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1.
Science ; 383(6690): 1499-1504, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38547284

ABSTRACT

Methane emissions from solid waste may represent a substantial fraction of the global anthropogenic budget, but few comprehensive studies exist to assess inventory assumptions. We quantified emissions at hundreds of large landfills across 18 states in the United States between 2016 and 2022 using airborne imaging spectrometers. Spanning 20% of open United States landfills, this represents the most systematic measurement-based study of methane point sources of the waste sector. We detected significant point source emissions at a majority (52%) of these sites, many with emissions persisting over multiple revisits (weeks to years). We compared these against independent contemporaneous in situ airborne observations at 15 landfills and established good agreement. Our findings indicate a need for long-term, synoptic-scale monitoring of landfill emissions in the context of climate change mitigation policy.

2.
Sci Adv ; 9(46): eadh2391, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-37976355

ABSTRACT

Carbon dioxide and methane emissions are the two primary anthropogenic climate-forcing agents and an important source of uncertainty in the global carbon budget. Uncertainties are further magnified when emissions occur at fine spatial scales (<1 km), making attribution challenging. We present the first observations from NASA's Earth Surface Mineral Dust Source Investigation (EMIT) imaging spectrometer showing quantification and attribution of fine-scale methane (0.3 to 73 tonnes CH4 hour-1) and carbon dioxide sources (1571 to 3511 tonnes CO2 hour-1) spanning the oil and gas, waste, and energy sectors. For selected countries observed during the first 30 days of EMIT operations, methane emissions varied at a regional scale, with the largest total emissions observed for Turkmenistan (731 ± 148 tonnes CH4 hour-1). These results highlight the contributions of current and planned point source imagers in closing global carbon budgets.

3.
Laryngoscope Investig Otolaryngol ; 8(4): 1094-1107, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37621295

ABSTRACT

Objective: This systematic review aims to establish the expected hearing and speech outcomes following cochlear implantation (CI) in patients with profound congenital deafness secondary to Waardenburg syndrome (WS). Methods: A systematic review of the literature and narrative synthesis was performed in accordance with the PRISMA statement. Databases searched: Medline, Pubmed, Embase, Web of Science, Cochrane Collection, and ClinicalTrials.gov. No limits were placed on language or year of publication. Results: Searches identified 186 abstracts and full texts. Of these, 16 studies met inclusion criteria reporting outcomes in 179 patients and at least 194 implants. Hearing outcomes of those receiving cochlear implantation were generally good. Five studies included genetic analysis of one or more of the participants. A total of 11 peri/post-operative complications were reported. The methodological quality of included studies was modest, mainly comprising noncontrolled case series with small cohort size. All studies were OCEBM grade III-IV. Conclusion: Cochlear implantation in congenitally deafened children with Waardenburg Syndrome is a well-established intervention as a method of auditory rehabilitation. Due to the uncommon nature of the condition, there is a lack of large-scale high-quality studies examining the use of cochlear implantation in this patient group. However, overall outcomes following implantation are positive with the majority of patients demonstrating improved audiometry, speech perception and speech intelligibility supporting its use in appropriately selected cases.

