bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune Cell Plasticity Allows for Resetting of Phenotype From Effector to Regulator With Combined Inhibition of Notch/eIF5A Pathways
Authors: Imam Shahnawaz , Dar Pervaiz , Aziz Saba Wasim , Zahid Zeeshan A. , Sarwar Haider , Karim Tamanna , Faisal Sarah , Haseeb Ibrahim , Naqvi Ahmed S. , Shah Rayyan , Haque Amna , Salim Nancy , Jaume Juan C.
Published: November 2021

Type 1 diabetes (T1D) results from the destruction of pancreatic β-cells caused by an altered immune balance in the pancreatic microenvironment. In humans as well as in mouse models, T cells are well recognized as key orchestrators of T1D, which is characterized by T helper (Th) 1 and Th17 cell bias and/or low/defective T-regulatory cells (Treg), and culminates in cytotoxic T-cell (CTL)-mediated destruction of β-cells. Refitting of immune cells toward the non-inflammatory phenotype in the pancreas may represent a way to prevent/treat T1D. Recently we developed a unique spontaneous humanized mouse model of type 1 diabetes, wherein mouse MHC-II molecules were replaced by human DQ8, and β-cells were made to express human glutamic acid decarboxylase (GAD) 65 auto-antigen. The mice spontaneously developed T1D resembling the human disease. Humanized T1D mice showed hyperglycemic (250–300 mg/dl) symptoms by the 4th week of life. The diabetogenic T cells (CD4, CD8) present in our model are GAD65 antigen-specific in nature. Intermolecular antigen spreading recorded during 3rd–6th week of age is like that observed in the human preclinical period of T1D. In this paper, we tested our hypothesis in our spontaneous humanized T1D mouse model. We targeted two cell-signaling pathways and their inhibitions: eIF5A pathway inhibition influences T helper cell dynamics toward the non-inflammatory phenotype and Notch signaling inhibition enrich Tregs and targets auto-reactive CTLs, rescues the pancreatic islet structure, and increases the functionality of β-cells in terms of insulin production. We report that inhibition of (eIF5A + Notch) signaling mediates suppression of diabetogenic T cells by inducing plasticity in CD4 + T cells co-expressing IL-17 and IFNγ (IL-17 + IFNγ +) toward the Treg cells phenotype.
Postoperative Hepatic Dysfunction After Frozen Elephant Trunk for Type A Aortic Dissection
Authors: Liang Shenghua , Liu Yanxiang , Zhang Bowen , Dun Yaojun , Guo Hongwei , Qian Xiangyang , Sun Xiaogang
Published: November 2021

Background: This study was aimed to investigate the incidence, risk factors, and outcomes of patients with postoperative hepatic dysfunction (PHD) after frozen elephant trunk (FET) for type A aortic dissection (TAAD).

Method: A retrospective study was performed with 492 patients who underwent FET for TAAD between 2015 and 2019. Independent risk factors for PHD were determined by multivariate mixed-effect logistic analysis with surgeon-specific factor as a random effect.

Results: The incidence of PHD was 25.4% (n = 125) in our cohort. Patients with PHD presented higher early mortality (10.4 vs. 1.1%, p < 0.001), rates of acute kidney injury (42.4 vs. 12.8%, p < 0.001), and newly required dialysis (23.2 vs. 3.0%, p < 0.001) compared with those without PHD. Moreover, with the median follow-up period of 41.3 months, the survival curve was worse in patients with PHD compared with no PHD group (log-rank p < 0.001), whereas it was similar after excluding patients who died within 30 days (log-rank p = 0.761). Multivariable analyses suggested that PHD was predicted by preoperative aspartate transferase [odds ratio (OR), 1.057; 95% confidence intervals (CI), 1.036–1.079; p < 0.001], celiac trunk malperfusion (OR, 3.121; 95% CI, 1.008–9.662; p = 0.048), and cardiopulmonary bypass time (OR, 1.014; 95% CI, 1.005–1.023; p = 0.003). Retrograde perfusion (OR, 0.474; 95% CI, 0.268–0.837; p = 0.010) was associated with a reduced risk of PHD. Celiac trunk malperfusion was an independent predictor for PHD but not associated with early mortality and midterm survival.

Conclusions: PHD was associated with increased early mortality and morbidity, but not with late death in midterm survival. PHD was predicted by preoperative aspartate transferase, celiac trunk malperfusion, and cardiopulmonary bypass (CPB) time, and retrograde perfusion was associated with a reduced risk of PHD.
Validity of the ESC Risk Assessment in Idiopathic Pulmonary Arterial Hypertension in China
Authors: Gong Su-Gang , Wu Wen-Hui , Li Chao , Zhao Qin-Hua , Jiang Rong , Luo Ci-Jun , Qiu Hong-Ling , Liu Jin-Ming , Wang Lan , Zhang Rui
Published: November 2021

Background: The 2015 European pulmonary hypertension (PH) guidelines recommend a risk stratification strategy for pulmonary arterial hypertension (PAH). We aimed to investigate the validation and potential prognostic information in Chinese patients.

Methods: The risk assessment variables proposed by the PH guidelines were performed by using the WHO function class, 6-min walking distance, brain natriuretic peptide or its N-terminal fragment, right arterial pressure, cardiac index, mixed venous saturation, right atrium area, pericardial effusion, peak oxygen consumption, and ventilatory equivalents for carbon dioxide. An abbreviated version also was applied.

Results: A total of 392 patients with idiopathic PAH (IPAH) were enrolled between 2009 and 2018. After a median interval of 13 months, re-evaluation assessments were available for 386 subjects. The PAH guidelines risk tool may effectively discriminate three risk groups and mortality (p < 0.001) both at the baseline and re-evaluation. Meanwhile, its simplified risk version was valid for baseline and accurately predicted the risk of death in all the risk groups (p < 0.001). At the time of re-evaluation, the percentage of low-risk group has an increase, but a greater proportion achieved the high-risk group and a lesser proportion maintained in the intermediate-risk group.

Conclusion: The 2015 European PH guidelines and its simplified version risk stratification assessment present an effective discrimination of different risk groups and accurate mortality estimates in Chinese patients with IPAH. Changes of risk proportion at re-evaluation implicated that natural treatment decisions may not be consistently with goal-oriented treatment strategy.
In Utero Chlordecone Exposure and Thyroid, Metabolic, and Sex-Steroid Hormones at the Age of Seven Years: A Study From the TIMOUN Mother-Child Cohort in Guadeloupe
Authors: Ayhan Gülen , Rouget Florence , Giton Frank , Costet Nathalie , Michineau Léah , Monfort Christine , Thomé Jean-Pierre , Kadhel Philippe , Cordier Sylvaine , Oliva Alejandro , Multigner Luc
Published: November 2021

Background

Chlordecone is an endocrine-disrupting chemical with well recognized estrogenic and progestagenic properties. This organochlorine insecticide was extensively used in the French West Indies from 1973 to 1993 to control the banana root borer. Due to its poor degradation in the environment, permanently polluted soil is responsible for the current contamination of the food chain and human beings. We aimed to examine the relationship of in utero exposure to chlordecone and thyroid (thyroid stimulating hormone [TSH], free tri-iodothyronine [FT3], free thyroxine [FT4]), metabolic (insulin growth-factor 1, leptin, adiponectin), and sex-steroid (dehydroepiandrosterone [DHEA], total testosterone [TT], dihydrotestosterone [DHT], estradiol [E2]) hormone levels in children at the age of seven years who participated in TIMOUN, an ongoing birth cohort in Guadeloupe.

Methods

Chlordecone concentrations were measured in cord-blood at delivery. Thyroid, metabolic, and sex-steroid hormone levels were determined in the blood of children at seven years of age. Associations between in utero chlordecone exposure and hormone levels at seven years of age were assessed by multiple linear or logistic regression, controlling for confounding factors.

Results

Among the study population (210 boys and 228 girls), chlordecone and hormone measurements were available for 124 boys and 161 girls. We found the third quartile of in utero chlordecone exposure relative to the lowest quartile to be associated with elevated TSH levels in girls and elevated DHEA, TT, and DHT levels in both sexes. Complementary non-linear analysis (spline regression) confirmed a significant non-linear trend for TSH in girls and DHEA and DHT in boys.

Conclusion

In utero chlordecone exposure was associated with elevated levels of selected thyroid (TSH) and sex-steroid (DHEA, TT, and DHT) hormones at seven years in a non-monotonic dose response (inverted U) relationship. The implications for future health and reproductive function in puberty and adulthood should be determined.
Study on Preparation of Oxygen Carrier Using Copper Slag as Precursor
Authors: Feng Yan , Yang Qianhui , Zuo Zongliang , Luo Siyi , Ren Dongdong , Lin Huan
Published: November 2021

Copper slag, an important by-product of the copper smelting process, is mainly composed of 2FeO SiO2, Fe3O4, and SiO2. Due to the sufficient metal oxides, copper slag is regard as a potential oxygen carrier (OC), which can be applied in chemical looping technology. This research proposed to use the granulated copper slag particles as precursor to produce oxygen carrier. Through this method, waste heat of the high-temperature slag can be fully recovered, eliminating the complicated copper slag pretreatment process. In this paper, the reactivity of granulated copper slag after redox calcination was studied by X-ray diffractometer (XRD) and Scanning Electron Microscope (SEM), the highest reactivity occurred at 1,000°C. In addition, the oxygen release and absorption performance of OC were tested in thermal-gravimetric (TG). According to theoretical calculations, the mass loss caused by oxygen release accounts for 70.57% of the total loss and the mass reached by 4.2% at 1,000°C in oxygen absorption experiment. The copper slag modified through calcining in redox condition was proved to be a promising oxygen carrier in chemical looping process. Furthermore, the performance research on OC also provided theoretical references for the operating paraments of OC circulating between air reactor and fuel reactor in practical chemical looping processes.
Comparing Cars With Apples? Identifying the Appropriate Benchmark Countries for Relative Ecological Pollution Rankings and International Learning
Authors: Hartmann Dominik , Ferraz Diogo , Bezerra Mayra , Pyka Andreas , Pinheiro Flávio L.
Published: November 2021

One of the most difficult tasks that economies face is how to generate economic growth without causing environmental damage. Research in economic complexity has provided new methods to reveal structural constraints and opportunities for green economic diversification and sophistication, as well as the effects of economic complexity on environmental pollution indicators. However, no research so far has compared the ecological efficiency of countries with similar productive structures and levels of economic complexity, and used this information to identify the best learning partners. This matters, because there are substantial differences in the environmental damage caused by the same product in different countries, and green diversification needs to be complemented by substantial efficiency improvements of existing products. In this article, we use data on 774 different types of exports, CO2 emissions, and the ecological footprint of 99 countries to create first a relative ecological pollution ranking (REPR). Then, we use methods from network science to reveal a benchmark network of the best learning partners based on country pairs with a large extent of export similarity, yet significant differences in pollution values. This is important because it helps to reveal adequate benchmark countries for efficiency improvements and sustainable production, considering that countries may specialize in substantially different types of economic activities. Finally, the article i) illustrates large efficiency improvements within current global output levels, ii) helps to identify countries that can best learn from each other, and iii) improves the information base in international negotiations for the sake of a cleaner global production system.
Prediction of Potentially Suitable Distributions of Codonopsis pilosula in China Based on an Optimized MaxEnt Model
Authors: Yan Huyong , He Jiao , Xu Xiaochuan , Yao Xinyu , Wang Guoyin , Tang Lianggui , Feng Lei , Zou Limin , Gu Xiaolong , Qu Yingfei , Qu Linfa
Published: November 2021

Species distribution models are widely used in conservation biology and invasive biology. MaxEnt models are the most widely used models among the existing modeling tools. In the MaxEnt modeling process, the default parameters are used most often to build the model. However, these models tend to be overfit. Aiming at this problem, this study uses an optimized MaxEnt model to analyze the impact of past, present and future climate on the distributions of Codonopsis pilosula, an economic species, to provide a theoretical basis for its introduction and cultivation. Based on 264 distribution records and eight environmental variables, the potential distribution areas of C. pilosula in the last interglacial, middle Holocene and current periods and 2050 and 2070 were simulated. Combined with the percentage contribution, permutation importance, and jackknife test, the environmental factors affecting the suitable distribution area of this species were discussed. The results show that the parameters of the optimal model are: the regularization multiplier is 1.5, and the feature combination is LQHP (linear, quadratic, hinge, product). The main temperature factors affecting the distribution of C. pilosula are the annual mean temperature, mean diurnal range, and isothermality. The main precipitation factors are the precipitation seasonality, precipitation in the wettest quarter, and precipitation in the driest quarter, among which the annual average temperature contributes the most to the distribution area of this species. With climate warming, the suitable area of C. pilosula exhibits a northward expansion trend. It is estimated that in 2070, the suitable area of this species will expand to its maximum, reaching 2.5108 million square kilometers. The highly suitable areas of C. pilosula are mainly in Sichuan, Gansu, Shaanxi, Shanxi, and Henan Provinces. Our findings can be used to provide theoretical support related to avoiding the blind introduction of C. pilosula.
Identification and Validation of Prognostic Factors of Lipid Metabolism in Obstructive Sleep Apnea
Authors: Peng Lu , Wang Xiaodi , Bing Dan
Published: November 2021

Background: Obstructive sleep apnea (OSA) is considered to be an independent factor affecting lipid metabolism. This study explored the relationship between immune genes and lipid metabolism in OSA.

Methods: Immune-related Differentially Expressed Genes (DEGs) were identified by analyzing microarray data sets from the Gene Expression Omnibus (GEO) database. Subsequently, we conducted protein-protein interaction (PPI) network analysis and calculated their Gene Ontology (GO) semantic similarity. The GO, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Disease Ontology (DO), gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were employed for functional enrichment analyses and to determine the most significant functional terms. Combined with the results of boruta and random forest, we selected predictors to build a prognostic model, along with seeking out the potential TFs and target drugs for the predictive genes.

Results: Immune-related DEGs included 64 genes upregulated and 98 genes downregulated. The enrichment analysis might closely associate with cell adhesion and T cell-mediated immunity pathways and there were many DEGs involved in lipid and atherosclerosis signaling pathways. The highest-ranking hub gene in PPI network have been reported lowly expressed in OSA. In line with the enrichment analysis, DO analysis reveal that respiratory diseases may be associated with OSA besides immune system disorders. Consistent with the result of the KEGG pathway, the analysis of GSVA revealed that the pro-inflammation pathways are associated with OSA. Monocytes and CD8 T cells were the predominant immune cells in adipose tissue. We built a prognostic model with the top six genes, and the prognostic genes were involved in the polarization of macrophage and differentiation of T lymphocyte subsets. In vivo experimental verification revealed that EPGN, LGR5, NCK1 and VIP were significantly down-regulated while PGRMC2 was significantly up-regulated in mouse model of OSA.

Conclusions: Our study demonstrated strong associations between immune genes and the development of dyslipidemia in OSA. This work promoted the molecular mechanisms and potential targets for the regulation of lipid metabolism in OSA.
Differential Gene Expression in Host Ubiquitination Processes in Childhood Malarial Anemia
Authors: Anyona Samuel B. , Raballah Evans , Cheng Qiuying , Hurwitz Ivy , Ndege Caroline , Munde Elly , Otieno Walter , Seidenberg Philip D. , Schneider Kristan A. , Lambert Christophe G. , McMahon Benjamin H. , Ouma Collins , Perkins Douglas J.
Published: November 2021

Background: Malaria remains one of the leading global causes of childhood morbidity and mortality. In holoendemic Plasmodium falciparum transmission regions, such as western Kenya, severe malarial anemia [SMA, hemoglobin (Hb) < 6.0 g/dl] is the primary form of severe disease. Ubiquitination is essential for regulating intracellular processes involved in innate and adaptive immunity. Although dysregulation in ubiquitin molecular processes is central to the pathogenesis of multiple human diseases, the expression patterns of ubiquitination genes in SMA remain unexplored.

Methods: To examine the role of the ubiquitination processes in pathogenesis of SMA, differential gene expression profiles were determined in Kenyan children (n = 44, aged <48 mos) with either mild malarial anemia (MlMA; Hb ≥9.0 g/dl; n = 23) or SMA (Hb <6.0 g/dl; n = 21) using the Qiagen Human Ubiquitination Pathway RT2 Profiler PCR Array containing a set of 84 human ubiquitination genes.

Results: In children with SMA, 10 genes were down-regulated (BRCC3, FBXO3, MARCH5, RFWD2, SMURF2, UBA6, UBE2A, UBE2D1, UBE2L3, UBR1), and five genes were up-regulated (MDM2, PARK2, STUB1, UBE2E3, UBE2M). Enrichment analyses revealed Ubiquitin-Proteasomal Proteolysis as the top disrupted process, along with altered sub-networks involved in proteasomal, protein, and ubiquitin-dependent catabolic processes.

Conclusion: Collectively, these novel results show that protein coding genes of the ubiquitination processes are involved in the pathogenesis of SMA.
Mechanism of Hip Arthropathy in Ankylosing Spondylitis: Abnormal Myeloperoxidase and Phagosome
Authors: Yu Chaojie , Zhan Xinli , Liang Tuo , Chen Liyi , Zhang Zide , Jiang Jie , Xue Jiang , Chen Jiarui , Liu Chong
Published: November 2021

Background

The pathogenesis of Ankylosing spondylitis (AS) has not been elucidated, especially involving hip joint disease. The purpose of this study was to analyze the proteome of diseased hip in AS and to identify key protein biomarkers.

Material and Methods

We used label-free quantification combined with liquid chromatography mass spectrometry (LC–MS/MS) to screen for differentially expressed proteins in hip ligament samples between AS and No-AS groups. Key protein was screened by Bioinformatics methods. and verified by in vitro experiments.

Results

There were 3,755 identified proteins, of which 92.916% were quantified. A total of 193 DEPs (49 upregulated proteins and 144 downregulated proteins) were identified according to P < 0.01 and Log|FC| > 1. DEPs were mainly involved in cell compartment, including the vacuolar lumen, azurophil granule, primary lysosome, etc. The main KEGG pathway included Phagosome, Glycerophospholipid metabolism, Lysine degradation, Pentose phosphate pathway. Myeloperoxidase (MPO) was identified as a key protein involved in Phagosome pathway. The experiment of siRNA interfering with cells further confirmed that the upregulated MPO may promote the inflammatory response of fibroblasts.

Conclusions

The overexpression of MPO may contribute to the autoimmune inflammatory response of AS-affected hip joint through the phagosome pathway.
The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?
Authors: Ravindranath Mepur H. , El Hilali Fatiha , Filippone Edward J.
Published: November 2021

Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell “cross-dressing” by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).
Immunoproteomic and Immunopeptidomic Analyses of Histoplasma capsulatum Reveal Promiscuous and Conserved Epitopes Among Fungi With Vaccine Potential
Authors: Kischkel Brenda , Boniche-Alfaro Camila , Menezes Isabela de Godoy , Rossi Suelen Andreia , Angeli Claudia Blanes , de Almeida Sandro Rogério , Palmisano Giuseppe , Lopes-Bezerra Leila , Nosanchuk Joshua D. , Taborda Carlos Pelleschi
Published: November 2021

As there are more than 6 million human deaths due to mycoses each year, there is an urgent need to develop fungal vaccines. Moreover, given the similarities among pathogenic fungi, it may be possible to create a multi-fungi vaccine. In this study, we combined immunoproteomic and immunopeptidomic methods, for which we have adapted a technique based on co-immunoprecipitation (Co-IP) that made it possible to map Histoplasma capsulatum epitopes for the first time in a natural context using murine dendritic cells (DCs) and macrophages (Mφ). Although polysaccharide epitopes exist, this research focused on mapping protein epitopes as these are more immunogenic. We used different algorithms to screen proteins and peptides identified by two-dimensional electrophoresis (2-D) and Co-IP. Seventeen proteins were revealed by 2-D gels, and 45 and 24 peptides from distinct proteins were presented by DCs and Mφ, respectively. We then determined which epitopes were restricted to MHC-I and II from humans and mice and showed high promiscuity, but lacked identity with human proteins. The 4 most promising peptides were synthesized, and the peptides with and without incorporation into glucan particles induced CD4+ and CD8+ T cell proliferation and produced a Th1 and Th17 response marked by the secretion of high levels of IFN-γ, IL-17 and IL-2. These epitopes were from heat shock protein 60, enolase, and the ATP-dependent molecular chaperone HSC82, and they each have a high degree of identity with proteins expressed by other medically important pathogenic fungi. Thus, the epitopes described in this study have the potential for use in the development of vaccines that could result in cross-protection among fungal species.
Conditioned Medium of Human Amniotic Epithelial Cells Alleviates Experimental Allergic Conjunctivitis Mainly by IL-1ra and IL-10
Authors: Wu Binxin , Gao Furong , Lin Jianhua , Lu Lixia , Xu Huiming , Xu Guo-Tong
Published: November 2021

Allergic conjunctivitis (AC) is the most prevalent form of mucosal allergy, and the conditioned medium (CM) from mesenchymal stem cells has been reported to attenuate some allergic diseases. However, the therapeutic effects of CM from different tissue stem cells (TSC-CM) on allergic diseases have not been tested. Here, we studied the effects of topical administration of different human TSC-CM on experimental AC (EAC) mice. Only human amniotic epithelial cell-CM (AECM) significantly attenuated allergic eye symptoms and reduced the infiltration of immune cells and the levels of local inflammatory factors in the conjunctiva compared to EAC mice. In addition, AECM treatment decreased immunoglobulin E (IgE) release, histamine production, and the hyperpermeability of conjunctival vessels. Protein chip assays revealed that the levels of anti-inflammatory factors, interleukin-1 receptor antagonist (IL-1ra) and IL-10, were higher in AECM compared to other TSC-CM. Furthermore, the anti-allergic effects of AECM on EAC mice were abrogated when neutralized with IL-1ra or IL-10 antibody, and the similar phenomenon was for the activation and function of B cells and mast cells. Together, the present study demonstrated that AECM alleviates EAC symptoms by multiple anti-allergic mechanisms mainlyviaIL-1ra and IL-10. Such topical AECM therapy may represent a novel and feasible strategy for treating AC.
IRF4 Has a Unique Role in Early B Cell Development and Acts Prior to CD21 Expression to Control Marginal Zone B Cell Numbers
Authors: Ottens Kristina , Satterthwaite Anne B.
Published: November 2021

Strict control of B lymphocyte development is required for the ability to mount humoral immune responses to diverse foreign antigens while remaining self-tolerant. In the bone marrow, B lineage cells transit through several developmental stages in which they assemble a functional B cell receptor in a stepwise manner. The immunoglobulin heavy chain gene is rearranged at the pro-B stage. At the large pre-B stage, cells with a functional heavy chain expand in response to signals from IL-7 and the pre-BCR. Cells then cease proliferation at the small pre-B stage and rearrange the immunoglobulin light chain gene. The fully formed BCR is subsequently expressed on the surface of immature B cells and autoreactive cells are culled by central tolerance mechanisms. Once in the periphery, transitional B cells develop into mature B cell subsets such as marginal zone and follicular B cells. These developmental processes are controlled by transcription factor networks, central to which are IRF4 and IRF8. These were thought to act redundantly during B cell development in the bone marrow, with their functions diverging in the periphery where IRF4 limits the number of marginal zone B cells and is required for germinal center responses and plasma cell differentiation. Because of IRF4’s unique role in mature B cells, we hypothesized that it may also have functions earlier in B cell development that cannot be compensated for by IRF8. Indeed, we find that IRF4 has a unique role in upregulating the pre-B cell marker CD25, limiting IL-7 responsiveness, and promoting migration to CXCR4 such that IRF4-deficient mice have a partial block at the pre-B cell stage. We also find that IRF4 acts in early transitional B cells to restrict marginal zone B cell development, as deletion of IRF4 in mature B cells with CD21-cre impairs plasma cell differentiation but has no effect on marginal zone B cell numbers. These studies highlight IRF4 as the dominant IRF family member in early B lymphopoiesis.
Characterization of M Cells in Tear Duct-Associated Lymphoid Tissue of Mice: A Potential Role in Immunosurveillance on the Ocular Surface
Authors: Oya Yuki , Kimura Shunsuke , Nakamura Yutaka , Ishihara Narumi , Takano Shunsuke , Morita Ryo , Endo Mayumi , Hase Koji
Published: November 2021

The ocular mucosal tissues are exposed to potentially harmful foreign antigens in the air and tear fluid. The tear duct-associated lymphoid tissue (TALT) may contribute to immune surveillance in the eye region. Follicle-associated epithelium (FAE) of TALTs is classified as stratified squamous epithelium and consists of squamous epithelial cells arranged in layers on the basement membrane. In contrast, most mucosa-associated lymphoid tissue is covered by a monolayer of epithelium containing microfold (M) cells. Therefore, antigen uptake and the presence of M cells in TALT are not fully understood. The present study found that a small population of FAE cells in the TALT expressed intestinal M-cell markers, namely Sox8, Tnfaip2, GP2, and OPG. This cell population was identified as functional M cells because of their uptake capacity of luminal nanoparticles. In addition, RANKL, which is essential for M-cell differentiation, was expressed by stroma-like cells at the subepithelial region and its receptor RANK by the FAE in the TALT. The administration of RANKL markedly increased the number of Sox8+ M cells. In contrast, deficiency in OPG, an endogenous inhibitor of RANKL, increased the number of M cells in the TALT. These data demonstrate that the RANKL-RANK axis is essential for M-cell differentiation in the TALT. Furthermore, immunization via eye drops elicited the production of antigen-specific antibodies in tears, which was enhanced by RANKL administration. Thus, TALT M cells play an important role in the immunosurveillance of the eye region.
Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease
Authors: Isola Ignacio , Brasó-Maristany Fara , Moreno David F. , Mena Mari-Pau , Oliver-Calders Aina , Paré Laia , Rodríguez-Lobato Luis Gerardo , Martin-Antonio Beatriz , Cibeira María Teresa , Bladé Joan , Rosiñol Laura , Prat Aleix , Lozano Ester , Fernández de Larrea Carlos
Published: November 2021

Background

We previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression.

Methods

Gene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology.

Results

BM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival.

Conclusions

Our results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.
Relationship of Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratio With Visual Acuity After Surgical Repair of Open Globe Injury
Authors: Mohamed-Noriega Karim , Treviño-Herrera Alan B. , Mohamed-Noriega Jibran , Velasco-Sepúlveda Braulio H. , Martínez-Pacheco Víctor A. , Guevara-Villarreal Dante A. , Rodríguez-Medellín Delia L. , Sepúlveda-Salinas Anna G. , Villarreal-Méndez Gerardo , González-Cortés Jesús H. , Elizondo-Omaña Rodrigo E. , Guzmán-López Santos , Mohamed-Hamsho Jesús
Published: November 2021

Purpose: To assess the relationship and prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with poor final best-corrected visual acuity (BCVA) after surgical repair of open globe injuries (OGI) in adults.

Design: Retrospective analysis of data from an ongoing prospective cohort of consecutive patients.

Methods: In a tertiary university hospital, 197 eyes of 197 patients were included between 2013 and 2017. NLR and PLR were obtained from pre-operative blood tests to analyze its relationship with poor final BCVA.

Results: Severe visual impairment (SVI) was defined as ≤20/200, and was observed in 96 (48.7%) patients after surgical repair of OGI. SVI patients had higher NLR (7.4 ± 6.6 vs. 4.0 ± 3.2, p < 0.001), and PLR (167 ± 92 vs. 139 ± 64; p = 0.021) than non-SVI. NLR ≥ 3.47 and PLR ≥ 112.2 were the best cut-off values for SVI, were univariate risk factors for SVI, and had sensitivity: 69.0, 71.4, and specificity: 63.6, 44.8, respectively. In multivariate analysis, only OTS, athalamia, and hyphema remained as risk factors. NLR had significant correlation with ocular trauma score (OTS) (r = −0.389, p < 0.001) and final BCVA (r = 0.345, p < 0.001).

Limitations: Simultaneous trauma in other parts of the body that could influence the laboratory findings.

Conclusion: Patients with SVI after a repaired OGI had increased pre-operative NLR and PLR levels. High NLR and PLR are risk factors for SVI in univariate analysis. It is confirmed that low OTS is a risk factor for SVI. High NLR and PLR could be used as a prognostic tool to identify patients at higher risk for SVI after repair of OGI.
High-Throughput Sequencing Profiles About lncRNAs and mRNAs of Ovarian Granulosa Cells in Polycystic Ovary Syndrome
Authors: Zheng Yanjun , Bian Yuehong , Wu Richao , Chen Wei , Fu Linlin , Li Ping , Wang Ying , Yang Xiao , Zhao Shigang , Shi Yuhua
Published: November 2021

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, which is characterized by ovulatory dysfunction, clinical and/or biochemical androgen excess, polycystic ovaries on ultrasound and genetic heterogeneity. It was well-accepted that many lncRNAs and mRNAs were associated with PCOS, however, remain unclear. Therefore, the purpose of our study was to examine different expression profiles of lncRNAs and mRNAs in ovarian granulosa cells (GCs) in PCOS and Controls, and identify the correlation between lncRNAs, mRNAs and clinical parameters. Sixty five PCOS patients and 65 Controls were enrolled in this study and adopted standard long agonist protocols or GnRH antagonist protocols. Then 6 GCs samples in each group were subjected to high-thoughput sequencing and the remaining samples were used for the further verification by quantitative real-time PCR (qRT-PCR). Gene Oncology (GO), Kyoto Encyclopedia Genes and Genomes (KEGG) enrichment analysis were performed. We predicted the relationship between lncRNAs and mRNAs by Cytoscape software. According to the expression level of lncRNAs, mRNAs and the clinical parameters, we also explored their relationship and evaluate their predictive values for embryos quality and PCOS. We identified 1,049 differential expressed lncRNAs and 3,246 mRNAs (fold-change ≥2, p-value < 0.05). Seven lncRNAs (NONHSAT101926.2, NONHSAT136825.2, NONHSAT227177.1, NONHSAT010538.2, NONHSAT191377.1, NONHSAT230904.1, ENST00000607307) and 3 mRNAs (EREG, ENTPD6, YAP1) were validated consistent with sequence profile. Seven lncRNAs were related to hormone level and follicle counts, 3 mRNAs had connections with lipid metabolism. The area under curve (AUC) of 7 lncRNAs were valuable in distinguishing patients with PCOS from Controls. The AUC of NONHSAT230904.1 and NONHSAT227177.1 were 0.6807 and 0.6410, respectively, for distinguishing whether the rate of high-quality embryos exceeds 50%. Our study showed that the GCs lncRNAs and mRNAs were involved in the occurrence and development of PCOS, which contribute to clarify the pathogenesis mechanism of PCOS.
Persistence of Symptoms After Discharge of Patients Hospitalized Due to COVID-19
Authors: Wu Lili , Wu Yongxin , Xiong Haiyan , Mei Biqi , You Tianhui
Published: November 2021

