Mechanisms Of Adaptive Changes Research Articles

Електроенцефалограми у дітей з сенсорною та руховою деприваціями

Sensorineural hearing loss and cerebral palsy (CP) are natural models of deprivation. In individuals with these pathologies, the rhythmic components of the electroencephalogram (EEG) of individual zones provide an opportunity to identify the central mechanisms of adaptive changes that develop at the system level. The normalized spectral power of EEG derivation was used in our study to assess the effect of auditory and motor deprivation on the functional state of the brain. The study involved 240 children aged 8 to 15 years who were divided into four groups: group I included 40 muffled boys and 42 girls; to II - 40 guys and 40 girls who heard; to III - 40 boys and 38 girls with impaired motor activity; to IV - 50 guys and 50 girls with normal physical activity. We found that children with limited motor activity had a lower normalized spectral power of the δ-rhythm in the posterior leads on the right side (respectively, girls - 27.23 ± 0.84 and 33.99 ± 1.94; boys - 27.80 ± 1.78 and 36.82 ± 2.04) and temporal from the left (respectively, girls - 27.40 ± 0.98 and 37.82 ± 1.66; boys - 39.88 ± 1.63 and 42.17 ± 2.04). An increase in the normalized spectral power of the θ-rhythm in the temporo-parietal-occipital region of the brain (respectively, girls – 25.73 ± 1.18 and 13.64 ± 0.47; boys – 19.86 ± 0.95 and 12.74 ± 0.78,), a lower normalized spectral power of the α-rhythm and a greater normalized spectral power of the β-rhythm (α-rhythm: respectively, girls – 24.34 ± 1.54 and 41.71 ± 2.54; boys – 27.84 ± 1.48 and 45.01 ± 2.41; β-rhythm: girls – 25.00 ± 1.14 and 9.95 ± 0.48; boys – 19.94 ± 0.86 and 9.20 ± 0.66) over almost the entire scalp compared to children with sensorineural hearing loss.

Unique Features of the Tissue Structure in the Naked Mole Rat (Heterocephalus glaber): Hypertrophy of the Endoplasmic Reticulum and Spatial Mitochondrial Rearrangements in Hepatocytes.

The reason for the exceptional longevity of the naked mole rat (Heterocephalus glaber) remains a mystery to researchers. We assumed that evolutionarily, H. glaber acquired the ability to quickly stabilize the functioning of mitochondria and endoplasmic reticulum (ER) to adjust metabolism to external challenges. To test this, a comparison of the hepatic mitochondria and ER of H. glaber and C57BL/6 mice was done. Electron microscopy showed that 2-months-old mice have more developed rough ER (RER) than smooth ER (SER), occupying ~17 and 2.5% of the hepatocytic area correspondingly, and these values do not change with age. On the other hand, in 1-week-old H. glaber, RER occupies only 13% constantly decreasing with age, while SER occupies 35% in a 1-week-old animal, constantly rising with age. The different localization of mitochondria in H. glaber and mouse hepatocytes was confirmed by confocal and electron microscopy: while in H. glaber, mitochondria were mainly clustered around the nucleus and on the periphery of the cell, in mouse hepatocytes they were evenly distributed throughout the cell. We suggest that the noted structural and spatial features of ER and mitochondria in H. glaber reflect adaptive rearrangements aimed at greater tolerance of the cellular system to challenges, primarily hypoxia and endogenous and exogenous toxins. Different mechanisms of adaptive changes including an activated hepatic detoxification system as a hormetic response, are discussed considering the specific metabolic features of the naked mole rat.

Ontogeny, phylogeny and mechanisms of adaptive changes in evaporative water loss in geckos.

