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Robert A Quaife, Jennifer Dorosz, John C Messenger, Ernesto E Salcedo Division of Cardiology, University of Colorado, Aurora, CO, USA Abstract: Calcific aortic stenosis is now understood as a complex valvular degenerative process sharing many risk factors with atherosclerosis. Once patients develop symptomatic calcific aortic stenosis, the only effective treatment is aortic valve replacement. In the past decade, transcatheter aortic valve replacement (TAVR) has been developed as an alternative to surgery to treat severe calcific aortic stenosis. Cardiac imaging plays a pivotal role in the contemporary management of patients with calcific aortic stenosis, and particularly in patients being considered for TAVR, who demand detailed imaging of the aortic valve apparatus. In this review, we highlight the role of cardiac imaging for patient selection, procedural guidance, and evaluation of results of TAVR. Keywords: aortic stenosis, cardiovascular imaging, transcutaneous aortic valve replacement

In the paper the luminescence optical fiber used as a temperature sensor is presented. The new construction of rhodamine B doped, polymethyl methacrylate optical fibre with silver coating is shown. The fabrication process and luminescent properties of rhodamine B in sensing fibre are investigated. The attenuation and spectral shift of luminescence peak vs. the fibre length were measured and used for optimization of sensor construction. The characteristics of sensor for temperature range from 293 up to 343 K are shown. The relative sensitivity equal to -5:4 × 10-4 K-1 was obtained. The article presents also the potential applications of presented sensor. [ABSTRACT FROM AUTHOR]

In the paper the research on rare-earth doped and co-doped optical fibre conducted in the Laboratory of Optical Fiber Technology at the Bialystok University of Technology is presented. Novel active fibre constructions like multicore, helical-core and side detecting ribbon/core optical fibers were developed with a targeted focus into application. First construction i.e. multicore RE doped optical fibers enable supermode generation due to phase - locking of laser radiation achieved in a consequence of exchanging radiation between the cores during the laser action. In the paper a far - field pattern of 19 - core optical fiber-doped with Yb3+ ions, registered in the MOFPA system, showed centrally located peak of relatively high radiation intensity together with smaller side-lobes. Another new construction presented here is helical-core optical fibers with the helix pitch from several mm and the off-set ranging from 10 μm to 200 μm. The properties of helical-core optical fiber co-doped with Nd3+/Yb3+ were also discussed. In the field of sensor applications novel construction of a sidedetecting luminescent optical fiber for an UV sensor application has been presented. The developed optical fiber with an active core/ribbon, made of phosphate glass doped with 0.5 mol% Tb3+ ions, was used as a UV sensing element. [ABSTRACT FROM AUTHOR]

The article presents physicochemical, thermal and spectroscopic properties of two different glass systems: TeO2-GeO2-PbO-PbF2- BaO-Nb2O5-LaF3 and SiO2-Al2O3-Sb2O3, co-doped with Yb3+/Tm3+ ions. Blue upconversion luminescence at a wavelength of 478 nm corresponding to the thulium 1G4 ⇥3H6 transition was observed under 976 nm pump radiation in both of the co-doped glasses. This indicated the existence of efficient Yb3+ ⇥ Tm3+ energy transfer via three-photon absorption mechanism. Thermal and optical results substantiate the claim for practical applicability of the manufactured glasses in design of optical fiber sources. [ABSTRACT FROM AUTHOR]

In the paper the spectroscopic properties of antimony-germanate glass co-doped with Yb3+/Ho3+ has been investigated. Fabricated Yb3+/Tm3+/Ho3+ co-doped glass is characterised by the emission of simultaneous multicolour upconversion luminescence. Strong blue 1G4 → 3H6 (Tm3+), green 5F4 → 5I8 (Ho3+) and red 5F5 → 5I8 (Ho3+) upconversion emission bands have been measured under 976 nm excitation at room temperature. Influence of molar ratio of active ions and excitation power on the colour coordinates (CIE-1931) have been investigated. [ABSTRACT FROM AUTHOR]

The infrared emission of Tm3+/Ho3+-doped antimony-silicate optical fiber has been presented. Luminescence at 2.1 μm corresponding to 5I7 → 5I8 transition in holmium was obtained by energy transfer between Tm3+ and Ho3+ ions. According to the Forster-Dexter theory, the efficiency of energy transfer of the 3F4 (Tm3+) → 5I7 (Ho3+) transition was calculated. The optimization of the activator content and the donor (Tm3+)/acceptor (Ho3+) ions concentration ratio were conducted with the purpose of maximizing the efficiency of energy transfer. It made possible to select best-suited glass which was used to manufacture double-clad optical fiber. Strong and narrow bands of amplified spontaneous emission which formed as a result of energy transfer between thulium and holmium ions were observed in the fiber under exciting with radiation at 795 nm wavelength. [ABSTRACT FROM AUTHOR]

