bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Biomarkers for Congenital Heart Disease Based on Maternal Amniotic Fluid Metabolomics
Authors: Li Yahong , Sun Yun , Yang Lan , Huang Mingtao , Zhang Xiaojuan , Wang Xin , Guan Xianwei , Yang Peiying , Wang Yan , Meng Lulu , Zhou Ran , Zhou Xiaoyan , Luo Chunyu , Hu Ping , Jiang Tao , Xu Zhengfeng
Published: June 2021

Congenital heart disease (CHD) is the most common birth defect. The prenatal diagnosis of fetal CHD is completely dependent on ultrasound testing, but only ~40% of CHD can be detected. The purpose of this study is to find good biomarkers in amniotic fluid (AF) to detect CHD in the second trimester, so as to better manage this group of people and reduce the harm of CHD to the fetus. Metabolites analysis were performed in two separate sets. The discovery set consisted of 18 CHD fetal maternal AF samples and 35 control samples, and the validation set consisted of 53 CHD fetal maternal AF samples and 114 control samples. Untargeted metabolite profiles were analyzed by gas chromatography/time-of-flight-mass spectrometry (GC-TOF/MS). Orthogonal partial least square discrimination analysis (OPLS-DA) demonstrated that CHD and control samples had significantly different metabolic profiles. Two metabolites, uric acid and proline, were significantly elevated in CHD and verified in two data sets. Uric acid was associated with CHD [odds ratio (OR): 7.69 (95% CI: 1.18–50.13) in the discovery set and 3.24 (95% CI:1.62–6.48) in the validation set]. Additionally, uric acid showed moderate predictive power; the area under curve (AUC) was 0.890 in the discovery set and 0.741 in the validation set. The sensitivity and specificity of uric acid to detect CHD was, respectively, 94.4 and 74.3% in the discovery set and 67.9 and 71.9% in the validation set. The identification of uric acid as a biomarker for CHD has the potential to stimulate research on the pathological mechanism of CHD and the development of a diagnostic test for clinical applications.
Silencing of ANGPTL8 Alleviates Insulin Resistance in Trophoblast Cells
Authors: Bai Yu , Du Qiang , Zhang Le , Li Ling , Wang Nana , Wu Bo , Li Ping , Li Ling
Published: June 2021

This study aims to investigate the effect of angiopoietin like 8 (ANGPTL8) on gestational diabetes mellitus (GDM) and insulin resistance (IR). The GDM model was induced by high fat diet in mice, and IR was observed. The expression and secretion of ANGPTL8 were promoted in placenta of GDM mice. IR was induced in trophoblast cell HTR-8/SVneo by treatment of high concentration of insulin, and the expression levels of ANGPTL8 were increased. Silencing of ANGPTL8 alleviated IR and decreased glucose uptake in HTR-8/SVneo cells. However, the inflammation and oxidative stress in IR cells were not restrained by ANGPTL8 knockdown. In addition, c-Jun N-terminal kinase (JNK) signaling was activated by IR, which was inhibited by silencing of ANGPTL8. The effect of ANGPTL8 knockdown on IR was attenuated by JNK antagonist, and aggravated by JNK agonist, suggesting that ANGPTL8 affected IR by regulating JNK signaling. In conclusion, we demonstrated that the silencing of ANGPTL8 ameliorated IR by inhibiting JNK signaling in trophoblast cells. These findings may provide novel insights for diagnosis and treatment of GDM in clinic.
Wetland Utilization and Adaptation Practice of a Coastal Megacity: A Case Study of Chongming Island, Shanghai, China
Authors: Bao Junlin , Gao Shu
Published: June 2021

Coastal urban areas are faced with risks induced by global warming and sea level rise, which puts pressure on regional sustainable development. In particular, land use adjustment is closely related to climate change for a coastal megacity. Coastal wetlands on the edge of the megacity represent a vulnerable ecosystem and a key area in terms of the resilient adaptation strategy. However, the interrelationship between the development of these wetlands and the megacity’s adaptation practice has not been sufficiently analyzed. From a historical perspective, based on document synthesis and field investigation, we attempt in this study to reveal long-term land use stages and driving factors in association with urban marginal wetlands, with a special reference to eastern Chongming Island, Shanghai. On such a basis, the future adaptation strategy of the megacity is evaluated. The analytical results show that this island has witnessed three periods of time for wetland utilization: traditional land use for salt production, fishery and agriculture before 1950, industrialization with rapid reclamation during 1950–2001, and the land use pattern orientated toward wetland ecosystem protection after 2002. The driving forces include sediment budget on the coast, wetland morphodynamic processes, sea level rise, population growth, and resource management policy changes. Transformation occurred between the wetland utilization stages in response to the changes of these forces. Furthermore, facing future climate change, there are different options of adaptation, e.g., retreatment and adherence. It may not be suitable for coastal cities with a large population to take the first option. It will be suitable for coastal communities to adhere to the location, if solutions to the problems of flooding risk, coastal erosion, and the maintenance of coastal facilities can be found. For eastern Chongming wetlands, as a key experimental area for ecosystem-oriented development in Shanghai, the transformation from the reclamation-oriented utilization toward the protection of wetland ecosystems represents the first step toward the latter option. We suggest that the next steps would be to maintain the ecological niche of the wetlands, to create new approaches to coastal engineering with contributions from the ecosystem, and to provide better ecosystem services.
Water Level Regulation for Eco-social Services Under Climate Change in Erhai Lake Over the Past 68 years in China
Authors: Wen Zihao , Ma Yiwei , Wang Hao , Cao Yu , Yuan Changbo , Ren Wenjing , Ni Leyi , Cai Qinghua , Xiao Wen , Fu Hui , Cao Te , Zhang Xiaolin
Published: June 2021

Water level plays a crucial role in the function and social services of lakes. Studies on historical changes in water level and its eco-social function can give insights into future water conservation and management. In this study, interannual and seasonal changes in the water level of Erhai Lake were analyzed from 1952 to 2019 to explore water level responses to human activities and climate change. The time series was divided into three distinct periods, i.e., 1952–1971, 1972–2003, and 2004–2019. Results showed that the water level and fluctuation amplitude differed among the different time periods, i.e., 1965.8 and 1.3 m (1952–1971), 1964.4 and 1.9 m (1972–2003), and 1965.2 and 1.2 m (1972–2003), respectively. The construction and operation of a hydroelectric power plant along the outlet river significantly decreased the water level and increased fluctuation amplitude in the 1972–2003 period. Since 2004, due to the implementation of local government water level management laws for Erhai Lake, the water level has remained relatively high, with moderate fluctuation amplitude. In addition, compared to the increase in water level amplitude in response to increased wet season (May–October) precipitation in the 1952–1971 period, response sensitivity increased in the 1972–2003 period, but became non-significant in the 2004–2019 period. In regard to the multi-timescale relationship between water level and precipitation, precipitation decreased by 89 mm in the 2004–2019 period compared with that from 1952 to 1971, and artificial water-level regulation resulted in a time-lag of 2, 3–3.5, and 4 months between water level and precipitation during the 1952–1971, 1972–2003, and 2004–2019 periods, respectively. The eco-social aspects of changes in water level are discussed below, and water level regulation from an ecological perspective is recommended to gain economic returns in the future.
Recent Carbon Storage and Burial Exceed Historic Rates in the San Juan Bay Estuary Peri-Urban Mangrove Forests (Puerto Rico, United States)
Authors: Wigand Cathleen , Eagle Meagan , Branoff Benjamin L. , Balogh Stephen , Miller Kenneth M. , Martin Rose M. , Hanson Alana , Oczkowski Autumn J. , Huertas Evelyn , Loffredo Joseph , Watson Elizabeth B.
Published: June 2021

Mangroves sequester significant quantities of organic carbon (C) because of high rates of burial in the soil and storage in biomass. We estimated mangrove forest C storage and accumulation rates in aboveground and belowground components among five sites along an urbanization gradient in the San Juan Bay Estuary, Puerto Rico. Sites included the highly urbanized and clogged Caño Martin Peña in the western half of the estuary, a series of lagoons in the center of the estuary, and a tropical forest reserve (Piñones) in the easternmost part. Radiometrically dated cores were used to determine sediment accretion and soil C storage and burial rates. Measurements of tree dendrometers coupled with allometric equations were used to estimate aboveground biomass. Estuary-wide mangrove forest C storage and accumulation rates were estimated using interpolation methods and coastal vegetation cover data. In recent decades (1970–2016), the highly urbanized Martin Peña East (MPE) site with low flushing had the highest C storage and burial rates among sites. The MPE soil carbon burial rate was over twice as great as global estimates. Mangrove forest C burial rates in recent decades were significantly greater than historic decades (1930–1970) at Caño Martin Peña and Piñones. Although MPE and Piñones had similarly low flushing, the landscape settings (clogged canal vs forest reserve) and urbanization (high vs low) were different. Apparently, not only urbanization, but site-specific flushing patterns, landscape setting, and soil fertility affected soil C storage and burial rates. There was no difference in C burial rates between historic and recent decades at the San José and La Torrecilla lagoons. Mangrove forests had soil C burial rates ranging from 88 g m–2 y–1 at the San José lagoon to 469 g m–2 y–1 at the MPE in recent decades. Watershed anthropogenic CO2 emissions (1.56 million Mg C y–1) far exceeded the annual mangrove forest C storage rates (aboveground biomass plus soils: 17,713 Mg C y–1). A combination of maintaining healthy mangrove forests and reducing anthropogenic emissions might be necessary to mitigate greenhouse gas emissions in urban, tropical areas.
HBOS-CNV: A New Approach to Detect Copy Number Variations From Next-Generation Sequencing Data
Authors: Guo Yang , Wang Shuzhen , Yuan Xiguo
Published: June 2021

Copy number variation (CNV) is a genomic mutation that plays an important role in tumor evolution and tumor genesis. Accurate detection of CNVs from next-generation sequencing (NGS) data is still a challenging task due to artifacts such as uneven mapped reads and unbalanced amplitudes of gains and losses. This study proposes a new approach called HBOS-CNV to detect CNVs from NGS data. The central point of HBOS-CNV is that it uses a new statistic, the histogram-based outlier score (HBOS), to evaluate the fluctuation of genome bins to determine those of changed copy numbers. In comparison with existing statistics in the evaluation of CNVs, HBOS is a non-linearly transformed value from the observed read depth (RD) value of each genome bin, having the potential ability to relieve the effects resulted from the above artifacts. In the calculation of HBOS values, a dynamic width histogram is utilized to depict the density of bins on the genome being analyzed, which can reduce the effects of noises partially contributed by mapping and sequencing errors. The evaluation of genome bins using such a new statistic can lead to less extremely significant CNVs having a high probability of detection. We evaluated this method using a large number of simulation datasets and compared it with four existing methods (CNVnator, CNV-IFTV, CNV-LOF, and iCopyDav). The results demonstrated that our proposed method outperforms the others in terms of sensitivity, precision, and F1-measure. Furthermore, we applied the proposed method to a set of real sequencing samples from the 1000 Genomes Project and determined a number of CNVs with biological meanings. Thus, the proposed method can be regarded as a routine approach in the field of genome mutation analysis for cancer samples.
Expression and Diagnostic Value of miR-497 and miR-1246 in Hepatocellular Carcinoma
Authors: Chen Shuying , Fu Zile , Wen Shuzhan , Yang Xiaoyi , Yu Chengxuan , Zhou Wenhan , Lin Yong , Lv Yuan
Published: June 2021

Objective

Serum microRNAs (miRNAs) may serve as biomarkers in various cancers. Our study aims to explore the roles of miR-497 and miR-1246 in hepatocellular carcinoma (HCC).

Methods

The expression levels of miR-497 and miR-1246 were measured by RT-PCR. A correlation analysis was conducted between the expression levels of miR-497 and miR-1246 and clinicopathological characteristics of patients. The receiver operating characteristic (ROC) curve was applied to evaluate the diagnostic efficacy in HCC. In addition, bioinformatics tools were also utilized to predict the potential targets of miR-497 and miR-1246.

Results

The expression level of miR-497 in HCC was significantly down-regulated compared with the control group while the miR-1246 revealed a significantly higher expression level in HCC. There was a significant correlation demonstrated between the expression levels of miR-497 and miR-1246 in preoperative serum of HCC and the differentiation degree, Tumor Node Metastasis (TNM) classification, and metastasis. The expression levels of serum miR-497 and miR-1246 were significantly associated with the diagnosis, prognosis, and overall survival rate of patients with HCC. Moreover, the potential target genes of miR-497 in HCC include ARL2, UBE2Q1, PHF19, APLN, CHEK1, CASK, SUCO, CCNE1, and KIF23. The low expression of these nine genes is associated with a better prognosis of HCC patients. AUTS2 is a novel target gene of miR-1246, and its low expression is significantly related to the low overall survival rate of HCC patients.

Conclusions

miR-497 and miR-1246 are possibly involved in the progression of HCC by regulating target genes, respectively, and could serve as biomarkers in HCC.
Phenotypic Characterization of Postharvest Fruit Qualities in Astringent and Non-astringent Persimmon (Diospyros kaki) Cultivars
Authors: Yadav Akhilesh , Fennec Anton , Guan Changfei , Yang Yong , Kochanek Bettina , Israel David , Izhaki Anat , Zilkah Shmuel , Friedman Haya
Published: June 2021

Phenotypic characterization of postharvest traits is essential for the breeding of high-quality fruits. To compare postharvest traits of different genetic lines, it is essential to use a reference point during fruit development that will be common to all the lines. In this study, we employed a non-destructive parameter of chlorophyll levels to establish a similar physiological age and compared several postharvest traits of ten astringent and seven non-astringent persimmon cultivars. The fruit’s traits examined were astringency, weight, total soluble solids (TSS), titratable acidity (TA), chlorophyll levels (IAD), color (hue), firmness, color development and firmness loss during storage, crack development, and susceptibility to Alternaria infection. Although the chlorophyll (IAD) index and color (hue) showed a high correlation among mature fruits of all cultivars, the chlorophyll parameter could detect higher variability in each cultivar, suggesting that IAD is a more rigorous parameter for detecting the developmental stage. The average weight, TSS, and TA were similar between astringent and non-astringent cultivars. Cracks appeared only on a few cultivars at harvest. Resistance to Alternaria infection and firmness were lower in astringent than in non-astringent cultivars. Only the astringent cultivar “32” was resistant to infection possibly due to the existence of an efficient peel barrier. It was concluded that a high correlation existed between astringency, susceptibility to Alternaria infection, and firmness. Cracks did not correlate with astringency or firmness. The phenotypic traits evaluated in this work can be used in future breeding programs for elite persimmon fruits.
Identification of a Genome Instability-Associated LncRNA Signature for Prognosis Prediction in Colon Cancer
Authors: Yin Tengfei , Zhao Dongyan , Yao Shukun
Published: June 2021

Long non-coding RNAs (lncRNAs) were reported to have the potential in maintaining genome instability, but the identification of lncRNAs related to genome instability and their prognostic value have not been largely explored in colon cancer. In this study, we obtained 155 genome instability-associated lncRNAs based on somatic mutation profiles in colon cancer from The Cancer Genome Atlas (TCGA) database. Functional enrichment analysis revealed the possible roles of genes co-expressed with those lncRNAs involved in some cancer, genome instability and immune related biological processes. Combined with overall survival data, a seven-lncRNA signature was established for prognosis prediction. According to the risk score calculated by this signature, high-risk patients characterized by high somatic mutation count, high microsatellite instability, significantly poorer clinical outcomes and specific tumor immune infiltration status compared with low-risk patients. The lncRNA signature was validated to be an independent prognostic indicator with good predictive performance in TCGA cohort. Furthermore, the prognostic value of the ZNF503-AS1 in lncRNA signature was confirmed in another independent dataset from Gene Expression Omnibus database. In summary, the genome instability-associated lncRNA signature in this study could be a promising tool for effectively predicting survival outcomes in colon cancer.
Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study
Authors: Li Mengyu , Yeung Chris Ho Ching , Schooling C. Mary
Published: June 2021

Background

Immune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19.

Methods

We assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls).

Results

Macrophage inflammatory protein-1β (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96–0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89–0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction.

Conclusion

A crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.
The Role of B and T Lymphocyte Attenuator in Respiratory System Diseases
Authors: Deng Zheng , Zheng Yi , Cai Pei , Zheng Zheng
Published: June 2021

B and T lymphocyte attenuator (BTLA), an immunomodulatory molecule widely expressed on the surface of immune cells, can influence various signaling pathways and negatively regulate the activation and proliferation of immune cells by binding to its ligand herpes virus entry mediator (HVEM). BTLA plays an important role in immunoregulation and is involved in the pathogenesis of various respiratory diseases, including airway inflammation, asthma, infection, pneumonia, acute respiratory distress syndrome and lung cancer. In recent years, some studies have found that BTLA also has played a positive regulatory effect on immunity system in the occurrence and development of respiratory diseases. Since severe pulmonary infection is a risk factor for sepsis, this review also summarized the new findings on the role of BTLA in sepsis.
New Insights on End-Stage Renal Disease and Healthy Individual Gut Bacterial Translocation: Different Carbon Composition of Lipopolysaccharides and Different Impact on Monocyte Inflammatory Response
Authors: Adda-Rezig Hanane , Carron Clémence , Pais de Barros Jean-Paul , Choubley Hélène , Charron Émilie , Rérole Anne-Laure , Laheurte Caroline , Louvat Pascale , Gaiffe Émilie , Simula-Faivre Dominique , Deckert Valérie , Lagrost Laurent , Saas Philippe , Ducloux Didier , Bamoulid Jamal
Published: June 2021

Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.
Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor
Authors: Shibuya Takumi , Kamiyama Asami , Sawada Hirotaka , Kikuchi Kenta , Maruyama Mayu , Sawado Rie , Ikeda Naoki , Asano Kenichi , Kurotaki Daisuke , Tamura Tomohiko , Yoneda Atsuko , Imada Keisuke , Satoh Takashi , Akira Shizuo , Tanaka Masato , Yotsumoto Satoshi
Published: June 2021

Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1+Ly6Chi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1+Ly6Chi monocytes into naïve mice promoted lung metastasis in the mice. Ym1+Ly6Chi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1+Ly6Chi-monocyte-promoted lung metastasis. These findings indicate that Ym1+Ly6Chi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor.
Syncytiotrophoblast Extracellular Vesicles From Late-Onset Preeclampsia Placentae Suppress Pro-Inflammatory Immune Response in THP-1 Macrophages
Authors: Awoyemi Toluwalase , Motta-Mejia Carolina , Zhang Wei , Kouser Lubna , White Kirsten , Kandzija Neva , Alhamlan Fatimah S. , Cribbs Adam P. , Tannetta Dionne , Mazey Emily , Redman Christopher , Kishore Uday , Vatish Manu
Published: June 2021

