Photonic generation of phase-modulated RF signals for pulse compression techniques in coherent radars

A novel and flexible photonics-based scheme is proposed for generating phase-coded RF pulses suitable for coherent radar systems with pulse compression techniques. After selecting two modes from a mode-locked laser (MLL), the technique exploits an optical in-phase/quadrature modulator driven by a low-sample rate and low-noise direct digital synthesizer to modulate the phase of only one mode. The two laser modes are then heterodyned in a photodiode, and the RF pulse is properly filtered out. The scheme is experimentally validated implementing a 4-bit Barker code and a linear chirp on radar pulses with a carrier frequency of about 25 GHz, starting from an MLL at about 10 GHz. The measures of phase noise, amplitude- and phase-transients, and autocorrelation functions confirm the effectiveness of the scheme in producing compressed radar pulses without affecting the phase stability of the optically generated high-frequency carriers. An increase in the radar resolution from 150 to 37.5 m is calculated. The proposed scheme is capable of flexibly generating software-defined phase-modulated RF pulses with high stability, even at very high carrier frequency, using only a single commercial device with potentials for wideband modulation. It can therefore allow a new generation of high-resolution coherent radars with reduced complexity and cost. © 1983-2012 IEEE

Phase coding of RF pulses in photonics-aided frequency-agile coherent radar systems

An innovative optical scheme to generate software-defined phase-modulated radio frequency (RF) pulses with carrier frequency agility from a mode-locked laser (MLL) is proposed. The technique exploits a direct digital synthesizer and a Mach-Zehnder modulator to apply an intermediate frequency modulation to the MLL's modes. The heterodyne detection of the optical signal allows the generation of amplitude- and phase-modulated RF carriers with very high phase stability, suitable for coherent radar applications. Further, a single MLL can be used to generate carriers simultaneously at different frequencies, enabling frequency hopping or multifunctional radars, with no need to increase the complexity of the transmitter. Results show chirped and Barker-coded pulses at around 10 or 40 GHz in a single setup, without any performance degradation while increasing the carrier frequency. The proposed technique allows the practical realization of compressed pulses for coherent radars over a wide carrier frequency range, allowing the development of software-defined radar systems with improved functionalities. © 1965-2012 IEEE

Flexible multi-band OFDM receiver based on optical down-conversion for millimeter waveband wireless base stations

A novel and flexible photonics-based down-conversion scheme is proposed for wireless receivers in base stations. It allows simultaneous detection of multiple signals at carriers up to tens of GHz, enabling communications at millimeter waves. Experiments demonstrate the effective down-conversion of Wi-Fi signals at 2.4 and 39.8GHz with EVM<;-43dB

Reconfigurable radar transmitter based on photonic microwave signal generation

In this paper we propose a photonic technique for a reconfigurable microwave signal generation based on the beating in a photodiode of two laser modes from a regenerative Fiber Mode-Locked Laser (FMLL). The excellent performance of this kind of pulsed laser guarantees high stability to the generated microwave signal even at ultra high frequencies (up to W band). Therefore, by using the proposed architecture, the performance of a reconfigurable full digital coherent radar system can be enhanced in terms of Moving Target Indicator (MTI) improvement factor. Moreover, thanks to the achievable high repetition rates and the coherence properties of the FMLL, this laser scheme has also been proposed for digitizing the received signal by electro-optical sampling. Thus the advantage of using just one device for signal generation in both the transmitter and receiver chain, makes the proposed solution a cost effective architecture for microwave signal generation. Differently from the microwave synthesizers, whose performance strongly deteriorate with increasing frequencies, the photonic radio frequency generation always shows an excellent spectral purity. The results show excellent spectral purity above 5 KHz for the proposed technique compared to a state of the art Agilent synthesizer even though the timing jitter increases for integration time greater than 10 msec. In order to achieve the same stability performance at both high and low frequencies a Phase Locked Loop between the laser and a synthesizer could be used

(2-Aminobenzothiazole)-Methyl-1,1-bisphosphonic acids: Targeting matrix metalloproteinase 13 inhibition to the bone

Matrix Metalloproteinases (MMPs) are a family of secreted and membrane-bound enzymes, of which 24 isoforms are known in humans. These enzymes degrade the proteins of the extracellular matrix and play a role of utmost importance in the physiological remodeling of all tissues. However, certain MMPs, such as MMP-2, -9, and -13, can be overexpressed in pathological states, including cancer and metastasis. Consequently, the development of MMP inhibitors (MMPIs) has been explored for a long time as a strategy to prevent and hinder metastatic growth, but the important side effects linked to promiscuous inhibition of MMPs prevented the clinical use of MMPIs. Therefore, several strategies were proposed to improve the therapeutic profile of this pharmaceutical class, including improved selectivity toward specific MMP isoforms and targeting of specific organs and tissues. Combining both approaches, we conducted the synthesis and preliminary biological evaluation of a series of (2-aminobenzothiazole)-methyl-1,1-bisphosphonic acids active as selective inhibitors of MMP-13 via in vitro and in silico studies, which could prove useful for the treatment of bone metastases thanks to the bone-targeting capabilities granted by the bisphosphonic acid group

Insights into the Complex Formed by Matrix Metalloproteinase-2 and Alloxan Inhibitors: Molecular Dynamics Simulations and Free Energy Calculations

Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S1′ specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S1′ subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC50 = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases

Multicentre observational study on multisystem inflammatory syndrome related to COVID-19 in Argentina

Background: The impact of the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in low- and middle-income countries remains poorly understood. Our aim was to understand the characteristics and outcomes of PIMS-TS in Argentina. Methods: This observational, prospective, and retrospective multicenter study enrolled patients younger than 18 years-old manifesting PIMS-TS, Kawasaki disease (KD) or Kawasaki shock syndrome (KSS) between March 2020 and May 2021. Patients were followed-up until hospital discharge or death (one case). The primary outcome was pediatric intensive care unit (PICU) admission. Multiple logistic regression was used to identify variables predicting PICU admission. Results: Eighty-one percent, 82%, and 14% of the 176 enrolled patients fulfilled the suspect case criteria for PIMS-TS, KD, and KSS, respectively. Temporal association with SARS-CoV-2 was confirmed in 85% of the patients and 38% were admitted to the PICU. The more common clinical manifestations were fever, abdominal pain, rash, and conjunctival injection. Lymphopenia was more common among PICU-admitted patients (87% vs. 51%, p < 0.0001), who also showed a lower platelet count and higher plasmatic levels of inflammatory and cardiac markers. Mitral valve insufficiency, left ventricular wall motion alterations, pericardial effusion, and coronary artery alterations were observed in 30%, 30%, 19.8%, and 18.6% of the patients, respectively. Days to initiation of treatment, rash, lymphopenia, and low platelet count were significant independent contributions to PICU admission. Conclusion: Rates of severe outcomes of PIMS-TS in the present study agreed with those observed in high-income countries. Together with other published studies, this work helps clinicians to better understand this novel clinical entity.Fil: Vainstein, Eduardo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Baleani, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Urrutia, Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Affranchino, Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ackerman, Judith. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Cazalas, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Goldsman, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Sardella, Angela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Tolin, Ana Laura. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Goldaracena, Pablo. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Fabi, Mariana. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Cosentino, Mariana. Hospital Británico de Buenos Aires; ArgentinaFil: Magliola, Ricardo. Hospital Británico de Buenos Aires; ArgentinaFil: Roggiero, Gustavo. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Manso, Paula. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Triguy, Jésica. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Ballester, Celeste. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Cervetto, Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Vaccarello, María. Sanatorio de la Trinidad; ArgentinaFil: De Carli, Domingo Norberto. Clínica del Niño de Quilmes; ArgentinaFil: De Carli, Maria Estela. Clínica del Niño de Quilmes; ArgentinaFil: Ciotti, Ana Laura. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Sicurello, María Irene. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Rios Leiva, Cecilia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Villalba, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Hortas, María. Sanatorio de la Trinidad; ArgentinaFil: Peña, Sonia. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: González, Gabriela. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Zold, Camila Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Grippo, M.. No especifíca;Fil: Vázquez, H.. No especifíca;Fil: Morós, C.. No especifíca;Fil: Di Santo, M.. No especifíca;Fil: Villa, A.. No especifíca;Fil: Lazota, P.. No especifíca;Fil: Foti, M.. No especifíca;Fil: Napoli, N.. No especifíca;Fil: Katsikas, M. M.. No especifíca;Fil: Tonello, L.. No especifíca;Fil: Peña, J.. No especifíca;Fil: Etcheverry, M.. No especifíca;Fil: Iglesias, D.. No especifíca;Fil: Alcalde, A. L.. No especifíca;Fil: Bruera, M.J.. No especifíca;Fil: Bruzzo, V.. No especifíca;Fil: Giordano, P.. No especifíca;Fil: Pena Acero, F.. No especifíca;Fil: Netri Pelandi, G.. No especifíca;Fil: Pastaro, D.. No especifíca;Fil: Bleiz, J.. No especifíca;Fil: Rodríguez, M. F.. No especifíca;Fil: Laghezza, L.. No especifíca;Fil: Molina, M. B.. No especifíca;Fil: Patynok, N.. No especifíca;Fil: Chatelain, M. S.. No especifíca;Fil: Aguilar, M. J.. No especifíca;Fil: Gamboa, J.. No especifíca;Fil: Cervan, M.. No especifíca;Fil: Ruggeri, A.. No especifíca;Fil: Marinelli, I.. No especifíca;Fil: Checcacci, E.. No especifíca;Fil: Meregalli, C.. No especifíca;Fil: Damksy Barbosa, J.. No especifíca;Fil: Fernie, L.. No especifíca;Fil: Fernández, M. J.. No especifíca;Fil: Saenz Tejeira, M.M.. No especifíca;Fil: Cereigido, C.. No especifíca;Fil: Nunell, A.. No especifíca;Fil: Villar, D.. No especifíca;Fil: Mansilla, A. D.. No especifíca;Fil: Darduin, M. D.. No especifíca

