Structural and functional characterization of the aryl hydrocarbon receptor ligand binding domain by homology modeling and mutational analysis

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is activated by a structurally diverse array of synthetic and natural chemicals, including toxic halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Analysis of the occurring in the AhR ligand binding and activation processes requires structural information on the AhR Per-Arnt-Sim (PAS) B-containing ligand binding domain, for which no experimentally determined structure has been reported. With the availability of extensive structural information on homologous PAS-containing proteins, a reliable model of the mouse AhR PAS B domain was developed by comparative modeling techniques. The PAS domain structures of the functionally related hypoxia-inducible factor 2α (HIF-2α) and AhR nuclear translocator (ARNT) proteins, which exhibit the highest degree of sequence identity and similarity with AhR, were chosen to develop a two-template model. To confirm the features of the modeled domain, the effects of point mutations in selected residue positions on both TCDD binding to the AhR and TCDD-dependent transformation and DNA binding were analyzed. Mutagenesis and functional analysis results are consistent with the proposed model and confirm that the cavity modeled in the interior of the domain is indeed involved in ligand binding. Moreover, the physicochemical characteristics of some residues and of their mutants, along with the effects of mutagenesis on TCDD and DNA binding, also suggest some key features that are required for ligand binding and activation of mAhR at a molecular level, thus providing a framework for further studies. © 2007 American Chemical Society

Detection of the TCDD binding-fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis

The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-Arnt-Sim (PAS)-containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Our previous three-dimensional homology model of the mouse AhR (mAhR) PAS B ligand binding domain allowed identification of the binding site and its experimental validation. We have extended this analysis by conducting comparative structural modeling studies of the ligand binding domains of six additional highaffinity mammalian AhRs. These results, coupled with site-directed mutagenesis and AhR functional analysis, have allowed detection of the "TCDD binding-fingerprint" of conserved residues within the ligand binding cavity necessary for high-affinity TCDD binding and TCDD-dependent AhR transformation DNA binding. The essential role of selected residues was further evaluated using molecular docking simulations of TCDD with both wild-type and mutant mAhRs. Taken together, our results dramatically improve our understanding of the molecular determinants of TCDD binding and provide a basis for future studies directed toward rationalizing the observed species differences in AhR sensitivity to TCDD and understanding the mechanistic basis for the dramatic diversity in AhR ligand structure. © 2009 American Chemical Society

Investigating Self-Directed Learning Dimensions: Adapting the Bouchard Framework

Self-Directed Learning (SDL) is gaining interest, as online learning is increasingly learner-centered. FutureLearn courses provide an array of online interactions and content deliveries, which have allowed the authors to investigate a diversity of SDL elements. This preliminary research examines the SDL taking place in three FutureLearn courses, and categorises those learner actions into meaningful elements and dimensions for the learners. The SDL framework by Bouchard [1] is used to interpret the self-reported findings coming from active learners. The research uses a grounded theory approach to look for learner experiences related to four dimensions (algorithmic, conative, semiotic, and economic) of the Bouchard [1] framework, and to discover new dimensions. Various research instruments are used: online surveys, learning logs, and one-on-one interviews, all collected pre-, during, or post-course. The initial adaptation of Bouchard’s framework offers insights into SDL, its meaning, and value as perceived by the learners

Enhanced thermal conductivity of carbon fiber/phenolic resin composites by the introduction of carbon nanotubes

This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in APPLIED PHYSICS LETTERS. 90(9):093125 (2007) and may be found at https://doi.org/10.1063/1.2710778 .ArticleAPPLIED PHYSICS LETTERS. 90(9):093125 (2007)journal articl

Mobile Communication Signatures of Unemployment

The mapping of populations socio-economic well-being is highly constrained by the logistics of censuses and surveys. Consequently, spatially detailed changes across scales of days, weeks, or months, or even year to year, are difficult to assess; thus the speed of which policies can be designed and evaluated is limited. However, recent studies have shown the value of mobile phone data as an enabling methodology for demographic modeling and measurement. In this work, we investigate whether indicators extracted from mobile phone usage can reveal information about the socio-economical status of microregions such as districts (i.e., average spatial resolution < 2.7km). For this we examine anonymized mobile phone metadata combined with beneficiaries records from unemployment benefit program. We find that aggregated activity, social, and mobility patterns strongly correlate with unemployment. Furthermore, we construct a simple model to produce accurate reconstruction of district level unemployment from their mobile communication patterns alone. Our results suggest that reliable and cost-effective economical indicators could be built based on passively collected and anonymized mobile phone data. With similar data being collected every day by telecommunication services across the world, survey-based methods of measuring community socioeconomic status could potentially be augmented or replaced by such passive sensing methods in the future

Subgroup analyses from a phase 3, open-label, randomized study of eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer

Purpose and methods: Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m² on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m² on days 1–14 (21-day cycles). Results: In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies

Carbonaceous Materials Coated Carbon Fibre Reinforced Polymer Matrix Composites

Carbon fibre reinforced polymer composites have high mechanical properties that make them exemplary engineered materials to carry loads and stresses. Coupling fibre and matrix together require good understanding of not only fibre morphology but also matrix rheology. One way of having a strongly coupled fibre and matrix interface is to size the reinforcing fibres by means of micro- or nanocarbon materials coating on the fibre surface. Common coating materials used are carbon nanotubes and nanofibres and graphene, and more recently carbon black (colloidal particles of virtually pure elemental carbon) and graphite. There are several chemical, thermal, and electrochemical processes that are used for coating the carbonous materials onto a carbon fibre surface. Sizing of fibres provides higher interfacial adhesion between fibre and matrix and allows better fibre wetting by the surrounded matrix material. This review paper goes over numerous techniques that are used for engineering the interface between both fibre and matrix systems, which is eventually the key to better mechanical properties of the composite systems

Impact of visceral fat on skeletal muscle mass and vice versa in a prospective cohort study: The Korean Sarcopenic Obesity Study (KSOS)

Objectives: Sarcopenia and visceral obesity have been suggested to aggravate each other, resulting in a vicious cycle. However, evidence based on prospective study is very limited. Our purpose was to investigate whether visceral fat promotes a decrease in skeletal muscle mass and vice versa. Methods: We observed changes in anthropometric and body composition data during a follow-up period of 27.6±2.8 months in 379 Korean men and women (mean age 51.9±14.6 years) from the Korean Sarcopenic Obesity Study (KSOS). Appendicular lean soft tissue (ALST) mass was calculated using dual-energy X-ray absorptiometry, and visceral fat area (VFA) was measured using computed tomography at baseline and follow-up examination. Results: ALST mass significantly decreased, whereas trunk and total fat mass increased in both men and women despite no significant change in weight and body mass index. In particular, women with visceral obesity at baseline had a greater decrease in ALST mass than those without visceral obesity (P=0.001). In multiple linear regression analysis, baseline VFA was an independent negative predictor of the changes in ALST after adjusting for confounding factors including age, gender, life style and body composition parameters, insulin resistance, high sensitivity C-reactive protein and vitamin D levels (P=0.001), whereas the association between baseline ALST mass and changes in VFA was not statistically significant (P=0.555). Conclusions: This longitudinal study showed that visceral obesity was associated with future loss of skeletal muscle mass in Korean adults. These results may provide novel insight into sarcopenic obesity in an aging society

Complexity without chaos: Plasticity within random recurrent networks generates robust timing and motor control

It is widely accepted that the complex dynamics characteristic of recurrent neural circuits contributes in a fundamental manner to brain function. Progress has been slow in understanding and exploiting the computational power of recurrent dynamics for two main reasons: nonlinear recurrent networks often exhibit chaotic behavior and most known learning rules do not work in robust fashion in recurrent networks. Here we address both these problems by demonstrating how random recurrent networks (RRN) that initially exhibit chaotic dynamics can be tuned through a supervised learning rule to generate locally stable neural patterns of activity that are both complex and robust to noise. The outcome is a novel neural network regime that exhibits both transiently stable and chaotic trajectories. We further show that the recurrent learning rule dramatically increases the ability of RRNs to generate complex spatiotemporal motor patterns, and accounts for recent experimental data showing a decrease in neural variability in response to stimulus onset

Quantum Hall effect and Landau level crossing of Dirac fermions in trilayer graphene

We investigate electronic transport in high mobility (\textgreater 100,000 cm$^2$/V$\cdot$s) trilayer graphene devices on hexagonal boron nitride, which enables the observation of Shubnikov-de Haas oscillations and an unconventional quantum Hall effect. The massless and massive characters of the TLG subbands lead to a set of Landau level crossings, whose magnetic field and filling factor coordinates enable the direct determination of the Slonczewski-Weiss-McClure (SWMcC) parameters used to describe the peculiar electronic structure of trilayer graphene. Moreover, at high magnetic fields, the degenerate crossing points split into manifolds indicating the existence of broken-symmetry quantum Hall states.Comment: Supplementary Information at http://jarilloherrero.mit.edu/wp-content/uploads/2011/04/Supplementary_Taychatanapat.pd