On the geometric P=W conjecture

We formulate the geometric P=W conjecture for singular character varieties. We establish it for compact Riemann surfaces of genus one, and obtain partial results in arbitrary genus. To this end, we employ non-Archimedean, birational and degeneration techniques to study the topology of the dual boundary complex of certain character varieties. We also clarify the relation between the geometric and the cohomological P=W conjectures

Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.

Myrtucommulone a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-α and interleukin-1 β in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B 4, but not prostaglandin E2, levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics

Higher Fano manifolds

In this paper we address Fano manifolds with positive higher Chern characters. They are expected to enjoy stronger versions of several of the nice properties of Fano manifolds. For instance, they should be covered by higher dimensional rational varieties, and families of higher Fano manifolds over higher dimensional bases should admit meromorphic sections (modulo the Brauer obstruction). Aiming at finding new examples of higher Fano manifolds, we investigate positivity of higher Chern characters of rational homogeneous spaces. We determine which rational homogeneous spaces of Picard rank $1$ have positive second Chern character, and show that the only rational homogeneous spaces of Picard rank $1$ having positive second and third Chern characters are projective spaces and quadric hypersurfaces. We also classify Fano manifolds of large index having positive second and third Chern characters. We conclude by discussing conjectural characterizations of projective spaces and complete intersections in terms of these higher Fano conditions

Protective role of PI3-kinase-Akt-eNOS signalling pathway in intestinal injury associated with splanchnic artery occlusion shock.

Background and purpose: Endothelial NO synthase (eNOS) is a dynamic enzyme tightly controlled by co- and post-translational lipid modifications, phosphorylation and regulated by protein-protein interactions. Here we have pharmacologically modulated the activation of eNOS, at different post-translational levels, to assess the role of eNOS-derived NO and of these regulatory mechanisms in intestinal injury associated with splanchnic artery occlusion (SAO) shock. Experimental approach: SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk for 45 min followed by 30 min of reperfusion. During ischemia, 15 min prior to reperfusion, mice were given geldanamycin, an inhibitor of hsp90 recruitment to eNOS, or LY-294002 an inhibitor of phosphatidylinositol 3-kinase (PI3K), an enzyme that initiates Akt-catalysed phosphorylation of eNOS on Ser 1179. After 30 min of reperfusion, samples of ileum were taken for histological examination or for biochemical studies. Key results: Either LY-294002 or geldanamycin reversed the increased activation of eNOS and Akt observed following SAO shock. These molecular effects were mirrored in vivo by an exacerbation of the intestinal damage. Histological damage also correlated with neutrophil infiltration, assessed as myeloperoxidase activity, and with an increased expression of the adhesion proteins: ICAM-I, VCAM, P-selectin and E-selectin. Conclusions and implications: Overall these results suggest that activation of the Akt pathway in ischemic regions of reperfused ileum is a protective event, triggered in order to protect the intestinal tissue from damage induced by ischaemia/reperfusion through a fine tuning of the endothelial NO pathway. © 2007 Nature Publishing Group All rights reserved

The Italian document: decisions for intensive care when there is an imbalance between care needs and resources during the COVID-19 pandemic

Background: In early 2020, the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) published clinical ethics recommendations for the allocation of intensive care during COVID-19 pandemic emergency. Later the Italian National Institute of Health (ISS) invited SIAARTI and the Italian Society of Legal and Insurance Medicine to prepare a draft document for the definition of triage criteria for intensive care during the emergency, to be implemented in case of complete saturation of care resources. Methods: Following formal methods, including two Delphi rounds, a multidisciplinary group with expertise in intensive care, legal medicine and law developed 12 statements addressing: (1) principles and responsibilities; (2) triage; (3) previously expressed wishes; (4) reassessment and shifting to palliative care; (5) collegiality and transparency of decisions. The draft of the statements, with their explanatory comments, underwent a public consultation opened to Italian scientific or technical-professional societies and other stakeholders (i.e., associations of citizens, patients and caregivers; religious communities; industry; public institutions; universities and research institutes). Individual healthcare providers, lay people, or other associations could address their comments by e-mail. Results: Eight stakeholders (including scientific societies, ethics organizations, and a religious community), and 8 individuals (including medical experts, ethicists and an association) participated to the public consultation. The stakeholders’ agreement with statements was on average very high (ranging from 4.1 to 4.9, on a scale from 1—full disagreement to 5—full agreement). The 4 statements concerning triage stated that in case of saturation of care resources, the intensive care triage had to be oriented to ensuring life-sustaining treatments to as many patients as possible who could benefit from them. The decision should follow full assessment of each patient, taking into account comorbidities, previous functional status and frailty, current clinical condition, likely impact of intensive treatment, and the patient's wishes. Age should be considered as part of the global assessment of the patient. Conclusions: Lacking national guidelines, the document is the reference standard for healthcare professionals in case of imbalance between care needs and available resources during a COVID-19 pandemic in Italy, and a point of reference for the medico-legal assessment in cases of dispute

GW0742, a high affinity PPAR-β/δ agonist reduces lung inflammation induced by bleomycin instillation in mice.

