In his early career, August Krogh made fundamental discoveries of the properties of cutaneous respiration in fish, frogs and other vertebrates. Following Krogh's example, the study of amphibious ...fishes provides an excellent model to understand how the skin morphology and physiological mechanisms evolved to meet the dual challenges of aquatic and terrestrial environments. The skin of air-exposed fishes takes on many of the functions that are typically associated with the gills of fish in water: gas exchange, gas sensing, iono- and osmoregulation, and nitrogen excretion. The skin of amphibious fishes has capillaries close to the surface in the epidermis. Skin ionocytes or mitochondrial-rich cells (MRCs) in the epidermis are thought to be responsible for ion exchange, as well as ammonia excretion in the amphibious mangrove rivulus Kryptolebias marmoratus. Ammonia gas (NH3) moves down the partial pressure gradient from skin capillaries to the surface through ammonia transporters (e.g., Rhcg) and NH3 is volatilized from the mucus film on the skin. Future studies are needed on the skin of amphibious fishes from diverse habitats to understand more broadly the role of the skin as a multifunctional organ.
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•The skin is a major site of respiration and osmoregulation in fish out of water.•The epidermis of air-exposed Kryptolebias marmoratus is highly plastic.•Ammonia volatilization across the skin is linked to regulation of Rhcg expression and H+ excretion.
Amphibious fishes spend part of their life in terrestrial habitats. The ability to tolerate life on land has evolved independently many times, with more than 200 extant species of amphibious fishes ...spanning 17 orders now reported. Many adaptations for life out of water have been described in the literature, and adaptive phenotypic plasticity may play an equally important role in promoting favourable matches between the terrestrial habitat and behavioural, physiological, biochemical and morphological characteristics. Amphibious fishes living at the interface of two very different environments must respond to issues relating to buoyancy/gravity, hydration/desiccation, low/high O2 availability, low/high CO2 accumulation and high/low NH3 solubility each time they traverse the air-water interface. Here, we review the literature for examples of plastic traits associated with the response to each of these challenges. Because there is evidence that phenotypic plasticity can facilitate the evolution of fixed traits in general, we summarize the types of investigations needed to more fully determine whether plasticity in extant amphibious fishes can provide indications of the strategies used during the evolution of terrestriality in tetrapods.
Ammonia excretion at the gills of fish has been studied for 80 years, but the mechanism(s) involved remain controversial. The relatively recent discovery of the ammonia-transporting function of the ...Rhesus (Rh) proteins, a family related to the Mep/Amt family of methyl ammonia and ammonia transporters in bacteria, yeast and plants, and the occurrence of these genes and glycosylated proteins in fish gills has opened a new paradigm. We provide background on the evolution and function of the Rh proteins, and review recent studies employing molecular physiology which demonstrate their important contribution to branchial ammonia efflux. Rhag occurs in red blood cells, whereas several isoforms of both Rhbg and Rhcg occur in many tissues. In the branchial epithelium, Rhcg appears to be localized in apical membranes and Rhbg in basolateral membranes. Their gene expression is upregulated during exposure to high environmental ammonia or internal ammonia infusion, and may be sensitive to synergistic stimulation by ammonia and cortisol. Rhcg in particular appears to be coupled to H(+) excretion and Na(+) uptake mechanisms. We propose a new model for ammonia excretion in freshwater fish and its variable linkage to Na(+) uptake and acid excretion. In this model, Rhag facilitates NH(3) flux out of the erythrocyte, Rhbg moves it across the basolateral membrane of the branchial ionocyte, and an apical "Na(+)/NH (+)(4) exchange complex" consisting of several membrane transporters (Rhcg, V-type H(+)-ATPase, Na(+)/H(+) exchanger NHE-2 and/or NHE-3, Na(+) channel) working together as a metabolon provides an acid trapping mechanism for apical excretion. Intracellular carbonic anhydrase (CA-2) and basolateral Na(+)/HCO (-)(3) cotransporter (NBC-1) and Na(+)/K(+)-ATPase play indirect roles. These mechanisms are normally superimposed on a substantial outward movement of NH(3) by simple diffusion, which is probably dependent on acid trapping in boundary layer water by H(+) ions created by the catalysed or non-catalysed hydration of expired metabolic CO(2). Profitable areas for future investigation of Rh proteins in fish are highlighted: their involvement in the mechanism of ammonia excretion across the gills in seawater fish, their possible importance in ammonia excretion across the skin, their potential dual role as CO(2) transporters, their responses to feeding, and their roles in early life stages prior to the full development of gills.
Summary Background Congenital anomalies are a leading cause of infant death and disability and their incidence varies between ethnic groups in the UK. Rates of infant death are highest in children of ...Pakistani origin, and congenital anomalies are the most common cause of death in children younger than 12 in this ethnic group. We investigated the incidence of congenital anomalies in a large multiethnic birth cohort to identify the causes of the excess of congenital anomalies in this community. Methods We obtained questionnaire data from the mothers of children with one or more anomalies from the Born in Bradford study, a prospective birth cohort study of 13 776 babies and their families in which recruitment was undertaken between 2007 and 2011. Details of anomalies were prospectively reported to the study and we cross checked these details against medical records. We linked data for anomalies to maternal questionnaire and clinical data gathered as part of the Born in Bradford study. We calculated univariate and multivariate risk ratios (RRs) with 95% CIs for various maternal risk factors. Findings Of 11 396 babies for whom questionnaire data were available, 386 (3%) had a congenital anomaly. Rates for congenital anomaly were 305·74 per 10 000 livebirths, compared with a national rate of 165·90 per 10 000. The risk was greater for mothers of Pakistani origin than for those of white British origin (univariate RR 1·96, 95% CI 1·56–2·46). Overall, 2013 (18%) babies were the offspring of first-cousin unions. These babies were mainly of Pakistani origin—1922 (37%) of 5127 babies of Pakistani origin had parents in first-cousin unions. Consanguinity was associated with a doubling of risk for congenital anomaly (multivariate RR 2·19, 95% CI 1·67–2·85); we noted no association with increasing deprivation. 31% of all anomalies in children of Pakistani origin could be attributed to consanguinity. We noted a similar increase in risk for mothers of white British origin older than 34 years (multivariate RR 1·83, 95% CI 1·14–3·00). Maternal education to degree level was protective (0·53, 95% CI 0·38–0·75), irrespective of ethnic origin. Interpretation Consanguinity is a major risk factor for congenital anomaly. The risk remains even after adjustment for deprivation, and accounts for almost a third of anomalies in babies of Pakistani origin. High levels of educational attainment are associated with reduced risk in all ethnic groups. Our findings will be valuable in health promotion and public health, and to those commissioning antenatal, paediatric, and clinical genetic services. Sensitive advice about the risks should be provided to communities at increased risk, and to couples in consanguineous unions, to assist in reproductive decision making. Funding National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care programme.
Highlights ► A review of the role of Rh proteins in branchial ammonia excretion in freshwater and seawater fish. ► Impact of environmental ammonia on gill remodeling, trans epithelial potential and ...ventilation in fish. ► Authors pose questions and/or suggestions for research approaches to shed light on questions related to ammonia in fish.
Air‐breathing and amphibious fishes are essential study organisms to shed insight into the required physiological shifts that supported the full transition from aquatic water‐breathing fishes to ...terrestrial air‐breathing tetrapods. While the origin of air‐breathing in the evolutionary history of the tetrapods has received considerable focus, much less is known about the evolutionary physiology of air‐breathing among fishes. This review summarizes recent advances within the field with specific emphasis on the cardiorespiratory regulation associated with air‐breathing and terrestrial excursions, and how respiratory physiology of these living transitional forms are affected by development and personality. Finally, we provide a detailed and re‐evaluated model of the evolution of air‐breathing among fishes that serves as a framework for addressing new questions on the cardiorespiratory changes associated with it. This review highlights the importance of combining detailed studies on piscine air‐breathing model species with comparative multi‐species studies, to add an additional dimension to our understanding of the evolutionary physiology of air‐breathing in vertebrates.
Amphibious fishes transition between aquatic and terrestrial habitats, and must therefore learn to navigate two dramatically different environments. We used the amphibious killifish
to test the ...hypothesis that the spatial learning ability of amphibious fishes would be altered by exposure to terrestrial environments because of neural plasticity in the brain region linked to spatial cognition (dorsolateral pallium). We subjected fish to eight weeks of fluctuating air-water conditions or terrestrial exercise before assessing spatial learning using a bifurcating T-maze, and neurogenesis in the dorsolateral pallium by immunostaining for proliferating cell nuclear antigen. In support of our hypothesis, we found that air-water fluctuations and terrestrial exercise improved some markers of spatial learning. Moreover, air-water and exercised fish had 39% and 46% more proliferating cells in their dorsolateral pallium relative to control fish, respectively. Overall, our findings suggest that fish with more terrestrial tendencies may have a cognitive advantage over those that remain in water, which ultimately may influence their fitness in both aquatic and terrestrial settings. More broadly, understanding the factors that promote neural and behavioural plasticity in extant amphibious fishes may provide insights into how ancestral fishes successfully colonized novel terrestrial environments before giving rise to land-dwelling tetrapods.
This review describes the translational in vivo and non-clinical pharmacokinetics/pharmacodynamics (PK/PD) research that supported clinical trialling and subsequently licensing approval of ...ceftazidime/avibactam, a new β-lactam/β-lactamase inhibitor combination aimed at the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. The review thematically follows on from the co-published article, Nichols et al. (J Antimicrob Chemother 2022; dkac171). Avibactam protected ceftazidime in animal models of infection with ceftazidime-resistant, β-lactamase-producing bacteria. For example, a single subcutaneous dose of ceftazidime at 1024 mg/kg yielded little effect on the growth of ceftazidime-resistant, blaKPC-2-carrying Klebsiella pneumoniae in the thighs of neutropenic mice (final counts of 4 × 108 to 8 × 108 cfu/thigh). In contrast, co-administration of avibactam in a 4:1 ratio (ceftazidime:avibactam) was bactericidal in the same model (final counts of 2 × 104 to 3 × 104 cfu/thigh). In a rat abdominal abscess model, therapy with ceftazidime or ceftazidime/avibactam (4:1 w/w) against blaKPC-2-positive K. pneumoniae resulted in 9.3 versus 3.3 log cfu/abscess, respectively, after 52 h. With respect to PK/PD, in Monte Carlo simulations, attainment of unbound drug exposure targets (ceftazidime fT>8 mg/L and avibactam fT>1 mg/L, each for 50% of the dosing interval) for the labelled dose of ceftazidime/avibactam (2 and 0.5 g, respectively, q8h by 2 h IV infusion), including dose adjustments for patients with impaired renal function, ranged between 94.8% and 99.6% of patients, depending on the infection modelled.
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