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Thiol-reactive Michael acceptors are commonly used for the formation of chemically cross-linked hydrogels. In this paper, we address the drawbacks of many Michael acceptors by introducing pyridazinediones as new cross-linking agents. Through the use of pyridazinediones and their mono- or dibrominated analogues, we show that the mechanical strength, swelling ratio, and rate of gelation can all be controlled in a pH-sensitive manner. Moreover, we demonstrate that the degradation of pyridazinedione-gels can be induced by the addition of thiols, thus providing a route to responsive or dynamic gels, and that monobromo-pyridazinedione gels are able to support the proliferation of human cells. We anticipate that our results will provide a valuable and complementary addition to the existing toolkit of cross-linking agents, allowing researchers to tune and rationally design the properties of biomedical hydrogels.

The group 7 complexes [M(κ 3 -2,6-(R 2 PO) 2 C 5 H 3 N)(CO) 2 L][BAr F 4 ] [M = Mn, R = i Pr, L = THF; M = Re, R = t Bu, L = vacant site] undergo in crystallo solid-gas reactivity with CO to form the products of THF substitution or CO addition respectively. There is a large, local, adaptive change of [BAr F 4 ] anions for M = Mn, whereas for M = Re the changes are smaller and also remote to the site of reactivity.

Background: Scapular spine insufficiency fractures following reverse shoulder arthroplasty are poorly understood. There exists limited literature regarding the role of reverse shoulder arthroplasty lateralization on scapular spine strains and fractures. The purpose of this cadaveric biomechanical simulator study was to evaluate the role of glenoid lateralization on scapular spine strain., Methods: Eight cadaveric shoulders were tested using an in-vitro simulator. A custom modular reverse shoulder arthroplasty was implanted that allowed for in-situ glenoid lateralization adjustment. Scapular spine strain was measured by strain gauges placed in clinically relevant Levy zones along the scapular spine. All specimens were tested in loaded forward elevation and abduction., Results: Glenoid lateralization from 0 to 5 mm caused negligible changes in scapular spine strains. Lateralization from 5 to 10 mm, however, caused significant increases in strain at 0° forward elevation in all strain gauges (p < 0.026). Strains measured in Levy zone 2 were significantly higher than all other locations (p < 0.039). Additionally, forward elevation resulted in significantly higher strain values than abduction (p = 0.001)., Conclusions: Glenoid lateralization is an important parameter in reverse shoulder arthroplasty; however, our results demonstrate higher degrees of lateralization may place higher strains on the scapular spine. An understanding of reverse shoulder arthroplasty lateralization and scapular spine strains is important to optimize parameters and to mitigate negative effects., Level of Evidence: Basic Sciences Study, Cadaveric Model, Biomechanics., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2020 The British Elbow & Shoulder Society.)

Background: Reverse shoulder arthroplasty (RSA) humeral implant parameters have been previously studied with respect to range of motion, deltoid function, and stability. However, limited literature exists on the influence of humeral design features on scapular spine strain. The purpose of this cadaveric biomechanical simulator study was to evaluate the role of humeral component lateralization and neck-shaft angle (NSA) on scapular spine strain., Methods: Eight fresh-frozen cadaveric shoulders were tested using an in vitro shoulder simulator. A custom-designed modular RSA system was implanted that allowed for the in situ adjustment of humeral lateralization and NSA. Scapular spine strain was measured by strain gauges placed along the acromion and scapular spine in clinically relevant positions representative of the Levy fracture zones. All testing was conducted in both abduction and forward elevation., Results: In Levy zones 2 and 3, increasing humeral lateralization caused significant incremental decreases in scapular spine strain at 0° and 90° abduction (P < .042). Strain decreases as high as 34% were noted with increases in humeral lateralization from -5 to 15 mm (P = .042). Changing NSA had no statistically significant effect on scapular spine strain (P > .14)., Conclusions: Some humeral implant design features in RSA have effects on scapular spine strain. Humeral component lateralization had significant effects, whereas adjusting NSA resulted in no substantial differences in scapular spine strain. Understanding humeral component variables is important to allow for design optimization of future RSA implants., (Copyright © 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

In recent decades, there has been a steady rise in immunocompromised populations and consequently a dramatic increase in the clinical relevance of normally non-pathogenic and commensal fungi such as Aspergillus fumigatus and Candida albicans. Understanding how these fungi interact with the host immune system is important for the development of immunotherapeutic approaches. Here, we describe a number of methods which have been developed to investigate the interactions of fungi with host leukocytes in vitro, including measuring fungal binding and induction of cytokines, phagocytosis, the respiratory burst, and fungal killing.

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung.

A new mechanistic model based on the formation of a phagocytic synapse explains how immune cells detect and respond to direct contact with fungal pathogens., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Syk-coupled C-type lectin receptor Dectin-1 was the first non-Toll like receptor described that could mediate its own intracellular signalling. It was initially identified as important for the innate recognition of and response to fungal pathogens but later studies revealed that it is also involved in triggering adaptive immune responses. It subsequently emerged that Dectin-1 is one of a number of spleen tyrosine kinase-coupled C-type lectin receptors that have been implicated not just in fungal immunity, but also in viral, mycobacterial and helminth infections. Here, we consider the ability of these receptors to trigger different aspects of immunity and highlight their emerging roles in a number of infection scenarios., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The clinical relevance of fungal infections has increased dramatically in recent decades as a consequence of the rise of immunocompromised populations, and efforts to understand the underlying mechanisms of protective immunity have attracted renewed interest. Here we review Dectin-1, a pattern recognition receptor involved in antifungal immunity, and discuss recent discoveries of polymorphisms in the gene encoding this receptor which result in human disease.

Different dendritic cell (DC) subsets have distinct specialized functions contributed in part by their differential expression of pattern recognition receptors (PRRs). C-type lectin receptors (CLRs) are a group of PRRs expressed by DCs and other myeloid cells that can recognize endogenous ligands as well as a wide range of exogenous structures present on pathogens. Dual roles in homeostasis and immunity have been demonstrated for some members of this receptor family. Largely due to their endocytic ability and subset specific expression, DC-expressed CLRs have been the focus of significant antigen-targeting studies. A number of CLRs function on the basis of signaling via association with immunoreceptor tyrosine-based activation motif (ITAM)-containing adapter proteins. Others contain ITAM-related motifs or immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tails. Here we review CLRs that induce intracellular signaling via a single tyrosine-based ITAM-like motif and highlight their relevance in terms of DC function.

Objectives: to establish the incidence of obesity in the pregnant population in a large city in the North West of England, identify links between obesity and social deprivation, and compare outcomes of pregnancy in obese and non-obese women., Design: retrospective cohort study using maternal records., Setting: largest maternity hospital in Europe., Participants: 8176 women who gave birth at the study hospital in 2006., Findings: data showed that 17.7% of women were clinically obese. Obesity rates increased with advancing age. The incidence of pre-eclampsia, gestational diabetes, induction of labour, caesarean section and fetal macrosomia was significantly higher amongst the obese population. No relationship was found between obesity and social deprivation., Conclusions: this study ascertained the exact incidence of maternal obesity in the local area and showed the increased risks associated with obesity and pregnancy., Implications for Practice: this study supports the need for a shared-care approach to antenatal care and that obese women should give birth in consultant-led units. The support of a named midwife should be available to these women throughout the childbearing experience, and preconception care advocated., (Copyright 2008 Elsevier Ltd. All rights reserved.)

An intein is a polypeptide that interrupts the functional domains of a protein, called the exteins. The intein can facilitate its own excision from the exteins, concomitant with the ligation of the exteins, in a process called protein splicing. The alpha subunit of the ribonucleotide reductase of the extreme thermophile Pyrococcus abyssi is interrupted by three inteins in separate insertion sites. Each intein can facilitate protein splicing when over-expressed in Escherichia coli, with affinity domains serving as the exteins. The influence of the N-terminal flanking residue on the efficiency of splicing is specific to each intein. Each intein has a different downstream nucleophilic residue, and cannot tolerate substitution to a residue of lesser or equal nucleophilicity. The influence of the conserved penultimate His also differs between the inteins.

The innate recognition of fungal pathogens is a crucial first step in the induction of protective antifungal immunity. Complement is thought to be one key component in this process, facilitating fungal recognition and inducing early inflammation. However, the roles of the individual complement components have not been examined extensively. Here we have used mice lacking C3 to examine its role in immunity to opportunistic fungal pathogens and show that this complement component is essential for resistance to infections with Candida albicans and Candida glabrata. We demonstrate that the absence of C3 impairs fungal clearance but does not affect inflammatory responses. We also show that the presence of C3 contributes to mortality in mice challenged with very high doses of Saccharomyces cerevisiae, although these effects were found to be mouse strain dependent.

CLEC-2 is a member of the "dectin-1 cluster" of C-type lectin-like receptors and was originally thought to be restricted to platelets. In this study, we demonstrate that murine CLEC-2 is also expressed by peripheral blood neutrophils, but only weakly by bone marrow or elicited inflammatory neutrophils. On circulating neutrophils, CLEC-2 can mediate phagocytosis of Ab-coated beads and the production of proinflammatory cytokines, including TNF-alpha, in response to the CLEC-2 ligand, rhodocytin. CLEC-2 possesses a tyrosine-based cytoplasmic motif similar to that of dectin-1, and we show using chimeric analyses that the activities of this receptor are dependent on this tyrosine. Like dectin-1, CLEC-2 can recruit the signaling kinase Syk in myeloid cells, however, stimulation of this pathway does not induce the respiratory burst. These data therefore demonstrate that CLEC-2 expression is not restricted to platelets and that it functions as an activation receptor on neutrophils.

To recognise and respond to pathogens, germ-line encoded pattern recognition receptors (PRRs) bind to conserved microbial structures and activate host defence systems, including microbial uptake by phagocytosis. Phagocytosis is a complex process that is instrumental in the control of extracellular pathogens, and this activity is mediated by several PRRs, including a number of C-type lectins. While some of these receptors have clearly been shown to mediate or regulate the uptake of pathogens, others are more contentious and are less well understood in terms of their phagocytic potential. Furthermore, very little is known about the underlying phagocytic mechanisms. Here, we review the phagocytic roles of the mannose receptor, Dectin-1, dendritic cell-specific ICAM grabbing non-integrin (DC-SIGN), DCL-1, mannose binding lectin and surfactant proteins A and D.