Changes In Regulatory Mechanisms Research Articles

Flexible modeling of regulatory networks improves transcription factor activity estimation

Transcriptional regulation plays a crucial role in determining cell fate and disease, yet inferring the key regulators from gene expression data remains a significant challenge. Existing methods for estimating transcription factor (TF) activity often rely on static TF-gene interaction databases and cannot adapt to changes in regulatory mechanisms across different cell types and disease conditions. Here, we present a new algorithm - Transcriptional Inference using Gene Expression and Regulatory data (TIGER) - that overcomes these limitations by flexibly modeling activation and inhibition events, up-weighting essential edges, shrinking irrelevant edges towards zero through a sparse Bayesian prior, and simultaneously estimating both TF activity levels and changes in the underlying regulatory network. When applied to yeast and cancer TF knock-out datasets, TIGER outperforms comparable methods in terms of prediction accuracy. Moreover, our application of TIGER to tissue- and cell-type-specific RNA-seq data demonstrates its ability to uncover differences in regulatory mechanisms. Collectively, our findings highlight the utility of modeling context-specific regulation when inferring transcription factor activities.

The control of transitions along the main body axis.

Although vertebrates display a large variety of forms and sizes, the mechanisms controlling the layout of the basic body plan are substantially conserved throughout the clade. Following gastrulation, head, trunk, and tail are sequentially generated through the continuous addition of tissue at the caudal embryonic end. Development of each of these major embryonic regions is regulated by a distinct genetic network. The transitions from head-to-trunk and from trunk-to-tail development thus involve major changes in regulatory mechanisms, requiring proper coordination to guarantee smooth progression of embryonic development. In this review, we will discuss the key cellular and embryological events associated with those transitions giving particular attention to their regulation, aiming to provide a cohesive outlook of this important component of vertebrate development.

Heart Rate Variability as an Indicator of the Regulatory Mechanism Condition in Body Physiological Adaptation

Research relevance: this article deals with aspects of heart rate variability (HRV) indicators as an indicator of the state of regulatory mechanisms of physiological adaptation of the body of foreign students in the process of education. Research purpose: analysis of HRV indicators, the state of the cardiovascular system (CVS), and the pulmonary ventilation system, as indicators of the state of the regulatory mechanisms of physiological adaptation of the body of foreign students in the process of education. Research materials and methods: students at the international school of medicine (ISM) were invited to the International University of Kyrgyzstan (IUK) (from the Republic of Pakistan) for 3 years of study. Anthropometric data (body mass index (BMI), pulse and arterial pressure indicators, vital capacity of the lungs (PE) (peak flowmetry), which are indicators of the physiological state of the body; particular changes in the spectral characteristics of the heart rhythm of foreign students during mental load (measurement VSR at rest and with load); the level of load endurance CVS. Research results: the main role in changes in regulatory mechanisms belongs to the cardiorespiratory system, which is responsible for supplying organs and tissues with oxygen and nutrients. Parameters of VSR allow assessing not only the existing state of health of a person, but also his potential opportunities. Conclusions: these research results are an important aspect for the development of concepts of regulation of psychological and physical stress during the development of the curriculum of medical faculties.

The State of Vegetative Regulation in Patients with Ischemic Stroke in the Acute and Peracute Periods: an Observational Cohort Study

Background. The high number of stroke cases is predetermined by risk factors, pathogenetic heterogeneity, genetic predisposition to the disease. Neurovascular changes can serve as a marker for the severity of the patient’s condition. By means of cardiointervalography, the reactions of the autonomic nervous system in patients with ischemic stroke were studied, depending on the territory of the cerebral infarction and its period. With a favorable outcome of the disease, the detected changes in regulatory mechanisms can be considered adaptive, while with fatal outcome — disadaptive. Objectives. Determination of the state of the autonomic nervous system by means of cardiointervalography in patients with stroke in various pools of blood supply.Methods. 52 patients with a verifi ed diagnosis of ischemic stroke in the acute and peracute periods were examined. All patients were divided into 3 groups. Group 1 — patients with ischemic stroke in the middle cerebral artery territory on the left. Group 2 — with ischemic stroke in the middle cerebral artery territory on the right. Group 3 — with ischemic stroke in the vertebrobasilar territory. Patients with a fatal outcome are separately described. The functional state of the autonomic nervous system was assessed by the method of mathematical analysis of heart rate variability according to R.M. Baevsky (1984). Cardiointervalography was performed in the morning on the 1st day from the onset of the stroke and on the 10th day.Results. The state of autonomic regulation in patients with ischemic stroke depends on the localization and size of the lesion. According to cardiointervalography, parasympathetic effects on the rhythm of the heart prevailed in patients with ischemic stroke in the middle cerebral artery territory on the left and in the vertebrobasilar territory in the peracute period, while the sympathetic one predominated in patients with ischemic stroke in the middle cerebral artery territory on the right. In the acute period, the general tendency for the increase in activity of the opposite part of the autonomic nervous system was observed.Conclusion. Statistically signifi cant changes in the indicators of the total power of the wave oscillation spectrum and the indicator of ultra-low-frequency waves in the peracute and acute periods of stroke in the examined patients indicate the importance of neurohumoral mechanisms of regulation in the dynamics of the pathological state

