Interaction of SMAC with a survivin-derived peptide alters essential cancer hallmarks: Tumor growth, inflammation, and immunosuppression.

Second mitochondrial-derived activator of caspase (SMAC), also known as direct inhibitor of apoptosis-binding proteins with low pI (Diablo), is known as a pro-apoptotic mitochondrial protein released into the cytosol in response to apoptotic signals. We recently reported SMAC overexpression in cancers as essential for cell proliferation and tumor growth due to non-apoptotic functions, including phospholipid synthesis regulation. These functions may be associated with its interactions with partner proteins. Using a peptide array with 768 peptides derived from 11 selected SMAC-interacting proteins, we identified SMAC-interacting sequences. These SMAC-binding sequences were produced as cell-penetrating peptides targeted to the cytosol, mitochondria, or nucleus, inhibiting cell proliferation and inducing apoptosis in several cell lines. For in vivo study, a survivin/baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)-derived peptide was selected, due to its overexpression in many cancers and its involvement in mitosis, apoptosis, autophagy, cell proliferation, inflammation, and immune responses, as a target for cancer therapy. Specifically, a SMAC-targeting survivin/BIRC5-derived peptide, given intratumorally or intravenously, strongly inhibited lung tumor growth, cell proliferation, angiogenesis, and inflammation, induced apoptosis, and remodeled the tumor microenvironment. The peptide promoted tumor infiltration of CD-8+ cells and increased cell-intrinsic programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, resulting in cancer cell self-destruction and increased tumor cell death, preserving immune cells. Thus, targeting the interaction between the multifunctional proteins SMAC and survivin represents an innovative therapeutic cancer paradigm.

Bifunctional Role of Methyl Viologen in UV and X-ray Sensitive Switchable Organophosphonate Single Crystal.

Finding X-ray and UV responsive hybrid single crystals including their versatile properties is highly desirable though the fabrication of such material is a very challenging task to researchers. Herein, a methyl viologen assisted hybrid nickel organophosphonate structure (i.e., NIT1) is demonstrated by adapting an in situ solvothermal strategy to investigate the X-ray effect and photochromic behaviors. The bifunctional coordinated and templated roles of monocationic and bicationic methyl viologen units present in the hybrid structure are noteworthy and can manifest prominent structural enhancement and reversible photochromism behaviors.

Intrinsic Specific Activity Enhancement for Bifunctional Electrocatalytic Activity toward Oxygen and Hydrogen Evolution Reactions via Structural Modification of Nickel Organophosphonates.

A comprehensive knowledge of the structure-activity relationship of the framework material is decisive to develop efficient multifunctional electrocatalysts. In this regard, two different metal organophosphonate compounds, [Ni(Hhedp)2]·4H2O (I) and [Ni3(H3hedp)2(C4H4N2)3]·6H2O (II) have been isolated through one-pot hydrothermal strategy by using H4hedp (1-hydroxyethane 1,1-diphosphonic acid) and N-donor auxiliary ligand (pyrazine; C4H4N2). The structures of synthesized materials have been established through single-crystal X-ray diffraction studies, which confirm that compound I formed a one-dimensional molecular chain structure, while compound II exhibited a three-dimensional extended structure. Further, the crystalline materials have participated as efficient electrocatalysts for the oxygen evolution and hydrogen evolution reactions (OER and HER) as compared to the state-of-the-art electrocatalyst RuO2. The electrocatalytic OER and HER performances show that compound II displayed better electrocatalytic performances toward OER (η10 = 305 mV) and HER (η10 = 230 mV) in alkaline (1 M KOH) and acidic (0.5 M H2SO4) media, respectively. Substantially, the specific activity has been assessed in order to measure the inherent electrocatalytic activity of the title electrocatalyst, which displays an enrichment of fourfold higher activity of compound II (0.64 mA/cm2) than compound I (0.16 mA/cm2) for the OER experiments. Remarkably, inclusion of an auxiliary pyrazine ligand into the metal organophosphonate structure (compound II) not only offers higher dimensionality along with significant enhancement of the overall bifunctional electrocatalytic performances but also improves the long-term stability, which is noteworthy for the family of hybrid framework materials.

1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a KI value of 0.7 µM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10-7 M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC50 values lower than 100 µM.

Synthesis, antimicrobial, antibiofilm and computational studies of isatin-semicarbazone tethered 1,2,3-triazoles.

In present era, heterocyclic compounds containing two or three nitrogen atoms play a vital role in drug discovery. In this context, a new class of isatin-semicarbazone tethered 1,2,3-triazole hybrids was synthesized via Cu(I)-mediated azide alkyne cycloaddition reaction. Structural characteristics of the newly derived compounds were identified by various spectral techniques like FTIR, 1H NMR, 13C NMR, HRMS and single crystal X-ray crystallography. Synthesized derivatives were also screened for in vitro antimicrobial and antibiofilm activity against different microbial species. Triazole hybrid 7e showed significant efficacy towards E. coli having MIC of 0.0063 µmol/mL, whereas 6a, 6b, 7a, 7c, 7e, and 7f showed highest percentage of biofilm inhibition against P. aeruginosa. Bioassay results suggested that these triazole hybrids could act as biomaterial for antimicrobial and antibiofilm applications and may constitute a new promising class of antimicrobial and antibiofilm agents. These results were further supported by in silico docking, DFT calculations and ADME studies.

Psychophysics may be the game-changer for deep neural networks (DNNs) to imitate the human vision.

Psychologically faithful deep neural networks (DNNs) could be constructed by training with psychophysics data. Moreover, conventional DNNs are mostly monocular vision based, whereas the human brain relies mainly on binocular vision. DNNs developed as smaller vision agent networks associated with fundamental and less intelligent visual activities, can be combined to simulate more intelligent visual activities done by the biological brain.

Organoamine Templated Multifunctional Hybrid Metal Phosphonate Frameworks: Promising Candidates for Tailoring Electrochemical Behaviors and Size-Selective Efficient Heterogeneous Lewis Acid Catalysis.

The successful discovery of novel multifunctional metal phosphonate framework materials that incorporate newer organoamines and their utilization as a potential electroactive material for energy storage applications (supercapacitors) and as efficient heterogeneous catalysts are the most enduring challenges at present. From this perspective, herein, four new inorganic-organic hybrid zinc organodiphosphonate materials, namely, [C5H14N2]2[Zn6(hedp)4] (I), [C5H14N2]0.5[Zn3(Hhedp) (hedp)]·2H2O (II), [C6H16N2][Zn3(hedp)2] (III), and [C10H24N4][Zn6(Hhedp)2(hedp)2] (IV) (H4hedp = 1-hydroxyethane 1,1-diphosphonic acid), have been synthesized through the introduction of different organoamines and then structurally analyzed using various techniques. The compounds (I-IV) possess a three-dimensional network through alternate connectivity of zinc ions and diphosphonate ligands, as confirmed using single-crystal X-ray diffraction. The investigations of electrochemical charge storage behaviors of the present compounds indicate that compound III exhibits a high specific capacitance of 190 F g-1 (76 C g-1) at 1 A g-1, while compound II shows an excellent cycling stability of 90.11% even after 5000 cycles at 5 A g-1 in the 6 M KOH solution. Further, the present materials have also been utilized as active heterogeneous Lewis acid catalysts in the ketalization reaction. The screening of various substrate scopes during the catalytic process confirms the size-selective heterogeneous catalytic nature of the framework compounds. To our utmost knowledge, such a size-selective heterogeneous Lewis acid catalytic behavior has been observed for the first time in the amine templated inorganic-organic hybrid framework family. Moreover, the excellent size-selective catalytic efficiencies with the d10 metal system and recyclability performances make the compounds (I-IV) more efficient and promising Lewis acid heterogeneous catalysts.

Antiferromagnetically coupled double perovskite as an efficient and robust catalyst for visible light driven water splitting at neutral pH.

Green and sustainable energy production through renewable sources is an enormously exciting field of research. Herein, we report an A-site lanthanum doped oxygen excess ruthenate (predominantly Ru5+-ions) double perovskite system, CaLaScRuO6+δ (CLSR), as an excellent photocatalyst for water splitting. The well characterized polycrystalline compound shows canted antiferromagnetic (AFM) behavior due to the existence of disordered Ru-ions at the B-site. Based on density functional theory + U (Hubbard U) calculations, we have estimated various magnetic exchange interactions and found that the ground state is antiferromagnetic in nature which is in perfect agreement with our experimental results. Detailed analysis of the electronic structure further reveals that the present system belongs to the family of charge transfer semiconductors with an energy gap of ∼0.45 eV. Finally, the material is found to proficiently work for the oxygen evolution reaction (OER) via visible-light driven water splitting at neutral pH in an ecofriendly manner.

Tail-approach based design and synthesis of Arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide as human carbonic anhydrase I, II, IV and IX inhibitors.

A library of twenty-two arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide moieties have been synthesized by utilizing tail-approach and characterized by their IR, 1H NMR, 13C NMR, HRMS and single crystal studies. Further, these newly synthesized compounds were screened in-vitro for their inhibition efficacy against physiologically relevant hCA I, II, IV and IX isoforms. Inhibition data revealed that, in broader sense, sulfanilamide analogues (4a-4k) were comparatively better inhibitors of cytosolic hCA I and II isoforms than metanilamide analogues (5a-5k), whereas exactly opposite trend was observed in case of inhibition of membrane bound hCA IV and transmembrane hCA IX. For hCA I, more than half of the synthesized compounds were found to be moderate inhibitors and three compounds 4b, 5b and 5e (Ki of 40.6, 224.7 and 74.4 nM, respectively) appeared as better inhibitors than reference drug AAZ (Ki = 250 nM). hCA II was potently inhibited by 4e-4g and 5e with Ki of 18.1, 14.1, 14.9 and 17.8 nM, respectively. Interestingly, 4e-4g selectively inhibited hCA II with selectivity of > 15-fold over hCA I, IV and IX isoforms. All the compounds presented moderate to weak inhibition profiles against glaucoma associated hCA IV with Ki of 88 nM-8.87 µM and except 4f, 5k, significant inhibition profiles against tumor associated hCA IX isoform with Ki spanning in range of 0.113 µM-0.318 µM. Moreover, 5e was the only compound among the whole series which effectively inhibited all the tested isoforms.

Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer.

The cross-talk between the mitochondrion and the nucleus regulates cellular functions, including differentiation and adaptation to stress. Mitochondria supply metabolites for epigenetic modifications and other nuclear-associated activities and certain mitochondrial proteins were found in the nucleus. The voltage-dependent anion channel 1 (VDAC1), localized at the outer mitochondrial membrane (OMM) is a central protein in controlling energy production, cell growth, Ca2+ homeostasis, and apoptosis. To alter the cross-talk between the mitochondria and the nucleus, we used specific siRNA to silence the expression of VDAC1 in glioblastoma (GBM) U87-MG and U118-MG cell-derived tumors, and then monitored the nuclear localization of mitochondrial proteins and the methylation and acetylation of histones. Depletion of VDAC1 from tumor cells reduced metabolism, leading to inhibition of tumor growth, and several tumor-associated processes and signaling pathways linked to cancer development. In addition, we demonstrate that certain mitochondrial pro-apoptotic proteins such as caspases 3, 8, and 9, and p53 were unexpectedly overexpressed in tumors, suggesting that they possess additional non-apoptotic functions. VDAC1 depletion and metabolic reprograming altered their expression levels and subcellular localization, specifically their translocation to the nucleus. In addition, VDAC1 depletion also leads to epigenetic modifications of histone acetylation and methylation, suggesting that the interchange between metabolism and cancer signaling pathways involves mitochondria-nucleus cross-talk. The mechanisms regulating mitochondrial protein trafficking into and out of the nucleus and the role these proteins play in the nucleus remain to be elucidated.

Charge Separated One-Dimensional Hybrid Cobalt/Nickel Phosphonate Frameworks: A Facile Approach to Design Bifunctional Electrocatalyst for Oxygen Evolution and Hydrogen Evolution Reactions.

Two new organoamine templated one-dimensional transition metal phosphonate compounds are synthesized, and their bifunctional electrocatalytic activities are examined in highly alkaline and acidic media. Compared with state-of-the-art materials, the cobalt phosphonate system is a new fabrication of sustainable and highly efficient catalysts toward electrochemical water splitting systems.

Evolution of transition metal charge states in correlation with the structural and magnetic properties in disordered double perovskites Ca2-xLaxFeRuO6 (0.5 ≤ x ≤ 2).

A series of disordered Ca1.5La0.5FeRuO6, CaLaFeRuO6 and La2FeRuO6 double perovskites were prepared by the solid-state reaction method and investigated by neutron powder diffraction, X-ray absorption near-edge structure (XANES) analysis at the Ru-K edge, Mössbauer spectroscopy, DC magnetization and resistivity measurements. All compounds crystallize in the orthorhombic crystal structure with the space group Pbnm down to 3 K, showing a random distribution of Fe and Ru at the B site. Thermogravimetric analysis indicates oxygen deficiency in the Ca-rich and formal oxygen hyperstoichiometry in the La-rich members of the present series. While Mössbauer spectra verify the Fe3+ state for all compositions, the XANES study reveals a variable Run+ oxidation state which decreases with increasing La content. The end member actually is a Ru3+/Ru4+ compound with possibly some cation vacancies. From magnetic susceptibility and neutron diffraction measurements, the presence of a G-type antiferromagnetic ordering was observed with a drastic increase in transition temperature from 275 K (Ca1.5La0.5FeRuO6) to 570 K (La2FeRuO6). Mössbauer spectroscopy confirms the presence of long-range ordering but, due to local variations in the exchange interactions, the magnetic states are microscopically inhomogeneous. All the samples are variable range hopping semiconductors. A complex interplay between structural features, charge states, anion or cation defects, and atomic disorder determines the magnetic properties of the present disordered 3d/4d double perovskite series.

Triggering Lewis Acidic Nature through the Variation of Coordination Environment of Cd-Centers in 2D-Coordination Polymers.

The rational design and successful synthesis of novel functional metal-organic frameworks relies on careful selection of metals and versatile organic ligands. A newly designed pyrazole-based dicarboxylate ligand, 5-(3,5-dimethyl-1H-pyrazol-1-yl) 1,3-benzenedicarboxylic acid (H2L), was utilized to obtain two new Cd-based coordination polymers I [Cd(L)(H2O)]·H2O and II [Cd(L)] under similar reaction conditions via solvothermal strategy. Single-crystal X-ray data confirmed that compound I exhibits a two-dimensional (2D) skeleton comprising pentagonal bipyramidal Cd-ions and an organic ligand moiety. Compound II has also formed a two-dimensional layer arrangement with the connectivity between trigonal bipyramidal Cd-ions and the organic ligand. Topological analysis revealed that compound I has formed unique 43.63 net topology while compound II has displayed a 44.62 sql net topology with 2D frameworks. The Lewis acidic nature of both I and II containing a Cd2+ metal center has been correlated with the coordination number through dye adsorption-desorption and catalysis studies. The selective adsorption of anionic dye and the extent of adsorption are interrelated with the Cd-ion geometry. For the first time, the role of coordinated water molecule has been analyzed through heterogeneous catalysis reaction (i.e., cyanosilylation) with Cd-based 2D-coordination polymers (CPs). The plausible mechanisms have been proposed to explain the subsequent role of coordination number and environment in CPs.

Colossal Dielectric Responses from the Wide Band Gap 2D-Semiconducting Amine Templated Hybrid Framework Materials.

Two unprecedented organic amine templated silver organophosphonate hybrid solids have been synthesized hydrothermally by varying the molar ratio of the reactants. Both of the compounds consist of novel tetra- and penta-nuclear silver phosphonate basic building units. The dielectric constants are extremely large due to the charge separation of anionic metal phosphonate frameworks and cationic templated piperazine moieties in the compounds, as found for the first time in a hybrid organophosphate family. The conductivity and UV-visible absorption studies provide strong evidence about the semiconducting nature of the present compounds.

Isatin as a 2-aminobenzaldehyde surrogate: transition metal-free efficient synthesis of 2-(2'-aminophenyl)benzothiazole derivatives.

A transition metal-free, convenient, and efficient practical approach has been devised for the synthesis of substituted 2-(2'-aminophenyl)benzothiazoles via a sulfur insertion strategy using isatin derivatives as 2-aminobenzaldehyde surrogates. KI assisted one-pot operation of isatin, arylamines and elemental sulfur resulted in the formation of a C-N and two C-S bonds and cascade cleavage of the isatin ring resulting in the formation of 2-(2'-aminophenyl)benzothiazoles. The significant features of this strategy are the readily available and inexpensive starting materials, broad substrate scope, sustainable reaction conditions and high yield of products. Importantly, the strategy was found to be appropriate for gram scale synthesis (>10 g) of 2-(2'-aminophenyl)benzothiazole derivatives. Moreover, the excellent photophysical properties (ΦF up to 60%) of 2-(2'-aminophenyl)benzothiazole derivatives provide huge scope in materials science.

Systematic analysis of frequency dependent differential photoacoustic cross-section data for source size estimation.

A frequency dependent differential photoacoustic cross-section (DPACS) over a large frequency band (100-1000 MHz) was computed, and subsequently, morphological parameters of a photoacoustic (PA) source were quantified. The Green's function approach was utilized for calculating the DPACS for spheroidal droplets with varying aspect ratios, Chebyshev particles with different waviness and deformation parameters, and normal red blood cells and cells affected by hereditary disorders (e.g., spherocytosis, elliptocytosis, and stomatocytosis). The theoretical framework considers that PA waves propagate through an acoustically dispersive and absorbing medium and are detected by a planar detector of finite size. The frequency dependent DPACS profile was fitted with tri-axial ellipsoid, finite cylinder, and toroid form factor models to obtain size and shape information of the PA source. The tri-axial ellipsoid form factor model was found to provide better estimates of the shape parameters compared to other models for a variety of sources. The inverse problem framework may motivate developing PA-based technology to assess single-cell morphology.

A New Role for the Mitochondrial Pro-apoptotic Protein SMAC/Diablo in Phospholipid Synthesis Associated with Tumorigenesis.

The mitochondrial pro-apoptotic protein SMAC/Diablo participates in apoptosis by negatively regulating IAPs and activating caspases, thus encouraging apoptosis. Unexpectedly, we found that SMAC/Diablo is overexpressed in cancer. This paradox was addressed here by silencing SMAC/Diablo expression using specific siRNA (si-hSMAC). In cancer cell lines and subcutaneous lung cancer xenografts in mice, such silencing reduced cell and tumor growth. Immunohistochemistry and electron microscopy of the si-hSMAC-treated residual tumor demonstrated morphological changes, including cell differentiation and reorganization into glandular/alveoli-like structures and elimination of lamellar bodies, surfactant-producing organs. Next-generation sequencing of non-targeted or si-hSMAC-treated tumors revealed altered expression of genes associated with the cellular membrane and extracellular matrix, of genes found in the ER and Golgi lumen and in exosomal networks, of genes involved in lipid metabolism, and of lipid, metabolite, and ion transporters. SMAC/Diablo silencing decreased the levels of phospholipids, including phosphatidylcholine. These findings suggest that SMAC/Diablo possesses additional non-apoptotic functions related to regulating lipid synthesis essential for cancer growth and development and that this may explain SMAC/Diablo overexpression in cancer. The new lipid synthesis-related function of the pro-apoptotic protein SMAC/Diablo in cancer cells makes SMAC/Diablo a promising therapeutic target.

Design, synthesis, characterization, antimicrobial evaluation and molecular modeling studies of some dehydroacetic acid-chalcone-1,2,3-triazole hybrids.

A series of new dehydroacetic acid chalcone-1,2,3-triazole hybrids as potential antimicrobial agents was designed, synthesized and characterized by FTIR, NMR and HRMS spectral techniques. All the synthesized compounds were screened in vitro against four bacterial strains (Staphylococcus epidermidis, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) and two fungal strains (Aspergillus niger and Candida albicans). The antimicrobial results indicated that some of the compounds showed remarkable activities comparable to the standard drugs. Most of the compounds exhibited better efficacy compared to the DHA, which is itself an antimicrobial agent. The synergistic effect in biological activity was observed when DHA, chalcone and 1,2,3-triazole are conjugated. The molecular modeling studies of compound 5j into E. coli topoisomerase II DNA gyrase B were also performed.

Lattice-site-specific spin dynamics in double perovskite Sr2CoOsO6.

Magnetic properties and spin dynamics have been studied for the structurally ordered double perovskite Sr2CoOsO6. Neutron diffraction, muon-spin relaxation, and ac-susceptibility measurements reveal two antiferromagnetic (AFM) phases on cooling from room temperature down to 2 K. In the first AFM phase, with transition temperature TN1=108 K, cobalt (3d7, S=3/2) and osmium (5d2, S=1) moments fluctuate dynamically, while their average effective moments undergo long-range order. In the second AFM phase below TN2=67 K, cobalt moments first become frozen and induce a noncollinear spin-canted AFM state, while dynamically fluctuating osmium moments are later frozen into a randomly canted state at T≈5 K. Ab initio calculations indicate that the effective exchange coupling between cobalt and osmium sites is rather weak, so that cobalt and osmium sublattices exhibit different ground states and spin dynamics, making Sr2CoOsO6 distinct from previously reported double-perovskite compounds.

U-Net enhanced real-time LED-based photoacoustic imaging.

Photoacoustic (PA) imaging is hybrid imaging modality with good optical contrast and spatial resolution. Portable, cost-effective, smaller footprint light emitting diodes (LEDs) are rapidly becoming important PA optical sources. However, the key challenge faced by the LED-based systems is the low light fluence that is generally compensated by high frame averaging, consequently reducing acquisition frame-rate. In this study, we present a simple deep learning U-Net framework that enhances the signal-to-noise ratio (SNR) and contrast of PA image obtained by averaging low number of frames. The SNR increased by approximately four-fold for both in-class in vitro phantoms (4.39 ± 2.55) and out-of-class in vivo models (4.27 ± 0.87). We also demonstrate the noise invariancy of the network and discuss the downsides (blurry outcome and failure to reduce the salt & pepper noise). Overall, the developed U-Net framework can provide a real-time image enhancement platform for clinically translatable low-cost and low-energy light source-based PA imaging systems.