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1.
J Exp Anal Behav ; 121(3): 327-345, 2024 May.
Article in English | MEDLINE | ID: mdl-38629655

ABSTRACT

Can simple choice conditional-discrimination choice be accounted for by recent quantitative models of combined stimulus and reinforcer control? In Experiment 1, two sets of five blackout durations, one using shorter intervals and one using longer intervals, conditionally signaled which subsequent choice response might provide food. In seven conditions, the distribution of blackout durations across the sets was varied. An updated version of the generalization-across-dimensions model nicely described the way that choice changed across durations. In Experiment 2, just two blackout durations acted as the conditional stimuli and the durations were varied over 10 conditions. The parameters of the model obtained in Experiment 1 failed adequately to predict choice in Experiment 2, but the model again fitted the data nicely. The failure to predict the Experiment 2 data from the Experiment 1 parameters occurred because in Experiment 1 differential control by reinforcer locations progressively decreased with blackout durations, whereas in Experiment 2 this control remained constant. These experiments extend the ability of the model to describe data from procedures based on concurrent schedules in which reinforcer ratios reverse at fixed times to those from conditional-discrimination procedures. Further research is needed to understand why control by reinforcer location differed between the two experiments.


Subject(s)
Choice Behavior , Discrimination Learning , Generalization, Psychological , Models, Psychological , Reinforcement Schedule , Animals , Reinforcement, Psychology , Conditioning, Operant , Discrimination, Psychological , Columbidae , Time Factors
2.
Curr Biol ; 33(23): 5215-5224.e5, 2023 12 04.
Article in English | MEDLINE | ID: mdl-37949064

ABSTRACT

Understanding how population-size homeostasis emerges from stochastic individual cell behaviors remains a challenge in biology.1,2,3,4,5,6,7 The unicellular green alga Chlamydomonas reinhardtii (Chlamydomonas) proliferates using a multiple fission cell cycle, where a prolonged G1 phase is followed by n rounds of alternating division cycles (S/M) to produce 2n daughters. A "Commitment" sizer in mid-G1 phase ensures sufficient cell growth before completing the cell cycle. A mitotic sizer couples mother-cell size to division number (n) such that daughter size distributions are uniform regardless of mother size distributions. Although daughter size distributions were highly robust to altered growth conditions, ∼40% of daughter cells fell outside of the 2-fold range expected from a "perfect" multiple fission sizer.7,8 A simple intuitive power law model with stochastic noise failed to reproduce individual division behaviors of tracked single cells. Through additional iterative modeling, we identified an alternative modified threshold (MT) model, where cells need to cross a threshold greater than 2-fold their median starting size to become division-competent (i.e., Committed), after which their behaviors followed a power law model. The Commitment versus mitotic size threshold uncoupling in the MT model was likely a key pre-adaptation in the evolution of volvocine algal multicellularity. A similar experimental approach was used in size mutants mat3/rbr and dp1 that are, respectively, missing repressor or activator subunits of the retinoblastoma tumor suppressor complex (RBC). Both mutants showed altered relationships between Commitment and mitotic sizer, suggesting that RBC functions to decouple the two sizers.


Subject(s)
Chlamydomonas reinhardtii , Chlamydomonas , Chlamydomonas reinhardtii/genetics , Cell Division , Cell Cycle , Cell Proliferation
3.
Heliyon ; 9(9): e20170, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37809729

ABSTRACT

Landslides are one of the natural phenomena with more negative impacts on landscape, natural resources, and human health worldwide. Andean geomorphology, urbanization, poverty, and inequality make it more vulnerable to landslides. This research focuses on understanding explanatory landslide factors and promoting quantitative susceptibility mapping. Both tasks supply valuable knowledge for the Andean region, focusing on territorial planning and risk management support. This work addresses the following questions using the province of Azuay-Ecuador as a study area: (i) How do EFA and LR assess the significance of landslide occurrence factors? (ii) Which are the most significant landslide occurrence factors for susceptibility analysis in an Andean context? (iii) What is the landslide susceptibility map for the study area? The methodological framework uses quantitative techniques to describe landslide behavior. EFA and LR models are based on a historical inventory of 665 records. Both identified NDVI, NDWI, altitude, fault density, road density, and PC2 as the most significant factors. The latter factor represents the standard deviation, maximum value of precipitation, and rainfall in the wet season (January, February, and March). The EFA model was built from 7 latent factors, which explained 55% of the accumulated variance, with a medium item complexity of 1.5, a RMSR of 0.02, and a TLI of 0.89. This technique also identified TWI, fault distance, plane curvature, and road distance as important factors. LR's model, with AIC of 964.63, residual deviance of 924.63, AUC of 0.92, accuracy of 0.84, and Kappa of 0.68, also shows statistical significance for slope, roads density, geology, and land cover factors. This research encompasses a time-series analysis of NDVI, NDWI, and precipitation, including vegetation and weather dynamism for landslide occurrence. Finally, this methodological framework replaces traditional qualitative models based on expert knowledge, for quantitative approaches for the study area and the Andean region.

4.
Methods Mol Biol ; 2634: 267-284, 2023.
Article in English | MEDLINE | ID: mdl-37074583

ABSTRACT

Crosstalk between signaling pathways can modulate the cellular response to stimuli and is therefore an important part of signal transduction. For a comprehensive understanding of cellular responses, identifying points of interaction between the underlying molecular networks is essential. Here, we present an approach that allows the systematic prediction of such interactions by perturbing one pathway and quantifying the concomitant alterations in the response of a second pathway. As the observed alterations contain information about the crosstalk, we use an ordinary differential equation-based model to extract this information by linking altered dynamics to individual processes. Consequently, we can predict the interaction points between two pathways. As an example, we employed our approach to investigate the crosstalk between the NF-κB and p53 signaling pathway. We monitored the response of p53 to genotoxic stress using time-resolved single cell data and perturbed NF-κB signaling by inhibiting the kinase IKK2. Employing a subpopulation-based modeling approach enabled us to identify multiple interaction points that are simultaneously affected by perturbation of NF-κB signaling. Hence, our approach can be used to analyze crosstalk between two signaling pathways in a systematic manner.


Subject(s)
NF-kappa B , Tumor Suppressor Protein p53 , NF-kappa B/metabolism , Tumor Suppressor Protein p53/metabolism , Signal Transduction , Models, Biological , DNA Damage
5.
Proc Natl Acad Sci U S A ; 120(4): e2205796120, 2023 01 24.
Article in English | MEDLINE | ID: mdl-36656856

ABSTRACT

DNA-binding proteins play important roles in various cellular processes, but the mechanisms by which proteins recognize genomic target sites remain incompletely understood. Functional groups at the edges of the base pairs (bp) exposed in the DNA grooves represent physicochemical signatures. As these signatures enable proteins to form specific contacts between protein residues and bp, their study can provide mechanistic insights into protein-DNA binding. Existing experimental methods, such as X-ray crystallography, can reveal such mechanisms based on physicochemical interactions between proteins and their DNA target sites. However, the low throughput of structural biology methods limits mechanistic insights for selection of many genomic sites. High-throughput binding assays enable prediction of potential target sites by determining relative binding affinities of a protein to massive numbers of DNA sequences. Many currently available computational methods are based on the sequence of standard Watson-Crick bp. They assume that the contribution of overall binding affinity is independent for each base pair, or alternatively include dinucleotides or short k-mers. These methods cannot directly expand to physicochemical contacts, and they are not suitable to apply to DNA modifications or non-Watson-Crick bp. These variations include DNA methylation, and synthetic or mismatched bp. The proposed method, DeepRec, can predict relative binding affinities as function of physicochemical signatures and the effect of DNA methylation or other chemical modifications on binding. Sequence-based modeling methods are in comparison a coarse-grain description and cannot achieve such insights. Our chemistry-based modeling framework provides a path towards understanding genome function at a mechanistic level.


Subject(s)
DNA-Binding Proteins , DNA , Base Pairing , DNA/metabolism , Protein Binding , DNA-Binding Proteins/metabolism , Binding Sites
6.
Obes Rev ; 24 Suppl 1: e13519, 2023 02.
Article in English | MEDLINE | ID: mdl-36416189

ABSTRACT

Adolescent overweight and obesity (AdOWOB) in Europe has proven to be a persistent and complex problem, and appropriate systems methods may help in evaluating potential policy options. This paper describes the development of a system dynamics model of AdOWOB as part of the EU-funded CO-CREATE project. The model was developed using literature and data from the Health Behavior in School-Aged Children (HBSC) study across 31 European countries. We identified 10 HBSC variables that were included as direct or indirect drivers of AdOWOB in the dynamic model, seven at the level of the individual, and three related to the social environment. The model was calibrated to 24 separate cases based on four gender and perceived wealth segments for each of the five CO-CREATE countries (The Netherlands, Norway, Poland, Portugal, and the UK) and for Europe overall. Out of 10 possible intervention points tested, exercise, fruit, life dissatisfaction, school pressure, and skipping breakfast were identified as the top five most influential ones across the 24 cases. These model-based priorities can be compared with the policy ideas suggested by the CO-CREATE adolescents.


