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关键词： IL-35   Immunosuppression   IL-15R alpha   Neutrophil   Grass carp  

摘要： IL-35 plays a key role in regulatory T (Treg) and regulatory B (Breg) cell functions in mammals. CD25 has been demonstrated as one of the markers of Treg cells, and CD19(+)CD25(hi)CD71(hi) cells have been verified as a type of Breg cells in humans. These results indicate that there is a close relationship between IL-35 and CD25(+) cells. In mammals, CD25 (alias IL-2R alpha) has been identified as having high affinity and specificity for IL-2 binding, and is closely linked and structurally related to IL-15R alpha, which having high affinity for IL-15 binding. In teleost, IL15R alpha can bind to both IL-2 and IL-15, with higher affinity to IL-15 than IL-2, and has been termed a CD25-like molecule in some research studies. To date, no studies of IL-35 and IL-15R alpha have been documented in fish. In this work, five isoforms of IL-15R alpha were cloned from grass carp, and a monoclonal antibody to the protein was developed. The results of flow cytometry and quantitative real-time PCR analyses demonstrated that grass carp IL-35 subunit genes EBI3a and IL-12p35 were mainly expressed in IL-15R alpha(+) cells, while the expression levels of IL-10 and TGF-beta in IL-15R alpha(+) and IL-15R alpha- cells were insignificant. Recombinant grass carp IL-35 (rgcIL-35) could increase the proportion of IL-15R alpha(+) cells in leukocytes, and a certain proportion of IL-15R alpha(+) cells also appeared in myeloid cell subset II after stimulation with rgcIL-35. Meanwhile, the migration, phagocytic ability, and bactericidal ability of grass carp neutrophils were significantly decreased after stimulation with certain concentrations of rgcIL-35. Moreover, neutrophil apoptosis could be significantly inhibited by rgcIL-35.

关键词： Synchronous   Metachronous   Lung cancer   Follow-up   Surgery   Guidelines  

摘要： Multiple lung cancers can be found simultaneously, with incidence ranging from 1% to 8%. Documentation of more than 1 pulmonary lesion can be challenging, because these solid, ground-glass, or mixed-density tumors may represent multicentric malignant disease or intrapulmonary metastases. If mediastinal nodal and distant deposits are excluded, surgery should be contemplated. After surgical treatment of lung cancer, patients should be followed closely for an undetermined period of time. Good clinical judgment is of outmost importance in deciding which individuals will benefit from those surgical interventions and which are candidates for alternate therapies. Every case should be discussed in a multidisciplinary meeting.

关键词： Sickle cell disease   Primary prevention   Newborn screening   Ghana   Nigeria  

摘要： Sickle cell disease (SCD), an inherited blood disorder, impacts 2% of newborns in Nigeria and Ghana. Despite devastating health consequences, SCD prevention is not a priority in either country. This article describes our U.S. research team's feasibility assessment for adapting CHOICES, a computer-based SCD education program, for use in Ghana and Nigeria. We identified indigenous collaborators by reviewing published research and investigating advocacy organizations online. This led to a fact-finding trip to Africa to discuss SCD prevention with local boards of advisors. Three major recommendations emerged from the group discussions: design a culturally appropriate intervention;enlist community healthcare workers to deliver the CHOICES program;and collaborate with religious and community leaders and elders in public awareness campaigns. Based on extensive advisor input, we will modify the content and delivery of the CHOICES intervention to meet the needs of those impacted by SCD in Ghana and Nigeria.

关键词： Beta cell mass   Beta cell number   Beta cell size   Human pancreas   Japanese  

摘要： Aims/hypothesis Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. Methods Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. Results Both beta cell size (548.7 +/- 58.5 vs 606.7 +/- 65.0 mu m(3), p < 0.01) and number (5.10 x 10(8) +/- 2.35 x 10(8) vs 8.16 x 10(8) +/- 4.27 x 10(8), p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA(1c) (r = -0.45, p < 0.01). Conclusions/interpretation Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes.

关键词： Long-term cognitive networks   Recurrent neural networks   Backpropagation   Multi-label classification  

摘要： This paper presents a neural system to deal with multi-label classification problems that might involve sparse features. The architecture of this model involves three sequential blocks with well-defined functions. The first block consists of a multilayered feed-forward structure that extracts hidden features, thus reducing the problem dimensionality. This block is useful when dealing with sparse problems. The second block consists of a Long-term Cognitive Network-based model that operates on features extracted by the first block. The activation rule of this recurrent neural network is modified to prevent the vanishing of the input signal during the recurrent inference process. The modified activation rule combines the neurons' state in the previous abstract layer (iteration) with the initial state. Moreover, we add a bias component to shift the transfer functions as needed to obtain good approximations. Finally, the third block consists of an output layer that adapts the second block's outputs to the label space. We propose a backpropagation learning algorithm that uses a squared hinge loss function to maximize the margins between labels to train this network. The results show that our model outperforms the state-of-the-art algorithms in most datasets. (C) 2021 The Author(s). Published by Elsevier Ltd.

关键词： case-control study   odd-chain saturated fatty acids   serine palmitoyl-transferase long-chain base subunit 3 gene polymorphism   SPTLC3   type 2 diabetes   T2D   very-long-chain saturated fatty acids   VLSFAs  

摘要： Background: Several individual studies have shown that circulating levels of odd-chain SFAs and very-long-chain SFAs (VLSFAs) may have beneficial effects, but the results are mixed. While the dietary and metabolic factors that may influence VLSFAs are not well-known, a previous study observed associations of VLSFA concentrations with variants in serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3) gene. Objectives: We investigated the associations of individual plasma SFAs and SPTLC3 gene rs680379 polymorphism with metabolic risk factors and type 2 diabetes (T2D). Methods: We measured plasma SFAs using gas chromatography among 898 T2D cases and 1618 matched controls, and genotyped the SPTLC3 gene rs680379 polymorphism using the MassArray System among 1178 T2D cases and 1907 matched controls. Conditional logistic regression was used to estimate ORs and 95% CIs. Results: We found that plasma odd-chain SFAs and VLSFAs were correlated with favorable blood lipids and insulin resistance marker profiles. After multivariable adjustment, pentadecanoic acid (15:0) was inversely associated with the odds of T2D (OR per 1 SD difference: 0.63;95% CI: 0.57, 0.70), as were measurements of 3 individual VLSFAs [arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)], with ORs ranging from 0.60 to 0.72 (95% CIs ranging between 0.52 and 0.79). The associations between 3 individual VLSFAs and T2D were attenuated after further adjustment for triglycerides. Meanwhile, compared with the rs680379 GG genotype carriers, the ORs of T2D for the GA and AA genotype carriers were 0.81 (95% CI: 0.68-0.97) and 0.76 (95% CI: 0.61-0.96), respectively. Conclusions: Plasma 15:0 and VLSFAs were inversely associated with T2D. Meanwhile, compared with the rs680379 GG genotype carriers, subjects with GA and AA genotypes were associated with decreased odds of T2D. More investigations are warranted to confirm our findings.

关键词： Virology   Medical Microbiology   Infectious Diseases  

摘要： Infectious bronchitis virus (IBV), an avian coronavirus, is highly contagious. Chickens with IBV infection develop acute pathogenesis in multiple organs, including the respiratory and urogenital tracts. Frequent recombination in the spike (S) glycoprotein gene has made vaccine strategies ineffective. To understand IBV pathogenesis, we analyzed the genetic distance between Korean IBV isolates and other coronaviruses, including SARS-CoV-2. To obtain comprehensive information about early immune responses such as innate cytokine production and associated immune regulation during IBV infection, we infected primary chicken embryonic kidney cells and performed transcriptome analysis. We observed that the functional pathways of innate immunity are regulated and confirmed expression of genes that coordinate early immune responses. Understanding the immune profile of the host cell may assist in vaccine development.

