Functional resilience of mutually repressing motifs embedded in larger regulatory networks

Elucidating the design principles of regulatory networks driving cellular decision-making has important implications in understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between 'master regulators' of cell-fates can exhibit multistable dynamics, thus enabling multiple 'single-positive' phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two network motifs has been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these network motifs in complex larger networks of varying sizes and connectivity and identify conditions under which these motifs maintain their canonical dynamical behavior, thus identifying hallmarks of their functional resilience. We show that the in-degree of a motif - defined as the number of incoming edges onto a motif - determines its functional properties. For a smaller in-degree, the functional traits for both these motifs (bimodality, pairwise correlation coefficient(s), and the frequency of 'single-positive' phenotypes) are largely conserved, but increasing the in-degree can lead to a divergence from their stand-alone behaviors. These observations offer insights into design principles of biological networks containing these network motifs, as well as help devise optimal strategies for integration of these motifs into larger synthetic networks.

Immune correlates of Mycobacterium Tuberculosis patients in Zambia stratified by HIV serostatus and level of immunity-a cross-sectional analytical laboratory based study

Background People living with HIV (PLHIV) co-infected with tuberculosis (TB) have a distinct clinical presentation and poorer treatment outcomes compared to HIV-seronegative TB patients. Excluding low CD4 count, innate immune factors associated with TB are not fully elucidated. We, therefore, characterised and compared the expression of IL-6, TNF-α, IFN-γ, and IL-10 in whole blood of treatment naïve TB patients stimulated with heat-killed Mycobacterium tuberculosis stratified by HIV status and the level of CD4 count. Results We recruited 39 HIV seropositive and 31 HIV seronegative TB patients. Median (IQR) age was 35(28–42) years and 31(25–36) years respectively, and a majority had pulmonary tuberculosis i.e. 38(95%) and 30(97%), respectively. The two groups were significantly different in the distribution of CD4 count, 563 [465–702.5 cells/mm3] vs 345 [157–483 cell/mm3] in HIV negative vs HIV positive respectively p = <0.001. Post stimulation, the expression of IL-6 in HIV negative TB patients was significantly higher than in the HIV positive 16,757366 [8,827–23,686 pg/ml] vs. 9,508 [5,514–15,008 pg/ml], respectively; p = 0.0360. TNF-α and IFN-γ were highly expressed in HIV negative TB patients compared to the HIV positive though not statistically significant. We only observed higher expression of IL-6 in HIV negative patients in comparison to the HIV positive when stratified by level of CD4 counts as < 500 and ≥ 500 cell/mm3 for both cohorts. 21,953 [8,990–24,206 pg/ml] vs 9,505 [5,400–15,313 pg/ml], p value = 0.0585 in patients with CD4 count < 500 cell/mm3 and 13,168 [7,087–22,584 pg/ml] vs 10,413 [7,397–14,806 pg/ml], p value = 0.3744 for patients with CD4 count of ≥ 500 cell/mm3 respectively. We found a positive pairwise correlation between TNF-α -alpha and IL-6 in both HIV positive and HIV negative patients, r = 0.61 (95% CI 0.36–0.72; p < 0.0001) and r = 0.48 (95% CI 0.15–0.68; p = 0.005) respectively. The IFNγ/IL-10 ratio was higher in HIV negative when compared to HIV positive individuals, 0.052 [0.0–0.28] vs 0.007 [0–0.32] respectively; p = 0.05759. IL-6 independently reduced the probability of TB/HIV, Adjusted odds ratio 0.99, p value 0.007. Conclusions This study suggests that HIV seronegative TB patients have a higher pro-inflammatory response to MTB than HIV seropositive TB patients. Further, it also shows that the level of CD4 influences immunomodulation. The findings suggest that the difference in cytokine expression may be responsible for the distinct patterns of TB presentation between HIV positive and HIV negative patient.

