Rare earth and transition metal based entropy stabilised perovskite type oxides

Multicomponent oxides with perovskite type of structure containing up to 10 different cations in equiatomic amounts have been synthesised for the first time. Out of eleven systems synthesised, only six systems crystallised as single phase perovskite type compounds with random and homogenous cation distribution on the respective sites. The formation of phase pure 10-cationic system, (Gd_0.2La_0.2Nd_0.2Sm_0.2Y_0.2)(Co_0.2Cr_0.2Fe_0.2Mn_0.2Ni_0.2)O₃, in contrast to the multiphase mixtures observed in five of the lower entropy systems (containing 6 cations) indicates a possible role of entropy in the stabilisation of a single phase crystal structure. The entropy driven structural stabilisation effect is further supported by the reversible phase transformation, from single phase to multiple phase upon cyclic heat treatment, observed in the (Gd_0.2La_0.2Nd_0.2Sm_0.2Y_0.2)MnO₃ system. This type of entropic signature has been observed in rocksalt based high entropy oxide systems. However, it has not been reported before for perovskite based compounds, as shown in this study.     

Unpacking Pandora from Its Box: Deciphering the Molecular Basis of the SARS-CoV-2 Coronavirus

An enigmatic localized pneumonia escalated into a worldwide COVID-19 pandemic from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This review aims to consolidate the extensive biological minutiae of SARS-CoV-2 which requires decipherment. Having one of the largest RNA viral genomes, the single strand contains the genes ORF1ab, S, E, M, N and ten open reading frames. Highlighting unique features such as stem-loop formation, slippery frameshifting sequences and ribosomal mimicry, SARS-CoV-2 represents a formidable cellular invader. Hijacking the hosts translational engine, it produces two polyprotein repositories (pp1a and pp1ab), armed with self-cleavage capacity for production of sixteen non-structural proteins. Novel glycosylation sites on the spike trimer reveal unique SARS-CoV-2 features for shielding and cellular internalization. Affording complexity for superior fitness and camouflage, SARS-CoV-2 challenges diagnosis and vaccine vigilance. This review serves the scientific community seeking in-depth molecular details when designing drugs to curb transmission of this biological armament.     

HaloTag-Targeted Sirtuin-Rearranging Ligand (SirReal) for the Development of Proteolysis-Targeting Chimeras (PROTACs) against the Lysine Deacetylase Sirtuin 2 (Sirt2)**

We have discovered the sirtuin-rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD⁺-dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so-called proteolysis-targeting chimera (PROTAC) enabled small-molecule-induced degradation of Sirt2. Herein, we report the structure-based development of a chloroalkylated SirReal that induces the degradation of Sirt2 mediated by Halo-tagged E3 ubiquitin ligases. Using this orthogonal approach for Sirt2 degradation, we show that other E3 ligases than cereblon, such as the E3 ubiquitin ligase parkin, can also be harnessed for small-molecule-induced Sirt2 degradation, thereby emphasizing the great potential of parkin to be used as an E3 ligase for new PROTACs approaches. Thus, our study provides new insights into targeted protein degradation in general and Sirt2 degradation in particular.     

Characterization of Structure and Dynamics of the Guanidine-II Riboswitch from Escherichia coli by NMR Spectroscopy and Small-Angle X-ray Scattering (SAXS)

Riboswitches are regulatory RNA elements that undergo functionally important allosteric conformational switching upon binding of specific ligands. The here investigated guanidine-II riboswitch binds the small cation, guanidinium, and forms a kissing loop-loop interaction between its P1 and P2 hairpins. We investigated the structural changes to support previous studies regarding the binding mechanism. Using NMR spectroscopy, we confirmed the structure as observed in crystal structures and we characterized the kissing loop interaction upon addition of Mg²⁺ and ligand for the riboswitch aptamer from Escherichia coli. We further investigated closely related mutant constructs providing further insight into functional differences between the two (different) hairpins P1 and P2. Formation of intermolecular interactions were probed by small-angle X-ray scattering (SAXS) and NMR DOSY data. All data are consistent and show the formation of oligomeric states of the riboswitch induced by Mg²⁺ and ligand binding.     

