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Single-Cell Determination of Cardiac Microtissue structure and function Using Light Sheet Microscopy

TISSUE ENGINEERING PART C-METHODS 2020年第4期26卷 207-215页

作者： Turaga, Diwakar Matthys, Oriane B. Hookway, Tracy A. Joy, David A. Calvert, Meredith McDevitt, Todd C. Gladstone Inst San Francisco CA 94158 USA UC Berkeley UCSF Grad Program Bioengn San Francisco CA USA Univ Calif San Francisco Dept Bioengn & Therapeut Sci San Francisco CA 94143 USA

Native cardiac tissue is composed of heterogeneous cell populations that work cooperatively for proper tissue function;thus, engineered tissue models have moved toward incorporating multiple cardiac cell types in an effort to recapitulate native multicellular composition and organization. Cardiac tissue models composed of stem cell-derived cardiomyocytes (CMs) require inclusion of non-myocytes to promote stable tissue formation, yet the specific contributions of the supporting non-myocyte population on the parenchymal CMs and cardiac microtissues have to be fully dissected. This gap can be partly attributed to limitations in technologies able to accurately study the individual cellular structure and function that comprise intact three-dimensional (3D) tissues. The ability to interrogate the cell-cell interactions in 3D tissue constructs has been restricted by conventional optical imaging techniques that fail to adequately penetrate multicellular microtissues with sufficient spatial resolution. Light sheet fluorescence microscopy (LSFM) overcomes these constraints to enable single-cell resolution structural and functional imaging of intact cardiac microtissues. Multicellular spatial distribution analysis of heterotypic cardiac cell populations revealed that CMs and cardiac fibroblasts were randomly distributed throughout 3D microtissues. Furthermore, calcium imaging of live cardiac microtissues enabled single-cell detection of CM calcium activity, which showed that functional heterogeneity correlated with spatial location within the tissues. This study demonstrates that LSFM can be utilized to determine single-cell spatial and functional interactions of multiple cell types within intact 3D engineered microtissues, thereby facilitating the determination of structure-function relationships at both tissue-level and single-cell resolution. Impact statement The ability to achieve single-cell resolution by advanced three-dimensional light imaging techniques enables exquisi

关键词： light sheet microscopy cardiac microtissues heterotypic interactions structure-function live imaging

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structure and function of lipid A-modifying enzymes

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 2020年第1期1459卷 19-37页

作者： Anandan, Anandhi Vrielink, Alice Univ Western Australia Sch Mol Sci 35 Stirling Highway Perth WA 6009 Australia

Lipopolysaccharides are complex molecules found in the cell envelop of many Gram-negative bacteria. The toxic activity of these molecules has led to the terminology of endotoxins. They provide bacteria with structural integrity and protection from external environmental conditions, and they interact with host signaling receptors to induce host immune responses. Bacteria have evolved enzymes that act to modify lipopolysaccharides, particularly the lipid A region of the molecule, to enable the circumvention of host immune system responses. These modifications include changes to lipopolysaccharide by the addition of positively charged sugars, such as N-Ara4N, and phosphoethanolamine (pEtN). Other modifications include hydroxylation, acylation, and deacylation of fatty acyl chains. We review the two-component regulatory mechanisms for enzymes that carry out these modifications and provide details of the structures of four enzymes (PagP, PagL, pEtN transferases, and ArnT) that modify the lipid A portion of lipopolysaccharides. We focus largely on the three-dimensional structures of these enzymes, which provide an understanding of how their substrate binding and catalytic activities are mediated. A structure-function-based understanding of these enzymes provides a platform for the development of novel therapeutics to treat antibiotic resistance.

关键词： lipid A modification PagL PagP pEtN transferase ArnT antibiotics bacteria multidrug resistance structure-function

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A global view of structure-function relationships in the tautomerase superfamily

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JOURNAL OF BIOLOGICAL CHEMISTRY 2018年第7期293卷 2342-2357页

作者： Davidson, Rebecca Baas, Bert-Jan Akiva, Eyal Holliday, Gemma L. Polacco, Benjamin J. LeVieux, Jake A. Pullara, Collin R. Zhang, Yan Jessie Whitman, Christian P. Babbitt, Patricia C. Univ Calif San Francisco Dept Bioengn & Therapeut Sci San Francisco CA 94143 USA Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA Univ Calif San Francisco Quantitat Biosci Inst San Francisco CA 94143 USA Univ Texas Austin Div Chem Biol & Med Chem Coll Pharm Austin TX 78712 USA Univ Texas Austin Dept Mol Biosci Austin TX 78712 USA Univ Texas Austin Inst Cellular & Mol Biol Austin TX 78712 USA

The tautomerase superfamily (TSF) consists of more than 11,000 nonredundant sequences present throughout the biosphere. Characterized members have attracted much attention because of the unusual and key catalytic role of an N-terminal proline. These few characterized members catalyze a diverse range of chemical reactions, but the full scale of their chemical capabilities and biological functions remains unknown. To gain new insight into TSF structure-function relationships, we performed a global analysis of similarities across the entire superfamily and computed a sequence similarity network to guide classification into distinct subgroups. Our results indicate that TSF members are found in all domains of life, with most being present in bacteria. The eukaryotic members of the cis-3-chloroacrylic acid dehalogenase subgroup are limited to fungal species, whereas the macrophage migration inhibitory factor subgroup has wide eukaryotic representation (including mammals). Unexpectedly, we found that 346 TSF sequences lack Pro-1, of which 85% are present in the malonate semialdehyde decarboxylase subgroup. The computed network also enabled the identification of similarity paths, namely sequences that link functionally diverse subgroups and exhibit transitional structural features that may help explain reaction divergence. A structure-guided comparison of these linker proteins identified conserved transitions between them, and kinetic analysis paralleled these observations. Phylogenetic reconstruction of the linker set was consistent with these findings. Our results also suggest that contemporary TSF members may have evolved from a short 4-oxalocrotonate tautomerase-like ancestor followed by gene dupli-cation and fusion. Our new linker-guided strategy can be used to enrich the discovery of sequence/structure/function transitions in other enzyme superfamilies.

关键词： enzyme structure evolution protein evolution protein sequence protein structure structure-function enzyme superfamily structure-function relationships tautomerase superfamily

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Highlighting membrane protein structure and function: A celebration of the Protein Data Bank

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JOURNAL OF BIOLOGICAL CHEMISTRY 2021年第1期296卷 100557页

作者： Li, Fei Egea, Pascal F. Vecchio, Alex J. Asial, Ignacio Gupta, Meghna Paulino, Joana Bajaj, Ruchika Dickinson, Miles Sasha Ferguson-Miller, Shelagh Monk, Brian C. Stroud, Robert M. Univ Calif San Francisco Dept Biochem & Biophys San Francisco CA 94143 USA Univ Calif San Francisco Dept Neurol San Francisco CA USA Univ Calif Los Angeles Sch Med Dept Biol Chem Los Angeles CA 90024 USA Univ Nebraska Dept Biochem Lincoln NE 68583 USA DotBio Pte Ltd Singapore Singapore Univ Calif San Francisco Dept Bioengn & Therapeut Sci San Francisco CA 94143 USA Michigan State Univ Dept Biochem & Mol Biol E Lansing MI 48824 USA Univ Otago Sir John Walsh Res Inst Dunedin New Zealand Univ Otago Dept Oral Sci Dunedin New Zealand Univ Texas Austin Sauer Lab Struct Biol CryoEM Austin TX 78712 USA

Biological membranes define the boundaries of cells and compartmentalize the chemical and physical processes required for life. Many biological processes are carried out by proteins embedded in or associated with such membranes. Determination of membrane protein (MP) structures at atomic or near-atomic resolution plays a vital role in elucidating their structural and functional impact in biology. This endeavor has determined 1198 unique MP structures as of early 2021. The value of these structures is expanded greatly by deposition of their three-dimensional (3D) coordinates into the Protein Data Bank (PDB) after the first atomic MP structure was elucidated in 1985. Since then, free access to MP structures facilitates broader and deeper understanding of MPs, which provides crucial new insights into their biological functions. Here we highlight the structural and functional biology of representative MPs and landmarks in the evolution of new technologies, with insights into key developments influenced by the PDB in magnifying their impact.

