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Small airways vs large airways in asthma: time for a new perspective

JOURNAL OF APPLIED PHYSIOLOGY 2021年第6期131卷 1839-1841页

作者： Donovan, Graham M. Noble, Peter B. Univ Auckland Dept Math Auckland New Zealand Univ Western Australia Sch Human Sci Crawley WA Australia

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Biochemical and biomechanical characterization of the cervical, thoracic, and lumbar facet joint cartilage in the Yucatan minipig

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JOURNAL OF BIOMECHANICS 2022年 142卷 111238-111238页

作者： Nordberg, Rachel C. Kim, Andrew N. Hight, Justin M. Meka, Rithika S. Elder, Benjamin D. Hu, Jerry C. Athanasiou, Kyriacos A. Univ Calif Irvine Dept Biomed Engn 3131 Engn Hall Irvine CA 92617 USA Mayo Clin Sch Med Dept Neurosurg Orthoped & Biomed Engn 200 1st St SW Rochester MN 55905 USA Univ Calif Irvine Samueli Sch Engn Dept Biomed Engn 3418 Engn Hall Irvine CA 92697 USA

Facet joint arthrosis causes pain in approximately 7 % of the U.S. population, but current treatments are palliative. The objective of this study was to elucidate structure-function relationships and aid in the development of future treatments for the facet joint. This study characterized the articular surfaces of cervical, thoracic, and lumbar facet cartilage from skeletally mature (18-24 mo) Yucatan minipigs. The minipig was selected as the animal model because it is recognized by the U.S. Food and Drug Administration (FDA) and the American Society for Testing and Materials (ASTM) as a translationally relevant model for spine-related indications. It was found that the thoracic facets had a similar to 2 times higher aspect ratio than lumbar and cervical facets. Lumbar facets had 6.9-9.6 times higher % depth than the cervical and thoracic facets. Aggregate modulus values ranged from 135 to 262 kPa, much lower than reported aggregate modulus in the human knee (reported to be 530-701 kPa). The tensile Young's modulus values ranged from 6.7 to 20.3 MPa, with the lumbar superior facet being 304 % and 286 % higher than the cervical inferior and thoracic superior facets, respectively. Moreover, 3D reconstructions of entire vertebral segments were generated. The results of this study imply that structure-function relationships in the facet cartilage are different from other joint cartilages because biochemical properties are analogous to other articular cartilage sources whereas mechanical properties are not. By providing functional properties and a 3D database of minipig facet geometries, this work may supply design criteria for future facet tissue engineering efforts.

关键词： Facet joint Zygapophyseal joint Cartilage Biomechanics structure-function relationships Minipig Characterization

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Addressing high excitation conditions in time-resolved X-ray diffraction experiments and issues of biological relevance

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CURRENT OPINION IN STRUCTURAL BIOLOGY 2023年第1期81卷 102624页

作者： Besaw, Jessica E. Miller, R. J. Dwayne Univ Toronto Dept Biochem 1 Kings Coll Circle Toronto ON M5S 1A8 Canada Univ Toronto Dept Chem 80 St George St Toronto ON M5S 3H6 Canada Univ Toronto Dept Phys 80 St George St Toronto ON M5S 3H6 Canada

One of the most important fundamental questions connecting chemistry to biology is how chemistry scales in complexity up to biological systems where there are innumerable possible pathways and competing processes. With the development of ultrabright electron and x-ray sources, it has been possible to literally light up atomic motions to directly observe the reduction in dimensionality in the barrier crossing region to a few key reaction modes. How do these chemical processes further couple to the surrounding protein or macromolecular assembly to drive biological functions? Optical methods to trigger photoactive biological processes are needed to probe this issue on the relevant timescales. However, the excitation conditions have been in the highly nonlinear regime, which questions the biological relevance of the observed structural dynamics.

关键词： Time-resolved crystallography Laser illumination guidelines structure-function relationships

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Fluorescent substrates enable specific detection and structure-function insights into human aldehyde dehydrogenase isoforms

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Chemico-Biological Interactions 2025年 418卷

作者： Raquel Pequerul Daniela Covaleda Andrés S. Sánchez-Vaca Laura Torres Andrada Constantinescu Mileidys Perez-Alea Xavier Parés Jaume Farrés Department of Biochemistry and Molecular Biology Faculty of Biosciences Universitat Autònoma de Barcelona Bellaterra Cerdanyola del Vallès Barcelona 08193 Spain Unit of Research in Cellular and Molecular Biology Advanced BioDesign-ABD Saint Priest France