4.
Teach Learn Med ; 35(1): 1-9, 2023.
Article in English | MEDLINE | ID: mdl-34968155

ABSTRACT

PHENOMENON: Development of teaching skills is an important aspect of medical student training. One method of developing teaching skills is participation in peer teaching with observation and feedback from peers. This study aims to explore student teachers' experiences of peer observation of teaching and how they intend to utilize this feedback. APPROACH: We conducted individual semi-structured interviews with peer tutors who had experienced peer observation of their small group teaching and subsequent feedback. The interviews were conducted by a medical student peer not involved in the peer observation of teaching scheme. They were audio recorded and transcribed. The pseudonymised transcripts were coded independently by two researchers using thematic analysis. FINDINGS: Nine students participated in interviews lasting a mean of 42 minutes. We identified three main themes: motivations for observation, experiences of observation, and responses to feedback. Students were motivated to have their teaching observed by both intrinsic and extrinsic factors: to develop their skills and competence as a teacher, in recognition of the important role this plays in their career, to provide reassurance that they are providing good quality teaching, to ensure the content of their teaching is appropriate and accurate, and to provide evidence of engagement in, and development of, teaching. Students described feeling nervous before the observations and preparing more for their teaching than they might normally, however, during the observations they felt more comfortable which they attributed to the peer-peer relationship. Students described finding the narrative feedback more useful than the quantitative elements as it provided more detail as to how they might improve. Several students described how they have used the feedback they have received on their teaching to improve subsequent sessions. INSIGHTS: Peer observation of teaching is a useful and acceptable method of providing feedback on student teaching and recipients intend to use this feedback to improve their teaching.


Subject(s)
Education, Medical, Undergraduate , Students, Medical , Humans , Peer Group , Feedback , Qualitative Research , Motivation , Teaching , Education, Medical, Undergraduate/methods
5.
Proc Natl Acad Sci U S A ; 119(38): e2202338119, 2022 09 20.
Article in English | MEDLINE | ID: mdl-36099297

ABSTRACT

Understanding, prioritizing, and mitigating methane (CH4) emissions requires quantifying CH4 budgets from facility scales to regional scales with the ability to differentiate between source sectors. We deployed a tiered observing system for multiple basins in the United States (San Joaquin Valley, Uinta, Denver-Julesburg, Permian, Marcellus). We quantify strong point source emissions (>10 kg CH4 h-1) using airborne imaging spectrometers, attribute them to sectors, and assess their intermittency with multiple revisits. We compare these point source emissions to total basin CH4 fluxes derived from inversion of Sentinel-5p satellite CH4 observations. Across basins, point sources make up on average 40% of the regional flux. We sampled some basins several times across multiple months and years and find a distinct bimodal structure to emission timescales: the total point source budget is split nearly in half by short-lasting and long-lasting emission events. With the increasing airborne and satellite observing capabilities planned for the near future, tiered observing systems will more fully quantify and attribute CH4 emissions from facility to regional scales, which is needed to effectively and efficiently reduce methane emissions.


Subject(s)
Air Pollutants , Methane , Air Pollutants/analysis , Methane/analysis , United States
6.
J Geophys Res Biogeosci ; 127(6): e2021JG006711, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35859986

ABSTRACT

Future global Visible Shortwave Infrared Imaging Spectrometers, such as the Surface Biology and Geology (SBG) mission, will regularly cover the Earth's entire terrestrial land area. These missions need high fidelity atmospheric correction to produce consistent maps of terrestrial and aquatic ecosystem traits. However, estimation of surface reflectance and atmospheric state is computationally challenging, and the terabyte data volumes of global missions will exceed available processing capacity. This article describes how missions can overcome this bottleneck using the spatial continuity of atmospheric fields. Contemporary imaging spectrometers oversample atmospheric spatial variability, so it is not necessary to invert every pixel. Spatially sparse solutions can train local linear emulators that provide fast, exact inversions in their vicinity. We find that estimating the atmosphere at 200 m scales can outperform traditional atmospheric correction, improving speed by one to two orders of magnitude with no measurable penalty to accuracy. We validate performance with an airborne field campaign, showing reflectance accuracies with RMSE of 1.1% or better compared to ground measurements of diverse targets. These errors are statistically consistent with retrieval uncertainty budgets. Local emulators can close the efficiency gap and make rigorous model inversion algorithms feasible for global missions such as SBG.

7.
Otol Neurotol ; 43(5): 530-537, 2022 06 01.
Article in English | MEDLINE | ID: mdl-35213475

ABSTRACT

OBJECTIVE: To systematically review the evidence for the use of bisphosphonate therapy in otosclerosis through clinically relevant outcomes. DATABASES REVIEWED: MEDLINE, EMBASE, PubMed, and CINAHL databases were searched up to July 12, 2021. METHODS: RCTs and cohort studies investigating the effect of bisphosphate therapy on adults or children diagnosed with otosclerosis were included. The risk of bias within trials was examined using the ROB2 tool for RCTs, and the ROBINS-I for non-RCTs. RESULTS: Three studies reported over five publications were included in the systematic review. Data from one RCT at 6 months did not demonstrate any improvement nor deterioration in audiological outcomes in participants treated with Sodium Alendronate. Data from MRI in this group demonstrated improvements in the SI of the otosclerotic foci at the RAOW compared to participants taking placebo. In another RCT, improvements in audiological outcomes were seen at 12 and 24 months in individuals treated with Etidronate Sodium. Long-term data from a retrospective cohort study demonstrated stabilisation of hearing in individuals with otosclerosis and progressive SNHL. CONCLUSION: There is insufficient evidence to recommend the routine use of bisphosphonates in otosclerosis patients at present. Long-term retrospective data has suggested a role for bisphosphonates in the subset of patients with deteriorating sensorineural hearing loss with the aim of hearing stabilisation. Adequately powered RCTs with long term follow up will be required to evaluate this further.


Subject(s)
Hearing Loss, Sensorineural , Otosclerosis , Adult , Child , Diphosphonates/therapeutic use , Etidronic Acid/therapeutic use , Hearing Loss, Sensorineural/drug therapy , Humans , Otosclerosis/drug therapy , Retrospective Studies , Sodium
9.
J Int Adv Otol ; 17(2): 162-174, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33893787

ABSTRACT

Establish outcomes following cochlear implantation (CI) in patients following temporal bone trauma. Systematic review and narrative synthesis. Medline, Pubmed, Embase, Web of Science, Cochrane Collection, and ClinicalTrials.gov. No limits are placed on language or year of publication. The review conducted in accordance with the PRISMA statement. Searches identified 223 abstracts and 64 full texts. Of these, 23 studies met the inclusion criteria reporting outcomes in 77 patients with at least 96 implants. Hearing outcomes were generally good with most patients demonstrating improved audiological and functional outcomes. Complications were reported in 14 cases with 10 of these being major. The methodological quality of included studies was modest, predominantly consisting of case reports and non-controlled case series with small numbers of patients. All studies were OCEBM grade IV. Hearing outcomes following CI in temporal bone trauma are good with useful functional improvement demonstrated in the majority of patients. It appears to be an effective method of aural rehabilitation and should be considered in selected cases following hearing loss due to temporal bone fracture.


Subject(s)
Cochlear Implantation , Hearing Loss , Hearing Loss/surgery , Humans , Temporal Bone/surgery
10.
Nature ; 575(7781): 180-184, 2019 11.
Article in English | MEDLINE | ID: mdl-31695210

ABSTRACT

Methane is a powerful greenhouse gas and is targeted for emissions mitigation by the US state of California and other jurisdictions worldwide1,2. Unique opportunities for mitigation are presented by point-source emitters-surface features or infrastructure components that are typically less than 10 metres in diameter and emit plumes of highly concentrated methane3. However, data on point-source emissions are sparse and typically lack sufficient spatial and temporal resolution to guide their mitigation and to accurately assess their magnitude4. Here we survey more than 272,000 infrastructure elements in California using an airborne imaging spectrometer that can rapidly map methane plumes5-7. We conduct five campaigns over several months from 2016 to 2018, spanning the oil and gas, manure-management and waste-management sectors, resulting in the detection, geolocation and quantification of emissions from 564 strong methane point sources. Our remote sensing approach enables the rapid and repeated assessment of large areas at high spatial resolution for a poorly characterized population of methane emitters that often appear intermittently and stochastically. We estimate net methane point-source emissions in California to be 0.618 teragrams per year (95 per cent confidence interval 0.523-0.725), equivalent to 34-46 per cent of the state's methane inventory8 for 2016. Methane 'super-emitter' activity occurs in every sector surveyed, with 10 per cent of point sources contributing roughly 60 per cent of point-source emissions-consistent with a study of the US Four Corners region that had a different sectoral mix9. The largest methane emitters in California are a subset of landfills, which exhibit persistent anomalous activity. Methane point-source emissions in California are dominated by landfills (41 per cent), followed by dairies (26 per cent) and the oil and gas sector (26 per cent). Our data have enabled the identification of the 0.2 per cent of California's infrastructure that is responsible for these emissions. Sharing these data with collaborating infrastructure operators has led to the mitigation of anomalous methane-emission activity10.


Subject(s)
Environmental Monitoring , Methane/analysis , Waste Management , California , Greenhouse Effect , Manure , Methane/chemistry , Methane/metabolism , Natural Gas , Oil and Gas Industry/methods , Petroleum , Wastewater
11.
PLoS Genet ; 14(7): e1007417, 2018 07.
Article in English | MEDLINE | ID: mdl-30024879

ABSTRACT

Cell death plays a major role during C. elegans oogenesis, where over half of the oogenic germ cells die in a process termed physiological apoptosis. How germ cells are selected for physiological apoptosis, or instead become oocytes, is not understood. Most oocytes produce viable embryos when apoptosis is blocked, suggesting that physiological apoptosis does not function to cull defective germ cells. Instead, cells targeted for apoptosis may function as nurse cells; the germline is syncytial, and all germ cells appear to contribute cytoplasm to developing oocytes. C. elegans has been a leading model for the genetics and molecular biology of apoptosis and phagocytosis, but comparatively few studies have examined the cell biology of apoptotic cells. We used live imaging to identify and examine pre-apoptotic germ cells in the adult gonad. After initiating apoptosis, germ cells selectively export their mitochondria into the shared pool of syncytial cytoplasm; this transport appears to use the microtubule motor kinesin. The apoptotic cells then shrink as they expel most of their remaining cytoplasm, and close off from the syncytium. Shortly thereafter the apoptotic cells restructure their microtubule and actin cytoskeletons, possibly to maintain cell integrity; the microtubules form a novel, cortical array of stabilized microtubules, and actin and cofilin organize into giant cofilin-actin rods. We discovered that some apoptotic germ cells are binucleate; the binucleate germ cells can develop into binucleate oocytes in apoptosis-defective strains, and appear capable of producing triploid offspring. Our results suggest that the nuclear layer of the germline syncytium becomes folded during mitosis and growth, and that binucleate cells arise as the layer unfolds or everts; all of the binucleate cells are subsequently removed by apoptosis. These results show that physiological apoptosis targets at least two distinct populations of germ cells, and that the apoptosis machinery efficiently recognizes cells with two nuclei.


Subject(s)
Apoptosis/physiology , Caenorhabditis elegans/physiology , Cell Nucleus/pathology , Germ Cells/physiology , Microtubules/physiology , Animals , Animals, Genetically Modified , Caenorhabditis elegans Proteins/genetics , Caspases/genetics , Cell Nucleus/physiology , Cytoplasm/physiology , Female , Male , Oocytes/physiology , Oogenesis/physiology , Ovary/cytology , Ovary/physiology
12.
Otolaryngol Head Neck Surg ; 159(2): 300-302, 2018 08.
Article in English | MEDLINE | ID: mdl-29558244

ABSTRACT

Intraoperative identification of the spinal accessory nerve (SAN) is key in reducing nerve injury. This study aims to explore the surgical anatomy of the SAN and 2 landmarks for its identification-the sternocleidomastoid branch of the occipital artery (SBOA) and superior sternocleidomastoid tendon (SST)-to propose a novel method of identifying the SAN during surgical neck dissections. Twelve cadavers underwent bilateral level II-V neck dissection identifying the SAN, SBOA, and SST. Variation was documented and distance between landmarks and the SAN measured. The most common arrangement had the SST most superficially followed by the SBOA and then the SAN. The SAN was 3.63 ± 4.02 mm from the artery and 2.31 ± 1.72 mm from the tendon. A triangle-bordered by the tendon laterally, artery medially, and digastric muscle superiorly-contained the SAN in 95.8% of cases. This relationship translated into a reliable technique to identify the SAN intraoperatively, which has been used successfully in practice.


