抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Qualitative methods for health research , Qualitative methods for health research , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

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Qualitative methods for health research

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Activation of the NF-κB/Rel transcription family, by nuclear translocation of cytoplasmic complexes, plays a central role in inflammation through its ability to induce transcription of proinflammatory genes (1). This pathway is activated upon appropriate cellular stimulation, most often by signals related to pathogens or stress. Here we will discuss the specificity of various NF-κB proteins, their role in inflammatory disease, the regulation of NF-κB activity by IκB proteins and IκB kinase (IKK), and the development of therapeutic strategies aimed at inhibition of NF-κB.

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NF-κB: a key role in inflammatory diseases

Ogawa and colleagues reported the presence of three distinct stromal subtypes in pancreatic ductal adenocarcinoma (PDAC), associated with alternative disease characteristics (1). These data are important as stromal heterogeneity defining PDAC subtypes supports developing anti-stromal therapy (1). Intriguingly, the authors report the presence of a fibroblast-activating protein (FAP)-dominant stroma (F-stroma), that compared with other stromal types was low in CD8 T cells and associated with poor survival. T-cell exclusion is well recognized as a disease progression-promoting factor and appears to be the dominant immune phenotype in PDAC (Fig. 1A). The authors suggest that F-stroma may contribute to T-cell exclusion but do not test this notion directly. Thus prompted, we performed a morphometric analysis of the spatial distribution of both T cells and FAP on 31 treatmentna€ ve resected PDACs. We found that T cells indeed were excluded from the tumor per se (Fig. 1A and B), while FAP expression did not show a specific centromarginal gradient in our analysis. Importantly, no association between local FAP expression and T-cell presence was found (Fig. 1C). The most straightforward interpretation of our results, in conjunction with those of Ogawa and colleagues, is that the appearance of F-stroma could be a manifestation of a T cell–excluding phenotype rather than a standalone driver of exclusion itself. In this sense, the relation with Hedgehog signaling, as also pointed out of Ogawa and colleagues is interesting, as it has been shown in experimental rodents that Hedgehog can both suppress immune responses through regulating CXCL12 expression, and concomitantly enlarge the size of specific stromal compartments (2). Furthermore, as discussed by Ogawa and colleagues, F-stroma may facilitate other stromal subsets, for example, tumor-associated macrophages that have been implemented in tumor evasion via multiple mechanisms (e.g., by direct cell–cell interaction and/or secretion of stromamodifying soluble factors) but obviously further work is necessary to substantiate these notions. The observation that T cells are generally excluded in PDAC (Fig. 1D) has major implications in the field and will direct research toward stromal factors. Counteracting T-cell exclusion with immune checkpoint inhibition by targeting PD-(L)1 might not be optimal as mainly inflamed cancer types (melanoma or microsatellite instability-high gastrointestinal cancers) benefit from this type of therapy, but unfortunately not PDAC (3, 4). The goal would certainly be to convert excluded (cold) tumors into inflamed (hot) tumors and subsequently consider combinations with treatments that further potentiates such T-cell responses (5). The key stromal target in PDAC, however, that will allow restoration of the tumor immunity cycle remains, unfortunately, obscure at best.

Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen—Letter

Correlating Fecal Calprotectin With Hemoglobin Levels Within 1 Sample

Background. Primary sclerosing cholangitis (PSC) is a chronic progressive pathological process, related to inflammatory bowel disease and subsequent bacterial translocation. Liver transplantation (LT) is the only curative therapy, but outcomes are compromised by recurrence of PSC (rPSC). The aim of the study was to investigate a potential link between intestinal bacteremia, fucosyltransferase-2 (FUT2), and rPSC after LT. Methods. LT recipients with PSC (n = 81) or without PSC (n = 271) were analyzed for clinical outcomes and positive bacterial blood cultures. A link between bacteremia and the genetic variant of the FUT2 gene was investigated. Results. The incidence of inflammatory bowel disease was significantly higher in PSC recipients but not associated with rPSC. Bacteremia occurred in 31% of PSC recipients. The incidence of rPSC was 37% and was significantly more common in patients with intestinal bacteremia versus no bacteremia (82% versus 30%; P = 0.003). The nonsecretor polymorphism of the FUT2 gene was identified as a genetic risk factor for both intestinal bacteremia and rPSC. Combined FUT2 genotype and intestinal bacteremia in recipients resulted in the highest risk for rPSC (hazard ratio, 15.3; P < 0.001). Conclusions. Thus, in this article, we showed that bacterial translocation is associated with rPSC after LT and related to the FUT2 nonsecretor status.

Intestinal Bacteremia After Liver Transplantation Is a Risk Factor for Recurrence of Primary Sclerosing Cholangitis

RNF43 is an important negative regulator of β-catenin signaling by removing Wnt-receptors from the membrane. It is often mutated in cancers, leading to aberrant Wnt-dependent nuclear translocation of β-catenin. RNF43 has also been suggested to regulate β-catenin signaling directly within the nucleus, among other proposed nuclear functions. Given the importance of RNF43 in regulating Wnt/β-catenin signaling and its potential therapeutic relevance, a proper understanding of RNF43 biology is required. However, the presumed nuclear location is mainly based on available antibodies. These same antibodies have also been used extensively for immunoblotting or immunohistochemical purposes. However, a proper evaluation of their quality to reliably detect endogenous RNF43 has not been performed. Here, using genome editing we have generated a cell line that entirely misses RNF43 exons 8 and 9, encoding the epitopes of commonly used RNF43 antibodies. Using this clone in addition to various other cell line tools, we show that four RNF43 antibodies only yield non-specific signals when applied in immunoblotting, immunofluorescence and immunohistochemical experiments. In other words, they cannot reliably detect endogenous RNF43. Our results suggest that the nuclear staining patterns are an antibody artifact and that RNF43 is unlikely to localize within the nucleus. More generally, reports using RNF43 antibodies should be interpreted with caution, at least for the RNF43 protein aspects described in these papers.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0283894&type=printable

Maikel P. Peppelenbosch

Papers

Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen—Letter

Correlating Fecal Calprotectin With Hemoglobin Levels Within 1 Sample

Intestinal Bacteremia After Liver Transplantation Is a Risk Factor for Recurrence of Primary Sclerosing Cholangitis

Issues with RNF43 antibodies to reliably detect intracellular location

CD14-Dependent and CD14-Independent Pathways Lipopolysaccharide Regulates Macrophage Fluid Phase Pinocytosis Via