Osteogenic Differentiation of Human Adipose-Derived Stem Cells Seeded on a Biomimetic Spongiosa-like Scaffold: Bone Morphogenetic Protein-2 Delivery by Overexpressing Fascia

Human adipose-derived stem cells (hADSCs) have the capacity for osteogenic differentiation and, in combination with suitable biomaterials and growth factors, the regeneration of bone defects. In order to differentiate hADSCs into the osteogenic lineage, bone morphogenetic proteins (BMPs) have been proven to be highly effective, especially when expressed locally by route of gene transfer, providing a constant stimulus over an extended period of time. However, the creation of genetically modified hADSCs is laborious and time-consuming, which hinders clinical translation of the approach. Instead, expedited single-surgery gene therapy strategies must be developed. Therefore, in an in vitro experiment, we evaluated a novel growth factor delivery system, comprising adenoviral BMP-2 transduced fascia tissue in terms of BMP-2 release kinetics and osteogenic effects, on hADSCs seeded on an innovative biomimetic spongiosa-like scaffold. As compared to direct BMP-2 transduction of hADSCs or addition of recombinant BMP-2, overexpressing fascia provided a more uniform, constant level of BMP-2 over 30 days. Despite considerably higher BMP-2 peak levels in the comparison groups, delivery by overexpressing fascia led to a strong osteogenic response of hADSCs. The use of BMP-2 transduced fascia in combination with hADSCs may evolve into an expedited single-surgery gene transfer approach to bone repair.     

Hyperforin and Myrtucommulone Derivatives Act as Natural Modulators of Wnt/β-Catenin Signaling in HCT116 Colon Cancer Cells

The therapeutic activities of natural plant extracts have been well known for centuries. Many of them, in addition to antiviral and antibiotic effects, turned out to have anti-tumor activities by targeting different signaling pathways. The canonical Wnt pathway represents a major tumorigenic pathway deregulated in numerous tumor entities, including colon cancer. Here, we investigated the acylphloroglucinols hyperforin (HF) from St. John’s wort (Hypericum perforatum L.) and myrtucommulone A (MC A) from myrtle (Myrtus communis) and semi-synthetic derivatives thereof (HM 177, HM 297, HM298) for their effects on Wnt/β-catenin signaling. None of these substances revealed major cytotoxicity on STF293 embryonic kidney and HCT116 colon carcinoma cells at concentrations up to 10 μM. At this concentration, HF and HM 177 showed the strongest effect on cell proliferation, whereas MC A and HM 177 most prominently inhibited anchorage-independent growth of HCT116 cells. Western blot analyses of active β-catenin and β-catenin/TCF reporter gene assays in STF293 cells revealed inhibitory activities of HF, MC A and HM 177. In line with this, the expression of endogenous Wnt target genes, Axin and Sp5, in HCT116 cells was significantly reduced. Our data suggest that the acylphloroglucinols hyperforin, myrtucommulone A and its derivative HM 177 represent potential new therapeutic agents to inhibit Wnt/β-catenin signaling in colon cancer.     

Exploring the Potential of Norbornene‐Modified Mannosamine Derivatives for Metabolic Glycoengineering

Metabolic glycoengineering (MGE) allows the introduction of unnaturally modified carbohydrates into cellular glycans and their visualization through bioorthogonal ligation. Alkenes, for example, have been used as reporters that can react through inverse‐electron‐demand Diels–Alder cycloaddition with tetrazines. Earlier, norbornenes were shown to be suitable dienophiles; however, they had not previously been applied for MGE. We synthesized two norbornene‐modified mannosamine derivatives that differ in the stereochemistry at the norbornene (exo/endo linkage). Kinetic investigations revealed that the exo derivative reacts more than twice as rapidly as the endo derivative. Through derivatization with 1,2‐diamino‐4,5‐methylenedioxybenzene (DMB) we confirmed that both derivatives are accepted by cells and incorporated after conversion to a sialic acid. In further MGE experiments the incorporated sugars were ligated to a fluorophore and visualized through confocal fluorescence microscopy and flow cytometry.     

Catalysis of a β-elimination applying membranes with incorporated molecularly imprinted polymer particles

Summary Molecularly imprinted membranes are known to be applicable as recognition elements in separation, extraction and sensors, however, not as catalysts. In this paper, two different formats of molecularly imprinted membranes were generated and used as catalysts in a dehydrofluorination reaction. The first format was based on cellulose filter membranes which were coated with a polymer imprinted with a transition-state analogue of the chosen reaction. Alternatively, ground bulk polymers have been incorporated in polyvinyl alcohol (PVA) matrices on cellulose membranes. Both types of membranes were evaluated in membrane reactors. Either the substrate solution was pumped once only through the membrane, or the substrate solution was recirculated through the membrane. The coated membranes did not show any specific catalytic effect when comparing the molecularly imprinted with a non-imprinted control polymer membrane. Nevertheless, the PVA membranes containing the imprinted polymer particles showed specific catalytic effects, compared to PVA membranes with incorporated non-imprinted control polymer particles.     

Impulse noise reduction using hybrid neuro-fuzzy filter with improved firefly algorithm from X-ray bio-images

Noise filtering performance in medical images is improved using a neuro-fuzy network developed with the combination of a post processor and two neuro-fuzzy (NF) filters. By the fact, the Sugeno-type is found to be less accurate during impulse noise reduction process. In this paper, we propose an improved firefly algorithm based hybrid neuro-fuzzy filter in both the NF filters to improve noise reduction performance. The proposed noise reduction system combines the advantages of the neural, fuzzy and firefly algorithms. In addition, an improved version of firefly algorithm called searching diversity based particle swarm firefly algorithm is used to reduce the local trapping problem as well as to determine the optimal shape of membership function in fuzzy system. Experimental results show that the proposed filter has proved its effectiveness on reducing the impulse noise in medical images against different impulse noise density levels.     

Thermal expansion behavior of aluminum alloys reinforced with alumina planar random short fibers

The thermal expansion behavior of two aluminum alloys (Al-4%Cu and Al-12%Si) reinforced with alumina planar random short fibers has been studied, both experimentally and theoretically. The metal matrix composites (MMCs) were manufactured by pressure infiltration of molten metal into short fiber preforms with a planar random distribution of fibers. Dilatometric testing was used to investigate the influence of fiber volume fraction and architecture, and the effects of thermal cycling between 25 °C to 560 °C. Thermal expansion measurements showed that, by increasing the fiber content in the composites, both the thermal strains and the effective coefficient of thermal expansion (CTE) were reduced in the whole temperature range. Furthermore, the thermal strains of MMCs increased almost linearly up to a critical temperature, T _cr, where the metallic matrix began to yield macroscopically due to internal thermal stresses. For temperatures higher than T _cr the thermal strains of MMCs showed a marked hysteresis during heating/cooling cycles due to the elasto-plastic response of the metallic matrix. In this temperature range, the thermal expansion curves deviated appreciably from linearity and the planar (in the plane of fibers) and transverse (normal to the plane of fibers) responses were very different: while the planar CTE was strongly reduced, the transverse CTE increased sharply with temperature, being even larger than the CTE of the unreinforced alloy. Thermal cycling produced a net dimensional change of composites during the first 2-3 cycles but, on the subsequent cycles, the permanent deformation disappeared almost completely and the successive thermal expansion curves were identical. Experimental results were compared to the theoretical predictions of an analytical model based on the Eshelby's equivalent inclusion method, and an excellent agreement was obtained.