Joint Observation of the Galactic Center with MAGIC and CTA-LST-1

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes (IACTs), designed to detect very-high-energy gamma rays, and is operating in stereoscopic mode since 2009 at the Observatorio del Roque de Los Muchachos in La Palma, Spain. In 2018, the prototype IACT of the Large-Sized Telescope (LST-1) for the Cherenkov Telescope Array, a next-generation ground-based gamma-ray observatory, was inaugurated at the same site, at a distance of approximately 100 meters from the MAGIC telescopes. Using joint observations between MAGIC and LST-1, we developed a dedicated analysis pipeline and established the threefold telescope system via software, achieving the highest sensitivity in the northern hemisphere. Based on this enhanced performance, MAGIC and LST-1 have been jointly and regularly observing the Galactic Center, a region of paramount importance and complexity for IACTs. In particular, the gamma-ray emission from the dynamical center of the Milky Way is under debate. Although previous measurements suggested that a supermassive black hole Sagittarius A* plays a primary role, its radiation mechanism remains unclear, mainly due to limited angular resolution and sensitivity. The enhanced sensitivity in our novel approach is thus expected to provide new insights into the question. We here present the current status of the data analysis for the Galactic Center joint MAGIC and LST-1 observations

Ultrasound in Sepsis and Septic Shock—From Diagnosis to Treatment

Sepsis and septic shock are among the leading causes of in-hospital mortality worldwide, causing a considerable burden for healthcare. The early identification of sepsis as well as the individuation of the septic focus is pivotal, followed by the prompt initiation of antibiotic therapy, appropriate source control as well as adequate hemodynamic resuscitation. For years now, both emergency department (ED) doctors and intensivists have used ultrasound as an adjunctive tool for the correct diagnosis and treatment of these patients. Our aim was to better understand the state-of-the art role of ultrasound in the diagnosis and treatment of sepsis and septic shock. Methods: We conducted an extensive literature search about the topic and reported on the data from the most significant papers over the last 20 years. Results: We divided each article by topic and exposed the results accordingly, identifying four main aspects: sepsis diagnosis, source control and procedure, fluid resuscitation and hemodynamic optimization, and echocardiography in septic cardiomyopathy. Conclusion: The use of ultrasound throughout the process of the diagnosis and treatment of sepsis and septic shock provides the clinician with an adjunctive tool to better characterize patients and ensure early, aggressive, as well as individualized therapy, when needed. More data are needed to conclude that the use of ultrasound might improve survival in this subset of patients

An enzymatic, stereoselective synthesis of (S)-norcoclaurine

An efficient, stereoselective, green synthesis of (S)-norcoclaurine (higenamine) has been developed using the recombinant (S)-norcoclaurine synthase (NCS) enzyme, starting from the cheap tyrosine and dopamine substrates in a one-pot, two step process. Key steps in the biotransformation consist of the oxidative decarboxylation of tyrosine by stoichiometric amounts of sodium hypochlorite in order to generate 4-hydroxyphenylacetadehyde, followed by the addition of enzyme and dopamine substrate in the presence of ascorbate, a necessary ingredient in order to avoid oxidation of the catechol moiety. Quantitative extraction of the product from an aqueous solution was achieved by adsorption onto active charcoal dispersed in the reaction mixture. The optimized process afforded enantiomerically pure (S)-norcoclaurine (93%) in a yield higher than 80% and allowed good recovery of the enzyme for recycling. The process thus developed represents the first example of a green Pictet-Spengler synthesis, which may pave the way to novel strategies in benzylisoquinoline alkaloid synthesis

Duodenal bleeding in a patient with Covid-19-Related Acute Respiratory Distress Syndrome

High incidence of thrombotic complications was observed in patients with Acute Respiratory Distress Syndrome (ARDS) related to Coronavirus Disease 2019 (COVID-19) [1]. The pathophysiology seems related to systemic thrombophilia by hyper-immune reaction, inducing a “cytokine storm” [1].&nbsp;</p

Liver Injury in Patients Hospitalized for COVID-19: Possible Role of Therapy

Patients with COVID-19 show a high prevalence of liver injury. The pattern of this liver damage is still not fully understood. Different etiopathogenetic factors may concur; from a direct cytopathic effect, once the virus binds to the ACE-2 receptors, to the immune-mediated collateral damage, due to cytokine storm. The presence of pre-existing chronic liver disease is a contributing factor for acute organ damage during SARS-CoV2 infection. Last but not least, treatments probably play a role, also, in determining hepatotoxicity: many of the drugs we have used or are still using to treat COVID-19, combined with non-invasive ventilation, are known to sometimes determine acute liver injury. Although liver damage associated with COVID-19 is often transient and can resolve without any special treatment, it is important to understand the underlying mechanisms, particularly to better treat its more severe forms

Novel in vitro booster vaccination to rapidly generate antigen-specific human monoclonal antibodies

Vaccines remain the most effective tool to prevent infectious diseases. Here, we introduce an in vitro booster vaccination approach that relies on antigen-dependent activation of human memory B cells in culture. This stimulation induces antigen-specific B cell proliferation, differentiation of B cells into plasma cells, and robust antibody secretion after a few days of culture. We validated this strategy using cells from healthy donors to retrieve human antibodies against tetanus toxoid and influenza hemagglutinin (HA) from H1N1 and newly emergent subtypes such as H5N1 and H7N9. Anti-HA antibodies were cross-reactive against multiple subtypes, and some showed neutralizing activity. Although these antibodies may have arisen as a result of previous influenza infection, we also obtained gp120-reactive antibodies from non–HIV-infected donors, indicating that we can generate antibodies without prior antigenic exposure. Overall, our novel approach can be used to rapidly produce therapeutic antibodies and has the potential to assess the immunogenicity of candidate antigens, which could be exploited in future vaccine development

RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition

Background: The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. Methods: After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results: Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Conclusions: Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner