First record of Rhabdoceras suessi (Ammonoidea, Late Triassic) from the Transylvanian Triassic Series of the Eastern Carpathians (Romania) and a review of its biochronology, paleobiogeography and paleoecology

Abstract The occurrence of the heteromorphic ammonoid Rhabdoceras suessi Hauer, 1860, is recorded for the first time in the Upper Triassic limestone of the Timon-Ciungi olistolith in the Rarău Syncline, Eastern Carpathians. A single specimen of Rhabdoceras suessi co-occurs with Monotis (Monotis) salinaria that constrains its occurrence here to the Upper Norian (Sevatian 1). It is the only known heteromorphic ammonoid in the Upper Triassic of the Romanian Carpathians. Rhabdoceras suessi is a cosmopolitan species widely recorded in low and mid-paleolatitude faunas. It ranges from the Late Norian to the Rhaetian and is suitable for high-resolution worldwide correlations only when it co-occurs with shorter-ranging choristoceratids, monotid bivalves, or the hydrozoan Heterastridium. Formerly considered as the index fossil for the Upper Norian (Sevatian) Suessi Zone, by the latest 1970s this species lost its key biochronologic status among Late Triassic ammonoids, and it generated a controversy in the 1980s concerning the status of the Rhaetian stage. New stratigraphic data from North America and Europe in the subsequent decades resulted in a revised ammonoid biostratigraphy for the uppermost Triassic, the Rhaetian being reinstalled as the topmost stage in the current standard timescale of the Triassic. The geographic distribution of Rhabdoceras is compiled from published worldwide records, and its paleobiogeography and paleoecology are discussed

Discovery of a first-in-class small molecule antagonist against the adrenomedullin-2 receptor: structure–activity relationships and optimization

Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structure–activity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists

Discovery of a first-in-class potent small molecule antagonist against the adrenomedullin-2 receptor

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumour progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same orphan G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). CLR with RAMP2 forms an adrenomedullin-1 receptor and CLR with RAMP3 forms an adrenomedullin-2receptor. Recent research suggests that selective blockade of adrenomedullin-2 receptors would be valuable therapeutically. Here we describe the design, synthesis and characterization of potent small molecule adrenomedullin-2 receptor antagonists with 1,000-foldselectivity over the adrenomedullin-1 receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties and inhibit xenograft tumour growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anti-cancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers

Characteristics of populations of granulosa cells from individual follicles in women undergoing 'coasting' during controlled ovarian stimulation (COS) for IVF

BACKGROUND: The aim of this study was to evaluate the functional characteristics of granulosa cell populations of individual follicles of women undergoing controlled ovarian stimulation (COS) for IVF/ICSI in whom gonadotrophin had been withheld (‘coasted’) for the prevention of OHSS. METHODS: Follicular fluid and granulosa cells were isolated from 224 individual follicles in 41 women who had been coasted and from 257 individual follicles in 50 women who had a ‘normal’ response to COS. Cells were cultured at 10 000 cells per well, to evaluate progesterone secretion. Follicular fluid was assayed for progesterone and estradiol (E2). RESULTS: No significant differences were observed between the two groups with respect to granulosa cell number or follicular fluid progesterone and E2 and follicle size, the retrieval of an oocyte and the subsequent fertilization of the oocyte. However, the granulosa cells derived from the coasted group showed a higher rate of progesterone secretion per cell at 72 h which was sustained for longer. Differences were also seen at 72 and 120 h of culture with a loss of correlation between progesterone secretion and follicle diameter in the coasted group. CONCLUSIONS: Our findings suggest that coasting has an effect on the functional capacity of the granulosa cells and the duration of their function. It is likely that in women at risk of OHSS who are not coasted, the granulosa cells have the capacity to produce significantly more chemical mediators per cell and for a more prolonged period of time

WO2018211275 - COMPOUNDS

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: (I) wherein R1, R2, R3, R4, R5, R6, R8, R9, X, X1, X2, X3, L1 and n are as defined herein. The compounds are inhibitors of adrenomedullin receptor subtype 2 (AM2). Also disclosed are the compounds for use in the treatment of diseases modulated AM2, including proliferative diseases such as cancer; pharmaceutical compositions comprising the compounds; methods for preparing the compounds;and intermediates useful in the preparation of the compounds

Geology, Geochronology, Lithogeochemistry and Metamorphism of the Mahatta Creek Area, Northern Vancouver Island

BC Ministry of Energy and Mines, Geoscience Map 2011-3, 1:50 000 scale

Modelling the Impact of Pericyte Migration and Coverage of Vessels on the Efficacy of Vascular Disrupting Agents

Over the past decade or so, there have been a large number of modelling approaches aimed at elucidating the most important mechanisms affecting the formation of new capillaries from parent blood vessels — a process known as angiogenesis. Most studies have focussed upon the way in which capillary sprouts are initiated and migrate in response to diffusible chemical stimuli supplied by hypoxic stromal cells and leukocytes in the contexts of solid tumour growth and wound healing. However, relatively few studies have examined the important role played by blood perfusion during angiogenesis and fewer still have explored the ways in which a dynamically evolving vascular bed architecture can affect the distribution of flow within it. From the perspective of solid tumour growth and, perhaps more importantly, its treatment (e.g. chemotherapy), it would clearly be of some benefit to understand this coupling between vascular structure and perfusion more fully. This paper focuses on the implications of such a coupling upon chemotherapeutic, anti-angiogenic, and anti-vascular treatments. In an extension to previous work by the authors, the issue of pericyte recruitment during vessel maturation is considered in order to study the effects of different anti-vascular and anti-angiogenic therapies from a more rigorous modelling standpoint. Pericytes are a prime target for new vascular disrupting agents (VDAs) currently in clinical trials. However, different compounds attack different components of the vascular network and the implications of targeting only certain elements of the capillary bed are not immediately clear. In light of these uncertainties, the effects of anti-angiogenic and anti-vascular drugs are re-examined by using an extended model that includes an interdependency between vessel remodelling potential and local pericyte density. Two- and three-dimensional simulation results are presented and suggest that it may be possible to identify a VDA-specific “plasticity window” (a time period corresponding to low pericyte density), within which a given VDA would be most effective