Syncytiotrophoblast derived Extracellular Vesicles (STBEV) from normal pregnancy (NP) have previously been shown to interact with circulating monocytes and B cells and induce pro-inflammatory cytokine release. Early-onset preeclampsia (EOPE) is associated with an exacerbated inflammatory response, yet there is little data regarding late-onset PE (LOPE) and immune function. Here, using a macrophage/monocyte cell line THP-1, we investigated the inflammatory potential of STBEV, comprising medium/large-STBEV (>200nm) and small-STBEV (<200nm), isolated from LOPE (n=6) and normal (NP) (n=6) placentae via dual-lobe ex-vivo placental perfusion and differential centrifugation. THP-1 cells bound and internalised STBEV isolated from NP and LOPE placentae, as revealed by flow cytometry, confocal microscopy, and ELISA. STBEV-treated THP-1 cells were examined for cytokine gene expression by RT-qPCR and the cell culture media examined for secreted cytokines/chemokines. As expected, NP medium/large-STBEV significantly upregulated the transcriptional expression of TNF-α, IL-10, IL-6, IL-12, IL-8 and TGF-β compared to PE medium/large-STBEV. However, there was no significant difference in the small STBEV population between the two groups, although in general, NP small STBEVs slightly upregulated the same cytokines. In contrast, LOPE STBEV (medium and large) did not induce pro-inflammatory responses by differentiated THP-1 macrophages. This decreased effect of LOPE STBEV was echoed in cytokine/chemokine release. Our results appear to suggest that STBEV from LOPE placentae do not have a major immune-modulatory effect on macrophages. In contrast, NP STBEV caused THP-1 cells to release pro-inflammatory cytokines. Thus, syncytiotrophoblast extracellular vesicles from LOPE dampen immune functions of THP-1 macrophages, suggesting an alternative mechanism leading to the pro-inflammatory environment observed in LOPE.
Evaluation and Differential Diagnosis of a Genetic Marked Brucella Vaccine A19ΔvirB12 for Cattle
Authors: Yang Jianghua , He Chuanyu , Zhang Huan , Liu Mengzhi , Zhao Hailong , Ren Lisong , Wu Dongling , Du Fangyuan , Liu Baoshan , Han Xiaohu , He Sun , Chen Zeliang
Published: June 2021

Brucella abortus is an important zoonotic pathogen that causes severe economic loss to husbandry and poses a threat to human health. The B. abortus A19 live vaccine has been extensively used to prevent bovine brucellosis in China. However, it is difficult to distinguish the serological response induced by A19 from that induced by natural infection. In this study, a novel genetically marked vaccine, A19ΔvirB12, was generated and evaluated. The results indicated that A19ΔvirB12 was able to provide effective protection against B. abortus 2308 (S2308) challenge in mice. Furthermore, the safety and protective efficacy of A19ΔvirB12 have been confirmed in natural host cattle. Additionally, the VirB12 protein allowed for serological differentiation between the S2308 challenge/natural infection and A19ΔvirB12 vaccination. However, previous studies have found that the accuracy of the serological detection based on VirB12 needs to be improved. Therefore, we attempted to identify potential supplementary antigens with differential diagnostic functions by combining label-free quantitative proteomics and protein chip technology. Twenty-six proteins identified only in S2308 were screened; among them, five proteins were considered as potential supplementary antigens. Thus, the accuracy of the differential diagnosis between A19ΔvirB12 immunization and field infection may be improved through multi-antigen detection. In addition, we explored the possible attenuation factors of Brucella vaccine strain. Nine virulence factors were downregulated in A19ΔvirB12. The downregulation pathways of A19ΔvirB12 were significantly enriched in quorum sensing, ATP-binding cassette transporter, and metabolism. Several proteins related to cell division were significantly downregulated, while some proteins involved in transcription were upregulated in S2308. In conclusion, our results contribute to the control and eradication of brucellosis and provide insights into the mechanisms underlying the attenuation of A19ΔvirB12.
B Cell Metabolism and Autophagy in Autoimmunity
Authors: Raza Iwan G. A. , Clarke Alexander J.
Published: June 2021

B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.
Metformin, Macrophage Dysfunction and Atherosclerosis
Authors: Feng Xiaojun , Chen Wenxu , Ni Xiayun , Little Peter J. , Xu Suowen , Tang Liqin , Weng Jianping
Published: June 2021

Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging.
Reversing Post-Infectious Epigenetic-Mediated Immune Suppression
Authors: Abhimanyu  , Ontiveros Carlos O. , Guerra-Resendez Rosa S. , Nishiguchi Tomoki , Ladki Malik , Hilton Isaac B. , Schlesinger Larry S. , DiNardo Andrew R.
Published: June 2021

The immune response must balance the pro-inflammatory, cell-mediated cytotoxicity with the anti-inflammatory and wound repair response. Epigenetic mechanisms mediate this balance and limit host immunity from inducing exuberant collateral damage to host tissue after severe and chronic infections. However, following treatment for these infections, including sepsis, pneumonia, hepatitis B, hepatitis C, HIV, tuberculosis (TB) or schistosomiasis, detrimental epigenetic scars persist, and result in long-lasting immune suppression. This is hypothesized to be one of the contributing mechanisms explaining why survivors of infection have increased all-cause mortality and increased rates of unrelated secondary infections. The mechanisms that induce epigenetic-mediated immune suppression have been demonstrated in-vitro and in animal models. Modulation of the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR), nuclear factor of activated T cells (NFAT) or nuclear receptor (NR4A) pathways is able to block or reverse the development of detrimental epigenetic scars. Similarly, drugs that directly modify epigenetic enzymes, such as those that inhibit histone deacetylases (HDAC) inhibitors, DNA hypomethylating agents or modifiers of the Nucleosome Remodeling and DNA methylation (NuRD) complex or Polycomb Repressive Complex (PRC) have demonstrated capacity to restore host immunity in the setting of cancer-, LCMV- or murine sepsis-induced epigenetic-mediated immune suppression. A third clinically feasible strategy for reversing detrimental epigenetic scars includes bioengineering approaches to either directly reverse the detrimental epigenetic marks or to modify the epigenetic enzymes or transcription factors that induce detrimental epigenetic scars. Each of these approaches, alone or in combination, have ablated or reversed detrimental epigenetic marks in in-vitro or in animal models; translational studies are now required to evaluate clinical applicability.
CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis
Authors: Bourne Joshua H. , Beristain-Covarrubias Nonantzin , Zuidscherwoude Malou , Campos Joana , Di Ying , Garlick Evelyn , Colicchia Martina , Terry Lauren V. , Thomas Steven G. , Brill Alexander , Bayry Jagadeesh , Watson Steve P. , Rayes Julie
Published: June 2021

Platelets play a key role in the development, progression and resolution of the inflammatory response during sterile inflammation and infection, although the mechanism is not well understood. Here we show that platelet CLEC-2 reduces tissue inflammation by regulating inflammatory macrophage activation and trafficking from the inflamed tissues. The immune regulatory function of CLEC-2 depends on the expression of its ligand, podoplanin, upregulated on inflammatory macrophages and is independent of platelet activation and secretion. Mechanistically, platelet CLEC-2 and also recombinant CLEC-2-Fc accelerates actin rearrangement and macrophage migration by increasing the expression of podoplanin and CD44, and their interaction with the ERM proteins. During ongoing inflammation, induced by lipopolysaccharide, treatment with rCLEC-2-Fc induces the rapid emigration of peritoneal inflammatory macrophages to mesenteric lymph nodes, thus reducing the accumulation of inflammatory macrophages in the inflamed peritoneum. This is associated with a significant decrease in pro-inflammatory cytokine, TNF-α and an increase in levels of immunosuppressive, IL-10 in the peritoneum. Increased podoplanin expression and actin remodelling favour macrophage migration towards CCL21, a soluble ligand for podoplanin and chemoattractant secreted by lymph node lymphatic endothelial cells. Macrophage efflux to draining lymph nodes induces T cell priming. In conclusion, we show that platelet CLEC-2 reduces the inflammatory phenotype of macrophages and their accumulation, leading to diminished tissue inflammation. These immunomodulatory functions of CLEC-2 are a novel strategy to reduce tissue inflammation and could be therapeutically exploited through rCLEC-2-Fc, to limit the progression to chronic inflammation.
The Identification and Prediction in Abundance Variation of Atlantic Cod via Long Short-Term Memory With Periodicity, Time–Frequency Co-movement, and Lead-Lag Effect Across Sea Surface Temperature, Sea Surface Salinity, Catches, and Prey Biomass From 1919 to 2016
Authors: Nian Rui , Yuan Qiang , He Hui , Geng Xue , Su Chi-Wei , He Bo , Lendasse Amaury
Published: June 2021

The population of Atlantic cod significantly contributes to the prosperity of fishery production in the world. In this paper, we quantitatively investigate the global abundance variation in Atlantic cod from 1919 to 2016, in favor of spatiotemporal interactions over manifold impact factors at local observation sites, and propose to explore the predictive mechanism with the help of its periodicity, time–frequency co-movement, and lead-lag effects, via long short-term memory (LSTM). We first integrate evidences yielded from wavelet coefficients, to suggest that the abundance variation potentially follows a 36-year major cycle and 24-year secondary cycle at the time scales of 55 years and 37 years. We further evaluate the responses of Atlantic cod abundance to the external impact factors, including sea surface temperature (SST), catches, prey biomass, and sea surface salinity (SSS), in aid of the wavelet coherence and phase difference, which allows us to identify the dominantly correlative factors and capture the leading roles along the time domain and then divide the responses around the recent 60 years into three stages: before 1985, 1985–1995, and after 1995. At the first stage, the reason for the decline in abundance could be mainly attributed to the rapid rise of fish catches. At the second stage, the impact of SST and SSS also provides significant indices, besides overfishing; meanwhile, the mortality of primary producers and forced migration of fish species indirectly cause the decline. At the third stage, warming SST and growing SSS directly led to the decrease of abundance. Finally, we establish one ensemble of LSTM-SAE architecture to comprehensively reflect the predictive patterns at each stage. It has been demonstrated from experimental results that the models behaved better when intentionally feeding with the dominantly correlative multivariate inputs, instead of either all factors or only the abundance. The proposed scheme provides opportunities to symmetrically identify the underlying predictive attributes of Atlantic cod abundance and potentially perform as the quantitative references in reasonably making fishing decision. With the rapid development in deep learning capabilities, it is hopeful to expect better predictions of the responses to global changes, not only for Atlantic cod but also for other fish species and the ecosystem as a whole.
Gas Bubble Evolution in Polycrystalline UMo Fuels Under Elastic-Plastic Deformation: A Phase-Field Model With Crystal-Plasticity
Authors: Hu Shenyang , Beeler Benjamin
Published: June 2021

In monolithic UMo fuels, the interaction between the Al cladding and large gas bubble volumetric swelling causes both elastic-plastic and creep deformation. In this work, a phase-field model of gas bubble evolution in polycrystalline UMo under elastic-plastic deformation was developed for studying the dynamic interaction between evolving gas bubble/voids and deformation. A crystal plasticity model, which assumes that the plastic strain rate is proportional to resolved shear stresses of dislocation slip systems on their slip planes, was used to describe plastic deformation in polycrystalline UMo. Xe diffusion and gas bubble evolution are driven by the minimization of chemical and deformation energies in the phase-field model, while evolving gas bubble structure was used to update the mechanical properties in the crystal plasticity model. With the developed model, we simulated the effect of gas bubble structures (different volume fractions and internal gas pressures) on stress-strain curves and the effect of local stresses on gas bubble evolution. The results show that 1) the effective Young’s modulus and yield stress decrease with the increase of gas bubble volume fraction; 2) the hardening coefficient increases with the increase of gas bubble volume fraction, especially for gas bubbles with higher internal pressure; and 3) the pressure dependence of Xe thermodynamic and kinetic properties in addition to the local stress state determine gas bubble growth or shrinkage. The simulated results can serve as a guide to improve material property models for macroscale fuel performance modeling.
HMGB1 Activates Myeloid Dendritic Cells by Up-Regulating mTOR Pathway in Systemic Lupus Erythematosus
Authors: Song Xinghui , Zhang Hui , Zhao Yun , Lin Yuanzhen , Tang Qiya , Zhou Xiu , Zhong Xiaoning
Published: June 2021

Research has shown that HMGB1 can activate dendritic cells (DCs), but its molecular mechanisms are not clear. In this study, we reported that the myeloid dendritic cells (mDCs) were activated in the peripheral blood of SLE patients, and the activation of mDCs was associated with the up-regulation of HMGB1 and mTOR. After stimulated by HMGB1, expression of mTOR and its substrates P70S6K and 4EBP1 in dendritic cells increased considerably (P< 0.01). The expression of HLA-DR, CD40, and CD86 on dendritic cells also significantly increased following these stimuli (P< 0.01). In addition, stimulation with HMGB1 enhanced cytokine (IL-1β, IL-6, and TNF-a) production in dendritic cells. In contrast, the HMGB1-mediated expression of HLA-DR, CD40, and CD86 on dendritic cells and production of IL-1β, IL-6, and TNF-α were reduced by rapamycin. Rapamycin can inhibit HMGB1-induced activation of mDCs and secretion of pro-inflammatory cytokines. These findings indicated that HMGB1activates mDCs by up-regulating the mTOR pathway in SLE.
The Association of Osteosarcopenia With Functional Disability in Community-Dwelling Mexican Adults 50 and Older
Authors: López-Teros Miriam T. , Rosas-Carrasco Oscar , Sánchez-García Sergio , Castro-Porras Lilia , Luna-López Armando , Agudelo-Botero Marcela
Published: June 2021

Background: Osteosarcopenia (OS) has recently been described as a predictor of negative outcomes in older adults. However, this alteration in body composition has not been widely studied. In Mexico and Latin America, no information is available on its frequency or associated factors.

Objective: To analyze the association between OS with FD in community-dwelling Mexican adults 50 and older.

Design: Cross-sectional secondary data analysis was performed using primary data from a prospective study Frailty, Dynapenia and Sarcopenia Study in Mexican Adults (FraDySMex).

Setting and Participants: Eight hundred and twenty-five people were included, 77.1% women, aged 70.3 ± 10.8 years old.

