Postjunctional Vascular Alpha-2 Adrenoceptors: Modulation and Interactions

The work presented herein represents an examination of the alpha-adrenoceptors mediating contractions in isolated vascular preparations from the rabbit and the factors involved in modulating these responses. 1) The alpha-adrenoceptor population in the rabbit isolated lateral saphenous vein, based upon agonist and antagonist potency profiles, could not be ascribed to be either a homogeneous population of either postjunctional alpha1- or alpha2-adrenoceptors, but had characteristics of both. 2) A homogeneous population of postjunctional alpha2-adrenoceptors could be isolated in the lateral saphenous vein using receptor protection experiments with the combination of rauwolscine and phenoxybenzamine. 3) Only limited success was achieved in attempting to isolate a homogeneous population of postjunctional alpha1-adrenoceptors in the lateral saphenous vein using receptor protection experiments with the combination of YM 12617 and phenoxybenzamine. The residual response to NA remaining after this procedure had characteristics of a mixed population of both postjunctional alpha1- and alpha2-adrenoceptors. 4) A comparison of the effects of angiotensin II and Bay K 8644 revealed marked differences in their ability to modulate responses to NA mediated via postjunctional alpha1- and alpha2-adrenoceptors. AII produced a selective enhancement of responses mediated via postjunctional alpha2-adrenoceptors, while the action of Bay K 8644 was not dependent upon receptor subtype. 5) In the lateral saphenous vein after isolation of postjunctional alpha2-adrenoceptors, both Bay K 8644 enhanced responses to NA. The mechanism of this potentiation also appears to differ for these agents. Bay K 8644 enhanced responses mediated via voltage-dependent Ca2+ channels, while AII inhibited the influx of Ca2+ mediated via these channels. 6) The effects of A II on responses mediated via postjunctional alpha2-adrenoceptors, was mimicked by its physiological precursor angiotensin I, suggesting that local vascular production of A II may be important for the facilitatory action of this peptide. 7) Nifedipine, like Bay K 8644, had a non-differential effect on responses to NA mediated via postjunctional alpha1 and alpha2-adrenoceptors in a number of isolated vascular preparations. 8) Under normal experimental conditions, based upon agonist and antagonist potencies, the rabbit isolated distal saphenous artery contains a homogeneous population of postjunctional alpha1-adrenoceptors. 9) In the presence of A II, there was a marked increase in the responsiveness of the distal saphenous artery to UK-14304, which was prazosin-resistant, rauwolscine-sensitive, and so mediated via postjunctional alpha2-adrenoceptors. 10) After attempted isolation of postjunctional alpha2-adrenoceptors in the distal saphenous artery using receptor protection experiments, with the combination of rauwolscine and phenoxybenzamine, no responses were observed. 11) AII uncovered responses to alpha-adrenoceptor agonists after the combination of rauwolscine and phenoxybenzamine. The agonist and antagonist potencies after this protocol were consistent with a homogeneous population of postjunctional alpha2-adrenoceptors. 12) Some of the results in the present study indicate an interaction between postjunctional alpha1- and alpha2-adrenoceptors in vascular smooth muscle. The implications for such an interaction is discussed in detail. Furthermore, evidence is presented demonstrating an interaction between postjunctional alpha2-adrenoceptors and a number of vasoactive agents. 13) Sympathetic neurotransmission in the rabbit isolated distal saphenous artery is the resultant of an interaction between three receptor systems, postjunctional alpha1-and alpha2-adrenoceptors and purinoceptors. alpha1-adrenoceptors are of principal importance, although a role for the two other receptor systems can be demonstrated under the appropriate experimental conditions

Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes

Several cDNA clones coding for the high molecular weight (alpha) subunit of the voltage-sensitive Na channel have been selected by immunoscreening a rat brain cDNA library constructed in the expression vector lambda gt11. As will be reported elsewhere, the amino acid sequence translated from the DNA sequence shows considerable homology to that reported for the Electrophorus electricus electroplax Na channel. Several of the cDNA inserts hybridized with a low-abundance 9-kilobase RNA species from rat brain, muscle, and heart. Sucrose-gradient fractionation of rat brain poly(A) RNA yielded a high molecular weight fraction containing this mRNA, which resulted in functional Na channels when injected into oocytes. This fraction contained undetectable amounts of low molecular weight RNA. The high molecular weight Na channel RNA was selected from rat brain poly(A) RNA by hybridization to a single-strand antisense cDNA clone. Translation of this RNA in Xenopus oocytes resulted in the appearance of tetrodotoxin-sensitive voltage-sensitive Na channels in the oocyte membrane. These results demonstrate that mRNA encoding the alpha subunit of the rat brain Na channel, in the absence of any beta-subunit mRNA, is sufficient for translation to give functional channels in oocytes

The Northwest Tropical Atlantic Station (NTAS) : NTAS-1 mooring deployment cruise report

A surface mooring outfitted for meteorological and oceanographic measurement was deployed near 14°50'N, 51°00'W in the northwest tropical Atlantic on 30 March 2001. This was the initial deployment of the Northwest Tropical Atlantic Station (NTAS) project for air–sea flux measurement. These observations will be used to investigate air–sea interaction processes related to climate variability. The deployment was done on R/V Oceanus Cruise 365, Leg 5 by the Upper Ocean Processes Group (UOP) of the Woods Hole Oceanographic Institution. The 3-meter discus buoy was outfitted with two Air–Sea Interaction Meteorology (ASIMET) systems. Each system measures, records, and transmits via Argos satellite the surface meteorological variables necessary to compute air–sea fluxes of heat, moisture and momentum. The upper 120 m of the mooring line was outfitted with oceanographic sensors for the measurement of temperature and velocity. This report describes the initial deployment of the NTAS mooring (NTAS-1), including some of the pre-cruise buoy preparations and post cruise data comparisons.Funding was provided by the National Oceanic and Atmospheric Administration (NOAA) through the Cooperative Institute for Climate and Ocean Research (CICOR) under Grant No. NA87RJ0445

Seismological imaging of ridge–arc interaction beneath the Eastern Lau Spreading Center from OBS ambient noise tomography

The Lau Basin displays large along-strike variations in ridge characters with the changing proximity of the adjacent subduction zone. The mechanism governing these changes is not well understood but one hypotheses relates them to interaction between the arc and back-arc magmatic systems. We present a 3D seismic velocity model of the shallow mantle beneath the Eastern Lau back-arc Spreading Center (ELSC) and the adjacent Tofua volcanic arc obtained from ambient noise tomography of ocean bottom seismograph data. Our seismic images reveal an asymmetric upper mantle low velocity zone (LVZ) beneath the ELSC. Two major trends are present as the ridge-to-arc distance increases: (1) the LVZ becomes increasingly offset from the ridge to the north, where crust is thinner and the ridge less magmatically active; (2) the LVZ becomes increasingly connected to a sub-arc low velocity zone to the south. The separation of the ridge and arc low velocity zones is spatially coincident with the abrupt transition in crustal composition and ridge morphology. Our results present the first mantle imaging confirmation of a direct connection between crustal properties and uppermost mantle processes at ELSC, and support the prediction that as ELSC migrates away from the arc, a changing mantle wedge flow pattern leads to the separation of the arc and ridge melting regions. Slab-derived water is cutoff from the ridge, resulting in abrupt changes in crustal lava composition and crustal porosity. The larger offset between mantle melt supply and the ridge along the northern ELSC may reduce melt extraction efficiency along the ridge, further decreasing the melt budget and leading to the observed flat and faulted ridge morphology, thinner crust and the lack of an axial melt lens

Nonstop mRNAs generate a ground state of mitochondrial gene expression noise

Funding Information: This work was supported by the Academy of Finland (307431 and 314706 to B.J.B.), the Sigrid Juselius Foundation Senior Investigator Award to B.J.B., and United Mitochondrial Disease Foundation (PI-16-0598 to B.J.B.) and donations from the Hereditary Neuropathy Foundation, Lindsey Flynt, and Medtronic to B.J.B.; the Orion Research Foundation and the Finnish Cultural Foundation to K.Y.N.; the Academy of Finland (321961 to U.R.); the Sigrid Juselius Foundation, the Academy of Finland (331556), and the Jane and Aatos Erkko Foundation to C.D.D.; Action Medical Research (GN2494 to W.G.N.) and the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007 to W.G.N.); the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z to R.W.T.), the Mitochondrial Disease Patient Cohort (UK) (G0800674 to R.W.T.), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1 to R.W.T.), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the Pathological Society, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children to R.W.T.; Medical Research Council (MR/W019027/1 to W.G.N. and R.W.T.); the Academy of Finland (338836 and 314672 to V.O.P.); and the Sigrid Juselius Foundation and the Jane and Aatos Erkko Foundation. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved;A stop codon within the mRNA facilitates coordinated termination of protein synthesis, releasing the nascent polypeptide from the ribosome. This essential step in gene expression is impeded with transcripts lacking a stop codon, generating nonstop ribosome complexes. Here, we use deep sequencing to investigate sources of nonstop mRNAs generated from the human mitochondrial genome. We identify diverse types of nonstop mRNAs on mitochondrial ribosomes that are resistant to translation termination by canonical release factors. Failure to resolve these aberrations by the mitochondrial release factor in rescue (MTRFR) imparts a negative regulatory effect on protein synthesis that is associated with human disease. Our findings reveal a source of underlying noise in mitochondrial gene expression and the importance of responsive ribosome quality control mechanisms for cell fitness and human health.Peer reviewe

Universal typological dependencies should be detectable in the history of language families

1. Introduction We claim that making sense of the typological diversity of languages demands a historical/evolutionary approach.We are pleased that the target paper (Dunn et al. 2011a) has served to bring discussion of this claim into prominence, and are grateful that leading typologists have taken the time to respond (commentaries denoted by boldface). It is unfortunate though that a number of the commentaries in this issue of LT show significant misunderstandings of our paper. Donohue thinks we were out to show the stability of typological features, but that was not our target at all (although related methods can be used to do that: see, e.g., Greenhill et al. 2010a, Dediu 2011a). Plank seems to think we were arguing against universals of any type, but our target was in fact just the implicational universals of word order that have been the bread and butter of typology. He also seems to think we ignore diachrony, whereas in fact the method introduces diachrony centrally into typological reasoning, thereby potentially revolutionising typology (see Cysouw’s commentary). Levy & Daumé think we were testing for lineage-specificity, whereas that was in fact an outcome (the main finding) of our testing for correlated evolution. Dryer thinks we must account for the distribution of language types around the world, but that was not our aim: our aim was to test the causal connection between linguistic variables by taking the perspective of language evolution (diversification and change). Longobardi & Roberts seem to think we set out to extract family trees from syntactic features, but our goal was in fact to use trees based on lexical cognates and hang reconstructed syntactic states on each node of these trees, thereby reconstructing the processes of language change

The Global Ant Genomics Alliance (GAGA)

Peer reviewe

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting

Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets