Gravitational waves from inflation

The production of a stochastic background of gravitational waves is a fundamental prediction of any cosmological inflationary model. The features of such a signal encode unique information about the physics of the Early Universe and beyond, thus representing an exciting, powerful window on the origin and evolution of the Universe. We review the main mechanisms of gravitational-wave production, ranging from quantum fluctuations of the gravitational field to other mechanisms that can take place during or after inflation. These include e.g. gravitational waves generated as a consequence of extra particle production during inflation, or during the (p)reheating phase. Gravitational waves produced in inflation scenarios based on modified gravity theories and second-order gravitational waves are also considered. For each analyzed case, the expected power-spectrum is given. We discuss the discriminating power among different models, associated with the validity/violation of the standard consistency relation between tensor-to-scalar ratio $r$ and tensor spectral index $n_{\rm T}$. In light of the prospects for (directly/indirectly) detecting primordial gravitational waves, we give the expected present-day gravitational radiation spectral energy-density, highlighting the main characteristics imprinted by the cosmic thermal history, and we outline the signatures left by gravitational waves on the Cosmic Microwave Background and some imprints in the Large-Scale Structure of the Universe. Finally, current bounds and prospects of detection for inflationary gravitational waves are summarized.Comment: 85 pages, 4 tables, 9 figures; table 2 added, references added; matches published versio

LA RICCHEZZA PROVENIENTE DALLA MONTAGNA: GESTIONE DELLA RISORSA IDRICA ED INDIVIDUAZIONE DEI PROVENTI A FAVORE DELLE COMUNITÀ LOCALI.

Lo Stato è il gestore della risorsa idrica (conferisce le concessioni delle grandi derivazioni idroelettriche, organizza le politiche in vista del rifornimento energetico nazionale), ma il diritto alla risorsa non appartiene allo Stato ma alle collettività locali, quali espressione del loro diritto al territorio. In diretta attuazione dell’art. 44 della Costituzione è disposta l’adozione di provvedimenti legislativi a favore delle zone montane. In merito al regime giuridico delle acque, queste sono beni immobili suscettibili di appartenere sia all’Amministrazione pubblica, sia ai privati; le acque pubbliche sono comunque beni oggetto di proprietà pubblica, né possono appartenere a soggetti diversi dall’Amministrazione pubblica. Le acque pubbliche appartengono allo Stato (art. 822 del Codice civile, art. 1 T.U. n. 1775/1933 ) o alle Regioni a statuto speciale. L’eventuale necessità di soddisfare interessi di livello nazionale o comunque di attuare un programma di utilizzazione di risorse collettive, per ragioni di sviluppo economico nazionale o di ridistribuzione di ricchezza, importa la competenza statale a disporre delle acque pubbliche, esistenti nel territorio regionale, e conseguenzialmente l’inclusione nel demanio statale delle acque pubbliche utilizzate per servizi di competenza statale. La disciplina del demanio deriva, infatti, direttamente dalla scelta della collettività statale circa il suo rapporto con il territorio e con gli usi possibili di questo. Nel momento in cui l’utilizzo di quantità rilevanti di acqua è destinato alla produzione di energia elettrica, la legge riserva espressamente una parte dei proventi scaturenti da tali attività produttiva alle collettività locali. Il ritorno può avvenire attraverso il “sovracanone”. Il sovracanone per Bacini Imbriferi Montani (BIM) è previsto dall’art. 1 della legge n. 959 del 27 dicembre 1953. Il sovracanone è una prestazione patrimoniale imposta con scopo solidaristico per il sostegno delle autonomie locali nelle zone montane e costituisce un elemento della finanza comunale. Le risorse derivanti dal sovracanone appartengono esclusivamente ai Comuni e vengono gestite dai Consorzi BIM e reinvestite sui territori comunali. Il Consorzio BIM è un ente funzionale a carattere associativo e volontario previsto ex legge (art. 1 della legge n. 959 del 27 dicembre 1953) per la gestione dei fondi provenienti dal sovracanone. Proprio dal suo carattere associativo e volontario deriva il diritto per il Comune di non aderire al Consorzio

E-Learning for Rare Diseases: An Example Using Fabry Disease

Rare diseases represent a challenge for physicians because patients are rarely seen, and they can manifest with symptoms similar to those of common diseases. In this work, genetic confirmation of diagnosis is derived from DNA sequencing. We present a tutorial for the molecular analysis of a rare disease using Fabry disease as an example

Chapter Il Piccolo Masaccio e le Terre Nuove. Creativity and Computer Graphics for Museum Edutainment

Since its opening, the Museum of the New Towns, housed in the Palazzo di Arnolfo in San Giovanni Valdarno, has dedicated a particular attention to the relationship with its audiences. In this context, the video “Il piccolo Masaccio e le Terre Nuove” has the purpose of bringing children and young people, in particular, closer to the museum main themes. The video presents a series of very different techniques, such as live shots, taken also by drone, Computer Graphics, 2D drawings executed with a tablet, drawings sketched with traditional techniques, such as India ink and watercolours, and digital videos taken from Google Earth

