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1
McPherson, Alexander, e Yurii G. Kuznetsov. "Mechanisms, kinetics, impurities and defects: consequences in macromolecular crystallization". Acta Crystallographica Section F Structural Biology Communications 70, n. 4 (29 marzo 2014): 384–403. http://dx.doi.org/10.1107/s2053230x14004816.
Testo completoAbstract (sommario):
The nucleation and growth of protein, nucleic acid and virus crystals from solution are functions of underlying kinetic and thermodynamic parameters that govern the process, and these are all supersaturation-dependent. While the mechanisms of macromolecular crystal growth are essentially the same as for conventional crystals, the underlying parameters are vastly different, in some cases orders of magnitude lower, and this produces very different crystallization processes. Numerous physical features of macromolecular crystals are of serious interest to X-ray diffractionists; the resolution limit and mosaicity, for example, reflect the degree of molecular and lattice order. The defect structure of crystals has an impact on their response to flash-cooling, and terminal crystal size is dependent on impurity absorption and incorporation. The variety and extent of these issues are further unique to crystals of biological macromolecules. All of these features are amenable to study using atomic force microscopy, which provides direct images at the nanoscale level. Some of those images are presented here.
2
Paganini, Chiara, Chiara Gramegna Tota, Andrea Superti-Furga e Antonio Rossi. "Skeletal Dysplasias Caused by Sulfation Defects". International Journal of Molecular Sciences 21, n. 8 (14 aprile 2020): 2710. http://dx.doi.org/10.3390/ijms21082710.
Testo completoAbstract (sommario):
Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.
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Ciesielski, Peter N., Ryan Wagner, Vivek S. Bharadwaj, Jason Killgore, Ashutosh Mittal, Gregg T. Beckham, Stephen R. Decker, Michael E. Himmel e Michael F. Crowley. "Nanomechanics of cellulose deformation reveal molecular defects that facilitate natural deconstruction". Proceedings of the National Academy of Sciences 116, n. 20 (29 aprile 2019): 9825–30. http://dx.doi.org/10.1073/pnas.1900161116.
Testo completoAbstract (sommario):
Technologies surrounding utilization of cellulosic materials have been integral to human society for millennia. In many materials, controlled introduction of defects provides a means to tailor properties, introduce reactivity, and modulate functionality for various applications. The importance of defects in defining the behavior of cellulose is becoming increasingly recognized. However, fully exploiting defects in cellulose to benefit biobased materials and conversion applications will require an improved understanding of the mechanisms of defect induction and corresponding molecular-level consequences. We have identified a fundamental relationship between the macromolecular structure and mechanical behavior of cellulose nanofibrils whereby molecular defects may be induced when the fibrils are subjected to bending stress exceeding a certain threshold. By nanomanipulation, imaging, and molecular modeling, we demonstrate that cellulose nanofibrils tend to form kink defects in response to bending stress, and that these macromolecular features are often accompanied by breakages in the glucan chains. Direct observation of deformed cellulose fibrils following partial enzymatic digestion reveals that processive cellulases exploit these defects as initiation sites for hydrolysis. Collectively, our findings provide a refined understanding of the interplay between the structure, mechanics, and reactivity of cellulose assemblies.
4
Dauter, Zbigniew, e Mariusz Jaskólski. "Crystal pathologies in macromolecular crystallography". Postępy Biochemii 62, n. 3 (15 novembre 2016): 401–7. http://dx.doi.org/10.18388/pb.2016_45.
Testo completoAbstract (sommario):
Macromolecules, such as proteins or nucleic acids, form crystals with a large volume fraction of water, ~50% on average. Apart from typical physical defects and rather trivial poor quality problems, macromolecular crystals, as essentially any crystals, can also suffer from several kinds of pathologies, in which everything seems to be perfect, except that from the structural point of view the interpretation may be very difficult, sometimes even im-possible. A frequent nuisance is pseudosymmetry, or non-crystallographic symmetry (NCS), which is particularly nasty when it has translational character. Lattice-translocation defects, also called order-disorder twinning (OD-twinning), occur when molecules are packed regularly in layers but the layers are stacked (without rotation) in two (or more) discrete modes, with a unique translocation vector. Crystal twinning arises when twin domains have different orientations, incompatible with the symmetry of the crystal structure. There are also crystals in which the periodic (lattice) order is broken or absent altogether. When the strict short-range translational order from one unit cell to the next is lost but the long-range order is restored by a periodic modulation, we have a modulated crystal structure. In quasicrystals (not observed for macromolecules yet), the periodic order (in 3D space) is lost completely and the diffraction pattern (which is still discrete) cannot be even indexed using three hkl indices. In addition, there are other physical defects and phenomena (such as high mosaicity, diffraction anisotropy, diffuse scattering, etc.) which make diffraction data processing and structure solution difficult or even impossible.
5
Zhang, Liangfang, e Steve Granick. "Dynamical Heterogeneity in Supported Lipid Bilayers". MRS Bulletin 31, n. 7 (luglio 2006): 527–31. http://dx.doi.org/10.1557/mrs2006.137.
Testo completoAbstract (sommario):
Planar-supported phospholipid bilayers are responsive surfaces that reconstruct when macromolecules adsorb. This review outlines the phenomenon of lipid diffusion “slaved” to or significantly controlled by that of macromolecular adsorbates. To elucidate such systems, we discuss the value of spatially resolved experiments at the few-molecule level, lipid diffusion compared in outer and inner leaflets of the supported bilayer, and a simple method to minimize defects by the strategy of “electrostatic stitching.”
6
Li, Xiaoshi, Yiwen Ju, Quanlin Hou, Zhuo Li e Junjia Fan. "FTIR and Raman Spectral Research on Metamorphism and Deformation of Coal". Journal of Geological Research 2012 (10 luglio 2012): 1–8. http://dx.doi.org/10.1155/2012/590857.
Testo completoAbstract (sommario):
Under different metamorphic environments, coal will form different types of tectonically deformed coal (TDC) by tectonic stress and even the macromolecular structure can be changed. The structure and composition evolution of TDC have been investigated in details using Fourier transform infrared spectroscopy and Raman spectroscopy. The ductile deformation can generate strain energy via increase of dislocation in molecular structure of TDC, and it can exert an obvious influence on degradation and polycondensation. The brittle deformation can generate frictional heat energy and promote the metamorphism and degradation, but less effect on polycondensation. Furthermore, degradation affects the structural evolution of coal in lower metamorphic stage primarily, whereas polycondensation is the most important controlling factor in higher metamorphic stage. Tectonic deformation can produce secondary structural defects in macromolecular structure of TDC. Under the control of metamorphism and deformation, the small molecules which break and fall off from the macromolecular structure of TDC are replenished and embedded into the secondary structural defects preferentially and form aromatic rings by polycondensation. These processes improved the stability of macromolecular structure greatly. It is easier for ductile deformation to induce secondary structural defects than in brittle deformation.
7
Cao, Yi, Min Liu, Kunchi Zhang, Jingjin Dong, Guangyue Zu, Yang Chen, Tingting Zhang, Dangsheng Xiong e Renjun Pei. "Preparation of linear poly(glycerol) as a T1 contrast agent for tumor-targeted magnetic resonance imaging". Journal of Materials Chemistry B 4, n. 41 (2016): 6716–25. http://dx.doi.org/10.1039/c6tb01514j.
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Song, Yu, Bo Jiang e Meijun Qu. "Macromolecular evolution and structural defects in tectonically deformed coals". Fuel 236 (gennaio 2019): 1432–45. http://dx.doi.org/10.1016/j.fuel.2018.09.080.
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Wang, Anmin, Daiyong Cao, Yingchun Wei e Zhifei Liu. "Macromolecular Structure Controlling Micro Mechanical Properties of Vitrinite and Inertinite in Tectonically Deformed Coals—A Case Study in Fengfeng Coal Mine of Taihangshan Fault Zone (North China)". Energies 13, n. 24 (15 dicembre 2020): 6618. http://dx.doi.org/10.3390/en13246618.
Testo completoAbstract (sommario):
In order to study the evolution of the mechanical properties and macromolecular structures in different macerals of tectonically deformed coal (TDC), vitrinite and inertinite samples were handpicked from six block TDCs in the same coal seam with an increasing deformation degree (unaltered, cataclastic, porphyroclast, scaly and powdery coal). The micro mechanical properties were tested by the nanoindentation experiment and the macromolecular structures were measured using 13C nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR). The results show that the range of hardness and elastic modulus of inertinite is 0.373–1.517 GPa and 4.339–12.158 GPa, respectively, which is significantly higher than that of vitrinite with values of 0.278–0.456 GPa and 4.857–7.810 GPa, respectively. From unaltered coal to powdery coal, the hardness of vitrinite and inertinite gradually decreases, with the difference between these macerals becomes smaller and the elastic modulus of vitrinite shows an increasing trend, while that of inertinite was more variable. Both the NMR and FITR results reveal that the macromolecular structure of inertinite has similar structural transitions as vitrinite. As the degree of deformation increases, the aliphatic side chains become shorter and the aromaticity is increasing. Macromolecular alterations caused by tectonic stress is expected to produce defects in the TDCs, therefore there should be more interspacing among the macromolecular groups for the extrusion of macromolecules caused by the indenter of the nanoindentation experiment, thereby reducing the hardness. The elastic modulus of coal is believed to be related to intermolecular forces, which are positively correlated to the dipole moment. By calculating the dipole moments of the typical aromatic molecular structures with aliphatic side chains, the detachment of the aliphatic side chains and the growth of benzene rings can both increase the dipole moment, which can promote elastic modulus. In addition, the increasing number of benzene rings can create more π-π bonds between the molecules, which can lead to an increase in the intermolecular forces, further increasing the elastic modulus.
10
Sun, Zhe, Koki Ikemoto, Toshiya M. Fukunaga, Takashi Koretsune, Ryotaro Arita, Sota Sato e Hiroyuki Isobe. "Finite phenine nanotubes with periodic vacancy defects". Science 363, n. 6423 (10 gennaio 2019): 151–55. http://dx.doi.org/10.1126/science.aau5441.
Testo completoAbstract (sommario):
Discrete graphitic carbon compounds serve as tunable models for the properties of extended macromolecular structures such as nanotubes. Here, we report synthesis and characterization of a cylindrical C304H264molecule composed of 40 benzene (phenine) units mutually bonded at the 1, 3, and 5 positions. The concise nine-step synthesis featuring successive borylations and couplings proceeded with an average yield for each benzene-benzene bond formation of 91%. The molecular structure of the nanometer-sized cylinder with periodic vacancy defects was confirmed spectroscopically and crystallographically. The nanoporous nature of the compound further enabled inclusion of multiple fullerene guests. Computations suggest that fusing many such cylinders could produce carbon nanotubes with electronic properties modulated by the periodic vacancy defects.
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Walz, J., A. J. Koster, T. Tamura e W. Baumeister. "Macromolecular Assemblies Designed for Controlled Proteolysis". Microscopy and Microanalysis 4, S2 (luglio 1998): 980–81. http://dx.doi.org/10.1017/s1431927600025022.
Testo completoAbstract (sommario):
Since cellular structures are rebuilt continually, protein degradation is essential for the maintenance of homeostasis. Misfolded proteins ensuing from genetic defects or environmental stress, are prone to aggregation; chaperones and proteases cooperate in minimizing such unproductive interactions. Last, but not least, protein degradation serves to terminate the lifespan of many regulatory proteins at distinct times and thus features as a key regulatory element itself. Proteins destined for degradation must be recognized and selected within the crowded environment of the cell. The stratagem of self-compartmentalization is key to controlling cellular proteolysis (1).In recent years, a number of multisubunit proteolytic complexes have been described which possess large internal cavities or nano-compartments. This allows them to confine the proteolytic action to their interior; access to these inner compartments is usually restricted to the unfolded proteins. This, in turn, makes it necessary for these proteases to interact - either in a transient or in a permanent manner
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Mohler, Peter J., e Xander H. T. Wehrens. "Mechanisms of Human Arrhythmia Syndromes: Abnormal Cardiac Macromolecular Interactions". Physiology 22, n. 5 (ottobre 2007): 342–50. http://dx.doi.org/10.1152/physiol.00018.2007.
Testo completoAbstract (sommario):
Many cardiac ion channels exist within macromolecular signaling complexes, comprised of pore-forming subunits that associate with auxiliary subunits, regulatory enzymes, and targeting proteins. This complex protein assembly ensures proper modulation of channel activity and ion homeostasis. The association of genetic defects in regulatory and targeting proteins to inherited arrhythmia syndromes has led to a better understanding of the critical role these proteins play in ion channel modulation.
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Polikarpov, Maxim, Gleb Bourenkov, Irina Snigireva, Anatoly Snigirev, Sophie Zimmermann, Krisztian Csanko, Sandor Brockhauser e Thomas R. Schneider. "Visualization of protein crystals by high-energy phase-contrast X-ray imaging". Acta Crystallographica Section D Structural Biology 75, n. 11 (31 ottobre 2019): 947–58. http://dx.doi.org/10.1107/s2059798319011379.
Testo completoAbstract (sommario):
For the extraction of the best possible X-ray diffraction data from macromolecular crystals, accurate positioning of the crystals with respect to the X-ray beam is crucial. In addition, information about the shape and internal defects of crystals allows the optimization of data-collection strategies. Here, it is demonstrated that the X-ray beam available on the macromolecular crystallography beamline P14 at the high-brilliance synchrotron-radiation source PETRA III at DESY, Hamburg, Germany can be used for high-energy phase-contrast microtomography of protein crystals mounted in an optically opaque lipidic cubic phase matrix. Three-dimensional tomograms have been obtained at X-ray doses that are substantially smaller and on time scales that are substantially shorter than those used for diffraction-scanning approaches that display protein crystals at micrometre resolution. Adding a compound refractive lens as an objective to the imaging setup, two-dimensional imaging at sub-micrometre resolution has been achieved. All experiments were performed on a standard macromolecular crystallography beamline and are compatible with standard diffraction data-collection workflows and apparatus. Phase-contrast X-ray imaging of macromolecular crystals could find wide application at existing and upcoming low-emittance synchrotron-radiation sources.
14
Adams, W. W., D. L. Vezie e E. L. Thomas. "Low-voltage high-resolution SEM investigations of novel macromolecular liquid crystals". Proceedings, annual meeting, Electron Microscopy Society of America 50, n. 1 (agosto 1992): 266–67. http://dx.doi.org/10.1017/s0424820100121739.
Testo completoAbstract (sommario):
The ability to visualize detailed 3-dimensional surface topology with SEM at low voltage and high resolution holds profound promise for analyzing liquid crystal textures, both in polymers and other macromolecular forms. Director textures, domain boundaries, and defects such as inversion walls, disclinations and dislocations can now be easily visualized with this technique. Studies concerning the effects of shear flow and magnetic fields on these defects are currently under way.Resolution of 4.0 nm at 1.0 keV is now possible with commercial SEM's, which incorporate the latest advances in lens design optimized for low voltage operation, and use high brightness, low energy spread field emission electron guns. The low energy spread of the field emission gun reduces chromatic aberration effects and facilitates successful operation at low keV. Low voltage operation provides dramatically improved image contrast due to the smaller beam/sample interaction volume and also greatly reduces sample charging artifacts. By operating at near crossover conditions, the need for coating nonconducting specimens with a conducting layer of metal or carbon is greatly reduced or eliminated.
15
Campi, Gaetano, Gabriele Ciasca, Nicola Poccia, Alessandro Ricci, Michela Fratini e Antonio Bianconi. "Controlling Photoinduced Electron Transfer Via Defects Self-Organization for Novel Functional Macromolecular Systems". Current Protein & Peptide Science 15, n. 4 (aprile 2014): 394–99. http://dx.doi.org/10.2174/1389203715666140327104023.
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Quist, A. P., J. Ahlbom, C. T. Reimann e B. U. R. Sundqvist. "Scanning force microscopy studies of surface defects induced by incident energetic macromolecular ions". Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms 88, n. 1-2 (aprile 1994): 164–69. http://dx.doi.org/10.1016/0168-583x(94)96098-4.
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Gladfelter, Amy S., Indrani Bose, Trevin R. Zyla, Elaine S. G. Bardes e Daniel J. Lew. "Septin ring assembly involves cycles of GTP loading and hydrolysis by Cdc42p". Journal of Cell Biology 156, n. 2 (21 gennaio 2002): 315–26. http://dx.doi.org/10.1083/jcb.200109062.
Testo completoAbstract (sommario):
At the beginning of the budding yeast cell cycle, the GTPase Cdc42p promotes the assembly of a ring of septins at the site of future bud emergence. Here, we present an analysis of cdc42 mutants that display specific defects in septin organization, which identifies an important role for GTP hydrolysis by Cdc42p in the assembly of the septin ring. The mutants show defects in basal or stimulated GTP hydrolysis, and the septin misorganization is suppressed by overexpression of a Cdc42p GTPase-activating protein (GAP). Other mutants known to affect GTP hydrolysis by Cdc42p also caused septin misorganization, as did deletion of Cdc42p GAPs. In performing its roles in actin polarization and transcriptional activation, GTP-Cdc42p is thought to function by activating and/or recruiting effectors to the site of polarization. Excess accumulation of GTP-Cdc42p due to a defect in GTP hydrolysis by the septin-specific alleles might cause unphysiological activation of effectors, interfering with septin assembly. However, the recessive and dose-sensitive genetic behavior of the septin-specific cdc42 mutants is inconsistent with the septin defect stemming from a dominant interference of this type. Instead, we suggest that assembly of the septin ring involves repeated cycles of GTP loading and GTP hydrolysis by Cdc42p. These results suggest that a single GTPase, Cdc42p, can act either as a ras-like GTP-dependent “switch” to turn on effectors or as an EF-Tu–like “assembly factor” using the GTPase cycle to assemble a macromolecular structure.
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Chandika, Pathum, Pipuni Tennakoon, Tae-Hee Kim, Se-Chang Kim, Jae-Young Je, Jae-Il Kim, Bonggi Lee et al. "Marine Biological Macromolecules and Chemically Modified Macromolecules; Potential Anticoagulants". Marine Drugs 20, n. 10 (21 ottobre 2022): 654. http://dx.doi.org/10.3390/md20100654.
Testo completoAbstract (sommario):
Coagulation is a potential defense mechanism that involves activating a series of zymogens to convert soluble fibrinogen to insoluble fibrin clots to prevent bleeding and hemorrhagic complications. To prevent the extra formation and diffusion of clots, the counterbalance inhibitory mechanism is activated at levels of the coagulation pathway. Contrariwise, this system can evade normal control due to either inherited or acquired defects or aging which leads to unusual clots formation. The abnormal formations and deposition of excess fibrin trigger serious arterial and cardiovascular diseases. Although heparin and heparin-based anticoagulants are a widely prescribed class of anticoagulants, the clinical use of heparin has limitations due to the unpredictable anticoagulation, risk of bleeding, and other complications. Hence, significant interest has been established over the years to investigate alternative therapeutic anticoagulants from natural sources, especially from marine sources with good safety and potency due to their unique chemical structure and biological activity. This review summarizes the coagulation cascade and potential macromolecular anticoagulants derived from marine flora and fauna.
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dos Passos, Patricia M., Erandika H. Hemamali, Lohany D. Mamede, Lindsey R. Hayes e Yuna M. Ayala. "RNA-mediated ribonucleoprotein assembly controls TDP-43 nuclear retention". PLOS Biology 22, n. 2 (29 febbraio 2024): e3002527. http://dx.doi.org/10.1371/journal.pbio.3002527.
Testo completoAbstract (sommario):
TDP-43 is an essential RNA-binding protein strongly implicated in the pathogenesis of neurodegenerative disorders characterized by cytoplasmic aggregates and loss of nuclear TDP-43. The protein shuttles between nucleus and cytoplasm, yet maintaining predominantly nuclear TDP-43 localization is important for TDP-43 function and for inhibiting cytoplasmic aggregation. We previously demonstrated that specific RNA binding mediates TDP-43 self-assembly and biomolecular condensation, requiring multivalent interactions via N- and C-terminal domains. Here, we show that these complexes play a key role in TDP-43 nuclear retention. TDP-43 forms macromolecular complexes with a wide range of size distribution in cells and we find that defects in RNA binding or inter-domain interactions, including phase separation, impair the assembly of the largest species. Our findings suggest that recruitment into these macromolecular complexes prevents cytoplasmic egress of TDP-43 in a size-dependent manner. Our observations uncover fundamental mechanisms controlling TDP-43 cellular homeostasis, whereby regulation of RNA-mediated self-assembly modulates TDP-43 nucleocytoplasmic distribution. Moreover, these findings highlight pathways that may be implicated in TDP-43 proteinopathies and identify potential therapeutic targets.
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Yuan, Yue, Le Zhang, Lei Jin, Jufen Liu, Zhiwen Li, Linlin Wang e Aiguo Ren. "Markers of macromolecular oxidative damage in maternal serum and risk of neural tube defects in offspring". Free Radical Biology and Medicine 80 (marzo 2015): 27–32. http://dx.doi.org/10.1016/j.freeradbiomed.2014.12.014.
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Garge, Riddhiman K., Jon M. Laurent, Aashiq H. Kachroo e Edward M. Marcotte. "Systematic Humanization of the Yeast Cytoskeleton Discerns Functionally Replaceable from Divergent Human Genes". Genetics 215, n. 4 (10 giugno 2020): 1153–69. http://dx.doi.org/10.1534/genetics.120.303378.
Testo completoAbstract (sommario):
Many gene families have been expanded by gene duplications along the human lineage, relative to ancestral opisthokonts, but the extent to which the duplicated genes function similarly is understudied. Here, we focused on structural cytoskeletal genes involved in critical cellular processes, including chromosome segregation, macromolecular transport, and cell shape maintenance. To determine functional redundancy and divergence of duplicated human genes, we systematically humanized the yeast actin, myosin, tubulin, and septin genes, testing ∼81% of human cytoskeletal genes across seven gene families for their ability to complement a growth defect induced by inactivation or deletion of the corresponding yeast ortholog. In five of seven families—all but α-tubulin and light myosin, we found at least one human gene capable of complementing loss of the yeast gene. Despite rescuing growth defects, we observed differential abilities of human genes to rescue cell morphology, meiosis, and mating defects. By comparing phenotypes of humanized strains with deletion phenotypes of their interaction partners, we identify instances of human genes in the actin and septin families capable of carrying out essential functions, but failing to fully complement the cytoskeletal roles of their yeast orthologs, thus leading to abnormal cell morphologies. Overall, we show that duplicated human cytoskeletal genes appear to have diverged such that only a few human genes within each family are capable of replacing the essential roles of their yeast orthologs. The resulting yeast strains with humanized cytoskeletal components now provide surrogate platforms to characterize human genes in simplified eukaryotic contexts.
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Acimovic, Ivana, Marwan Refaat, Adrien Moreau, Anton Salykin, Steve Reiken, Yvonne Sleiman, Monia Souidi et al. "Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes". Journal of Clinical Medicine 7, n. 11 (8 novembre 2018): 423. http://dx.doi.org/10.3390/jcm7110423.
Testo completoAbstract (sommario):
Background: Sarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. Objective: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. Methods: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. Results: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. Conclusion: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband’s resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms.
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Patel, S., e K. E. Weaver. "Addiction Toxin Fst Has Unique Effects on Chromosome Segregation and Cell Division in Enterococcus faecalis and Bacillussubtilis". Journal of Bacteriology 188, n. 15 (1 agosto 2006): 5374–84. http://dx.doi.org/10.1128/jb.00513-06.
Testo completoAbstract (sommario):
ABSTRACT The Fst toxin of the Enterococcus faecalis pAD1-encoded par addiction module functions intracellularly to kill plasmid-free segregants. Previous results had shown that Fst induction results in membrane permeabilization and cessation of macromolecular synthesis, but only after 45 min. Electron micrographs of toxin-induced cells showed no obvious membrane abnormalities but did reveal defects in nucleoid segregation and cell division, begging the question of which is the primary effect of Fst. To distinguish the possibilities, division septae and nucleoids were visualized simultaneously with fluorescent vancomycin and a variety of DNA stains. Results showed that division and segregation defects occurred in some cells within 15 min after induction. At these early time points, affected cells remained resistant to membrane-impermeant DNA stains, suggesting that loss of membrane integrity is a secondary effect caused by ongoing division and/or segregation defects. Fst-resistant mutants showed greater variability in cell length and formed multiple septal rings even in the absence of Fst. Fst induction was also toxic to Bacillus subtilis. In this species, Fst induction caused only minor division abnormalities, but all cells showed a condensation of the nucleoid, suggesting that effects on the structure of the chromosomal DNA might be paramount.
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Weaver, Keith E., Dariel M. Weaver, Carol L. Wells, Christopher M. Waters, Marshall E. Gardner e Erik A. Ehli. "Enterococcus faecalis Plasmid pAD1-Encoded Fst Toxin Affects Membrane Permeability and Alters Cellular Responses to Lantibiotics". Journal of Bacteriology 185, n. 7 (1 aprile 2003): 2169–77. http://dx.doi.org/10.1128/jb.185.7.2169-2177.2003.
Testo completoAbstract (sommario):
ABSTRACT Fst is a peptide toxin encoded by the par toxin-antitoxin stability determinant of Enterococcus faecalis plasmid pAD1. Intracellular overproduction of Fst resulted in simultaneous inhibition of all cellular macromolecular synthesis concomitant with cell growth inhibition and compromised the integrity of the cell membrane. Cells did not lyse or noticeably leak intracellular contents but had specific defects in chromosome partitioning and cell division. Extracellular addition of synthetic Fst had no effect on cell growth. Spontaneous Fst-resistant mutants had a phenotype consistent with changes in membrane composition. Interestingly, overproduction of Fst sensitized cells to the lantibiotic nisin, and Fst-resistant mutants were cross-resistant to nisin and the pAD1-encoded cytolysin.
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Porter, Iain M., Sarah E. McClelland, Guennadi A. Khoudoli, Christopher J. Hunter, Jens S. Andersen, Andrew D. McAinsh, J. Julian Blow e Jason R. Swedlow. "Bod1, a novel kinetochore protein required for chromosome biorientation". Journal of Cell Biology 179, n. 2 (15 ottobre 2007): 187–97. http://dx.doi.org/10.1083/jcb.200704098.
Testo completoAbstract (sommario):
We have combined the proteomic analysis of Xenopus laevis in vitro–assembled chromosomes with RNA interference and live cell imaging in HeLa cells to identify novel factors required for proper chromosome segregation. The first of these is Bod1, a protein conserved throughout metazoans that associates with a large macromolecular complex and localizes with kinetochores and spindle poles during mitosis. Small interfering RNA depletion of Bod1 in HeLa cells produces elongated mitotic spindles with severe biorientation defects. Bod1-depleted cells form syntelic attachments that can oscillate and generate enough force to separate sister kinetochores, suggesting that microtubule–kinetochore interactions were intact. Releasing Bod1-depleted cells from a monastrol block increases the frequency of syntelic attachments and the number of cells displaying biorientation defects. Bod1 depletion does not affect the activity or localization of Aurora B but does cause mislocalization of the microtubule depolymerase mitotic centromere- associated kinesin and prevents its efficient phosphorylation by Aurora B. Therefore, Bod1 is a novel kinetochore protein that is required for the detection or resolution of syntelic attachments in mitotic spindles.
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Han, Yuzhen, Jin Wang, Yijing Dong, Quanlin Hou e Jienan Pan. "The role of structure defects in the deformation of anthracite and their influence on the macromolecular structure". Fuel 206 (ottobre 2017): 1–9. http://dx.doi.org/10.1016/j.fuel.2017.05.085.
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Nassal, Drew, Jane Yu, Dennison Min, Cemantha Lane, Rebecca Shaheen, Daniel Gratz e Thomas J. Hund. "Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes". Journal of Cardiovascular Development and Disease 8, n. 5 (29 aprile 2021): 48. http://dx.doi.org/10.3390/jcdd8050048.
Testo completoAbstract (sommario):
The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout the conduction system. Importantly, inherited or acquired defects in a wide class of ion channels has been linked to dysfunction at various stages of the conduction system resulting in life-threatening cardiac arrhythmia. There is growing appreciation of the role that adapter and cytoskeletal proteins play in organizing ion channel macromolecular complexes critical for proper function of the cardiac conduction system. In particular, members of the ankyrin and spectrin families have emerged as important nodes for normal expression and regulation of ion channels in myocytes throughout the conduction system. Human variants impacting ankyrin/spectrin function give rise to a broad constellation of cardiac arrhythmias. Furthermore, chronic neurohumoral and biomechanical stress promotes ankyrin/spectrin loss of function that likely contributes to conduction disturbances in the setting of acquired cardiac disease. Collectively, this review seeks to bring attention to the significance of these cytoskeletal players and emphasize the potential therapeutic role they represent in a myriad of cardiac disease states.
28
Elion, E. A., J. Trueheart e G. R. Fink. "Fus2 localizes near the site of cell fusion and is required for both cell fusion and nuclear alignment during zygote formation." Journal of Cell Biology 130, n. 6 (15 settembre 1995): 1283–96. http://dx.doi.org/10.1083/jcb.130.6.1283.
Testo completoAbstract (sommario):
Zygote formation occurs through tightly coordinated cell and nuclear fusion events. Genetic evidence suggests that the FUS2 gene product promotes cell fusion during zygote formation in Saccharomyces cerevisiae, functioning with the Fus1 plasma membrane protein at or before cell wall and plasma membrane fusion. Here we report the sequence of the FUS2 gene, localization of Fus2 protein, and show that fus1 and fus2 mutants have distinct defects in cell fusion. FUS2 encodes a unique open reading frame of 617 residues that only is expressed in haploid cells in response to mating pheromone. Consistent with a role in cell fusion, Fus2 protein localizes with discrete structures that could be of cytoskeletal or vesicular origin that accumulate at the tip of pheromone-induced shmoos and at the junction of paired cells in zygotes. Fus2 is predicted to be a coiled-coil protein and fractionates with a 100,000 g pellet, suggesting that it is associated with cytoskeleton, membranes, or other macromolecular structures. Fus2 may interact with structures involved in the alignment of the nuclei during cell fusion, because fus2 mutants have strong defects in karyogamy and fail to orient microtubules between parental nuclei in zygotes. In contrast, fus1 mutants show no karyogamy defects. These, and other results suggest that Fus2 defines a novel cell fusion function and subcellular structure that is also required for the alignment of parental nuclei before nuclear fusion.
29
Catalanotto, Caterina, Christian Barbato, Carlo Cogoni e Dario Benelli. "The RNA-Binding Function of Ribosomal Proteins and Ribosome Biogenesis Factors in Human Health and Disease". Biomedicines 11, n. 11 (4 novembre 2023): 2969. http://dx.doi.org/10.3390/biomedicines11112969.
Testo completoAbstract (sommario):
The ribosome is a macromolecular complex composed of RNA and proteins that interact through an integrated and interconnected network to preserve its ancient core activities. In this review, we emphasize the pivotal role played by RNA-binding proteins as a driving force in the evolution of the current form of the ribosome, underscoring their importance in ensuring accurate protein synthesis. This category of proteins includes both ribosomal proteins and ribosome biogenesis factors. Impairment of their RNA-binding activity can also lead to ribosomopathies, which is a group of disorders characterized by defects in ribosome biogenesis that are detrimental to protein synthesis and cellular homeostasis. A comprehensive understanding of these intricate processes is essential for elucidating the mechanisms underlying the resulting diseases and advancing potential therapeutic interventions.
30
Ayyagari, R., K. J. Impellizzeri, B. L. Yoder, S. L. Gary e P. M. Burgers. "A mutational analysis of the yeast proliferating cell nuclear antigen indicates distinct roles in DNA replication and DNA repair." Molecular and Cellular Biology 15, n. 8 (agosto 1995): 4420–29. http://dx.doi.org/10.1128/mcb.15.8.4420.
Testo completoAbstract (sommario):
The saccharomyces cerevisiae proliferating cell nuclear antigen (PCNA), encoded by the POL30 gene, is essential for DNA replication and DNA repair processes. Twenty-one site-directed mutations were constructed in the POL30 gene, each mutation changing two adjacently located charged amino acids to alanines. Although none of the mutant strains containing these double-alanine mutations as the sole source of PCNA were temperature sensitive or cold sensitive for growth, about a third of the mutants showed sensitivity to UV light. Some of those UV-sensitive mutants had elevated spontaneous mutation rates. In addition, several mutants suppressed a cold-sensitive mutation in the CDC44 gene, which encodes the large subunit of replication factor C. A cold-sensitive mutant, which was isolated by random mutagenesis, showed a terminal phenotype at the restrictive temperature consistent with a defect in DNA replication. Several mutant PCNAs were expressed and purified from Escherichia coli, and their in vitro properties were determined. The cold-sensitive mutant (pol30-52, S115P) was a monomer, rather than a trimer, in solution. This mutant was deficient for DNA synthesis in vitro. Partial restoration of DNA polymerase delta holoenzyme activity was achieved at 37 degrees C but not at 14 degrees C by inclusion of the macromolecular crowding agent polyethylene glycol in the assay. The only other mutant (pol30-6, DD41,42AA) that showed a growth defect was partially defective for interaction with replication factor C and DNA polymerase delta but completely defective for interaction with DNA polymerase epsilon. Two other mutants sensitive to DNA damage showed no defect in vitro. These results indicate that the latter mutants are specifically impaired in one or more DNA repair processes whereas pol30-6 and pol30-52 mutants show their primary defects in the basic DNA replication machinery with probable associated defects in DNA repair. Therefore, DNA repair requires interactions between repair-specific protein(s) and PCNA, which are distinct from those required for DNA replication.
31
Salina, Davide, Khaldon Bodoor, Paul Enarson, Wahyu Hendrati Raharjo e Brian Burke. "Nuclear envelope dynamics". Biochemistry and Cell Biology 79, n. 5 (1 ottobre 2001): 533–42. http://dx.doi.org/10.1139/o01-130.
Testo completoAbstract (sommario):
The nuclear envelope (NE) provides a semi permeable barrier between the nucleus and cytoplasm and plays a central role in the regulation of macromolecular trafficking between these two compartments. In addition to this transport function, the NE is a key determinant of interphase nuclear architecture. Defects in NE proteins such as A-type lamins and the inner nuclear membrane protein, emerin, result in several human diseases that include cardiac and skeletal myopathies as well as lipodystrophy. Certain disease-linked A-type lamin defects cause profound changes in nuclear organization such as loss of peripheral heterochromatin and redistribution of other nuclear envelope components. While clearly essential in maintenance of nuclear integrity, the NE is a highly dynamic organelle. In interphase it is constantly remodeled to accommodate nuclear growth. During mitosis it must be completely dispersed so that the condensed chromosomes may gain access to the mitotic spindle. Upon completion of mitosis, dispersed NE components are reutilized in the assembly of nuclei within each daughter cell. These complex NE rearrangements are under precise temporal and spatial control and involve interactions with microtubules, chromatin, and a variety of cell-cycle regulatory molecules.Key words: nuclear envelope, lamin, nuclear pore complex, nuclear membranes, mitosis.
32
Hamada, Masakazu, Anna Haeger, Karthik B. Jeganathan, Janine H. van Ree, Liviu Malureanu, Sarah Wälde, Jomon Joseph, Ralph H. Kehlenbach e Jan M. van Deursen. "Ran-dependent docking of importin-β to RanBP2/Nup358 filaments is essential for protein import and cell viability". Journal of Cell Biology 194, n. 4 (22 agosto 2011): 597–612. http://dx.doi.org/10.1083/jcb.201102018.
Testo completoAbstract (sommario):
RanBP2/Nup358, the major component of the cytoplasmic filaments of the nuclear pore complex (NPC), is essential for mouse embryogenesis and is implicated in both macromolecular transport and mitosis, but its specific molecular functions are unknown. Using RanBP2 conditional knockout mouse embryonic fibroblasts and a series of mutant constructs, we show that transport, rather than mitotic, functions of RanBP2 are required for cell viability. Cre-mediated RanBP2 inactivation caused cell death with defects in M9- and classical nuclear localization signal (cNLS)–mediated protein import, nuclear export signal–mediated protein export, and messenger ribonucleic acid export but no apparent mitotic failure. A short N-terminal RanBP2 fragment harboring the NPC-binding domain, three phenylalanine-glycine motifs, and one Ran-binding domain (RBD) corrected all transport defects and restored viability. Mutation of the RBD within this fragment caused lethality and perturbed binding to Ran guanosine triphosphate (GTP)–importin-β, accumulation of importin-β at nuclear pores, and cNLS-mediated protein import. These data suggest that a critical function of RanBP2 is to capture recycling RanGTP–importin-β complexes at cytoplasmic fibrils to allow for adequate cNLS-mediated cargo import.
33
Lyakhovitch, A. M., A. M. Dorfman e M. A. Shirobokov. "Peculiarities of Formation and Growth of Thin Polymer Plasma-Deposited Films". Solid State Phenomena 99-100 (luglio 2004): 169–74. http://dx.doi.org/10.4028/www.scientific.net/ssp.99-100.169.
Testo completoAbstract (sommario):
Special features of the formation and growth of polymer films, formed on steel under the effect of glow discharge in heptane were studied by means of atomic force microscopy, X-ray photoelectron spectroscopy and contact wetting angle. At low film thickness a thin sticky layer is formed, from which macromolecular cone-shaped formations protrude. With an increase in film thickness the sticky layer disappears and the number of cone-shaped formations increase and they eventually coalesce. As the surface coverage with cones increases the films become thicker and stronger. The cones are assumed to be the film growth sites, which arise during the relaxation of the film’s internal stresses. In addition these growth sites can form under the effect of the stresses from extended defects in the substrate.
34
Rahman, Mohammad Alinoor, Farhana Nasrin, Sonali Bhattacharjee e Saikat Nandi. "Hallmarks of Splicing Defects in Cancer: Clinical Applications in the Era of Personalized Medicine". Cancers 12, n. 6 (28 maggio 2020): 1381. http://dx.doi.org/10.3390/cancers12061381.
Testo completoAbstract (sommario):
Alternative splicing promotes proteome diversity by using limited number of genes, a key control point of gene expression. Splicing is carried out by large macromolecular machineries, called spliceosome, composed of small RNAs and proteins. Alternative splicing is regulated by splicing regulatory cis-elements in RNA and trans-acting splicing factors that are often tightly regulated in a tissue-specific and developmental stage-specific manner. The biogenesis of ribonucleoprotein (RNP) complexes is strictly regulated to ensure that correct complements of RNA and proteins are coordinated in the right cell at the right time to support physiological functions. Any perturbations that impair formation of functional spliceosomes by disrupting the cis-elements, or by compromising RNA-binding or function of trans-factors can be deleterious to cells and result in pathological consequences. The recent discovery of oncogenic mutations in splicing factors, and growing evidence of the perturbed splicing in multiple types of cancer, underscores RNA processing defects as a critical driver of oncogenesis. These findings have resulted in a growing interest in targeting RNA splicing as a therapeutic approach for cancer treatment. This review summarizes our current understanding of splicing alterations in cancer, recent therapeutic efforts targeting splicing defects in cancer, and future potentials to develop novel cancer therapies.
35
Metternich, Justus, Linda Sistemich, Svenja Herbertz e Sebastian Kruss. "A Generic Covalent Functionalization Concept for Near-Infrared Fluorescent Carbon Nanotube Biosensors". ECS Meeting Abstracts MA2023-01, n. 10 (28 agosto 2023): 1216. http://dx.doi.org/10.1149/ma2023-01101216mtgabs.
Testo completoAbstract (sommario):
Biosensors are powerful tools with wide applications in basic research and biomedical diagnostics. In the last decades, the use of nanomaterials decorated with biological recognition units have attracted significant attention and reformed the field. However, this development requires substantial input from the chemical sciences. In this context, semiconducting single-walled carbon nanotubes (SWCNTs) are versatile near infrared (NIR, 870 – 2400 nm) emitting fluorophores. They have been non-covalently modified to create sensors that change their fluorescence when interacting with biomolecules. However, non-covalent chemistry has several disadvantages and prevents a consistent way to signal transduction and rational design. Here, we introduce a widely applicable covalent approach to create molecular sensors without destroying the fluorescence in the NIR. For this purpose, a new class of quantum defects in the SWCNT lattice is used to bind biomolecules and to guarantee colloidal stability. To showcase the potential of this approach we demonstrate sensing for different classes of biomolecular analytes (nucleic acids, proteins as well as macromolecular complexes). We analyze sensitivity and selectivity of this recognition approach and present a straightforward way for the generation of novel sensors. In summary, we introduce a novel quantum defect-based covalent functionalization approach of fluorescent SWCNTs with great potential for biosensing.
36
Read, Randy J., e Airlie J. McCoy. "A log-likelihood-gain intensity target for crystallographic phasing that accounts for experimental error". Acta Crystallographica Section D Structural Biology 72, n. 3 (1 marzo 2016): 375–87. http://dx.doi.org/10.1107/s2059798315013236.
Testo completoAbstract (sommario):
The crystallographic diffraction experiment measures Bragg intensities; crystallographic electron-density maps and other crystallographic calculations in phasing require structure-factor amplitudes. If data were measured with no errors, the structure-factor amplitudes would be trivially proportional to the square roots of the intensities. When the experimental errors are large, and especially when random errors yield negative net intensities, the conversion of intensities and their error estimates into amplitudes and associated error estimates becomes nontrivial. Although this problem has been addressed intermittently in the history of crystallographic phasing, current approaches to accounting for experimental errors in macromolecular crystallography have numerous significant defects. These have been addressed with the formulation of LLGI, a log-likelihood-gain function in terms of the Bragg intensities and their associated experimental error estimates. LLGI has the correct asymptotic behaviour for data with large experimental error, appropriately downweighting these reflections without introducing bias. LLGI abrogates the need for the conversion of intensity data to amplitudes, which is usually performed with the French and Wilson method [French & Wilson (1978),Acta Cryst.A35, 517–525], wherever likelihood target functions are required. It has general applicability for a wide variety of algorithms in macromolecular crystallography, including scaling, characterizing anisotropy and translational noncrystallographic symmetry, detecting outliers, experimental phasing, molecular replacement and refinement. Because it is impossible to reliably recover the original intensity data from amplitudes, it is suggested that crystallographers should always deposit the intensity data in the Protein Data Bank.
37
Davis, R. H., P. Lieu e J. L. Ristow. "Neurospora mutants affecting polyamine-dependent processes and basic amino acid transport mutants resistant to the polyamine inhibitor, alpha-difluoromethylornithine." Genetics 138, n. 3 (1 novembre 1994): 649–55. http://dx.doi.org/10.1093/genetics/138.3.649.
Testo completoAbstract (sommario):
Abstract Polyamines (spermidine and spermine) are required by living cells, but their functions are poorly understood. Mutants of Neurospora crassa with enhanced or diminished sensitivity to interference with polyamine synthesis, originally selected to study the regulation of the pathway, were found to have unexpected defects. A group of four non-allelic mutations, causing no interference with polyamine synthesis, each imparted spermidine auxotrophy to a genotype already partially impaired in spermidine synthesis. Strains carrying only the new mutations displayed unconditional delay or weakness at the onset of growth, but grew well thereafter and had a normal or overly active polyamine pathway. These mutants may have defects in vital macromolecular activities that are especially dependent upon the polyamines-activities that have not been identified with certainty in studies to date. Another group of mutants, selected as resistant to the polyamine inhibitor difluoromethylornithine (DFMO), had normal activity and regulation of ornithine decarboxylase, the target of the drug. All but one of thirty mutants were allelic, and were specifically deficient in the basic amino acid permease. This mechanism of DFMO resistance is unprecedented among the many DFMO-resistant cell types of other organisms and demonstrates that DFMO can be used for efficient genetic studies of this transport locus in N. crassa.
38
Scharf, R. E. "Molecular Basis and Clinical Aspects of Hereditary Megakaryocyte and Platelet Membrane Glycoprotein Disorders". Hämostaseologie 16, n. 02 (aprile 1996): 114–38. http://dx.doi.org/10.1055/s-0038-1656647.
Testo completoAbstract (sommario):
SummarySpecific membrane glycoproteins (GP) expressed by the megakaryocyte-platelet system, including GPIa-lla, GPIb-V-IX, GPIIb-llla, and GPIV are involved in mediat-ing platelet adhesion to the subendothelial matrix. Among these glycoproteins, GPIIb-llla plays a pivotal role since platelet aggregation is exclusively mediated by this receptor and its interaction with soluble macromolecular proteins. Inherited defects of the GPIIb-llla or GPIb-V-IX receptor complexes are associated with bleeding disorders, known as Glanzmann's thrombasthenia, Bernard-Soulier syndrome, or platelet-type von Willebrand's disease, respectively. Using immuno-chemical and molecular biology techniques, rapid advances in our understanding of the molecular genetic basis of these disorders have been made during the last few years. Moreover, analyses of patients with congenital platelet membrane glycoprotein abnormalities have provided valuable insights into molecular mechanisms that are required for structural and functional integrity, normal biosynthesis of the glycoprotein complexes and coordinated membrane expression of their constituents. The present article reviews the current state of knowledge of the major membrane glycoproteins in health and disease. The spectrum of clinical bleeding manifestations and established diagnostic criteria for each of these dis-orders are summarized. In particular, the variety of molecular defects that have been identified so far and their genetic basis will be discussed.
39
Bunnell, Stephen C., Andrew L. Singer, David I. Hong, Berri H. Jacque, Martha S. Jordan, Maria-Cristina Seminario, Valarie A. Barr, Gary A. Koretzky e Lawrence E. Samelson. "Persistence of Cooperatively Stabilized Signaling Clusters Drives T-Cell Activation". Molecular and Cellular Biology 26, n. 19 (1 ottobre 2006): 7155–66. http://dx.doi.org/10.1128/mcb.00507-06.
Testo completoAbstract (sommario):
ABSTRACT Antigen recognition triggers the recruitment of the critical adaptor protein SLP-76 to small macromolecular clusters nucleated by the T-cell receptor (TCR). These structures develop rapidly, in parallel with TCR-induced increases in tyrosine phosphorylation and cytosolic calcium, and are likely to contribute to TCR-proximal signaling. Previously, we demonstrated that these SLP-76-containing clusters segregate from the TCR and move towards the center of the contact interface. Neither the function of these clusters nor the structural requirements governing their persistence have been examined extensively. Here we demonstrate that defects in cluster assembly and persistence are associated with defects in T-cell activation in the absence of Lck, ZAP-70, or LAT. Clusters persist normally in the absence of phospholipase C-γ1, indicating that in the absence of a critical effector, these structures are insufficient to drive T-cell activation. Furthermore, we show that the critical adaptors LAT and Gads localize with SLP-76 in persistent clusters. Mutational analyses of LAT, Gads, and SLP-76 indicated that multiple domains within each of these proteins contribute to cluster persistence. These data indicate that multivalent cooperative interactions stabilize these persistent signaling clusters, which may correspond to the functional complexes predicted by kinetic proofreading models of T-cell activation.
40
Sztretye, Mónika, Beatrix Dienes, Mónika Gönczi, Tamás Czirják, László Csernoch, László Dux, Péter Szentesi e Anikó Keller-Pintér. "Astaxanthin: A Potential Mitochondrial-Targeted Antioxidant Treatment in Diseases and with Aging". Oxidative Medicine and Cellular Longevity 2019 (11 novembre 2019): 1–14. http://dx.doi.org/10.1155/2019/3849692.
Testo completoAbstract (sommario):
Oxidative stress is characterized by an imbalance between prooxidant and antioxidant species, leading to macromolecular damage and disruption of redox signaling and cellular control. It is a hallmark of various diseases including metabolic syndrome, chronic fatigue syndrome, neurodegenerative, cardiovascular, inflammatory, and age-related diseases. Several mitochondrial defects have been considered to contribute to the development of oxidative stress and known as the major mediators of the aging process and subsequent age-associated diseases. Thus, mitochondrial-targeted antioxidants should prevent or slow down these processes and prolong longevity. This is the reason why antioxidant treatments are extensively studied and newer and newer compounds with such an effect appear. Astaxanthin, a xanthophyll carotenoid, is the most abundant carotenoid in marine organisms and is one of the most powerful natural compounds with remarkable antioxidant activity. Here, we summarize its antioxidant targets, effects, and benefits in diseases and with aging.
41
Barón, Máximo. "Definitions of basic terms relating to low-molar-mass and polymer liquid crystals (IUPAC Recommendations 2001)". Pure and Applied Chemistry 73, n. 5 (1 maggio 2001): 845–95. http://dx.doi.org/10.1351/pac200173050845.
Testo completoAbstract (sommario):
This document is the first published by the IUPAC Commission on Macromolecular Nomenclature dealing specifically with liquid crystals. Because of the breadth of its scope, it has been prepared in collaboration with representatives of the International Liquid Crystal Society.The document gives definitions of terms related to low-molar-mass and polymer liquid crystals. It relies on basic definitions of terms that are widely used in the field of liquid crystals and in polymer science. The terms are arranged in five sections dealing with general definitions of liquid-crystalline and mesomorphic states of matter, types of mesophases, optical textures and defects of liquid crystals, the physical characteristics of liquid crystals (including electro-optical and magneto-optical properties), and finally liquid-crystal polymers. The terms that have been selected are those most commonly encountered in the conventional structural, thermal, and electro-optical characterization of liquid-crystalline materials.
42
Hwang, Sunyoung, Paola Cavaliere, Rui Li, Lihua Julie Zhu, Noah Dephoure e Eduardo M. Torres. "Consequences of aneuploidy in human fibroblasts with trisomy 21". Proceedings of the National Academy of Sciences 118, n. 6 (1 febbraio 2021): e2014723118. http://dx.doi.org/10.1073/pnas.2014723118.
Testo completoAbstract (sommario):
An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels were increased by 1.5-fold in all trisomies, with a subset of proteins enriched for subunits of macromolecular complexes showing signs of posttranscriptional regulation. These results support the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes. Furthermore, we show that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.
43
Correll, Carl C., Jiri Bartek e Miroslav Dundr. "The Nucleolus: A Multiphase Condensate Balancing Ribosome Synthesis and Translational Capacity in Health, Aging and Ribosomopathies". Cells 8, n. 8 (10 agosto 2019): 869. http://dx.doi.org/10.3390/cells8080869.
Testo completoAbstract (sommario):
The nucleolus is the largest membrane-less structure in the eukaryotic nucleus. It is involved in the biogenesis of ribosomes, essential macromolecular machines responsible for synthesizing all proteins required by the cell. The assembly of ribosomes is evolutionarily conserved and is the most energy-consuming cellular process needed for cell growth, proliferation, and homeostasis. Despite the significance of this process, the intricate pathophysiological relationship between the nucleolus and protein synthesis has only recently begun to emerge. Here, we provide perspective on new principles governing nucleolar formation and the resulting multiphase organization driven by liquid-liquid phase separation. With recent advances in the structural analysis of ribosome formation, we highlight the current understanding of the step-wise assembly of pre-ribosomal subunits and the quality control required for proper function. Finally, we address how aging affects ribosome genesis and how genetic defects in ribosome formation cause ribosomopathies, complex diseases with a predisposition to cancer.
44
Gupta, Kushol, Ying Wen, Nisha S. Ninan, Amanda C. Raimer, Robert Sharp, Ashlyn M. Spring, Kathryn L. Sarachan, Meghan C. Johnson, Gregory D. Van Duyne e A. Gregory Matera. "Assembly of higher-order SMN oligomers is essential for metazoan viability and requires an exposed structural motif present in the YG zipper dimer". Nucleic Acids Research 49, n. 13 (28 giugno 2021): 7644–64. http://dx.doi.org/10.1093/nar/gkab508.
Testo completoAbstract (sommario):
Abstract Protein oligomerization is one mechanism by which homogenous solutions can separate into distinct liquid phases, enabling assembly of membraneless organelles. Survival Motor Neuron (SMN) is the eponymous component of a large macromolecular complex that chaperones biogenesis of eukaryotic ribonucleoproteins and localizes to distinct membraneless organelles in both the nucleus and cytoplasm. SMN forms the oligomeric core of this complex, and missense mutations within its YG box domain are known to cause Spinal Muscular Atrophy (SMA). The SMN YG box utilizes a unique variant of the glycine zipper motif to form dimers, but the mechanism of higher-order oligomerization remains unknown. Here, we use a combination of molecular genetic, phylogenetic, biophysical, biochemical and computational approaches to show that formation of higher-order SMN oligomers depends on a set of YG box residues that are not involved in dimerization. Mutation of key residues within this new structural motif restricts assembly of SMN to dimers and causes locomotor dysfunction and viability defects in animal models.
45
Rodzen, Krzysztof. "The route to achieve isotropy in 3D printing parts via Fused Filament Fabrication with Advanced Semicrystalline Thermoplastics". MATEC Web of Conferences 401 (2024): 02006. http://dx.doi.org/10.1051/matecconf/202440102006.
Testo completoAbstract (sommario):
This review investigates the challenges of Additive Manufacturing using commodity, engineering, and advanced materials, both amorphous and semicrystalline. It explains the reasons behind the weaker mechanical performance of semicrystalline materials compared to amorphous polymers used in the 3D printing process. The performance of 3D printing is discussed to demonstrate the current position of additive manufacturing as one of the promising techniques meeting the requirements of the 5.0 Industrial Revolution, particularly in terms of delivering personalized products. The differences between amorphous and semicrystalline materials on a macromolecular level, including the strength of the single bond in the polymer backbone chain and the effect of electron donation to the backbone, are discussed. Interlayer imperfections are classified into several groups: moisture in the feedstock filament, inconsistent filament diameter, shrinkage of the deposited materials, and, most importantly, crystallization kinetics of semicrystalline materials. Finally, insights on how to achieve properties closer to an isotropic body when advanced semicrystalline materials are printed, in order to overcome layer-layer defects, are provided.
