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International Journal of Biological... Jun 2024Low molecular weight heparin and synthetic mimetics such as fondaparinux show different binding kinetics, protease specificity, and clinical effects. A combination of...
Low molecular weight heparin and synthetic mimetics such as fondaparinux show different binding kinetics, protease specificity, and clinical effects. A combination of allosteric and template-mediated bridging mechanisms have been proposed to explain the differences in rate acceleration and specificity. The difficulty in working with heterogeneous heparin species has rendered a crystallographic interpretation of the differences in antithrombin activation between mimetics and natural heparin inaccessible. In this study, we examine the allosteric changes in antithrombin caused by binding fondaparinux, enoxaparin and depolymerized natural heparins using millisecond hydrogen deuterium exchange mass spectrometry (TRESI-HDX MS) and relate these conformational changes to complex stability in the gas phase using collision induced unfolding (CIU). This exploration reveals that in addition to the dynamic changes caused by fondaparinux, long chain heparins reduce structural flexibility proximal to Arg393, the cleavable residue in the reactive centre loop of the protein. These local changes in protein dynamics are associated with an increase in overall complex stability that increases with heparin chain length. Ultimately, these results shed light on the molecular mechanisms underlying differences in activity and specificity between heparin mimetics and natural heparins.
PubMed: 38838881
DOI: 10.1016/j.ijbiomac.2024.132868 -
Medical Physics Jun 2024There currently exists no widespread high dose-rate (HDR) brachytherapy afterloader quality assurance (QA) tool for simultaneously assessing the afterloader's...
BACKGROUND
There currently exists no widespread high dose-rate (HDR) brachytherapy afterloader quality assurance (QA) tool for simultaneously assessing the afterloader's positional, temporal, transit velocity and air kerma strength accuracy.
PURPOSE
The purpose of this study was to develop a precise and rigorous technique for performing daily QA of HDR brachytherapy afterloaders, incorporating QA of: dwell position accuracy, dwell time accuracy, transit velocity consistency and relative air kerma strength (AKS) of an Ir-192 source.
METHOD
A Sharp ProGuide 240 mm catheter (Elekta Brachytherapy, Veenendaal, The Netherlands) was fixed 5 mm above a 256 channel epitaxial diode array 'dose magnifying glass' (DMG256) (Centre for Medical and Radiation Physics, University of Wollongong). Three dwell positions, each of 5.0 s dwell times, were spaced 13.0 mm apart along the array with the Flexitron HDR afterloader (Elekta Brachytherapy, Veenendaal, The Netherlands). The DMG256 was connected to a data acquisition system (DAQ) and a computer via USB2.0 link for live readout and post-processing. The outputted data files were analyzed using a Python script to provide positional and temporal localization of the Ir-192 source by tracking the centroid of the detected response. Measurements were repeated on a weekly basis, for a period of 5 weeks to determine the consistency of the measured parameters over an extended period.
RESULTS
Using the DMG256 for relative AKS measurements resulted in measured values within 0.6%-3.0% of the expected activity over a 7-week period. The sub-millisecond temporal accuracy of the device allowed for measurements of the transit velocity with an average of (10.88 ± 1.01) cm/s for 13 mm steps. The dwell position localization for 1, 2, 3, 5, and 10 mm steps had an accuracy between 0.1 and 0.3 mm (3σ), with a fixed temporal accuracy of 10 ms.
CONCLUSION
The DMG256 silicon strip detector allows for clinics to perform rigorous daily QA of HDR afterloader dwell position and dwell time accuracy with greater precision than the current standard methodology using closed circuit television and a stopwatch. Additionally, DMG256 unlocks the ability to perform measurements of transit velocity/time and relative AKS, which are not possible using current standard techniques.
PubMed: 38837408
DOI: 10.1002/mp.17240 -
Light, Science & Applications Jun 2024Mechanical forces are key regulators of cellular behavior and function, affecting many fundamental biological processes such as cell migration, embryogenesis,...
