2,874 research outputs found
High affinity binding of the peptide agonist TIP-39 to the parathyroid hormone 2 (PTH₂) receptor requires the hydroxyl group of Tyr-318 on transmembrane helix 5
TIP39 (“tuberoinfundibular peptide of 39 residues”) acts via the parathyroid hormone 2 receptor, PTH₂, a Family B G protein-coupled receptor (GPCR). Despite the importance of GPCRs in human physiology and pharmacotherapy, little is known about the molecular details of the TIP39-PTH₂ interaction. To address this, we utilised the different pharmacological profiles of TIP39 and PTH(1-34) at PTH₂ and its related receptor PTH₁: TIP39 being an agonist at the former but an antagonist at the latter, while PTH(1-34) activates both. A total of 23 site-directed mutations of PTH₂, in which residues were substituted to the equivalent in PTH₁, were made and pharmacologically screened for agonist activity. Follow-up mutations were analysed by radioligand binding and cAMP assays. A model of the TIP39-PTH₂ complex was built and analysed using molecular dynamics. Only Tyr318-Ile displayed reduced TIP39 potency, despite having increased PTH(1-34) potency, and further mutagenesis and analysis at this site demonstrated that this was due to reduced TIP39 affinity at Tyr318-Ile (pIC50 = 6.01±0.03) compared with wild type (pIC₅₀ = 7.81±0.03). The hydroxyl group of the Tyr-318’s side chain was shown to be important for TIP39 binding, with the Tyr318-Phe mutant displaying 13-fold lower affinity and 35-fold lower potency compared with wild type. TIP39 truncated by up to 5 residues at the N-terminus was still sensitive to the mutations at Tyr-318, suggesting that it interacts with a region within TIP39(6-39). Molecular modelling and molecular dynamics simulations suggest that the selectivity is based on an interaction between the Tyr-318 hydroxyl group with the carboxylate side chain of Asp-7 of the peptide
We do things differently here : the Greater Manchester approach to preventing alcohol-exposed pregnancy
Increased gravitational force reveals the mechanical, resonant nature of physiological tremor
Human physiological hand tremor has a resonant component. Proof of this is that its frequency can be modified by adding mass. However, adding mass also increases the load which must be supported. The necessary force requires muscular contraction which will change motor output and is likely to increase limb stiffness. The increased stiffness will partly offset the effect of the increased mass and this can lead to the erroneous conclusion that factors other than resonance are involved in determining tremor frequency. Using a human centrifuge to increase head-to-foot gravitational field strength, we were able to control for the increased effort by increasing force without changing mass. This revealed that the peak frequency of human hand tremor is 99% predictable on the basis of a resonant mechanism. We ask what, if anything, the peak frequency of physiological tremor can reveal about the operation of the nervous system.This work was funded by a BBSRC Industry Interchange Award
to J.P.R.S. and R.F.R. C.J.O. was funded by BBSRC grant
BB/I00579X/1. C.A.V. was funded by A∗Midex (Aix-Marseille
Initiative of Excellence
A Simple Iterative Model Accurately Captures Complex Trapline Formation by Bumblebees Across Spatial Scales and Flower Arrangements
PMCID: PMC3591286This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Long-term trends in tropical cyclone tracks around Korea and Japan in late summer and early fall
This study investigates long-term trends in tropical cyclones (TCs) over the extratropical western North Pacific (WNP) over a period of 35 years (1982-2016). The area analyzed extended across 30-45 degrees N and 120-150 degrees E, including the regions of Korea and Japan that were seriously affected by TCs. The northward migration of TCs over the WNP to the mid-latitudes showed a sharp increase in early fall. In addition, the duration of TCs over the WNP that migrated northwards showed an increase, specifically in early to mid-September. Therefore, more recently, TC tracks have been observed to significantly extend into the mid-latitudes. The recent northward extension of TC tracks over the WNP in early fall was observed to be associated with changes in environmental conditions that were favorable for TC activities, including an increase in sea surface temperature (SST), decrease in vertical wind shear, expansion of subtropical highs, strong easterly steering winds, and an increase in relative vorticity. In contrast, northward migrations of TCs to Korea and Japan showed a decline in late August, because of the presence of unfavorable environmental conditions for TC activities. These changes in environmental conditions, such as SST and vertical wind shear, can be partially associated with the Pacific decadal oscillation
Fluid dynamics - Turbulence without inertia
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62901/1/405027a0.pd
Association between the c.*229C>T polymorphism of the topoisomerase IIb binding protein 1 (TopBP1) gene and breast cancer
Topoisomerase IIb binding protein 1 (TopBP1)
is involved in cell survival, DNA replication, DNA damage
repair and cell cycle checkpoint control. The biological
function of TopBP1 and its close relation with BRCA1
prompted us to investigate whether alterations in the
TopBP1 gene can influence the risk of breast cancer.
The aim of this study was to examine the association
between five polymorphisms (rs185903567, rs116645643,
rs115160714, rs116195487, and rs112843513) located in
the 30UTR region of the TopBP1 gene and breast cancer
risk as well as allele-specific gene expression. Five hundred
thirty-four breast cancer patients and 556 population controls
were genotyped for these SNPs. Allele-specific Top-
BP1 mRNA and protein expressions were determined by
using real time PCR and western blotting methods,
respectively. Only one SNP (rs115160714) showed an
association with breast cancer. Compared to homozygous
common allele carriers, heterozygous and homozygous for
the T variant had significantly increased risk of breast
cancer (adjusted odds ratio = 3.81, 95 % confidence
interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and
protein expression were higher in the individuals with the
CT or TT genotype. There was a significant association
between the rs115160714 and tumor grade and stage. Most
carriers of minor allele had a high grade (G3) tumors
classified as T2-T4N1M0. Our study raises a possibility
that a genetic variation of TopBP1 may be implicated in
the etiology of breast cancer
Mapped aboveground carbon stocks to advance forest conservation and recovery in Malaysian Borneo
Forest carbon stocks in rapidly developing tropical regions are highly heterogeneous, which challenges efforts to develop spatially-explicit conservation actions. In addition to field-based biodiversity information, mapping of carbon stocks can greatly accelerate the identification, protection and recovery of forests deemed to be of high conservation value (HCV). We combined airborne Light Detection and Ranging (LiDAR) with satellite imaging and other geospatial data to map forest aboveground carbon density at 30m (0.09ha) resolution throughout the Malaysian state of Sabah on the island of Borneo. We used the mapping results to assess how carbon stocks vary spatially based on forest use, deforestation, regrowth, and current forest protections. We found that unlogged, intact forests contain aboveground carbon densities averaging over 200MgCha−1, with peaks of 500MgCha−1. Critically, more than 40% of the highest carbon stock forests were discovered outside of areas designated for maximum protection. Previously logged forests have suppressed, but still high, carbon densities of 60–140MgCha−1. Our mapped distributions of forest carbon stock suggest that the state of Sabah could double its total aboveground carbon storage if previously logged forests are allowed to recover in the future. Our results guide ongoing efforts to identify HCV forests and to determine new areas for forest protection in Borneo
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