Structural biology of glycoprotein hormones and their receptors: insights to signaling.

Abstract This article reviews the progress made in the field of glycoprotein hormones (GPH) and their receptors (GPHR) by several groups of structural biologists including ourselves aiming to gain insight into GPH signaling mechanisms. The GPH family consists of four members, with follicle-stimulating hormone (FSH) being the prototypic member. GPH members belong to the cystine-knot growth factor superfamily, and their receptors (GPHR), possessing unusually large N-terminal ectodomains, belong to the G-protein coupled receptor Family A. GPHR ectodomains can be divided into two subdomains: a high-affinity hormone binding subdomain primarily centered on the N-terminus, and a second subdomain that is located on the C-terminal region of the ectodomain that is involved in signal specificity. The two subdomains unexpectedly form an integral structure comprised of leucine-rich repeats (LRRs). Following the structure determination of hCG in 1994, the field of FSH structural biology has progressively advanced. Initially, the FSH structure was determined in partially glycosylated free form in 2001, followed by a structure of FSH bound to a truncated FSHR ectodomain in 2005, and the structure of FSH bound to the entire ectodomain in 2012. Comparisons of the structures in three forms led a proposal of a two-step monomeric receptor activation mechanism. First, binding of FSH to the FSHR high-affinity hormone-binding subdomain induces a conformational change in the hormone to form a binding pocket that is specific for a sulfated-tyrosine found as sTyr 335 in FSHR. Subsequently, the sTyr is drawn into the newly formed binding pocket, producing a lever effect on a helical pivot whereby the docking sTyr provides as the 'pull & lift' force. The pivot helix is flanked by rigid LRRs and locked by two disulfide bonds on both sides: the hormone-binding subdomain on one side and the last short loop before the first transmembrane helix on the other side. The lift of the sTyr loop frees the tethered extracellular loops of the 7TM domain, thereby releasing a putative inhibitory influence of the ectodomain, ultimately leading to the activating conformation of the 7TM domain. Moreover, the data lead us to propose that FSHR exists as a trimer and to present an FSHR activation mechanism consistent with the observed trimeric crystal form. A trimeric receptor provides resolution of the enigmatic, but important, biological roles played by GPH residues that are removed from the primary FSH-binding site, as well as several important GPCR phenomena, including negative cooperativity and asymmetric activation. Further reflection pursuant to this review process revealed additional novel structural characteristics such as the identification of a 'seat' sequence in GPH. Together with the 'seatbelt', the 'seat' enables a common heteodimeric mode of association of the common α subunit non-covalently and non-specifically with each of the three different β subunits. Moreover, it was possible to establish a dimensional order that can be used to estimate LRR curvatures. A potential binding pocket for small molecular allosteric modulators in the FSHR 7TM domain has also been identified

Criteria of evaluating initial model for effective dynamic model updating

Finite element model updating is an important research field in structural dynamics. Though a variety of updating methods have been proposed in the past decades, all the methods could be effective only on the assumption that the initial finite element model is updatable. The assumption has led to the fact that many researchers study on how to update the model while little attention is paid to studies on whether the model is updatable. This has become inevitable obstacle between research and engineering applications because the assumption is not a tenable hypothesis in practice. To circumvent this problem, the evaluation of model updatability is studied in this paper. Firstly, two conditional statements about mapping are proved as a theoretical basis. Then, two criteria for evaluation of initial models are deduced. A beam is employed in the numerical simulations. Two different initial models for the beam are constructed with different boundary conditions. The models are evaluated using the proposed criteria. The results indicate that the criteria are able to distinguish the model updatability

Finite element model updating using base excitation response function

Finite element model updating is an effective way to build accurate analytical models for structures. Most of the available updating methods employ information from modal testing. However, in astronautics engineering, information provided by vibration table testing is more valuable than those from modal testing. Therefore, it is necessary to study updating methods which can adopt information from vibration table testing. This paper presents the study on such issue. The base excitation response function is analyzed with the assumption that the vibration table gives the structure a single direction motion excitation. Model updating method which adopts the response function is then proposed. In the numerical simulation, several case studies are constructed for a truss structure with small or significant modeling errors respectively. Data selection, which has great influence on the success of updating, is carefully studied. A novel adaptive data selection approach is suggested. Simulation results show that model updating converge with good accuracy when the adaptive data selection approach is used

Distinct neural correlates for pragmatic and semantic meaning processing: An event-related potential investigation of scalar implicature processing using picture-sentence verification

The present study examines the brain-level representation and composition of meaning in scalar quantifiers (e.g., some), which have both a semantic meaning (at least one) and a pragmatic meaning (not all). We adopted a picture-sentence verification design to examine event-related potential (ERP) effects of reading infelicitous quantifiers for which the semantic meaning was correct with respect to the context but the pragmatic meaning was not, compared to quantifiers for which the semantic meaning was inconsistent with the context and no additional pragmatic meaning is available. In the first experiment, only pragmatically inconsistent quantifiers, not semantically inconsistent quantifiers, elicited a sustained posterior negative component. This late negativity contrasts with the N400 effect typically elicited by nouns that are incongruent with their context, suggesting that the recognition of scalar implicature errors elicits a qualitatively different ERP signature than the recognition of lexico-semantic errors. We hypothesize that the sustained negativity reflects cancellation of the pragmatic inference and retrieval of the semantic meaning. In our second experiment, we found that the process of re-interpreting the quantifier was independent from lexico-semantic processing: the N400 elicited by lexico-semantic violations was not modulated by the presence of a pragmatic inconsistency. These findings suggest that inferential pragmatic aspects of meaning are processed using different mechanisms than lexical or combinatorial semantic aspects of meaning, that inferential pragmatic meaning can be realized rapidly, and that the computation of meaning involves continuous negotiation between different aspects of meaning

Vertical deformation monitoring of the suspension bridge tower using GNSS: a case study of the Forth Road Bridge in the UK

The vertical deformation monitoring of a suspension bridge tower is of paramount importance to maintain the operational safety since nearly all forces are eventually transferred as the vertical stress on the tower. This paper analyses the components affecting the vertical deformation and attempts to reveal its deformation mechanism. Firstly, we designed a strategy for high-precision GNSS data processing aiming at facilitating deformation extraction and analysis. Then, 33 months of vertical deformation time series of the southern tower of the Forth Road Bridge (FRB) in the UK were processed, and the accurate subsidence and the parameters of seasonal signals were estimated based on a classic function model that has been widely studied to analyse GNSS coordinate time series. We found that the subsidence rate is about 4.7 mm/year, with 0.1 mm uncertainty. Meanwhile, a 15-month meteorological dataset was utilised with a thermal expansion model (TEM) to explain the effects of seasonal signals on tower deformation. The amplitude of the annual signals correlated quite well that obtained by the TEM, with the consistency reaching 98.9%, demonstrating that the thermal effect contributes significantly to the annual signals. The amplitude of daily signals displays poor consistency with the ambient temperature data. However, the phase variation tendencies between the daily signals of the vertical deformation and the ambient temperature are highly consistent after February 2016. Finally, the potential contribution of the North Atlantic Drift (NAD) to the characteristics of annual and daily signals is discussed because of the special geographical location of the FRB. Meanwhile, this paper emphasizes the importance of collecting more detailed meteorological and other loading data for the investigation of the vertical deformation mechanism of the bridge towers over time with the support of GNSS

SDFE-LV: A Large-Scale, Multi-Source, and Unconstrained Database for Spotting Dynamic Facial Expressions in Long Videos

In this paper, we present a large-scale, multi-source, and unconstrained database called SDFE-LV for spotting the onset and offset frames of a complete dynamic facial expression from long videos, which is known as the topic of dynamic facial expression spotting (DFES) and a vital prior step for lots of facial expression analysis tasks. Specifically, SDFE-LV consists of 1,191 long videos, each of which contains one or more complete dynamic facial expressions. Moreover, each complete dynamic facial expression in its corresponding long video was independently labeled for five times by 10 well-trained annotators. To the best of our knowledge, SDFE-LV is the first unconstrained large-scale database for the DFES task whose long videos are collected from multiple real-world/closely real-world media sources, e.g., TV interviews, documentaries, movies, and we-media short videos. Therefore, DFES tasks on SDFE-LV database will encounter numerous difficulties in practice such as head posture changes, occlusions, and illumination. We also provided a comprehensive benchmark evaluation from different angles by using lots of recent state-of-the-art deep spotting methods and hence researchers interested in DFES can quickly and easily get started. Finally, with the deep discussions on the experimental evaluation results, we attempt to point out several meaningful directions to deal with DFES tasks and hope that DFES can be better advanced in the future. In addition, SDFE-LV will be freely released for academic use only as soon as possible

Risk Assessment of Urban Gas Pipeline Based on Different Unknown Measure Functions

Several risk factors threaten the safety of urban gas pipeline. How to effectively identify various risk factors affecting urban gas pipeline and put forward scientific risk assessment method is the focus in the field of urban safety research. To explore the uncertain factors in the process of gas pipeline risk assessment, and propose a practical assessment method, a three-layer index system for the risk assessment of urban gas pipeline was established using unascertained measure theory, which included 5 first-class evaluation factors and 34 second-class evaluation indexes. Four unascertained measure models (linear, parabolic, exponential and sinusoidal) were constructed, and the unascertained measure values of each evaluation index under four unknown measure function models were calculated. The weight of evaluation factors was determined by Analytic Hierarchy Process (AHP), and the confidence criterion was used for discriminant evaluation. Results demonstrate that the risk assessment models constructed with different measurement functions can effectively reduce the uncertainty of urban gas pipeline risk assessment, but for the same object, the risk level of the linear measurement model in 4# pipeline is lower than other measurement functions, and the risk level of sinusoidal measurement model in 8# pipeline is higher than other measurement functions. Therefore, considering the evaluation results under different measure functions and focusing on monitoring objects with different results is necessary when using unascertained measure theory for risk assessment. The conclusions obtained from this study clarify the application conditions of unascertained measure theory in urban gas pipeline risk assessment, which helps to reduce the uncertainty in the assessment process and improve the accuracy of the assessment results

GPS/GLONASS carrier phase elevation-dependent stochastic modelling estimation and its application in bridge monitoring

The Global Positioning System (GPS) based monitoring technology has been recognised as an essential tool in the long-span bridge health monitoring throughout the world in recent years. However, the high observation noise is still a big problem that limits the high precision displacement extraction and vibration response detection. To solve this problem, GPS double-difference model and many other specific function models have been developed to eliminate systematic errors e.g. unmodeled atmospheric delays, multipath effect and hardware delays. However, relatively less attention has been given to the noise reduction in the deformation monitoring area. In this paper, we first proposed a new carrier phase elevation-dependent precision estimation method with Geometry-Free (GF) and Melbourne-Wü bbena (MW) linear combinations, which is appropriate to regardless of Code Division Multiple Access (CDMA) system (GPS) or Frequency Division Multiple Access (FDMA) system (GLONASS). Then, the method is used to estimate the receiver internal noise and the realistic GNSS stochastic model with a group of zero-baselines and short-baselines (served for the GNSS and Earth Observation for Structural Health Monitoring of Bridges (GeoSHM) project), and to demonstrate their impacts on the positioning. At last, the contribution of integration of GPS and GLONASS is introduced to see the performance of noise reduction with multi-GNSS. The results show that the higher level receiver internal noise in cost effective receivers has less influences on the short-baseline data processing. The high noise effects introduced by the low elevation satellite and the geometry variation caused by rising and dropping satellites, can be reduced by 10–20% with the refined carrier phase elevation-dependent stochastic model. Furthermore, based on observations from GPS and GLONASS with the refined stochastic model, the noise can be reduced by 30–40%, and the spurious signals in the real-life bridge displacements tend to be completely eliminated