关键词： membrane protein structure-function lipid mimetics bioenergetics membrane protein biogenesis transmembrane transport channel receptor drug discovery protein design

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New insights into the structure and function of an emerging drug target CysE

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3 BIOTECH 2021年第8期11卷 373-373页

作者： Verma, Deepali Gupta, Vibha Jaypee Inst Informat Technol Dept Biotechnol A-10Sect 62 Noida 201309 Uttar Pradesh India

The antimicrobial resistant strains of several pathogens are major culprits of hospital-acquired nosocomial infections. An active and urgent action is necessary against these pathogens for the development of unique therapeutics. The cysteine biosynthetic pathway or genes (that are absent in humans) involved in the production of L-cysteine appear to be an attractive target for developing novel antibiotics. CysE, a Serine Acetyltransferase (SAT), catalyzes the first step of cysteine synthesis and is reported to be essential for the survival of persistence in several microbes including Mycobacterium tuberculosis. structure determination provides fundamental insight into structure and function of protein and aid in drug design/discovery efforts. This review focuses on the overview of current knowledge of structure function, regulatory mechanism, and potential inhibitors (active site as well as allosteric site) of CysE. Despite having conserved structure, slight modification in CysE structure lead to altered the regulatory mechanism and hence affects the cysteine production. Due to its possible role in virulence and vital metabolism of pathogens makes it a potential target in the quest to develop novel therapeutics to treat multi-drug-resistant bacteria.

关键词： Antimicrobial resistance Cysteine biosynthetic pathway CysE SAT L-cysteine structure-function Regulatory mechanism Inhibitor

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Accelerating structure-function mapping using the ViVa webtool to mine natural variation

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PLANT DIRECT 2019年第7期3卷 e00147页

作者： Hamm, Morgan O. Moss, Britney L. Leydon, Alexander R. Gala, Hardik P. Lanctot, Amy Ramos, Roman Klaeser, Hannah Lemmex, Andrew C. Zahler, Mollye L. Nemhauser, Jennifer L. Wright, R. Clay Univ Washington Dept Biol Seattle WA 98195 USA Whitman Coll Dept Biol Walla Walla WA 99362 USA Virginia Tech Biol Syst Engn Blacksburg VA 24061 USA

Thousands of sequenced genomes are now publicly available capturing a significant amount of natural variation within plant species;yet, much of these data remain inaccessible to researchers without significant bioinformatics experience. Here, we present a webtool called ViVa (Visualizing Variation) which aims to empower any researcher to take advantage of the amazing genetic resource collected in the Arabidopsis thaliana 1001 Genomes Project (http://***). ViVa facilitates data mining on the gene, gene family, or gene network level. To test the utility and accessibility of ViVa, we assembled a team with a range of expertise within biology and bioinformatics to analyze the natural variation within the well-studied nuclear auxin signaling pathway. Our analysis has provided further confirmation of existing knowledge and has also helped generate new hypotheses regarding this well-studied pathway. These results highlight how natural variation could be used to generate and test hypotheses about less-studied gene families and networks, especially when paired with biochemical and genetic characterization. ViVa is also readily extensible to databases of interspecific genetic variation in plants as well as other organisms, such as the 3,000 Rice Genomes Project (http://***/) and human genetic variation (https://***/clinvar/).

关键词： accessibility Arabidopsis thaliana genome diversity genotype-phenotype natural variation structure-function

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structure-function Relationship between Flicker-Defined Form Perimetry and Spectral-Domain Optical Coherence Tomography in Glaucoma Suspects

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CURRENT EYE RESEARCH 2017年第3期42卷 418-423页

作者： Reznicek, Lukas Muth, Daniel Vogel, Michaela Hirneiss, Christoph Tech Univ Munich Dept Ophthalmol Munich Germany Ludwig Maximilians Univ Munchen Dept Ophthalmol Munich Germany

Purpose: To evaluate the relationship between functional parameters of repeated flicker-defined form perimetry (FDF) and structural parameters of spectral-domain optical coherence tomography (SD-OCT) in glaucoma suspects with normal findings in achromatic standard automated perimetry (SAP).Methods: Patients with optic nerve heads (ONH) clinically suspicious for glaucoma and normal SAP findings were enrolled in this prospective study. Each participant underwent visual field (VF) testing with FDF perimetry, using the Heidelberg Edge Perimeter (HEP, Heidelberg Engineering, Heidelberg, Germany) at two consecutive visits. Peripapillary RNFL thickness was obtained by SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany). Correlations and regression analyses of global and sectoral peripapillary RNFL thickness with corresponding global and regional VF sensitivities were ***: A consecutive series of 65 study eyes of 36 patients were prospectively included. The second FDF test (HEP II) was used for analysis. Cluster-point based suspicious VF defects were found in 34 eyes (52%). Significant correlations were observed between mean global MD (PSD) of HEP II and SD-OCT-based global peripapillary RNFL thickness (r = 0.380, p = 0.003 for MD and r = -0.516, p < 0.001 for PSD) and RNFL classification scores (R-2 = 0.157, p = 0.002 for MD and R-2 = 0.172, p = 0.001 for PSD). Correlations between mean global MD and PSD of HEP II and sectoral peripapillary RNFL thickness and classification scores showed highest correlations between function and structure for the temporal superior and temporal inferior sectors whereas sectoral MD and PSD correlated weaker with sectoral RNFL thickness. Correlations between linear RNFL values and untransformed logarithmic MD values for each segment were less significant than correlations between logarithmic MD values and RNFL ***: In glaucoma suspects with normal SAP, global and sectoral peripapillary RNFL thic

关键词： Glaucoma structure-function FDF perimetry OCT HEP

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structure-function relations in physiology education: Where's the mechanism?

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ADVANCES IN PHYSIOLOGY EDUCATION 2017年第2期41卷 270-278页

作者： Lira, Matthew E. Gardner, Stephanie M. Purdue Univ Dept Biol Sci Lilly 2-226915 West State St W Lafayette IN 47907 USA

Physiology demands systems thinking: reasoning within and between levels of biological organization and across different organ systems. Many physiological mechanisms explain how structures and their properties interact at one level of organization to produce emergent functions at a higher level of organization. Current physiology principles, such as structure-function relations, selectively neglect mechanisms by not mentioning this term explicitly. We explored how students characterized mechanisms and functions to shed light on how students make sense of these terms. Students characterized mechanisms as 1) processes that occur at levels of organization lower than that of functions;and 2) as detailed events with many steps involved. We also found that students produced more variability in how they characterized functions compared with mechanisms: students characterized functions in relation to multiple levels of organization and multiple definitions. We interpret these results as evidence that students see mechanisms as holding a more narrow definition than used in the biological sciences, and that students struggle to coordinate and distinguish mechanisms from functions due to cognitive processes germane to learning in many domains. We offer the instructional suggestion that we scaffold student learning by affording students opportunities to relate and also distinguish between these terms so central to understanding physiology.

关键词： systems thinking structure-function mechanism causation instructional scaffolds mechanistic reasoning

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The Yucatan Minipig Temporomandibular Joint Disc structure-function Relationships Support Its Suitability for Human Comparative Studies

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TISSUE ENGINEERING PART C-METHODS 2017年第11期23卷 700-709页

作者： Vapniarsky, Natalia Aryaei, Ashkan Arzi, Boaz Hatcher, David C. Hu, Jerry C. Athanasiou, Kyriacos A. Univ Calif Davis Dept Biomed Engn Davis CA 95616 USA Univ Calif Davis Dept Surg & Radiol Sci Sch Vet Med Davis CA 95616 USA Diagnost Digital Imaging Ctr Sacramento CA USA Univ Calif Davis Dept Orthoped Surg Sch Med Davis CA 95616 USA

Frequent involvement of the disc in temporomandibular joint (TMJ) disorders warrants attempts to tissue engineer TMJ disc replacements. Physiologically, a great degree of similarity is seen between humans and farm pigs (FPs), but the pig's rapid growth confers a significant challenge for in vivo experiments. Minipigs have a slower growth rate and are smaller than FPs, but minipig TMJ discs have yet to be fully characterized. The objective of this study was to determine the suitability of the minipig for TMJ studies by extensive structural and functional characterization. The properties of minipig TMJ discs closely reproduced previously reported morphological, biochemical, and biomechanical values of human and FP discs. The width/length dimension ratio of the minipig TMJ disc was 1.95 (1.69 for human and 1.94 for FP). The biochemical evaluation revealed, on average per wet weight, 24.3% collagen (22.8% for human and 24.9% for FP);0.8% glycosaminoglycan (GAG;0.5% for human and 0.4% for FP);and 0.03% DNA (0.008% for human and 0.02% for FP). Biomechanical testing revealed, on average, compressive relaxation modulus of 50kPa (37kPa for human and 32kPa for FP), compressive instantaneous modulus of 1121kPa (1315kPa for human and 1134kPa for FP), and coefficient of viscosity of 13MPas (9MPas for human and 3MPas for FP) at 20% strain. These properties also varied topographically in accordance to those of human and FP TMJ discs. Anisotropy, quantified by bidirectional tensile testing and histology, again was analogous among minipig, human, and FP TMJ discs. The minipig TMJ's ginglymoarthrodial nature was verified through cone beam computer tomography. Collectively, the similarities between minipig and human TMJ discs support the use of minipig as a relevant model for TMJ research;considering the practical advantages conferred by its growth rate and size, the minipig may be a preferred model over FP.

关键词： temporomandibular joint disc characterization structure-function large animal model translation anisotropy

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Design and structure-function Characterization of 3D Printed Synthetic Porous Biomaterials for Tissue Engineering

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ADVANCED HEALTHCARE MATERIALS 2018年第7期7卷 1701095-1701095页

作者： Kelly, Cambre N. Miller, Andrew T. Hollister, Scott J. Guldberg, Robert E. Gall, Ken Duke Univ Dept Mech Engn & Mat Sci Box 90300 Hudson Hall Durham NC 27708 USA Georgia Inst Technol Coulter Dept Biomed Engn 313 Ferst DrRoom 2127 Atlanta GA 30332 USA Georgia Inst Technol Parker H Petit Inst Bioengn & Biosci 315 Ferst Dr Atlanta GA 30332 USA

3D printing is now adopted for use in a variety of industries and functions. In biomedical engineering, 3D printing has prevailed over more traditional manufacturing methods in tissue engineering due to its high degree of control over both macro- and microarchitecture of porous tissue scaffolds. However, with the improved flexibility in design come new challenges in characterizing the structure-function relationships between various architectures and both mechanical and biological properties in an assortment of clinical applications. Presently, the field of tissue engineering lacks a comprehensive body of literature that is capable of drawing meaningful relationships between the designed structure and resulting function of 3D printed porous biomaterial scaffolds. This work first discusses the role of design on 3D printed porous scaffold function and then reviews characterization of these structure-function relationships for 3D printed synthetic metallic, polymeric, and ceramic biomaterials.

关键词： 3D printing printed architecture scaffolds structure-function tissue engineering

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