Subject(s)
Accessory Nerve/anatomy & histology , Anatomic Landmarks , Neck Dissection/methods , Neck Muscles/innervation , Cadaver , Humans
13.
Opt Express ; 25(8): 9186-9195, 2017 Apr 17.
Article in English | MEDLINE | ID: mdl-28437992

ABSTRACT

The intrinsic spectral dimensionality indicates the observable degrees of freedom in Earth's solar-reflected light field, quantifying the diversity of spectral content accessible by visible and infrared remote sensing. The solar-reflected regime spans the 0.38 - 2.5 µm interval, and is captured by a wide range of current and planned instruments on both airborne and orbital platforms. To date there has been no systematic study of its spectral dimensionality as a function of space, time, and land cover. Here we report a multi-site, multi-year statistical survey by NASA's "Classic" Airborne Visible Near InfraRed Spectrometer (AVIRIS-C). AVIRIS-C measured large regions of California, USA, spanning wide latitudinal and elevation gradients containing all canonical MODIS land cover types. The spectral uniformity of the AVIRIS-C design enabled consistent in-scene assessment of measurement noise across acquisitions. The estimated dimensionality as a function of cover type ranged from the low 20s to the high 40s, and was approximately 50 for the combined dataset. This result indicates the high diversity of physical processes distinguishable by imaging spectrometers like AVIRIS-C for one region of the Earth.

14.
Protein Sci ; 25(1): 19-29, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26266489

ABSTRACT

Molecular dynamics (MD) simulation is a well-established tool for the computational study of protein structure and dynamics, but its application to the important problem of protein structure prediction remains challenging, in part because extremely long timescales can be required to reach the native structure. Here, we examine the extent to which the use of low-resolution information in the form of residue-residue contacts, which can often be inferred from bioinformatics or experimental studies, can accelerate the determination of protein structure in simulation. We incorporated sets of 62, 31, or 15 contact-based restraints in MD simulations of ubiquitin, a benchmark system known to fold to the native state on the millisecond timescale in unrestrained simulations. One-third of the restrained simulations folded to the native state within a few tens of microseconds-a speedup of over an order of magnitude compared with unrestrained simulations and a demonstration of the potential for limited amounts of structural information to accelerate structure determination. Almost all of the remaining ubiquitin simulations reached near-native conformations within a few tens of microseconds, but remained trapped there, apparently due to the restraints. We discuss potential methodological improvements that would facilitate escape from these near-native traps and allow more simulations to quickly reach the native state. Finally, using a target from the Critical Assessment of protein Structure Prediction (CASP) experiment, we show that distance restraints can improve simulation accuracy: In our simulations, restraints stabilized the native state of the protein, enabling a reasonable structural model to be inferred.


Subject(s)
Molecular Dynamics Simulation , Ubiquitin/chemistry , Protein Conformation , Protein Folding
15.
Perspect Med Educ ; 4(5): 268-271, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26358978

ABSTRACT

With the increasing popularity and scale of peer teaching, it is imperative to develop methods that ensure the quality of teaching provided by undergraduate students. We used an established faculty development and quality assurance process in a novel context: peer observation of teaching for undergraduate peer tutors. We have developed a form to record observations and aid the facilitation of feedback. In addition, experienced peer tutors have been trained to observe peer-taught sessions and provide tutors with verbal and written feedback. We have found peer observation of teaching to be a feasible and acceptable process for improving quality of teaching provided by undergraduate medical students. However, feedback regarding the quality of peer observer's feedback may help to develop students' abilities further.

16.
Eukaryot Cell ; 14(9): 858-67, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26092920

ABSTRACT

The gametogenesis program of the budding yeast Saccharomyces cerevisiae, also known as sporulation, employs unusual internal meiotic divisions, after which all four meiotic products differentiate within the parental cell. We showed previously that sporulation is typically accompanied by the destruction of discarded immature meiotic products through their exposure to proteases released from the mother cell vacuole, which undergoes an apparent programmed rupture. Here we demonstrate that vacuolar rupture contributes to de facto programmed cell death (PCD) of the meiotic mother cell itself. Meiotic mother cell PCD is accompanied by an accumulation of depolarized mitochondria, organelle swelling, altered plasma membrane characteristics, and cytoplasmic clearance. To ensure that the gametes survive the destructive consequences of developing within a cell that is executing PCD, we hypothesized that PCD is restrained from occurring until spores have attained a threshold degree of differentiation. Consistent with this hypothesis, gene deletions that perturb all but the most terminal postmeiotic spore developmental stages are associated with altered PCD. In these mutants, meiotic mother cells exhibit a delay in vacuolar rupture and then appear to undergo an alternative form of PCD associated with catastrophic consequences for the underdeveloped spores. Our findings reveal yeast sporulation as a context of bona fide PCD that is developmentally coordinated with gamete differentiation.


Subject(s)
Apoptosis , Meiosis , Saccharomyces cerevisiae/physiology , Spores, Fungal/physiology , Gene Deletion , Membrane Potential, Mitochondrial , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/genetics , Spores, Fungal/cytology , Spores, Fungal/genetics
17.
Appl Opt ; 53(7): 1363-80, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24663366

ABSTRACT

The design, characteristics, and first test flight results are described of the Portable Remote Imaging Spectrometer, an airborne sensor specifically designed to address the challenges of coastal ocean remote sensing. The sensor incorporates several technologies that are demonstrated for the first time, to the best of our knowledge, in a working system in order to achieve a high performance level in terms of uniformity, signal-to-noise ratio, low polarization sensitivity, low stray light, and high spatial resolution. The instrument covers the 350-1050 nm spectral range with a 2.83 nm sampling per pixel, and a 0.88 mrad instantaneous field of view, with 608 cross-track pixels in a pushbroom configuration. Two additional infrared channels (1240 and 1610 nm) are measured by a spot radiometer housed in the same head. The spectrometer design is based on an optically fast (F/1.8) Dyson design form coupled to a wide angle two-mirror telescope in a configuration that minimizes polarization sensitivity without the use of a depolarizer. A grating with minimum polarization sensitivity and broadband efficiency was fabricated as well as a slit assembly with black (etched) silicon surface to minimize backscatter. First flight results over calibration sites as well as Monterey Bay in California have demonstrated good agreement between in situ and remotely sensed data, confirming the potential value of the sensor to the coastal ocean science community.


Subject(s)
Aircraft/instrumentation , Environmental Monitoring/instrumentation , Remote Sensing Technology/instrumentation , Seawater/analysis , Seawater/chemistry , Spectrum Analysis/instrumentation , Equipment Design , Equipment Failure Analysis , Miniaturization , Oceans and Seas , Pilot Projects
18.
J Chem Phys ; 139(16): 164106, 2013 Oct 28.
Article in English | MEDLINE | ID: mdl-24182003

ABSTRACT

In molecular dynamics simulations, control over temperature and pressure is typically achieved by augmenting the original system with additional dynamical variables to create a thermostat and a barostat, respectively. These variables generally evolve on timescales much longer than those of particle motion, but typical integrator implementations update the additional variables along with the particle positions and momenta at each time step. We present a framework that replaces the traditional integration procedure with separate barostat, thermostat, and Newtonian particle motion updates, allowing thermostat and barostat updates to be applied infrequently. Such infrequent updates provide a particularly substantial performance advantage for simulations parallelized across many computer processors, because thermostat and barostat updates typically require communication among all processors. Infrequent updates can also improve accuracy by alleviating certain sources of error associated with limited-precision arithmetic. In addition, separating the barostat, thermostat, and particle motion update steps reduces certain truncation errors, bringing the time-average pressure closer to its target value. Finally, this framework, which we have implemented on both general-purpose and special-purpose hardware, reduces software complexity and improves software modularity.


