Repurposing of the enhancer-promoter communication underlies the compensation of Mesp2 by Mesp1

Organisms are inherently equipped with buffering systems against genetic perturbations. Genetic compensation, the compensatory response by upregulating another gene or genes, is one such buffering mechanism. Recently, a well-conserved compensatory mechanism was proposed: transcriptional adaptation of homologs under the nonsense-mediated mRNA decay pathways. However, this model cannot explain the onset of all compensatory events. We report a novel genetic compensation mechanism operating over the Mesp gene locus. Mesp1 and Mesp2 are paralogs located adjacently in the genome. Mesp2 loss is partially rescued by Mesp1 upregulation in the presomitic mesoderm (PSM). Using a cultured PSM induction system, we reproduced the compensatory response in vitro and found that the Mesp2-enhancer is required to promote Mesp1. We revealed that the Mesp2-enhancer directly interacts with the Mesp1 promoter, thereby upregulating Mesp1 expression upon the loss of Mesp2. Of note, this interaction is established by genomic arrangement upon PSM development independently of Mesp2 disruption. We propose that the repurposing of this established enhancer-promoter communication is the mechanism underlying this compensatory response for the upregulation of the adjacent gene.

Insulin Clearance in Obesity and Type 2 Diabetes

Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.

Multiple metals and agricultural use affects oxidative stress biomarkers in freshwater Aegla crabs

Metals and agrochemicals are among the main aquatic contaminants, being able to trigger oxidative stress in exposed organisms. The objective of this work was to evaluate the correlation between the level of oxidative stress biomarkers in Aegla crabs (Crustacea, Anomura) with (i) the set of metals present in the streams sediment and (ii) with land uses of three hydrographic basins. The study was carried out in streams (≤ 2nd order) of hydrographic basins in southern Brazil (Basins of Rio Suzana, Rio Ligeirinho-Leãozinho and Rio Dourado). In these streams were quantified the land uses and Cu, Cr, Cd, Fe, Mn and Zn concentrations in the sediment. The enzymes Catalase (CAT) and Glutathione Reductase (GR), as well as the level of membrane lipid peroxidation (TBARS), were analyzed in adult females. The PCA analysis showed that the distribution of metals was different between the basins. Cd, Cr and Fe were correlated positively with CAT and negatively with TBARS and GR. The Dourado basin had the lowest concentrations of these three metals and the highest levels of TBARS. However, in Dourado basin there is predominance of agriculture land use, and TBARS was positively correlated with agricultural land use. Besides in Dourado basin, GR activity was higher than in the others basins, indicating a compensatory response in relation to CAT inhibition. The basins of Suzana and Ligeirinho-Leãozinho rivers had lower TBARS values, which may be due to the induction of CAT in response to metals accumulated in sediment. In summary, this work indicates that in the basins with a higher concentration of toxic metals there is an adaptive response of CAT induction, which reduces TBARS in Aegla. On the other hand, in the basin with lower metallic contamination, TBARS occurrence was primarily influenced by agricultural land use.

Connectomic Analysis of Alzheimer’s Disease using Percolation Theory

Alzheimer’s disease (AD) is a severe neurodegenerative disorder that affects a growing worldwide elderly population. Identification of brain functional biomarkers is expected to help determine preclinical stages for targeted mechanistic studies and development of therapeutic interventions to deter disease progression. Connectomic analysis, a graph theory-based methodology used in the analysis of brain-derived connectivity matrices was used in conjunction with percolation theory targeted attack model to investigate the network effects of AD-related amyloid deposition. We used matrices derived from resting state functional magnetic resonance imaging collected on mice with extracellular amyloidosis (TgCRND8 mice, n = 17) and control littermates (n = 17). Global, nodal, spatial, and percolation-based analysis was performed comparing AD and control mice. These data indicate a short-term compensatory response to neurodegeneration in the AD brain via a strongly connected core network with highly vulnerable or disconnected hubs. Targeted attacks demonstrated a greater vulnerability of AD brains to all types of attacks and identified progression models to mimic AD brain functional connectivity through betweenness centrality and collective influence metrics. Furthermore, both spatial analysis and percolation theory identified a key disconnect between the anterior brain of the AD mice to the rest of the brain network.

