CFTR structure and function: is there a role in the kidney?

Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective protein processing that leads to changes in function and regulation of this chloride channel. Despite of the expression of CFTR in the kidney, patients with CF do not present major renal dysfunction, but it is known that both the urinary excretion of proteins and renal capacity to concentrate and dilute urine are altered in these patients. CFTR mRNA is expressed in all nephron segments of rat and human, and this abundance is more prominent in renal cortex and outer medulla renal areas. CFTR protein was detected in apical surface of both proximal and distal tubules of rat kidney but not in the outer medullary collecting ducts. Studies have demonstrated that CFTR does not only transport Cl⁻ but also ATP. ATP transport by CFTR could be involved in the control of other ion transporters such as Na⁺ (ENaC) and K⁺ (renal outer medullary potassium) channels, especially in TAL and CCD. In the kidney, CFTR also might be involved in the endocytosis of low-molecular-weight proteins by proximal tubules. This review is focused on the CFTR function and structure, its role in the renal physiology, and its modulation by hormones involved in the control of extracellular fluid volume.     

The chemistry of copper binding to PrP: is there sufficient evidence to elucidate a role for copper in protein function?

There has been an enormous body of literature published in the last 10 years concerning copper and PrP (prion protein). Despite this, there is still no generally accepted role for copper in the function of PrP or any real consensus as to how and to what affinity copper associates with the protein. The present review attempts to look at all the evidence for the chemistry, co-ordination and affinity of copper binding to PrP, and then looks at what effect this has on the protein. We then connect this evidence with possible roles for PrP when bound to copper. No clear conclusions can be made from the available data, but it is clear from the present review what aspects of copper association with PrP need to be re-investigated.     

Cannabinoids for SARS-CoV-2 and is there evidence of their therapeutic efficacy?

To combat the coronaviruses and their novel variants, therapeutic drugs and the development of vaccines that are to be effective throughout human life are urgently needed. The endocannabinoid system (ECS) acts as a modulator in the activation of the microcirculation, immune system, and autonomic nervous system, along with controlling pharmacological functions such as emotional responses, homeostasis, motor functions, cognition, and motivation. The ECS contains endogenous cannabinoids, cannabinoid receptor (CBRs), and enzymes that regulate their biosynthesis, transport, and degradation. Moreover, phytocannabinoids and synthetic cannabinoids that mimic the action of endocannabinoids also play an essential role in the modulation of the ECS. Cannabinoids, the main constituents of cannabis (Cannabis sativa L.), are therapeutic compounds that have received international attention in the health field due to their therapeutic properties. Recently, they have been tested for the treatment of COVID-19 due to their antiviral properties. Indeed, cannabinoid-type compounds, and in particular cannabidiol (CBD), isolated from glandular trichomes found in the calyx of cannabis flowers with reported antiviral properties is hypothesized to be a therapeutic option in the ministration of SARS-CoV-2 consorted with COVID-19 disease. The relevant articles were determined from the database search published mainly in Web of Science, Google scholar, PubMed, Crossref, and ClinicalTrials.gov database during the pandemic period. The articles were evaluated for the therapeutic potentials, mechanisms of action of cannabinoids, the roles of the ECS in the immune system, impact of cannabinoids in SARS-CoV-2 septic, especially if they address the application of cannabinoids as drugs for the curability and management of SARS-CoV-2 and its novel variants. Although the evidence needed to be considered using cannabinoids in the control and treatment of viral diseases is currently in its infancy, they already offer an opportunity for clinicians due to their effects in relieving pain, improving appetite, and improving childhood epilepsy, especially in cancer and human immunodeficiency virus (HIV/AIDS) patients. In addition to these, the most recent scientific evidence emphasizes their use in the treatment of the coronavirus infected patients. In brief, all preclinic and clinic studies that have been reported show that, through the cannabinoid system, cannabinoids, particularly CBD, have many mechanisms that are effective in the treatment of patients infected by SARS-CoV-2. Thus, more extensive studies are necessary in this area to fully identify the effects of cannabinoids on SARS-CoV-2.     

Invasive and native Rhododendron ponticum populations: is there evidence for genotypic differences in germination and growth?

Previous studies have shown that the invasive spread of Rhododendron ponticum in the British Isles is influenced by the more favourable environmental conditions in the new territory than in the species' home range. In this study, we asked whether the species' invasion success might also involve a genotypic background for higher growth and germination rates in invasive populations. We tested the hypotheses that invasive populations have higher absolute germination rates, germinate faster and exhibit higher growth rates. We present data from greenhouse and climate chamber experiments with seed material and Rhododendron cuttings from six populations each of native Georgian, native Spanish and invasive Irish populations subjected to different temperature environments.
There were no differences in the maximum germination rate and optimum germination temperature between native and invasive origins. We found significant differences in germination velocity with the Irish seeds responding most rapidly to all germination treatments. Accordingly, in the growth experiment the invasive Irish origins had the highest relative growth rates in all environments tested.
Our results provide evidence for a genetic shift in invasive populations towards an increased investment in growth and towards a faster germination rate. Both traits would contribute to explaining this species' range expansion. The underlying evolutionary mechanisms for this shift are discussed, including the possibility of hybridisation or of an ecological release from hitherto experienced constraints in the native area.     

Biomass and morphology of fine roots in temperate broad-leaved forests differing in tree species diversity: is there evidence of below-ground overyielding?

Biodiversity effects on ecosystem functioning in forests have only recently attracted increasing attention. The vast majority of studies in forests have focused on above-ground responses to differences in tree species diversity, while systematic analyses of the effects of biodiversity on root systems are virtually non-existent. By investigating the fine root systems in 12 temperate deciduous forest stands in Central Europe, we tested the hypotheses that (1) stand fine root biomass increases with tree diversity, and (2) ‘below-ground overyielding’ of species-rich stands in terms of fine root biomass is the consequence of spatial niche segregation of the roots of different species. The selected stands represent a gradient in tree species diversity on similar bedrock from almost pure beech forests to medium-diverse forests built by beech, ash, and lime, and highly-diverse stands dominated by beech, ash, lime, maple, and hornbeam. We investigated fine root biomass and necromass at 24 profiles per stand and analyzed species differences in fine root morphology by microscopic analysis. Fine root biomass ranged from 440 to 480 g m⁻² in the species-poor to species-rich stands, with 63–77% being concentrated in the upper 20 cm of the soil. In contradiction to our two hypotheses, the differences in tree species diversity affected neither stand fine root biomass nor vertical root distribution patterns. Fine root morphology showed marked distinctions between species, but these root morphological differences did not lead to significant differences in fine root surface area or root tip number on a stand area basis. Moreover, differences in species composition of the stands did not alter fine root morphology of the species. We conclude that ‘below-ground overyielding’ in terms of fine root biomass does not occur in the species-rich stands, which is most likely caused by the absence of significant spatial segregation of the root systems of these late-successional species.     

Limits of life in hostile environments: no barriers to biosphere function?

Environments that are hostile to life are characterized by reduced microbial activity which results in poor soil‐ and plant‐health, low biomass and biodiversity, and feeble ecosystem development. Whereas the functional biosphere may primarily be constrained by water activity (a_w) the mechanism(s) by which this occurs have not been fully elucidated. Remarkably we found that, for diverse species of xerophilic fungi at a_w values of ≤ 0.72, water activity per se did not limit cellular function. We provide evidence that chaotropic activity determined their biotic window, and obtained mycelial growth at water activities as low as 0.647 (below that recorded for any microbial species) by addition of compounds that reduced the net chaotropicity. Unexpectedly we found that some fungi grew optimally under chaotropic conditions, providing evidence for a previously uncharacterized class of extremophilic microbes. Further studies to elucidate the way in which solute activities interact to determine the limits of life may lead to enhanced biotechnological processes, and increased productivity of agricultural and natural ecosystems in arid and semiarid regions.     

Do thyroid hormones function in insects?

Earlier work demonstrated that phenoxy-phenyl compounds such as fenoxycarb and thyroxine mimicked the effects of JH III in causing a reduction in volume of the follicle cells of Locusta migratoria. While these compounds were only moderately effective, a derivative of thyroxine, 3,3',5-triiodothyronine (T3) was as effective as JH III, and T3 has been shown to bind to the same membrane receptor and activate the same pathway as JH III. The current paper shows that other thyroxine derivatives vary in activity. 3,3', 5'-Triiodothyronine (reverse T3) is inactive. 3,5-Diiodothyronine (T2) is more active than JH III, while its relatives (iodines at 3', 5' or at 3,3') are inactive. When follicles are exposed in vitro to rhodamine conjugated T3, the fluorescent compound can be seen to enter the cells and accumulate there: this process is inhibited by cycloheximide or by a temperature of 0 degrees C. The accumulation is antagonised by JH III but not JH I (which does not bind to the JH III membrane receptor) and by an antiserum raised against the putative membrane receptor protein. The action of T3, but not T2, is inhibited by 6-n-propyl-2-thiouracil or by aurothioglucose, both known to inhibit deiodinases. The activity of T3, but not of T2, increases with time of exposure to the follicle cells. These facts suggest that T3 enters the cells by receptor mediated endocytosis and is converted to a more active compound. Immunoreactivity to T3, but not thyroxine, can be detected in the haemolymph of locusts, and the titre varies slightly with the gonotrophic cycle. The food shows immunoreactivity for both thyroxine and T3. These findings suggest that thyroid hormones are ingested by locusts and have the potential to be used as hormonal signals in the control of egg production.     

Activation of development in mammals: is there a role for a sperm cytosolic factor?

In mammalian oocytes, fertilization-associated calcium [Ca2+]i oscillations are responsible for the activation of development. The mechanism(s) by which the sperm triggers the initial [Ca2+]i rise and supports long-lasting oscillations is not resolved. It has been proposed that the sperm may interact with receptors in the oocyte's plasma membrane and engage intracellular signaling pathways that result in Ca2+ release. A different line of investigation suggests that upon sperm-oocyte fusion, a sperm cytosolic factor is released into the oocyte which interacts with unknown cytosolic targets, and generates [Ca2+]i oscillations. We will discuss the most recent evidence for both lines of thought and demonstrate that injections of sperm crude extracts (SF) into mammalian oocytes trigger [Ca2+]i oscillations that support in vitro parthenogenetic development to the blastocyst stage.     

Endoplasmic reticulum stress-induced apoptosis in the development of diabetes: is there a role for adipose tissue and liver?

Diabetes mellitus (DM) is a multifactorial chronic metabolic disease characterized by hyperglycaemia. Several different mechanisms have been implicated in the development of the disease, including endoplasmic reticulum (ER) stress. ER stress is increasingly acknowledged as an important mechanism in the development of DM, not only for β-cell loss but also for insulin resistance. Accumulating evidence suggests that ER stress-induced apoptosis may be an important mode of β-cell loss and therefore important in the development of diabetes. Recent data also suggest a role of ER stress-induced apoptosis in liver and adipose tissue in relation to diabetes, but more extensive studies on human adipocyte and hepatocyte (patho)physiology and ER stress are needed to identify the exact interactions between environmental signals, ER stress and apoptosis in these organs.     

Is there evidence of learned helplessness in horses?

Learned helplessness is a psychological condition whereby individuals learn that they have no control over unpleasant or harmful conditions, that their actions are futile, and that they are helpless. In a series of experiments in which dogs were exposed to inescapable shocks, this lack of control subsequently interfered with the ability to learn an avoidance task. There is evidence that both neural adaptations and behavioral despair occur in response to uncontrollable aversive experiences in rodents, although this has yet to be demonstrated in other species such as horses. However, certain traditional methods of horse training and some behavioral modification techniques--it has been suggested--may involve aversive conditions over which the horse has little or no control. When training and management procedures are repeatedly unpleasant for the horse and there is no clear association between behavior and outcome, this is likely to interfere with learning and performance-in addition to compromising welfare. This article reviews published literature and anecdotal evidence to explore the possibility that the phenomenon, learned helplessness, occurs in the horse.     

Are TRP channels involved in sperm development and function?

Spermatozoa must translate information from their environment and the egg to achieve fertilization in sexually reproducing animals. These tasks require decoding a variety of signals in the form of intracellular Ca(2+) changes. As TRP channels constitute a large family of versatile multi-signal transducers, they are interesting subjects in which to explore their possible participation in sperm function. Here, we review the evidence for their presence and involvement in sperm motility, maturation, and the acrosome reaction, an exocytotic process required for sperm-egg fusion. Since store-operated Ca(2+) entry (SOCE) has been proposed to play an important role in these three functions, the main proteins responsible for this transport (STIM and ORAI) and their interaction with TRPs are also discussed. Improving our tools to solve infertility, improve animal breeding, and preserve biodiversity requires a better understanding of how Ca(2+) is regulated in spermatozoa.     

Activation loop phosphorylation and catalysis in protein kinases: is there functional evidence for the autoinhibitor model?

Many protein kinases are activated strongly by the phosphorylation of a polypeptide region (activation loop) that lies outside the active-site cleft. Analysis of the X-ray crystallographic structures of the insulin receptor with the activation loop in the phosphorylated and dephosphorylated forms offers a testable model for the mechanism of activity regulation by the loop. In this model, the dephosphorylated activation loop can act as an autoinhibitor by blocking substrate access to the active site. Phosphorylation of the loop could then release the autoinhibitor from the active site, allowing substrate binding and catalysis. While this model has been widely invoked, it was not clear if solution studies would support an autoinhibitory model for kinase regulation, in general. We review the results of solution studies on six protein kinases that test the role of the activation loop in controlling active-site access. While loop phosphorylation enhances substrate binding in two cases, four protein kinases display little or no effect on substrate dissociation constants. By comparison, phosphorylation increases catalysis by 2-4 orders of magnitude in all cases. These findings can be used to place the phosphorylatable activation loops into two broad, functional subcategories. (i) Gated activation loops exhibit bifunctional properties restricting substrate access and controlling catalysis. (ii) Nongated activation loops allow free movement of the substrate in and out of the active site irrespective of phosphorylation state but potently modulate the phosphoryl transfer step. Thus, while activation loop phosphorylation greatly modulates catalytic potential, it does not necessarily affect substrate binding, as once widely believed.     

Fluctuating asymmetry,fecundity and development time in Drosophila: is there an association under optimal and stress conditions?

A number of studies have reported a significant negative association between fluctuating asymmetry (FA) of bilateral morphological traits and individual fitness traits, but almost all of these are unreplicated and based on small sample sizes using single trait estimates of FA. We therefore tested if there was a relationship between the FA of five bilateral traits and fecundity and development time in Drosophila in a multiple replicated experimental design. Stressed treatments were included to increase the variability of traits and to test whether associations among traits were affected by changes in the environment. Significant positive relationships were found between the size of wing characters and mean fecundity for the 5‐day period and this relationship tended to be stronger in the stress treatments. No association was found between FA and mean fecundity for any of the traits measured. Similarly, a significant positive relationship was detected between wing trait size and development time but no association was detected between trait FA and development time. There were no differences between mean fecundity or development time of extreme asymmetry phenotypes compared with modal phenotypes. These results are discussed with reference to suggestions in the literature that FA can be used to estimate individual fitness.     

Age-specific calibration for in vivo monitoring of thyroid: is it necessary?

Usually, an age-specific calibration of detectors used for in vivo monitoring of ¹³¹I thyroid radioactivity is not performed in practice. This study aimed to investigate the reduction in uncertainty that one can expect if an age-specific calibration is performed. For this, voxel and stylized computational phantoms of the thyroid, corresponding to children at different age groups, were used to simulate the calibration process of ¹³¹I detectors used for thyroid monitoring. SCK?CEN physical phantoms were also used for this purpose. Both analytical and Monte Carlo methods (MCNPX version 2.6.0) were used to estimate the counting efficiencies of the considered detectors. The results show that the uncertainties in the assessment of thyroid activity at a distance of 20 cm would be reduced from a range of?+8% to?+30%, to a range from ? 6% to?+15% when age-specific calibration was performed. Using a calibration based on thyroids of adults would result in an overestimation of the thyroid activity for children by up to 30% at a detector-neck distance of about 20 cm; a larger overestimation may be expected at closer distances. It is concluded that age-specific calibration of in vivo monitoring systems for the thyroid is important and has to be taken into consideration to improve the reliability of thyroid dose assessment for children.

     

Developmental programming of reproduction and fertility: what is the evidence?

The concept of the foetal/developmental origins of adult disease has been around for ~20 years and from the original epidemiological studies in human populations much more evidence has accumulated from the many studies in animal models. The majority of these have focused upon the role of early dietary intake before conception, through gestation and/or lactation and subsequent interactions with the postnatal environment, e.g. dietary and physical activity exposures. Whilst a number of theoretical models have been proposed to place the experimental data into a biological context, the underlying phenomena remain the same; developmental deficits (of single (micro) nutrients) during critical or sensitive periods of tissue growth alter the developmental pathway to ultimately constrain later functional capacity when the individual is adult. Ageing, without exception, exacerbates any programmed sequelae. Thus, adult phenotypes that have been relatively easy to characterise (e.g. blood pressure, insulin sensitivity, body fat mass) have received most attention in the literature. To date, relatively few studies have considered the effect of differential early environmental exposures on reproductive function and fecundity in predominantly mono-ovular species such as the sheep, cow and human. The available evidence suggests that prenatal insults, undernutrition for example, have little effect on lifetime reproductive capacity despite subtle effects on the hypothalamic-pituitary-gonadal axis and gonadal progenitor cell complement. The postnatal environment is clearly important, however, since neonatal/adolescent growth acceleration (itself not independent from prenatal experience) has been shown to significantly influence fecundity in farm animals. The present paper will expand these interesting areas of investigation and review the available evidence regarding developmental programming of reproduction and fertility. However, it appears there is little strong evidence to indicate that offspring fertility and reproductive senescence in the human and in farm animal species are overtly affected by prenatal nutrient exposure. Nevertheless, it is clear that the developing gonad is sensitive to its immediate environment but more detailed investigation is required to specifically test the long-term consequences of nutritional perturbations during pregnancy on adult reproductive well-being.     

Mutual replacement of species in space in a grassland community: is there an evidence for functional complementarity of replacement groups?

Many plant communities show strong fine‐scale spatiotemporal dynamics due to frequent natality and mortality events. This process is often non‐random, implying that the community can be broken into groups within which species mutually replace each other in time and are distinct from the other such groups. We examined whether such groups fill separate niches and are functionally complementary in a species‐rich mountain grassland. We used cluster analysis of fine‐scale spatial data time series to discern which species were more likely to replace each other in space. Next, a four‐year removal experiment (removing one group in each experimental treatment, or similar amount of biomass across all groups) was used to determine whether simultaneous occurrence of all these groups would maintain a greater total biomass than if an entire group were eliminated. The results do not support the hypothesis that the simultaneous presence of groups of species that replace each other in space is necessary for the community to attain its maximum biomass. However, the experiment showed strong differences among the replacement groups in their capacity for opportunistic behaviour: some groups responded quickly to space made available by removal while others did not. Furthermore, there were strong differences between groups composed primarily of grasses and groups composed primarily of dicots. In spite of the large differences among these groups, they are not functionally complementary. We therefore conclude that replacement processes in this grassland community more closely resemble a neutral process with sets of species differing in the speed at which they fill empty spaces.