Subject(s)
Adolescent Behavior , Pediatric Obesity , Adolescent , Humans , Child , Overweight , Exercise , Schools , Health Behavior
7.
J Exp Anal Behav ; 119(1): 169-191, 2023 01.
Article in English | MEDLINE | ID: mdl-36562640

ABSTRACT

Behavioral economics has been a fruitful area of research in substance use. Mathematical descriptions of how individuals temporally discount the value of a commodity have been correlated with substance use and mathematical descriptions of drug consumption decreasing as a function of price (i.e., demand) predict maladaptive substance use. While there is a logical assumption that temporal factors affect demand for a drug, little has been done to merge these models. Thus, the purpose of this study was to combine models of discounting and demand, extending Howard Rachlin's work and contributions to novel areas of study. Data from 85 participants from Amazon Mechanical Turk (MTurk) who completed a hypothetical cigarette purchase task that included price of and delay to cigarettes were analyzed. Multilevel modeling was used to determine descriptive accuracy of combined additive and multiplicative models of discounting and demand. Of the discounting models used in conjunction with the exponentiated demand equation, the Rachlin hyperboloid best described the delay dimension of consumption. The multiplicative version of the Rachlin equation applied to both delay and price outperformed other models tested. Therefore, existing models of discounting and demand can be extended to modeling consumption data from complex multidimensional experimental arrangements.


Subject(s)
Delay Discounting , Substance-Related Disorders , Tobacco Products , Humans , Economics, Behavioral
8.
Psicol. (Univ. Brasília, Online) ; 39: e39515, 2023. graf
Article in English | LILACS-Express | LILACS, Index Psychology - journals | ID: biblio-1448916

ABSTRACT

ABSTRACT In most areas, psychological phenomena tend to be explained only through textual constructions. Several authors, however, point to the need for theories that have a more formal nature, based on mathematical reasoning. In order to encourage broader access to its applications, we present the models and advantages of a mathematical psychology approach to the study of behavior. We review the limitations of verbal theorizing, then a common taxonomy in mathematical psychology follows, that classifies formal models as descriptive, process characterization, and explanatory. As well succeeded cases, we examine the mathematical psychology of decision making, of helping behavior, of memory, and of romantic relationships. Finally, we discuss the potential benefits and uses of this approach. Welcome to mathematical psychology.


RESUMO Na maior parte das áreas os fenômenos psicológicos tendem a ser explicados apenas por meio de construções textuais. Diversos autores, no entanto, apontam para a necessidade de teorias que tenham uma natureza mais formal, baseada em raciocínio matemático. A fim de incentivar acesso mais amplo às suas aplicações, apresentamos os modelos e vantagens da abordagem da psicologia matemática para o estudo do comportamento. Revisamos as limitações da teorização verbal, apresentando em seguida uma taxonomia, comum na psicologia matemática, que classifica os modelos de dados como descritivos, explicativos e de caracterização. Como casos bem sucedidos, examinamos a psicologia matemática da tomada de decisão, do comportamento de ajuda, da memória e dos relacionamentos românticos. Por fim, discutimos os benefícios e usos potenciais da abordagem. Bem-vindo(a) à psicologia matemática.

9.
Front Psychiatry ; 13: 757961, 2022.
Article in English | MEDLINE | ID: mdl-35308879

ABSTRACT

Anxiety induction is widely used in the investigations of the mechanism and treatment of state anxiety. State anxiety is accompanied by immediate psychological and physiological responses. However, the existing state anxiety measurement, such as the commonly used state anxiety subscale of the State-Trait Anxiety Inventory, mainly relies on questionnaires with low temporal resolution. This study aims to develop a tracking model of state anxiety with high temporal resolution. To capture the dynamic changes of state anxiety levels, we induced the participants' state anxiety through exposure to aversive pictures or the risk of electric shocks and simultaneously recorded multi-modal data, including dimensional emotion ratings, electrocardiogram, and galvanic skin response. Using the paired self-reported state anxiety levels and multi-modal measures, we trained and validated machine learning models to predict state anxiety based on psychological and physiological features extracted from the multi-modal data. The prediction model achieved a high correlation between the predicted and self-reported state anxiety levels. This quantitative model provides fine-grained and sensitive measures of state anxiety levels for future affective brain-computer interaction and anxiety modulation studies.

10.
Cell Rep ; 37(6): 109952, 2021 11 09.
Article in English | MEDLINE | ID: mdl-34758318

ABSTRACT

Gene regulation often results from the action of multiple transcription factors (TFs) acting at a promoter, obscuring the individual regulatory effect of each TF on RNA polymerase (RNAP). Here we measure the fundamental regulatory interactions of TFs in E. coli by designing synthetic target genes that isolate individual TFs' regulatory effects. Using a thermodynamic model, each TF's regulatory interactions are decoupled from TF occupancy and interpreted as acting through (de)stabilization of RNAP and (de)acceleration of transcription initiation. We find that the contribution of each mechanism depends on TF identity and binding location; regulation immediately downstream of the promoter is insensitive to TF identity, but the same TFs regulate by distinct mechanisms upstream of the promoter. These two mechanisms are uncoupled and can act coherently, to reinforce the observed regulatory role (activation/repression), or incoherently, wherein the TF regulates two distinct steps with opposing effects.


Subject(s)
DNA-Directed RNA Polymerases/metabolism , Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Gene Expression Regulation, Bacterial , Gene Regulatory Networks , Transcription Factors/metabolism , DNA-Directed RNA Polymerases/genetics , Escherichia coli/genetics , Escherichia coli/growth & development , Escherichia coli Proteins/genetics , Promoter Regions, Genetic , Regulatory Sequences, Nucleic Acid , Transcription Factors/genetics
11.
BMC Infect Dis ; 21(1): 1194, 2021 Nov 27.
Article in English | MEDLINE | ID: mdl-34837983

ABSTRACT

BACKGROUND: To examine whether outdoor transmission may contribute to the COVID-19 epidemic, we hypothesized that slower outdoor wind speed is associated with increased risk of transmission when individuals socialize outside. METHODS: Daily COVID-19 incidence reported in Suffolk County, NY, between March 16th and December 31st, 2020, was the outcome. Average wind speed and maximal daily temperature were collated by the National Oceanic and Atmospheric Administration. Negative binomial regression was used to model incidence rates while adjusting for susceptible population size. RESULTS: Cases were very high in the initial wave but diminished once lockdown procedures were enacted. Most days between May 1st, 2020, and October 24th, 2020, had temperatures 16-28 °C and wind speed diminished slowly over the year and began to increase again in December 2020. Unadjusted and multivariable-adjusted analyses revealed that days with temperatures ranging between 16 and 28 °C where wind speed was < 8.85 km per hour (KPH) had increased COVID-19 incidence (aIRR = 1.45, 95% C.I. = [1.28-1.64], P < 0.001) as compared to days with average wind speed ≥ 8.85 KPH. CONCLUSION: Throughout the U.S. epidemic, the role of outdoor shared spaces such as parks and beaches has been a topic of considerable interest. This study suggests that outdoor transmission of COVID-19 may occur by noting that the risk of transmission of COVID-19 in the summer was higher on days with low wind speed. Outdoor use of increased physical distance between individuals, improved air circulation, and use of masks may be helpful in some outdoor environments where airflow is limited.


Subject(s)
COVID-19 , Wind , Communicable Disease Control , Humans , SARS-CoV-2 , Temperature
12.
mSystems ; 6(4): e0097821, 2021 Aug 31.
Article in English | MEDLINE | ID: mdl-34427530

ABSTRACT

DNA supercoiling acts as a global transcriptional regulator that contributes to the rapid transcriptional response of bacteria to many environmental changes. Although a large fraction of promoters from phylogenetically distant species respond to superhelical variations, the sequence or structural determinants of this behavior remain elusive. Here, we focus on the sequence of the "discriminator" element that was shown to modulate this response in several promoters. We develop a quantitative thermodynamic model of this regulatory effect, focusing on open complex formation during transcription initiation independently from promoter-specific regulatory proteins. We analyze previous and new expression data and show that the model predictions quantitatively match the in vitro and in vivo supercoiling response of selected promoters with mutated discriminator sequences. We then test the universality of this mechanism by a statistical analysis of promoter sequences from transcriptomes of phylogenetically distant bacteria under conditions of supercoiling variations (i) by gyrase inhibitors, (ii) by environmental stresses, or (iii) inherited in the longest-running evolution experiment. In all cases, we identify a robust and significant sequence signature in the discriminator region, suggesting that supercoiling-modulated promoter opening underpins a ubiquitous regulatory mechanism in the prokaryotic kingdom based on the fundamental mechanical properties of DNA and its basal interaction with RNA polymerase. IMPORTANCE In this study, we highlight the role of the discriminator as a global sensor of supercoiling variations and propose the first quantitative regulatory model of this principle, based on the specific step of promoter opening during transcription initiation. It defines the predictive rule by which DNA supercoiling quantitatively modulates the expression rate of bacterial promoters, depending on the G/C content of their discriminator and independently from promoter-specific regulatory proteins. This basal mechanism affects a wide range of species, which is tested by an extensive analysis of global high-throughput expression data. Altogether, ours results confirm and provide a quantitative framework for the long-proposed notion that the discriminator sequence is a significant determinant of promoter supercoiling sensitivity, underpinning the ubiquitous regulatory action of DNA supercoiling on the core transcriptional machinery, in particular in response to quick environmental changes.

13.
Front Mol Biosci ; 8: 688700, 2021.
Article in English | MEDLINE | ID: mdl-34262940

ABSTRACT

Quantitative prediction on protein synthesis requires accurate translation initiation and codon translation rates. Ribosome profiling data, which provide steady-state distribution of relative ribosome occupancies along a transcript, can be used to extract these rate parameters. Various methods have been developed in the past few years to measure translation-initiation and codon translation rates from ribosome profiling data. In the review, we provide a detailed analysis of the key methods employed to extract the translation rate parameters from ribosome profiling data. We further discuss how these approaches were used to decipher the role of various structural and sequence-based features of mRNA molecules in the regulation of gene expression. The utilization of these accurate rate parameters in computational modeling of protein synthesis may provide new insights into the kinetic control of the process of gene expression.

14.
Sleep ; 44(11)2021 11 12.
Article in English | MEDLINE | ID: mdl-34111278

ABSTRACT

STUDY OBJECTIVES: The study aimed to, for the first time, (1) compare sleep, circadian phase, and alertness of intensive care unit (ICU) nurses working rotating shifts with those predicted by a model of arousal dynamics; and (2) investigate how different environmental constraints affect predictions and agreement with data. METHODS: The model was used to simulate individual sleep-wake cycles, urinary 6-sulphatoxymelatonin (aMT6s) profiles, subjective sleepiness on the Karolinska Sleepiness Scale (KSS), and performance on a Psychomotor Vigilance Task (PVT) of 21 ICU nurses working day, evening, and night shifts. Combinations of individual shift schedules, forced wake time before/after work and lighting, were used as inputs to the model. Predictions were compared to empirical data. Simulations with self-reported sleep as an input were performed for comparison. RESULTS: All input constraints produced similar prediction for KSS, with 56%-60% of KSS scores predicted within ±1 on a day and 48%-52% on a night shift. Accurate prediction of an individual's circadian phase required individualized light input. Combinations including light information predicted aMT6s acrophase within ±1 h of the study data for 65% and 35%-47% of nurses on diurnal and nocturnal schedules. Minute-by-minute sleep-wake state overlap between the model and the data was between 81 ± 6% and 87 ± 5% depending on choice of input constraint. CONCLUSIONS: The use of individualized environmental constraints in the model of arousal dynamics allowed for accurate prediction of alertness, circadian phase, and sleep for more than half of the nurses. Individual differences in physiological parameters will need to be accounted for in the future to further improve predictions.


Subject(s)
Sleep Disorders, Circadian Rhythm , Arousal , Circadian Rhythm/physiology , Humans , Sleep/physiology , Wakefulness/physiology , Work Schedule Tolerance/physiology
15.
J Exp Anal Behav ; 115(3): 729-746, 2021 05.
Article in English | MEDLINE | ID: mdl-33586193

ABSTRACT

Contemporary approaches for evaluating the demand for reinforcers use either the Exponential or the Exponentiated model of operant demand, both derived from the framework of Hursh and Silberberg (2008). This report summarizes the strengths and complications of this framework and proposes a novel implementation. This novel implementation incorporates earlier strengths and resolves existing shortcomings that are due to the use of a logarithmic scale for consumption. The Inverse Hyperbolic Sine (IHS) transformation is reviewed and evaluated as a replacement for the logarithmic scale in models of operant demand. Modeling consumption in the "log10 -like" IHS scale reflects relative changes in consumption (as with a log scale) and accommodates a true zero bound (i.e., zero consumption values). The presence of a zero bound obviates the need for a separate span parameter (i.e., k) and the span of the model may be more simply defined by maximum demand at zero price (i.e., Q0 ). Further, this reformulated model serves to decouple the exponential rate constant (i.e., α) from variations in span, thus normalizing the rate constant to the span of consumption in IHS units and permitting comparisons when spans vary. This model, called the Zero-bounded Exponential (ZBE), is evaluated using simulated and real-world data. The direct reinstatement ZBE model showed strong correspondence with empirical indicators of demand and with a normalization of α (ZBEn) across empirical data that varied in reinforcing efficacy (dose, time to onset of peak effects). Future directions in demand curve analysis are discussed with recommendations for additional replication and exploration of scales beyond the logarithm when accommodating zero consumption data.

16.
Perspect Psychol Sci ; 16(4): 767-778, 2021 07.
Article in English | MEDLINE | ID: mdl-33513319

ABSTRACT

Paul Meehl's famous critique detailed many of the problematic practices and conceptual confusions that stand in the way of meaningful theoretical progress in psychological science. By integrating many of Meehl's points, we argue that one of the reasons for the slow progress in psychology is the failure to acknowledge the problem of coordination. This problem arises whenever we attempt to measure quantities that are not directly observable but can be inferred from observable variables. The solution to this problem is far from trivial, as demonstrated by a historical analysis of thermometry. The key challenge is the specification of a functional relationship between theoretical concepts and observations. As we demonstrate, empirical means alone cannot determine this relationship. In the case of psychology, the problem of coordination has dramatic implications in the sense that it severely constrains our ability to make meaningful theoretical claims. We discuss several examples and outline some of the solutions that are currently available.


Subject(s)
Psychology , Humans
17.
J Pharm Sci ; 110(3): 1385-1391, 2021 03.
Article in English | MEDLINE | ID: mdl-33217427

ABSTRACT

Bteich and coworkers recently demonstrated in a companion manuscript (J Pharm Sci 109: https://doi.org/10.1016/j.xphs.2020.07.003) that a protein-mediated hepatic uptake have occurred in an isolated perfused rat liver (IPRL) model for two drugs (Perampanel; PER and Fluoxetine; FLU) that bind extensively to the albumin (ALB) and alpha-1-acid glycoprotein (AGP). However, to our knowledge, there is no quantitative model available to predict the impact of a plasma protein-mediated hepatic uptake on the extent of hepatic clearance (CLh) for a drug binding extensively to these two proteins. Therefore, the main objective was to predict the corresponding CLh, which is an extension of the companion manuscript. The method consisted of extrapolating the intrinsic clearance from the unbound fraction measured in the perfusate or the unbound fraction extrapolated to the surface of the hepatocyte membrane by adapting an existing model of protein-mediated hepatic uptake (i.e., the fup-adjusted model) to include a binding ratio between the ALB and AGP. This new approach showed a relevant improvement compared to the free drug hypothesis particularly for FLU that showed the highest degree of ALB-mediated uptake. Overall, this study is a first step towards the development of predictive methods of CLh by considering the binding to ALB and AGP.


Subject(s)
Orosomucoid , Pharmaceutical Preparations , Albumins/metabolism , Animals , Blood Proteins/metabolism , Liver/metabolism , Models, Biological , Orosomucoid/metabolism , Pharmaceutical Preparations/metabolism , Protein Binding , Rats
18.
Front Physiol ; 11: 896, 2020.
Article in English | MEDLINE | ID: mdl-32848849

ABSTRACT

Signaling pathways involve complex molecular interactions and are controled by non-linear regulatory mechanisms. If details of regulatory mechanisms are not fully elucidated, they can be implemented by different, equally reasonable mathematical representations in computational models. The study presented here focusses on NF-κB signaling, which is regulated by negative feedbacks via IκBα and A20. A20 inhibits NF-κB activation indirectly through interference with proteins that transduce the signal from the TNF receptor complex to activate the IκB kinase (IKK) complex. A number of pathway models has been developed implementing the A20 effect in different ways. We here focus on the question how different A20 feedback implementations impact the dynamics of NF-κB. To this end, we develop a modular modeling approach that allows combining previously published A20 modules with a common pathway core module. The resulting models are fitted to a published comprehensive experimental data set and therefore show quantitatively comparable NF-κB dynamics. Based on defined measures for the initial and long-term behavior we analyze the effects of a wide range of changes in the A20 feedback strength, the IκBα feedback strength and the TNFα stimulation strength on NF-κB dynamics. This shows similarities between the models but also model-specific differences. In particular, the A20 feedback strength and the TNFα stimulation strength affect initial and long-term NF-κB concentrations differently in the analyzed models. We validated our model predictions experimentally by varying TNFα concentrations applied to HeLa cells. These time course data indicate that only one of the A20 feedback models appropriately describes the impact of A20 on the NF-κB dynamics in this cell type.

19.
Curr Biol ; 30(13): 2532-2550.e8, 2020 07 06.
Article in English | MEDLINE | ID: mdl-32442466

ABSTRACT

Visual systems are often equipped with neurons that detect small moving objects, which may represent prey, predators, or conspecifics. Although the processing properties of those neurons have been studied in diverse organisms, links between the proposed algorithms and animal behaviors or circuit mechanisms remain elusive. Here, we have investigated behavioral function, computational algorithm, and neurochemical mechanisms of an object-selective neuron, LC11, in Drosophila. With genetic silencing and optogenetic activation, we show that LC11 is necessary for a visual object-induced stopping behavior in walking flies, a form of short-term freezing, and its activity can promote stopping. We propose a new quantitative model for small object selectivity based on the physiology and anatomy of LC11 and its inputs. The model accurately reproduces LC11 responses by pooling fast-adapting, tightly size-tuned inputs. Direct visualization of neurotransmitter inputs to LC11 confirmed the model conjectures about upstream processing. Our results demonstrate how adaptation can enhance selectivity for behaviorally relevant, dynamic visual features.


Subject(s)
Motion Perception/physiology , Neurons/physiology , Visual Pathways/physiology , Animals , Drosophila melanogaster , Female , Male
20.
Magn Reson Med ; 83(4): 1380-1389, 2020 04.
Article in English | MEDLINE | ID: mdl-31631408

ABSTRACT

PURPOSE: During MRI-guided breast biopsy, a metallic biopsy marker is deployed at the biopsy site to guide future interventions. Conventional MRI during biopsy cannot distinguish such markers from biopsy site air, and a post-biopsy mammogram is therefore performed to localize marker placement. The purpose of this pilot study is to develop dipole modeling of multispectral signal (DIMMS) as an MRI alternative to eliminate the cost, inefficiency, inconvenience, and ionizing radiation of a mammogram for biopsy marker localization. METHODS: DIMMS detects and localizes the biopsy marker by fitting the measured multispectral imaging (MSI) signal to the MRI signal model and marker properties. MSI was performed on phantoms containing titanium biopsy markers and air to illustrate the clinical challenge that DIMMS addresses and on 20 patients undergoing MRI-guided breast biopsy to assess DIMMS feasibility for marker detection. DIMMS was compared to conventional MSI field map thresholding, using the post-procedure mammogram as the reference standard. RESULTS: Biopsy markers were detected and localized in 20 of 20 cases using MSI with automated DIMMS post-processing (using a threshold of 0.7) and in 18 of 20 cases using MSI field mapping (using a threshold of 0.65 kHz). CONCLUSION: MSI with DIMMS post-processing is a feasible technique for biopsy marker detection and localization during MRI-guided breast biopsy. With a 2-min MSI scan, DIMMS is a promising MRI alternative to the standard-of-care post-biopsy mammogram.


Subject(s)
Breast Neoplasms , Breast , Biopsy , Breast/diagnostic imaging , Breast Neoplasms/diagnostic imaging , Humans , Magnetic Resonance Imaging , Phantoms, Imaging , Pilot Projects
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