expression of alpha-2-delta subunits in people with autism and the processing of neural information.Disclosure of InterestNone Declared

MEMPHYS (MEgaton Mass PHYSics) is a proposed large-scale water-Cherenkov experiment to be performed deep underground. It is dedicated to nucleon decay searches and the detection of neutrinos from supernovae, solar, and atmospheric neutrinos, as well as neutrinos from a future beam to measure the CP violating phase in the leptonic sector and the mass hierarchy. This paper provides an overview of the latest studies on the expected performance of MEMPHYS in view of detailed estimates of its physics reach, mainly concerning neutrino beams.

IntroductionAutism Spectrum Disorder (ASD) includes a group of developmental disabilities characterized by patterns of delay and deviance in the development of social, communicative, cognitive skills and the presence of repetitive and stereotyped behaviors as well as restricted interests (APA, 2013 DSM 5th ed.). Although the etiopathogenesis of autism has not yet been elucidated, past literature has highlighted an imbalance between glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmission (Harada et al. J Autism Dev Disord 2011;41:447-54.). A cortical deficiency of GABA in young people with ASD has been reported (Rojas et al. Neuroimage 2013;86:28-34.). Endocannabinoids act in numerous synapses of the central nervous system, maintaining an adequate synaptic homeostasis, preventing excess stimulation at the level of excitatory or inhibitory synapses. They therefore appear to be fundamental for the short- and long-term control of synaptic plasticity (Castillo et al. Neuron 2012;76,70-81). The endocannabinoid system appears to play an important role in some clinical presentations of autism, such as socialization. Indeed, Autism Spectrum Disorder seems to be characterized by a hypo-functionality of the endocannabinoid system (Aran et al. Mol Autism 2019;10, 2).ObjectivesThe present work aims to describe the current state of the art regarding the possible role of cannabinoids in the modulation of the excitatory and inhibitory systems in individuals with ASD.MethodsWe carried out a search on PubMed concerning the randomized clinical trials on the modulating effect of excitatory and inhibitory cannabinoid systems in autism. Three eligible articles were found according to the purpose of the present study.ResultsThe results of the three articles considered highlighted a cannabinoid (CBD)-related increase in glutamate in subcortical regions (basal ganglia) and a decrease in cortical regions (dorsomedial prefrontal cortex), both in subjects with and without ASD. CBD increased GABA transmission in the subcortical regions of neurotypical subjects, while it decreased it in the same areas of the ASD group. Furthermore, CBD modulated low-frequency activity, used as a measure of brain activity and functional connectivity in the brains of adults with ASD.ConclusionsData from the three functional MRI studies demonstrated that CBD influences cortical and subcortical connectivity on an adult sample. This effect was notable only in the ASD group but not in the controls. However, further studies are needed to confirm the results obtained so far.Disclosure of InterestNone Declared

Identifying the genes underlying adaptation is a major challenge in evolutionary biology. Here, we describe the molecular changes underlying adaptive coat color variation in a natural population of rock pocket mice, Chaetodipus intermedius. Rock pocket mice are generally light-colored and live on light-colored rocks. However, populations of dark (melanic) mice are found on dark lava, and this concealing coloration provides protection from avian and mammalian predators. We conducted association studies by using markers in candidate pigmentation genes and discovered four mutations in the melanocortin-1-receptor gene, Mc1r, that seem to be responsible for adaptive melanism in one population of lava-dwelling pocket mice. Interestingly, another melanic population of these mice on a different lava flow shows no association with Mc1r mutations, indicating that adaptive dark color has evolved independently in this species through changes at different genes.

The article expands on the ongoing assessment of the reduced order model proposed by some of the authors for the geometric definition and noncavitating performance evaluation in the preliminary design and parametric optimization of mixed-flow centrifugal turbopumps. Some of the dynamically most significant predictions of the model are compared with the experimentally validated URANS (Unsteady Reynolds-Averaged Navier-Stokes) simulations of the non-cavitating flow through a typical six-bladed unshrouded mixed-flow turbopump for liquid propellant rocket engines operating at both design and off-design flow conditions and different values of the impeller clearance. The observed discrepancies can be explained in terms of the simplifying assumptions introduced for the development of the model and their relative magnitude (< ±10%) does not adversely interfere with the accurate prediction of the turbopump performance over a wide range of operating conditions above and below design flow rate. Together with earlier experimental validations, the results dramatically confirm the capability of the proposed model to generate useful engineering solutions of the turbopump preliminary design problem at a negligible fraction of the computational cost required by 3D numerical simulations.

We investigate the effect of research and development (R&D) offshoring from highincome regions to prominent emerging economies. Specifically, we examine whether there is a complementary relationship between a region’s home and foreign investments in R&D that affects home’s regional knowledge production. Using a theoretical framework based on economic geography and the literature on international knowledge sourcing, we conjecture that high-income regions would have a comparative advantage in high-tech R&D, while emerging economies would have an advantage in medium/low R&D. Complementarity should obtain when the comparative advantages of the geographical areas are utilized. We find overall empirical support for this prediction.

The lecture presents an overview of some recent results of the work carried out at Alta on the hydrodynamic design and rotordynamic fluid forces of cavitating turbopumps for liquid propellant feed systems of modern rocket engines. The reduced order models recently developed for preliminary geometric definition and noncavitating performance prediction of tapered-hub axial inducers and centrifugal turbopumps are illustrated. The experimental characterization of the rotordynamic forces acting on a whirling four-bladed, tapered-hub, variable-pitch high-head inducer, under different load and cavitation conditions is presented. Future perspectives of the work to be carried out at Alta in this area of research are briefly illustrated.

This dissertation presents an investigation of molecular gas inside the nuclei of merging and/or active galaxies. Molecular gas is the primary fuel for star formation and supermassive black hole growth in galaxies. Its distribution and physical state on < 1 kiloparsec scales outside of the Milky Way has become more evident as new and upgraded observatories have revolutionized the spatial scales on which we view the Universe. This thesis uses data from the W. M. Keck Observatory and Atacama Large Millimeter/submillimeter Array (ALMA) on scales ranging from 2-500 parsecs to glean information on the physical conditions of molecular gas in merging and/or active galaxies. To understand whether two ”overmassive” black holes in merging luminous galaxies are overmassive, we measure the cold molecular gas mass inside 10s of pc from the black holes. We then subtract that gas mass from previous enclosed mass estimates, which was used prior as a proxy for black hole mass, to determine whether the black holes are truly overmassive. We independently model the rotation of the nuclear gas around the supermassive black holes and make a higher resolution enclosed mass estimate than the previous studies. We discuss the implications of the existence (or not) of overmassive black holes, focusing on what they mean to simulated models for black hole accretion. In the next study, we tested the Bondi accretion formalism, a commonly used prescription for black hole accretion in simulations using observed input parameters. We measured these parameters using ALMA and Keck/OSIRIS interferometry and near-infrared integral field spectroscopy on 2-500 parsec scales in the prototypical Seyfert 2 galaxy, NGC 1068. We then spatially estimated the Bondi black hole accretion rate for comparison to the real accretion rate as estimated via X-ray measurements from the BAT AGN Spectroscopic Survey. Finally, we contextualize the meaning of the results in the paradigm of Bondi accretion as applied to modern large-scale cosmological simulations.