Breaking Up (Amyloid) Is Hard to Do

Gandy and Heppner discuss the implications of a new animal study on our understanding of the pathogenesis and treatment of Alzheimer disease

Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics

© 2019 Protein disulfide isomerases (PDI) are a family of redox chaperones that catalyze formation or isomerization of disulfide bonds in proteins. Previous studies have shown that one member, PDIA3, interacts with influenza A virus (IAV) hemagglutinin (HA), and this interaction is required for efficient oxidative folding of HA in vitro. However, it is unknown whether these host-viral protein interactions occur during active infection and whether such interactions represent a putative target for the treatment of influenza infection. Here we show that PDIA3 is specifically upregulated in IAV-infected mouse or human lung epithelial cells and PDIA3 directly interacts with IAV-HA. Treatment with a PDI inhibitor, LOC14 inhibited PDIA3 activity in lung epithelial cells, decreased intramolecular disulfide bonds and subsequent oligomerization (maturation) of HA in both H1N1 (A/PR8/34) and H3N2 (X31, A/Aichi/68) infected lung epithelial cells. These reduced disulfide bond formation significantly decreased viral burden, and also pro-inflammatory responses from lung epithelial cells. Lung epithelial-specific deletion of PDIA3 in mice resulted in a significant decrease in viral burden and lung inflammatory-immune markers upon IAV infection, as well as significantly improved airway mechanics. Taken together, these results indicate that PDIA3 is required for effective influenza pathogenesis in vivo, and pharmacological inhibition of PDIs represents a promising new anti-influenza therapeutic strategy during pandemic and severe influenza seasons

Testing nowcasts of the ionospheric convection from the expanding and contracting polar cap model

The expanding/contracting polar cap (ECPC) model, or the time-dependent Dungey cycle, provides a theoretical framework for understanding solar wind-magnetosphere-ionosphere coupling. The ECPC describes the relationship between magnetopause reconnection and substorm growth phase, magnetotail reconnection and substorm expansion phase, associated changes in auroral morphology, and ionospheric convective motions. Despite the many successes of the model, there has yet to be a rigorous test of the predictions or nowcasts made regarding ionospheric convection, which remains a final hurdle for the validation of the ECPC. In this study we undertake a comparison of ionospheric convection, as measured in situ by ion drift meters on board DMSP (Defense Meteorological Satellite Program) satellites and from the ground by SuperDARN (Super Dual Auroral Radar Network), with motions nowcasted by a theoretical model. The model is coupled to measurements of changes in the size of the polar cap made using global auroral imagery from the IMAGE FUV (Imager for Magnetopause to Aurora Global Exploration Far Ultraviolet) instrument, as well as the dayside reconnection rate, estimated using the OMNI data set. The results show that we can largely nowcast the magnitudes of ionospheric convection flows using the context of our understanding of magnetic reconnection at the magnetopause and in the magnetotail

Tumor heterogeneity in neoplasms of breast, colon, and skin

<p>Abstract</p> <p>Background</p> <p>Different cell subpopulations in a single tumor may show diverse capacities for growth, differentiation, metastasis formation, and sensitivity to treatments. Thus, heterogeneity is an important feature of tumors. However, due to limitations in experimental and analytical techniques, tumor heterogeneity has rarely been studied in detail.</p> <p>Presentation of the hypothesis</p> <p>Different tumor types have different heterogeneity patterns, thus heterogeneity could be a characteristic feature of a particular tumor type.</p> <p>Testing the hypothesis</p> <p>We applied our previously published mathematical heterogeneity model to decipher tumor heterogeneity through the analysis of genetic copy number aberrations revealed by array CGH data for tumors of three different tissues: breast, colon, and skin. The model estimates the number of subpopulations present in each tumor. The analysis confirms that different tumor types have different heterogeneity patterns. Computationally derived genomic copy number profiles from each subpopulation have also been analyzed and discussed with reference to the multiple hypothetical relationships between subpopulations in origin-related samples.</p> <p>Implications of the hypothesis</p> <p>Our observations imply that tumor heterogeneity could be seen as an independent parameter for determining the characteristics of tumors. In the context of more comprehensive usage of array CGH or genome sequencing in a clinical setting our study provides a new way to realize the full potential of tumor genetic analysis.</p

Oropharyngeal dysphagia in older persons - from pathophysiology to adequate intervention : a review and summary of an international expert meeting

Oropharyngeal dysphagia (OD) is a highly prevalent and growing condition in the older population. Although OD may cause very severe complications, it is often not detected, explored, and treated. Older patients are frequently unaware of their swallowing dysfunction which is one of the reasons why the consequences of OD, ie, aspiration, dehydration, and malnutrition, are regularly not attributed to dysphagia. Older patients are particularly vulnerable to dysphagia because multiple age-related changes increase the risk of dysphagia. Physicians in charge of older patients should be aware that malnutrition, dehydration, and pneumonia are frequently caused by (unrecognized) dysphagia. The diagnosis is particularly difficult in the case of silent aspiration. In addition to numerous screening tools, videofluoroscopy was the traditional gold standard of diagnosing OD. Recently, the fiberoptic endoscopic evaluation of swallowing is increasingly utilized because it has several advantages. Besides making a diagnosis, fiberoptic endoscopic evaluation of swallowing is applied to evaluate the effectiveness of therapeutic maneuvers and texture modification of food and liquids. In addition to swallowing training and nutritional interventions, newer rehabilitation approaches of stimulation techniques are showing promise and may significantly impact future treatment strategies

Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

IL-12 is a well-established driver of type 1 immune responses. Paradoxically, in several autoimmune conditions including neuroinflammation, IL-12 reduces pathology and exhibits regulatory properties. Yet, the mechanism and the involved cellular players behind this immune regulation remain elusive. To identify the IL-12-responsive elements which prevent immunopathology, we generated mouse models lacking a functional IL-12 receptor either in all cells or in specific populations within the immune or central nervous system (CNS) compartments, and induced experimental autoimmune encephalomyelitis (EAE), which models human Multiple Sclerosis (MS). This revealed that the CNS tissue-protective features of IL-12 are mediated by cells of the neuroectoderm, and not immune cells. Importantly, sections of brain from patients with MS show comparable patterns of expression, indicating parallel mechanisms in humans. By combining spectral flow cytometry, bulk and single-nucleus RNA sequencing, we uncovered an IL-12-induced neuroprotective adaption of the neuroectoderm critically involved in maintaining CNS tissue integrity during inflammation

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice

Nontransgenic models of breast cancer

Numerous models have been developed to address key elements in the biology of breast cancer development and progression. No model is ideal, but the most useful are those that reflect the natural history and histopathology of human disease, and allow for basic investigations into underlying cellular and molecular mechanisms. We describe two types of models: those that are directed toward early events in breast cancer development (hyperplastic alveolar nodules [HAN] murine model, MCF10AT human xenograft model); and those that seek to reflect the spectrum of metastatic disease (murine sister cell lines 67, 168, 4T07, 4T1). Collectively, these models provide cell lines that represent all of the sequential stages of progression in breast disease, which can be modified to test the effect of genetic changes