Il Gargano e la geografia del sacro: lo spazio, i luoghi, le devozioni

The three sanctuaries of St. Michael at Monte Sant'Angelo, St. Matthew at San Marco in Lamis and St. Pius at San Giovanni Rotondo, along with other minor sacred places (hermitages, churches, chapels, hospitia) can be considered the key-features of the “sacred geography” at the promontory of Gargano (Apulia). Their existence covers a period lasting over than 1500 years. To the shaping of this peculiar geography has also contributed a network of roads and trails, crossed by people – not only pilgrims – who uninterruptedly walked these paths for diverse reasons. The Gargano is therefore to be considered a cultural melting pot, effective both for its inhabitants and for the people who travel along its roads. In this contribution we investigate the most important sacred places in Gargano and we argue that, although they seem to be heterogeneous, they prove to be deeply connected both in a concrete and a symbolic way. Moreover, they are associated by dynamics of identity-construction, which are reflected in patronages, hagiographic traditions, devotions.Il promontorio garganico si presenta come un unico spazio sacro, definito dai tre grandi santuari di S. Michele a Monte S. Angelo, S. Matteo a S. Marco in Lamis e S. Pio a San Giovanni Rotondo e da una serie di luoghi sacri “minori” (eremi, chiese, abbazie, hospitia), collegati da una rete di strade, sentieri, tratturi. Singoli individui e gruppi, percorrendo nel tempo queste vie per ragioni non solo di fede, hanno espresso una koiné culturale e cultuale, la quale, nel tempo, ha costruito l’identità del territorio. Tale processo di costruzione identitaria, sviluppatosi nel segno di una continuità di lunga durata, si riflette nei patronati, nelle tradizioni agiografiche, nelle devozioni ed è testimoniato anche dalle tavolette votive presenti nei santuari. Nel complesso, i luoghi sacri del Gargano intercettano, e a loro volta realizzano, una “geografia del sacro” in cui fenomeni cultuali molteplici, emersi in epoche e in contesti storico-culturali differenti, si intrecciano e persistono da oltre 1500 anni. Questo paper evidenzia come tali luoghi, apparentemente eterogenei, siano connessi sul piano concreto e simbolico dalle vie di pellegrinaggio e dalle pratiche devozionali dei fedeli. Il contributo è l’occasione per presentare le ricerche condotte nell’ambito del Progetto FIRB Spazi sacri e percorsi identitari. Testi di fondazione, iconografia, culto e tradizioni nei santuari cristiani italiani fra tarda antichità e medioevo, che si è focalizzato sull’area garganica

Abstract P6-12-10: Bone seeking matrix metalloproteinase-2 inhibitors prevent bone metastatic breast cancer growth

Bone metastasis is a common event during breast cancer progression. The resultant lesions are painful and currently, despite medical advances, are incurable. The progression of bone metastatic breast cancer is critically dependent on interactions with the surrounding microenvironment. Therefore, identifying the underpinning molecular mechanisms is vital for the development of new therapies. Rationale: Gene expression analysis and validation in human and murine specimens of bone metastases revealed that matrix metalloproteinases, such as MMP-2, are highly expressed in the bone metastatic microenvironment and significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor or host derived MMP-2 contributes to breast cancer growth and does so by processing substrates including type I collagen and transforming growth factor beta (TGFβ) latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. Methods: We utilized a novel chemical approach to synthesize bone seeking MMP inhibitors (BMMPIs) on a bisphosphonic backbone, with specificity for MMP-2 in the nanomolar range (IC50=140 nM). Results: In vitro, we tested the effect of BMMPIs at varying doses (1nM-100μM) on the viability of the major cellular components of the cancer-bone microenvironment, namely breast cancer cells, (PyMT, 4T1, MDA-MB-231, MCF-7), osteoblasts (MC3T3) and osteoclasts (primary monocytes and RAW 264.7). In vivo, we demonstrated using two bone metastatic models (PyMT-R221A-Luc and 4T1-Luc) that BMMPI treatment significantly reduced tumor growth and tumor associated bone destruction. Additionally, BMMPIs are superior in promoting tumor apoptosis compared to the standard of care bisphosphonate, zoledronate. MMP activity was also lower in the BMMPI treated groups (using tumor burden to normalize values). μCT/Xray/Histomorphometry analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions (up to 80% by μCT; p&lt;0.05). We demonstrated MMP-2 selective inhibition in the bone microenvironment using specific and broad spectrum MMP probes. Further, compared to zoledronate, BMMPI treated mice had significantly lower levels of TGFβ signaling and MMP generated type I collagen carboxy-terminal (ICTP) fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. Conclusions. MMP-2 specific inhibition was achieved in the bone microenvironment. BMMPIs significantly inhibit breast cancer growth in bone, they are able to induce breast cancer cell apoptosis and prevent cancer induced bone destruction. Given that bisphosphonates are well tolerated in the clinical setting, we predict that BMMPIs could be translated to the clinical setting for the treatment and eradication of bone metastatic breast cancer