Mechanical forces are key regulators of cellular behavior and function, affecting many fundamental biological processes such as cell migration, embryogenesis, immunological responses, and pathological states. Specialized force sensors and imaging techniques have been developed to quantify these otherwise invisible forces in single cells and in vivo. However, current techniques rely heavily on high-resolution microscopy and do not allow interrogation of optically dense tissue, reducing their application to 2D cell cultures and highly transparent biological tissue. Here, we introduce DEFORM, deformable microlaser force sensing, a spectroscopic technique that detects sub-nanonewton forces with unprecedented spatio-temporal resolution. DEFORM is based on the spectral analysis of laser emission from dye-doped oil microdroplets and uses the force-induced lifting of laser mode degeneracy in these droplets to detect nanometer deformations. Following validation by atomic force microscopy and development of a model that links changes in laser spectrum to applied force, DEFORM is used to measure forces in 3D and at depths of hundreds of microns within tumor spheroids and late-stage Drosophila larva. We furthermore show continuous force sensing with single-cell spatial and millisecond temporal resolution, thus paving the way for non-invasive studies of biomechanical forces in advanced stages of embryogenesis, tissue remodeling, and tumor invasion.
PubMed: 38834554
DOI: 10.1038/s41377-024-01471-9 -
The Review of Scientific Instruments Jun 2024In this article, we present a transient temperature detection device for silicon carbide (SiC) Schottky barrier diodes (SBDs) based on thermal reflection theory. We...
In this article, we present a transient temperature detection device for silicon carbide (SiC) Schottky barrier diodes (SBDs) based on thermal reflection theory. We constructed a thermal reflection temperature measurement device based on a 530-nm green laser. This device is more suitable for transient temperature measurement of SiC SBDs than previous thermal reflection equipment. The accuracy of temperature measurement by our device was confirmed by comparison with the results of infrared thermal imaging. The high temporal resolution characteristics of the thermal reflection technology allowed the detection of millisecond-level transient temperature changes in SiC SBDs. In addition, we investigated the complementarity of transient temperature change curves during heating and cooling processes, as well as the reasons for the differences between these curves. Finally, we used the structural function method combined with the Bayesian deconvolution algorithm to obtain the thermal resistance along the heat flow path of the device and validated the results using an established thermal resistance testing method.
PubMed: 38829219
DOI: 10.1063/5.0198713 -
European Journal of Vascular and... May 2024Pedal acceleration time (PAT) is a novel non-invasive perfusion measurement that may have usefulness in the management of patients with ulceration and gangrene. The...
OBJECTIVE
Pedal acceleration time (PAT) is a novel non-invasive perfusion measurement that may have usefulness in the management of patients with ulceration and gangrene. The objective of this study was to report the association of PAT with wound healing, amputation free survival (AFS), and mortality at one year.
METHODS
This observational prospective study reviewed all patients who underwent PAT after presentation with ulceration or gangrene from 1 January 2020 to 30 June 2022. PAT was defined as the time (in milliseconds) from the onset of systole to the peak of systole in the mid artery. The final PAT of a limb was used to assess outcomes (presenting PAT if no revascularisation, or post-revascularisation PAT). Wound healing, major limb amputation, and death at one year were collected. Healing was assessed with Fine-Gray competing risks model, AFS via logistic regression, and survival using Cox proportional hazards model.