In the article the cooperative energy transfer in Ge02-GaO-BaO glass system doped with Yb3+/Tb3+ under 980 nm laser diode excitation was investigated. The influence of Tb3+ concentration on the luminescent properties was determined. Measured strong luminescence at 489, 543, 586, 621 corresponds to 5D4→7FJ (J = 6, 4, 3) transitions and luminescence at 381, 415, 435 nm results from 5D3, 5G6→7FJ (J = 6, 5, 4) transitions. Mechanism and energy diagram involved in observed emission were discussed. The highest upconversion emission intensity was obtained in the germanate glass doped with 0.7 Yb2O3/0.7 Tb2C>3. [ABSTRACT FROM AUTHOR]

The paper presents luminescence properties of telluride glass doped with Yb3+/Tm3+ ions. Strong blue emission at 477 nm corresponding to the transition ¹G4 → ³H6 in thulium ions was measured under the excitation of a 976 nm diode laser. The dependence of the upconversion emission upon the thulium ions concentration was studied in order to determine the optimal ion content. The results showed that intensity of upconversion emission enhances, with the increase of Tm3+ content up to 0.1 mol.%. The most effective energy transfer Yb3+ → Tm3+ occurs in the glassy matrix with molar ratio of dopant 1 Yb3+ : 0.1 Tm3+. Double-clad optical fibre was made of glass with the highest upconversion intensity at the wavelength of λ = 477 nm (TGPF101). As a result of optical excitation (λ = 976 nm) of the produced optical fibre, an additional emission line, which was not noticed in the glass, was observed at the wavelength of 351 nm corresponding to the ¹D2 → ³H6 transition. [ABSTRACT FROM AUTHOR]

In the paper the beam quality of the phase-locked multicore fibre lasers was investigated. The beam quality factor (BQF) of the coherently combined beam of the multicore fibre lasers should be determinate as the laser optical output power in a central peak far-field bucket divided by the total optical output power radiating from the effective near-field. Classical M² factor is not proper for evaluating the beam quality of phase-locked multicore fibre lasers because it degrades with the increasing number of cores. The beam quality factor of the manufactured multicore fibres equals: 7-core hexagonal structure fibre (BQF = 0:71, V = 2:4), 5-core (BQF = 0:70, V = 2:4), 30-core circular structure of core optical fibre laser possesses the lowest beam quality factor (BQF = 0:48, V = 2:4). However, the angular divergence of the central peak is reduced in proportion to the number of cores generating mutually coherent radiation. Numerical simulation shows that standard deviation of the phase error below 15° has an inconsiderable impact on the laser beam quality. The luminescence spectra of the fabricated constructions: 5-core, 7-core and 30-core double clad multicore optical fibres doped with Nd3+ were measured. [ABSTRACT FROM AUTHOR]

In the article there are presented two different series of glass: fluorophosphate with molar composition: 65P2O5-8Al2O3-2BaO-5BaF2-6ZnF2-5Na2O-6MgF2-3B2O3 and antimony glasses 40Sb2O3-3Al2O3-57SiO2 doped with Nd3+ and Yb3+ ions. Dopant contents influence efficient spatial overlapping of emission level for neodymium and absorption level for ytterbium was analyzed. While exciting the produced glasses with a laser diode (λ = 808 nm) a broad luminescence spectrum (Δλ = 100 nm) has been obtained in both cases in the vicinity of 1 μm, being the superposition of the following transitions: 4F3/2→4I11/2 for Nd3+ and ²F5/2→²F7/2 for Yb3+. Based on the luminescence measurements the probability of non-radiative energy transfer was described. Because of a small difference in energy (≈ 1190 cm-1) between the laser levels of neodymium and ytterbium the resonant process of energy transfer has been obtained. [ABSTRACT FROM AUTHOR]

In the article effect of temperature on the cooperative energy transfer in germanate glass co-doped with Yb3+/Tb3+ under 976 nm laser diode pumping was investigated. The optimization of Tb3+ concentration on the upconversion luminescence was determined. Strong luminescence at 489, 543, 586, 621 nm corresponding to 5D4 → 7FJ (J = 6, 4, 3) transitions and luminescence at 381, 415, 435 nm resulting from 5D3, 5G6 → 7FJ (J = 6, 5, 4) transitions were presented. The highest upconversion emission intensity was obtained in glass co-doped with 0.7 Yb2O3/0.7 Tb2O3 (mol%). The effect of temperature on the luminescent properties of germanate glass in the range of 5-250 °C indicates the presence of competing phenomena: an increase in the effective absorption cross- -section of Yb3+ ions donor as a function of temperature and migration of energy between pairs of ions Yb3+-Yb3+ and of multiphonon excitation levels 7FJ . [ABSTRACT FROM AUTHOR]

The paper deals with the optical fibre current sensor based on new optical fibre made of glass with a high value of refractive index. This kind of glass was developed to meet the requirements of these optical fibres. The aim of investigations was to develop a new optical fibre with adequate magneto-optical properties and a relatively weak linear birefringence resulting from the process of its production. These features are of essential importance for optical fibre current sensors. The results of investigations concerning such optical fibres have been presented, displaying satisfactory magneto-optical properties, as well as only low linear birefringence induced by stresses arising in the course of their manufacturing. [ABSTRACT FROM AUTHOR]

In this work structural and luminescence properties of gallo-germanate glasses were investigated. The mentioned glass system was modified with barium and antimony oxides and doped with Eu3+ ions. The starting glass consisted of barium oxide as a modifier which was then gradually replaced by antimony oxide to form six glass samples. The gallo-germanate glass as a low-phonon host for RE (Rare Earths) ions is a promising material for optoelectronics. However, luminescence properties closely depend on material composition. For this reason, structural changes in studied materials were induced by changing its chemical composition and the luminescence properties were tested. The FT-IR (Fourier-Transform Infrared Spectroscopy) and the Raman spectra of studied glasses illustrate the tendency to increasing quantity of bridging oxygen connecting germanium ions and decreasing quantity of non-bridging oxygen along with antimony oxide addition. Simultaneously the BP (Boson Peak) measurements and emission spectra of Eu3+ ions show an increasing tendency to the examined glass structure ordering along with modifier oxide addition. [ABSTRACT FROM AUTHOR]

The fluorescence intensity ratio (FIR) of the green upconversion in Yb3+/Er3+ and blue upconversion in the Yb3+/Tm3+ co-doped tellurite glass as a function of temperature in the range of 20–220°C was investigated. The influence of temperature on FIR upconversion emission spectra of the thermally coupled Er3+: 2H11/2 and 4S3/2 levels enabled to achieve maximum sensitivity of 0.0036°C−1 at 225°C. Despite the lack of thermally coupled levels Yb3+/Tm3+ co-doped tellurite glass is proposed for construction of a temperature sensor. The maximum sensitivity of 0.0044°C−1 at 240°C was obtained using the FIR technique of the upconversion emission at 651nm (Tm3+: 1G4→3F4) and 698nm (Tm3+: 3F3→3H6). [ABSTRACT FROM AUTHOR]

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pirotte Bernard reports financial support was provided by Servier Laboratories Suresnes. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

LMA (Large Mode Area) optical fibers are presently under active investigation to explore their potential for generating laser action or broadband emission directly within the optical fiber structure. Additionally, a wide mode profile significantly reduces the power distribution density in the fiber cross-section, minimizing the power density, photodegradation, or thermal damage. Multi-stage deposition in the MCVD-CDT system was used to obtain the structural doping profile of the LMA fiber multi-ring core doped with Tm 3+ and Tm 3+ /Ho 3+ layer profiles. The low alumina content (Al 2 O 3 : 0.03wt%) results in low refractive index modification. The maximum concentrations of the lanthanide oxides were Tm 2 O 3 : 0.18wt % and Ho 2 O 3 : 0.15wt%. The double-clad construction of optical fiber with emission spectra in the eye-safe spectral range of (1.55-2.10 µm). The calculated LP 01 Mode Field Diameter (MFD) was 69.7 µm (@ 2000 nm, and 1/e of maximum intensity), which confirms LMA fundamental mode guiding conditions. The FWHM and λmax vs. fiber length are presented and analyzed as a luminescence profile modification. The proposed structured optical fiber with a ring core can be used in new broadband optical radiation source designs.

