Convergent and divergent mechanisms of sugar recognition across kingdoms

Protein modules that bind specific oligosaccharides are found across all kingdoms of life from single-celled organisms to man. Different, overlapping and evolving designations for sugar-binding domains in proteins can sometimes obscure common features that often reflect convergent solutions to the problem of distinguishing sugars with closely similar structures and binding them with sufficient affinity to achieve biologically meaningful results. Structural and functional analysis has revealed striking parallels between protein domains with widely different structures and evolutionary histories that employ common solutions to the sugar recognition problem. Recent studies also demonstrate that domains descended from common ancestors through divergent evolution appear more widely across the kingdoms of life than had previously been recognized

Recent insights into structures and functions of C-type lectins in the immune system

The majority of the C-type lectin-like domains in the human genome likely to bind sugars have been investigated structurally, although novel mechanisms of sugar binding are still being discovered. In the immune system, adhesion and endocytic receptors that bind endogenous mammalian glycans are often conserved, while pathogen-binding C-type lectins on cells of the innate immune system are more divergent. Lack of orthology between some human and mouse receptors, as well as overlapping specificities of many receptors and formation of receptor hetero-oligomers, can make it difficult to define the roles of individual receptors. There is good evidence that C-type lectins initiate signalling pathways in several different ways, but this function remains the least well understood from a mechanistic perspective

Application of a Novel Stability Control System for Coordination of Power Flow Control Devices in the Future GB Transmission System

With increasing large-scale renewable energy sources in the UK and the need for adequate transmission capacity to accommodate the upcoming renewable generations, more state-of-the-art power flow control devices such as embedded High Voltage DC (HVDC) links will soon be commissioned in the GB HV transmission system to provide the additional capacity. An operational stability control system is required to ensure the coordinated control of power flow control devices in order to achieve better dynamic performance and stability. The focus of this paper is to demonstrate the capability of a multi-variable controller for the coordinated control using a non-parametric sampled regulator control design method. This method is practical for applications in large power systems since the complexity of the controller design does not increase with the size and dynamic of the power system. Also, this design method is demonstrated in two power system applications in this paper

A novel mechanism for binding of galactose-terminated glycans by the C-type carbohydrate recognition domain in blood dendritic cell antigen 2

Blood dendritic cell antigen 2 (BDCA-2; also designated CLEC4C or CD303) is uniquely expressed on plasmacytoid dendritic cells. Stimulation of BDCA-2 with antibodies leads to an anti-inflammatory response in these cells, but the natural ligands for the receptor are not known. The C-type carbohydrate recognition domain in the extracellular portion of BDCA-2 contains a signature motif typical of C-type animal lectins that bind mannose, glucose, or GlcNAc, yet it has been reported that BDCA-2 binds selectively to galactose-terminated, biantennary N-linked glycans. A combination of glycan array analysis and binding competition studies with monosaccharides and natural and synthetic oligosaccharides have been used to define the binding epitope for BDCA-2 as the trisaccharide Galβ1–3/4GlcNAcβ1–2Man. X-ray crystallography and mutagenesis studies show that mannose is ligated to the conserved Ca2+ in the primary binding site that is characteristic of C-type carbohydrate recognition domains, and the GlcNAc and galactose residues make additional interactions in a wide, shallow groove adjacent to the primary binding site. As predicted from these studies, BDCA-2 binds to IgG, which bears galactose-terminated glycans that are not commonly found attached to other serum glycoproteins. Thus, BDCA-2 has the potential to serve as a previously unrecognized immunoglobulin Fc receptor

New insights into the physics of inertial microfluidics in curved microchannels. I. Relaxing the fixed inflection point assumption.

Inertial microfluidics represents a powerful new tool for accurately positioning cells and microparticles within fluids for a variety of biomedical, clinical, and industrial applications. In spite of enormous advancements in the science and design of these devices, particularly in curved microfluidic channels, contradictory experimental results have confounded researchers and limited progress. Thus, at present, a complete theory which describes the underlying physics is lacking. We propose that this bottleneck is due to one simple mistaken assumption-the locations of inflection points of the Dean velocity profile in curved microchannels are not fixed, but can actually shift with the flow rate. Herein, we propose that the dynamic distance (δ) between the real equilibrium positions and their nearest inflection points can clearly explain several (previously) unexplained phenomena in inertial microfluidic systems. More interestingly, we found that this parameter, δ, is a function of several geometric and operational parameters, all of which are investigated (in detail) here with a series of experiments and simulations of different spiral microchannels. This key piece of understanding is expected to open the door for researchers to develop new and more effective inertial microfluidic designs

Mammalian sugar-binding receptors: known functions and unexplored roles

Mammalian glycan-binding receptors, sometimes known as lectins, interact withglycans, the oligosaccharide portions ofendogenous mammalian glycoproteins and glycolipids as well as sugars on the surfaces of microbes.Thesereceptors guide glycoproteins out of and back into cells, facilitate communication between cells through both adhesion and signaling, and allow the innate immune system to respond quickly to viral, fungal, bacterial,and parasiticpathogens.For many of the roughly one hundred glycan-binding receptors that are known in humans,there aregood descriptions of what types of glycans they bind and how selectivity for these ligands is achievedat the molecular level.In some cases, there is also comprehensive evidencefor the roles thatthe receptors playat the cellular and organismal levels. In addition to highlighting these well-understood paradigms for glycan-binding receptors, this review will suggest where gaps remain in our understandingof the physiological functions that they can serve

Common Polymorphisms in Human Langerin Change Specificity for Glycan Ligands

Langerin, a C-type lectin on Langerhans cells, mediates carbohydrate-dependent uptake of pathogens in the first step of antigen presentation to the adaptive immune system. Langerin binds a diverse range of carbohydrates including high mannose structures, fucosylated blood group antigens, and glycans with terminal 6-sulfated galactose. Mutagenesis and quantitative binding assays indicate that salt bridges between the sulfate group and two lysine residues compensate for the nonoptimal binding of galactose at the primary Ca(2+) site. A commonly occurring single nucleotide polymorphism (SNP) in human langerin results in change of one of these lysine residues, Lys-313, to isoleucine. Glycan array screening reveals that this amino acid change abolishes binding to oligosaccharides with terminal 6SO(4)-Gal and enhances binding to oligosaccharides with terminal GlcNAc residues. Structural analysis shows that enhanced binding to GlcNAc may result from Ile-313 packing against the N-acetyl group. The K313I polymorphism is tightly linked to another SNP that results in the change N288D, which reduces affinity for glycan ligands by destabilizing the Ca(2+)-binding site. Langerin with Asp-288 and Ile-313 shows no binding to 6SO(4)-Gal-terminated glycans and increased binding to GlcNAc-terminated structures, but overall decreased binding to glycans. Altered langerin function in individuals with the linked N288D and K313I polymorphisms may affect susceptibility to infection by microorganisms

Modeling the anchoring and performance of downhole equipment using an extended Gurson model

In oil and gas (O&G) exploration the well casing, in the form of a long steel tube, maintains the opening of the drilled well hole. Mechanical equipment is often inserted into the well for the purpose of well monitoring, pressure control and various operations. This downhole equipment may be mechanically connected to the pipe casing by the outward radial motion of anchoring teeth such that the inner wall casing is indented. The connection between the tool and the casing must support significant mechanical loads in the longitudinal (axial) direction of the casing, i.e. transverse to the direction of indentation, while minimizing the indentation depth in order to preserve the stiffness and strength of the casing. Consequently, a determination of the ultimate strength of the connection is of critical importance. Failure of this connection involves intense shear of the inner wall of the casing, akin to a machining operation. The critical load for axial slip can be determined experimentally or numerically (or by combination of both). In this study, detailed simulations are performed using the shear-extended GTN (Gurson-Tvergaard-Needleman) model. The choice of model is motivated by the need to accurately the extensive plastic deformation associated with indentation as well as shear-dominated ductile failure on a sub-millimeter scale. The shear-extended GTN model requires a careful calibration of the model parameters by an accurate measurement of the material response. Accordingly, the casing steel was characterized by appropriate measurements under a range of stress states. The calibrated model was used to investigate an idealized two-dimensional representation of the anchoring problem, with a focus on the effect of indentation depth upon connection strength. Both the indentation of the casing inner wall by the anchoring teeth and the subsequent shear of the casing wall were simulated in detail to determine the load required to initiate and progress slip of the anchoring teeth. The results of these analyses show that the connection strength increases linearly with increasing indentation depth

Transcultural adaptation to the Brazilian Portuguese of the Postpartum Bonding Questionnaire for assessing the postpartum bond between mother and baby

The establishment of the bond between mother and baby in the postpartum period is important for ensuring the physical and psychological health of both. This short communication reports the first phase of the cross-cultural translation and adaptation to the Brazilian context of the Postpartum Bonding Questionnaire (PBQ). Four aspects of equivalence between the original scale and the Portuguese version were evaluated: the conceptual, semantic, operational and item equivalences. Literature review, the study of PBQ history, translation, expert evaluation, back-translation and pretests involving 30 mothers with children aging up to 7 months using a primary healthcare unit were conducted. Each step demonstrated the need for adjustments, which were made during the adaptation process. At the end of the study, a version of PBQ in Brazilian Portuguese equivalent to the original one was obtained, offering promise for national studies on the mother-baby bond, and its influence on health, and for use in health services