Embryonic origin and serial homology of gill arches and paired fins in the skate, Leucoraja erinacea.

Paired fins are a defining feature of the jawed vertebrate body plan, but their evolutionary origin remains unresolved. Gegenbaur proposed that paired fins evolved as gill arch serial homologues, but this hypothesis is now widely discounted, owing largely to the presumed distinct embryonic origins of these structures from mesoderm and neural crest, respectively. Here, we use cell lineage tracing to test the embryonic origin of the pharyngeal and paired fin skeleton in the skate (Leucoraja erinacea). We find that while the jaw and hyoid arch skeleton derive from neural crest, and the pectoral fin skeleton from mesoderm, the gill arches are of dual origin, receiving contributions from both germ layers. We propose that gill arches and paired fins are serially homologous as derivatives of a continuous, dual-origin mesenchyme with common skeletogenic competence, and that this serial homology accounts for their parallel anatomical organization and shared responses to axial patterning signals

Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro04-6790

Rationale: Accumulating evidence suggests a potential role for the 5-HT6 receptor in cognitive function and the potential use of 5-HT6 receptor antagonists in the treatment of learning and memory disorders. Objectives: The aim of the current study was to investigate the effect of the selective 5-HT6 receptor antagonist, Ro04-6790, on both the performance of normal adult rats and restoration of a pharmacological disruption of memory function produced by the non-selective muscarinic receptor antagonist, scopolamine, or the dopamine D2 receptor antagonist, raclopride, in a rodent model of recognition memory. Methods: Passive, perceptually based, recognition memory was assessed using a novel object discrimination task. Following habituation to an arena, rats were presented with two identical objects during trial 1 (T1) and a novel and familiar object during trial 2 (T2). The time spent exploring the two objects in each trial was measured and novel object discrimination assessed in T2. Results: In the absence of drug all rats spent an equal time exploring the two identical objects in T1 but more time exploring the novel object in T2. Scopolamine (but not N-methylscopolamine) and raclopride both produced a dose-dependent reduction in novel object discrimination whilst the 5-HT6 receptor antagonist, Ro04-6790, had no effect on discrimination when given alone but completely reversed the scopolamine- but not the raclopride-induced deficit. Conclusion: This study demonstrates that acute administration of Ro04-6790 reverses a cholinergic but not a dopaminergic deficit in a rodent model of recognition memory and provides further support for a role of the 5-HT6 receptor in the regulation of cognitive functio

Ectodermal Wnt signaling, cell fate determination, and polarity of the skate gill arch skeleton

Funding Information: With thanks to Dr Kate Criswell and Dr Christine Hirschberger for advice, and to the University of Cambridge Wellcome PhD. Programme in Developmental Mechanisms. The authors were funded by a Wellcome PhD studentship (214953/Z/18/Z) to JMR, and by a Royal Society University Research Fellowship (UF130182 and URF\R\191007) and Royal Society Research Grant (RG140377) to JAG. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Hirschberger, C., Sleight, V. A., Criswell, K. E., Clark, S. J., & Gillis, J. A. Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw. Molecular Biology and Evolution, (2021): msab123, https://doi.org/10.1093/molbev/msab123The origin of the jaw is a long-standing problem in vertebrate evolutionary biology. Classical hypotheses of serial homology propose that the upper and lower jaw evolved through modifications of dorsal and ventral gill arch skeletal elements, respectively. If the jaw and gill arches are derived members of a primitive branchial series, we predict that they would share common developmental patterning mechanisms. Using candidate and RNAseq/differential gene expression analyses, we find broad conservation of dorsoventral patterning mechanisms within the developing mandibular, hyoid and gill arches of a cartilaginous fish, the skate (Leucoraja erinacea). Shared features include expression of genes encoding members of the ventralising BMP and endothelin signalling pathways and their effectors, the joint markers nkx3.2 and gdf5 and pro-chondrogenic transcription factor barx1, and the dorsal territory marker pou3f3. Additionally, we find that mesenchymal expression of eya1/six1 is an ancestral feature of the mandibular arch of jawed vertebrates, while differences in notch signalling distinguish the mandibular and gill arches in skate. Comparative transcriptomic analyses of mandibular and gill arch tissues reveal additional genes differentially expressed along the dorsoventral axis of the pharyngeal arches, including scamp5 as a novel marker of the dorsal mandibular arch, as well as distinct transcriptional features of mandibular and gill arch muscle progenitors and developing gill buds. Taken together, our findings reveal conserved patterning mechanisms in the pharyngeal arches of jawed vertebrates, consistent with serial homology of their skeletal derivatives, as well as unique transcriptional features that may underpin distinct jaw and gill arch morphologies.This work was supported by a Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentship to CH, by a Wolfson College Junior Research Fellowship and MBL Whitman Early Career Fellowship to VAS, and by a Royal Society University Research Fellowship (UF130182 and URF\R\191007), Royal Society Research Grant (RG140377) and University of Cambridge Sir Isaac Newton Trust Grant (14.23z) to JAG

Buckling Design and Imperfection Sensitivity of Sandwich Composite Launch-Vehicle Shell Structures

Composite materials are increasingly being considered and used for launch-vehicle structures. For shell structures, such as interstages, skirts, and shrouds, honeycomb-core sandwich composites are often selected for their structural efficiency. Therefore, it is becoming increasingly important to understand the structural response, including buckling, of sandwich composite shell structures. Additionally, small geometric imperfections can significantly influence the buckling response, including considerably reducing the buckling load, of shell structures. Thus, both the response of the theoretically perfect structure and the buckling imperfection sensitivity must be considered during the design of such structures. To address the latter, empirically derived design factors, called buckling knockdown factors (KDFs), were developed by NASA in the 1960s to account for this buckling imperfection sensitivity during design. However, most of the test-article designs used in the development of these recommendations are not relevant to modern launch-vehicle constructions and material systems, and in particular, no composite test articles were considered. Herein, a two-part study on composite sandwich shells to (1) examine the relationship between the buckling knockdown factor and the areal mass of optimized designs, and (2) to interrogate the imperfection sensitivity of those optimized designs is presented. Four structures from recent NASA launch-vehicle development activities are considered. First, designs optimized for both strength and stability were generated for each of these structures using design optimization software and a range of buckling knockdown factors; it was found that the designed areal masses varied by between 6.1% and 19.6% over knockdown factors ranging from 0.6 to 0.9. Next, the buckling imperfection sensitivity of the optimized designs is explored using nonlinear finite-element analysis and the as-measured shape of a large-scale composite cylindrical shell. When compared with the current buckling design recommendations, the results suggest that the current recommendations are overly conservative and that the development of new recommendations could reduce the acreage areal mass of many composite sandwich shell designs by between 4% and 19%, depending on the structure

5-Hydroxytryptamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

oai:ojs.pkp.sfu.ca:article/31555-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [194] and subsequently revised [176]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 482]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [463, 382])

5-Hydroxytryptamine receptors in GtoPdb v.2023.1

5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [198] and subsequently revised [180]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 491]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [471, 387])

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups. Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence. Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials. Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation