Multiphasic Response Research Articles

Pharmacologic ascorbate induces transient hypoxia sensitizing pancreatic ductal adenocarcinoma to a hypoxia activated prodrug

Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbate's pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation.To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated that the generation of hydrogen peroxide consumes oxygen, which is offset at later time points by a reduction in oxygen consumption due to hydrogen peroxide's cytotoxic effect.In vivo, photoacoustic imaging showed pharmacologic ascorbate treatment at sublethal levels triggered a complex, multi-phasic response in tumor oxygenation across both cell lines. Initially, ascorbate generated transient hypoxia within minutes through hydrogen peroxide production, via reactions that consume oxygen. This initial hypoxic phase peaked at around 150 s and then gradually subsided. However, at longer time scales (approximately 300 s) a vasodilation effect triggered by ascorbate resulted in increased blood flow and subsequent reoxygenation. Combining sublethal levels of i. p. Ascorbate with evofosfamide significantly prolonged tumor doubling time in MIA Paca-2 and A549 xenografts compared to either treatment alone. This improvement, however, was only observed in a subpopulation of tumors, highlighting the complexity of the oxygenation response.

The Integration of Top-down and Bottom-up Inputs to the Striatal Cholinergic Interneurons.

Cholinergic interneurons (ChIs) are important for learning and memory. They exhibit a multiphasic excitation-pause-rebound response to reward or sensory cues indicating a reward, believed to gate dopamine-dependent learning. Although ChIs receive extensive top-down inputs from the cortex and bottom-up inputs from the thalamus and midbrain, it is unclear which inputs are involved in the development of ChI multiphasic activity. We used a single-unit recording of putative ChIs (pChIs) in response to cortical and visual stimulation to investigate how top-down and bottom-up inputs regulate the firing pattern of ChIs. We demonstrated that cortical stimulation strongly regulates pChIs, with the maximum firing rate occurring at the peak of the inverted local field potential (iLFP), reflecting maximum cortical stimulation. Pauses in pChIs occurred during the descending phase of iLFP, indicating withdrawal of excitatory cortical input. Visual stimulation induced long pauses in pChIs, but it is unlikely that bottom- up inputs alone induce pauses in behaving animals. Also, the firing pattern of ChIs triggered by visual stimulation did not correlate with the iLFP as it did after cortical stimulation. Top-down and bottom-up inputs independently regulate the firing pattern of ChIs with similar efficacy but notably produce a well-defined pause in ChI firing. This study provides in vivo evidence that the multiphasic ChI response may require both top-down and bottom-up inputs. The findings suggest that the firing pattern of ChIs correlated to the iLFP might be a useful tool for estimating the degree of contribution of top-down and bottom-up inputs in regulating the firing activity of ChIs.

Modulation of neuronal activity in human centromedian nucleus during an auditory attention and working memory task

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5–45 Hz). Average peri‑stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13–45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.

Alkaline in-situ leaching of uranium in low-permeability sandstone: An experimental study using online low field nuclear magnetic resonance (LF-NMR) spectroscopy on multiphase response

Uranium leaching was influenced by multiphase flow and geological structure during in-situ recovery of uranium (ISRU). In this study, the characteristics of multiphase flow and pore structure responding to the alkaline ISRU was investigated, using a real-time triaxial coupling nuclear magnetic resonance experiment system. The component of leaching solute, flow regime and pore structure evolution was monitored online through the T2 spectrum and magnetic resonance imaging (MRI), and corresponding coupling correlation of uranium recovery and pore conductivity was analyzed. The result demonstrates that the uranium sandstone was composed of micropore (1–10 ms), mesopore (10–100 ms), and macropore (>100 ms) corresponding to different relaxation times (ms). The uranium migration was mainly dominated by mesopore, and mineral dissolution and precipitation were influenced by micropore and macropore. Uranium recovery based on colloidal tetravalent and hexavalent uranium particles was exponentially correlated with the volume of leaching solution passed through the solute (solid phase/pores) and slightly contributed by the seal pore and matrix-bearing uranium. The physical migration, mineral dissolution, carbonate precipitation, and alternation by reactive transport occurred and was influenced by the hydrodynamic pressure. The dissolution of U, Ca, and Si experienced a dynamic period (0–5 PV), buffer period (5–37 PV), transition period (37–200 PV), and stable period (200–319 PV); peak concentration of U occurred at 5 PV, and 73.4% of uranium was recovered in the scope of 0–37 PV. Here, 1 PV represents the sample pore volume of 3.95 cm3. The porosity and permeability were enlarged under the influence of the chemical dissolution and physical migration, but decreased with the precipitation of CaCO3 and SiO2 colloids. Permeability and porosity exhibited a positive correlation with the volume of solution passed through in the range of 0–100 PV, but a negative correlation was observed in the range of 100–319 PV. The findings provide significant insight into ISRU engineering practice.

