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Structural basis for C-type inactivation in a Shaker family voltage-gated K[superscript +[ channel
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Analysis of heat transfer and AuNPs-mediated photo-thermal inactivation of E. coli at varying laser powers using single-phase CFD modeling
In the wake of the COVID-19 pandemics, the demand for innovative and effective methods of bacterial inactivation has become a critical area of research, providing the impetus for this study. The purpose of this research is to analyze the AuNPs-mediated photothermal inactivation of E. coli. Gold nanoparticles irradiated by laser represent a promising technique for combating bacterial infection that combines high-tech and scientific progress. The intermediate aim of the work was to present the calibration of the model with respect to the gold nanorods experiment. The purpose of this work is to study the effect of initial concentration of E. coli bacteria, the design of the chamber and the laser power on heat transfer and inactivation of E. coli bacteria. Using the CFD simulation, the work combines three main concepts. 1. The conversion of laser light to heat has been described by a combination of three distinctive approximations: a- Discrete particle integration to take into account every nanoparticle within the system, b- Rayleigh-Drude approximation to determine the scattering and extinction coefficients and c- Lambert–Beer–Bourger law to describe the decrease in laser intensity across the AuNPs. 2. The contribution of the presence of E. coli bacteria to the thermal and fluid-dynamic fields in the microdevice was modeled by single-phase approach by determining the effective thermophysical properties of the water-bacteria mixture. 3. An approach based on a temperature threshold attained at which bacteria will be inactivated, has been used to predict bacterial response to temperature increases. The comparison of the thermal fields and temporal temperature changes obtained by the CFD simulation with those obtained experimentally confirms the accuracy of the light-heat conversion model derived from the aforementioned approximations. The results show a linear relationship between maximum temperature and variation in laser power over the range studied, which is in line with previous experimental results. It was also found that the temperature inside the microchamber can exceed 55 °C only when a laser power higher than 0.8 W is used, so bacterial inactivation begins. The experimental data allows to determinate the concentration of nanoparticles. This parameter is introduced into the mathematical model obtaining the same number of AuNPs. However, this assumption introduces a certain simplification, as in the mathematical model the distribution of nanoparticles is uniform. This work is directly connected to the use of gold nanoparticles for energy conversion, as well as the field of bacterial inactivation in microfluidic systems such as lab-on-a-chip. Presented mathematical and numerical models can be extended to the entire spectrum of wavelengths with particular use of white light in the inactivation of bacteria. This work represents a significant advancement in the field, as to the best of the authors’ knowledge, it is the first to employ a single-phase computational fluid dynamics (CFD) approach specifically combined with the thermal inactivation of bacteria. Moreover, this research pioneers the use of a numerical simulation to analyze the temperature threshold of photothermal inactivation of E. coli mediated by gold nanorods (AuNRs). The integration of these methodologies offers a new perspective on optimizing bacterial inactivation techniques, making this study a valuable contribution to both computational modeling and biomedical applications.
Structural and Mechanistic Basis for the Inactivation of Human Ornithine Aminotransferase by (3 S ,4 S )-3-Amino-4-fluorocyclopentenecarboxylic Acid
Ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), and we previously showed that inactivation of OAT inhibits the growth of HCC. Recently, we found that (3S,4S)-3-amino-4-fluorocyclopentenecarboxylic acid (5) was a potent inactivator of γ-aminobutyric acid aminotransferase (GABA-AT), proceeding by an enamine mechanism. Here we describe our investigations into the activity and mechanism of 5 as an inactivator of human OAT. We have found that 5 exhibits 10-fold less inactivation efficiency (k inact /K I ) against hOAT than GABA-AT. A comprehensive mechanistic study was carried out to understand its inactivation mechanism with hOAT. pK a and electrostatic potential calculations were performed to further support the notion that the α,β-unsaturated alkene of 5 is critical for enhancing acidity and nucleophilicity of the corresponding intermediates and ultimately responsible for the improved inactivation efficiency of 5 over the corresponding saturated analogue (4). Intact protein mass spectrometry and the crystal structure complex with hOAT provide evidence to conclude that 5 mainly inactivates hOAT through noncovalent interactions, and that, unlike with GABA-AT, covalent binding with hOAT is a minor component of the total inhibition which is unique relative to other monofluoro-substituted derivatives. Furthermore, based on the results of transient-state measurements and free energy calculations, it is suggested that the α,β-unsaturated carboxylate group of PLP-bound 5 may be directly involved in the inactivation cascade by forming an enolate intermediate. Overall, compound 5 exhibits unusual structural conversions which are catalyzed by specific residues within hOAT, ultimately leading to an enamine mechanism-based inactivation of hOAT through noncovalent interactions and covalent modification.
Effects of track structure and cell inactivation on the calculation of heavy ion mutation rates in mammalian cells
It has long been suggested that inactivation severely effects the probability of mutation by heavy ions in mammalian cells. Heavy ions have observed cross sections of inactivation that approach and sometimes exceed the geometric size of the cell nucleus in mammalian cells. In the track structure model of Katz the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated using the dose-response of the system to gamma-rays and the radial dose of the ions and may be equal to unity at small impact parameters for some ions. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections from heavy ions in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT mutations in Chinese hamster cells and good agreement is found. The resulting calculations qualitatively show that mutation cross sections for heavy ions display minima at velocities where inactivation cross sections display maxima. Also, calculations show the high probability of mutation by relativistic heavy ions due to the radial extension of ions track from delta-rays in agreement with the microlesion concept. The effects of inactivation on mutations rates make it very unlikely that a single parameter such as LET or Z*2/beta(2) can be used to specify radiation quality for heavy ion bombardment.
Calculation of Heavy Ion Inactivation and Mutation Rates in Radial Dose Model of Track Structure
In the track structure model, the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated by using the dose response of the system to gamma rays and the radial dose of the ions and may be equal to unity at small impact parameters. We apply the track structure model to recent data with heavy ion beams irradiating biological samples of E. Coli, B. Subtilis spores, and Chinese hamster (V79) cells. Heavy ions have observed cross sections for inactivation that approach and sometimes exceed the geometric size of the cell nucleus. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT (hypoxanthine guanine phosphoribosyl transferase) mutations in V79 cells, and good agreement is found. Calculations show the high probability for mutation by relativistic ions due to the radial extension of ions track from delta rays. The effects of inactivation on mutation rates make it very unlikely that a single parameter such as LET (linear energy transfer) can be used to specify radiation quality for heavy ion bombardment.
405 nm violet-blue light inactivates hepatitis C cell culture virus (HCVcc) in ex vivo human platelet concentrates and plasma
Abstract Added safety measures coupled with the development and use of pathogen reduction technologies (PRT) significantly reduces the risk of transfusion-transmitted infections (TTIs) from blood products. Current approved PRTs utilize chemical and/or UV-light based inactivation methods. While the effectiveness of these PRTs in reducing pathogens are well documented, these can cause tolerable yet unintended consequences on the quality and efficacy of the transfusion products. As an alternative to UV-based approaches, we have previously demonstrated that 405 nm violet-blue light exposure successfully inactivates a variety of pathogens, including bacteria, parasites, and viruses, in both platelet concentrates (PCs) and plasma. Herein, we show that 405 nm light treatment effectively inactivates hepatitis C cell culture virus (HCVcc) by up to ~ 3.8 log10 in small volumes of a variety of matrices, such as cell culture media, PBS, plasma, and PCs with 27 J/cm 2 of light exposure, and total inactivation of HCVcc after 162 J/cm 2 light exposure. Furthermore, we demonstrate that carry-over of media supplemented with fetal bovine serum enhances the production of reactive oxygen species (ROS), providing mechanistic insights to 405 nm light-mediated viral inactivation. Overall, 405 nm light successfully inactivates HCVcc, further strengthening this method as a novel PRT for platelets and plasma.
Machine learning-guided discovery of gas evolving electrode bubble inactivation
The adverse effects of electrochemical bubbles on the performance of gas-evolving electrodes are well known, but studies on the degree of adhered bubble-caused inactivation, and how inactivation changes during bubble evolution are limited. We study electrode inactivation caused by oxygen evolution while using surface engineering to control bubble formation. We find that the inactivation of the entire projected area, as is currently believed, is a poor approximation which leads to non-physical results. Using a machine learning-based image-based bubble detection method to analyze large quantities of experimental data, we show that bubble impacts are small for surface engineered electrodes which promote high bubble projected areas while maintaining low direct bubble contact. We thus propose a simple methodology for more accurately estimating the true extent of bubble inactivation, which is closer to the area which is directly in contact with the bubbles.
Inactivation of highly transmissible livestock and avian viruses including influenza A and Newcastle disease virus for molecular diagnostics
There is a critical need for an inactivation method that completely inactivates pathogens at the time of sample collection while maintaining the nucleic acid quality required for diagnostic PCR testing. This inactivation method is required to alleviate concerns about transmission potential, minimize shipping complications and cost, and enable testing in lower containment laboratories, thereby enhancing disease diagnostics through improved turn-around time. This study evaluated a panel of 10 surrogate viruses that represent highly pathogenic animal diseases. These results showed that a commercial PrimeStore® molecular transport media (PSMTM) completely inactivated all viruses tested by >99.99%, as determined by infectivity and serial passage assays. However, the detection of viral nucleic acid by qRT-PCR was comparable in PSMTM and control-treated conditions. These results were consistent when viruses were evaluated in the presence of biological material such as sera and cloacal swabs to mimic diagnostic sample conditions for non-avian and avian viruses, respectively. The results of this study may be utilized by diagnostic testing laboratories for highly pathogenic agents affecting animal and human populations. These results may be used to revise guidance for select agent diagnostic testing and the shipment of infectious substances.
Inactivation of Human Coronavirus by FATHHOME’s Dry Sanitizer Device: Rapid and Eco-Friendly Ozone-Based Disinfection of SARS-CoV-2
The pandemic of SARS-CoV-2/COVID-19 was reported in December 2019 in Wuhan, China. Pertaining to its high transmissibility and wide host adaptability, this unique human coronavirus spread across the planet inflicting 115 million people and causing 2.5 million deaths (as of March 3rd, 2021). Limited or negligible pre-existing immunity to multiple SARS-CoV-2 variants has resulted in severe morbidity and mortality worldwide, as well as a record-breaking surge in the use of medical-surgical supplies and personal protective equipment. In response to the global need for effective sterilization techniques, this study evaluated the virucidal efficacy of FATHHOME’s self-contained, ozone-based dry-sanitizing device, by dose and time response assessment. We tested inactivation of human coronavirus, HCoV-OC43, a close genetic model of SARS-CoV-2, on porous (N95 filtering facepiece respirator/FFR) and nonporous (glass) surfaces. We started our assays with 20 ppm-10 min ozone exposure, and effectively reduced 99.8% and 99.9% of virus from glass and N95 FFR surfaces, respectively. Importantly, the virus was completely inactivated, below the detection limit (over 6-log10 reduction) with 25 ppm-15 min ozone exposure on both tested surfaces. As expected, a higher ozone exposure (50 ppm-10 min) resulted in faster inactivation of HCoV-OC43 with 100% inactivation from both the surfaces, with no residual ozone present after completion of the 5-min post exposure recapture cycle and no measurable increase in ambient ozone levels. These results confirmed that FATHHOME’s device is suitable for rapid decontamination of SARS-CoV-2- from worn items, frequently touched items, and PPE including N95 FFRs, face shields, and other personal items. View Full-Text
Adaptation of primate vestibuloocular reflex to altered peripheral vestibular inputs. I. Frequency-specific recovery of horizontal VOR after inactivation of the lateral semicircular canals
