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The structure-based design of small-molecule inhibitors targeting protein–protein interactions (PPIs) remains a huge challenge as the drug must bind typically wide and shallow protein sites. A PPI target of high interest for hematological cancer therapy is myeloid cell leukemia 1 (Mcl-1), a prosurvival guardian protein from the Bcl-2 family. Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315. Our X-ray data reveal high plasticity of Mcl-1 and a remarkable ligand-induced pocket deepening. Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.

RAS proteins are central in the proliferation of many types of cancer, but a general approach toward the identification of pan-mutant RAS inhibitors has remained unresolved. In this work, we describe the application of a binding pharmacophore identified from analysis of known RAS binding peptides to the design of novel peptides. Using a chemically divergent approach, we generated a library of small stapled peptides from which we identified compounds with weak binding activity. Exploration of structure-activity relationships (SARs) and optimization of these early compounds led to low-micromolar binders of KRAS that block nucleotide exchange.

Several porous materials, especially natural fibres and polyurethane foams, are frequently used as sound absorbers in multiple noise reduction applications. Notwithstanding their excellent absorption performance, these materials usually lack the structural strength and fire resistance required for use in aggressive environments or situations requiring structural stability. This paper proposes the design of open-pore polymer and aluminum cellular materials with non-stochastic structures for sound absorption. These materials were fabricated using additive manufacturing (polymeric materials) and the replication method (aluminum materials), which involves infiltrating porous preforms formed by compacting spheres of a martyr material, such as NaCl, with liquid aluminum. The proposed materials can be employed as a resonator system when backed by an air cavity, with the change in cavity depth used to tune its sound absorption peak. Following the standard ASTM E1050, the sound absorption of these materials was investigated. In addition, the sound absorption performance of the materials was predicted using an Equivalent Circuit Method model. The experimental results are consistent with those predicted by the model, highlighting the potential of the microstructural and configurational design of these materials as sound absorbers. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research was undertaken at the Department of Mechanical Engineering at the Massachusetts Institute of Technology with support from the University of Alicante (Grants. ACIE19-04 and ACIE20-04). J.M. Molina gratefully acknowledges partial financial support from the Spanish “Agencia Estatal de Investigación” (AEI) and European Union (FEDER funds) through grant PDC2021-121617-C21 and the financial support from the Conselleria d'Innovació, Universitats, Ciència, i Societat Digital of the Generalitat Valenciana through grant GVA-COVID19/2021/097. L.P. Maiorano also acknowledges the financial support from the University of Alicante through grant UAFPU2019-33 "Programa Propio para el fomento de la I+D+i del Vicerrectorado de Investigación y Transferencia de Conocimiento".

Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as a possible therapeutic target. Therefore, determination of the structure of hSMOX is an important step to enable drug discovery and validate hSMOX as a drug target. Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered a hSMOX construct to obtain the first crystal structure of hSMOX bound to the known polyamine oxidase inhibitor MDL72527 at 2.4 Å resolution. While the overall fold of hSMOX is similar to its homolog, murine N1-acetylpolyamine oxidase (mPAOX), the two structures contain significant differences, notably in their substrate-binding domains and active site pockets. Subsequently, we employed a sensitive biochemical assay to conduct a high-throughput screen that identified a potent and selective hSMOX inhibitor, JNJ-1289. The co-crystal structure of hSMOX with JNJ-1289 was determined at 2.1 Å resolution, revealing that JNJ-1289 binds to an allosteric site, providing JNJ-1289 with a high degree of selectivity towards hSMOX. These results provide crucial insights into understanding the substrate specificity and enzymatic mechanism of hSMOX, and for the design of highly selective inhibitors.

An efficient macrocyclisation approach based on the double aromatic nucleophilic substitution (SNACK) was developed. This methodology allows a facile incorporation of heterocyclic motifs into macrocyclic rings and rapid synthesis of a significant number of structurally diverse macrocycles. SNACK macrocyclisation enables preparation of stable diastereoisomers of conformationally restricted macrocycles (atropisomers). Practical application of SNACK macrocyclisation in a drug discovery project was exemplified by the identification of high affinity macrocyclic binders of B-cell lymphoma 6 (BCL6).

Perovskite oxides BaFeyTi1-yO3, with y = 0, 0.6, 0.8 and 1, were prepared by ceramic (CM) and complex polymerization methods (CPM) and utilized in UV-LED (365 nm) photocatalytic degradation assays of 25 mg L-1 diclofenac (DIC) model solutions. BaTiO3-CM was also used in the photocatalytic degradation test of a real mineral water for human consumption spiked with 2 mg L-1 DIC. The XRD patterns of the synthesized perovskites showed cubic structure for those prepared by CPM, with distortions of the cubic lattice to hexagonal or tetragonal when prepared by CM, except for BaTiO3. All the perovskites showed good catalytic activity, higher than photolysis, except BaFeO3-CM that presented similar results. BaTiO3-CM and CPM and BaFeO3-CPM were also utilized in UV-LED photocatalytic DIC degradation assays with peroxydisulfate addition. BaFeO3-CPM and BaTiO3-CPM showed better ability to persulfate activation, but the highest mineralization degree was obtained with BaTiO3-CM. This last perovskite was also able to perform DIC degradation in a real matrix. The studied oxides show potentiality for photocatalytic degradation of organic compounds, with or without persulfate addition. A degradation mechanism is proposed.