Body size dependence of metabolic rate, body surface and scale morphology complicate disentangling the contribution of these characteristics to adaptive changes in total evaporative water loss (TEWL) of reptiles. To separate adaptive changes from size-related dependence, we compared intra- and interspecific scaling of several candidate traits in eyelid geckos (Eublepharidae), a group exhibiting large variation in body size and TEWL. The intraspecific allometry of TEWL of a eublepharid species fits the geometric surface-mass relationship. However, evolutionary shifts to both higher and lower evaporation were strongly correlated with habitat aridity and cannot be explained by shifts in body size alone. The intraspecific allometry of standard metabolic rate is nearly the same as the interspecific allometry. Unlike for mammals and birds, this pattern rules out respiratory water loss as a driver of the adaptive changes in TEWL among eublepharids. Scale morphology was independent of TEWL variation as well, but the correlation between cutaneous water loss and TEWL suggests a crucial role of skin permeability in adaptation to habitat aridity. Our analyses demonstrate how powerful a comparison between intra- and interspecific allometries can be for detecting body size-dependent mechanisms of adaptive changes in ecophysiological traits correlated with body size.

Effect of 8-Day Fasting on Leukocytes Expression of Genes and Proteins Involved in Iron Metabolism in Healthy Men.

The popularity of fasting and restricted food intake is increasing. While the body’s adaptability to dietary insufficiency is crucial for health, molecular mechanisms of adaptive changes are not well understood. Here, we compared the effects of fasting and exercise on the expression of leukocyte genes and proteins involved in the storage, export, and acquisition of iron, an essential element with physiological roles. Healthy men participated in the study (age, 30–70 years; body weight, 60–100 kg; body mass index, 20–29.9 kg/m2). The participants performed an exercise test with a gradually increasing intensity until the individual maximum exercise capacity was reached, before and after 8-d fast. Blood samples were collected before, immediately after, and 3 h after exercise. Gene expression was analyzed by reverse-transcription quantitative polymerase chain reaction and protein levels were analyzed by immunobloting. Eight days of total starvation diet affected the body composition and decreased exercise capacity. Further, fasting decreased the expression of genes associated with iron storage and export, and increased the expression of genes involved in iron acquisition. Conversely, only PCBP2 protein increased after fasting; however, an upward trend was apparent for all proteins. In conclusion, the body adapts to starvation by adjusting iron economy.

Abstract 2070: Exploration of markers of synergistic lethality of PARP and PI3K-Akt-mTOR inhibitors in women's cancers

Abstract Introduction: The objective was to identify molecular mechanisms and protein networks involved in synthetic lethality as well as mechanisms of adaptive changes to the combination of olaparib (O) combined with inhibitors of the PI3K-AKT axis. Methods: 110 patients with recurrent ovarian, endometrial, and triple negative breast cancer were treated with a combination of O and vistusertib (V) or capivasertib (C) (mTORC1/2 and AKT inhibitors, respectively). We have previously reported durable clinical efficacy of these combinations, regardless of BRCA status. Tumor samples were collected pre-treatment and 30 days post-treatment and reverse-phase protein array (RPPA) was performed. Baseline expression was assessed and change in expression was calculated. Bioinformatics and statistical methods were developed to assess activity of signaling pathways. Pathway scores were determined based on the expression of sets of proteins known to be involved in a specific pathway, including PI3K, RAS/RAF, and DNA damage repair. Association between protein expression and treatment efficacy was determined. Results: We analyzed a total of 55 paired samples from patients treated with O/V (n=25) and O/C (n=30). These included 20 endometrial (37% PR, 31.5% SD, 31.5% PD), 21 ovarian (10% PR, 55% SD, 35% PD) and 14 triple negative breast (15% PR, 23% SD, 62% PD) tumors. Response to O/V was associated with low pre-treatment mTOR pathway activity and led to altered immune activity based on decreased CD4 and PD1 expression. Resistance to O/V was associated with high pre-treatment cell proliferation (high CCNB1, CDK1 and PLK1 protein expression). In contrast, response to O/C was associated with adaptive responses indicated by decreased mTOR activity and induction of the DNA damage checkpoint (high phospho-CHK1, -WEE1 and -CDC2). Resistance was associated with high pre-treatment RTK activity levels (high phospho-HER3, -EGFR, -IGFR, -MET) and AKT-independent activation of mTOR in the on-treatment samples. Conclusion: Analysis of pre- and on-treatment samples from responders and non-responders to PARP and PI3K pathway combination therapy identified biomarkers of patients likely to benefit from therapy and helps to understand molecular mechanisms involved in response and resistance to these drug combinations. Citation Format: Marilyne Labrie, Zhenlin Ju, Jennifer K. Litton, Tae-Beom Kim, Sanghoon Lee, Ken Chen, Pamela T. Soliman, Michael Frumovitz, Larissa A. Meyer, Stacy Moulder, Amir A. Jazaeri, Karen H. Lu, Anil K. Sood, Robert L. Coleman, Gordon B. Mills, Shannon N. Westin. Exploration of markers of synergistic lethality of PARP and PI3K-Akt-mTOR inhibitors in women's cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2070.

Microviscosity of erythrocyte membranes during chronic heart failure in patients of middle and senior age groups

Microviscosity coefficients were studied in the area of integrated and annular lipids of erythrocyte membranes in the peripheral blood of patients aged 35–50 and 60–75 with chronic coronary heart disease (CHD), as well as healthy donors of corresponding age. It was found in healthy donors that the microviscosity coefficients in the area of integrated and of annular lipids are significantly higher in the senior age group (60–75 years). In CHD, both an increase and a decrease in the microviscosity parameters in the area of lipid–lipid interactions can be characteristic for erythrocyte membranes, regardless of the patient age. In the protein–lipid contacts, an increase in microviscosity parameters is characteristic for patients aged 35–50 and, in contrast, a decrease in the microviscosity coefficient was observed in 60- to 75-year-old patients. It was concluded that the indicators of erythrocyte membrane microviscosity in patients of different age groups reflect both the implementation of general mechanisms of adaptive changes in cell membranes and the individual characteristics determined by their lipid and protein composition during the development of chronic CHD.

Microviscosity of erythrocyte membranes in chronic coronary insufficiency in patients of middle and older age groups

We examined the ratios microviscosity in the area of integral and annularly lipid membranes of erythrocytes of peripheral blood in patients of 35-50 and 60-75 years with chronic ischemic heart disease, as well as age-matched healthy controls. In healthy donors coefficients microviscosity in the area of integral and annularly lipids proved to be significantly higher in the older age group (60-75 years). In CHD, regardless of the age of the patients, erythrocyte membranes can be characterized as raising and lowering the parameters microviscosity of lipid-lipid interactions. In the protein-lipid contacts for patients aged 35-50 years an increase is typical, while for patients of 60-75 years, on the contrary, a decrease of the coefficient of microviscosity. It is concluded that the values of the microviscosity of erythrocyte membranes in patients of different age groups in the development of chronic ischemic heart disease, reflect both the implementation of the general mechanisms of adaptive changes of cell membranes, and the specifics of an individual, determined by their lipid and protein composition.

Transcriptional dynamics of a conserved gene expression network associated with craniofacial divergence in Arctic charr.

BackgroundUnderstanding the molecular basis of craniofacial variation can provide insights into key developmental mechanisms of adaptive changes and their role in trophic divergence and speciation. Arctic charr (Salvelinus alpinus) is a polymorphic fish species, and, in Lake Thingvallavatn in Iceland, four sympatric morphs have evolved distinct craniofacial structures. We conducted a gene expression study on candidates from a conserved gene coexpression network, focusing on the development of craniofacial elements in embryos of two contrasting Arctic charr morphotypes (benthic and limnetic).ResultsFour Arctic charr morphs were studied: one limnetic and two benthic morphs from Lake Thingvallavatn and a limnetic reference aquaculture morph. The presence of morphological differences at developmental stages before the onset of feeding was verified by morphometric analysis. Following up on our previous findings that Mmp2 and Sparc were differentially expressed between morphotypes, we identified a network of genes with conserved coexpression across diverse vertebrate species. A comparative expression study of candidates from this network in developing heads of the four Arctic charr morphs verified the coexpression relationship of these genes and revealed distinct transcriptional dynamics strongly correlated with contrasting craniofacial morphologies (benthic versus limnetic). A literature review and Gene Ontology analysis indicated that a significant proportion of the network genes play a role in extracellular matrix organization and skeletogenesis, and motif enrichment analysis of conserved noncoding regions of network candidates predicted a handful of transcription factors, including Ap1 and Ets2, as potential regulators of the gene network. The expression of Ets2 itself was also found to associate with network gene expression. Genes linked to glucocorticoid signalling were also studied, as both Mmp2 and Sparc are responsive to this pathway. Among those, several transcriptional targets and upstream regulators showed differential expression between the contrasting morphotypes. Interestingly, although selected network genes showed overlapping expression patterns in situ and no morph differences, Timp2 expression patterns differed between morphs.ConclusionOur comparative study of transcriptional dynamics in divergent craniofacial morphologies of Arctic charr revealed a conserved network of coexpressed genes sharing functional roles in structural morphogenesis. We also implicate transcriptional regulators of the network as targets for future functional studies.Electronic supplementary materialThe online version of this article (doi:10.1186/2041-9139-5-40) contains supplementary material, which is available to authorized users.

Crosstalk between G protein-coupled receptors (GPCRs) and tyrosine kinase receptor (TXR) in the heart after morphine withdrawal

G protein-coupled receptors (GPCRs) comprise a large family of membrane receptors involved in signal transduction. These receptors are linked to a variety of physiological and biological processes such as regulation of neurotransmission, growth, and cell differentiation among others. Some of the effects of GPCRs are known to be mediated by the activation of mitogen-activated extracellular kinase (MAPK) pathways. Cross-talk among various signal pathways plays an important role in activation of intracellular and intranuclear signal transduction cascades. Naloxone-induced morphine withdrawal leads to an up-regulation of adenyl cyclase-mediated signaling, resulting in high expression of protein kinase (PK) A. In addition, there is also an increased expression of extracellular signal regulated kinase (ERK), one member of MAPK. For this reason, the crosstalk between these GPCRs and receptors with tyrosine kinase activity (TKR) can be considered a possible mechanism for adaptive changes that occurs after morphine withdrawal. Morphine withdrawal activates ERK1/2 and phosphorylated tyrosine hydroxylase (TH) at Ser31 in the right and left ventricle. When N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), a PKA inhibitor was infused, the ability of morphine withdrawal to activate ERK, which phosphorylates TH at Ser31, was reduced. The present finding demonstrated that the enhancement of ERK1/2 expression and the phosphorylation state of TH at Ser31 during morphine withdrawal are dependent on PKA and suggest cross-talk between PKA and ERK1/2 transduction pathway mediating morphine withdrawal-induced activation of TH. Increasing understanding of the mechanisms that interconnect the two pathway regulated by GPCRs and TKRs may facilitate the design of new therapeutic strategies.

Adaptation to cold of homeothermic organism: changes in afferent and efferent links of the thermoregulatory system

This review focuses on mechanisms of cold adaptation and with the interaction of the afferent and efferent links of the system of thermal homeostasis found through major research advances in our department. Certain mechanisms of adaptive changes in metabolic and heat loss processes were disclosed mostly concentrated on muscle and respiratory functions. It was shown that, as a result of cold adaptation, there occur changes in the functional characteristics of the central and peripheral thermoreceptors, which form the input signal and determine the regulatory parameters of the system of thermal homeostasis. The adaptive changes in the afferent link are consistent also with the re-arrangement in the work of the respiratory system. The accumulated facts give grounds for believing that the important role of thermoreceptors in maintenance of adaptive re-arrangement is due to the direct and feedback relation to the neurohumoral systems of the organism. The direct relation makes possible the implementation of a wide range of effector responses to thermal stimulus; while the feedback relation makes possible various modulations of the thermoreceptors, which are the initial link of the thermoregulatory system.

DESTRUCTION OF HYDROXYCINNAMIC ACIDS COUPLED TO OXIDATION OF INDOLYL-3-ACETIC ACID BY PEROXIDASE AS A POSSIBLE MECHANISM FOR ADAPTIVE CHANGES OF INDOLYL-3-ACETIC ACID OXIDASE ACTIVITY.

Destruction of Hydroxycinnamic Acids coupled to Oxidation of Indolyl-3-acetic Acid by Peroxidase as a Possible Mechanism for Adaptive Changes of Indolyl-3-acetic Acid Oxidase Activity