RESULTS
Overall, 265 patients (307 limbs) were included. Median patient age was 71 years and 74.0% (196/265) had diabetes mellitus. Patient demographics were similar among the final PAT category cohorts. Compared with a final PAT category 1, analysis of one year outcomes showed that the final PAT categories 2 - 4 had lower wound healing (category 2, hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.43 - 0.9) p = .012; category 3, HR 0.21, 95% CI 0.08 - 0.58, p = .002; category 4, HR 0.12, 95% CI 0.04 - 0.34, p < .001), lower AFS (category 2, odds ratio [OR] 2.86, 95% CI 1.64 - 5.0, p < .001; category 3, OR 5.1, 95% CI 1.71 - 15.22, p = .003; category 4, OR 12.59, 95% CI 4.34 - 36.56, p < .001), and lower survival (category 2, HR 1.89, 95% CI 1.17 - 3.03, p =.009; category 3, HR 2.37, 95% CI 1.05 - 5.36, p = .039; category 4, HR 4.52, 95% CI 2.48 - 8.21, p < .001) CONCLUSION: The final PAT measurement is associated with wound healing, AFS, and mortality at one year. PAT may be a valuable tool to assess perfusion of the foot.
PubMed: 38825036
DOI: 10.1016/j.ejvs.2024.05.043 -
Journal of the American Chemical Society Jun 2024Aerosol droplets are unique microcompartments with relevance to areas as diverse as materials and chemical synthesis, atmospheric chemistry, and cloud formation....
Aerosol droplets are unique microcompartments with relevance to areas as diverse as materials and chemical synthesis, atmospheric chemistry, and cloud formation. Observations of highly accelerated and unusual chemistry taking place in such droplets have challenged our understanding of chemical kinetics in these microscopic systems. Due to their large surface-area-to-volume ratios, interfacial processes can play a dominant role in governing chemical reactivity and other processes in droplets. Quantitative knowledge about droplet surface properties is required to explain reaction mechanisms and product yields. However, our understanding of the compositions and properties of these dynamic, microscopic interfaces is poor compared to our understanding of bulk processes. Here, we measure the dynamic surface tensions of 14-25 μm radius (11-65 pL) droplets containing a strong surfactant (either sodium dodecyl sulfate or octyl-β-D-thioglucopyranoside) using a stroboscopic imaging approach, enabling observation of the dynamics of surfactant partitioning to the droplet-air interface on time scales of 10s to 100s of microseconds after droplet generation. The experimental results are interpreted with a state-of-the-art kinetic model accounting for the unique high surface-area-to-volume ratio inherent to aerosol droplets, providing insights into both the surfactant diffusion and adsorption kinetics as well as the time-dependence of the interfacial surfactant concentration. This study demonstrates that microscopic droplet interfaces can take up to many milliseconds to reach equilibrium. Such time scales should be considered when attempting to explain observations of accelerated chemistry in microcompartments.
PubMed: 38822805
DOI: 10.1021/jacs.4c03041 -
Brain Stimulation May 2024Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently,...
BACKGROUND
Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently, a white matter tract termed the hyperdirect pathway (HDP), directly connecting the motor cortex to STN, has gained interest as HDP stimulation is hypothesized to drive DBS therapeutic effects. Previously, we have investigated EEG-based evoked potentials (EPs) to better understand the neuroanatomical origins of the DBS clinical effect. We found a 3-millisecond peak (P3) relating to clinical benefit, and a 10-millisecond peak (P10) suggesting nigral side effects. Here, we aimed to investigate the neuroanatomical origins of DBS EPs using probabilistic mapping.
METHODS
EPs were recorded using EEG whilst low-frequency stimulation was delivered at all DBS-contacts individually. Next, EPs were mapped onto the patients' individual space and then transformed to MNI standard space. Using voxel-wise and fiber-wise probabilistic mapping, we determined hotspots/hottracts and coldspots/coldtracts for P3 and P10. Topography analysis was also performed to determine the spatial distribution of the DBS EPs.
RESULTS
In all 13 patients (18 hemispheres), voxel- and fiber-wise probabilistic mapping resulted in a P3-hotspot/hottract centered on the posterodorsomedial STN border indicative of HDP stimulation, while the P10-hotspot/hottract covered large parts of the substantia nigra.
CONCLUSION
This study investigated EP-based probabilistic mapping in PD patients during STN-DBS, revealing a P3-hotspot/hottract in line with HDP stimulation and P10-hotspot/hottract related to nigral stimulation. Results from this study provide key evidence for an electrophysiological measure of HDP and nigral stimulation.
PubMed: 38821395
DOI: 10.1016/j.brs.2024.05.013 -
Science (New York, N.Y.) May 2024In this work, we show that particles of common minerals break down spontaneously to form nanoparticles in charged water microdroplets within milliseconds. We transformed...
In this work, we show that particles of common minerals break down spontaneously to form nanoparticles in charged water microdroplets within milliseconds. We transformed micron-sized natural minerals like quartz and ruby into 5- to 10-nanometer particles when integrated into aqueous microdroplets generated via electrospray. We deposited the droplets on a substrate, which allowed nanoparticle characterization. We determined through simulations that quartz undergoes proton-induced slip, especially when reduced in size and exposed to an electric field. This leads to particle scission and the formation of silicate fragments, which we confirmed with mass spectrometry. This rapid weathering process may be important for soil formation, given the prevalence of charged aerosols in the atmosphere.
PubMed: 38815034
DOI: 10.1126/science.adl3364 -
IEEE Journal of Biomedical and Health... May 2024Upper extremity pain and injury are among the most common musculoskeletal complications manual wheelchair users face. Assessing the temporal parameters of manual...
Upper extremity pain and injury are among the most common musculoskeletal complications manual wheelchair users face. Assessing the temporal parameters of manual wheelchair propulsion, such as propulsion duration, cadence, push duration, and recovery duration, is essential for providing a deep insight into the mobility, level of activity, energy expenditure, and cumulative exposure to repetitive tasks and thus providing personalized feedback. The purpose of this paper is to investigate the use of inertial measurement units (IMUs) to estimate these temporal parameters by identifying the start and end time of hand contact with the push-rim during each propulsion cycle. We presented a model based on data collected from 23 participants (14 males and 9 females, including 9 experienced manual wheelchair users) to guarantee the reliability and generalizability of our method. The obtained outcomes from our IMU-based model were then compared against an instrumented wheelchair (SMARTWheel) as a reference criterion. The results illustrated that our model was able to accurately detect hand contact and hand release and predict temporal parameters, including the push duration and recovery duration in manual wheelchair users, with the mean error ± standard deviation of 10 ± 60 milliseconds and -20 ± 80 milliseconds, respectively. The findings of this study demonstrate the potential of hand-mounted IMUs as a reliable and objective tool for analyzing temporal parameters in manual wheelchair propulsion. IMUs offer significant strides towards inclusivity and accessibility due to their portability and user-friendliness and can democratize health monitoring of manual wheelchair users by making it accessible to a broader range of users compared to traditional technologies.
PubMed: 38814765
DOI: 10.1109/JBHI.2024.3407525 -
Communications Biology May 2024Neurons grow neurites of several tens of micrometers in length, necessitating active transport from the cell body by motor proteins. By tracking fluorophores as...
Neurons grow neurites of several tens of micrometers in length, necessitating active transport from the cell body by motor proteins. By tracking fluorophores as minimally invasive labels, MINFLUX is able to quantify the motion of those proteins with nanometer/millisecond resolution. Here we study the substeps of a truncated kinesin-1 mutant in primary rat hippocampal neurons, which have so far been mainly observed on polymerized microtubules deposited onto glass coverslips. A gentle fixation protocol largely maintains the structure and surface modifications of the microtubules in the cell. By analyzing the time between the substeps, we identify the ATP-binding state of kinesin-1 and observe the associated rotation of the kinesin-1 head in neurites. We also observed kinesin-1 switching microtubules mid-walk, highlighting the potential of MINFLUX to study the details of active cellular transport.
Topics: Kinesins; Animals; Rats; Neurites; Microtubules; Hippocampus; Cells, Cultured
PubMed: 38811803
DOI: 10.1038/s42003-024-06358-4