Fraud and retraction in perioperative medicine publications: what we learned and what can be implemented to prevent future recurrence

Fraud in medical publications is an increasing concern. In particular, disciplines related to perioperative medicine—including anaesthesia and critical care—currently hold the highest rankings in terms of retracted papers for research...

Modified kinetics of generation of reactive species in peripheral blood of patients with type 2 diabetes

Level of reactive species in blood is an important pathogenic factor in diabetes mellitus leading to dysfunctions of vascular endothelial and smooth muscle cells and coagulation system abnormality. A massive release of reactive species (respiratory burst), catalyzed by NADPH oxidase in blood phagocytes, is not well understood in diabetes. The work aimed to study kinetics of response to microbial particles in blood to specify changes in regulatory mechanisms of generation of reactive species in patients with type 2 diabetes. Production of reactive species in blood and isolated granulocytes was measured by luminol-dependent chemiluminescence. Respiratory burst was initiated by serum opsonized zymosan in blood samples and phorbol ester in cell samples. Kinetic parameters were calculated from experimental kinetic curves of chemiluminescence intensity. ROC curve analysis and mathematical modeling were used to reveal the most significant predictors and clarify specific mechanisms of NADPH oxidase activation. It was shown that kinetic parameters of response to opsonized zymosan (lag-time, response rate, amplitude, production of reactive species) were higher in blood of patients than controls. Amplitude and response rate were the most statistically significant predictors for distinguishing patients and controls at high glucose. It indicated NADPH oxidase activation was the target of hyperglycemia. Mathematical modeling showed hyperglycemia increased stability of NADPH oxidase complex, decreased synchronization of its assembling and elevated neutrophil capacity to phagocytosis in patients. Weak or no dependence of response kinetics on ionomycin concentration was shown in patients indicating changed Ca2+-dependent mechanism of NADPH oxidase activation. Hyperglycemia in type 2 diabetes causes disturbances in mechanisms of NADPH oxidase activation associated with both phagocytosis and the state of intracellular signaling systems, including Ca2+-dependent. We suggest that NADPH oxidase in blood granulocytes can be a promising target for clinical intervention improving management of diabetic complications associated with inflammation.

FGFR3 – a Central Player in Bladder Cancer Pathogenesis?

The identification of mutations in FGFR3 in bladder tumors in 1999 led to major interest in this receptor and during the subsequent 20 years much has been learnt about the mutational profiles found in bladder cancer, the phenotypes associated with these and the potential of this mutated protein as a target for therapy. Based on mutational and expression data, it is estimated that >80% of non-muscle-invasive bladder cancers (NMIBC) and ∼40% of muscle-invasive bladder cancers (MIBC) have upregulated FGFR3 signalling, and these frequencies are likely to be even higher if alternative splicing of the receptor, expression of ligands and changes in regulatory mechanisms are taken into account. Major efforts by the pharmaceutical industry have led to development of a range of agents targeting FGFR3 and other FGF receptors. Several of these have entered clinical trials, and some have presented very encouraging early results in advanced bladder cancer. Recent reviews have summarised the drugs and related clinical trials in this area. This review will summarise what is known about the effects of FGFR3 and its mutant forms in normal urothelium and bladder tumors, will suggest when and how this protein contributes to urothelial cancer pathogenesis and will highlight areas that may benefit from further study.

Aging women and their endothelium: probing the relative role of estrogen on vasodilator function.

Despite significant decreases in cardiovascular disease (CVD) mortality in the past three decades, it still remains the leading cause of death in women. Following menopause and the accompanying loss of estrogen, women experience a unique, accelerated rise in CVD risk factors. Dysfunction of the endothelium represents an important antecedent to CVD development, with rapid declines in endothelial vasodilator function reportedly taking place across the menopause transition. Importantly, the decline in endothelial function is independent of chronological age and is associated with estrogen deficiency. Estrogen-mediated effects, including increasing nitric oxide bioavailability and attenuating oxidative stress and inflammation, contribute to preserving endothelial health. This review will discuss studies that have probed the role of estrogen on endothelial vasodilator function in women at discrete stages of the menopause transition and the effects of estradiol supplementation in postmenopausal women. Estrogen receptor signaling is also an important aspect of endothelial function in women, and studies suggest that expression is reduced with both acute and prolonged estrogen deficiency. Changes in regulatory mechanisms of estrogen receptor-α expression as well as sensitivity to estrogen may underlie the differential effects of estrogen therapy in early (≤5 yr past final menstrual period) and late postmenopausal women (>5 yr past final menstrual period). Lastly, this review presents potential therapeutic targets that include increasing l-arginine bioavailability and estrogen receptor activation to prevent endothelial dysfunction in postmenopausal women as a strategy for decreasing CVD mortality in this high-risk population.

Genomic Variability among Field Isolates and Laboratory-Adapted Strains ofLeptospira borgpeterseniiSerovar Hardjo

Leptospira borgpetersenii serovar Hardjo colonizes cattle kidneys and may occasionally infect humans and other mammals. Strains belonging to two clonal subtypes (types A and B) with marked differences in their pathogenicity in the hamster experimental model have been described for this serovar. Such differences have been attributed to point mutations in individual genes, although those genes have not yet been characterized. In order to better understand genetic variability among L. borgpetersenii serovar Hardjo isolates, we sequenced and compared the genomes of two laboratory-adapted strains and three abattoir-derived field isolates of L. borgpetersenii serovar Hardjo. Relatively low genetic variability was observed within isolates of the same subtype, with most of the mutations of moderate or high impact found in the laboratory-adapted isolates. In contrast, several differences regarding gene content and genetic variants were observed between the two subtypes. Putative type-specific genes appear to encode proteins associated with functions that are critical for infection. Some of these genes seem to be involved in transcriptional regulation, possibly leading to a distinct regulatory pattern in each type. These results show that changes in regulatory mechanisms, previously suggested to be critical during Leptospira speciation, may occur in L. borgpetersenii. In addition, the bioinformatics methodology used in this study for variant calling can be useful to other groups working with nonmodel prokaryotic organisms such as Leptospira species.

Identifying differentially coexpressed module during HIV disease progression: A multiobjective approach

Microarray analysis based on gene coexpression is widely used to investigate the coregulation pattern of a group (or cluster) of genes in a specific phenotype condition. Recent approaches go one step beyond and look for differential coexpression pattern, wherein there exists a significant difference in coexpression pattern between two phenotype conditions. These changes of coexpression patterns generally arise due to significant change in regulatory mechanism across different conditions governed by natural progression of diseases. Here we develop a novel multiobjective framework DiffCoMO, to identify differentially coexpressed modules that capture altered coexpression in gene modules across different stages of HIV-1 progression. The objectives are built to emphasize the distance between coexpression pattern of two phenotype stages. The proposed method is assessed by comparing with some state-of-the-art techniques. We show that DiffCoMO outperforms the state-of-the-art for detecting differential coexpressed modules. Moreover, we have compared the performance of all the methods using simulated data. The biological significance of the discovered modules is also investigated using GO and pathway enrichment analysis. Additionally, miRNA enrichment analysis is carried out to identify TF to miRNA and miRNA to TF connections. The gene modules discovered by DiffCoMO manifest regulation by miRNA-28, miRNA-29 and miRNA-125 families.

The Landscape of Evolution: Reconciling Structural and Dynamic Properties of Metabolic Networks in Adaptive Diversifications.