摘要： Objectives: To define the incidence, prognosis, and treatment patterns associated with multiple primary lower genital tract squamous cell carcinoma (LGTSCC). Methods: Surveillance, Epidemiology, and End Results (SEER) database patients diagnosed with synchronous cervical, vaginal, vulvar, and/or anal SCC from 2000-2016 were included. Incidence and mortality were evaluated using Kaplan-Meier curves. Multivariable Cox proportional hazards regression was used to identify treatment patterns, risk factors, and mortality associated with LGTSCC. Results: Among 15,424 women with any LGTSCC, 138 patients had multiple primary LGTSCC (0.89%). Vulvar and vaginal SCC was the most common combination (49.3%), and cervical with anal SCC was the least common (1.4%). Only one patient had 3 or more primary LGTSCC (vulvar, cervical, and anal). Multiple primary LGTSCC was independently associated with higher mortality compared to single site LGTSCC (adjusted hazards ratio [aHR]=1.67; p<0.001). Multiple primary LGTSCC was significantly associated with older age (63 vs. 58 years, p<0.001) and have lower stage (adjusted odds ratio [aOR]=0.38; p<0.001) and grade of disease (aOR=0.32; p<0.001). Patients with multiple primary LGTSCC were more likely to receive radiation overall (aOR=1.74, p=0.005) and were more likely to receive adjuvant radiation after primary surgical resection compared to single site LGTSCC (aOR=1.88, p=0.007). Receipt of any treatment including radiation (aHR=0.85; p<0.001), chemotherapy (aHR=0.50; p<0.001), and surgery (aHR=0.70; p<0.001) was independently associated with decreased mortality hazard. Conclusions: Multiple primary LGTSCC is rare but is associated with increased mortality, and higher rates of adjuvant radiation compared to single site LGTSCC despite lower stage and grade at diagnosis. More research is needed to define optimal therapy for patients with multiple primary LGTSCC.

关键词： FFPE   formalin fixed and paraffin embedded   HC   healthy control   HCQ   hydroxychloroquine   HPF   high-power field   KC   keratinocyte   LCM   laser-capture microdissection   mDC   myeloid dendritic cell   pDC   plasmacytoid dendritic cell  

摘要： Dermatomyositis pathogenesis remains incompletely understood;however, recent work suggests a predominant IFN-1 response. We explored dermatomyositis pathogenesis by quantifying the inflammatory cells in the skin, comparing myeloid with plasmacytoid dendritic cell release of IFN-beta, and assessing myeloid dendritic cell (mDC) contribution to hydroxychloroquine refractoriness. Immunohistochemistry was performed to assess cell-type expression in lesional skin biopsies from 12 patients with moderate-to-severe cutaneous dermatomyositis. Immunofluorescence, laser-capture microdissection, and flow cytometry were used to assess mDC release of IFN-beta in lesional skin biopsies and blood of patients with dermatomyositis. Immunohistochemistry was utilized to determine whether myeloid or plasmacytoid dendritic cells were increased in hydroxychloroquine nonresponders. CD4+, CD11c+, and CD69+ cells were more populous in lesional skin of patients with dermatomyositis. mDCs colocalized with IFN-beta by immunofluorescence and laser-capture microdissection revealed increased IFN-beta mRNA expression by mDCs in lesional skin of patients with dermatomyositis. In blood, both mDCs and plasmacytoid dendritic cells were major producers of IFN-beta in patients with dermatomyositis, whereas plasmacytoid dendritic cells predominately released IFN-beta in healthy controls (P < 0.01). mDCs were significantly increased in the skin of hydroxychloroquine nonresponders compared with that in the skin of responders (P < 0.05). mDCs cells appear to play an important role in dermatomyositis pathogenesis and IFN-beta production.

关键词： Besnoitia besnoiti   Ezetimibe   Neospora caninum   Toxoplasma gondii  

摘要： Coccidia are obligate apicomplexan parasites that affect humans and animals. In fast replicating species, in vitro merogony takes only 24-48 h. In this context, successful parasite proliferation requires nutrients and other building blocks. Coccidian parasites are auxotrophic for cholesterol, so they need to obtain this molecule from host cells. In humans, ezetimibe has been applied successfully as hypolipidaemic compound, since it reduces intestinal cholesterol absorption via blockage of Niemann-Pick C-1 like-1 protein (NPC1L1), a transmembrane protein expressed in enterocytes. To date, few data are available on its potential anti-parasitic effects in primary host cells infected with apicomplexan parasites of human and veterinary importance, such as Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti. Current inhibition experiments show that ezetimibe effectively blocks T. gondii, B. besnoiti and N. caninum tachyzoite infectivity and replication in primary bovine endothelial host cells. Thus, 20 mu m ezetimibe blocked parasite proliferation by 73.1-99.2%, via marked reduction of the number of tachyzoites per meront, confirmed by 3D-holotomographic analyses. The effects were parasitostatic since withdrawal of the compound led to parasite recovery with resumed proliferation. Ezetimibe-glucuronide, the in vivo most effective metabolite, failed to affect parasite proliferation in vitro, thereby suggesting that ezetimibe effects might be NPC1L1-independent.