Subject(s)
Molecular Dynamics Simulation , Pressure , Temperature , Artifacts
19.
J Phys Chem B ; 117(42): 12898-907, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-23841719

ABSTRACT

Understanding the nature of the glass transition--the dramatic slowing of dynamics and eventual emergence of a disordered solid from a cooling liquid--is a fundamental challenge in physical science. A central characteristic of glass-forming liquids is a non-exponential main relaxation process. The extent of deviation from exponential relaxation typically becomes more pronounced on cooling. Theories that predict a growth of spatially heterogeneous dynamics as temperature is lowered can explain these observations. In apparent contradiction to these theories, however, some experiments suggest that certain substances--notably including the intensely studied molecular glass-former ortho-terphenyl (OTP)--have a main relaxation process whose shape is essentially temperature independent, even though other observables predicted to be correlated with the degree of dynamical heterogeneity are temperature dependent. Here we report the first simulations based on an atomistic model of OTP that reach equilibrium at temperatures well into the supercooled regime. We first show that the results of these simulations are in reasonable quantitative agreement with experimental data for several basic properties over a wide range of temperatures. We then focus on rotational relaxation, finding nearly exponential behavior at high temperatures with clearly increasing deviations as temperature is lowered. The much weaker temperature dependence observed in light-scattering experiments also emerges from the same simulation data when we calculate correlation functions similar to those probed experimentally; this highlights the diversity of temperature dependencies that can be obtained with different probes. Further analysis suggests that the temperature insensitivity observed in the light-scattering experiments stems from the dependence of these measurements on internal as well as rotational molecular motion. Within the temperature range of our OTP simulations, our results strongly suggest that this archetypal glass-former behaves as anticipated by theories of the glass transition that predict increasing non-exponentiality with cooling, and our simulations thus strengthen the evidence supporting such theories.


Subject(s)
Terphenyl Compounds/chemistry , Molecular Dynamics Simulation , Rotation , Temperature , Thermodynamics
20.
J Gen Physiol ; 141(5): 619-32, 2013 May.
Article in English | MEDLINE | ID: mdl-23589581

ABSTRACT

The difficulty in characterizing ion conduction through membrane channels at the level of individual permeation events has made it challenging to elucidate the mechanistic principles underpinning this fundamental physiological process. Using long, all-atom simulations enabled by special-purpose hardware, we studied K(+) permeation across the KV1.2/2.1 voltage-gated potassium channel. At experimentally accessible voltages, which include the physiological range, the simulated permeation rate was substantially lower than the experimentally observed rate. The current-voltage relationship was also nonlinear but became linear at much higher voltages. We observed permeation consistent with a "knock-on" mechanism at all voltages. At high voltages, the permeation rate was in accordance with our previously reported KV1.2 pore-only simulations, after the simulated voltages from the previous study were recalculated using the correct method, new insight into which is provided here. Including the voltage-sensing domains in the simulated channel brought the linear current-voltage regime closer to the experimentally accessible voltages. The simulated permeation rate, however, still underestimated the experimental rate, because formation of the knock-on intermediate occurred too infrequently. Reducing the interaction strength between the ion and the selectivity filter did not increase conductance. In complementary simulations of gramicidin A, similar changes in interaction strength did increase the observed permeation rate. Permeation nevertheless remained substantially below the experimental value, largely because of infrequent ion recruitment into the pore lumen. Despite the need to apply large voltages to simulate the permeation process, the apparent voltage insensitivity of the permeation mechanism suggests that the direct simulation of permeation at the single-ion level can provide fundamental physiological insight into ion channel function. Notably, our simulations suggest that the knock-on permeation mechanisms in KV1.2 and KcsA may be different.


Subject(s)
Ion Channel Gating/physiology , Kv1.2 Potassium Channel/metabolism , Shab Potassium Channels/metabolism , Electric Conductivity , Membrane Potentials/physiology , Models, Biological , Permeability , Potassium/metabolism
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