A large deformation multiphase continuum mechanics model for shock loading of soft porous materials

AbstractA large deformation, coupled finite‐element (FE) model is developed to simulate the multiphase response of soft porous materials subjected to high strain‐rate loading. The approach is based on the theory of porous media (TPM) at large deformations. Simplifications to the one‐dimensional regime studied in the numerical simulations follow. An overview of several different time integration schemes is presented for the purpose of solving the nonlinear dynamic coupled balance of momenta (mixture and fluid) and balance of mass of the mixture equations. Numerical examples are presented for (i) verification against closed‐form analytical solutions assuming small loads, (ii) demonstrating large deformation effects at high strain‐rate, and (iii) showing differences in deformations between a single‐phase elastodynamics model with occluded compressible pore fluid and a multiphase poroelastodynamics model at high strain‐rate. The multiphase model shows that the relative motion of the pore fluid significantly dampens the deformation response of the solid skeleton as compared to the single‐phase model, and makes it possible to extract quantitative values for the stresses of the different constituents, thereby allowing one to form preliminary conclusions about the onset of damage in the solid skeleton. The novelty of the current work is developing a multiphase, large deformation, mixture theory numerical model for high strain‐rate loading of soft porous materials. It was discovered that explicit, adaptive time‐stepping Runge–Kutta schemes offer high accuracy at relatively low cost when compared to traditional implicit or explicit central difference time‐stepping schemes for shock‐like loadings. Shock viscosity is added to the mixture momentum balance equation to regularize the shock front, and a stabilization term is added to the mixture mass balance equation to stabilize equal order interpolation finite elements for the coupled finite element solution of multiphase materials.

Thermotolerant PGPR consortium B3P modulates physio-biochemical and molecular machinery for enhanced heat tolerance in maize during early vegetative growth

BackgroundGlobal warming and irregular changes in temperature are a serious threat to plant growth with a significant negative impact on yield. Global maize productivity has decreased significantly due to sudden temperature fluctuations and heat waves especially in the regions severely hit by climate change.ResultsThe current study demonstrates the potential of beneficial bacteria for inducing heat tolerance in maize during early growth. Three Bacillus spp. AH-08, AH-67, SH-16, and one Pseudomonas spp. SH-29 showed the ability to grow and exhibited multiple plant-beneficial traits up to 45 ± 2 °C. At temperatures of 45 and 50 °C, Bacillus sp. SH-16 exhibited upregulation of two small heat shock proteins (HSP) of 15 and 30 kDa, while SH-16 and AH-67 showed upregulation of two large HSP of 65 and 100 kDa. Plant-inoculation with the consortium B3P (3 Bacillus + 1 Pseudomonas spp.) was carried out on six hybrid maize varieties pre-grown at 25 ± 2 ºC. Heat shock was applied to 10-day-old seedlings as: 3 h at 38ºC, 48 h recovery period, and then 48 h at 42ºC. The B3P treatment showed significant improvement in the overall plant growth (plant height, root & shoot fresh & dry weight, root and leaf area) with a higher level of CAT, POD, total chlorophyll, and carotenoids, while low concentration of MDA. A non-significant difference was observed in case of total cell protein and amino acids after B3P-treatment under stress. The expression of HSP1 and HSP18 in Malka and YH-5427 while HSP70 and HSP101 were higher in FH-1046 and Gohar as compared to non-inoculated treatment.ConclusionsThese findings indicate that heat-tolerant plant-growth promoting rhizobacteria (Ht-PGPR) exert versatile, multiphasic and differential response to improve plant growth and heat-tolerance in different maize varieties during seedling/ early vegetative growth. Subsequent research will be focused on the field evaluation of these PGPR to see the field and yield response of this consortium under natural temperature fluctuations in field.

Natural variation in salt-induced root growth phases and their contribution to root architecture plasticity.

The root system architecture of a plant changes during salt stress exposure. Different accessions of Arabidopsis thaliana have adopted different strategies in remodeling their root architecture during salt stress. Salt induces a multiphase growth response in roots, consisting of a stop phase, quiescent phase, recovery phase and eventually a new level of homeostasis. We explored natural variation in the length of and growth rate during these phases in both main and lateral roots and find that some accessions lack the quiescent phase. Using mathematical models and correlation-based network, allowed us to correlate dynamic traits to overall root architecture and discover that both the main root growth rate during homeostasis and lateral root appearance are the strongest determinants of overall root architecture. In addition, this approach revealed a trade-off between investing in main or lateral root length during salt stress. By studying natural variation in high-resolution temporal root growth using mathematical modeling, we gained new insights in the interactions between dynamic root growth traits and we identified key traits that modulate overall root architecture during salt stress. This article is protected by copyright. All rights reserved.

Assessment of the cytoskeletal impact of beta-actin mutations leading to non-muscle actinopathies by means of dual laser optical tweezers (DLOT).

Actin plays crucial roles in critical cellular processes, like the dynamic remodeling of the cytoskeleton. Non-muscle actinopathies (NMAs) are disorders caused by heterozygous mutations in the genes encoding for the β- and γ-isoforms of cytoskeletal actin, whose underlying mechanisms remain to be resolved. We used a Dual Laser Optical Tweezers (DLOT) to characterize the viscoelastic properties of the membrane-cytoskeleton system of neurons wild-type and expressing the β-actin mutation R196H associated with malformations of cortical development. Ramp-and-hold pulls to generate a tether were imposed on the membrane of neuron progenitor cells (NPC) and mature neurons (NC). Tether formation-elongation is characterized by a multiphase force response: an early rise to a peak associated with the formation of the tether and followed by a drop to a minimum; a continuous rise during the ramp at a rate that exponentially decreases to a steady rate; an exponential force relaxation to a constant value during the hold. The force responses were simulated by using a 2nd order Maxwell viscoelastic arrangement that provides the estimates of both undamped (k0) and damped elastic coefficients (k1 and k2) and the friction coefficients (η1 and η2) of tether formation. In both WT and R196H neurons the undamped elastic coefficient is not significantly affected by the maturation process. During maturation, friction and damped elastic coefficients show significant reductions in WT neurons, while in mutant neurons all the coefficients in NPCs are already reduced to values similar to those in NCs. The work provides the mechanical evidence that R196H mutation induces a faster differentiation of the NPC toward the greater connectivity of the mature neuron. Supported by EJP RD 2019.

High-frequency neuronal signal better explains multi-phase BOLD response

Visual stimulation-evoked blood-oxygen-level dependent (BOLD) responses can exhibit more complex temporal dynamics than a simple monophasic response. For instance, BOLD responses sometimes include a phase of positive response followed by a phase of post-stimulus undershoot. Whether the BOLD response during these phases reflects the underlying neuronal signal fluctuations or is contributed by non-neuronal physiological factors remains elusive. When presenting blocks of sustained (i.e. DC) light ON-OFF stimulations to unanesthetized rats, we observed that the response following a decrease in illumination (i.e. OFF stimulation-evoked BOLD response) in the visual cortices displayed reproducible multiple phases, including an initial positive BOLD response, followed by an undershoot and then an overshoot before the next ON trial. This multi-phase BOLD response did not result from the entrainment of the periodic stimulation structure. When we measured the neural correlates of these responses, we found that the high-frequency band from the LFP power (300 – 3000 Hz, multi-unit activity (MUA)), but not the power in the gamma band (30 – 100 Hz) exhibited the same multiphasic dynamics as the BOLD signal. This study suggests that the post-stimulus phases of the BOLD response can be better explained by the high-frequency neuronal signal.

Predictive value of tachycardia for mortality in trauma-related haemorrhagic shock: a systematic review and meta-regression

ObjectivesHeart rate (HR) is one of the physiological variables in the early assessment of trauma-related haemorrhagic shock, according to Advanced Trauma Life Support (ATLS). However, its efficiency as predictor of...

Soil degradation kinetics of oxybenzone (Benzophenone-3) and toxicopathological assessment in the earthworm, Eisenia fetida

A preponderance of recent evidence indicates that oxybenzone and other personal-care product chemicals threaten the biota inhabiting various ecological niches. What is understudied is the ecotoxicological impact of oxybenzone, a UV filter in sunscreens and anti-aging products, to terrestrial/soil organisms that are keystone species in these habitats. In the present study, acute exposure (14-day) to oxybenzone resulted in earthworm mortality (LC50 of 364 mg/kg) and growth rate inhibition. Environmentally relevant concentration of oxybenzone (3.64, 7.28 and 36.4 mg/kg) at exposures of 7-day, 14-day, 28-day induced oxidative stress and neurotoxicity followed by perturbations in reproduction processes and changes in vital organs. Decreased levels of superoxide dismutase (SOD) and catalase (CAT) activity were statistically lower than controls (p < 0.05) on day 14 for all three concentrations, while glutathione-s-transferase (GST) activity was significantly elevated from controls on days 7 and 14. On day 28, SOD and CAT activities were either not significantly different from the control or were higher, demonstrating a temporal multiphasic response of anti-oxidant enzymes. GST activity on day 28 was significantly reduced compared to controls. Acetylcholinesterase levels across the three-time points exhibited a complicated behaviour, with every exposure concentration being significantly different from the control. Chronic exposure negatively influences earthworm health status with elevated biomarker values analysed using IBRv2 index. This, in turn, impacted higher levels of hierarchical organization, significantly impairing reproduction and organismal homeostasis at the histological level and manifesting as decreasing cocoon formation and successful hatching events. Thus, the overall findings demonstrate that oxybenzone is toxic to Eisenia fetida at low-level, long-term exposure. Based on the concentration verification analysis and application of the EPA PestDF tool, oxybenzone undergoes single first-order kinetics degradation in OECD soil with DT50 and DT90 as 8.7–28.9 days, respectively.

Stability and Effect of Parkinsonian State on Deep Brain Stimulation Cortical Evoked Potentials

ObjectivesTo characterize and compare the stability of cortical potentials evoked by deep brain stimulation (DBS) of the subthalamic nucleus (STN) across the naïve, parkinsonian, and pharmacologically treated parkinsonian states. To advance cortical potentials as possible biomarkers for DBS programming. Materials and MethodsSerial electrocorticographic (ECoG) recordings were made more than nine months from a single non-human primate instrumented with bilateral ECoG grids spanning anterior parietal to prefrontal cortex. Cortical evoked potentials (CEPs) were generated through time-lock averaging of the ECoG recordings to DBS pulses delivered unilaterally in the STN region using a chronically implanted, six-contact, scaled DBS lead. Recordings were made across the naïve followed by mild and moderate parkinsonian conditions achieved by staged injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin. In addition to characterizing the spatial distribution and stability of the response within each state, changes in the amplitude and latency of CEP components as well as in the frequency content were examined in relation to parkinsonian severity and dopamine replacement. ResultsIn the naïve state, the STN DBS CEP presented as a multiphase response maximal over M1 cortex, with components attributable to physiological activity distinguishable from stimulus artifact as early as 0.45–0.75 msec poststimulation. When delivered using therapeutically effective parameters in the parkinsonian state, the CEP was highly stable across multiple recording sessions within each behavioral state. Across states, significant differences were present with respect to both the latency and amplitude of individual response components, with greater differences present for longer-latency components (all p < 0.05). Power spectral density analysis revealed a high-beta peak within the evoked response, with significant changes in power between disease states across multiple frequency bands. ConclusionsOur findings underscore the spatiotemporal specificity and relative stability of the DBS-CEP associated with different disease states and with therapeutic benefit. DBS-CEP may be a viable biomarker for therapeutic programming.

A 3D in vitro model of the device-tissue interface: functional and structural symptoms of innate neuroinflammation are mitigated by antioxidant ceria nanoparticles

Objective. The recording instability of neural implants due to neuroinflammation at the device-tissue interface is a primary roadblock to broad adoption of brain-machine interfaces. While a multiphasic immune response, marked by glial scaring, oxidative stress (OS), and neurodegeneration, is well-characterized, the independent contributions of systemic and local ‘innate’ immune responses are not well-understood. We aimed to understand and mitigate the isolated the innate neuroinflammatory response to devices. Approach. Three-dimensional primary neural cultures provide a unique environment for studying the drivers of neuroinflammation by decoupling the innate and systemic immune systems, while conserving an endogenous extracellular matrix and structural and functional network complexity. We created a three-dimensional in vitro model of the device-tissue interface by seeding primary cortical cells around microwires. Live imaging of both dye and Adeno-Associated Virus (AAV) - mediated functional, structural, and lipid peroxidation fluorescence was employed to characterize the neuroinflammatory response. Main results. Live imaging of microtissues over time revealed independent innate neuroinflammation, marked by increased OS, decreased neuronal density, and increased functional connectivity. We demonstrated the use of this model for therapeutic screening by directly applying drugs to neural tissue, bypassing low bioavailability through the in vivo blood brain barrier. As there is growing interest in long-acting antioxidant therapies, we tested efficacy of ‘perpetual’ antioxidant ceria nanoparticles, which reduced OS, increased neuronal density, and protected functional connectivity. Significance. Our three-dimensional in vitro model of the device-tissue interface exhibited symptoms of OS-mediated innate neuroinflammation, indicating a significant local immune response to devices. The dysregulation of functional connectivity of microcircuits surround implants suggests the presence of an observer effect, in which the process of recording neural activity may fundamentally change the neural signal. Finally, the demonstration of antioxidant ceria nanoparticle treatment exhibited substantial promise as a neuroprotective and anti-inflammatory treatment strategy.

Multi-infrastructure energy systems resiliency assessment in the presence of multi-hazards disasters

The continuous operation of critical infrastructures such as electricity, gas, and water networks is one of the major fundamentals of a sustainable city considering their interdependency. Regarding the interdependency of these infrastructures, an interruption in each one can cause severe deficiencies and a lack of energy supply sustainability in the other infrastructures. Additionally, multi-hazard disasters have always been a threat to a well-constructed multi-infrastructure energy system (MIESs). MIESs can simultaneously be exposed to multiple high impacts of different disasters with a low probability. Its consequences may overlap with other hazards and lead to temporal or permanent damages for infrastructures’ components. This paper studies the resiliency of a MIES, including the interdependence of natural gas and electricity networks affected by multi-hazard disasters such as hurricane and earthquakes. The impacts of different hazards with various levels are modeled using multi-phase performance response curves to determine the time-dependent performance levels of the MIES in different phases. The impacts of hazard levels on component and system performance are analyzed, and node resilience criteria are employed for various energy subsystems to evaluate the resilience of the MIES. Based on the results, the simultaneous occurrence of the different hazards on interdependent infrastructures can boost and overlap the impact of a single hazard on the MIES.

The role of water in environmental migration

AbstractWater has always been a driver of human mobility, migration, and displacement. But water is increasingly central to explaining environmental migration in the context of climate change. Most studies of the relationship between water and environmental migration are framed around punctuated, extreme weather events and disasters that either limit agricultural or livestock productivity or make a community physically unlivable. The chronic experiences of household water insecurity and poor water governance also shape migration decision‐making through a variety of social, political, and economic factors, but these relationships have received considerably less attention. This article provides an overview of punctuated and chronic water‐related triggers of environmental migration at the household level. We also offer a conceptual framework based on multiphasic response theory that highlights water's multiple roles in migration decision‐making. We close by reflecting on key gaps in the climate‐water‐migration literature, identifying research questions that might help us better understand these relationships, and considering the implications for sustainable development policies that could potentially ease pressures on water‐related displacement.

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning.

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and point to a role of this response in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).

Regulations of expressions of rat/human sulfotransferases by anticancer drug, nolatrexed, and micronutrients.

Cancer is related to the cellular proliferative state. Increase in cell-cycle regulatory function augments cellular folate pool. This pathway is therapeutically targeted. A number of drugs influences this metabolism, that is, folic acid, folinic acid, nolatrexed, and methotrexate. Our previous study showed methotrexate influences on rat/human sulfotransferases. Present study explains the effect of nolatrexed (widely used in different cancers) and some micronutrients on the expressions of rat/human sulfotransferases. Female Sprague-Dawley rats were treated with nolatrexed (01-100 mg/kg) and rats of both sexes were treated to folic acid (100, 200, or 400 mg/kg) for 2-weeks and their aryl sulfotransferase-IV (AST-IV; β-napthol sulfation) and sulfotransferase (STa; DHEA sulfation) activities, protein expression (western blot) and mRNA expression (RT-PCR) were tested. In human-cultured hepatocarcinoma (HepG2) cells nolatrexed (1 nM-1.2 mM) or folinic acid (10 nM-10 μM) were applied for 10 days. Folic acid (0-10 μM) was treated to HepG2 cells. PPST (phenol catalyzing), MPST (dopamine and monoamine), DHEAST (dehydroepiandrosterone and DHEA), and EST (estradiol sulfating) protein expressions (western-blot) were tested in HepG2 cells. Present results suggest that nolatrexed significantly increased sulfotransferases expressions in rat (protein, STa, F = 4.87, P < 0.05/mRNA, AST-IV, F = 6.702, P < 0.014; Student's t test, P < 0.01-0.05) and HepG2 cells. Folic acid increased sulfotransferases activity/protein in gender-dependant manner. Both folic and folinic acid increased several human sulfotransferases isoforms with varied level of significance (least or no increase at highest dose) in HepG2 cells pointing its dose-dependent multiphasic responses. The clinical importance of this study may be furthered in the verification of sulfation metabolism of several exogenous/endogenous molecules, drug-drug interaction and their influences on cancer pathophysiological processes. Further studies are necessary.