46
Hosseini, Motahare Sadat, Issa Amjadi e Nooshin Haghighipour. "Preparation of Poly(vinyl alcohol)/Chitosan-Blended Hydrogels: Properties, In Vitro Studies and Kinetic Evaluation". Journal of Biomimetics, Biomaterials and Tissue Engineering 15 (ottobre 2012): 63–72. http://dx.doi.org/10.4028/www.scientific.net/jbbte.15.63.
Testo completoAbstract (sommario):
Articular Cartilage Defects Are a Recent Critical Orthopaedic Issue. Hydrogels Have Been Widely Used in Soft Tissue Engineering Scaffolds as their Structures Are Similar to the Macromolecular-Based Components in the Human Body. Hydrogels Including those Based on Poly(vinyl Alcohol) (PVA) and Chitosan Are of Considerable Interest for Utilization in the Field of Tissue Engineering because of their Appropriate Biocompatibility. PVA Gels Can Be Formed by Chemical or Physical Crosslinking. the “freezing-Thawing” (FT) Process Is the Most Mild, Facile and Effective Method to Produce Physically Crosslinked PVA Gel, because it Does Not Require the Presence of the Crosslinking Agent that May Cause Toxicity. in this Study Hydrogels Based on PVA and Chitosan in Different Blend Ratios Were Prepared, and the Effect of the Freeze-Thaw Cycles and Glutaraldehyde on the Hydrogel Properties Was Investigated. the Results Showed that Freeze-Thaw Cycles Increased the Tensile Strength and the Samples’ Resistance to Degradation. the Biocompatibility of the Hydrogels Was Analysed Using Chondrocyte Cells Separated from Distal Femur of Men. Cell Toxicity Assay Performed for Measurement of Cell Viability of the Samples Indicated Biocompatibility.
47
Fahrenkrog, Birthe. "Nucleoporin Gene Fusions and Hematopoietic Malignancies". New Journal of Science 2014 (27 maggio 2014): 1–18. http://dx.doi.org/10.1155/2014/468306.
Testo completoAbstract (sommario):
Nuclear pore complexes (NPCs) are the sole gateways between the nucleus and the cytoplasm of eukaryotic cells and they mediate all macromolecular trafficking between these cellular compartments. Nucleocytoplasmic transport is highly selective and precisely regulated and as such an important aspect of normal cellular function. Defects in this process or in its machinery have been linked to various human diseases, including cancer. Nucleoporins, which are about 30 proteins that built up NPCs, are critical players in nucleocytoplasmic transport and have also been shown to be key players in numerous other cellular processes, such as cell cycle control and gene expression regulation. This review will focus on the three nucleoporins Nup98, Nup214, and Nup358. Common to them is their significance in nucleocytoplasmic transport, their multiple other functions, and being targets for chromosomal translocations that lead to haematopoietic malignancies, in particular acute myeloid leukaemia. The underlying molecular mechanisms of nucleoporin-associated leukaemias are only poorly understood but share some characteristics and are distinguished by their poor prognosis and therapy outcome.
48
Aitchison, J. D., G. Blobel e M. P. Rout. "Nup120p: a yeast nucleoporin required for NPC distribution and mRNA transport." Journal of Cell Biology 131, n. 6 (15 dicembre 1995): 1659–75. http://dx.doi.org/10.1083/jcb.131.6.1659.
Testo completoAbstract (sommario):
To extend our understanding of the mechanism by which the nuclear pore complex (NPC) mediates macromolecular transport across the nuclear envelope we have focused on defining the composition and molecular organization of the yeast NPC. Peptide sequence analysis of a polypeptide with a M(r) of approximately 100,000 present in a highly enriched yeast NPC fraction identified a novel yeast nucleoporin we term Nup120p. Nup120p corresponds to the open reading frame (ORF) YKL057c identified by the yeast genome sequencing project. The ORF predicts a protein with a calculated molecular mass of 120.5 kD containing two leucine zipper motifs, a short coiled-coil region and limited primary sequence similarity to Nup133p. Nup120p was localized to the NPC using a protein A-tagged chimera in situ by indirect immunofluorescence microscopy. Deletion of the NUP120 gene caused clustering of NPCs at one side of the nuclear envelope, moderate nucleolar fragmentation and slower cell growth. Transfer of nup120 delta cells to 37 degrees C resulted in the nuclear accumulation of poly(A)+ mRNA, extensive fragmentation of the nucleolus, spindle defects, and cell death.
49
Martin, MaryAnn, Shawn M. Ahern-Djamali, F. Michael Hoffmann e William M. Saxton. "Abl Tyrosine Kinase and Its Substrate Ena/VASP Have Functional Interactions with Kinesin-1". Molecular Biology of the Cell 16, n. 9 (settembre 2005): 4225–30. http://dx.doi.org/10.1091/mbc.e05-02-0116.
Testo completoAbstract (sommario):
Relatively little is known about how microtubule motors are controlled or about how the functions of different cytoskeletal systems are integrated. A yeast two-hybrid screen for proteins that bind to Drosophila Enabled (Ena), an actin polymerization factor that is negatively regulated by Abl tyrosine kinase, identified kinesin heavy chain (Khc), a member of the kinesin-1 subfamily of microtubule motors. Coimmunoprecipitation from Drosophila cytosol confirmed a physical interaction between Khc and Ena. Kinesin-1 motors can carry organelles and other macromolecular cargoes from neuronal cell bodies toward terminals in fast-axonal-transport. Ena distribution in larval axons was not affected by mutations in the Khc gene, suggesting that Ena is not itself a fast transport cargo of Drosophila kinesin-1. Genetic interaction tests showed that in a background sensitized by reduced Khc gene dosage, a reduction in Abl gene dosage caused distal paralysis and axonal swellings. A concomitant reduction in ena dosage rescued those defects. These results suggest that Ena/VASP, when not inhibited by the Abl pathway, can bind Khc and reduce its transport activity in axons.
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Dermody, J. J., B. E. Wojcik, H. Du e H. L. Ozer. "Identification of temperature-sensitive DNA- mutants of Chinese hamster cells affected in cellular and viral DNA synthesis". Molecular and Cellular Biology 6, n. 12 (dicembre 1986): 4594–601. http://dx.doi.org/10.1128/mcb.6.12.4594-4601.1986.
Testo completoAbstract (sommario):
We described a strategy which facilitates the identification of cell mutants which are restricted in DNA synthesis in a temperature-dependent manner. A collection of over 200 cell mutants temperature-sensitive for growth was isolated in established Chinese hamster cell lines (CHO and V79) by a variety of selective and nonselective techniques. Approximately 10% of these mutants were identified as ts DNA- based on differential inhibition of macromolecular synthesis at the restrictive temperature (39 degrees C) as assessed by incorporation of [3H]thymidine and [35S]methionine. Nine such mutants, selected for further study, demonstrated rapid shutoff of DNA replication at 39 degrees C. Infections with two classes of DNA viruses extensively dependent on host-cell functions for their replication were used to distinguish defects in DNA synthesis itself from those predominantly affecting other aspects of DNA replication. All cell mutants supported human adenovirus type 2 (Ad2) and mouse polyomavirus DNA synthesis at the permissive temperature. Five of the nine mutants (JB3-B, JB3-O, JB7-K, JB8-D, and JB11-J) restricted polyomavirus DNA replication upon transfection with viral sequences at 33 degrees C and subsequent shift to 39 degrees C either before or after the onset of viral DNA synthesis. Only one of these mutants (JB3-B) also restricted Ad2 DNA synthesis after virion infection under comparable conditions. No mutant was both restrictive for Ad2 and permissive for polyomavirus DNA synthesis at 39 degrees C. The differential effect of these cell mutants on viral DNA synthesis is expected to assist subsequent definition of the biochemical defect responsible.