Search Results (414)

Amphibian conservation concerns frequently center on the idea of ‘saving’ them, with the underlying assumption they are the passive victims of anthropogenic environmental change. But this approach ignores the physiological, biochemical, and behavioral flexibility amphibians have employed since they first evolved ~365 million years ago. One overlooked advantage amphibians possess in the struggle for survival, and one humans might use in their efforts to conserve them, is their brains share the same blueprint as human brains, which allows them to acquire knowledge and understanding through experiences—in other words, amphibians have cognitive capabilities that assist them in their effort to survive. Here, we use four examples from our work on the behavioral ecology of Crawfish Frogs (Rana areolata) to form hypotheses about how cognition affects amphibian reaction to environmental and social change. The first two examples describe Crawfish Frog responses to seasonality and reproductive status, the third details their reaction to ecological disturbance, and the fourth describes how their response to the same stimulus changes with growth/age. In each example, we detail the neuronal circuitry thought to be involved and hypothesize the role of cognition. We propose that as one component of our fight to conserve amphibians, researchers should consider the full range of anatomical, physiological, biochemical, and behavioral features amphibians themselves employ in their defense, which are features responsible for their historical evolutionary success up until the Anthropocene. Further, we submit that acknowledging amphibians possess cognitive abilities can enrich interpretations of not only behavioral and ecological observations but also of neuroanatomical and neurophysiological results. Full article

Background/Objectives: Spironolactone (SP) has been used off-label in pediatrics since its approval, but its use is challenged by limited pharmacokinetic (PK) data in adults and especially in children. Methods: Physiologically based pharmacokinetic (PBPK) models for SP and its active metabolites, canrenone (CAN) and 7α thio-methyl spironolactone (TMS), in adults were developed. These models aim to enhance understanding of SP’s PK and provide a basis for predicting PK and optimizing SP dosing in infants and neonates. Given SP’s complex metabolism, we assumed complete conversion to CAN and TMS by CES1 enzymes, fitting CES1-mediated metabolism to the parent-metabolite model using PK data. We incorporated ontogeny for CES1 and CYP3A4 and other age-related physiological changes into the model to anticipate PK in the pediatric population. Results: The PBPK models for SP, CAN, and TMS accurately captured the observed PK data in healthy adults across various dosing regimens, including the impact of food on drug exposure. The pediatric PBPK model was evaluated using PK data from infants and neonates. Simulations indicate that 2.5 mg/kg in 6-month to 2-year infants and 2 mg/kg in 1–6-months infants matched the total unbound systemic exposure equivalent to the standard recommended daily maintenance dose of 100 mg in adults for treating edema. Conclusions: The developed PBPK model provides valuable insights for dosing decisions and optimizing therapeutic outcomes, especially in populations where clinical studies are challenging. Full article

Cerebral lateralisation is a core organising principle of the brain that is characterised by a complex pattern of hemispheric specialisations and interhemispheric interactions. In various mental disorders, functional and/or structural hemispheric asymmetries are changed compared to healthy controls, and these alterations may contribute to the primary symptoms and cognitive impairments of a specific disorder. Since multiple genetic and epigenetic factors influence both the pathogenesis of mental illness and the development of brain asymmetries, it is likely that the neural developmental pathways overlap or are even causally intertwined, although the timing, magnitude, and direction of interactions may vary depending on the specific disorder. However, the underlying developmental steps and neuronal mechanisms are still unclear. In this review article, we briefly summarise what we know about structural, functional, and developmental relationships and outline hypothetical connections, which could be investigated in appropriate animal models. Altered cerebral asymmetries may causally contribute to the development of the structural and/or functional features of a disorder, as neural mechanisms that trigger neuropathogenesis are embedded in the asymmetrical organisation of the developing brain. Therefore, the occurrence and severity of impairments in neural processing and cognition probably cannot be understood independently of the development of the lateralised organisation of intra- and interhemispheric neuronal networks. Conversely, impaired cellular processes can also hinder favourable asymmetry development and lead to cognitive deficits in particular. Full article

Ultraviolet radiation (UV) represents a significant abiotic stress, affecting green plants. Phenolic compounds have been suggested as components involved in plant photoprotective adaptation. We used a unique combination of experimental (LED lighting and leaf tagging) and analytical (unbiased, or untargeted, metabolomics) approaches to study the effects of high (approximating mid-summer) and low (approximating winter) levels of UV_A on the expression of phenolic compounds. These consisted of river red gum (Eucalyptus camaldulensis ssp. camaldulensis) of five provenances. The geographically separated provenances used in our study spanned the lowest and highest latitudes of the range of this subspecies. The concentrations of gallotannins and ellagitannins (i.e., hydrolysable tannins) increased most under high levels of UV_A, but responses only differed slightly among provenances. The most substantial changes in the composition of phenolic compounds were associated with leaf age. Overall, 3-month-old (herein, termed ‘young’) leaves had substantially different phenolic compositions to 6- and 12-month-old (‘old’) leaves. Hydrolysable tannins were more abundant in young leaves, whereas pedunculagin, catechin, and kaempferol galloyl glucoses were more abundant in old leaves. High levels of UV_A altered the expression of phenolic compounds, but our experimental saplings were unlikely to experience photoinhibition because they were not exposed to high levels of light and low temperatures, nor were they nitrogen-limited. We expect that changes in phenolic compounds would have been more pronounced if we had induced photoinhibition. Full article

Quercus longispica is a dominant shrub in the Himalayan subalpine region, demonstrating high levels of persistence despite high seed predation and extreme climatic conditions. However, its seed germination ecology and adaptations for seedling recruitment remain poorly understood. This study investigated the effects of temperature, water potential, and insect damage on seed germination and seedling establishment. Pre-germination seed traits and seed-to-seedling ontogeny were systematically analyzed. Our results demonstrated that seed germination percentages decreased with increasing insect damage across all temperature and water potential treatments. Cool temperatures (5–10 °C) yielded the highest germination percentages, potentially due to the suppression of parasitoid activity and mildew growth. While drought conditions also suppressed parasitoid activity, they significantly increased seed mortality. Despite a decline in seedling performance with increasing seed damage, overall seedling establishment remained robust. Several adaptive traits enable Q. longispica to persist in its harsh environment. Multi-seeded, non-apical embryos combined with rapid germination help embryos evade or escape damage from parasitism and predation. The rapid elongation of cotyledonary petioles pushes the embryo axis into the soil, with rapid nutrient and water transfer from the cotyledon to the taproot, thereby avoiding the threats of predation, drought, cold, and wildfire. Additionally, temperature-regulated epicotyl dormancy at the post-germination stage prevents the emergence of cold-intolerant seedlings in winter. This study provides the first comprehensive description of seed-to-seedling ontogeny in this Himalayan subalpine oak, offering crucial insights into the adaptive mechanisms that facilitate successful seedling recruitment in the challenging subalpine habitats. Full article

Macrophages are members of the human innate immune system, and the majority reside in the liver. In recent years, they have been recognized as essential players in the maintenance of liver and intestinal homeostasis as well as key guardians of their respective immune systems, and they are increasingly being recognized as such. Paradoxically, they are also likely involved in chronic pathologies of the gastrointestinal tract and potentially in the alteration of the gut–liver axis in alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). To date, the causal relationship between macrophages, the pathogenesis of ALD, and the immune dysregulation of the gut remains unclear. In this review, we will discuss our current understanding of the heterogeneity of intestinal and hepatic macrophages, their ontogeny, the potential factors that regulate their origin, and the evidence of how they are associated with the manifestation of chronic inflammation. We will also illustrate how the micro-environment of the intestine shapes the phenotypes and functionality of the macrophage compartment in both the intestines and liver and how they change during chronic alcohol abuse. Finally, we highlight the obstacles to current research and the prospects for this field. Full article

