Efficient Spectral Domain MoM for the Design of Circularly Polarized Reflectarray Antennas Made of Split Rings

The method of moments (MoM) in the spectral domain is used for the analysis of the scattering of a plane wave by a multilayered periodic structure containing conducting concentric split rings in the unit cell. Basis functions accounting for edge singularities are used in the approximation of the current density on the split rings, which makes it possible a fast convergence of MoM with respect to the number of basis functions. Since the 2-D Fourier transforms of the basis functions cannot be obtained in closed-form, judicious tricks (controlled truncation of infinite summations, interpolations, etc.) are used for the efficient numerical determination of these Fourier transforms. The implemented spectral domain MoM software has been used in the design of a circularly polarized reflectarray antenna based on split rings under the local periodicity condition. The antenna has been analyzed with our spectral domain MoM software, with CST and with HFSS, and good agreement has been found among all sets of results. Our software has proven to be around 27 times faster than CST and HFSS

Structural stabilization of botulinum neurotoxins by tyrosine phosphorylation

AbstractTyrosine phosphorylation of botulinum neurotoxins augments their proteolytic activity and thermal stability, suggesting a substantial modification of the global protein conformation. We used Fourier-transform infrared (FTIR) spectroscopy to study changes of secondary structure and thermostability of tyrosine phosphorylated botulinum neurotoxins A (BoNT A) and E (BoNT E). Changes in the conformationally-sensitive amide I band upon phosphorylation indicated an increase of the α-helical content with a concomitant decrease of less ordered structures such as turns and random coils, and without changes in β-sheet content. These changes in secondary structure were accompanied by an increase in the residual amide II absorbance band remaining upon H-D exchange, consistent with a tighter packing of the phosphorylated proteins. FTIR and differential scanning calorimetry (DSC) analyses of the denaturation process show that phosphorylated neurotoxins denature at temperatures higher than those required by non-phosphorylated species. These findings indicate that tyrosine phosphorylation induced a transition to higher order and that the more compact structure presumably imparts to the phosphorylated neurotoxins the higher catalytic activity and thermostability

Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients

COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain

Bifocal design procedure for dual-reflectarray antennas in offset configurations

This letter presents a new bifocal design procedure for dual-reflectarray antennas (DRAAs) in offset configurations. The technique starts by considering an axially symmetric geometry with the reflectarrays placed in parallel planes, which allows the rotation of a two-dimensional bifocal design around the symmetry axis. To reach a more compact configuration and to obtain smoother phase distributions, the reflectarrays are tilted and their phases are adjusted by means of a ray-tracing routine. The technique has been validated by numerical simulations through the comparison with a previous center-fed dual-reflectarray prototype. Finally, the simulations of an offset DRAA with tilted reflectarrays are presented, providing 0.56° beam spacing at 20 GHz for multispot satellite applications in Ka-band.Agencia Estatal de Investigación | Ref. TEC2016-75103-C2-1-REuropean Space Agency | Ref. 4000117113/16/NL/A

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity

New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (alpha-glucosidase/alpha-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols

Dual-polarization reflectarray in Ku-band based on two layers of dipole arrays for a transmit–receive satellite antenna with South American coverage

A 1.1-m reflectarray antenna has been designed, manufactured and tested to fulfil the requirements of a satellite antenna in Ku-band that provides South American coverage in Tx and Rx. The reflectarray cells consist of four dipoles for each polarization in two dielectric layers, selected because of their simplicity and high performance. The dipole dimensions are optimized in all the reflectarray cells to accomplish the prescribed radiation patterns, by iteratively calling an analysis routine based on method of moments in spectral domain and local periodicity. The measured radiation patterns of the manufactured antenna have been satisfactorily compared with simulations and with a 3-layer reflectarray previously designed, manufactured and tested for the same mission

Parabolic reflectarray antenna to generate multiple beams for geostationary high throughput satellites in Ka-band

This contribution describes the design and simulations of a multibeam 1.8 m parabolic reflectarray antenna for geostationary high throughput satellites (HTS) in Ka-band. The parabolic reflectarray generates two orthogonal circularly polarized beams per feed simultaneously at 19.7 and 29.5 GHz, by the variable rotation technique. The antenna is made of 62 654 reflectarray cells, which include two types of printed elements independently rotated and adjusted. The elements have been optimized one by one to ensure the required phase-shift at each frequency. A novel design approach has made it possible to promptly obtain an initial layout of every element with a very low computational cost. The simulated radiation patterns show that the parabolic reflectarray, illuminated by 27 dual-circularly polarized feeds, can generate 54 spot-beams in two orthogonal polarizations, with a beam spacing of 0.56° between adjacent beams. The design and simulation tools have been validated by a parabolic reflectarray scaled in a factor of 0.5, which has been manufactured and tested. The proposed reflectarray would allow to generate a complete multi-spot coverage from a geostationary HTS with only two parabolic reflectarrays, instead of four reflector antennas, also reducing the number of feeds by half, since every feed generates two beams.Agencia Estatal de Investigación | Ref. PID2020-113979RB-C22Agencia Estatal de Investigación | Ref. PID2020-114172RB-C21-2Agencia Estatal de Investigación | Ref. PDC2021-120959-C2

The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes

SOX2 is a core pluripotency-associated transcription factor causally related to cancer initiation, aggressiveness, and drug resistance by driving the self-renewal and seeding capacity of cancer stem cells (CSC). Here, we tested the ability of the clinically proven inhibitor of the lysine-specific demethylase 1 (LSD1/KDM1A) iadademstat (ORY-100) to target SOX2-driven CSC in breast cancer. Iadademstat blocked CSC-driven mammosphere formation in breast cancer cell lines that are dependent on SOX2 expression to maintain their CSC phenotype. Iadademstat prevented the activation of an LSD1-targeted stemness-specific SOX2 enhancer in CSC-enriched 3-dimensional spheroids. Using high-throughput transcriptional data available from the METABRIC dataset, high expression of SOX2 was significantly more common in luminal-B and HER2-enriched subtypes according to PAM50 classifier and in IntClust1 (high proliferating luminal-B) and IntClust 5 (luminal-B and HER2-amplified) according to integrative clustering. Iadademstat significantly reduced mammospheres formation by CSC-like cells from a multidrug-resistant luminal-B breast cancer patient-derived xenograft but not of those from a treatment-naive luminal-A patient. Iadademstat reduced the expression of SOX2 in luminal-B but not in luminal-A mammospheres, likely indicating a selective targeting of SOX2-driven CSC. The therapeutic relevance of targeting SOX2-driven breast CSC suggests the potential clinical use of iadademstat as an epigenetic therapy in luminal-B and HER2-positive subtypes

G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERα and ERβ in pancreatic beta cells

17β-estradiol protects pancreatic β-cells from apoptosis via the estrogen receptors ERα, ERβ and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ERα and ERβ, or in dispersed islet cells from ERβ knockout (BERKO) mice. However, the ERα and ERβ agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERβ form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as GPER activation by G1 decreased ERαβ heterodimers. We propose that ERαβ heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ERαβ heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.This work was supported by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) grants BPU2017-86579-R (AN), PID2020-117294RB-I00 (AN, JM-P), Generalitat Valenciana PROMETEO II/2020/006 (AN) and European Union’s Horizon 2020 research and innovation programme under grant agreement GOLIATH No. 825489 (AN). Author laboratories hold grants from Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación y Fondo Europeo de Desarrollo Regional (FEDER) RTI2018-096724-B-C21 (J-AE) and PID2020-117569RA-I00 (LM). PROMETEO/2016/006 (J-AE) and SEJI/2018/023 (LM) supported by Generalitat Valenciana, Spain. Robert A. Welch Foundation (grant E-0004) (J-AG). CIBERDEM is an initiative of the Instituto de Salud Carlos III

Advanced multibeam antenna configurations based on reflectarrays: providing multispot coverage with a smaller number of apertures for satellite communications in the K- and Ka-bands

This article presents some recent developments in multiplebeam antennas (MBAs) based on reflectarrays for communication satellites in the Kurz (K) and Kurz-above (Ka) bands. The existing high-throughput satellites commonly employ four reflector antennas to provide cellular coverage that is formed by multiple spot beams in a four-color scheme. Reflectarray antennas are proposed as an attractive solution for the design of novel MBA configurations to produce multispot coverage, with a smaller number of apertures than conventional MBA systems based on reflector technology. Single and dual reflectarray configurations have been considered for the purpose of exploiting their ability to produce independent beams in different polarizations and frequencies.Agencia Estatal de Investigación | Ref. TEC2016-75103-C2-1-RMinisterio de Economía y Competitividad | Ref. TEC2015-65353-RXunta de Galicia | Ref. GRC2015/018European Space Agency | Ref. 4000117113/16/NL/A