"Hot loop" protein segments have variable structure and conformation and contribute crucially to protein-protein interactions. We describe a new hot loop mimicking modality, termed PepNats, in which natural product (NP)-inspired structures are incorporated as conformation-determining and -restricting structural elements into macrocyclic hot loop-derived peptides. Macrocyclic PepNats representing hot loops of inducible nitric oxide synthase (iNOS) and human agouti-related protein (AGRP) were synthesized on solid support employing macrocyclization by imine formation and subsequent stereoselective 1,3-dipolar cycloaddition as key steps. PepNats derived from the iNOS DINNN hot loop and the AGRP RFF hot spot sequence yielded novel and potent ligands of the SPRY domain-containing SOCS box protein 2 (SPSB2) that binds to iNOS, and selective ligands for AGRP-binding melanocortin (MC) receptors. NP-inspired fragment absolute configuration determines the conformation of the peptide part responsible for binding. These results demonstrate that combination of NP-inspired scaffolds with peptidic epitopes enables identification of novel hot loop mimics with conformationally constrained and biologically relevant structure.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

The conformational behavior of a small molecule free in solution is important to understand the free energy of binding to its target. This could be of special interest for proteolysis-targeting chimeras (PROTACs) due to their often flexible and lengthy linkers and the need to induce a ternary complex. Here, we report on the molecular dynamics (MD) simulations of two PROTACs, MZ1 and dBET6, revealing different linker conformational behaviors. The simulation of MZ1 in dimethyl sulfoxide (DMSO) agrees well with the nuclear magnetic resonance study, providing strong support for the relevance of our simulations. To further understand the role of linker plasticity in the formation of a ternary complex, the dissociation of the complex von Hippel-Lindau-MZ1-BRD4 is investigated in detail by steered simulations and is shown to follow a two-step pathway. Interestingly, both MZ1 and dBET6 display in water, a tendency toward an intramolecular lipophilic interaction between the two warheads. The hydrophobic contact of the two warheads would prevent them from binding to their respective proteins and might have an effect on the efficacy of induced cellular protein degradation. However, conformations featuring this hydrophobic contact of the two warheads are calculated to be marginally more favorable.

The dynamic elastic modulus is an important parameter for the study of solid mechanical elements. Even though there exist several well-established standardized methods that allow determining this parameter under a state of simple stresses, some of these may require sophisticated laboratory equipment or involve the use of multiple devices (impulser, sensor transducer…). The main purpose of this work is to propose an alternative approach that uses a single electrodynamic actuator both as an impulse exciter and vibration sensor simultaneously. By generating a random signal excitation and measuring the electrical input impedance of the actuator when coupled to a beam-type cylindrical element, the fundamental flexural mode of vibration of the latter can be identified and the dynamic elastic modulus of its material determined in a simple and straightforward manner. Preliminary experiments were performed over different size beams with rectangular cross-sections made of natural stone, marble, wood, and aluminium. Results were compared to those obtained using the standardized procedure described in the ASTM E1876 for the same specimens, these showing a good agreement in terms of dynamic elastic modulus.

International audience; Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation–activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer-specific lipophilicities (logp) is much less explored. Here we show how conformer-specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.

An efficient macrocyclisation approach based on the double aromatic nucleophilic substitution (SNACK) was developed. This methodology allows a facile incorporation of heterocyclic motifs into macrocyclic rings and rapid synthesis of a significant number of structurally diverse macrocycles. SNACK macrocyclisation enables preparation of stable diastereoisomers of conformationally restricted macrocycles (atropisomers). Practical application of SNACK macrocyclisation in a drug discovery project was exemplified by the identification of high affinity macrocyclic binders of B-cell lymphoma 6 (BCL6).

Using macro-perforations in a generic porous media may not only make the resonance frequency of a rigidly backed sound absorber lower but also its sound absorption amplitude increase. Given the rise of 3D-printing in the field of acoustic materials over the last years, it turns out of great interest to explore the possibilities of this technology on the fabrication of these absorbers. Unlike conventional fabrication processes, additive manufacturing lets design the material at the microscopic scale, thus allowing choosing the appropriate geometrical dimensions of both the macro-perforations and the micro-pores that let enhance its sound absorption. In this work, a preliminary insight into the use of additive manufacturing technology for the fabrication of macro-perforated porous media for sound absorption is reported. For this purpose, several specimens having different pore sizes and porosities in the microporous medium were produced and tested in an impedance tube. Experimental results showed an improved absorption performance for those samples having macro-perforations. Additionally, predictions through the double porosity theory together with the JCA approach using macroscopic parameters obtained by an inverse characterization procedure were compared to the absorption measurements showing a good agreement. This research suggests that the use of additive manufacturing technology may provide an excellent workbench for the optimal design of such absorbers. This work was developed in the framework of the COST Action CA15125 - DENORMS: “Designs for Noise Reducing Materials and Structures”. J. M. M-J. and L. P. M. acknowledge partial financial support from the Spanish Agencia Estatal de Investigación (AEI) and European Union (FEDER funds) through grant MAT2016-77742-C2-2-P.

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.

[Image: see text] Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.

This work evidences for the first time the production of CO and NOx during the removal of nitrogen containing pollutants in water by Fenton Process, the most popular method for Advanced Oxidation Processes. Four representative nitrogen containing pollutants were selected, viz. aniline, 4-nitrophenol, pyridine and monoethanolamine. The gas effluent accumulated after 3 h of reaction at 90 °C and 3 bar was analysed. In all cases, the carbon and nitrogen mass balance was assessed. Also, an on-line off-gas analysis system was set up to monitor the off-gas variation of CO and CO2 from the beginning of the reaction. CO2 was the major component of the gas effluent. It was progressively produced upon oxidation. In contrast, CO was detected in fairly lower amounts and it was immediately produced after H2O2 injection, due to the rupture and opening of the aromatic ring. The CO formation was more favorable upon degradation of aromatic than aliphatic compounds, or when the nitrogen was in the aromatic ring, as in the case of pyridine. The nitrogen functional groups were majorly transformed into NH4+ and NO3−, while NOx was detected in low amounts ( NO2 group. These results highlight the importance of monitoring the gas phase generated in the treatment of high-loaded wastewater by AOPs in order to guarantee the environmental sustainability of the processes.

The three-dimensional conformations adopted by a free ligand in solution impact bioactivity and physicochemical properties. Solution 1D NMR spectra inherently contain information on ligand conformational flexibility and three-dimensional shape, as well as the propensity of the free ligand to fully preorganize into the bioactive conformation. Herein we discuss some key learnings, distilled from our experience developing potent and selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been selected from recent oncology research projects, demonstrating how 1D NMR conformational signatures can complement X-ray protein-ligand structural information to guide medicinal chemistry optimization. Learning to extract free ligand conformational information from routinely available 1D NMR signatures has proven to be fast enough to guide medicinal chemistry decisions within design cycles for compound optimization.

Noise abatement provided by acoustic metamaterials is one of the peculiar features presented by these remarkable materials. In fact, the use of local resonant elements and their periodic distribution in the form of so-called sonic crystal arrangements have demonstrated to enhance those attenuation properties. In this work, the authors present an efficient three-dimensional (3D) numerical model based on the Boundary Element Method (BEM) to analyse the acoustic behaviour in the frequency domain of finite periodic arrays of acoustic resonators. Unlike most analytical methods, the proposed model captures the finite features of these systems and their associated effects. Furthermore, usual numerical tools such as the Finite Element Method (FEM) may become impractical because the detailed and complex geometry of these devices would lead to very large discretized spatial domains. Instead, in the proposed model, only the resonators have to be discretized. Actually, an efficient strategy has been devised to adequately take into account the periodicity of the finite array of resonators, resulting in significant savings of computational resources. Additionally, the Adaptive Cross Approximation (ACA) technique is used, further reducing the computational requirements since it is based on hierarchical representation of matrices and allows a very efficient storage of the system matrix. This work has been framed within POCI-01-0247-FEDER-017759 (SmartCore) and POCI-01-0247-FEDER-033691 (HLS - Hybrid Log Shield) Projects, funded by the COMPETE 2020, Portugal 2020 and FEDER funds. This work was partly financed by FEDER funds through the Competitivity Factors Operational Programme - COMPETE and by national funds through FCT – Foundation for Science and Technology within the scope of the project POCI-01-0145-FEDER-007633 and through the Regional Operational Programme CENTRO2020 within the scope of the project CENTRO-01-0145-FEDER-000006. This work was also developed in the scope of COST (European Cooperation in Science and Technology) through the COST Action CA15125 – DENORMS: “Designs for Noise Reducing Materials and Structures” and the EU funding support is here acknowledged.

Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.

This work analyzes the role of natural groundwater, as well as the effect of HCO3−, Ca2+, Mg2+, K+, SO42- and Cl− concentrations, upon the photocatalytic nitrate reduction using ilmenite as catalyst and oxalic acid as hole scavenger. The nitrate removal and the selectivity towards N2 are significantly limited compared to previous experiments using ultrapure water matrix. Calcium (Ca2+), bicarbonate (HCO3−) as well as pH are claimed as the major controlling factors related to the process yield. Thus, Ca2+ promotes the formation of insoluble oxalate microcrystals, reducing the amount of hole scavenger available. The presence of HCO3− leads to a steeply increase in the pH value, favoring the adsorption onto the ilmenite surface of ions OH−instead of NO3−, NO2− and C2O42. The aforementioned issues are overcome by working with C2O42−/NO3− ratio well above the stoichiometric one, that also maintains the pH value in an acid range. A completed depletion of the starting NO3−, the no detection of either NO2− or NH4+ in the aqueous phase, and a selectivity towards N2 above 95% were achieved using two times the stoichiometric dose, This work has been supported by AEI (10.13039/501100011033) through the project PID2019-106884GB-I00 and Comunidad de Madrid through the project P2018/EMT-4341. A.R.R thanks the Post-Doctoral scholarship awarded by the public agency São Paulo State Research Foundation (FAPESP), grant #2018/09697-8. J. Carbajo wants to thank the Ministerio de Ciencia, Innovación y Universidades (MICIU) for a grant under the Juan de la Cierva_Incorporación programme (IJCI-2017-32682)

Context: Open clusters (OCs) are widely used as test particles to investigate a variety of astrophysical phenomena, from stellar evolution to Galactic evolution. Gaia and the complementary massive spectroscopic surveys are providing an unprecedented wealth of information about these systems. Aims: The Open Cluster Chemical Abundances from Spanish Observatories (OCCASO) survey aims to complement all this work by determining OCs accurate radial velocities and chemical abundances from high-resolution, R$\geq$60\,000, spectra. Methods: Radial velocities have been obtained by cross-correlating the observed spectra with a library of synthetic spectra which covers from early M to A spectral types. Results: We provide radial velocities for 336 stars, including several Gaia Benchmark Stars and objects belonging to 51 open clusters. The internal uncertainties of the derived radial velocities go from 10 m/s to 21 m/s as a function of the instrumental configuration used. The derived radial velocities, together with the Gaia proper motions, have been used to investigate the cluster membership of the observed stars. After this careful membership analysis, we obtain average velocities for 47 open clusters. To our knowledge, this is the first radial velocity determination for 5 of these clusters. Finally, the radial velocities, proper motions, distances and ages have been used to investigate the kinematics of the observed clusters and in the integration of their orbits., Comment: 27 pages, accepted for publication in A&A

Gaia Multilateral Agreement, [Context] Precise chemical abundances coupled with reliable ages are key ingredients to understanding the chemical history of our Galaxy. Open clusters (OCs) are useful for this purpose because they provide ages with good precision. [Aims] The aim of this work is to investigate the relation between different chemical abundance ratios and age traced by red clump (RC) stars in OCs. [Methods] We analyzed a large sample of 209 reliable members in 47 OCs with available high-resolution spectroscopy. We applied a differential line-by-line analysis, performing a comprehensive chemical study of 25 chemical species. This sample is among the largest samples of OCs homogeneously characterized in terms of atmospheric parameters, detailed chemistry, and age. [Results] In our metallicity range (-0.2 < [M/H] < +0.2) we find that while most Fe-peak and α elements show a flat dependence on age, the s-process elements show a decreasing trend with increasing age with a remarkable knee at 1 Gyr. For Ba, Ce, Y, Mo, and Zr, we find a plateau at young ages (< 1 Gyr). We investigate the relations between all possible combinations among the computed chemical species and age. We find 19 combinations with significant slopes, including [Y/Mg] and [Y/Al]. The ratio [Ba/α] shows the most significant correlation. [Conclusions] We find that the [Y/Mg] relation found in the literature using solar twins is compatible with the one found here in the solar neighborhood. The age-abundance relations in clusters at large distances(d > 1 kpc) show larger scatter than those in clusters in the solar neighborhood, particularly in the outer disk. We conclude that, in addition to pure nucleosynthetic arguments, the complexity of the chemical space introduced by the Galactic dynamics must be taken into account in order to understand these relations, especially outside of the local bubble., L.C., C.S., Y.T. and N.L. acknowledge support from “programme national de physique stellaire” (PNPS) and from the “programme national cosmologie et galaxies” (PNCG) of CNRS/INSU. We acknowledge the support of the scientific cooperation program ECOS-ANID Number 180049. L.C. acknowledges the support of the postdoc fellowship from French Centre National d’Etudes Spatiales (CNES). P.J. acknowledges financial support of FONDECYT Iniciación grant Number 11170174 and FONDECYT Regular grant Number 1200703. This work was partially supported by the Spanish Ministry of Science, Innovation and University (MICIU/FEDER, UE) through grant RTI2018-095076-B-C21, and the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia ‘María de Maeztu’) through grant CEX2019-000918-M.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

Many different solutions exist to improve the low-frequency sound absorption performance of acoustic resonators, extending or coiling up space into the resonator being some of the most widespread. In this context, modern additive manufacturing processes pose a new scenario in which these devices can be engineered to yield outstanding acoustic properties. In a recent work by the authors, a solution consisting of a perforated panel with oblique perforations was analyzed, results showing an enhanced sound absorption performance when compared to traditional perforated panel absorbers. This technical note aims to show the potential of these panels when used in multi-layer arrangements both to widen their effective sound absorption bandwidth and to improve their low-frequency performance. A simplified approach that relies on the fluid-equivalent theory was used together with the Transfer Matrix Method (TMM) to analyse different configurations, prediction results showing a good agreement when compared to experiments in an impedance tube over additive manufactured samples. Unlike other perforated-based solutions, the proposed system avoids addressing the cavity design while showing improved sound absorption features. This work was supported by the COST (European Cooperation in Science and Technology) Action CA15125 - DENORMS: ‘‘Designs for Noise Reducing Materials and Structures”.

[EN] Hexagonal boron nitride (h-BN) has been explored as a catalyst for degrading persistent organic pollutants in wastewater by Catalytic Wet Peroxide Oxidation (CWPO). Herein, the superior activity of the h-BN on the phenol degradation (model pollutant) compared to other metal-free catalysts, such as carbon-based ones, and the lower selectivity to CO encourage the potential application of h-BN catalysts in CWPO processes. Through a combined density functional theory calculations, experimental reactions and catalyst characterization approach, a comprehensive study on the reaction mechanism has been conducted. According to this, only defected B atoms in the h-BN layer, protonated as B-(OH), decompose the hydrogen peroxide into highly reactive hydroxyl radicals. The radical species diffuse towards inner h-BN regions and react with the phenol adsorbed by π-π interaction on the h-BN surface. Oxidation by-products cause carbonaceous deposits and progressive deactivation of the h-BN catalyst that can be directly regenerated by burning off in air., The authors thank the financial support by the Community of Madrid and the Government of Spain through the projects: S2018/EMT- 4341 and RTI2018-095052-B-I00 (MCIU/AEI/FEDER, UE), respectively. The work done at the University of Sevilla was funded by Spanish Ministerio de Ciencia e Innovación and EU-FEDER, grant PID2019-106871 GB-I00, and the Junta de Andalucía-FEDER, grant: US-1381410. Also, G. Vega acknowledges the Community of Madrid for the Predoctoral contract PEJD-2018-PRE/AMB-9019, co-financed by the European Social Fund through the Youth Employment Operational Program and the Youth Employment Initiative (YEI) 2018. J. Carbajo thanks the financial support by the Government of Spain for a grant under the Juan de la Cierva_Incorporación programme (IJCI-2017- 32682). The authors would like to thank A. Pérez for performing the BET and TGA measurements.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS

Low-frequency airborne noise reduction is an issue of major concern in most practical cases due to the limiting space constraints. The applicability of acoustic resonators that not only work in this frequency range but can also be tuned is of great interest in many noise control applications such as muffler devices, noise barriers, or building isolation walls. This Letter studies the acoustic behavior of perforated panel absorbers with oblique perforations. Unlike more complex devices, the proposed absorber uses a simple concept that relies on the increase in the effective length of the panel by using perforations aligned obliquely with respect to the panel surface. In doing so, a shift of the resonance frequency toward low frequencies along with an increase in the sound absorption can be achieved provided that the geometrical characteristics of the absorber are properly chosen. A simple predictive model that relies on the fluid-equivalent theory was developed to investigate the acoustic properties of these absorbers, measurements in an impedance tube over additive manufactured samples serving to confirm the previous assertions. Preliminary results show the potential of these absorbers and encourage their further development for practical purposes. This work was supported by the COST (European Cooperation in Science and Technology) Action CA15125-DENORMS: “Designs for Noise Reducing Materials and Structures.”