Predictive Mechanistic Model of Creep Response of Single-Layered Pressure-Sensitive Adhesive (PSA) Joints.

This paper explores the uniaxial tensile creep response of acrylic-based pressure-sensitive adhesive (PSA), which exhibits a unique multi-phase creep response that does not have the classical steady-state region due to multiple transitions caused by several competing mechanisms: (i) cavity nucleation and growth in the interior of the adhesive material of the PSA system, as well as at the interfaces between the PSA and the substrate; (ii) fibrillation of the bulk adhesive, and (iii) interfacial mechanical locking between the adhesive and the bonding substrate. This results in multiple regimes of strain hardening and strain softening, evidenced by multiple regions of steady-state creep, separated by strong transitions in the creep rates. This complex, multi-phase, nonlinear creep response cannot be described by conventional creep constitutive models commonly used for polymers in commercial finite element codes. Accordingly, based on the empirical uniaxial tensile creep response and the mechanisms behind it, a new mechanistic model was proposed. This is capable of quantitatively capturing the characteristic features of the multiphase creep response of single-layered PSA joints as a function of viscoelastic bulk properties and free energy of the PSA material, substrate surface roughness, and interfacial surface energy between the adhesive and substrate. This is the first paper to present the modeling approach for capturing unique multi-phase creep behavior of PSA joint under tensile loading.

A hormetic approach to understanding antidepressant effectiveness and the development of antidepressant tolerance - A conceptual view.

Antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) have complex temporal effects. They may worsen symptoms during early treatment, they may reduce depressive symptoms over several weeks of treatment, and they may lose effectiveness over more prolonged treatment or after repeated treatment trials. Conceptually, these effects fall within the domain of hormesis, which refers to a biphasic or multiphasic response to a drug or toxin. Hormetic effects are commonly triggered when a drug interacts with homeostatic mechanisms. We develop and evaluate a theoretical framework for understanding how adaptations to SSRIs that restore synaptic homeostasis may partially contribute to their hormetic effects. Specifically, the serotonin system adapts to SSRIs by suppressing the firing of serotonergic neurons, inhibiting the synthesis of serotonin, and reducing the overall content of serotonin in the brain. Moreover, rodent models such as inescapable shock show that serotonin neurotransmission to specific forebrain regions is a necessary, but insufficient cause of depressive symptoms. Our review suggests: (1) early worsening of symptoms may be related to the direct effects of SSRIs on synaptic serotonin; (2) the symptom-reducing effects could be related to the loss of serotonin content in the brain during SSRI exposure; (3) the loss of efficacy over prolonged exposure could be related to the central nervous system equilibrating to the SSRIs. The serotonin system's adaptations to SSRIs may play a clinically meaningful role in their hormetic effects on depressive symptoms. A complete understanding of SSRIs' hormetic effects will require exploring temporal dynamics in other neurotransmitter systems.

Unified thixotropic fluid model for soil liquefaction

The geotechnical earthquake engineering profession has struggled with the inherent complexity of the multiphase soil response to cyclic loading owing to the progressive nature of the generation of excess pore pressure (EPP) and degradation of soil stiffness and strength. One approach to improve understanding of the cyclic response and correlate the transition from a two-phase saturated soil to a single, fluid-phase liquefied soil is to treat the soil as a non-Newtonian viscous liquid. However, the work to date suggests that the viscous fluid model approach can only be implemented following the onset of sustained soil liquefaction. This paper presents a unified thixotropic fluid model and framework that effectively links the pre-shear soil fabric and its progressive cyclic response to the onset and maintained state of soil liquefaction. The framework treats the soil fabric as a fluid net-type structure proposed for use with thixotropic fluids, and presents the constitutive state and rate equations describing the deconstruction of the liquefiable soil fabric in response to cyclic loading. The unified framework uses physically meaningful soil parameters that can be obtained from common cyclic laboratory tests to seamlessly link the state-dependent and shear-strain-rate-dependent nature of soils to the generation of EPP, the latter of which is shown to increase in significance as EPP accumulates. The proposed thixotropic-induced excess pore pressure model should prove advantageous for use in forward modelling of the stress–strain rate response of liquefiable soil and generation of EPP.