Fisher information matrix for single molecules with stochastic trajectories

Tracking of objects in cellular environments has become a vital tool in molecular cell biology. A particularly important example is single molecule tracking which enables the study of the motion of a molecule in cellular environments and provides quantitative information on the behavior of individual molecules in cellular environments, which were not available before through bulk studies. Here, we consider a dynamical system where the motion of an object is modeled by stochastic differential equations (SDEs), and measurements are the detected photons emitted by the moving fluorescently labeled object, which occur at discrete time points, corresponding to the arrival times of a Poisson process, in contrast to uniform time points which have been commonly used in similar dynamical systems. The measurements are distributed according to optical diffraction theory, and therefore, they would be modeled by different distributions, e.g., a Born and Wolf profile for an out-of-focus molecule. For some special circumstances, Gaussian image models have been proposed. In this paper, we introduce a stochastic framework in which we calculate the maximum likelihood estimates of the biophysical parameters of the molecular interactions, e.g., diffusion and drift coefficients. More importantly, we develop a general framework to calculate the Cram\'er-Rao lower bound (CRLB), given by the inverse of the Fisher information matrix, for the estimation of unknown parameters and use it as a benchmark in the evaluation of the standard deviation of the estimates. There exists no established method, even for Gaussian measurements, to systematically calculate the CRLB for the general motion model that we consider in this paper. We apply the developed methodology to simulated data of a molecule with linear trajectories and show that the standard deviation of the estimates matches well with the square root of the CRLB

Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology

Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear. Knowledge gained on the biological basis of Pavlovian conditioning has led to the general acceptance that fear extinction may be a useful model in understanding the underlying mechanisms in the pathophysiology of anxiety disorders and may also be a good model for current therapies treating these disorders. Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction. It is also unclear how the neural correlates of fear extinction may mediate sex differences in the etiology, maintenance, and prevalence of psychiatric disorders. In this review, we begin by highlighting the epidemiological differences in incidence rate. We then discuss how estradiol (E2), a primary gonadal hormone, may modulate the mechanisms of fear extinction and mediate some of the sex differences observed in psychiatric disorders

The relationship between extravascular lung water and oxygenation in three patients with influenza A (H1N1)-induced respiratory failure

Zusammenfassung: Diese Fallsammlung berichtet über die Korrelation zwischen extravaskulärem Lungenwasser (EVLW) und dem arteriellen Sauerstoffpartialdruck/fraktionierten inspiratorischen Sauerstoffkonzentration (PaO2/FiO2) Quotienten bei drei Patienten mit schwerem Influenza A (H1N1)-induziertem Lungenversagen. Alle Patienten erlitten eine ausgeprägte Hypoxie (PaO2, 26-42 mmHg), mussten mit dem Biphasic Airway Pressure Mode (PEEP, 12-15 mmHg; FiO2, 0,8-1) mechanisch beatmet werden und wurden in 12 stündlichen Intervallen in die Bauchlage gedreht. Alle Patienten waren während 8-11 Tagen mit dem PICCO® System monitorisiert. Während der mechanischen Beatmung wurden ingesamt 62 simultane Bestimmungen des PaO2/FiO2 Quotienten und des EVLW durchgeführt. Es zeigte sich ein signifikanter Zusammenhang zwischen dem EVLW und dem PaO2/FiO2 Quotienten (Spearman-rho Korrelationskoeffizient, -0,852; p < 0,001). Bei allen Patienten war eine Abnahme des EVLW von einer Verbesserung der Oxygenation begleitet. Die Serumkonzentrationen der Laktatdehydrogenase waren bei allen Patienten erhöht und korrelierten signifikant mit dem EVLW während des Intensivaufenthaltes (Spearman-rho Korrelationskoeffizient, 0,786; p < 0,001). Zusammenfassend erscheint es, dass das EVLW bei Patienten mit schwerem H1N1-induziertem Lungenversagen erhöht ist und dabei eng mit Einschränkungen der Oxygenationsfunktion korrelier

Mars Science Laboratory Heatshield Aerothermodynamics: Design and Reconstruction

The Mars Science Laboratory heatshield was designed to withstand a fully turbulent heat pulse based on test results and computational analysis on a pre-flight design trajectory. Instrumentation on the flight heatshield measured in-depth temperatures in the thermal protection system. The data indicate that boundary layer transition occurred at 5 of 7 thermocouple locations prior to peak heating. Data oscillations at 3 pressure measurement locations may also indicate transition. This paper presents the heatshield temperature and pressure data, possible explanations for the timing of boundary layer transition, and a qualitative comparison of reconstructed and computational heating on the as-flown trajectory. Boundary layer Reynolds numbers that are typically used to predict transition are compared to observed transition at various heatshield locations. A uniform smooth-wall transition Reynolds number does not explain the timing of boundary layer transition observed during flight. A roughness-based Reynolds number supports the possibility of transition due to discrete or distributed roughness elements on the heatshield. However, the distributed roughness height would have needed to be larger than the pre-flight assumption. The instrumentation confirmed the predicted location of maximum turbulent heat flux near the leeside shoulder. The reconstructed heat flux at that location is bounded by smooth-wall turbulent calculations on the reconstructed trajectory, indicating that augmentation due to surface roughness probably did not occur. Turbulent heating on the downstream side of the heatshield nose exceeded smooth-wall computations, indicating that roughness may have augmented heating. The stagnation region also experienced heating that exceeded computational levels, but shock layer radiation does not fully explain the differences

An fMRI study of unconditioned responses in post-traumatic stress disorder

BACKGROUND: Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response. RESULTS: Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD. CONCLUSIONS: Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased

Ethnic Differences in Physiological Responses to Fear Conditioned Stimuli

The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders

A parametric study of fear generalization to faces and non-face objects: relationship to discrimination thresholds

Fear generalization is the production of fear responses to a stimulus that is similar—but not identical—to a threatening stimulus. Although prior studies have found that fear generalization magnitudes are qualitatively related to the degree of perceptual similarity to the threatening stimulus, the precise relationship between these two functions has not been measured systematically. Also, it remains unknown whether fear generalization mechanisms differ for social and non-social information. To examine these questions, we measured perceptual discrimination and fear generalization in the same subjects, using images of human faces and non-face control stimuli (“blobs”) that were perceptually matched to the faces. First, each subject’s ability to discriminate between pairs of faces or blobs was measured. Each subject then underwent a Pavlovian fear conditioning procedure, in which each of the paired conditioned stimuli (CS) were either followed (CS+) or not followed (CS−) by a shock. Skin conductance responses (SCRs) were also measured. Subjects were then presented with the CS+, CS− and five levels of a CS+-to-CS− morph continuum between the paired stimuli, which were identified based on individual discrimination thresholds. Finally, subjects rated the likelihood that each stimulus had been followed by a shock. Subjects showed both autonomic (SCR-based) and conscious (ratings-based) fear responses to morphs that they could not discriminate from the CS+ (generalization). For both faces and non-face objects, fear generalization was not found above discrimination thresholds. However, subjects exhibited greater fear generalization in the shock likelihood ratings compared to the SCRs, particularly for faces. These findings reveal that autonomic threat detection mechanisms in humans are highly sensitive to small perceptual differences between stimuli. Also, the conscious evaluation of threat shows broader generalization than autonomic responses, biased towards labeling a stimulus as threatening

Pyrazole-based analogs as potential antibacterial agents against methicillin-resistance staphylococcus aureus (MRSA) and its SAR elucidation

Methicillin-resistant Staphylococcus aureus (MRSA) is becoming lethal to humanity due to easy transmission and difficult-to-treat skin and flimsy diseases. The most threatening aspect is the rapid resistance development of MRSA to any approved antibiotics, including vancomycin. The development of new, efficient, and nontoxic drug candidate to fight against MRSA isolates is the need of the hour. The intriguing molecular structure and versatile bioactive pyrazole core attracting to development required novel antibiotics. This review presents the decade developments of pyrazole-containing derivatives with a broad antibacterial movement against diverged bacterial strains. In specific, we correlated the efficacy of structurally diversified pyrazole analogs against MRSA and discussed different angles of structure-activity relationship (SAR). The current survey highlights pyrazole hybrids' present scenario on MRSA studies, covering articles published from 2011 to 2020. This collective information may become an excellent platform to plan and develop new pyrazole-based small MRSA growth inhibitors with minimal side effects. (C) 2020 Elsevier Masson SAS. All rights reserved

Radiative Heating in MSL Entry: Comparison of Flight Heating Discrepancy to Ground Test and Predictive Models

During the recent entry of the Mars Science Laboratory (MSL), the heat shield was equipped with thermocouple stacks to measure in-depth heating of the thermal protection system (TPS). When only convective heating was considered, the derived heat flux from gauges in the stagnation region was found to be underpredicted by as much as 17 W/sq cm, which is significant compared to the peak heating of 32 W/sq cm. In order to quantify the contribution of radiative heating phenomena to the discrepancy, ground tests and predictive simulations that replicated the MSL entry trajectory were performed. An analysis is carried through to assess the quality of the radiation model and the impact to stagnation line heating. The impact is shown to be significant, but does not fully explain the heating discrepancy

Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry

Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here, we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for anxiety disorders, underly compromised recruitment of fear extinction circuitry. Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction. Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU). Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated with no skin conductance discrimination and greater activity within the right amygdala to previously learned safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety. Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand pathological fear in anxiety disorders and inform potential treatment targets