Clusterix 2.0 is a web-based, Virtual Observatory compliant, interactive tool for the determination of membership probabilities in stellar clusters based on proper-motion data using a fully non-parametric method. In an area occupied by a cluster, the frequency function is made up of two contributions: cluster and field stars. The tool performs an empirical determination of the frequency functions from the vector point diagram without relying on any previous assumption about their profiles. Clusterix 2.0 allows us to search the appropriate spatial areas in an interactive way until an optimal separation of the two populations is obtained. Several parameters can be adjusted to make the calculation computationally feasible without interfering with the quality of the results. The system offers the possibility to query different catalogues, such as Gaia, or upload a user's own data. The results of the membership determination can be sent via Simple Application Messaging Protocol (SAMP) to Virtual Observatory (VO) tools such as Tool for OPerations on Catalogues And Tables (TOPCAT). We apply Clusterix 2.0 to several open clusters with different properties and environments to show the capabilities of the tool: an area of five degrees radius around NGC 2682 (M67), an old, well-known cluster; a young cluster NGC 2516 with a striking elongated structure extended up to four degrees; NGC 1750 and NGC 1758, a pair of partly overlapping clusters; the area of NGC 1817, where we confirm a little-known cluster, Juchert 23; and an area with many clusters, where we disentangle two overlapping clusters situated where only one was previously known: Ruprecht 26 and the new CLUSTERIX 1., With funding from the Spanish government through the "María de Maeztu Unit of Excellence" accreditation (MDM-2017-0737)

This work explores the feasibility of Fenton oxidation and Catalytic Wet Peroxide Oxidation (CWPO) at high temperature for the treatment of a complex cork-boiling wastewater (CBW) characterized by a high organic load (COD = 4906 mg/L) and substantial content of phenolics. Since CBW leaves the process at 100 °C, working at high temperature favors the integration of an on-site thermal water treatment, as explored in this work. Fenton oxidation of CBW at 100 °C employing 100 mg/L Fe2+ and the stoichiometric dose of H2O2 for complete mineralization (H2O2 = 9795 mg/L), yielded around 70% TOC removal after 180 min reaction. In CWPO, four different catalysts were tested, 0.5wt.%Fe/SiC, 4wt.%Fe/SiC, AC (activated carbon) and 4wt.%Fe/AC also at 100 °C. The Fe catalysts exhibited significant activity that makes possible the disposal of the treated water to the environment. Nonetheless, the occurrence of significant iron leaching jeopardizes their stability and the process implementation. On the contrary , AC showed a great stability as evidenced by the well maintained COD and TOC removal efficiencies of 78 and 58%,respectively, in a long term run (72 h) at 100 °C. Based on these results, CWPO at 100 °C using AC as catalyst can be considered a promising alternative for the integration of an on-site CBW treatment.

This work assesses the carbon monoxide formation upon Fenton process, the most popular method for Advanced Oxidation Processes (AOPs). CO concentrations in the order of 11,000 mg/Nm3 were measured in the Fenton oxidation of phenol after 180 min reaction at 90 °C and 3 bar. The Fenton oxidation performed on phenol and its oxidized intermediates such as hydroquinone, catechol and short-chain acids allows concluding that CO is produced through the oxidative cleavage of aromatic rings; the hydroquinone route being more selective to CO than catechol. In all cases, the carbon mass balance was satisfactorily closed to 100%. The study of the influence of the operational conditions shows that CO production is clearly favoured at H2O2 dosage above the stoichiometric value and low temperatures (T< 90º). The H2O2 dosage was the most influence variable. The results of this work evidence for the first time the production of noxious amounts of CO along with CO2 in Fenton processes. This finding highlights the importance of evaluating not only liquid phase intermediates due to their recalcitrant and/or toxic behavior, but also gas phase because of CO emissions., Financial support from the project CTM2016-76454-R (Ministerio de Economia y Competitividad-MINECO, Spain) is gratefully acknowledged

Effect of TiO2 hydrodynamic particle sizes and catalyst loading on the optical properties of three commercial photocatalysts has been analyzed (P25 Aeroxide®, P25/20 VP Aeroperl® and P90 Aeroxide®). These catalysts, characterized by similar structural and electronic properties, but with singular differences in morphology and aggregation particle sizes, have been studied to understand the corresponding crossed effects on their final photo-efficiencies throughout organic matter removal in aqueous suspensions, with a pollutant such as phenol, where photo-oxidation is regularly described as mediated by an indirect photo-mechanism via HO• radicals. Reflectance measurements in the range of visible wavelength, close to TiO2 absorption edge, could be comparable to extinction coefficient in the UV-A range and may well be suitable to optimize catalyst loadings. Phenol photocatalytic efficiency followed P25 > P90 > P25/20 order, emphasizing that increases in TiO2 hydrodynamic particle sizes are detrimental to phenol photo-efficiency, and highlighting that radiation–photocatalyst interactions are essential but not enough to guarantee an improved photodegradation rate. Finally, the higher values of HO● found in sonicated P25/20 catalyst could corroborates its better performance in phenol photodegradation, as a consequence of lowest hydrodynamic particle sizes in reaction media, which take advantage of light as a result of a significant increase in exposed surface area.