The near-infrared emission in fabricated low-phonon energy, gallo-germanate glass, and double-core optical fiber has been investigated. Broadband amplified spontaneous emission (ASE) was obtained in optical fiber with cores doped with: 1 st - 0.2Er 2 O 3 and 2 nd - 0.5Yb 2 O 3 /0.4Tm 2 O 3 /0.05Ho 2 O 3 as a result of the superposition of emission bands from both cores corresponding to the Er 3+ : 4 I 13/2 → 4 I 15/2 (1 st core) and Tm 3+ : 3 F 4 → 3 H 6 /Ho 3+ : 5 I 7 → 5 I 8 (2 nd core) transitions. The effect of fiber length and pump wavelength on the near-infrared amplified spontaneous emission (ASE) properties has been analyzed for 1 m and 5 m optical fiber. The widest emission bandwidth (355 nm - 3 dB level) was obtained for a 5 m length optical fiber pumped by a 940 nm laser.

Double-clad optical fiber with a multi-ring core profile doped with thulium and holmium fabricated by Modified Chemical Vapor Deposition Chelate Doping Technology (MCVD-CDT) is presented. The measured Tm 2 O 3 and Ho 2 O 3 complexes' weight concentrations were 0.5% and 0.2% respectively. Numerical analyses show weakly guiding conditions and 42.2 µm of MFD LP 01 at 2000 nm. The low NA numerical aperture (NA = 0.054) was obtained for the 20/250 µm core/cladding ratio optical fiber construction. The emission spectra in the range of 1.6-2.1 µm vs. the fiber length are presented. The full width at half maximum (FWHM) decreases from 318 to 270 nm for fiber lengths from 2 to 10 m. The presented fiber design is of interest for the development of new construction of optical fibers operating in the eye-safe spectral range., (© 2023. Springer Nature Limited.)

An investigation of fluoroindate glass and fiber co-doped with Yb 3+ /Er 3+ ions as a potential temperature sensor was assessed using the fluorescence intensity ratio (FIR) technique. Analysis of thermally coupled levels (TCLs- 2 H 11/2 and 4 S 3/2 ), non-thermally coupled levels (non-TCLs- 4 F 7/2 and 4 F 9/2 ), and their combination were examined. Additionally, the luminescent stability of the samples under constant NIR excitation using different density power at three different temperatures was carried out. The obtained values of absolute sensitivity (0.003 K -1 -glass, 0.0019 K -1 -glass fiber 2 H 11/2 → 4 S 3/2 transition) and relative sensitivity (2.05% K -1 -glass, 1.64% K -1 -glass fiber 4 F 7/2 → 4 F 9/2 transition), as well as high repeatability of the signal, indicate that this material could be used in temperature sensing applications.

Nanophosphors are widely used, especially in biological applications in the first and second biological windows. Currently, nanophosphors doped with lanthanide ions (Ln 3+ ) are attracting much attention. However, doping the matrix with lanthanide ions is associated with a narrow luminescence bandwidth. This paper describes the structural and luminescence properties of co-doped LaPO 4 nanophosphors, fabricated by the co-precipitation method. X-ray structural analysis, scanning electron microscope measurements with EDS analysis, and luminescence measurements (excitation 395 nm) of LaPO 4 :Eu 3+ /Nd 3+ and LaPO 4 :Eu 3+ /Nd 3+ /Yb 3+ nanophosphors were made and energy transfer between rare-earth ions was investigated. Tests performed confirmed the crystal structure of the produced phosphors and deposition of rare-earth ions in the structure of LaPO 4 nanocrystals. In the range of the first biological window (650-950 nm), strong luminescence bands at the wavelengths of 687 nm and 698 nm ( 5 D 0 → 7 F 4 :Eu 3+ ) and 867 nm, 873 nm, 889 nm, 896 nm, and 907 nm ( 4 F 3/2 → 4 I 9/2 :Nd 3+ ) were observed. At 980 nm, 991 nm, 1033 nm ( 2 F 5/2 → 2 F 7/2 :Yb 3+ ) and 1048 nm, 1060 nm, 1073 nm, and 1080 nm ( 4 F 3/2 → 4 I 9/2 :Nd 3+ ), strong bands of luminescence were visible in the 950 nm-1100 nm range, demonstrating that energy transfer took place.

Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4−8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1−10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.