Methods: OS was defined as when the person was diagnosed with sarcopenia (SP) plus osteopenia/osteoporosis. The SP diagnosis was evaluated in accordance with the criteria of the European Working Group for the Definition and Diagnosis of Sarcopenia (EWGSOP), and the osteoporosis diagnosis using World Health Organization (WHO) criteria. Muscle mass and bone mass were evaluated using dual-energy X-ray absorptiometry (DXA). FD was evaluated using the basic activities of daily living (BADL) and the instrumental activities of daily living (IADL). Additional sociodemographic and health co-variables were also included, such as sex, age, education, cognitive status, depression, comorbidity, hospitalization, polypharmacy, urinary incontinence, and nutrition variables such as risk of malnutrition and obesity. Associations between OS with FD were evaluated using multiple logistic regression.

Results: The prevalence of OS was 8.9% and that of FD was 8.9%. OS was associated with FD [odds ratio (OR): 1.92; CI 95%: 1.11–3.33].

Conclusions and Implications: Comprehensive OS assessment could help clinicians identify risk factors early, and thus mitigate the impact on FD in older people.
Pleural Fluid GSDMD Is a Novel Biomarker for the Early Differential Diagnosis of Pleural Effusion
Authors: Li Pu , Shi Jing , Zhou Lijing , Wang Bo , Zhang Li Jun , Duan Liang , Hu Qin , Zhou Xiaolan , Yuan Yuan , Li Dandan , Chen Hong , Zhao Qing , Peng Xuemei , Chen Weixian
Published: June 2021

Objective

Gasdermin D (GSDMD), controlling pyroptosis in cells, has multiple physiological functions. The diagnostic role of GSDMD in pleural effusion (PE) remains unknown.

Methods

Sandwich ELISA kits that we developed were applied to measure the level of GSDMD for 335 patients with a definite cause of PE, including transudative PE, tuberculous pleural effusion (TPE), parapneumonic pleural effusion (PPE), and malignant pleural effusion (MPE). The diagnostic accuracy of Light’s criteria vs. the new marker GSDMD was performed. Clinical follow-up of 40 cases of PPE was conducted and divided into efficacy and non-efficacy groups according to the therapeutic outcome. Nucleated cells (NCs) in PE were isolated and further infected with bacteria to verify the cell source of GSDMD.

Results

The diagnostic accuracy of GSDMD for the diagnosis of PE were 96% (sensitivity) and 94% (specificity). The receiver operating characteristic (ROC) curve indicated that GSDMD can be an efficient biomarker for the differential diagnosis of transudative PE and other groups (all AUC > 0.973). Noteworthily, the highest AUC belonged to tuberculosis diagnosis of 0.990, and the cut-off value was 18.40 ng/mL. Moreover, the same cut-off value of PPE and MPE was 9.35 ng/mL. The combination of GSDMD, adenosine deaminase (ADA), and lactate dehydrogenase (LDH) will further improve the diagnostic efficiency especially between TPE and PPE (AUC = 0.968). The AUC of GSDMD change at day 4, which could predict the therapeutic effect at an early stage, was 0.945 (P < 0.0001). Interestingly, bacterial infection experiments further confirm that the pleural fluid GSDMD was expressed and secreted mainly by the NCs.

Conclusion

GSDMD and its combination are candidates as a potentially novel biomarker not only to separate PEs early and effectively, but also monitor disease progression.
Metagenomic Insights Into the Structure and Function of Intestinal Microbiota of the Hadal Amphipods
Authors: Chan Jiulin , Geng Daoqiang , Pan Binbin , Zhang Qiming , Xu Qianghua
Published: June 2021

Hadal trenches are the deepest known areas of the ocean. Amphipods are considered to be the dominant scavengers in the hadal food webs. The studies on the structure and function of the hadal intestinal microbiotas are largely lacking. Here, the intestinal microbiotas of three hadal amphipods, Hirondellea gigas, Scopelocheirus schellenbergi, and Alicella gigantea, from Mariana Trench, Marceau Trench, and New Britain Trench, respectively, were investigated. The taxonomic analysis identified 358 microbial genera commonly shared within the three amphipods. Different amphipod species possessed their own characteristic dominant microbial component, Psychromonas in H. gigas and Candidatus Hepatoplasma in A. gigantea and S. schellenbergi. Functional composition analysis showed that “Carbohydrate Metabolism,” “Lipid Metabolism,” “Cell Motility,” “Replication and Repair,” and “Membrane Transport” were among the most represented Gene Ontology (GO) Categories in the gut microbiotas. To test the possible functions of “Bacterial Chemotaxis” within the “Cell Motility” category, the methyl-accepting chemotaxis protein (MCP) gene involved in the “Bacterial Chemotaxis” pathway was obtained and used for swarming motility assays. Results showed that bacteria transformed with the gut bacterial MCP gene showed significantly faster growths compared with the control group, suggesting MCP promoted the bacterial swimming capability and nutrient utilization ability. This result suggested that hadal gut microbes could promote their survival in poor nutrient conditions by enhancing chemotaxis and motility. In addition, large quantities of probiotic genera were detected in the hadal amphipod gut microbiotas, which indicated that those probiotics would be possible contributors for promoting the host’s growth and development, which could facilitate adaptation of hadal amphipods to the extreme environment.