Peroxisome Proliferator-Activated Receptor β/δ belongs to a family of ligand-activated transcription factors. Recent data have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target. Moreover, although its role in acute inflammation remains unclear, being the nuclear receptor PPAR β/δ widely expressed in many tissues, including the vascular endothelium, we assume that the infiltration of PMNs into tissues, a prominent feature in inflammation, may also be related to PPAR β/δ. Mice subjected to intratracheal instillation of bleomycin (BLEO, 1 mg/kg), a glycopeptide produced by the bacterium Streptomyces verticillus, develop lung inflammation and injury characterized by a significant neutrophil infiltration and tissue oedema. Therefore, the aim of this study is to investigate the effects of GW0742, a synthetic high affinity PPAR β/δ agonist, and its possible role in preventing the advance of inflammatory and apoptotic processes induced by bleomycin, that long-term leads to the appearance of pulmonary fibrosis. Our data showed that GW0742-treatment (0.3 mg/Kg, 10% DMSO, i.p.) has therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters detected by measurement of: 1) cytokine production; 2) leukocyte accumulation, indirectly measured as decrease of myeloperoxidase (MPO) activity; 3) IκBα degradation and NF-κB nuclear translocation; 4) ERK phosphorylation; 5) stress oxidative by NO formation due to iNOS expression; 6) nitrotyrosine and PAR localization; 7) the degree of apoptosis, evaluated by Bax and Bcl2 balance, FAS ligand expression and TUNEL staining. Taken together, our results clearly show that GW0742 reduces the lung injury and inflammation due to the intratracheal BLEO-instillation in mice

Characterization of the pathophysiological role of CD47 in uveal melanoma

Uveal melanoma (UM) represents the most frequent primary intraocular tumor, however, limited therapeutic options are still available. We have previously shown that cluster of differentiation 47 (CD47) is significantly upregulated in UM cells following inflammatory stimuli and that it represents a predictor of disease progression. Here, we aimed to better characterize the pathophysiological role of CD47 in UM. We show that CD47 is not modulated at different cancer stages, although patients with the lowest expression of CD47 show significant better progression-free survival, after correcting for the presence of BAP1, GNAQ, and GNA11 mutations. By stratifying patients based on the expression of CD47 in the tumor, we observed that patients with high levels of CD47 have a significant increase in immune score as compared to patients with low levels of CD47. In particular, deconvolution analysis of infiltrating immune cell populations revealed that a significantly higher number of CD4+ and CD8+ T cells can be found in patients with high CD47 levels, with the most enriched populations being the Th2, Treg, and CD8+ Tcm cells. We also show that a large number of transcripts are significantly modulated between the groups of patients with high and low levels of CD47, with a significant enrichment of interferon IFN-alpha regulated genes. The results from this study may propel the development of anti-CD47 therapies for UM patients

Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain

Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as their natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here, we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site-codon 70-within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of representatives of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72, and C105, mutation of each cysteine individually impairs virus restriction, and a triple C71A-C72A-C105A mutant loses all restriction activity, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation

N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy

N-Acetylcysteine, one of the most prescribed antioxidant drugs, enhances pain threshold in rodents and humans by activating mGlu2 metabotropic glutamate receptors. Here, we assessed the analgesic activity of N-acetylcysteine in the streptozotocin model of painful diabetic neuropathy and examined the effect of N-acetylcysteine on proteins that are involved in mechanisms of nociceptive sensitization. Mice with blood glucose levels ≥250 mg/dl in response to a single intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg) were used for the assessment of mechanical pain thresholds. Systemic treatment with N-acetylcysteine (100 mg/kg, i.p., either single injection or daily injections for seven days) caused analgesia in diabetic mice. N-acetylcysteine-induced analgesia was abrogated by the Sxc- inhibitors, sulfasalazine (8 mg/kg, i.p.), erastin (30 mg/kg, i.p.), and sorafenib (10 mg/kg, i.p.), or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). Repeated administrations of N-acetylcysteine in diabetic mice reduced ERK1/2 phosphorylation in the dorsal region of the lumbar spinal cord. The analgesic activity of N-acetylcysteine was occluded by the MEK inhibitor, PD0325901 (25 mg/kg, i.p.), the TRPV1 channel blocker, capsazepine (40 mg/kg, i.p.), or by a cocktail of NMDA and mGlu5 metabotropic glutamate receptor antagonists (memantine, 25 mg/kg, plus MTEP, 5 mg/kg, both i.p.). These findings offer the first demonstration that N-acetylcysteine relieves pain associated with diabetic neuropathy and holds promise for the use of N-acetylcysteine as an add-on drug in diabetic patients