The effect of BaF 2 , MgF 2 , and AlF 3 on the structural and luminescent properties of gallo-germanate glass (BGG) doped with erbium ions was investigated. A detailed analysis of infrared and Raman spectra shows that the local environment of erbium ions in the glass was influenced mainly by [GeO] 4 and [GeO] 6 units. Moreover, the highest number of non-bridging oxygens was found in the network of the BGG glass modified by MgF 2 . The 27 Al MAS NMR spectrum of BGG glass with AlF 3 suggests the presence of aluminum in tetra-, penta-, and octahedral coordination geometry. Therefore, the probability of the 4 I 13/2 → 4 I 15/2 transition of Er 3+ ions increases in the BGG + MgF 2 glass system. On the other hand, the luminescence spectra showed that the fluoride modifiers lead to an enhancement in the emission of each analyzed transition when different excitation sources are employed (808 nm and 980 nm). The analysis of energy transfer mechanisms shows that the fluoride compounds promote the emission intensity in different channels. These results represent a strong base for designing glasses with unique luminescent properties.

Glass-ceramic is semi-novel material with many applications, but it is still problematic in obtaining fibers. This paper aims to develop a new glass-ceramic material that is a compromise between crystallization, thermal stability, and optical properties required for optical fiber technology. This compromise is made possible by an alternative method with a controlled crystallization process and a suitable choice of the chemical composition of the core material. In this way, the annealing process is eliminated, and the core material adopts a glass-ceramic character with high transparency directly in the drawing process. In the experiment, low phonon antimony-germanate-silicate glass (SGS) doped with Eu 3+ ions and different concentrations of P 2 O 5 were fabricated. The glass material crystallized during the cooling process under conditions similar to the drawing processes'. Thermal stability (DSC), X-ray photo analysis (XRD), and spectroscopic were measured. Eu 3+ ions were used as spectral probes to determine the effect of P 2 O 5 on the asymmetry ratio for the selected transitions ( 5 D 0 → 7 F 1 and 5 D 0 → 7 F 2 ). From the measurements, it was observed that the material produced exhibited amorphous or glass-ceramic properties, strongly dependent on the nucleator concentration. In addition, the conducted study confirmed that europium ions co-form the EuPO 4 structure during the cooling process from 730 °C to room temperature. Moreover, the asymmetry ratio was changed from over 4 to under 1. The result obtained confirms that the developed material has properties typical of transparent glass-ceramic while maintaining high thermal stability, which will enable the fabrication of fibers with the glass-ceramic core.

This study presented an analysis of the TeO 2 /GeO 2 molar ratio in an oxide glass system. A family of melt-quenched glasses with the range of 0-35 mol% of GeO 2 has been characterized by using DSC, Raman, MIR, refractive index, PLE, PL spectra, and time-resolved spectral measurements. The increase in the content of germanium oxide caused an increase in the transition temperature but a decrease in the refractive index. The photoluminescence spectra of europium ions were examined under the excitation of 465 nm, corresponding to 7 F 0 → 5 D 2 transition. The PSB (phonon sidebands) analysis was carried out to determine the phonon energy of the glass hosts. It was reported that the red ( 5 D 0 → 7 F 2 ) to orange ( 5 D 0 → 7 F 1 ) fluorescence intensity ratio for Eu 3+ ions decreased from 4.49 (Te0Ge) to 3.33 (Te15Ge) and showed a constant increase from 4.58 (Te20Ge) to 4.88 (Te35Ge). These optical features were explained in structural studies, especially changes in the coordination of [4] Ge to [6] Ge. The most extended lifetime was reported for the Eu 3+ doped glass with the highest content of GeO 2 . This glass was successfully used for the drawing of optical fiber.

An investigation of the structural and luminescent properties of the transparent germanate glass-ceramics co-doped with Ni 2+ /Er 3+ for near-infrared optical fiber applications was presented. Modification of germanate glasses with 10-20 ZnO (mol.%) was focused to propose the additional heat treatment process controlled at 650 °C to obtain transparent glass-ceramics. The formation of 11 nm ZnGa 2 O 4 nanocrystals was confirmed by the X-ray diffraction (XRD) method. It followed the glass network changes analyzed in detail (MIR-Mid Infrared spectroscopy) with an increasing heating time of precursor glass. The broadband 1000-1650 nm luminescence (λ exc = 808 nm) was obtained as a result of Ni 2+ : 3 T 2 ( 3 F) → 3 A 2 ( 3 F) octahedral Ni 2+ ions and Er 3+ : 4 I 13/2 → 4 I 15/2 radiative transitions and energy transfer from Ni 2+ to Er 3+ with the efficiency of 19%. Elaborated glass-nanocrystalline material is a very promising candidate for use as a core of broadband luminescence optical fibers.

On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors in vitro , although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides ( 12a , 12b , 12e ) was examined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 ( 4 ). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of 4 . Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.

This work reports on the fabrication and analysis of near-infrared and mid-infrared luminescence spectra and their decays in fluoroindate glasses co-doped with Yb 3+ /Ho 3+ . The attention has been paid to the analysis of the Yb 3+ → Ho 3+ energy transfer processed ions in fluoroindate glasses pumped by 976 nm laser diode. The most effective sensitization for 2 μm luminescence has been obtained in glass co-doped with 0.8YbF 3 /1.6HoF 3 . Further study in the mid-infrared spectral range (2.85 μm) showed that the maximum emission intensity has been obtained in fluoroindate glass co-doped with 0.1YbF 3 /1.4HoF 3 . The obtained efficiency of Yb 3+ → Ho 3+ energy transfer was calculated to be up to 61% (0.8YbF 3 /1.6HoF 3 ), which confirms the possibility of obtaining an efficient glass or glass fiber infrared source for a MID-infrared (MID-IR) sensing application.

Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, noncompetitive (i.e., negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly results in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site. DATABASE: The atomic coordinates and structure factors from the crystal structure determination have been deposited in the Protein Data Bank under accession code https://doi.org/10.2210/pdb6RUQ/pdb. The electron microscopy 3D reconstruction volumes have been deposited in EMDB (EMD-4875: Apo; EMD-4920: ZK200775/GYKI53655; EMD-4921: AMPA compact; EMD-4922: AMPA/GYKI53655 bulgy; EMD-4923: GYKI53655; EMD-4924: AMPA bulgy; EMD-4925: AMPA/GYKI53655 compact)., (© 2020 Federation of European Biochemical Societies.)

The rapid development of a SARS-CoV-2 vaccine is a global priority. Here, we develop two capsid-like particle (CLP)-based vaccines displaying the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. RBD antigens are displayed on AP205 CLPs through a split-protein Tag/Catcher, ensuring unidirectional and high-density display of RBD. Both soluble recombinant RBD and RBD displayed on CLPs bind the ACE2 receptor with nanomolar affinity. Mice are vaccinated with soluble RBD or CLP-displayed RBD, formulated in Squalene-Water-Emulsion. The RBD-CLP vaccines induce higher levels of serum anti-spike antibodies than the soluble RBD vaccines. Remarkably, one injection with our lead RBD-CLP vaccine in mice elicits virus neutralization antibody titers comparable to those found in patients that had recovered from COVID-19. Following booster vaccinations, the virus neutralization titers exceed those measured after natural infection, at serum dilutions above 1:10,000. Thus, the RBD-CLP vaccine is a highly promising candidate for preventing COVID-19.

Fluoroindate glasses co-doped with Pr 3+ /Er 3+ ions were synthesized and their near-infrared luminescence properties have been examined under selective excitation wavelengths. For the Pr 3+ /Er 3+ co-doped glass samples several radiative and nonradiative relaxation channels and their mechanisms are proposed under direct excitation of Pr 3+ and/or Er 3+ . The energy transfer processes between Pr 3+ and Er 3+ ions in fluoroindate glasses were identified. In particular, broadband near-infrared luminescence (FWHM = 278 nm) associated to the 1 G 4  →  3 H 5  (Pr 3+ ), 1 D 2  →  1 G 4  (Pr 3+ ) and 4 I 13/2  →  4 I 15/2  (Er 3+ ) transitions of rare earth ions in fluoroindate glass is successfully observed under direct excitation at 483 nm. Near-infrared luminescence spectra and their decays for glass samples co-doped with Pr 3+ /Er 3+ are compared to the experimental results obtained for fluoroindate glasses singly doped with rare earth ions.