Aldehyde dehydrogenase (ALDH) isoforms are widely used as biomarkers and potential drug targets in cancer research. Quantitation of ALDH enzymatic activity in biological samples often relies on the use of commercially available assays that are quite unspecific and do not discriminate between the various ALDH isoforms. The availability of highly purified recombinant ALDH isoforms allowed us to perform a full kinetic characterization of ALDH isoforms with fluorogenic substrates, BODIPY™-aminoacetaldehyde (BAAA), the ALDEFLUOR™ assay reagent, and two naphthaldedyde derivatives, 6-methoxy-2-naphthaldehyde (MONAL-62) and 7-methoxy-1-naphthaldehyde (MONAL-71). All ALDH1A isoforms were active to different extend with BAAA, while ALDH3A1 did not show any activity. Remarkable kinetic differences between ALDH1A1, ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1 were observed with naphthaldehyde derivatives. Exquisite sensitivity was attained with MONAL-62 with a lower detection limit of 2 amol or 10 6 molecules of enzyme per microliter for ALDH1A1. The high substrate specificity of ALDH1A1 for MONAL-71 provides an alternative assay for the unambiguous identification of this isoform. Enzymatic properties of isoforms were accounted for by in silico simulations of substrate docking to the active site of ALDH structures. In addition to substrate specificity, inhibitor selectivity of each isoform, as assessed by incubation with DIMATE and ABD0171 inhibitors, provided additional information about isoform composition in low-activity samples isolated from cell extracts. The method was successfully applied to the detection of ALDH isoform activity in triple-negative breast cancer cells.

关键词： Breast cancer Enzyme inhibition Fluorescence Kinetic properties Oxidoreductases structure-function relationships ABD0171 S-methyl 4-[dimethyl(2-{2,4-dimethylphenoxy}ethyl)amino]-4-methylpent-2-ynethioate ALDH aldehyde dehydrogenase ALDH1A1 aldehyde dehydrogenase family 1 member A1 BAAA BODIPY™-aminoacetaldehyde DIMATE S-methyl 4-(dimethylamino)-4-methylpent-2-ynethioate MONAL-62 6-methoxy-2-naphthaldehyde MONAL-71 7-methoxy-1-naphthaldehyde RMSD root-mean-square deviation

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Designing Self-Assembling Chimeric Peptide Nanoparticles with High Stability for Combating Piglet Bacterial Infections

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ADVANCED SCIENCE 2022年第14期9卷 e2105955页

作者： Tan, Peng Tang, Qi Xu, Shenrui Zhang, Yucheng Fu, Huiyang Ma, Xi China Agr Univ State Key Lab Anim Nutr Coll Anim Sci & Technol Beijing 100193 Peoples R China

As a novel type of antibiotic alternative, peptide-based antibacterial drug shows potential application prospects attributable to their unique mechanism for lysing the membrane of pathogenic bacteria. However, peptide-based antibacterial drugs suffer from a series of problems, most notably their immature stability, which seriously hinders their application. In this study, self-assembling chimeric peptide nanoparticles (which offer excellent stability in the presence of proteases and salts) are constructed and applied to the treatment of bacterial infections. In vitro studies are used to demonstrate that peptide nanoparticles NPs1 and NPs2 offer broad-spectrum antibacterial activity and desirable biocompatibility, and they retain their antibacterial ability in physiological salt environments. Peptide nanoparticles NPs1 and NPs2 can resist degradation under high concentrations of proteases. In vivo studies illustrate that the toxicity caused by peptide nanoparticles NPs1 and NPs2 is negligible, and these nanoparticles can alleviate systemic bacterial infections in mice and piglets. The membrane permeation mechanism and interference with the cell cycle differ from that of antibiotics and mean that the nanoparticles are at a lower risk of inducing drug resistance. Collectively, these advances may accelerate the development of peptide-based antibacterial nanomaterials and can be applied to the construction of supramolecular nanomaterials.

关键词： nanoparticles peptide-based antibacterial drug self-assembling structure-function relationships

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Effect of pH on the structure and stability of irisin, a multifunctional protein: Multispectroscopic and molecular dynamics simulation approach

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JOURNAL OF MOLECULAR structure 2022年 1252卷

作者： Waseem, Rashid Shamsi, Anas Shahbaz, Mohd Khan, Tanzeel Kazim, Syed Naqui Ahmad, Faizan Hassan, Md Imtaiyaz Islam, Asimul Jamia Millia Islamia Ctr Interdisciplinary Res Basic Sci New Delhi 110025 India Univ Western Cape South African Natl Bioinformat Inst South African Med Res Council Bioinformat Unit Private Bag X17 ZA-7535 Cape Town South Africa South Ural State Univ Lab Computat Modeling Drugs 76 Lenin Prospekt Chelyabinsk 454080 Russia