Alla ricerca dei Monti Lattari: un percorso di sviluppo locale autosostenibile per la ricostruzione delle identita' perdute, storiche, culturali e rurali dei luoghi

Sintesi della ricerca eseguita da un gruppo di allievi della IX edizione del Master Operatori allo Sviluppo. Indice: Il percorso di analisi territoriale: dalla catena montuosa dei Monti Lattari alle specificita' dell'Unione dei Comuni. L'Unione dei comuni in cifre L'analisi di campo: il senso di identita' tra gli abitanti dei comuni e i servizi offerti sul territorio. La costruzione della strategia: l'analisi SWOT. L'alternativa possibile: il rafforzamento dell'identita' collettiva. La costruzione dell'ipotesi progettuale di sviluppo: identificazione degli obiettivi. L'ipotesi di un cambiamento effettivo: i portatori di interesse. Il passo successivo: costruzione della matrice del Quadro Logico. Il Progetto "Museo Enogastronomico e delle tradizioni contadine" Piano delle attivita

Controlled Release of H2S from Biomimetic Silk Fibroin-PLGA Multilayer Electrospun Scaffolds

The possibility of incorporating H2S slow-release donors inside biomimetic scaffolds can pave the way to new approaches in the field of tissue regeneration and anti-inflammatory treatment. In the present work, GYY4137, an easy-to-handle commercially available Lawesson's reagent derivative, has been successfully incorporated inside biomimetic silk fibroin-based electrospun scaffolds. Due to the instability of GYY4137 in the solvent needed to prepare silk fibroin solutions (formic acid), the electrospinning of the donor together with the silk fibroin turned out to be impossible. Therefore, a multilayer structure was realized, consisting of a PLGA mat containing GYY4137 sandwiched between two silk fibroin nanofibrous layers. Before their use in the multilayer scaffold, the silk fibroin mats were treated in ethanol to induce crystalline phase formation, which conferred water resistance and biomimetic properties. The morphological, thermal, and chemical properties of the obtained scaffolds were thoroughly characterized by SEM, TGA, DSC, FTIR, and WAXD. Multilayer devices showing two different concentrations of the H2S donor, i.e., 2 and 5% w/w with respect to the weight of PLGA, were analyzed to study their H2S release and biological properties, and the results were compared with those of the sample not containing GYY4137. The H2S release analysis was carried out according to an "ad-hoc" designed procedure based on a validated high-performance liquid chromatography method. The proposed analytical approach demonstrated the slow-release kinetics of H2S from the multilayer scaffolds and its tunability by acting on the donor's concentration inside the PLGA nanofibers. Finally, the devices were tested in biological assays using bone marrow derived mesenchymal stromal cells showing the capacity to support cell spreading throughout the scaffold and prevent cytotoxicity effects in serum starvation conditions. The resulting devices can be exploited for applications in the tissue engineering field since they combine the advantages of controlled H2S release kinetics and the biomimetic properties of silk fibroin nanofibers

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells.

Abstract BACKGROUND: The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. METHODS: Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAFV600E A375 and NRASQ61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro. RESULTS: BRAFV600E/V600K and NRASQ61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions (P = 0.002). COX-2 expression significantly correlated with PD-L1 expression in both primary (P = 0.001) and not matched metastatic (P = 0.048) lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAFV600E A375 and NRASQ61R SK-MEL-2 melanoma cell lines. CONCLUSIONS: COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations

TWNK in Parkinson's Disease: A Movement Disorder and Mitochondrial Disease Center Perspective Study

Background: Parkinsonian features have been described in patients harboring variants in nuclear genes encoding for proteins involved in mitochondrial DNA maintenance, such as TWNK. Objectives: The aim was to screen for TWNK variants in an Italian cohort of Parkinson's disease (PD) patients and to assess the occurrence of parkinsonism in patients presenting with TWNK-related autosomal dominant progressive external ophthalmoplegia (TWNK-adPEO). Methods: Genomic DNA of 263 consecutively collected PD patients who underwent diagnostic genetic testing was analyzed with a targeted custom gene panel including TWNK, as well as genes causative of monogenic PD. Genetic and clinical data of 18 TWNK-adPEO patients with parkinsonism were retrospectively analyzed. Results: Six of 263 PD patients (2%), presenting either with isolated PD (n = 4) or in combination with bilateral ptosis (n = 2), carried TWNK likely pathogenic variants. Among 18 TWNK-adPEO patients, 5 (28%) had parkinsonism. Conclusions: We show candidate TWNK variants occurring in PD without PEO. This finding will require further confirmatory studies. © 2022 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society

Narcolepsy is a common phenotype in HSAN IE and ADCA-DN

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria