Modules of generalized fractions, direct systems of determinantal maps and other topics in commutative algebra

SIGLEAvailable from British Library Document Supply Centre- DSC:D71691/87 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Integrins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis

Integrins in GtoPdb v.2023.1

Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.Several drugs that target integrins are in clinical use including: (1) abciximab (αIIbβ3) for short term prevention of coronary thrombosis, (2) vedolizumab (α4β7) to reduce gastrointestinal inflammation, and (3) natalizumab (α4β1) in some cases of severe multiple sclerosis

Underlying data supporting: Misjudging Early Embryo Mortality in Natural Human Reproduction

This file consists of transcripts of scientific witness statements submitted as evidence in R (on the application of Smeaton) v Secretary of State for Health [2002] EWHC 610 (admin) (18 April 2002) (Case No: CO/928/01). They are included to enable readers to evaluate claims made in the main article and to see the full extent of the evidence presented to The Honourable Mr Justice Munby. Where no explicit consent to publish the statements has been obtained from a witness, the content has been redacted, except where that content has been quoted by Munby J. in his judgment or directly referenced by me in the main article. The transcripts were made personally by the author of the main article from photocopies of documents in the archives of the Claimant. Every attempt has been made to ensure that the transcripts are faithful reproductions of these photocopies. This means that typographical or other errors in the original documents have been retained and transcribed. Copies of the unredacted transcript and original documents will be made available on request. Any errors of transcription are the responsibility of the author and will be corrected on notification. Personal addresses will remain redacted where indicated. Copyright (“all rights reserved”) for the contents of the individual witness statements remains with the respective authors

Early embryo mortality in natural human reproduction: What the data say [version 1; referees: 1 approved, 2 approved with reservations]

It is generally accepted that natural human embryo mortality during pregnancy is high – losses of 70% and higher from fertilisation to birth are frequently claimed. The first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period. Establishing the fate of embryos before this is challenging, and hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are cited to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in The Lancet  is widely cited but has no quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig’s data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data suggests that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, it is clear that some published estimates of natural embryo mortality are exaggerated. Although available data do not provide a precise estimate, natural human embryo mortality is lower than is often claimed

Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling.

Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5-HT-evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use-dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5-HT3 receptors (IC50 = 45 µg ml(-1)) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml(-1)) and guinea pig ileum (IC50 = 20 µg ml(-1)), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators.Our thanks are given to John Peters (University of Dundee) for the 5-HT3A subunit, to Martin Lochner (Bern University) for reviewing our chemical structures and providing G-FL, and to Ruth Murrell-Lagnado for hosting the experimental work. AJT was supported by the British Heart Foundation (PG/13/39/30293).This is the final version of the article. It first appeared from the American Society for Pharmacology and Experimental Therapeutics via https://doi.org/10.1124/jpet.115.230011

Towards an overheating risk tool for building design

PurposeThe work set out to design and develop an overheating risk tool using the UKCP09 climate projections that is compatible with building performance simulation software. The aim of the tool is to exploit the Weather Generator and give a reasonably accurate assessment of a building's performance in future climates, without adding significant time, cost or complexity to the design team's work.Methodology/approachBecause simulating every possible future climate is impracticable, the approach adopted was to use principal component analysis to give a statistically rigorous simplification of the climate projections. The perceptions and requirements of potential users were assessed through surveys, interviews and focus groups.FindingsIt is possible to convert a single dynamic simulation output into many hundreds of simulation results at hourly resolution for equally probable climates, giving a population of outcomes for the performance of a specific building in a future climate, thus helping the user choose adaptations that might reduce the risk of overheating. The tool outputs can be delivered as a probabilistic overheating curve and feed into a risk management matrix. Professionals recognized the need to quantify overheating risk, particularly for non‐domestic buildings, and were concerned about the ease of incorporating the UKCP09 projections into this process. The new tool has the potential to meet these concerns.Originality/valueThe paper is the first attempt to link UKCP09 climate projections and building performance simulation software in this way and the work offers the potential for design practitioners to use the tool to quickly assess the risk of overheating in their designs and adapt them accordingly.</jats:sec