The nonlinear dynamics and fluctuations of mRNA levels in cell cycle coupled transcription.
ABSTRACT: Gene transcription is a noisy process, and cell division cycle is an important source of gene transcription noise. In this work, we develop a mathematical approach by coupling transcription kinetics with cell division cycles to delineate how they are combined to regulate transcription output and noise. In view of gene dosage, a cell cycle is divided into an early stage [Formula: see text] and a late stage [Formula: see text]. The analytical forms for the mean and the noise of mRNA numbers are given in each stage. The analysis based on these formulas predicts precisely the fold change r* of mRNA numbers from [Formula: see text] to [Formula: see text] measured in a mouse embryonic stem cell line. When transcription follows similar kinetics in both stages, r* buffers against DNA dosage variation and r* ? (1, 2). Numerical simulations suggest that increasing cell cycle durations up-regulates transcription with less noise, whereas rapid stage transitions induce highly noisy transcription. A minimization of the transcription noise is observed when transcription homeostasis is attained by varying a single kinetic rate. When the transcription level scales with cellular volume, either by reducing the transcription burst frequency or by increasing the burst size in [Formula: see text], the noise shows only a minor variation over a wide range of cell cycle stage durations. The reduction level in the burst frequency is nearly a constant, whereas the increase in the burst size is conceivably sensitive, when responding to a large random variation of the cell cycle durations and the gene duplication time.
Project description:Ultrasound (US) has emerged as a promising noninvasive modality for neuromodulation. Despite previous evidence that US may mediate cellular response by activating mechanosensitive ion channels embedded in the cell membrane, the underlying mechanism is not well understood. In this work, we developed a vertically deployed surface acoustic wave (VD-SAW) platform that generates 30?MHz focused ultrasound wave for mechanical stimulation of single cells. We investigated the role of Piezo1 in mediating the intracellular calcium response ( [Formula: see text] ) of HEK293T cells in response to pulsed US operated at a peak pressure of 1.6?MPa with 20% duty cycle, and a total treatment time of 60?s. We observed that the elicited calcium response depends critically on the pulse repetition frequency (PRF) or burst duration of the US, as well as the presence of the Piezo1. Significantly higher [Formula: see text] increase was produced in the Piezo1-transfected (P1TF) than in the Piezo1-knockout (P1KO) HEK293T cells. Furthermore, higher calcium response probability, stronger and faster [Formula: see text] increase, and greater cell displacement were produced at 2?Hz PRF with 100?ms burst duration than 200?Hz PRF with 1?ms burst duration. Altogether, we have demonstrated that the VD-SAW platform provides a unique and versatile tool for investigating US-induced mechanotransduction at the single cell level.
Project description:BACKGROUND:Surrounding green, air pollution, and noise have been associated with cardiometabolic diseases, but most studies have assessed only one of these correlated exposures. OBJECTIVES:We aimed to evaluate associations of combined exposures to green, air pollution, and road traffic noise with cardiometabolic diseases. METHODS:In this cross-sectional study, we studied associations between self-reported physician-diagnosed diabetes, hypertension, heart attack, and stroke from a Dutch national health survey of 387,195 adults and residential surrounding green, annual average air pollutant concentrations [including particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]), PM with aerodynamic diameter [Formula: see text] ([Formula: see text]), nitrogen dioxide ([Formula: see text]), and oxidative potential (OP) with the dithiothreitol (DTT) assay ([Formula: see text])] and road traffic noise. Logistic regression models were used to analyze confounding and interaction of surrounding green, air pollution, and noise exposure. RESULTS:In single-exposure models, surrounding green was inversely associated with diabetes, while air pollutants ([Formula: see text], [Formula: see text]) and road traffic noise were positively associated with diabetes. In two-exposure analyses, associations with green and air pollution were attenuated but remained. The association between road traffic noise and diabetes was reduced to unity when adjusted for surrounding green or air pollution. Air pollution and surrounding green, but not road traffic noise, were associated with hypertension in single-exposure models. The weak inverse association of surrounding green with hypertension attenuated and lost significance when adjusted for air pollution. Only [Formula: see text] was associated with stroke and heart attack. CONCLUSIONS:Studies including only one of the correlated exposures surrounding green, air pollution, and road traffic noise may overestimate the association of diabetes and hypertension attributed to the studied exposure. https://doi.org/10.1289/EHP3857.
Project description:The fundamental noise limit of a phase-preserving amplifier at frequency [Formula: see text] is the standard quantum limit [Formula: see text]. In the microwave range, the best candidates have been amplifiers based on superconducting quantum interference devices (reaching the noise temperature [Formula: see text] at 700?MHz), and non-degenerate parametric amplifiers (reaching noise levels close to the quantum limit [Formula: see text] at 8?GHz). We introduce a new type of an amplifier based on the negative resistance of a selectively damped Josephson junction. Noise performance of our amplifier is limited by mixing of quantum noise from Josephson oscillation regime down to the signal frequency. Measurements yield nearly quantum-limited operation, [Formula: see text] at 2.8?GHz, owing to self-organization of the working point. Simulations describe the characteristics of our device well and indicate potential for wide bandwidth operation.
Project description:BACKGROUND:Evidence on the association between road traffic noise and diabetes risk is sparse and inconsistent with respect to how confounding by air pollution was treated. OBJECTIVES:In this study, we aimed to examine whether long-term exposure to road traffic noise over 25 years is associated with incidence of diabetes, independent of air pollution. METHODS:A total of 28,731 female nurses from the Danish Nurse cohort ([Formula: see text] at recruitment in 1993 or 1999) were linked to the Danish National Diabetes Register with information on incidence of diabetes from 1995 until 2013. The annual mean weighted levels of 24-h average road traffic noise ([Formula: see text]) at nurses' residences from 1970 until 2013 were estimated with the Nord2000 method and annual mean levels of particulate matter (PM) with diameter [Formula: see text] and [Formula: see text] ([Formula: see text] and [Formula: see text]), nitrogen dioxide ([Formula: see text]), and nitrogen oxide ([Formula: see text]) with the Danish AirGIS modeling system. Cox proportional hazards regression models were used to examine the association between residential [Formula: see text] in four different exposure windows (1-, 5-, 10-, and 25-years) and the incidence of diabetes, adjusted for lifestyle factors and air pollutants. RESULTS:Of 23,762 nurses free of diabetes at the cohort baseline, 1,158 developed diabetes during a mean follow-up of 15.2 years. We found weak positive associations between 5-y mean exposure to [Formula: see text] (per [Formula: see text] increase) and diabetes incidence in a crude model [hazard ratio (HR): 1.07; 95% confidence interval (CI): 0.99, 1.12], which attenuated in a model adjusted for lifestyle factors (HR:1.04; 95% CI: 0.97, 1.12), and reached unity after additional adjustment for [Formula: see text] (HR: 0.99; 0.91, 1.08). In analyses by level of urbanization, we found a positive association between noise and diabetes in urban areas (HR:1.27; 95% CI: 0.98, 1.63) that was unchanged after adjusting for [Formula: see text] (HR: 1.25; 95% CI: 0.97, 1.62), but we found no apparent association in provincial (HR: 1.02; 95% CI: 0.88, 1.18) or rural areas (HR: 0.97; 95% CI: 0.87, 1.08). CONCLUSION:In the nationwide cohort of Danish nurses 44 years of age and older, we found no association between long-term exposure to road traffic noise and diabetes incidence after adjustment for [Formula: see text] but found suggestive evidence of an association limited to urban areas. https://doi.org/10.1289/EHP4389.
Project description:<h4>Background</h4>Noise from wind turbines (WTs) is reported as more annoying than traffic noise at similar levels, raising concerns as to whether WT noise (WTN) increases risk for cardiovascular disease, as observed for traffic noise.<h4>Objectives</h4>We aimed to investigate whether long-term exposure to WTN increases risk of myocardial infarction (MI) and stroke.<h4>Methods</h4>We identified all Danish dwellings within a radius 20 times the height of the closest WT and 25% of the dwellings within [Formula: see text] the height of the closest WT. Using data on WT type and simulated hourly wind at each WT, we estimated hourly outdoor and low frequency (LF) indoor WTN for each dwelling and derived 1-y and 5-y running nighttime averages. We used hospital and mortality registries to identify all incident cases of MI ([Formula: see text]) and stroke ([Formula: see text]) among all adults age 25-85 y ([Formula: see text]), who lived in one of these dwellings for [Formula: see text] over the period 1982-2013. We used Poisson regression to estimate incidence rate ratios (IRRs) adjusted for individual- and area-level covariates.<h4>Results</h4>IRRs for MI in association with 5-y nighttime outdoor WTN [Formula: see text] (vs. [Formula: see text]) dB(A) and indoor LF WTN [Formula: see text] (vs. [Formula: see text]) dB(A) were 1.21 [95% confidence interval (CI): 0.91, 1.62; 47 exposed cases] and 1.29 (95% CI: 0.73, 2.28; 12 exposed cases), respectively. IRRs for intermediate categories of outdoor WTN [24-30, 30-36, and [Formula: see text] vs. [Formula: see text]] were slightly above the null and of similar size: 1.08 (95% CI: 1.04, 1.12), 1.07 (95% CI: 1.00, 1.12), and 1.06 (95% CI: 0.93, 1.22), respectively. For stroke, IRRs for the second and third outdoor exposure groups were similar to those for MI, but near or below the null for higher exposures.<h4>Conclusions</h4>We did not find convincing evidence of associations between WTN and MI or stroke. https://doi.org/10.1289/EHP3340.
Project description:Denitrifying bacteria accumulate [Formula: see text], NO, and N2O, the amounts depending on transcriptional regulation of core denitrification genes in response to O2-limiting conditions. The genes include nar, nir, nor and nosZ, encoding [Formula: see text]-, [Formula: see text]-, NO- and N2O reductase, respectively. We previously constructed a dynamic model to simulate growth and respiration in batch cultures of Paracoccus denitrificans. The observed denitrification kinetics were adequately simulated by assuming a stochastic initiation of nir-transcription in each cell with an extremely low probability (0.5% h-1), leading to product- and substrate-induced transcription of nir and nor, respectively, via NO. Thus, the model predicted cell diversification: after O2 depletion, only a small fraction was able to grow by reducing [Formula: see text]. Here we have extended the model to simulate batch cultivation with [Formula: see text], i.e., [Formula: see text], NO, N2O, and N2 kinetics, measured in a novel experiment including frequent measurements of [Formula: see text]. Pa. denitrificans reduced practically all [Formula: see text] to [Formula: see text] before initiating gas production. The [Formula: see text] production is adequately simulated by assuming stochastic nar-transcription, as that for nirS, but with a higher probability (0.035 h-1) and initiating at a higher O2 concentration. Our model assumes that all cells express nosZ, thus predicting that a majority of cells have only N2O-reductase (A), while a minority (B) has [Formula: see text]-, NO- and N2O-reductase. Population B has a higher cell-specific respiration rate than A because the latter can only use N2O produced by B. Thus, the ratio [Formula: see text] is low immediately after O2 depletion, but increases throughout the anoxic phase because B grows faster than A. As a result, the model predicts initially low but gradually increasing N2O concentration throughout the anoxic phase, as observed. The modelled cell diversification neatly explains the observed denitrification kinetics and transient intermediate accumulations. The result has major implications for understanding the relationship between genotype and phenotype in denitrification research.
Project description:Although multiple intraoperative cerebral blood flow (CBF) monitoring techniques are currently available, a quantitative method that allows for continuous monitoring and that can be easily integrated into the surgical workflow is still needed. Laser speckle contrast imaging (LSCI) is an optical imaging technique with a high spatiotemporal resolution that has been recently demonstrated as feasible and effective for intraoperative monitoring of CBF during neurosurgical procedures. This study demonstrates the impact of retrospective motion correction on the quantitative analysis of intraoperatively acquired LSCI images. LSCI images were acquired through a surgical microscope during brain tumor resection procedures from 10 patients under baseline conditions and after a cortical stimulation in three of those patients. The patient's electrocardiogram (ECG) was recorded during acquisition for postprocess correction of pulsatile artifacts. Automatic image registration was retrospectively performed to correct for tissue motion artifacts, and the performance of rigid and nonrigid transformations was compared. In baseline cases, the original images had [Formula: see text] noise across 16 regions of interest (ROIs). ECG filtering moderately reduced the noise to [Formula: see text], while image registration resulted in a further noise reduction of [Formula: see text]. Combined ECG filtering and image registration significantly reduced the noise to [Formula: see text] ([Formula: see text]). Using the combined motion correction, accuracy and sensitivity to small changes in CBF were improved in cortical stimulation cases. There was also excellent agreement between rigid and nonrigid registration methods (15/16 ROIs with [Formula: see text] difference). Results from this study demonstrate the importance of motion correction for improved visualization of CBF changes in clinical LSCI images.
Project description:Large initial condition ensembles of a climate model simulation provide many different realizations of internal variability noise superimposed on an externally forced signal. They have been used to estimate signal emergence time at individual grid points, but are rarely employed to identify global fingerprints of human influence. Here we analyze 50- and 40-member ensembles performed with 2 climate models; each was run with combined human and natural forcings. We apply a pattern-based method to determine signal detection time [Formula: see text] in individual ensemble members. Distributions of [Formula: see text] are characterized by the median [Formula: see text] and range [Formula: see text], computed for tropospheric and stratospheric temperatures over 1979 to 2018. Lower stratospheric cooling-primarily caused by ozone depletion-yields [Formula: see text] values between 1994 and 1996, depending on model ensemble, domain (global or hemispheric), and type of noise data. For greenhouse-gas-driven tropospheric warming, larger noise and slower recovery from the 1991 Pinatubo eruption lead to later signal detection (between 1997 and 2003). The stochastic uncertainty [Formula: see text] is greater for tropospheric warming (8 to 15 y) than for stratospheric cooling (1 to 3 y). In the ensemble generated by a high climate sensitivity model with low anthropogenic aerosol forcing, simulated tropospheric warming is larger than observed; detection times for tropospheric warming signals in satellite data are within [Formula: see text] ranges in 60% of all cases. The corresponding number is 88% for the second ensemble, which was produced by a model with even higher climate sensitivity but with large aerosol-induced cooling. Whether the latter result is physically plausible will require concerted efforts to reduce significant uncertainties in aerosol forcing.
Project description:This paper proposes the use of astrocytes to realize Boolean logic gates, through manipulation of the threshold of [Formula: see text] ion flows between the cells based on the input signals. Through wet-lab experiments that engineer the astrocytes cells with pcDNA3.1-hGPR17 genes as well as chemical compounds, we show that both AND and OR gates can be implemented by controlling [Formula: see text] signals that flow through the population. A reinforced learning platform is also presented in the paper to optimize the [Formula: see text] activated level and time slot of input signals [Formula: see text] into the gate. This design platform caters for any size and connectivity of the cell population, by taking into consideration the delay and noise produced from the signalling between the cells. To validate the effectiveness of the reinforced learning platform, a [Formula: see text] signalling simulator was used to simulate the signalling between the astrocyte cells. The results from the simulation show that an optimum value for both the [Formula: see text] activated level and time slot of input signals [Formula: see text] is required to achieve up to 90% accuracy for both the AND and OR gates. Our method can be used as the basis for future Neural-Molecular Computing chips, constructed from engineered astrocyte cells, which can form the basis for a new generation of brain implants.
Project description:<h4>Background</h4>The pyrethroid deltamethrin (DM) is broadly used for insect control. Although DM hyperexcites neuronal networks by delaying inactivation of axonal voltage-dependent [Formula: see text] channels, this mechanism is unlikely to mediate neurotoxicity at lower exposure levels during critical perinatal periods in mammals.<h4>Objectives</h4>We aimed to identify mechanisms by which acute and subchronic DM altered axonal and dendritic growth, patterns of synchronous [Formula: see text] oscillations (SCOs), and electrical spike activity (ESA) functions critical to neuronal network formation.<h4>Methods</h4>Measurements of SCOs using [Formula: see text] imaging, ESA using microelectrode array (MEA) technology, and dendritic complexity using Sholl analysis were performed in primary murine cortical neurons from wild-type (WT) and/or ryanodine receptor 1 ([Formula: see text]) mice between 5 and 14 d in vitro (DIV). [Formula: see text] binding analysis and a single-channel voltage clamp were utilized to measure engagement of RyRs as a direct target of DM.<h4>Results</h4>Neuronal networks responded to DM ([Formula: see text]) as early as 5 DIV, reducing SCO amplitude and depressing ESA and burst frequencies by 60-70%. DM ([Formula: see text]) enhanced axonal growth in a nonmonotonic manner. [Formula: see text] enhanced dendritic complexity. DM stabilized channel open states of RyR1, RyR2, and cortical preparations expressing all three isoforms. DM ([Formula: see text]) altered gating kinetics of RyR1 channels, increasing mean open time, decreasing mean closed time, and thereby enhancing overall open probability. SCO patterns from cortical networks expressing [Formula: see text] were more responsive to DM than WT. [Formula: see text] neurons showed inherently longer axonal lengths than WT neurons and maintained less length-promoting responses to nanomolar DM.<h4>Conclusions</h4>Our findings suggested that RyRs were sensitive molecular targets of DM with functional consequences likely relevant for mediating abnormal neuronal network connectivity in vitro. https://doi.org/10.1289/EHP4583.