Understanding hormonal and molecular changes during the transition from preterm to near-term gestation is essential for investigating how pregnancy complications impact fetal heart development and contribute to long-term cardiovascular risks for offspring. This study examines these cardiac changes in fetal sheep, focusing on the changes between 116 days (preterm) and 140 days (near term) of gestation (dG, term = 150) using Western blotting, LC-MS/MS, and histological techniques. We observed a strong correlation between cortisol and T₃ (Triiodothyronine) in heart tissue in near-term fetuses, highlighting the role of glucocorticoid signalling in fetal heart maturation. Protein expression patterns in the heart revealed a decrease in multiple glucocorticoid receptor isoforms (GRα-A, GR-P, GR-A, GRα-D2, and GRα-D3), alongside a decrease in IGF-1R (a marker of cardiac proliferative capacity) and p-FOXO1(Thr24) but an increase in PCNA (a marker of DNA replication), indicating a shift towards cardiomyocyte maturation from preterm to near term. The increased expression of proteins regulating mitochondrial biogenesis and OXPHOS complex 4 reflects the known transition from glycolysis to oxidative phosphorylation, essential for meeting the energy demands of the postnatal heart. We also found altered glucose transporter expression, with increased pIRS-1(ser789) and GLUT-4 but decreased GLUT-1 expression, suggesting improved insulin responsiveness as the heart approaches term. Notably, the reduced protein abundance of SIRT-1 and SERCA2, along with increased phosphorylation of cardiac Troponin I(Ser23/24), indicates adaptations for more energy-efficient contraction in the near-term heart. In conclusion, these findings show the complex interplay of hormonal, metabolic, and growth changes that regulate fetal heart development, providing new insights into heart development that are crucial for understanding pathological conditions at birth and throughout life. Full article

The ratio of the innate heterophils to the acquired lymphocytes (the H/L-ratio) has been advocated as a good indicator of physiological stress. Little is known, however, about their development in wild birds. The present study investigates how leucocyte profiles develop in nestlings of a long-lived seabird, the Black-legged Kittiwake (Rissa tridactyla). We counted blood leucocytes in nestlings of about 10 and 25 days of age (n = 23), and in breeding adults around the time of hatching (n = 40) and calculated the H/L-ratio for all three groups. We further investigated if any variation in the leucocyte counts could be explained by body condition or the stress-related hormone corticosterone. 10-day-old nestlings in better body condition showed greater investment in heterophils, which increased their H/L-ratio. The initial focus on innate immunity shifted towards acquired immunity by 25 days, aligning their H/L-ratio with that of adults. In adult Kittiwakes, however, better body condition correlated with lower H/L-ratio, the reverse of the pattern in young nestlings, and this variation was not linked to stress hormone (corticosterone) levels. Overall, our findings suggest that the H/L-ratio reflects the ontogeny of physiological traits and individual condition. As an indicator, values must be interpreted depending on age, in which its sensitivity may also vary. As such, the H/L-ratio may not always be a reliable indicator of physiological stress, in particular related to the release of glucocorticoid hormones. Full article

Bi-hormonal islet endocrine cells have been proposed to represent an intermediate state of cellular transdifferentiation, enabling an increase in beta-cell mass in response to severe metabolic stress. Beta-cell plasticity and regenerative capacity are thought to decrease with age. We investigated the ontogeny of bi-hormonal islet endocrine cell populations throughout the human lifespan. Immunofluorescence microscopy was performed for insulin, glucagon, and somatostatin presence on paraffin-embedded sections of pancreata from 20 donors without diabetes aged between 11 days and 79 years of age. The mean proportional presence of glucagon-, insulin-, and somatostatin-immunoreactive cells within islets was 27.5%, 62.1%, and 12.1%, respectively. There was no change in the relative presence of alpha- or beta-cells with advancing age, but delta-cell presence showed a decline with age (R² = 0.59, p < 0.001). The most abundant bi-hormonal cell phenotype observed co-stained for glucagon and insulin, representing 3.1 ± 0.3% of all islet cells. Glucagon/somatostatin and insulin/somatostatin bi-hormonal cells were also observed representing 2–3% abundance relative to islet cell number. Glucagon/insulin bi-hormonal cells increased with age (R² = 0.30, p < 0.05) whilst insulin/somatostatin (R² = 0.50, p < 0.01) and glucagon/somatostatin (R² = 0.35, p < 0.05) cells decreased with age of donor. Findings show that bi-hormonal cells are present within human pancreatic islets throughout life, perhaps reflecting an ongoing potential for endocrine cell plasticity. Full article

Mesosaurs have long been considered to be small to mid-sized aquatic to semiaquatic amniotes that lived in Gondwana during the Early Permian or Late Carboniferous, according to recent research that showed their ghost range extending back to the Pennsylvanian. Previous morphometric analyses based on several hundred mesosaur specimens, including materials from Uruguay, Brazil, South Africa, Namibia, and the Paris National History Museum, provided a comprehensive understanding of mesosaur ontogeny, documented from fetus to adults. As a result, it was possible to determine the approximate size of any individual, measuring just one isolated limb bone, vertebrae, or even cranial elements. Herein, we describe large, poorly preserved and incomplete skulls, as well as axial and appendicular bones, from the Mangrullo Formation Konservat-Lagerstätte of Uruguay that suggest the existence of gigantism in mature mesosaurs reaching more than twice the size of previously described adults and type specimens. The sporadic occurrence of these giant individuals contrasts sharply with the abundant remains of young mesosaurs and, in general, with what is commonly found in the fossil record of vertebrates. The poor preservation of the mature individuals and their presence in coastal areas of the basin is consistent with the hypothesis that older mesosaurs have spent more time near the coast. An alternative hypothesis suggesting pelagic lifestyles is less supported by the available data. Given the preservation of unborn and hatchlings, as well as early juvenile, mature and very mature individuals, the mesosaur record is considered exceptional among early amniotes. Full article

Leaf senescence in plants is the last stage of leaf development and is characterized by a decline in photosynthetic activity, an active degeneration of cellular structures, and the recycling of accumulated nutrients to areas of active growth, such as buds, young leaves, flowers, fruits, and seeds. This process holds economic significance as it can impact yield, influencing the plant’s ability to maintain an active photosynthetic system during prolonged periods, especially during the grain filling stage, which affects plant weight and oil content. It can be associated with different stresses or environmental conditions, manifesting itself widely in the context of climate change and limiting yield, especially in crops of agronomic relevance. In this work, we study the stability of two widely described sunflower (Helianthus annuus L.) genotypes belonging to the INTA Breeding Program against differential N conditions, to verify their yield stability in control conditions and under N supply. Two inbred lines were utilized, namely R453 (early senescence) and B481-6 (late senescence), with contrasting nitrogen availability in the soil but sharing the same ontogeny cycle length. It was observed that, starting from R5.5, the B481-6 genotype not only delayed senescence but also exhibited a positive response to increased nitrogen availability in the soil. This response included an increase in intercepted radiation, resulting in a statistically significant enhancement in grain yield. Conversely, the R453 genotype did not show significant differences under varying nitrogen availability and exhibited a tendency to decrease grain yield when nitrogen availability was increased. The response to nitrogen can vary depending on the specific genotype. Full article

Human cytomegalovirus (HCMV) rarely infects the brain following infection of adult individuals. However, the virus readily infects the brain during congenital HCMV (cHCMV) infection, frequently causing severe neurodevelopmental and neurological sequelae. Interestingly, although the incidence of cHCMV infection is 0.5–1%, the proportion of congenitally infected individuals in which the virus manages to gain access to the brain is unknown. In this study, we used infection of mice with mouse cytomegalovirus (MCMV), the most commonly used experimental system for modeling HCMV disease in humans, to determine the impact of age on the susceptibility of the brain to cytomegalovirus infection and infection-mediated neuroinflammation. We demonstrate that infection of mice during various stages of neonatal development can lead to CMV neuroinvasion and inflammation. In contrast, MCMV infection does not result in MCMV neuroinvasion and neuroinflammation in weanling and adult mice. The obtained results establish a basis for elucidating the mechanisms of CMV neuroinvasion and the deleterious inflammatory response during ontogeny. Full article