1. The adaptive plasticity of the vestibuloocular reflex (VOR) following a selective lesion of the peripheral vestibular organs was investigated in rhesus monkeys whose lateral semicircular canals were inactivated by plugging of the canal lumen in both ears. Gain and phase of horizontal, vertical, and torsional slow-phase eye velocity were determined from three-dimensional eye movement recordings obtained acutely after the plugging operation, as well as in regular intervals up to 10 mo later. 2. Acutely after plugging, horizontal VOR was minimal during yaw rotation with gains of < 0.1 at all frequencies. Horizontal VOR gain gradually increased over time, reaching gains of 0.4-0.5 for yaw oscillations at 1.1 Hz approximately 5 mo after lateral canal inactivation. This response recovery was strongly frequency dependent: horizontal VOR gains were largest at the highest frequency tested and progressively decreased for lower frequencies. Below approximately 0.1 Hz, no consistent horizontal VOR could be elicited even 10 mo after plugging. 3. The frequency-dependent changes in gain paralleled changes in horizontal VOR phase. Below approximately 0.1-0.05 Hz large phase leads were present, similarly as in semicircular canal primary afferents. Smaller phase leads were also present at higher frequencies, particularly at 1.1 Hz (the highest frequency tested). 4. Consistent with the afferent-like dynamics of the adapted horizontal VOR, per- and postrotatory horizontal responses to constant-velocity yaw rotations were short lasting. Time constants of the slow-phase eye velocity envelope of the horizontal postrotatory nystagmus were approximately 2 s. Nonetheless, a consistent horizontal optokinetic afternystagmus was evoked in plugged animals. 5. A torsional component that was absent in intact animals was consistently present during yaw rotation acutely after lateral canal inactivation and remained approximately constant thereafter. The frequency response characteristics of this torsional component resembled those of the adapted horizontal slow-phase responses: gain decreased and large phase leads were introduced at frequencies below approximately 0.05-0.1 Hz. Torsional responses elicited by roll oscillations in supine position, on the other hand, were indistinguishable in their dynamics from intact animals. No consistent vertical nystagmus was elicited during yaw rotation. 6. Our results show that there is a slow, frequency-specific recovery of horizontal VOR after selective inactivation of the lateral semicircular canals. Both the spatial organization and the dynamic properties of the adapted VOR responses are distinctly different from responses in intact animals, suggesting complex changes in the underlying vestibuloocular circuitry.
Metabolite, Protein, and Lipid Extraction (MPLEx): a method that simultaneously inactivates Middle East respiratory syndrome coronavirus and allows analysis of multiple host cell components following infection
Mass spectrometry (MS)-based, integrated proteomics, metabolomics, and lipidomics (collectively, multi-omics) studies provide a very detailed snap shot of virus-induced changes to the host following infection and can lead to the identification of novel prophylactic and therapeutic targets for preventing or lessening disease severity. Multi-omics studies with Middle East respiratory syndrome coronavirus (MERS-CoV) are challenging as the requirements of Biosafety Level 3 containment limit the numbers of samples that can be safely managed. To address these issues, the multi-omics sample preparation technique MPLEx (metabolite, protein, and lipid extraction) was developed to partition a single sample into three distinct parts (metabolites, proteins and lipids) for multi-omics analysis, while simultaneously inactivating MERS-CoV by solubilizing and disrupting the viral envelope and denaturing viral proteins. Here we describe the MPLEx protocol, highlight the step of inactivation, and describe the details of downstream processing, instrumental analysis of studies with Middle East respiratory syndrome coronavirus (MERS-CoV) are challenging as the requirements of Biosafety Level 3 containment limit the numbers of samples that can be safely managed. To address these issues, the multi-omics sample preparation technique MPLEx (metabolite, protein, and lipid extraction) was developed to partition a single sample into three distinct parts (metabolites, proteins and lipids) for multi-omics analysis, while simultaneously inactivating MERS-CoV by solubilizing and disrupting the viral envelope and denaturing viral proteins. Here we describe the MPLEx protocol, highlight the step of inactivation, and describe the details of downstream processing, instrumental analysis of the three separate analytes and their subsequent informatics pipelines.
Inactivation of multiple human pathogens by Fathhome's dry sanitizer device: Rapid and eco-friendly ozone-based disinfection
SARS-CoV-2 spread rapidly, causing millions of deaths across the globe. As a result, demand for medical supplies and personal protective equipment (PPE) surged and supplies dwindled. Separate entirely, hospital-acquired infections have become commonplace and challenging to treat. To explore the potential of novel sterilization techniques, this study evaluated the disinfection efficacy of Fathhome's ozone-based, dry-sanitizing device by dose and time response. Inactivation of human pathogens was tested on non-porous (plastic) surfaces. 95.42-100% inactivation was observed across all types of vegetative microorganisms and 27.36% inactivation of bacterial endospores tested, with no residual ozone detectable after completion. These results strongly support the hypothesis that Fathhome's commercial implementation of gas-based disinfection is suitable for rapid decontamination of a wide variety of pathogens on PPE and other industrially relevant materials.
A hierarchal model for bacterial cell inactivation in solution by direct and indirect treatment using cold atmospheric plasmas
Cold atmospheric plasma devices have shown promise for a variety of plasma medical applications, including wound healing and bacterial inactivation often performed in liquids. In the latter application, plasma-produced reactive oxygen and nitrogen species (RONS) interact with and damage bacterial cells, though the exact mechanism by which cell damage occurs is unclear. Computational models can help elucidate relationships between plasma-produced RONS and cell killing by enabling direct comparison between dissimilar plasma devices and by examining the effects of changing operating parameters in these devices. In biological applications, computational models of plasma-liquid interactions would be most effective in design and optimization of plasma devices if there is a corresponding prediction of the biological outcome. In this work, we propose a hierarchal model for planktonic bacterial cell inactivation by plasma produced RONS in liquid. A previously developed reaction mechanism for plasma induced modification of cysteine was extended to provide a basis for cell killing by plasma-produced RONS. Results from the model are compared to literature values to provide proof of concept. Differences in time to bacterial inactivation as a function of plasma operating parameters including gas composition and plasma source configuration are discussed. Results indicate that optimizing gas-phase reactive nitrogen species production may be key in the design of plasma devices for disinfection.
Strong intracellular signal inactivation produces sharper and more robust signaling from cell membrane to nucleus
For a chemical signal to propagate across a cell, it must navigate a tortuous environment involving a variety of organelle barriers. In this work we study mathematical models for a basic chemical signal, the arrival times at the nuclear membrane of proteins that are activated at the cell membrane and diffuse throughout the cytosol. Organelle surfaces within human B cells are reconstructed from soft X-ray tomographic images, and modeled as reflecting barriers to the molecules’ diffusion. We show that signal inactivation sharpens signals, reducing variability in the arrival time at the nuclear membrane. Inactivation can also compensate for an observed slowdown in signal propagation induced by the presence of organelle barriers, leading to arrival times at the nuclear membrane that are comparable to models in which the cytosol is treated as an open, empty region. In the limit of strong signal inactivation this is achieved by filtering out molecules that traverse non-geodesic paths.
Complete Inactivation of Blood Borne Pathogen Trypanosoma cruzi in Stored Human Platelet Concentrates and Plasma Treated With 405 nm Violet-Blue Light
The introduction of pathogen reduction technologies (PRTs) to inactivate bacteria, viruses and parasites in donated blood components stored for transfusion adds to the existing arsenal toward reducing the risk of transfusion-transmitted infectious diseases (TTIDs). We have previously demonstrated that 405 nm violet-blue light effectively reduces blood-borne bacteria in stored human plasma and platelet concentrates. In this report, we investigated the microbicidal effect of 405 nm light on one important bloodborne parasite Trypanosoma cruzi that causes Chagas disease in humans. Our results demonstrated that a light irradiance at 15 mWcm -2 for 5 h, equivalent to 270 Jcm -2 , effectively inactivated T. cruzi by over 9.0 Log 10 , in plasma and platelets that were evaluated by a MK2 cell infectivity assay. Giemsa stained T. cruzi infected MK2 cells showed that the light-treated parasites in plasma and platelets were deficient in infecting MK2 cells and did not differentiate further into intracellular amastigotes unlike the untreated parasites. The light-treated and untreated parasite samples were then evaluated for any residual infectivity by injecting the treated parasites into Swiss Webster mice, which did not develop infection even after the animals were immunosuppressed, further demonstrating that the light treatment was completely effective for inactivation of the parasite; the light-treated platelets had similar in vitro metabolic and biochemical indices to that of untreated platelets. Overall, these results provide a proof of concept toward developing 405 nm light treatment as a pathogen reduction technology (PRT) to enhance the safety of stored human plasma and platelet concentrates from bloodborne T. cruzi, which causes Chagas disease.
Thermoradiation inactivation of naturally occurring organisms in soil
Samples of soil collected from Kennedy Space Center near spacecraft assembly facilities were found to contain microorganisms very resistant to conventional sterilization techniques. The inactivation behavior of the naturally occurring spores in soil was investigated using dry heat and ionizing radiation, first separately, then in combination. Dry heat inactivation rates of spores were determined for 105 and 125 C. Radiation inactivation rates were determined for dose rates of 660 and 76 krad/hr at 25 C. Simultaneous combinations of heat and radiation were then investigated at 105, 110, 115, 120, and 125 C. Combined treatment was found to be highly synergistic requiring greatly reduced radiation doses to accomplish sterilization.
GCR Transport in the Brain: Assessment of Self-Shielding, Columnar Damage, and Nuclear Reactions on Cell Inactivation Rates
Radiation shield design is driven by the need to limit radiation risks while optimizing risk reduction with launch mass/expense penalties. Both limitation and optimization objectives require the development of accurate and complete means for evaluating the effectiveness of various shield materials and body-self shielding. For galactic cosmic rays (GCR), biophysical response models indicate that track structure effects lead to substantially different assessments of shielding effectiveness relative to assessments based on LET-dependent quality factors. Methods for assessing risk to the central nervous system (CNS) from heavy ions are poorly understood at this time. High-energy and charge (HZE) ion can produce tissue events resulting in damage to clusters of cells in a columnar fashion, especially for stopping heavy ions. Grahn (1973) and Todd (1986) have discussed a microlesion concept or model of stochastic tissue events in analyzing damage from HZE's. Some tissues, including the CNS, maybe sensitive to microlesion's or stochastic tissue events in a manner not illuminated by either conventional dosimetry or fluence-based risk factors. HZE ions may also produce important lateral damage to adjacent cells. Fluences of high-energy proton and alpha particles in the GCR are many times higher than HZE ions. Behind spacecraft and body self-shielding the ratio of protons, alpha particles, and neutrons to HZE ions increases several-fold from free-space values. Models of GCR damage behind shielding have placed large concern on the role of target fragments produced from tissue atoms. The self-shielding of the brain reduces the number of heavy ions reaching the interior regions by a large amount and the remaining light particle environment (protons, neutrons, deuterons. and alpha particles) may be the greatest concern. Tracks of high-energy proton produce nuclear reactions in tissue, which can deposit doses of more than 1 Gv within 5 - 10 cell layers. Information on rates of cell killing from GCR, including patterns of cell killing from single particle tracks. can provide useful information on expected differences between proton and HZE tracks and clinical experiences with photon irradiation. To model effects on cells in the brain, it is important that transport models accurately describe changes in the GCR due to interactions in the cranium and proximate tissues. We describe calculations of the attenuated GCR particle fluxes at three dose-points in the brain and associated patterns of cell killing using biophysical models. The effects of the brain self-shielding and bone-tissue interface of the skull in modulating the GCR environment are considered. For each brain dose-point, the mass distribution in the surrounding 4(pi) solid angle is characterized using the CAM model to trace 512 rays. The CAM model describes the self-shielding by converting the tissue distribution to mass-equivalent aluminum, and nominal values of spacecraft shielding is considered. Particle transport is performed with the proton, neutron, and heavy-ion transport code HZETRN with the nuclear fragmentation model QMSFRG. The distribution of cells killed along the path of individual GCR ions is modeled using in vitro cell inactivation data for cells with varying sensitivity. Monte Carlo simulations of arrays of inactivated cells are considered for protons and heavy ions and used to describe the absolute number of cell killing events of various magnitude in the brain from the GCR. Included are simulations of positions of inactivated cells from stopping heavy ions and nuclear stars produced by high-energy ions most importantly, protons and neutrons.