Irisin is a potential therapeutic agent to prevent or treat various metabolic-related disorders and neurodegenerative diseases viz. Alzheimer's disease (AD). In this study, we have employed a multispectroscopic approach to elucidate the structural and conformational changes in the irisin at varying pH (pH 2.0 to 12.0). The spectroscopic measurements revealed that irisin maintains its structure (both secondary and tertiary) in the alkaline pH range, with minimal structural changes observed across it. However, secondary and tertiary structural alterations were evident across the acidic pH range. CD spectroscopy suggested a gain of the secondary structure in the acidic pH range, implying that irisin is more stable at acidic pH, with maximum stability and compactness observed at pH 4.0. In vitro observations were further validated by in silico studies. Molecular dynamics simulation also suggested that irisin assumes higher stability in the conformational space at pH 4.0 and 6.0 than the rest of the system. This study can serve as a platform to delineate the enhanced functionality of irisin at lower pH that can be implicated in developing therapies for metabolic disorders, including diabetes and obesity. (C) 2021 Elsevier B.V. All rights reserved.

关键词： Irisin structure-function relationships Molecular dynamic simulation

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Deciphering structure, function and mechanism of Plasmodium IspD homologs from their evolutionary imprints

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JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 2019年第4期33卷 419-436页

作者： Chellapandi, P. Prathiviraj, R. Prisilla, A. Bharathidasan Univ Sch Life Sci Dept Bioinformat Mol Syst Engn Lab Tiruchirappalli 620024 Tamil Nadu India

Malaria is a life-threatening mosquito-borne blood disease caused by infection with Plasmodium parasites. Anti-malarial drug resistance is a global threat to control and eliminate malaria and therefore, it is very important to discover and evaluate new drug targets. The 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) homolog is a second in vivo target for fosmidomycin within isoprenoid biosynthesis in malarial parasites. In the present study, we have deciphered the sequence-structure-function integrity of IspD homologs based on their evolutionary imprints. The function and catalytic mechanism of them were also intensively studied by using sequence-structure homology, molecular modeling, and docking approach. Results of our study indicated that substrate-binding and dimer interface motifs in their structures were extensively conserved and part of them closely related to eubacterial origins. Amino acid substitutions in their coiled-coil regions found to bring a radical change in secondary structural elements, which in turn may change the local structural environment. Arg or Asp was identified as a catalytic site in plasmodium IspD homologs, contributing a direct role in the cytidylyltransferase activity similar to bacterial IspD. Results of molecular docking studies demonstrated how anti-malarial drugs such as fosmidomycin and FR-900098 have competitively interacted with the substrate-binding site of these homologs. As shown by our analysis, species-specific evolutionary imprints in these homologs determine the sequence-structure-function-virulence integrity and binding site alterations in order to confer anti-malarial drug resistance.

关键词： IspD Fosmidomycin Evolutionary imprints Non-mevalonate pathway Apicoplast structure-function relationships Drug target

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Exploring functional Materials by Understanding Beam-Sample Interactions

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ADVANCED functionAL MATERIALS 2022年第27期32卷

作者： Kisielowski, Christian Specht, Petra Rozeveld, Steve Freitag, Bert Kieft, Erik R. Kang, Joo Fielitz, Alyssa J. Fielitz, Thomas R. Dyck, Dirk Yancey, David F. Lawrence Berkeley Natl Lab Mol Foundry One Cyclotron Rd Berkeley CA 94720 USA Univ Calif Berkeley Dept MSE Berkeley CA 94720 USA Dow Chem Co USA Midland MI 48667 USA Thermo Fisher Sci Achtseweg Noord 5 NL-5651 GG Eindhoven Netherlands Univ Antwerp EMAT B-2020 Antwerp Belgium

Ultra-low-dose electron diffraction is performed with a double metal cyanide catalyst (DMC) to understand how electron irradiation stimulates structural alterations in functional materials. The commonly fading diffraction patterns with dose accumulation depend on the irradiated area and the beam current even when below 50 femto Amperes. Heat generation is observed and modeled by statistical, inelastic scattering events to describe how phonon excitations modulate radiation hardness. Specifically, the characteristic 1/e-decay of Bragg intensities from DMC is delayed from 6 to 30 e angstrom(-2) at room temperature, which is comparable to the effect of embedding radiation soft matter in ice. DMC's radiation hardness is enhanced by a latency dose that forms during a phase transformation. This unifying model predicts that a critical dose rate exists for any material that varies between 0.1 and 10(4) e angstrom(-2)s(-1) because of a material dependent competition of heat generation and spread. It shows that Brillouin scattering causes time dependent perturbations in electron irradiated solids that trigger time-temperature-transformations on a time scale of nanoseconds to microseconds at room temperature, which is not included in traditional models describing the decay of Bragg intensities by radiolysis.

