The Moraxella adhesin UspA1 binds to its human CEACAM1 receptor by a deformable trimeric coiled-coil

Moraxella catarrhalis is a ubiquitous human-specific bacterium commonly associated with upper and lower respiratory tract infections, including otitis media, sinusitis and chronic obstructive pulmonary disease. The bacterium uses an autotransporter protein UspA1 to target an important human cellular receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Using X-ray crystallography, we show that the CEACAM1 receptor-binding region of UspA1 unusually consists of an extended, rod-like left-handed trimeric coiled-coil. Mutagenesis and binding studies of UspA1 and the N-domain of CEACAM1 have been used to delineate the interacting surfaces between ligand and receptor and guide assembly of the complex. However, solution scattering, molecular modelling and electron microscopy analyses all indicate that significant bending of the UspA1 coiled-coil stalk also occurs. This explains how UspA1 can engage CEACAM1 at a site far distant from its head group, permitting closer proximity of the respective cell surfaces during infection

Structural Insights into the Evolution of a Non-Biological Protein: Importance of Surface Residues in Protein Fold Optimization

Phylogenetic profiling of amino acid substitution patterns in proteins has led many to conclude that most structural information is carried by interior core residues that are solvent inaccessible. This conclusion is based on the observation that buried residues generally tolerate only conserved sequence changes, while surface residues allow more diverse chemical substitutions. This notion is now changing as it has become apparent that both core and surface residues play important roles in protein folding and stability. Unfortunately, the ability to identify specific mutations that will lead to enhanced stability remains a challenging problem. Here we discuss two mutations that emerged from an in vitro selection experiment designed to improve the folding stability of a non-biological ATP binding protein. These mutations alter two solvent accessible residues, and dramatically enhance the expression, solubility, thermal stability, and ligand binding affinity of the protein. The significance of both mutations was investigated individually and together, and the X-ray crystal structures of the parent sequence and double mutant protein were solved to a resolution limit of 2.8 and 1.65 Å, respectively. Comparative structural analysis of the evolved protein to proteins found in nature reveals that our non-biological protein evolved certain structural features shared by many thermophilic proteins. This experimental result suggests that protein fold optimization by in vitro selection offers a viable approach to generating stable variants of many naturally occurring proteins whose structures and functions are otherwise difficult to study

Neuroregeneration in neurodegenerative disorders

<p>Abstract</p> <p>Background</p> <p>Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach.</p> <p>Discussion</p> <p>Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.</p> <p>Summary</p> <p>In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.</p

Reimagining invasions; the social and cultural impacts of Prosopis on pastoralists in Southern Afar

Abstract Whilst the environmental impacts of biological invasions are clearly conceptualised and there is growing evidence on the economic benefits and costs, the social and cultural dimensions remain poorly understood. This paper presents the perceptions of pastoralist communities in southern Afar, Ethiopian lowlands, on one invasive species, Prosopis juliflora. The socio-cultural impacts are assessed, and the manner in which they interact with other drivers of vulnerability, including political marginalisation, sedentarisation and conflict, is explored. The research studied 10 communities and undertook semi-structured interviews and focus group discussions with pastoralists and agro-pastoralists. These results were supported by interviews with community leaders and key informants. The benefits and costs were analysed using the asset-based framework of the Sustainable Livelihoods Framework and the subject-focused approach of Wellbeing in Development. The results demonstrate that the costs of invasive species are felt across all of the livelihood capital bases (financial, natural, physical, human and social) highlighted within the framework and that the impacts cross multiple assets, such as reducing access through blocking roads. The concept of Wellbeing in Development provides a lens to examine neglected impacts, like conflict, community standing, political marginalisation and cultural impoverishment, and a freedom of definition and vocabulary to allow the participants to define their own epistemologies. The research highlights that impacts spread across assets, transcend objective and subjective classification, but also that impacts interact with other drivers of vulnerability. Pastoralists report deepened and broadened conflict, complicated relationships with the state and increased sedentarisation within invaded areas. The paper demonstrates that biological invasions have complex social and cultural implications beyond the environmental and economic costs which are commonly presented. Through synthesising methodologies and tools which capture local knowledge and perceptions, these implications and relationships are conceptualised

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Soft Microtubule Muscle-Driven 3-Axis Skin-Stretch Haptic Devices

In the real world, people heavily rely on haptic or touch to manipulate objects. In emergingsystems such as assistive devices, remote surgery, self-driving cars and the guidance of human movements,visual or auditory feedback can be slow, unintuitive and increase the cognitive load. Skin stretch devices(SSDs) that apply tangential force to the skin via a tactor can encode a far richer haptic space, not beinglimited to force, motion, direction, stiffness, indentation and surface geometry. This paper introduces novelhand-worn hydraulic SSDs that can induce 3-axis tangential forces to the skin via a tactor. The developedSSDs are controlled by new soft microtubule muscles (SMMs) which are driven by hydraulic pressurevia custom miniature syringes and DC micromotors. An analytical model is developed to characterizethe responses of SMM output in terms of force and elongation. A kinematic model for the motion of the3-axis SSD is also developed. We evaluate the capability of the tactor head to track circular referencetrajectories within different working spaces using an optical tracking system. Experimental results showthat the developed SSDs have good durability, high-speed, and can generate omnidirectional shear forcesand desired displacement up to 1.8 N and 4.5 mm, respectively. The developed SMMs and SSDs created inthis paper will enable new forms of haptic communication to augment human performance during dailyactivities such as tactile textual language, motion guidance and navigational assistance, remote surgicalsystems, rehabilitation, education, training, entertainment, or virtual and augmented reality

Predicting the establishment of hair follicle patterns in the developing mouse

Symposium in Honor of Patrick Tam FRS "60 Years & Still Gastrulating"Conference Theme: From Embryology to Disease Mechanism

Smart surgical sutures using soft artificial muscles

Wound closure with surgical sutures is a critical challenge for flexible endoscopic surgeries. Substantial efforts have been introduced to develop functional and smart surgical sutures to either monitor wound conditions or ease the complexity of knot tying. Although research interests in smart sutures by soft robotic technologies have emerged for years, it is challenging to develop a soft robotic structure that possesses a similar physical structure as conventional sutures while offering a self-tightening knot or anchor to close the wound. This paper introduces a new concept of smart sutures that can be programmed to achieve desired and uniform tension distribution while offering self-tightening knots or automatically deploying secured anchors. The core technology is a soft hydraulic artificial muscle that can be elongated and contracted under applied fluid pressure. Each suture is equipped with a pressure locking mechanism to hold its temporary elongated state and to induce self-shrinking ability. The puncturing and holding force for the smart sutures with anchors are examined. Ex-vivo experiments on fresh porcine stomach and colon demonstrate the usefulness of the new smart sutures. The new approaches are expected to pave the way for the further development of smart sutures that will benefit research, training, and commercialization in the surgical field

Predicting the spatiotemporal dynamics of hair follicle patterns in the developing mouse

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