Root hairs (RHs) develop from specialized epidermal trichoblast cells, whereas epidermal cells that lack RHs are known as atrichoblasts. The mechanism controlling RH cell fate is only partially understood. RH cell fate is regulated by a transcription factor complex that promotes the expression of the homeodomain protein GLABRA 2 (GL2), which blocks RH development by inhibiting ROOT HAIR DEFECTIVE 6 (RHD6). Suppression of GL2 expression activates RHD6, a series of downstream TFs including ROOT HAIR DEFECTIVE 6 LIKE-4 (RSL4) and their target genes, and causes epidermal cells to develop into RHs. Brassinosteroids (BRs) influence RH cell fate. In the absence of BRs, phosphorylated BIN2 (a Type-II GSK3-like kinase) inhibits a protein complex that regulates GL2 expression. Perturbation of the arabinogalactan peptide (AGP21) in Arabidopsis thaliana triggers aberrant RH development, similar to that observed in plants with defective BR signaling. We reveal that an O-glycosylated AGP21 peptide, which is positively regulated by BZR1, a transcription factor activated by BR signaling, affects RH cell fate by altering GL2 expression in a BIN2-dependent manner. Changes in cell surface AGP disrupts BR responses and inhibits the downstream effect of BIN2 on the RH repressor GL2 in root epidermis., (© 2020 The Authors. New Phytologist © 2020 New Phytologist Trust.)

Glass and ceramic materials doped with rare earth (RE) ions have gained wide interest in photonics as active materials for lasers, optical amplifiers, and luminescent sensors. The emission properties of RE-doped glasses depend on their chemical composition, but they can also be tailored by modifying the surrounding active ions. Typically, this is achieved through heat treatment (including continuous-wave and pulsed lasers) after establishing the ordering mechanisms in the particular glass-RE system. Within the known systems, silicate glasses predominate, while much less work relates to materials with lower energy phonons, which allow more efficient radiation sources to be constructed for photonic applications. In the present work, the luminescent and structural properties of germanate glasses modified with phosphate oxide doped with Eu 3+ ions were investigated. Europium dopant was used as a "spectroscopic probe" in order to analyze the luminescence spectra, which characterizes the changes in the local site symmetries of Eu 3+ ions. Based on the spectroscopic results, a strong influence of P 2 O 5 content was observed on the excitation and luminescence spectra. The luminescence study of the most intense 5 D 0 → 7 F 2 (electric dipole) transition revealed that the increase in the P 2 O 5 content leads to the linewidth reduction (from 15 nm to 10 nm) and the blue shift (~2 nm) of the emission peak. According to the crystal field theory, the introduction of P 2 O 5 into the glass structure changes the splitting number of sublevels of the 5 D 0 → 7 F 1 (magnetic dipole) transition, confirming the higher polymerization of fabricated glass. The slightly different local environment of Eu 3+ centers the results in a number of sites and causes inhomogeneous broadening of spectral lines. It was found that the local asymmetry ratio estimated by the relation of ( 5 D 0 → 7 F 2 )/( 5 D 0 → 7 F 1 ) transitions also confirms greater changes in local symmetry around Eu 3+ ions. Our results indicate that modification of germanate glass by P 2 O 5 allows control of their structural properties in order to functionalize the emissions for application as luminescent light sources and sensors.

The full length human histone 3 lysine 4 demethylase KDM5B (PLU-1/Jarid1B) has been studied using Hydrogen/Deuterium exchange mass spectrometry, homology modelling, sequence analysis, small angle X-ray scattering and electron microscopy. This first structure on an intact multi-domain Jumonji histone demethylase reveal that the so-called PLU region, in the central region of KDM5B, has a curved α-helical three-dimensional structure, that acts as a rigid linker between the catalytic core and a region comprising four α-helices, a loop comprising the PHD2 domain, two large intrinsically disordered loops and the PHD3 domain in close proximity. The dumbbell shaped and curved KDM5B architecture observed by electron microscopy is complementary to the nucleosome surface and has a striking overall similarity to that of the functionally related KDM1A/CoREST complex. This could suggest that there are similarities between the demethylation mechanisms employed by the two histone 3 lysine 4 demethylases at the molecular level.