The network of the interactions among genes, proteins, and metabolites delineates a range of potential phenotypic diversifications in a lineage, and realized phenotypic changes are the result of differences in the dynamics of the expression of the elements and interactions in this deterministic network. Regulatory mechanisms, such as hormones, mediate the relationship between the structural and dynamic properties of networks by determining how and when the elements are expressed and form a functional unit or state. Changes in regulatory mechanisms lead to variable expression of functional states of a network within and among generations. Functional properties of network elements, and the magnitude and direction of evolutionary change they determine, depend on their location within a network. Here, we examine the relationship between network structure and the dynamic mechanisms that regulate flux through a metabolic network. We review the mechanisms that control metabolic flux in enzymatic reactions and examine structural properties of the network locations that are targets of flux control. We aim to establish a predictive framework to test the contributions of structural and dynamic properties of deterministic networks to evolutionary diversifications.

Principal Component Structuring of the Non-REM Sleep EEG Spectrum in Older Adults Yields Age-Related Changes in the Sleep and Wake Drives

Age-related disturbances of the sleep-wake cycle can reflect ontogenetic changes in regulatory mechanisms underlying normal and pathological aging, but the exact nature of these changes remains unclear. The present report is the first attempt to apply principal component analysis to the electroencephalographic (EEG) spectrum to examine of whether the observed age-related changes in the objective sleep measures can be linked to the opponent sleep-promoting and wake-promoting processes. The EEG indicators of these processes--scores on the 1st and 2nd principal components of the EEG spectrum, respectively--were compared in 15 older (57-74 years) and 16 younger (20-31 years) healthy volunteers. The scores were calculated for non-REM sleep episodes which occurred during ten 75-min naps scheduled every 150 min throughout a 40-h constant routine protocol. Both, a decrease of the 1st principal component score and an increase of the 2nd principal component score were found to contribute to such most obvious age-related modification of the sleep EEG spectrum as attenuation of EEG slow-wave activity in older people. Therefore, we concluded that the normal aging process can reflect both a weakening of the sleep-promoting process and a strengthening of the wake-promoting process, respectively. Such bidirectional changes in chronoregulatory processes may explain why sleep of older people is characterized by the few profitable and a number of detrimental features (i.e., a better ability to cope with daytime sleepiness and sleep loss vs. difficulty of falling asleep, decreased total nighttime sleep, "lightened" and fragmentized sleep, unwanted early morning awakenings, etc.).

Higher serum levels of tumour necrosis factor and its soluble receptors are associated with ovarian tumours

IntroductionTumour necrosis factor (TNF) and its soluble receptors type 1 (sTNF-R1) and type 2 (sTNF-R2) have been suggested as key mediators between apoptosis and cancer cell progression. The aim was to examine concentrations of the parameters in the serum of women with ovarian tumour and in the fluid from ovarian cysts of women with serous cystadenoma.Material and methodsThe study included 125 women with ovarian tumours. As a control, sera were obtained from 70 healthy female volunteers. Concentrations of TNF, sTNF-R1 and sTNF-R2 were measured by enzyme-linked immunosorbent assay (ELISA).ResultsSignificant increases of TNF, sTNF-R1 and sTNF-R2 were found in the serum of women with ovarian tumour in comparison to the control (p < 0.0001). The highest levels of all studied parameters were observed in women with ovarian cancer. In the ovarian cyst fluid the concentrations of the evaluated parameters increased significantly as compared to the serum (p < 0.0001).ConclusionsOur data showed changes in regulatory mechanisms of apoptosis in women with ovarian tumours which are associated with increased concentrations of all studied factors. Serum estimated TNF and especially sTNF-R may be used as complementary diagnostic markers in patients with ovarian tumours.

Correlated fluctuations carry signatures of gene regulatory network dynamics

The dynamics of transcriptional control involve small numbers of molecules and result in significant fluctuations in protein and mRNA concentrations. The correlations between these intrinsic fluctuations then offer, via the fluctuation dissipation relation, the possibility of capturing the system's response to external perturbations, and hence the nature of the regulatory activity itself. We show that for simple regulatory networks of activators and repressors, the correlated fluctuations between molecular species show distinct characteristics for changes in regulatory mechanism and for changes to the topology of causal influence. Here, we do a stochastic analysis and derive time-dependent correlation functions between molecular species of regulatory networks and present analytical and numerical results on peaks and delays in correlations between proteins within networks. Upon using these values of peaks and delays as a two-dimensional feature space, we find that different regulatory mechanisms separate into distinct clusters. This indicates that experimentally observable pairwise correlations can distinguish between gene regulatory networks.

Protein domain co-occurrences reveal functional changes of regulatory mechanisms during evolution

Protein domain co-occurrences reveal functional changes of regulatory mechanisms during evolution

New tricks with old genes: the genetic bases of novel cnidarian traits

Recent thought on genome evolution has focused on the creation of new genes and changes in regulatory mechanisms while ignoring the role of selective gene loss in shaping genomes. Using data from two cnidarians, the jellyfish Clytia and the coral Acropora, we examined the relative significance of new 'taxonomically restricted' genes and selectively retained ancestral genes in enabling the evolution of novel traits. Consistent with its more complex life-cycle, the proportion of novel genes identified in Clytia was higher than that in the 'polyp only' cnidarians Nematostella and Hydra, but each of these cnidarians has retained a proportion of ancestral genes not present in the other two. The ubiquity and near-stochastic nature of gene loss can explain the discord between patterns of gene distribution and taxonomy.

Influences of human activity and climate on the stock‐recruitment dynamics of whitefish, Coregonus lavaretus, in Lake Geneva

Abstract Analysis of long‐term catches from the deep peri‐alpine Lake Geneva, showed a shift in the stock‐recruitment relationship of Coregonus lavaretus (L.), a target species of commercial fishing. This change was mainly related to large‐scale meteorological factors. Higher spring water temperatures may have improved larval survival and hence recruitment of whitefish via: (1) a better match between the hatching date of whitefish larvae and development of their zooplankton prey; and (2) the positive temperature effect on larval growth. In Lake Geneva, changes in regulatory mechanisms coupled with stocking and improved water‐quality have led to an explosion in the C. lavaretus population in recent years. These results highlight the relevance of long‐term changes in the stock‐recruitment relationship for management of aquatic ecosystems that are sensitive to climate forcing.

The Concept of Human Functional State in Russian Applied Psychology

The concept of human functional states (HFS) is considered in the framework of activity regulation approach developed in Russian applied psychology. Aimed at the analysis of changes in regulatory mechanisms of on-going activity, structural methods for multilevel assessment of workers’ states are discussed. Three different strategies of data integration are proposed regarding the types of essential practical problems. Their usability is exemplified with the help of two empirical studies concerned with reliability of fire-fighters’ work in the Chernobyl Zone and effects of interruptions in computerized office environment. A general framework for applied HFS research is proposed in order to develop new ecologically valid psychodiagnostic procedures that can help to create efficient stress-management programs for enhancing human reliability and performance in complex job environment.

Structure and Regulatory Mechanism of Aquifex aeolicus NtrC4: Variability and Evolution in Bacterial Transcriptional Regulation

Genetic changes lead gradually to altered protein function, making deduction of the molecular basis for activity from a sequence difficult. Comparative studies provide insights into the functional consequences of specific changes. Here we present structural and biochemical studies of NtrC4, a sigma-54 activator from Aquifex aeolicus, and compare it with NtrC1 (a paralog) and NtrC (a homolog from Salmonella enterica) to provide insight into how a substantial change in regulatory mechanism may have occurred. Activity assays show that assembly of NtrC4's active oligomer is repressed by the N-terminal receiver domain, and that BeF3− addition (mimicking phosphorylation) removes this repression. Observation of assembly without activation for NtrC4 indicates that it is much less strongly repressed than NtrC1. The crystal structure of the unactivated receiver–ATPase domain combination shows a partially disrupted interface. NMR structures of the regulatory domain show that its activation mechanism is very similar to that of NtrC1. The crystal structure of the NtrC4 DNA-binding domain shows that it is dimeric and more similar in structure to NtrC than NtrC1. Electron microscope images of the ATPase–DNA-binding domain combination show formation of oligomeric rings. Sequence alignments provide insights into the distribution of activation mechanisms in this family of proteins.

Evolution of alternative transcriptional circuits with identical logic

Evolution of gene regulation is an important contributor to the variety of life. Here, we analyse the evolution of a combinatorial transcriptional circuit composed of sequence-specific DNA-binding proteins that are conserved among all eukaryotes. This circuit regulates mating in the ascomycete yeast lineage. We first identify a group of mating genes that was transcriptionally regulated by an activator in a fungal ancestor, but is now transcriptionally regulated by a repressor in modern bakers' yeast. Despite this change in regulatory mechanism, the logical output of the overall circuit remains the same. By examining the regulation of mating in modern yeasts that are related to different extents, we deduce specific, sequential changes in both cis- and trans-regulatory elements that constitute the transition from positive to negative regulation. These changes indicate specific mechanisms by which fitness barriers were traversed during the transition.