The genetic structures of past human populations are obscured by recent migrations and expansions and have been observed only indirectly by inference from modern samples. However, the unique link ...between a heritable cultural marker, the patrilineal surname, and a genetic marker, the Y chromosome, provides a means to target sets of modern individuals that might resemble populations at the time of surname establishment. As a test case, we studied samples from the Wirral Peninsula and West Lancashire, in northwest England. Place-names and archaeology show clear evidence of a past Viking presence, but heavy immigration and population growth since the industrial revolution are likely to have weakened the genetic signal of a 1,000-year-old Scandinavian contribution. Samples ascertained on the basis of 2 generations of residence were compared with independent samples based on known ancestry in the region plus the possession of a surname known from historical records to have been present there in medieval times. The Y-chromosomal haplotypes of these 2 sets of samples are significantly different, and in admixture analyses, the surname-ascertained samples show markedly greater Scandinavian ancestry proportions, supporting the idea that northwest England was once heavily populated by Scandinavian settlers. The method of historical surname-based ascertainment promises to allow investigation of the influence of migration and drift over the last few centuries in changing the population structure of Britain and will have general utility in other regions where surnames are patrilineal and suitable historical records survive.
The risk of myocardial infarction or stroke is greatly increased following bacteremia, which can create an inflammatory environment associated with thrombotic changes in the fibrin network.
Head-related transfer functions (HRTFs) depend on the shape of the human head and ears, motivating HRTF personalization methods that detect and exploit morphological similarities between subjects in ...an HRTF database and a new user. Prior work determined similarity from sets of morphological parameters. Here we propose a non-parametric morphological similarity based on a harmonic expansion of head scans. Two 3D spherical transforms are explored for this task, and an appropriate shape similarity metric is defined. A case study focusing on personalisation of interaural time differences (ITDs) is conducted by applying this similarity metric on a database of 3D head scans.
In-Office Treatment of Dentinal Hypersensitivity Al-Sabbagh, Mohanad, DDS, MS; Brown, Amanda; Thomas, Mark V., DMD
The Dental clinics of North America,
2009, 2009-Jan, 2009-1-00, 20090101, Letnik:
53, Številka:
1
Journal Article
Recenzirano
Dentinal hypersensitivity is a common dental complaint, especially in periodontal patients. It is believed to be mediated by a hydrodynamic mechanism in which various stimuli result in increased ...fluid flow in dentinal tubules, thereby generating action potentials in associated nerve fibers. Although it is often perceived as mild discomfort by the patient, it can be severe. A variety of interventions has been used, although few have been subjected to rigorous study. This article surveys those in-office treatments that are available, and suggests directions for research so that clinicians may treat patients based on best evidence. Until such evidence is available, it seems prudent to employ therapies that are least likely to cause harm and are reversible.
Walter M. Miller Jr's A Canticle for Leibowitz (1959) is an enigmatic text. It is a depressing tale of the evitability of technoscientific civilization ending in apocalypse, a comedic story of ...ignorant monks producing gold-embellished illuminated copies of electronic circuit blueprints and an ambiguous examination of the tensions between faith and science. This paper reads A Canticle for Leibowitz as an examination of legality. Drawing inspiration from Carl Schmitt's observation that Catholicism has a "juridical logic," this paper identifies that A Canticle for Leibowitz brings to life, and questions, the Thomist worldview of reason, reasonability and layered orders. It is a novel that brings to life, but also interrogates, Catholic intellectualism. It is tempting to conclude that Miller argues for a Thomist ethic of responsibility to temper technoscientific self-destruction. However, that is not where the novel ends. Its endings are hopeful, notwithstanding the nuclear holocaust in the final pages. There are suggestions of new nomoi: In the diasporic human extra-terrestrial colonies, ministered to by a nomadic Church, and a radiated Eden inherited by humanity's prelapsarian successors anticipated in the coming to life of Rachel.
Phosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a ...critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is thought to be involved in type-2 diabetes and obesity, conditions that could therefore be open to pharmacological modulation of the enzyme. However, rational design of SHIP2 inhibitors has been limited by the absence of a high-resolution structure. Here, we present a 2.1 Å resolution crystal structure of the phosphatase domain of SHIP2 bound to the synthetic ligand biphenyl 2,3′,4,5′,6-pentakisphosphate (BiPh(2,3′,4,5′,6)P5). BiPh(2,3′,4,5′,6)P5 is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P4 hydrolysis with an IC50 of 24.8 ± 3.0 μM, (K m for Ins(1,3,4,5)P4 is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh(2,3′,4,5′,6)P5 binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs.
A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)‐based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)‐based compounds. ...A steroid A,B‐ring‐mimicking DHIQ core was connected to methoxyaryl D‐ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl‐linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6‐hydroxy‐7‐methoxy‐2‐(3,4,5‐trimethoxybenzoyl)‐3,4‐dihydroisoquinolin‐1(2H)‐one (16 g): GI50 51 nM in DU‐145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60‐cell line assay giving a mean activity of 33 nM. Furthermore, 6‐hydroxy‐2‐(3,5‐dimethoxybenzoyl)‐7‐methoxy‐3,4‐dihydroisoquinolin‐1(2H)‐one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2‐(3,5‐dimethoxybenzoyl)‐7‐methoxy‐6‐sulfamoyloxy‐3,4‐dihydroisoquinolin‐1(2H)‐one and 7‐methoxy‐2‐(3,4,5‐trimethoxybenzoyl)‐6‐sulfamoyloxy‐3,4‐dihydroisoquinolin‐1(2H)‐one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A‐4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti‐angiogenic activity. Additionally, X‐ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a “steroid‐like” conformation that may partially explain the excellent in vitro activities.
Steroid‐oids: Steroidomimetic dihydroisoquinolinones (DHIQs) were evaluated against two cancer cell lines. Carbonyl‐linked DHIQs exhibit significant in vitro antiproliferative activity, show excellent activity against tubulin polymerisation, and compete at the colchicine binding site of tubulin. Crystal structure analysis and molecular modelling both suggest a preferred “steroid‐like” conformation as a result of intramolecular electrostatic repulsion for this compound class.
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