638 research outputs found
Smoluchowski dynamics and the ergodic-nonergodic transition
We use the recently introduced theory for the kinetics of systems of
classical particles to investigate systems driven by Smoluchowski dynamics. We
investigate the existence of ergodic-nonergodic (ENE) transitions near the
liquid-glass transition. We develop a self-consistent perturbation theory in
terms of an effective two-body potential. We work to second order in this
potential. At second order we have an explicit relationship between the static
structure factor and the effective potential. We choose the static structure
factor in the case of hard spheres to be given by the solution of the
Percus-Yevick approximation for hard spheres. Then using the analytically
determined ENE equation for the ergodicity function we find an ENE transition
for packing fraction, eta, greater than a critical value eta*=0.76 which is
physically unaccessible. The existence of a linear fluctuation-dissipation
theorem in the problem is shown and used to great advantage.Comment: 51 pages, 6 figure
Advanced cryo-tomography workflow developments - correlative microscopy, milling automation and cryo-lift-out
Cryo-electron tomography (cryo-ET) is a groundbreaking technology for 3D visualisation and analysis of biomolecules in the context of cellular structures. It allows structural investigations of single proteins as well as their spatial arrangements within the cell. Cryo-tomograms provide a snapshot of the complex, heterogeneous and transient subcellular environment. Due to the excellent structure preservation in amorphous ice, it is possible to study interactions and spatial relationships of proteins in their native state without interference caused by chemical fixatives or contrasting agents. With the introduction of focused ion beam (FIB) technology, the preparation of cellular samples for electron tomography has become much easier and faster. The latest generation of integrated FIB and scanning electron microscopy (SEM) instruments (dual beam microscopes), specifically designed for cryo-applications, provides advances in automation, imaging and the preparation of high-pressure frozen bulk samples using cryo-lift-out technology. In addition, correlative cryo-fluorescence microscopy provides cellular targeting information through integrated software and hardware interfaces. The rapid advances, based on the combination of correlative cryo-microscopy, cryo-FIB and cryo-ET, have already led to a wealth of new insights into cellular processes and provided new 3D image data of the cell. Here we introduce our recent developments within the cryo-tomography workflow, and we discuss the challenges that lie ahead. Lay Description This article describes our recent developments for the cryo-electron tomography (cryo-ET) workflow. Cryo-ET offers superior structural preservation and provides 3D snapshots of the interior of vitrified cells at molecular resolution. Before a cellular sample can be imaged by cryo-ET, it must be made accessible for transmission electron microscopy. This is achieved by preparing a 200-300 nm thin cryo-lamella from the cellular sample using a cryo-focused ion beam (cryo-FIB) microscope. Cryo-correlative light and electron microscopy (cryo-CLEM) is used within the workflow to guide the cryo-lamella preparation to the cellular areas of interest. We cover a basic introduction of the cryo-ET workflow and show new developments for cryo-CLEM, which facilitate the connection between the cryo-light microscope and the cryo-FIB. Next, we present our progress in cryo-FIB software automation to streamline cryo-lamella preparation. In the final section we demonstrate how the cryo-FIB can be used for 3D imaging and how bulk-frozen cellular samples (obtained by high-pressure freezing) can be processed using the newly developed cryo-lift-out technology
Dilatancy, Jamming, and the Physics of Granulation
Granulation is a process whereby a dense colloidal suspension is converted
into pasty granules (surrounded by air) by application of shear. Central to the
stability of the granules is the capillary force arising from the interfacial
tension between solvent and air. This force appears capable of maintaining a
solvent granule in a jammed solid state, under conditions where the same amount
of solvent and colloid could also exist as a flowable droplet. We argue that in
the early stages of granulation the physics of dilatancy, which requires that a
powder expand on shearing, is converted by capillary forces into the physics of
arrest. Using a schematic model of colloidal arrest under stress, we speculate
upon various jamming and granulation scenarios. Some preliminary experimental
results on aspects of granulation in hard-sphere colloidal suspensions are also
reported.Comment: Original article intended for J Phys Cond Mat special issue on
Granular Materials (M Nicodemi, Ed.
Age-dependent impairment of the erythropoietin response to reduced central venous pressure in HFpEF patients
Despite growing research interest in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), it remains unknown whether central hemodynamic alterations inherently present in this condition do affect blood pressure and blood volume (BV) regulation. The present study sought to determine hemodynamic and endocrine responses to prolonged orthostatic stress in HFpEF patients. Central venous pressure (CVP) assessed via the internal jugular vein (IJV) aspect ratio with ultrasonography, arterial pressure and heart rate were determined at supine rest and during 2 hours of moderate (25-30°) head-up tilt (HUT) in 18 stable HFpEF patients (71.2 ± 7.3 years), 14 elderly (EC), and 10 young (YC) healthy controls. Parallel endocrine measurements comprised main BV-regulating hormones: pro-atrial natriuretic peptide, copeptin, aldosterone, and erythropoietin (EPO). At supine rest, the IJV aspect ratio was higher (>30%) in HFpEF patients compared with EC and YC, while mean arterial pressure was elevated in HFpEF patients (98.0 ± 13.1 mm Hg) and EC (95.6 ± 8.3 mm Hg) versus YC (87.3 ± 5.0 mm Hg) (P < 0.05). HUT increased heart rate (+10%) and reduced the IJV aspect ratio (-52%), with similar hemodynamic effects in all groups (P for interaction ≥ 0.322). The analysis of endocrine responses to HUT revealed a group×time interaction for circulating EPO, which was increased in YC (+10%) but remained unaltered in HFpEF patients and EC. The EPO response to a given reduction in CVP is similarly impaired in HFpEF patients and elderly controls, suggesting an age-dependent dissociation of EPO production from hemodynamic regulation in the HFpEF condition
The Potential Energy Landscape and Mechanisms of Diffusion in Liquids
The mechanism of diffusion in supercooled liquids is investigated from the
potential energy landscape point of view, with emphasis on the crossover from
high- to low-T dynamics. Molecular dynamics simulations with a time dependent
mapping to the associated local mininum or inherent structure (IS) are
performed on unit-density Lennard-Jones (LJ). New dynamical quantities
introduced include r2_{is}(t), the mean-square displacement (MSD) within a
basin of attraction of an IS, R2(t), the MSD of the IS itself, and g_{loc}(t)
the mean waiting time in a cooperative region. At intermediate T, r2_{is}(t)
posesses an interval of linear t-dependence allowing calculation of an
intrabasin diffusion constant D_{is}. Near T_{c} diffusion is intrabasin
dominated with D = D_{is}. Below T_{c} the local waiting time tau_{loc} exceeds
the time, tau_{pl}, needed for the system to explore the basin, indicating the
action of barriers. The distinction between motion among the IS below T_{c} and
saddle, or border dynamics above T_{c} is discussed.Comment: submitted to pr
Performance of the first prototype of the CALICE scintillator strip electromagnetic calorimeter
A first prototype of a scintillator strip-based electromagnetic calorimeter
was built, consisting of 26 layers of tungsten absorber plates interleaved with
planes of 45x10x3 mm3 plastic scintillator strips. Data were collected using a
positron test beam at DESY with momenta between 1 and 6 GeV/c. The prototype's
performance is presented in terms of the linearity and resolution of the energy
measurement. These results represent an important milestone in the development
of highly granular calorimeters using scintillator strip technology. This
technology is being developed for a future linear collider experiment, aiming
at the precise measurement of jet energies using particle flow techniques
Structural model of FeoB, the iron transporter from Pseudomonas aeruginosa, predicts a cysteine lined, GTP-gated pore.
Iron is essential for the survival and virulence of pathogenic bacteria. The FeoB transporter allows the bacterial cell to acquire ferrous iron from its environment, making it an excellent drug target in intractable pathogens. The protein consists of an N-terminal GTP-binding domain and a C-terminal membrane domain. Despite the availability of X-ray crystal structures of the N-terminal domain, many aspects of the structure and function of FeoB remain unclear, such as the structure of the membrane domain, the oligomeric state of the protein, the molecular mechanism of iron transport, and how this is coupled to GTP hydrolysis at the N-terminal domain. In the present study, we describe the first homology model of FeoB. Due to the lack of sequence homology between FeoB and other transporters, the structures of four different proteins were used as templates to generate the homology model of full-length FeoB, which predicts a trimeric structure. We confirmed this trimeric structure by both blue-native-PAGE (BN-PAGE) and AFM. According to our model, the membrane domain of the trimeric protein forms a central pore lined by highly conserved cysteine residues. This pore aligns with a central pore in the N-terminal GTPase domain (G-domain) lined by aspartate residues. Biochemical analysis of FeoB from Pseudomonas aeruginosa further reveals a putative iron sensor domain that could connect GTP binding/hydrolysis to the opening of the pore. These results indicate that FeoB might not act as a transporter, but rather as a GTP-gated channel.This work was supported by the Wellcome Trust [grant number 089125/Z/09/Z (to T.A.G. and J.M.E.)]; the grants [Fondecyt 1120169, DPI-Conicyt 20140080, Anillo ACT-1108 and ICM-P10-035F (to N.P.B. and N.A.F.)]; the University of South Australia and the Sansom Institute for Health Research (to H.V.); and the BBSRC scholarship [grant number F017464/1 (to S.S.)]
An atlas of O-linked glycosylation on peptide hormones reveals diverse biological roles
Peptide hormones and neuropeptides encompass a large class of bioactive peptides that regulate physiological processes like anxiety, blood glucose, appetite, inflammation and blood pressure. Here, we execute a focused discovery strategy to provide an extensive map of O-glycans on peptide hormones. We find that almost one third of the 279 classified peptide hormones carry O-glycans. Many of the identified O-glycosites are conserved and are predicted to serve roles in proprotein processing, receptor interaction, biodistribution and biostability. We demonstrate that O-glycans positioned within the receptor binding motifs of members of the neuropeptide Y and glucagon families modulate receptor activation properties and substantially extend peptide half-lives. Our study highlights the importance of O-glycosylation in the biology of peptide hormones, and our map of O-glycosites in this large class of biomolecules serves as a discovery platform for an important class of molecules with potential opportunities for drug designs. O-glycosylation is an abundant post-translational modification but its relevance for bioactive peptides is unclear. Here, the authors detect O-glycans on almost one third of the classified peptide hormones and show that O-glycosylation can modulate peptide half-lives and receptor activation properties.This work was supported by the Novo Nordisk Foundation, the Lundbeck Foundation, Danish National Research Foundation Grant DNRF107
Violation of the fluctuation-dissipation theorem in glassy systems: basic notions and the numerical evidence
This review reports on the research done during the past years on violations
of the fluctuation-dissipation theorem (FDT) in glassy systems. It is focused
on the existence of a quasi-fluctuation-dissipation theorem (QFDT) in glassy
systems and the currently supporting knowledge gained from numerical simulation
studies. It covers a broad range of non-stationary aging and stationary driven
systems such as structural-glasses, spin-glasses, coarsening systems,
ferromagnetic models at criticality, trap models, models with entropy barriers,
kinetically constrained models, sheared systems and granular media. The review
is divided into four main parts: 1) An introductory section explaining basic
notions related to the existence of the FDT in equilibrium and its possible
extension to the glassy regime (QFDT), 2) A description of the basic analytical
tools and results derived in the framework of some exactly solvable models, 3)
A detailed report of the current evidence in favour of the QFDT and 4) A brief
digression on the experimental evidence in its favour. This review is intended
for inexpert readers who want to learn about the basic notions and concepts
related to the existence of the QFDT as well as for the more expert readers who
may be interested in more specific results.Comment: 120 pages, 37 figures. Topical review paper . Several typos and
misprints corrected, new references included and others updated. to be
published in J. Phys. A (Math. Gen.
Multi-centre analysis of incidental findings on low-resolution CT attenuation correction images
Objective: To review new incidental findings detected on
low-resolution CT attenuation correction (CTAC) images acquired
during single-photon emission CT (SPECT-CT) myocardial
perfusion imaging (MPI) and to determine whether
the CTAC images had diagnostic value and warrant reporting.
Methods: A multicentre study was performed in four UK
nuclear medicine departments. CTAC images acquired
as part of MPI performed using SPECT were evaluated to
identify incidental findings. New findings considered to
be clinically significant were evaluated further. Positive
predictive value (PPV) was determined at the time of
definitive diagnosis.
Results: Of 1819 patients studied, 497 (27.3%) had a
positive CTAC finding. 51 (2.8%) patients had findings
that were clinically significant at the time of the CTAC
report and had not been previously diagnosed. Only
four (0.2%) of these were potentially detrimental to
patient outcome.
Conclusion: One centre had a PPV of 0%, and the study
suggests that these CTAC images should not be reported.
Two centres with more modern equipment had low
PPVs of 0% and 6%, respectively, and further research is
suggested prior to drawing a conclusion. The centre with
best quality CT had a PPV of 67%, and the study suggests
that CTAC images from this equipment should be reported.
Advances in knowledge: This study is unique compared
with previous studies that have reported only the potential
to identify incidental findings on low-resolution CT images.
This study both identifies and evaluates new clinically
significant incidental findings, and it demonstrates that
the benefit of reporting the CTAC images depends on
the type of equipment used
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