Barrier-to-autointegration factor 1 protects against a basal cGAS-STING response

Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, includin

A half-second glimpse often lets radiologists identify breast cancer cases even when viewing the mammogram of the opposite breast

Humans are very adept at extracting the “gist” of a scene in a fraction of a second. We have found that radiologists can discriminate normal from abnormal mammograms at above-chance levels after a half-second viewing (d′ ∼ 1) but are at chance in localizing the abnormality. This pattern of results suggests that they are detecting a global signal of abnormality. What are the stimulus properties that might support this ability? We investigated the nature of the gist signal in four experiments by asking radiologists to make detection and localization responses about briefly presented mammograms in which the spatial frequency, symmetry, and/or size of the images was manipulated. We show that the signal is stronger in the higher spatial frequencies. Performance does not depend on detection of breaks in the normal symmetry of left and right breasts. Moreover, above-chance classification is possible using images from the normal breast of a patient with overt signs of cancer only in the other breast. Some signal is present in the portions of the parenchyma (breast tissue) that do not contain a lesion or that are in the contralateral breast. This signal does not appear to be a simple assessment of breast density but rather the detection of the abnormal gist may be based on a widely distributed image statistic, learned by experts. The finding that a global signal, related to disease, can be detected in parenchyma that does not contain a lesion has implications for improving breast cancer detection

Global Farm Animal Production and Global Warming: Impacting and Mitigating Climate Change

BACKGROUND: The farm animal sector is the single largest anthropogenic user of land, contributing to many environmental problems, including global warming and climate change. OBJECTIVES: The aim of this study was to synthesize and expand upon existing data on the contribution of farm animal production to climate change. METHODS: We analyzed the scientific literature on farm animal production and documented greenhouse gas (GHG) emissions, as well as various mitigation strategies. DISCUSSIONS: An analysis of meat, egg, and milk production encompasses not only the direct rearing and slaughtering of animals, but also grain and fertilizer production for animal feed, waste storage and disposal, water use, and energy expenditures on farms and in transporting feed and finished animal products, among other key impacts of the production process as a whole. CONCLUSIONS: Immediate and far-reaching changes in current animal agriculture practices and consumption patterns are both critical and timely if GHGs from the farm animal sector are to be mitigated

Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile Virus infection

Upon activation of Toll-like and RIG-I-like receptor signaling pathways, the transcription factor IRF5 translocates to the nucleus and induces antiviral immune programs. The recent discovery of a homozygous mutation in the immunoregulatory gene guanine exchange factor dedicator of cytokinesis 2 (Dock2(mu/mu)) in several Irf5(−/−) mouse colonies has complicated interpretation of immune functions previously ascribed to IRF5. To define the antiviral functions of IRF5 in vivo, we infected backcrossed Irf5(−/−) × Dock2(wt/wt) mice (here called Irf5(−/−) mice) and independently generated CMV-Cre Irf5(fl/fl) mice with West Nile virus (WNV), a pathogenic neurotropic flavivirus. Compared to congenic wild-type animals, Irf5(−/−) and CMV-Cre Irf5(fl/fl) mice were more vulnerable to WNV infection, and this phenotype was associated with increased infection in peripheral organs, which resulted in higher virus titers in the central nervous system. The loss of IRF5, however, was associated with only small differences in the type I interferon response systemically and in the draining lymph node during WNV infection. Instead, lower levels of several other proinflammatory cytokines and chemokines, as well as fewer and less activated immune cells, were detected in the draining lymph node 2 days after WNV infection. WNV-specific antibody responses in Irf5(−/−) mice also were blunted in the context of live or inactivated virus infection and this was associated with fewer antigen-specific memory B cells and long-lived plasma cells. Our results with Irf5(−/−) mice establish a key role for IRF5 in shaping the early innate immune response in the draining lymph node, which impacts the spread of virus infection, optimal B cell immunity, and disease pathogenesis. IMPORTANCE Although the roles of IRF3 and IRF7 in orchestrating innate and adaptive immunity after viral infection are established, the function of the related transcription factor IRF5 remains less certain. Prior studies in Irf5(−/−) mice reported conflicting results as to the contribution of IRF5 in regulating type I interferon and adaptive immune responses. The lack of clarity may stem from a recently discovered homozygous loss-of-function mutation of the immunoregulatory gene Dock2 in several colonies of Irf5(−/−) mice. Here, using a mouse model with a deficiency in IRF5 and wild-type Dock2 alleles, we investigated how IRF5 modulates West Nile virus (WNV) pathogenesis and host immune responses. Our in vivo studies indicate that IRF5 has a key role in shaping the early proinflammatory cytokine response in the draining lymph node, which impacts immunity and control of WNV infection

Three-dimensional electron microscopy reveals the evolution of glomerular barrier injury

Open access articleGlomeruli are highly sophisticated filters and glomerular disease is the leading cause of kidney failure. Morphological change in glomerular podocytes and the underlying basement membrane are frequently observed in disease, irrespective of the underlying molecular etiology. Standard electron microscopy techniques have enabled the identification and classification of glomerular diseases based on two-dimensional information, however complex three-dimensional ultrastructural relationships between cells and their extracellular matrix cannot be easily resolved with this approach. We employed serial block face-scanning electron microscopy to investigate Alport syndrome, the commonest monogenic glomerular disease, and compared findings to other genetic mouse models of glomerular disease (Myo1e−/−, Ptpro−/−). These analyses revealed the evolution of basement membrane and cellular defects through the progression of glomerular injury. Specifically we identified sub-podocyte expansions of the basement membrane with both cellular and matrix gene defects and found a corresponding reduction in podocyte foot process number. Furthermore, we discovered novel podocyte protrusions invading into the glomerular basement membrane in disease and these occurred frequently in expanded regions of basement membrane. These findings provide new insights into mechanisms of glomerular barrier dysfunction and suggest that common cell-matrix-adhesion pathways are involved in the progression of disease regardless of the primary insult

STING gain-of-function disrupts lymph node organogenesis and innate lymphoid cell development in mice

STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer\u27s patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β

Improving BDD Based Symbolic Model Checking with Isomorphism Exploiting Transition Relations

Symbolic model checking by using BDDs has greatly improved the applicability of model checking. Nevertheless, BDD based symbolic model checking can still be very memory and time consuming. One main reason is the complex transition relation of systems. Sometimes, it is even not possible to generate the transition relation, due to its exhaustive memory requirements. To diminish this problem, the use of partitioned transition relations has been proposed. However, there are still systems which can not be verified at all. Furthermore, if the granularity of the partitions is too fine, the time required for verification may increase. In this paper we target the symbolic verification of asynchronous concurrent systems. For such systems we present an approach which uses similarities in the transition relation to get further memory reductions and runtime improvements. By applying our approach, even the verification of systems with an previously intractable transition relation becomes feasible.Comment: In Proceedings GandALF 2011, arXiv:1106.081

Educating the public health workforce: Issues and challenges

Background: In public health, as well as other health education contexts, there is increasing recognition of the transformation in public health practice and the necessity for educational providers to keep pace. Traditionally, public health education has been at the postgraduate level; however, over the past decade an upsurge in the growth of undergraduate public health degrees has taken place. Discussion: This article explores the impact of these changes on the traditional sphere of Master of Public Health programs, the range of competencies required at undergraduate and postgraduate levels, and the relevance of these changes to the public health workforce. It raises questions about the complexity of educational issues facing tertiary institutions and discusses the implications of these issues on undergraduate and postgraduate programs in public health. Conclusion: The planning and provisioning of education in public health must differentiate between the requirements of undergraduate and postgraduate students – while also addressing the changing needs of the health workforce. Within Australia, although significant research has been undertaken regarding the competencies required by postgraduate public health students, the approach is still somewhat piecemeal, and does not address undergraduate public health. This paper argues for a consistent approach to competencies that describe and differentiate entry-level and advanced practice

Mobile technology use by people experiencing multiple sclerosis fatigue: a survey

BACKGROUND:Fatigue is one of the most commonly reported symptoms of multiple sclerosis (MS). It has a profound impact on all spheres of life, for people with MS and their relatives. It is one of the key precipitants of early retirement. Individual, group, and Internet cognitive behavioral therapy-based approaches to supporting people with MS to manage their fatigue have been shown to be effective. OBJECTIVE:The aim of this project was to (1) survey the types of mobile devices and level of Internet access people with MS use or would consider using for a health intervention and (2) characterize the levels of fatigue severity and their impact experienced by the people in our sample to provide an estimate of fatigue severity of people with MS in New Zealand. The ultimate goal of this work was to support the future development of a mobile intervention for the management of fatigue for people with MS. METHODS:Survey methodology using an online questionnaire was used to assess people with MS. A total of 51 people with MS participated. The average age was 48.5 years, and the large majority of the sample (77%) was female. RESULTS:Participants reported significant levels of fatigue as measured with the summary score of the Neurological Fatigue Index (mean 31.4 [SD 5.3]). Most (84%) respondents scored on average more than 3 on the fatigue severity questions, reflecting significant fatigue. Mobile phone usage was high with 86% of respondents reporting having a mobile phone; apps were used by 75% of respondents. Most participants (92%) accessed the Internet from home. CONCLUSIONS:New Zealand respondents with MS experienced high levels of both fatigue severity and fatigue impact. The majority of participants have a mobile device and access to the Internet. These findings, along with limited access to face-to-face cognitive behavioral therapy-based interventions, create an opportunity to develop a mobile technology platform for delivering a cognitive behavioral therapy-based intervention to decrease the severity and impact of fatigue in people with MS