关键词： catalysis coherent inelastic electron scattering electron microscopy perturbations structure-function relationships temperature

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Gradients of Orientation, Composition, and Hydration of Proteins for Efficient Light Collection by the Cornea of the Horseshoe Crab

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ADVANCED SCIENCE 2022年第33期9卷 e2203371页

作者： Spaeker, Oliver Taylor, Gavin J. Wilts, Bodo D. Slaby, Tomas Abdel-Rahman, Mohamed Ashraf Khalil Scoppola, Ernesto Schmitt, Clemens N. Z. Sztucki, Michael Liu, Jiliang Bertinetti, Luca Wagermaier, Wolfgang Scholtz, Gerhard Fratzl, Peter Politi, Yael Max Planck Inst Colloids & Interfaces Dept Biomat D-14476 Potsdam Germany Inst Globally Distributed Open Res & Educ IGDORE BR-14091310 Ribeirao Preto Brazil Univ Salzburg Chem & Phys Mat Jakob Haringer Str 2a A-5020 Salzburg Austria Univ Fribourg Adolphe Merkle Inst Chemin Verdiers 4 CH-1700 Fribourg Switzerland TELIGHT Libusina Trida 21 Brno 62300 Czech Republic European Synchrotron Radiat Facil ESRF 71 Ave MartyrsCS 40220 F-38043 Grenoble 9 France Tech Univ Dresden B CUBE Ctr Mol Bioengn D-01307 Dresden Germany Humboldt Univ Inst Biol Philippstr 13 D-10115 Berlin Germany

The lateral eyes of the horseshoe crab, Limulus polyphemus, are the largest compound eyes within recent Arthropoda. The cornea of these eyes contains hundreds of inward projecting elongated cuticular cones and concentrate light onto proximal photoreceptor cells. Although this visual system has been extensively studied before, the precise mechanism allowing vision has remained controversial. Correlating high-resolution quantitative refractive index (RI) mapping and structural analysis, it is demonstrated how gradients of RI in the cornea stem from structural and compositional gradients in the cornea. In particular, these RI variations result from the chitin-protein fibers architecture, heterogeneity in protein composition, and bromine doping, as well as spatial variation in water content resulting from matrix cross-linking on the one hand and cuticle porosity on the other hand. Combining the realistic cornea structure and measured RI gradients with full-wave optical modeling and ray tracing, it is revealed that the light collection mechanism switches from refraction-based graded index (GRIN) optics at normal light incidence to combined GRIN and total internal reflection mechanism at high incident angles. The optical properties of the cornea are governed by different mechanisms at different hierarchical levels, demonstrating the remarkable versatility of arthropod cuticle.

关键词： biomaterials chitin-based materials optical materials optical modeling protein composition structure-function relationships vision

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Computational Predictions and Experimental Validation of Alkane Oxidative Dehydrogenation by Fe2M MOF Nodes

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ACS CATALYSIS 2020年第2期10卷 1460-1469页

作者： Barona, Melissa Ahn, Sol Morris, William Hoover, William Notestein, Justin M. Farha, Omar K. Snurr, Randall Q. Northwestern Univ Dept Chem & Biol Engn 2145 Sheridan Rd Evanston IL 60208 USA Northwestern Univ Dept Chem 2145 Sheridan Rd Evanston IL 60208 USA NuMat Technol 8025 Lamon Ave Skokie IL 60077 USA

The modular structure of metal organic frameworks (MOFs) makes them promising platforms for catalyst design and for elucidating structure/performance relationships in catalysis. In this work, we systematically varied the composition of the metal nodes (Fe2M) of the MOF PCN-250 and used density functional theory (DFT) to identify promising catalysts for light alkane C-H bond activation. Oxidative dehydrogenation (ODH) of alkanes was studied using N2O as the oxidant to understand the reactivity of the oxocentered Fe2M nodes found in PCN-250, where the Fe ions are in the +3 oxidation state and M is a metal with the oxidation state of +2. We show that the N2O activation barrier is positively correlated with the oxygen-binding energy at the metal center, and the C-H activation barrier is negatively correlated with this same quantity. For clusters containing early transition metals, oxygen binds strongly, facilitating N2O activation but hindering C-H activation. To validate the DFT predictions, we synthesized and tested PCN-250(Fe2M) with M = Mn, Fe, Co, and Ni and found that PCN-250(Fe2Mn) and PCN-250(Fe-3) are more active than PCN-250(Fe2Co) and PCN-250(Fe2Ni) in agreement with the DFT predictions, demonstrating the power of DFT calculations to predict and identify promising MOF catalysts for alkane C-H bond activation in advance of experiments.

关键词： metal-organic frameworks C-H bond activation oxidation catalysis structure-function relationships density functional theory PCN-250 oxidative dehydrogenation

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