Molecular Investigation of miRNA Biomarkers as Chemoresistance Regulators in Melanoma: A Protocol for Systematic Review and Meta-Analysis

Introduction: Melanoma is a global disease that is predominant in Western countries. However, reliable data resources and comprehensive studies on the theragnostic efficiency of miRNAs in melanoma are scarce. Hence, a decisive study or comprehensive review is required to collate the evidence for profiling miRNAs as a theragnostic marker. This protocol details a comprehensive systematic review and meta-analysis on the impact of miRNAs on chemoresistance and their association with theragnosis in melanoma. Methods and analysis: The articles will be retrieved from online bibliographic databases, including Cochrane Review, EMBASE, MEDLINE, PubMed, Scopus, Science Direct, and Web of Science, with different permutations of ‘keywords’. To obtain full-text papers of relevant research, a stated search method will be used, along with selection criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Protocols 2015 (PRISMA-P) standards were used to create this study protocol. The hazard ratio (HR) with a 95% confidence interval will be analyzed using Comprehensive Meta-Analysis (CMA) software 3.0. (CI). The pooled effect size will be calculated using a random or fixed-effects meta-analysis model. Cochran’s Q test and the I2 statistic will be used to determine heterogeneity. Egger’s bias indicator test, Orwin’s and the classic fail-safe N tests, the Begg and Mazumdar rank collection test, and Duval and Tweedie’s trim and fill calculation will all be used to determine publication bias. The overall standard deviation will be evaluated using Z-statistics. Subgroup analyses will be performed according to the melanoma participants’ clinicopathological and biological characteristics and methodological factors if sufficient studies and retrieved data are identified and available. The source of heterogeneity will be assessed using a meta-regression analysis. A pairwise matrix could be developed using either a pairwise correlation or expression associations of miRNA with patients’ survival for the same studies.

Towards Modelling of Evacuation Behavior and Planning for Emergency Logistics Due to the Philippine Taal Volcanic Eruption in 2020

Emergency evacuation is the immediate escape of people away from a place of an imminent threat to a place of safety. The ability of the households to evacuate is a crucial component in reducing disaster risk. Logistical issues such as a lack of resources during and after the evacuation, as well as road congestion, might arise, especially in short and no-notice calamities such as a volcanic eruption. This study examines the relationship of variables of evacuation logistics of Barangay Banga, Talisay, Batangas in the context of the 2020 Taal Volcanic eruption. A survey was conducted based on the experience of the households during the volcanic eruption. A descriptive statistical analysis was performed for all the variables on household evacuation logistics to understand the behavior of households as they make decisions during emergencies. These variables include the type of evacuation, departure timing, evacuation mode choice, and destination choice. Additionally, a pairwise correlation was employed to identify the influential factors related to household evacuation logistics such as socio-demographic and household characteristics, hazard-related factors as well as their experience with Taal Volcano’s recurring activities. The results of this study aim to provide insights to a better understanding of the evacuation behavior of households in the context of a volcanic eruption and be useful in the evacuation logistics planning of the country.

High-Resolution Spatio-Temporal Model for County-Level COVID-19 Activity in the U.S.

We present an interpretable high-resolution spatio-temporal model to estimate COVID-19 deaths together with confirmed cases 1 week ahead of the current time, at the county level and weekly aggregated, in the United States. A notable feature of our spatio-temporal model is that it considers the (1) temporal auto- and pairwise correlation of the two local time series (confirmed cases and deaths from the COVID-19), (2) correlation between locations (propagation between counties), and (3) covariates such as local within-community mobility and social demographic factors. The within-community mobility and demographic factors, such as total population and the proportion of the elderly, are included as important predictors since they are hypothesized to be important in determining the dynamics of COVID-19. To reduce the model’s high dimensionality, we impose sparsity structures as constraints and emphasize the impact of the top 10 metropolitan areas in the nation, which we refer to (and treat within our models) as hubs in spreading the disease. Our retrospective out-of-sample county-level predictions were able to forecast the subsequently observed COVID-19 activity accurately. The proposed multivariate predictive models were designed to be highly interpretable, with clear identification and quantification of the most important factors that determine the dynamics of COVID-19. Ongoing work involves incorporating more covariates, such as education and income, to improve prediction accuracy and model interpretability.