Many patients who had coronavirus disease 2019 (COVID-19) had at least one symptom that persisted after recovery from the acute phase. Our purpose was to review the empirical evidence on symptom prevalence, complications, and management of patients with long COVID. We systematically reviewed the literature on the clinical manifestations of long COVID-19, defined by the persistence of symptoms beyond the acute phase of infection. Bibliographic searches in PubMed and Google Scholar were conducted to retrieve relevant studies on confirmed patients with long COVID that were published prior to August 30, 2021. The most common persistent symptoms were fatigue, cough, dyspnea, chest pains, chest tightness, joint pain, muscle pain, loss of taste or smell, hair loss, sleep difficulties, anxiety, and depression. Some of the less common persistent symptoms were skin rash, decreased appetite, sweating, inability to concentrate, and memory lapses. In addition to these general symptoms, some patients experienced dysfunctions of specific organs, mainly the lungs, heart, kidneys, and nervous system. A comprehensive understanding of the persistent clinical manifestations of COVID-19 can improve and facilitate patient management and referrals. Prompt rehabilitative care and targeted interventions of these patients may improve their recovery from physical, immune, and mental health symptoms.
Application of Near-Infrared Spectroscopy to Monitor Perfusion During Extracorporeal Membrane Oxygenation After Pediatric Heart Surgery
Authors: Zhang Mingjie , Yang Yinyu , Chen Xi , Song Yixiao , Zhu Limin , Gong Xiaolei , Zhang Haibo , Xu Zhuoming
Published: November 2021

Objective: Venoarterial extracorporeal membrane oxygenation is an effective mechanical circulatory support that is used to rescue critically ill patients after congenital heart surgery. As there was still no recommended guideline for monitoring parameters during extracorporeal membrane oxygenation (ECMO), this study aimed to investigate the role of near-infrared spectroscopy (NIRS) in the early period of venoarterial (VA)-ECMO.

Method: This study enrolled patients with NIRS monitoring during ECMO after pediatric cardiac surgery at Shanghai Children's Medical Center (2018–2020). The information obtained from the retrospective, the observational dataset included the demographic information, diagnoses, baseline characteristics, procedural details, ECMO data, monitoring data, in-hospital mortality, and complications of the patients.

Results: The overall mortality rate was 43.6%. Lactate was significantly higher in non-survivors compared to survivors at 12 h (11.25 ± 7.26 vs. 6.96 ± 5.95 mmol/l, p = 0.022) and 48 h [2.2 (0.7, 20) vs. 1.4 (0.7, 5.8) mmol/l, p = 0.008] after initiation of ECMO. The cranial regional oxygen saturation (CrSO2) was significantly higher in survivors compared to non-survivors at 24 h (62.5 ± 14.61 vs. 52.05 ± 13.98%, p = 0.028), 36 h (64.04 ± 14.12 vs. 51.27 ± 15.65%, p = 0.005), and 48 h (65.32 ± 11.51 vs. 55.00 ± 14.18%, p = 0.008). Multivariate logistics regression analysis of the hemodynamic and laboratory parameters revealed that the CrSO2 at 36 h (OR = 0.945, p = 0.049) and 48 h (OR = 0.919, p = 0.032) was related to mortality. The use of continuous renal replacement therapy (OR = 14.940, p = 0.039) was also related to mortality. The optimal cutoff values for CrSO2 for predicting mortality after weaning off ECMO at 36 and 48 h were 57% (sensitivity: 61.5%, specificity: 80%) and 56% (sensitivity: 76.9%, specificity: 70%), respectively. The risk of mortality was higher among patients with a CrSO2(36h) < 57% (p = 0.028) by Kaplan-Meier analysis.

Conclusion: Near-infrared spectroscopy may be a useful tool for monitoring the hemodynamic stability during the early period of ECMO, while CrSO2 can predict the in-hospital mortality after ECMO.
Antibacterial Activity Prediction Model of Traditional Chinese Medicine Based on Combined Data-Driven Approach and Machine Learning Algorithm: Constructed and Validated
Authors: Li Jin-Tong , Wei Ya-Wen , Wang Meng-Yu , Yan Chun-Xiao , Ren Xia , Fu Xian-Jun
Published: November 2021

Traditional Chinese medicines (TCMs), as a unique natural medicine resource, were used to prevent and treat bacterial diseases in China with a long history. To provide a prediction model of screening antibacterial TCMs for the design and discovery of novel antibacterial agents, the literature about antibacterial TCMs in the China National Knowledge Infrastructure (CNKI) and Web of Science database was retrieved. The data were extracted and standardized. A total of 28,786 pieces of data from 904 antibacterial TCMs were collected. The data of plant medicine were the most numerous. The result of association rules mining showed a high correlation between antibacterial activity with cold nature, bitter and sour tastes, hemostatic, and purging fire efficacies. Moreover, TCMs with antibacterial activity showed a specific aggregation in the phylogenetic tree; 92% of them came from Tracheophyta, of which 74% were mainly concentrated in rosids, asterids, Liliopsida, and Ranunculales. The prediction models of anti-Escherichia coli and anti-Staphylococcus aureus activity, with AUC values (the area under the ROC curve) of 77.5 and 80.0%, respectively, were constructed by the Neural Networks (NN) algorithm after Bagged Classification and Regression Tree (Bagged CART) and Linear Discriminant Analysis (LDA) selection. The in vitro experimental results showed the prediction accuracy of these two models was 75 and 60%, respectively. Four TCMs (Cirsii Japonici Herba Carbonisata, Changii Radix, Swertiae Herba, Callicarpae Formosanae Folium) were proposed for the first time to show antibacterial activity against E. coli and/or S. aureus. The results implied that the prediction model of antibacterial activity of TCMs based on properties and families showed certain prediction ability, which was of great significance to the screening of antibacterial TCMs and can be used to discover novel antibacterial agents.
Prevalence and Characteristics of Ceftriaxone-Resistant Salmonella in Children’s Hospital in Hangzhou, China
Authors: Shi Qiucheng , Ye Yihua , Lan Peng , Han Xinhong , Quan Jingjing , Zhou Mingming , Yu Yunsong , Jiang Yan
Published: November 2021

The non-Typhi Salmonella (NTS) infection is critical to children’s health, and the ceftriaxone is the important empirical treatment choice. With the increase resistance rate of ceftriaxone in Salmonella, the molecular epidemiology and resistance mechanism of ceftriaxone-resistant Salmonella needs to be studied. From July 2019 to July 2020, a total of 205 NTS isolates were collected, 195 of which (95.1%) were cultured from stool, but 10 isolates were isolated from an extraintestinal site. Serogroup B accounted for the vast majority (137/205) among the isolates. Fifty-three isolates were resistant to ceftriaxone, and 50 were isolated from children younger than 4years of age. The resistance rates for ceftriaxone, ciprofloxacin, and levofloxacin were significantly higher in younger children than the older children. The resistance genes in the ceftriaxone-susceptible isolates were detected by PCR, and ceftriaxone-resistant Salmonella were selected for further whole-genome sequencing. Whole-genome analysis showed that serotype Typhimurium and its monophasic variant was the most prevalent in ceftriaxone-resistant isolates (37/53), which comprised ST34 (33/53), ST19 (2/53), and ST99 (2/53), and they were close related in the phylogenetic tree. However, the other isolates were diverse, which included one Enteritidis (ST11), one Indiana (ST17), one Derby (ST40), four Kentucky (ST198), two Goldcoast (ST2529, ST358), one Muenster (ST321), one Virchow (ST359), one Rissen (ST469), one Kedougou (ST1543), two Uganda (ST684), and one Kottbus (ST8839). Moreover, CTX-M-55 ESBLs production (33/53) was found to be mainly responsible for ceftriaxone resistance, followed by blaCTX-M-65 (12/53), blaCTX-M-14 (4/53), blaCTX-M-9 (2/53), blaCTX-M-64 (1/53), blaCTX-M-130 (1/53), and blaCMY-2 (1/53). ISEcp1, IS903B, IS Kpn26, IS1F, and IS26 were connected to antimicrobial resistance genes transfer. In conclusion, the dissemination of ESBL-producing Salmonella isolates resulted in an increased prevalence of ceftriaxone resistance in young children. The high rate of multidrug resistance should be given additional attention.
Microbial Diversity of Bacteria Involved in Biomineralization Processes in Mine-Impacted Freshwaters
Authors: Paganin Patrizia , Alisi Chiara , Dore Elisabetta , Fancello Dario , Marras Pier Andrea , Medas Daniela , Montereali Maria Rita , Naitza Stefano , Rigonat Nicola , Sprocati Anna Rosa , Tasso Flavia , Vacca Salvatore , De Giudici Giovanni
Published: November 2021

In order to increase the knowledge about geo-bio interactions in extreme metal-polluted mine waters, we combined microbiological, mineralogical, and geochemical analyses to study the indigenous sulfate-reducing bacteria (SRB) involved in the heavy metal (HM) biomineralization processes occurring in Iglesiente and Arburese districts (SW Sardinia, Italy). Anaerobic cultures from sediments of two different mining-affected streams of this regional framework were enriched and analyzed by 16S rRNA next-generation sequencing (NGS) technique, showing sequences closely related to SRB classified in taxa typical of environments with high concentrations of metals (Desulfovibrionaceae, Desulfosporosinus). Nevertheless, the most abundant genera found in our samples did not belong to the traditional SRB groups (i.e., Rahnella, Acinetobacter). The bio-precipitation process mediated by these selected cultures was assessed by anaerobic batch tests performed with polluted river water showing a dramatic (more than 97%) Zn decrease. Scanning electron microscopy (SEM) analysis revealed the occurrence of Zn sulfide with tubular morphology, suggesting a bacteria-mediated bio-precipitation. The inocula represent two distinct communities of microorganisms, each adapted to peculiar environmental conditions. However, both the communities were able to use pollutants in their metabolism and tolerating HMs by detoxification mechanisms. The Zn precipitation mediated by the different enriched cultures suggests that SRB inocula selected in this study have great potentialities for the development of biotechnological techniques to reduce contaminant dispersion and for metal recovery.