Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects ...are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects.
Negative thermal expansion (NTE) is the phenomenon in which materials shrink rather than expand on heating. Although NTE had been previously observed in a few simple materials at low temperature, it ...was the realisation in 1996 that some materials have NTE over very wide ranges of temperature that kick-started current interest in this phenomenon. Now, nearly two decades later, a number of families of ceramic NTE materials have been identified. Increasingly quantitative studies focus on the mechanism of NTE, through techniques such as high-pressure diffraction, local structure probes, inelastic neutron scattering and atomistic simulation. In this paper we review our understanding of vibrational mechanisms of NTE for a range of materials. We identify a number of different cases, some of which involve a small number of phonons that can be described as involving rotations of rigid polyhedral groups of atoms, others where there are large bands of phonons involved, and some where the transverse acoustic modes provide the main contribution to NTE. In a few cases the elasticity of NTE materials has been studied under pressure, identifying an elastic softening under pressure. We propose that this property, called pressure-induced softening, is closely linked to NTE, which we can demonstrate using a simple model to describe NTE materials. There has also been recent interest in the role of intrinsic anharmonic interactions on NTE, particularly guided by calculations of the potential energy wells for relevant phonons. We review these effects, and show how anhamonicity affects the response of the properties of NTE materials to pressure.
Nonribosomal peptide synthetases (NRPSs) are incredible macromolecular machines that produce a wide range of biologically- and therapeutically-relevant molecules. During synthesis, peptide elongation ...is performed by the condensation (C) domain, as it catalyzes amide bond formation between the nascent peptide and the amino acid it adds to the chain. Since their discovery more than two decades ago, C domains have been subject to extensive biochemical, bioinformatic, mutagenic, and structural analyses. They are composed of two lobes, each with homology to chloramphenicol acetyltransferase, have two binding sites for their two peptidyl carrier protein-bound ligands, and have an active site with conserved motif HHxxxDG located between the two lobes. This review discusses some of the important insights into the structure, catalytic mechanism, specificity, and gatekeeping functions of C domains revealed since their discovery. In addition, C domains are the archetypal members of the C domain superfamily, which includes several other members that also function as NRPS domains. The other family members can replace the C domain in NRP synthesis, can work in concert with a C domain, or can fulfill diverse and novel functions. These domains include the epimerization (E) domain, the heterocyclization (Cy) domain, the ester-bond forming C domain, the fungal NRPS terminal C domain (CT), the β-lactam ring forming C domain, and the X domain. We also discuss structural and function insight into C, E, Cy, CT and X domains, to present a holistic overview of historical and current knowledge of the C domain superfamily. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman.
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•Condensation (C) domains catalyze amide bond formation in NRPSs.•C domains have been subject to extensive biochemical and structural analyses.•We review chemical mechanism, specificity, conformational flexibility, and interactions.•C superfamily domains perform several substantially different reactions or functions.
We describe Bioconductor infrastructure for representing and computing on annotated genomic ranges and integrating genomic data with the statistical computing features of R and its extensions. At the ...core of the infrastructure are three packages: IRanges, GenomicRanges, and GenomicFeatures. These packages provide scalable data structures for representing annotated ranges on the genome, with special support for transcript structures, read alignments and coverage vectors. Computational facilities include efficient algorithms for overlap and nearest neighbor detection, coverage calculation and other range operations. This infrastructure directly supports more than 80 other Bioconductor packages, including those for sequence analysis, differential expression analysis and visualization.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bone remodeling is essential for the repair and replacement of damaged and old bone. The major principle underlying this process is that osteoclast-mediated resorption of a quantum of bone is ...followed by osteoblast precursor recruitment; these cells differentiate to matrix-producing osteoblasts, which form new bone to replace what was resorbed. Evidence from osteopetrotic syndromes indicate that osteoclasts not only resorb bone, but also provide signals to promote bone formation. Osteoclasts act upon osteoblast lineage cells throughout their differentiation by facilitating growth factor release from resorbed matrix, producing secreted proteins and microvesicles, and expressing membrane-bound factors. These multiple mechanisms mediate the coupling of bone formation to resorption in remodeling. Additional interactions of osteoclasts with osteoblast lineage cells, including interactions with canopy and reversal cells, are required to achieve coordination between bone formation and resorption during bone remodeling.
Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of ...osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.
•Novel ORC system operating with two-phase expansion and radial-inflow turbine.•Single- and multi-objective cycle optimisation for 150, 200 and 250 °C heat sources.•MM and MDM are optimal fluids ...producing up to 28% more power than single-phase ORC.•Mean-line turbine optimisation completed for two-phase radial-inflow turbine.•Feasible subsonic rotor geometries obtained, and candidate turbines designs proposed.
Previous investigations suggest the power output from waste-heat recovery organic Rankine cycle (ORC) systems could be enhanced by up to 30% by operating with two-phase expansion, which could reduce cost and aid in the more widespread deployment of ORC technology. However, there are limited expander technologies suitable for such operation. The aim of this research is to investigate a novel ORC system that operates with wet-to-dry expansion permitting the use of a radial-inflow turbine. Specifically, through the exploitation of molecularly complex fluids the wet-to-dry expansion could be achieved across a single turbine stage, whilst the two-phase region is confined to the stator vane. Thermodynamic system optimisation is completed for potential fluids in which the degree of reaction is used to differentiate between the stator and rotor expansion processes. The results reveal that siloxanes are optimal fluids, and that for heat-source temperatures of 150, 200 and 250 °C the two-phase systems could generate up to 28%, 14% and 3% more power than single-phase systems, respectively. Following this, existing mean-line turbine methods are extended to two-phase turbines under the assumption of a two-phase homogeneous fluid under thermal equilibrium, which is supported with numerical simulations of a two-phase stator vane. The mean-line turbine optimisation for the 200 °C heat source is then conducted, with the optimal system corresponding to a turbine inlet vapour quality of 0.1 and degree of reaction of 0.4, with lower reaction leading to lower turbine efficiencies. More generally, feasible rotor geometries can be obtained, and conditions with the rotor are expected to remain subsonic. Whilst stator outlet Mach numbers range between 1.5 and 2.1, and stator throat widths below 1 mm are required, the CFD simulations indicate that wet-to-dry expansion can be successfully realised within the stator. In summary, these results provide the first positive demonstration that a 30% improvement in power output could be achieved with a two-phase ORC system operating with molecularly complex working fluids and a radial-inflow turbine.
Nonribosomal peptide synthetases (NRPSs) are very large proteins that produce small peptide molecules with wide-ranging biological activities, including environmentally friendly chemicals and many ...widely used therapeutics. NRPSs are macromolecular machines, with modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. In addition to the core domains required to link the substrates, they often include specialized tailoring domains, which introduce chemical modifications and allow the product to access a large expanse of chemical space. It is still unknown how the NRPS tailoring domains are structurally accommodated into megaenzymes or how they have adapted to function in nonribosomal peptide synthesis. Here we present a series of crystal structures of the initiation module of an antibiotic-producing NRPS, linear gramicidin synthetase. This module includes the specialized tailoring formylation domain, and states are captured that represent every major step of the assembly-line synthesis in the initiation module. The transitions between conformations are large in scale, with both the peptidyl carrier protein domain and the adenylation subdomain undergoing huge movements to transport substrate between distal active sites. The structures highlight the great versatility of NRPSs, as small domains repurpose and recycle their limited interfaces to interact with their various binding partners. Understanding tailoring domains is important if NRPSs are to be utilized in the production of novel therapeutics.
Nonribosomal peptide synthetases (NRPSs) are biosynthetic enzymes that synthesize natural product therapeutics using a modular synthetic logic, whereby each module adds one aminoacyl substrate to the ...nascent peptide. We have determined five x-ray crystal structures of large constructs of the NRPS linear gramicidin synthetase, including a structure of a full core dimodule in conformations organized for the condensation reaction and intermodular peptidyl substrate delivery. The structures reveal differences in the relative positions of adjacent modules, which are not strictly coupled to the catalytic cycle and are consistent with small-angle x-ray scattering data. The structures and covariation analysis of homologs allowed us to create mutants that improve the yield of a peptide from a module-swapped dimodular NRPS.
The Rigid Unit Mode model was initially developed to understand the origin of displacive phase transitions in network silicate structures. Here, we review the successes of the model, and consider how ...it might apply to a wider range of network structures. This article is part of the theme issue 'Mineralomimesis: natural and synthetic frameworks in science and technology'.
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