High Resistant Starch Rice: Variation in Starch Related SNPs, and Functional, and Sensory Properties

Human diets containing greater resistant starch (RS) are associated with superior glycemic control. Although high amylose rice has higher RS (29 g/kg to 44 g/kg) than lower amylose content varieties, sensory and processing properties associated with RS have not been evaluated. This study used variants of Waxy and starch synthase II a (SSIIa) genes to divide high amylose (256 g/kg to 284 g/kg) varieties into three haplotypes to examine their effects on RS, RVA parameters, and 14 cooked rice texture properties. RVA characteristics were influenced by both genes with peak and hotpaste viscosity differentiating the three haplotypes. Setback from hotpaste viscosity was the only RVA parameter correlated with RS content across three haplotypes (r = −0.76 to −0.93). Cooked rice texture attributes were impacted more by Waxy than by SSIIa with initial starch coating, roughness, and intact particles differentiating the three haplotypes. Pairwise correlation (r = 0.46) and PCA analyses suggested that roughness was the only texture attribute associated with RS content; while protein content influenced roughness (r = 0.49) and stickiness between grains (r = 0.45). In conclusion, variation exists among genetic haplotypes with high RS for sensory traits that will appeal to diverse consumers across the globe with limited concern for negatively affecting grain processing quality.

Thermal dependencies of fruit puree density

Density is among the key properties of liquid food media, affecting homogenisation and dispersion. The work aimed to study the temperature effect on fruit puree density, determine temperature constants and grade purees by density. The study included apple, pear and cherry plum purees. Pycnometric densities were measured at 20, 30, 40 and 50ºC temperatures. Different media were shown to vary in the density reduction rate at increasing measurement temperatures. The correlation coefficient was strongly dependent on the reference (baseline) density and extremely — on temperature coefficient. Correlation dynamics modelling of elevating temperature revealed the slope vs. temperature coefficient pairwise correlation to monotonously increase starting from very high baseline values of >0.999. The relative slope vs. baseline density pairwise correlation coefficient decreased monotonously from 0.9032. It was additionally found that the media density grading is temperature-dependent. Thus, the descending series was pear–apple–cherry plum at 0–+24.68ºC, pear–cherry plum–apple at +24.68–+84.34ºC, cherry plum–pear–apple at +84.34–+174.31ºC and cherry plum–apple–pear at ≥+174.31ºC. For three study media, the number of temperature ranges inducing puree density gradients was 4. This approach to study thermal impact on the density of food fluids is generally acknowledged and can be successfully applied in the areas, where physical density and its comparative assessment are substantive.

Comparative Analysis of Paired Correlations Structure Between Psychological Scales in Relation to Groups of Different Sizes

Purpose: To propose a procedure for comparative analysis of correlation relationships structure between psychological scales in samples of different sizes. Material and methods: A procedure of comparative analysis of correlation relationships structure between psychological indicators in groups of different sizes based on the «zet» method of R. Fisher is proposed. To illustrate the method, data from psychodiagnostic surveys of the nuclear power plant (NPP) personnel who worked in normal conditions and the personnel of the Chernobyl NPP at four different stages of aftermath activities in 1986–1987 were used. All the subjects performed the Minnesota Multiphasic Personality Inventory (MMPI); the results of each of the groups were subjected to a correlation analysis using the Pearson method. The analysis took into account average (0.5 ≤ r < 0.7) and strong (r ≥ 0.7) correlations. Results: Using the example of a number of psychodiagnostic examinations of the Chernobyl NPP personnel at various stages of aftermath activities, it is shown that the structure of correlation relationships between the MMPI scales can reflect the peculiarities of mental adaptation of professional teams working in regular and extreme conditions. It was shown that in the aftermath process by March–April 1987, the number of medium and strong pairwise Pearson correlations between the clinical MMPI scales increased. This fact apparently indicates that during this period, the NPP personnel were characterized by the simultaneous activation of various mechanisms of intrapsychic adaptation. The core of the correlation pleiad consisted of scales 1, 2, 7, and 8. Such a multidirectional reaction to the aftermath stressors was accompanied by a statistically significant increase in almost all clinical scales (except scale 6) of the average MMPI profile in comparison with the control group. The absence of stable correlations of clinical scales with the F scale indicates that the marked increase in the MMPI profile was not associated with a tendency to aggravation. By the period of November–December 1987, the hypochondria scale occupied a leading place in the correlation pleiad of the MMPI indicators of the Chernobyl NPP personnel, the number of its significant connections with other clinical scales (2, 3, 7 and 8) reached four. Apparently, the mechanism of anxiety somatization at that time could be considered as a syndrome-forming factor and taken into account when planning rehabilitation and health measures. Conclusion: The use of the proposed method of the strength standardization of pairwise correlation relationships between the MMPI scales allowed us to legitimately compare these indicators in groups that differ significantly in number. The chosen representation form of correlations facilitates the analysis of their structure.

Comprehensive study of selection-value lines of zucchini on the level of damage by the yellow mosaic virus (ZYMV) and manifestation of other diseases

The work is aimed at the selection of linear samples of zucchini (Cucurbita pepo L. var. Giromontia Duch.) with increased complex resistance to abiotic factors of cultivation – zucchini yellow mosaic virus (ZYMV), powdery mildew, bacteriosis and other viral pathogens. Selection studies on choosing virus-resistant zucchini lines from the United Kingdom, Italy, the United States and Spain have identified a number of important correlations levels of resistance to ZYMV and to harmful microorganisms and viruses, belonging to other genera. The assessment of the resistance of the selected zucchini lines to the complex of studied diseases was performed on a 9-point scale of the classifier of the Council for Mutual Economic Assistance (CMEA). In total, during 2017–2019, 20 lines of zucchini were studied in the field. According to the complex resistance to all pathogens (zucchini yellow mosaic virus, green speckled mosaic, white mosaic and cucumber mosaic, bacteriosis and fusarium wilt), four lines have been identified – LZ 17-11, RVL-19, LZ 17-45 and LZ 17-49, which were resistant at the level of points 7 and 9 on the scale of CMEA. The possibility of selecting potentially resistant linear zucchini genotypes for ZYMV based on correlations with the manifestation of other diseases that occurred in the field has been confirmed. The highest level of correlation 0.59<rp<1.0) is observed when comparing the degree of powdery mildew development and symptoms of ZYMV (17 statistically confirmed values of the pairwise correlation coefficient or 80.95 %). A similar indicator for the pair “bacteriosis/ZYMV” is 14 statistically confirmed values of the pairwise correlation coefficient or 66.67 % (–1.0<rp<0.99), and for the pair “field viruses of other origin/ZYMV” – 11 values, which is 52.38 % (–1.0<rp<0.93). Zucchini samples were identified, in which statistically significant correlations were observed for all pairs of comparative traits. Among them, the variety-standard Chaklun and 4 more lines – LZ 17-1, LZ 17-8, LZ 17-50 and LZ 17-44 (–1.0<rp<0.92). The analysis of correlations shows a complex genetic organization of signs of resistance in zucchini lines to the studied pathogens and a high dependence of the manifestation of these signs on the response of the genotype of the line. One of the proofs of this experimental fact is that in all comparative pairs of indicators of the degree of development of certain diseases there are linear genotypes with both positive and negative values of Pearson correlation coefficients (rp). The high level of statistically significant correlations revealed gives grounds for wide use of correlation analysis in selection work for choosing lines potentially resistant to the complex of the most common diseases in vegetable agrocenoses

Cheating with Models

Beliefs and decisions are often based on confronting models with data. What is the largest “fake” correlation that a misspecified model can generate, even when it passes an elementary misspecification test? We study an “analyst” who fits a model, represented by a directed acyclic graph, to an objective (multivariate) Gaussian distribution. We characterize the maximal estimated pairwise correlation for generic Gaussian objective distributions, subject to the constraint that the estimated model preserves the marginal distribution of any individual variable. As the number of model variables grows, the estimated correlation can become arbitrarily close to one regardless of the objective correlation. (JEL D83, C13, C46, C51)