UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity.

At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self-RNA and self-DNA, respectively. Despite the structural and functional similarities between these receptors, their contributions to autoimmune diseases such as systemic lupus erythematosus can differ. For example, TLR7 and TLR9 have opposing effects in mouse models of systemic lupus erythematosus-disease is exacerbated in TLR9-deficient mice but attenuated in TLR7-deficient mice1. However, the mechanisms of negative regulation that differentiate between TLR7 and TLR9 are unknown. Here we report a function for the TLR trafficking chaperone UNC93B1 that specifically limits signalling of TLR7, but not TLR9, and prevents TLR7-dependent autoimmunity in mice. Mutations in UNC93B1 that lead to enhanced TLR7 signalling also disrupt binding of UNC93B1 to syntenin-1, which has been implicated in the biogenesis of exosomes2. Both UNC93B1 and TLR7 can be detected in exosomes, suggesting that recruitment of syntenin-1 by UNC93B1 facilitates the sorting of TLR7 into intralumenal vesicles of multivesicular bodies, which terminates signalling. Binding of syntenin-1 requires phosphorylation of UNC93B1 and provides a mechanism for dynamic regulation of TLR7 activation and signalling. Thus, UNC93B1 not only enables the proper trafficking of nucleic acid-sensing TLRs, but also sets the activation threshold of potentially self-reactive TLR7

General Equations of Motion for a Damaged Asymmetric Aircraft

There is a renewed interest in dynamic characteristics of damaged aircraft both in order to assess survivability and to develop control laws to enhance survivability. This paper presents a set of flight dynamics equations of motion for a rigid body not necessarily referenced to the body's center of mass. Such equations can be used when the body loses a portion of its mass and it is desired to track the motion of the body s previous center of mass/reference frame now that the mass center has moved to a new position. Furthermore, results for equations presented in this paper and equations in standard aircraft simulations are compared for a scenario involving a generic transport aircraft configuration subject to wing damage

Cas9+ conditionally-immortalized macrophages as a tool for bacterial pathogenesis and beyond.

Macrophages play critical roles in immunity, development, tissue repair, and cancer, but studies of their function have been hampered by poorly-differentiated tumor cell lines and genetically-intractable primary cells. Here we report a facile system for genome editing in non-transformed macrophages by differentiating ER-Hoxb8 myeloid progenitors from Cas9-expressing transgenic mice. These conditionally immortalized macrophages (CIMs) retain characteristics of primary macrophages derived from the bone marrow yet allow for easy genetic manipulation and a virtually unlimited supply of cells. We demonstrate the utility of this system for dissection of host genetics during intracellular bacterial infection using two important human pathogens: Listeria monocytogenes and Mycobacterium tuberculosis

The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.

Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids

Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch

Variations in the management and survival of women under 50 years with breast cancer in the South East Thames region.

A retrospective, population-based study was undertaken to determine variations in the management of women aged less than 50 years with primary breast cancer in different hospital settings and the influence of these variations on survival. A total of 1757 women who were resident in the South East Thames Health Region aged less than 50 years at the time of diagnosis of breast cancer and who presented during a 5 year period (January 1984 to December 1988) were recorded by the Thames Cancer Registry. The hospitals at which primary surgery was undertaken were categorised as teaching or non-teaching hospitals. The non-teaching hospitals were grouped according to the mean number of patients treated annually during the study period (< or = 2, 3-9, > or = 10 each year). The following factors were compared between these groups: age, extent of disease, tumour morphology, extent of primary surgery (mastectomy vs less than mastectomy), use of axillary surgery (any vs none) and use of systemic adjuvant therapy. Survival rates for the different groups were compared. Registration rates did not differ significantly between health districts. A total of 1485 (85%) women underwent surgery in over 90 different hospitals. In 1324 (86%) of these cases the surgery was undertaken in a total of 42 NHS hospitals within SE Thames Health Region or in seven teaching hospitals in adjacent regions. Mastectomy rates decreased from 52% in 1984 to 28% in 1988 (P<0.0001), but were consistently higher in teaching hospitals (P=0.01). The use of any form of axillary surgery decreased from 49% to 36% over the 5 year period (P=0.003), with significantly lower rates of axillary surgery being performed in non-teaching hospitals (P<0.0001). The proportion of cases recorded as having non-specific morphology was higher in nonteaching than in teaching hospitals (P<0.0001). On multivariate analysis survival was significantly (P<0.001) influenced by stage and tumour histology. Among patients who underwent surgery, the type of hospital in which this was undertaken did not appear to influence survival significantly. This analysis of routine cancer registry data indicates that patients were widely dispersed in a large number of different hospitals and that there were marked variations in practice according to the type of hospital to which patients presented. The treatments provided were frequently at variance with those recommended at a consensus conference held during the study period, particularly in relation to the use of axillary surgery and adjuvant systemic therapy. The way in which services are currently provided may hamper the delivery of appropriate management and comprehensive support. These data thus have implications for the purchasing and provision of services for this common condition

Could an Impairment in Local Translation of mRNAs in Glia be Contributing to Pathogenesis in ALS?

One of the key pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis is abnormal RNA processing. Studies to date have focussed on defects in RNA stability, splicing, and translation, but this review article will focus on the largely overlooked RNA processing mechanism of RNA trafficking, with particular emphasis on the importance of glia. In the central nervous system (CNS), oligodendrocytes can extend processes to myelinate and metabolically support up to 50 axons and astrocytes can extend processes to cover up to 100,000 synapses, all with differing local functional requirements. Furthermore, many of the proteins required in these processes are large, aggregation-prone proteins which would be difficult to transport in their fully translated, terminally-folded state. This, therefore, highlights a critical requirement in these cells for local control of protein translation, which is achieved through specific trafficking of mRNAs to each process and local translation therein. Given that a large number of RNA-binding proteins have been implicated in ALS, and RNA-binding proteins are essential for trafficking mRNAs from the nucleus to glial processes for local translation, RNA misprocessing in glial cells is a likely source of cellular dysfunction in ALS. To date, neurons have been the focus of ALS research, but an intrinsic deficit in glia, namely astrocytes and oligodendrocytes, could have an additive effect on declining neuronal function in ALS. This review article aims to highlight the key evidence that supports the contention that RNA trafficking deficits in astrocytes and oligodendrocytes may contribute to in ALS

Sustaining the University of Johannesburg and Western Sydney University partnership in the time of COVID : a qualitative case study

Abstract: This article offers a qualitative case study of how COVID has changed an existing international education partnership between the University of Johannesburg (UJ) in South Africa and Western Sydney University (WSU) in Australia which involves collaboration with the not-for-profit Nsasani Trust and focuses on sustainability. Before COVID, both universities ran joint student mobility programs in the Kruger National Park (KNP) and were developing further plans for staff mobility and co-developed post- grad programs involving residency in both countries. These plans changed as a result of the COVID pandemic, which started in early 2020. Societal responses to the COVID pandemic, including national border closures, have forced academics, administrators and students to reconsider how internationalisation programs function during and after the pandemic. Using a qualitative case study based on personal experience, we argue that pre-existing university-to-university connections built before COVID will sustain linkages, but that the previous structure of engagement – based on physical mobility – can shift to new arrangements that can be run fully digitally or used to support limited mobility when international travel resumes in the future. We position the UJ-WSU relationship in the historical context of internationalisation to both highlight the enduring nature of international engagements and suggest that changes are required to make international education sustainable