2,069 research outputs found
Doctor of Philosophy
dissertationComputer simulations of biomolecules can provide insight into biological structure and dynamics at the atomic level. For simulations to be accurate and reliable, the underlying force eld that describes that system has to tested and assessed against experimental values. Evaluating the latest AMBER nucleic acids force elds at microsecond time scales is important for determining how updated force eld parameter sets compare to earlier models and updated, competing models. The latest two improvements to the AMBER nucleic acid force eld were compared to each other and previous, widely used versions. Both of the latest versions, bsc1 and OL15, showed improvement over earlier versions and reproduced many structural properties in agreement with nuclear magnetic resonance (NMR) and X-ray crystallography experiments. Having a force eld that accurately models duplex DNA is important, but it is also necessary to validate protein-nucleic acid simulations. To examine this, the E2-DNA system was chosen for simulations to see if DNA backbone substates observed in the X-ray structure were reproducible in simulations. In particular, the BI/BII substates were scrutinized. The BI substate is dominant in duplex DNA but and dihedrals populate both trans/gauche- (t/g-) and gauche-/trans (g-/t) conformations, the latter being the BII state. It was determined that dinucleotide steps crystallized in the BII were correspondingly highly-populated in simulations. Additionally, and dihedrals were manipulated to decoy states and found to converge to native distributions on the microsecond time scale in E2-bound DNA, and in less time for free DNA. During the investigation of BII substates in E2-DNA, the surprising observation was made that BI/BII transitions are dominant modes of motion in E2-bound DNA. This inspired research into whether these modes are sequence-dependent or completely induced by the E2 protein, and if the dynamics are conserved across E2 types. Simulations of E2-DNA found that the BII state is determined by a combination of DNA sequence and E2 binding partner
Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration
Regenerative medicine strategies for restoring articular cartilage face significant challenges to recreate the complex and dynamic biochemical and biomechanical functions of native tissues. As an approach to recapitulate the complexity of the extracellular matrix, collagen-mimetic proteins offer a modular template to incorporate bioactive and biodegradable moieties into a single construct. We modified a Streptococcal collagen-like 2 protein with hyaluronic acid (HA) or chondroitin sulfate (CS)-binding peptides and then cross-linked with a matrix metalloproteinase 7 (MMP7)-sensitive peptide to form biodegradable hydrogels. Human mesenchymal stem cells (hMSCs) encapsulated in these hydrogels exhibited improved viability and significantly enhanced chondrogenic differentiation compared to controls that were not functionalized with glycosaminoglycan-binding peptides. Hydrogels functionalized with CS-binding peptides also led to significantly higher MMP7 gene expression and activity while the HA-binding peptides significantly increased chondrogenic differentiation of the hMSCs. Our results highlight the potential of this novel biomaterial to modulate cell-mediated processes and create functional tissue engineered constructs for regenerative medicine applications
Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency
Although most components of the mitochondrial translation apparatus are encoded by nuclear genes, all known molecular defects associated with impaired mitochondrial translation are due to mutations in mitochondrial DNA. We investigated two siblings with a severe defect in mitochondrial translation, reduced levels of oxidative phosphorylation complexes containing mitochondrial DNA (mtDNA)–encoded subunits, and progressive hepatoencephalopathy. We mapped the defective gene to a region on chromosome 3q containing elongation factor G1 (EFG1), which encodes a mitochondrial translation factor. Sequencing of EFG1 revealed a mutation affecting a conserved residue of the guanosine triphosphate (GTP)–binding domain. These results define a new class of gene defects underlying disorders of oxidative phosphorylation
Context-dependent parasite infection affects trophic niche in populations of sympatric stickleback species
Glucose enhancement of memory is modulated by trait anxiety in healthy adolescent males
Glucose administration is associated with memory enhancement in healthy young individuals under conditions of divided attention at encoding. While the specific neurocognitive mechanisms underlying this ‘glucose memory facilitation effect’ are currently uncertain, it is thought that individual differences in glucoregulatory efficiency may alter an individual’s sensitivity to the glucose memory facilitation effect. In the present study, we sought to investigate whether basal hypothalamic–pituitary–adrenal axis function (itself a modulator of glucoregulatory efficiency), baseline self-reported stress and trait anxiety influence the glucose memory facilitation effect. Adolescent males (age range = 14–17 years) were administered glucose and placebo prior to completing a verbal episodic memory task on two separate testing days in a counter-balanced, within-subjects design. Glucose ingestion improved verbal episodic memory performance when memory recall was tested (i) within an hour of glucose ingestion and encoding, and (ii) one week subsequent to glucose ingestion and encoding. Basal hypothalamic–pituitary–adrenal axis function did not appear to influence the glucose memory facilitation effect; however, glucose ingestion only improved memory in participants reporting relatively higher trait anxiety. These findings suggest that the glucose memory facilitation effect may be mediated by biological mechanisms associated with trait anxiety
Characterization of perfluorocarbon relaxation times and their influence on the optimization of fluorine-19 MRI at 3 tesla.
To characterize and optimize javax.xml.bind.JAXBElement@7524a985 F MRI for different perfluorocarbons (PFCs) at 3T and quantify the loss of acquisition efficiency as a function of different temperature and cellular conditions.
The T javax.xml.bind.JAXBElement@1ef4ca84 and T javax.xml.bind.JAXBElement@295b7e6f relaxation times of the commonly used PFCs perfluoropolyether (PFPE), perfluoro-15-crown-5-ether (PFCE), and perfluorooctyl bromide (PFOB) were measured in phantoms and in several different conditions (cell types, presence of fixation agent, and temperatures). These relaxation times were used to optimize pulse sequences through numerical simulations. The acquisition efficiency in each cellular condition was then determined as the ratio of the signal after optimization with the reference relaxation times and after optimization with its proper relaxation times. Finally, PFC detection limits were determined.
The loss of acquisition efficiency due to parameter settings optimized for the wrong temperature and cellular condition was limited to 13%. The detection limits of all PFCs were lower at 24 °C than at 37 °C and varied from 11.8 ± 3.0 mM for PFCE at 24 °C to 379.9 ± 51.8 mM for PFOB at 37 °C.
Optimizing javax.xml.bind.JAXBElement@30187e57 F pulse sequences with a known phantom only leads to moderate loss in acquisition efficiency in cellular conditions that might be encountered in in vivo and in vitro experiments. Magn Reson Med 77:2263-2271, 2017. © 2016 International Society for Magnetic Resonance in Medicine
Hypoglycaemia symptom frequency, severity, burden, and utility among adults with type 1 diabetes and impaired awareness of hypoglycaemia: Baseline and 24-week findings from the HypoCOMPaSS study
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Emergent order in the kagome Ising magnet DyMgSbO
The Ising model-in which degrees of freedom (spins) are binary valued (up/down)-is a cornerstone of statistical physics that shows rich behaviour when spins occupy a highly frustrated lattice such as kagome. Here we show that the layered Ising magnet DyMgSbO hosts an emergent order predicted theoretically for individual kagome layers of in-plane Ising spins. Neutron-scattering and bulk thermomagnetic measurements reveal a phase transition at ~0.3 K from a disordered spin-ice-like regime to an emergent charge ordered state, in which emergent magnetic charge degrees of freedom exhibit three-dimensional order while spins remain partially disordered. Monte Carlo simulations show that an interplay of inter-layer interactions, spin canting and chemical disorder stabilizes this state. Our results establish DyMgSbO as a tuneable system to study interacting emergent charges arising from kagome Ising frustration.Work at Cambridge was supported through the Winton Programme for the Physics of Sustainability. The work of J.A.M.P., X.B. and M.M. and facilities at Georgia Tech were supported by the College of Sciences through M.M. start-up funds. J.A.M.P. gratefully acknowledges Churchill College, Cambridge for the provision of a Junior Research Fellowship. H.S.O. acknowledges a Teaching Scholarship (Overseas) from the Ministry of Education, Singapore. J.O.H. is grateful to the Engineering and Physical Sciences Research Council (EPSRC) for funding. C.C. was supported by EPSRC Grant No. EP/G049394/1, and the EPSRC NetworkPlus on ‘Emergence and Physics far from Equilibrium’. Experiments at the ISIS Pulsed Neutron and Muon Source were supported by a beamtime allocation from the Science and Technology Facilities Council. This work utilized facilities at the NIST Center for Neutron Research. Monte Carlo simulations were performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/) and the ARCHER UK National Supercomputing Service (http://www.archer.ac.uk/, for which access was provided by an ARCHER Instant Access scheme)
Pseudotumours, cobalt and clinical outcome in small head metal-on-metal versus conventional metal-on-polyethylene total hip arthroplasty
Background: Metal-on-metal total hip arthroplasty (MoM THA) is associated with the formation of pseudotumours. Studies mainly concern pseudotumour formation in large head MoM THA. We performed a long-term follow-up study, comparing pseudotumour incidence in small head metal-on-metal (SHMoM) THA with conventional metal-on-polyethylene (MoP) THA. Predisposing factors to pseudotumour formation were assessed. Methods: From a previous randomised controlled trial comparing SHMoM (28 mm) cemented THA with conventional MoP cemented THA, patients were screened using a standardised CT protocol for the presence of pseudotumours. Serum cobalt levels and functional outcome were assessed. Results: 56 patients (33 MoP and 23 MoM) were recruited after mean follow-up of 13.4 years (SD 0.5). The incidence of pseudotumours was 1 (5%) in the SHMoM THA cohort and 3 (9%) in the MoP THA cohort. Prosthesis survival was 96% for both SHMoM and MoP THAs. Serum cobalt levels did not exceed acceptable clinical values (<5 µg/L) whereas no differences in cobalt levels were detected at follow-up between both groups. Oxford and Harris Hip Scores were good and did not differ between SHMoM and MoP THA. Conclusions: This long-term follow-up study shows a low incidence of pseudotumour formation and good functional outcome in cemented head-taper matched SHMoM and MoP THA
Type-and-Scope Safe Programs and Their Proofs
We abstract the common type-and-scope safe structure fromcomputations on lambda-terms that deliver, e.g., renaming, substitution, evaluation, CPS-transformation, and printing witha name supply. By exposing this structure, we can prove generic simulation and fusion lemmas relating operations built this way. This work has been fully formalised in Agda
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