Decorin Concentrations in Aqueous Humor of Patients with Diabetic Retinopathy

Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, laser photocoagulation, or vitrectomy in severe cases. However, treatment may require multiple modalities or repeat treatments due to variable response. Though DR management has achieved great success, improved, long-lasting, and predictable treatments are needed, including new biomarkers and therapeutic approaches. Small-leucine rich proteoglycans, such as decorin, constitute an integral component of retinal endothelial ECM. Therefore, any damage to microvasculature can trigger its antifibrotic and antiangiogenic response against retinal vascular pathologies, including DR. We conducted a cross-sectional study to examine the association between aqueous humor (AH) decorin levels, if any, and severity of DR. A total of 82 subjects (26 control, 56 DR) were recruited. AH was collected and decorin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Decorin was significantly increased in the AH of DR subjects compared to controls (p = 0.0034). AH decorin levels were increased in severe DR groups in ETDRS and Gloucestershire classifications. Decorin concentrations also displayed a significant association with visual acuity (LogMAR) measurements. In conclusion, aqueous humor decorin concentrations were found elevated in DR subjects, possibly due to a compensatory response to the retinal microvascular changes during hyperglycemia.

Application of the Kohonen neural network for monitoring tissue oxygen supply under hypoxic conditions

The article presents the results of application of the Kohonen artificial neural network (KANN) in assessing the oxygen status of human tissues, as well as for studying the adaptive-compensatory response of the body to functional load. In the experiment, the registered digital oxygen images of the tissue of 31 subjects were distributed into three classes using the KANN. Each group is characterised by different resistance of the organism to hypoxia. The research results have shown the effectiveness of using an artificial neural network structure and the possibility of its implementation for recognition of the functional state of a person under conditions of metabolic hypoxia; it seems relevant and has theoretical and practical significance in the framework of ecological physiology.

Mapping the Endogenous Ketogenic System Across Ages, Sex and Diets

Understanding how our cells maintain energy homeostasis has long been a focus of aging biology. A decline in energy metabolism is central to many age-related diseases such as Alzheimer’s disease, heart failure, frailty, and delirium. Intervening on pathways involved in energy homeostasis can extend healthy lifespan. When our primary energy substrate glucose, is scarce, our bodies use ketone bodies (i.e. beta-hydroxybutyrate, acetoacetate, acetone). Aging is associated with glucose intolerance and insulin insensitivity, yet what role ketone body metabolism might play in compensating for impaired glucose utilization in age-related diseases is understudied. Here, we investigated how the body’s endogenous ketone body production and utilization pathways are modulated by age across the lifespan of female and male C57BL/6 mice (4 mo old, 12 mo old, 22 mo old). We show how different ages have different metabolic and gene expression responses to 1-week ketogenic diet (KD) or ketone ester diet. We observed an apparently compensatory ketogenic response in older animals fed normal diet, with a stronger compensatory response driven by KD. We observed tissue-specific changes, including induction of ketone body production enzymes in the aging heart. When comparing the ketogenic capacity between sexes, females had a higher basal level and less variation with age, underscoring the importance of sexual dimorphism in metabolism. Overall, these findings suggest that older animals use ketone bodies to meet energetic demands in a normal diet context. This study supports the potential roles of ketogenic therapies such as exogenous ketones to improve energy homeostasis in conditions of aging.

Catestatin as a Biomarker of Cardiovascular Diseases: A Clinical Perspective

Accounting for almost one-third of the global mortality, cardiovascular diseases (CVDs) represent a major global health issue. Emerging data suggest that most of the well-established mechanistic explanations regarding the cardiovascular pathophysiology are flawed, and cannot fully explain the progression and long-term effects of these diseases. On the other hand, dysregulation of the sympathetic nervous system (SNS) has emerged as an important player in the pathophysiology of CVDs. Even though upregulated SNS activity is an essential compensatory response to various stress conditions, in the long term, it becomes a major contributor to both cardiac dysfunction and vascular damage. Despite the fact that the importance of SNS hyperactivity in the setting of CVDs has been well-appreciated, its exact quantification and clinical application in either diagnostics or therapy of CVDs is still out of reach. Nevertheless, in recent years a number of novel laboratory biomarkers implicated in the pathophysiology of SNS activation have been explored. Specifically, in this review, we aimed to discuss the role of catestatin, a potent physiological inhibitor of catecholamine spillover that offers cardioprotective effects. Limited data indicate that catestatin could also be a reliable indirect marker of SNS activity and it is likely that high CST levels reflect advanced CV disease burden. Consequently, large-scale studies are required to validate these observations in the upcoming future.

Ecology of the Possum (Trichosurus Vulpecula Kerr) in the Karori Water Supply Reserve, Wellington, Sounds Ecological District

<p>The abundance and condition of possums in various areas of the Karori Reserve, Wellington - Sounds Ecological District was assessed. Possums were most abundant in the upper part of the reserve in an area dominated by bishop and radiata pines with an undergrowth of native species and in an area dominated by gorse and flax shrublands. In the lower part of the reserve, possums were less abundant and there a number of characteristics were observed: possums had a higher body weight for age, their reproductive output was higher and the population was marked by a higher proportion of females and juveniles. This was interpreted as a "compensatory response" characteristic of possum populations maintained at low densities. Possum stomachs were sampled in spring and their contents analysed in order to investigate the importance of Fuchsia excorticata and other plant species to possum diet. In the lower part of the reserve the leaves of Fuchsia excorticata and the flowers of Cytisus scoparius made up more than 50 percent of the possums' forage. In the upper part of the reserve exotic species such as the flowers of Cytisus scoparius and Ulex europeans as well as the leaves of native species such as Aristotelia serrata, Pseudopanax arboreus and Coprosma robusta made up the bulk of possum forage. Exotic plants accounted for a significant proportion of the spring possum diet in the reserve. Whereas most leaves originated from native plants, the exotic species contributed mainly carbohydrate-rich flowers and pollen. The canopy condition of two possum-susceptible tree species Fuchsia excorticata and Pseudopanax arboreus was assessed early in autumn over the years 1993, 1995 and 1996. Over these years, 47 percent of marked fuchsia trees were completely defoliated and most trees are unlikely to recover even if possums are eradicated from the reserve. All defoliated fuchsia trees were located in the upper part of the reserve. On the other hand, 37 percent of marked fuchsia trees exhibited only a little possum damage. Most of these trees were located in the lower part of the reserve where possum density was lower. Increasing possum densities could therefore be correlated with an increasing level of possum damage to fuchsia canopies. Even though Pseudopanax arboreus leaves and petioles were encountered in 10 percent of possum stomachs, the canopies leaves and petioles were encountered in 10 percent of possum stomachs, the canopies of assessed trees did not seem to be greatly affected. It appeared that due to the high abundance of this plant species in the reserve the effects of possum browse were spread over the whole reserve to levels which could be tolerated by an individual Pseudopanax arboreus tree.</p>

Ecology of the Possum (Trichosurus Vulpecula Kerr) in the Karori Water Supply Reserve, Wellington, Sounds Ecological District

<p>The abundance and condition of possums in various areas of the Karori Reserve, Wellington - Sounds Ecological District was assessed. Possums were most abundant in the upper part of the reserve in an area dominated by bishop and radiata pines with an undergrowth of native species and in an area dominated by gorse and flax shrublands. In the lower part of the reserve, possums were less abundant and there a number of characteristics were observed: possums had a higher body weight for age, their reproductive output was higher and the population was marked by a higher proportion of females and juveniles. This was interpreted as a "compensatory response" characteristic of possum populations maintained at low densities. Possum stomachs were sampled in spring and their contents analysed in order to investigate the importance of Fuchsia excorticata and other plant species to possum diet. In the lower part of the reserve the leaves of Fuchsia excorticata and the flowers of Cytisus scoparius made up more than 50 percent of the possums' forage. In the upper part of the reserve exotic species such as the flowers of Cytisus scoparius and Ulex europeans as well as the leaves of native species such as Aristotelia serrata, Pseudopanax arboreus and Coprosma robusta made up the bulk of possum forage. Exotic plants accounted for a significant proportion of the spring possum diet in the reserve. Whereas most leaves originated from native plants, the exotic species contributed mainly carbohydrate-rich flowers and pollen. The canopy condition of two possum-susceptible tree species Fuchsia excorticata and Pseudopanax arboreus was assessed early in autumn over the years 1993, 1995 and 1996. Over these years, 47 percent of marked fuchsia trees were completely defoliated and most trees are unlikely to recover even if possums are eradicated from the reserve. All defoliated fuchsia trees were located in the upper part of the reserve. On the other hand, 37 percent of marked fuchsia trees exhibited only a little possum damage. Most of these trees were located in the lower part of the reserve where possum density was lower. Increasing possum densities could therefore be correlated with an increasing level of possum damage to fuchsia canopies. Even though Pseudopanax arboreus leaves and petioles were encountered in 10 percent of possum stomachs, the canopies leaves and petioles were encountered in 10 percent of possum stomachs, the canopies of assessed trees did not seem to be greatly affected. It appeared that due to the high abundance of this plant species in the reserve the effects of possum browse were spread over the whole reserve to levels which could be tolerated by an individual Pseudopanax arboreus tree.</p>