Background: Diphenhydramine is an anti-tussive used periodically to treat seasonal colds, contact dermatitis, and anaphylactic reactions. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of diphenhydramine in predicting its systemic exposure among healthy pediatrics (children and adolescents) by leveraging data files from adults (young and elderly). Methods: The data profiles comprising serum/plasma concentration over time and parameters related to diphenhydramine were scrutinized via exhaustive literature analysis and consolidated in the PK-Sim software version 11.1. This modeling methodology commences with developing an adult model and then translating it to the pediatrics which compares the predicted concentration–time datasets with the reported values. Results: The accuracy of model anticipations was then assessed for each pharmacokinetics (PK) variable, i.e., the area under the curve from 0 to infinity (AUC_0-∞), maximal serum/plasma concentration (C_max), and clearance of the diphenhydramine in plasma (CL) by employing the predicted/observed ratios (R_pre/obs), and average fold error (AFE), which fell within the pre-defined benchmark of 2-fold. The predicted and observed C_max values for pediatrics were 3-fold greater in comparison to the young adults following a 25 mg dose depicting a need to monitor dosage schedules among children closely. Conclusions: These model-based anticipations confirmed the authenticity of the developed pediatric model and enhanced the comprehension of developmental variations on PK of diphenhydramine. This may assist healthcare professionals in ensuring the significance of lifespan applicability in personalized dose regimens, promoting therapeutic efficacy and minimizing side effects in chronic conditions among children. Full article

This study examined the pathophysiological effects of venoms from neonate and adult specimens of the viperid snake Macrovipera lebetina obtusa, focusing on their ability to activate various blood clotting factors in human plasma. All venoms exhibited strong procoagulant properties. In concentration–response tests, the clotting potency of the neonate venoms fell within the range of their parents’ maximum clotting velocities and areas under the curve. Intriguingly, females were more potent than males within each age group, but this requires a larger sample size to confirm. Antivenom neutralization efficacy was equipotent across age groups. The venoms potently activated Factor X (FX) robustly, consistent with previous knowledge of this genus. For the first time, the ability to activate Factors VII (FVII) and XII (FXII) was identified in this genus, with FXII exhibiting particularly strong activation. The study found no significant ontogenetic variation in procoagulant venom potency on human plasma, convergent with the Daboia genus, the other large-bodied lineage within the Palearctic viperid clade. However, the activation of FXII and FVII reveals previously undocumented pathways in the procoagulant activity of these venoms, contributing to the broader understanding of venom evolution and its clinical impacts. These findings have implications for venom biodiscovery and the development of antivenoms, highlighting the complexity of clotting factor activation beyond traditional investigations that have myopically focused upon FX and prothrombin pathways, thereby underscoring the importance of exploring additional clotting factors. Full article

The retina is crucial for converting light into neuronal signals for visual perception. Understanding the retina’s structure, function, and development is essential for vision research. It is known that the thyroid hormone (TH) receptor type beta 2 (TRβ2) is a key element in the regulation of cone differentiation in the retina, but other elements of TH signaling, such as transporters and enzyme deiodinases, have also been implicated in retinal cell development and survival. In the present study, we investigated the expression profile of genes involved in TH signaling and analyzed the impact of thyroidal status on retinal morphology, opsin expression, cell death/proliferation profile, as well as color preference behavior during the early retina development of zebrafish larvae. mRNA expression analysis on dissected whole eyes revealed that TH signaling elements gradually increase during eye development, with dio3b being the component that shows the most dramatic change. Mutations generated by CRISPR/CAS9 in the dio3b gene, but not in the thrb gene, modifies the structure of the retina. Disruption in TH level reduces the cell number of the ganglion cell layer, increases cell death, and modifies color preference, emphasizing the critical importance of precise TH regulation by its signaling elements for optimal retinal development and function. Full article