The AMPA receptor GluA2 belongs to the family of ionotropic glutamate receptors, which are responsible for most of the fast excitatory neuronal signalling in the central nervous system. These receptors are important for memory and learning, but have also been associated with brain diseases such as Alzheimer's disease and epilepsy. Today, one drug is on the market for the treatment of epilepsy targeting AMPA receptors, i.e. a negative allosteric modulator of these receptors. Recently, crystal structures and cryo-electron microscopy (cryo-EM) structures of full-length GluA2 in the resting (apo), activated and desensitized states have been reported. Here, solution structures of full-length GluA2 are reported using small-angle neutron scattering (SANS) with a novel, fully matched-out detergent. The GluA2 solution structure was investigated in the resting state as well as in the presence of AMPA and of the negative allosteric modulator GYKI-53655. In solution and at neutral pH, the SANS data clearly indicate that GluA2 is in a compact form in the resting state. The solution structure resembles the crystal structure of GluA2 in the resting state, with an estimated maximum distance ( D max ) of 179 ± 11 Å and a radius of gyration ( R g ) of 61.9 ± 0.4 Å. An ab initio model of GluA2 in solution generated using DAMMIF clearly showed the individual domains, i.e. the extracellular N-terminal domains and ligand-binding domains as well as the transmembrane domain. Solution structures revealed that GluA2 remained in a compact form in the presence of AMPA or GYKI-53655. At acidic pH only, GluA2 in the presence of AMPA adopted a more open conformation of the extracellular part (estimated D max of 189 ± 5 Å and R g of 65.2 ± 0.5 Å), resembling the most open, desensitized class 3 cryo-EM structure of GluA2 in the presence of quisqualate. In conclusion, this methodological study may serve as an example for future SANS studies on membrane proteins.

Lifespans of males and females frequently differ as a consequence of different life history strategies adopted to maximize fitness. It is well visible in cyclic parthenogens, such as water fleas of the genus Daphnia , where males appear in the population usually only for periods when receptive females are available. Moreover, even within one sex, different life history strategies and mechanisms regulating lifespan may exist. Previous studies suggested that Daphnia males may regulate their lifespan by staying in colder waters than females. We hypothesize that such behavioral mechanism should be associated with stronger reaction to low temperature-that is greater lifespan extension in males than in females. In this study, we monitored survivorship of Daphnia magna females and males of three clonal lines cultured at 16 or 20°C. The results did not provide a species-level corroboration of our hypothesis; instead, they revealed very strong intraspecific differences in the responses of male and female lifespan to temperature change. They further suggest the existence of parallel life history strategies, hypothesis whose tests would bring new insights into the ecology of males in cyclic parthenogens.

The KDM6 subfamily of histone lysine demethylases has recently been implicated as a putative target in the treatment of a number of diseases; this makes the availability of potent and selective inhibitors important. Due to high sequence similarity of the catalytic domain of Jumonji C histone demethylases, the development of small-molecule, family-specific inhibitors has, however, proven challenging. One approach to achieve the selective inhibition of these enzymes is the use of peptides derived from the substrate, the histone 3 C terminus. Here we used computational methods to optimize such inhibitors of the KDM6 family. Through natural amino acid substitution, it is shown that a K18I variant of a histone H3 derived peptide significantly increases affinity towards the KDM6 enzymes. The crystal structure of KDM6B in complex with a histone 3 derived K18I peptide reveals a tighter fit of the isoleucine side chain, compared with that of the arginine. As a consequence, the peptide R17 residue also has increased hydrophilic interactions. These interactions of the optimized peptide are likely to be responsible for the increased affinity to the KDM6 enzymes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Near-infrared luminescence properties of Nd 3+ and Ho 3+ ions in barium gallo-germanate glasses have been reported. Several spectroscopic parameters for Nd 3+ and Ho 3+ ions have been determined from the Judd-Ofelt analysis and absorption/luminescence measurements. Quite large luminescence lifetime, quantum efficiency and stimulated emission cross-section have been obtained for the main 4 F 3/2  →  4 I 11/2 (Nd 3+ ) and 5 I 7  →  5 I 8 (Ho 3+ ) laser transitions of rare earths in barium gallo-germanate glasses. It suggests that barium gallo-germanate glass is promising for near-infrared laser application at emission wavelengths 1064 nm (Nd 3+ ) and 2020 nm (Ho 3+ )., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function., Methods: Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m 2 ) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m 2 ) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO 2 peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables., Results: Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E' ( P  < 0.01), but did not change RH ( P  = 0.92), or VO 2 peak ( P  = 0.33) in any participants., Conclusion: Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets. Trial registration NCT00786019. Prospectively registered May 2008.

The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays. The inhibitor has significantly lower affinity towards KDM2 enzymes (the phylogenetically closest subfamily), and to KDM3 and KDM6 subfamilies. Selectivity is only marginal towards an enzyme from the KDM4 family, which shares histone tail specificity with PHF8. It is a substrate of KDM5B, thus implying that the free N terminus is not part of the KDM5 enzyme substrate recognition machinery. The cyclic peptide's ability to penetrate cells is achieved by incorporation of a sequence derived from HIV Tat. The derived cyclic peptide can be used as a starting compound in the search for potent and selective PHF8 inhibitors., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)