An important challenge for acoustic engineers in room acoustics design is related to the acoustic performance of multi-purpose auditoriums, which are typically designed to suit several performance requirements. With this intent, the analysis of several scenarios is usually performed individually, and then an acceptable solution, that may be adapted to several situations, is selected. One way of providing a more appropriate acoustic performance for each function of the auditorium is using variable sound absorption techniques to control reverberation and other relevant acoustic phenomena associated to sound perception. In this paper, the acoustic behavior of a perforated system that may be suitable for achieving a variable acoustic solution for room acoustic design is addressed. In the design of a cost-effective solution, the surface appearance is kept unchanged, while variable acoustic behavior is achieved either by closing the holes in the back face of the perforated panel or by placing a porous material in varying positions inside the backing cavity, thus accomplishing different acoustic requirements within a multipurpose auditorium. An analytical approach, based on the transfer matrix method is employed for preliminary acoustic sound absorption assessment provided by the system and to develop optimized solutions. Diffuse sound absorption is then computed and used to simulate, by the ray-tracing method, the acoustic behavior of a multipurpose auditorium to demonstrate efficient acoustic performance for different types of use. This work is financed by FEDER funds through the Competitivity Factors Operational Programme—COMPETE within the scope of the project ADJUST—Development of acoustic panels progressively adjustable with smart acting—SII & DT Project CENTRO-01-0247-FEDER-033884. This work was partly financed by FCT/MCTES through national funds (PIDDAC) under the R&D Unit Institute for Sustainability and Innovation in Structural Engineering (ISISE), under reference UIDB/04029/2020 and by Regional Operational Programme CENTRO2020 within the scope of project CENTRO-01-0145-FEDER-000006 (SUSpENsE).

The possibility to intensify the homogeneous photo-Fenton by increasing temperature (up to 90 °C) has been deeply investigated using phenol as model pollutant and treating a real landfill leachate effluent. TOC removal rate was significantly improved as temperature increases. The required irradiation time to mineralize 1 g/L of phenol using the stoichiometric amount of H2O2 and 10 mg/L Fe2+ decreases from 120 min at 50 °C to less than 30 min when the experiments were carried out at 90 °C. Besides, within this range, the value of H2O2 consumption efficiency (ηH2O2), defined here as g of TOC converted per g of H2O2 consumed, was maintained around 0.15, which confirm the scarce effect of thermal H2O2 decomposition into O2 and H2O. More interestingly, the Irradiation Energetic Efficiency, defined as the TOC converted per W-h of energy emitted to the solution, dramatically increased with temperature, with a maximum value of 1.04 g of TOC per W-h reached at 90 °C. These results significantly improve those reached using dark Fenton under comparable experimental conditions. Similar trend was observed when high temperature photo-Fenton was applied to landfill leachates, using the stoichiometric amount of H2O2 (2.12 g/g COD) and 10 mg/L Fe2+. The required irradiation time to achieve maximum TOC and COD removals (around 80%) was reduced from 180 to 45 min by increasing temperature from 50 to 90 °C and the irradiation efficiency increased 4-fold withing this range of temperature. In addition, a kinetic model has been proposed to fit TOC evolution in both phenol and the leachate treatment. According to this, firstly temperature promotes the rapid degradation of TOC by the hydroxyl radicals produced by Fenton reaction decreasing the wastewater turbidity and colour. Subsequently, photo-Fenton reaction plays a key role, promoting organic acids and other by-products mineralization. The results of this paper reveal that, far from being a drawback due to undesirable H2O2 thermal decomposition into O2 and H2O, high temperatures could be efficiently used to enhance the cost-efficiency of photoassisted processes. To the best of our knowledge, this is the first time that such a wide range of temperature up to 90 °C is explored. Thereby, the outcomes of this research confirm temperature as a promising way to intensify photoassisted treatments, reducing both the reaction time and the required energy (W-h) and operational costs to partially oxidized and/or mineralize organic matter in highly organic loaded wastewaters.

Engineering demonstration reactors are nuclear reactors built to establish proof of concept for technology options that have never been built. Examples of engineering demonstration reactors include Peach Bottom 1 for high temperature gas-cooled reactors and the Experimental Breeder Reactor-II for sodium-cooled fast reactors. Engineering demonstrations have historically played a vital role in advancing the technology readiness level of reactor concepts. This paper details a preconceptual design for a fluoride salt-cooled engineering demonstration reactor. The fluoride salt-cooled high-temperature reactor (FHR) demonstration reactor (DR) is a concept for a salt-cooled reactor with 100 megawatts of thermal output. It would use tristructural-isotropic (TRISO) particle fuel in compacts within prismatic graphite blocks. FLiBe (2 7LiF-BeF2) is the reference primary coolant. The FHR DR is designed to be small, simple, and affordable. Development of the FHR DR is an intermediate step to enable near-term commercial FHRs. The design philosophy of the FHR DR was focused on safety, near-term deployment, and flexibility. Lower risk technologies are purposely included in the initial FHR DR design to ensure that the reactor can be built, licensed, and operated as an engineering demonstration with minimal risk and cost. These technologies include TRISO particle fuel, replaceable core structures, and consistent structural material selection for core structures and the primary and intermediate loops, and tube-and-shell primary-to-intermediate heat exchangers. Important capabilities to be demonstrated by building and operating the FHR DR include: • core design methodologies, • heat exchanger performance (including passive decay heat removal), • pump performance, • reactivity control, • salt chemistry control to maximize plant life, • salt procurement, handling, maintenance and ultimate disposal, and • tritium management. Non-nuclear separate and integral test efforts (e.g., heated salt loops or loops using simulant fluids) are necessary to develop the technologies that will be demonstrated in the FHR DR.

Here, we reveal a different way of doing the voltammetric experiments that considers the electroactive species packaged in the electrodic phase instead of dissolved in solution. In this way, it is possible to obtain voltammograms of insoluble species. In this work, the method is exemplified by obtaining voltammograms for weakly soluble coumarins but it could be extrapolated to other weakly soluble compounds. We have studied a comprehensive series of 3-acetyl-hydroxycoumarins derivatives which are insoluble in aqueous medium but capable of being trapped in a three-dimensional multi-walled carbon nanotubes (MWCNT) network. Consequently, an electrodic phase composed of an MWCNT modified glassy carbon electrode (GCE) containing the coumarin derivative is prepared. The voltammetric experiment is performed with the above electrodic phase and an aqueous medium as the solution phase. All the coumarin derivatives show one anodic peak due to the oxidation of the hydroxyl group in the phenyl ring. The oxidation peaks follow a one-electron, one-proton irreversible, pH-dependent process for all monohydroxylated compounds. The Ep values are closely dependent of the substituent effect being the 7,8-cum derivative more easily oxidized due to both the electron donor effect of neighboring hydroxyls groups and hydrogen bonding interaction between them. On the other hand, the hydroxyl of the 7-cum derivative is the most difficult to oxidize due to the electron-attracting effect of the lactone carbonyl group at position 2 and acetyl carbonyl at position 3 which is conjugated with OH at 7 positions. From the breaks in the graphs Ep versus pH, we estimate the voltammetric pKa values for all the studied coumarin derivatives.

The photocatalytic activity of twelve TiO2 samples prepared by different sol-gel methods have been evaluated in order to comprehensively understand the role of the different TiO2 physico-chemical properties on the catalyst performance. These catalysts have been extensively characterized (analyzed by TEM, XRD, UV–vis, N2-isotherms, NH3-isotherms, DRIFTs and Laser Diffraction techniques) and tested to analyze the effect of each property by comparing, for example, samples with different rutile contents but with similar anatase crystal sizes and surface areas. The results of this work suggest that best efficiencies can be obtained with samples constituted by only anatase phase and characterized by a relatively high crystal size and a high degree of crystallinity. On the other hand, the results have shown that even though significantly high surfaces areas do not seem to be a prerequisite to achieve the best efficiencies when phenolic pollutants (poorly adsorbed substrates) are evaluated, a certain grade of textural properties must be maintained to keep the surface quality, and a high degree of TiO2 sample dispersion in aqueous media is also desirable to optimize the photocatalytic activity. The results of this work may provide valuable information to design and produce new highly efficient TiO2 photocatalysts materials for wastewater treatment applications.

Engineering demonstration reactors are nuclear reactors built to establish proof of concept for technology options that have never been built. Examples of engineering demonstration reactors include Peach Bottom 1 for high temperature gas-cooled reactors (HTGRs) and Experimental Breeder Reactor II (EBR-II) for sodium-cooled fast reactors. Engineering demonstrations have historically played a vital role in advancing the technology readiness level of reactor technologies. This paper details a preconceptual design for a fluoride salt-cooled engineering demonstration reactor. The fluoride salt-cooled high-temperature reactor (FHR) demonstration reactor (DR) is a concept for a salt-cooled reactor with 100 megawatts of thermal output (MWt). It would use tristructural-isotropic (TRISO) particle fuel within prismatic graphite blocks. FLiBe (2 7LiF-BeF2) is the reference primary coolant. The FHR DR is designed to be small, simple, and affordable. Core design characteristics, fuel cycle performance, and safety analysis of the FHR DR preconcept have been evaluated. The FHR DR core design features a negative or negligible void coefficient throughout a reactor operating cycle. Both single-batch (cartridge) and multiple-batch fuel cycles can be demonstrated in the FHR DR. The single-batch cycle length of the FHR DR core is estimated at between 12 and 18 months, assuming the successful qualification of composite carbon (C/C) or silicon carbide (SiC/SiC) structural fuel block tie rod material. Fuel cycle performance of the FHR DR is similar to a high temperature gas-cooled reactor. Preliminary safety analysis of the FHR DR indicates that the reactor could be used to demonstrate the inherent safety characteristics of FHR designs.