bluuebunny/crossref_metadata_2025 huggingface dataset:
Multigenomics Reveals the Causal Effect of Herpes Simplex Virus in Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study
Authors: Zhang Yuwei , Qu Jiaojiao , Luo Li , Xu Zhongshun , Zou Xiao
Published: January 2022

In recent years, the herpes virus infectious hypothesis for Alzheimer’s disease (AD) has gained support from an increasing number of researchers. Herpes simplex virus (HSV) is a potential risk factor associated with AD. This study assessed whether HSV has a causal relationship with AD using a two-sample Mendelian randomization analysis model. Six single-nucleotide polymorphisms (SNPs) associated with HSV-1 and thirteen SNPs associated with HSV-2 were used as instrumental variables in the MR analysis. We estimated MR values of relevance between exposure and the risk of AD using inverse-variance weighted (IVW) method, MR-Egger regression (Egger), and weighted median estimator (WME). To make the conclusion more robust and reliable, sensitivity analyses and RadialMR were performed to evaluate the pleiotropy and heterogeneity. We found that anti-HSV-1 IgG measurements were not associated with risk of AD (OR, 0.96; 95% CI, 0.79–1.18; p = 0.736), and the same was true for HSV-2 (OR, 1.03; 95% CI, 0.94–1.12; p = 0.533). The findings indicated that any HSV infection does not appear to be a genetically valid target of intervention in AD.
Sensitive Quantification of Cell-Free Tumor DNA for Early Detection of Recurrence in Colorectal Cancer
Authors: Stasik Sebastian , Mende Marika , Schuster Caroline , Mahler Sandra , Aust Daniela , Tannapfel Andrea , Reinacher-Schick Anke , Baretton Gustavo , Krippendorf Claudia , Bornhäuser Martin , Ehninger Gerhard , Folprecht Gunnar , Thiede Christian
Published: January 2022

The detection of plasma cell–free tumor DNA (ctDNA) is prognostic in colorectal cancer (CRC) and has potential for early prediction of disease recurrence. In clinical routine, ctDNA-based diagnostics are limited by the low concentration of ctDNA and error rates of standard next-generation sequencing (NGS) approaches. We evaluated the potential to increase the stability and yield of plasma cell–free DNA (cfDNA) for routine diagnostic purposes using different blood collection tubes and various manual or automated cfDNA extraction protocols. Sensitivity for low-level ctDNA was measured in KRAS-mutant cfDNA using an error-reduced NGS procedure. To test the applicability of rapid evaluation of ctDNA persistence in clinical routine, we prospectively analyzed postoperative samples of 67 CRC (stage II) patients. ctDNA detection was linear between 0.0045 and 45%, with high sensitivity (94%) and specificity (100%) for mutations at 0.1% VAF. The stability and yield of cfDNA were superior when using Streck BCT tubes and a protocol by Zymo Research. Sensitivity for ctDNA increased 1.5-fold by the integration of variant reads from triplicate PCRs and with PCR template concentration. In clinical samples, ctDNA persistence was found in ∼9% of samples, drawn 2 weeks after surgery. Moreover, in a retrospective analysis of 14 CRC patients with relapse during adjuvant therapy, we successfully detected ctDNA (median 0.38% VAF; range 0.18–5.04% VAF) in 92.85% of patients significantly prior (median 112 days) to imaging-based surveillance. Using optimized pre-analytical conditions, the detection of postoperative ctDNA is feasible with excellent sensitivity and allows the prediction of CRC recurrence in routine oncology testing.
Evolution of a New Testis-Specific Functional Promoter Within the Highly Conserved Map2k7 Gene of the Mouse
Authors: Heinen Tobias , Xie Chen , Keshavarz Maryam , Stappert Dominik , Künzel Sven , Tautz Diethard
Published: January 2022

Map2k7 (synonym Mkk7) is a conserved regulatory kinase gene and a central component of the JNK signaling cascade with key functions during cellular differentiation. It shows complex transcription patterns, and different transcript isoforms are known in the mouse (Mus musculus). We have previously identified a newly evolved testis-specific transcript for the Map2k7 gene in the subspecies M. m. domesticus. Here, we identify the new promoter that drives this transcript and find that it codes for an open reading frame (ORF) of 50 amino acids. The new promoter was gained in the stem lineage of closely related mouse species but was secondarily lost in the subspecies M. m. musculus and M. m. castaneus. A single mutation can be correlated with its transcriptional activity in M. m. domesticus, and cell culture assays demonstrate the capability of this mutation to drive expression. A mouse knockout line in which the promoter region of the new transcript is deleted reveals a functional contribution of the newly evolved promoter to sperm motility and the spermatid transcriptome. Our data show that a new functional transcript (and possibly protein) can evolve within an otherwise highly conserved gene, supporting the notion of regulatory changes contributing to the emergence of evolutionary novelties.
CD1dhiPD-L1hiCD27+ Regulatory Natural Killer Subset Suppresses Atopic Dermatitis
Authors: Min Keun Young , Koo Jimo , Noh Geunwoong , Lee Dajeong , Jo Min Geun , Lee Ji Eon , Kang Minseong , Hyun Seung Yeun , Choi Wahn Soo , Kim Hyuk Soon
Published: January 2022

Effector and regulatory functions of various leukocytes in allergic diseases have been well reported. Although the role of conventional natural killer (NK) cells has been established, information on its regulatory phenotype and function are very limited. Therefore, the objective of this study was to investigate the phenotype and inhibitory functions of transforming growth factor (TGF)-β-producing regulatory NK (NKreg) subset in mice with MC903-induced atopic dermatitis (AD). Interestingly, the population of TGF-β-producing NK cells in peripheral blood monocytes (PBMCs) was decreased in AD patients than in healthy subjects. The number of TGF-β+NK subsets was decreased in the spleen or cervical lymph node (cLN), but increased in ear tissues of mice with AD induced by MC903 than those of normal mice. We further observed that TGF-β+NK subsets were largely included in CD1dhiPD-L1hiCD27+NK cell subset. We also found that numbers of ILC2s and TH2 cells were significantly decreased by adoptive transfer of CD1dhiPD-L1hiCD27+NK subsets. Notably, the ratio of splenic Treg per TH2 was increased by the adoptive transfer of CD1dhiPD-L1hiCD27+NK cells in mice. Taken together, our findings demonstrate that the TGF-β-producing CD1dhiPD-L1hiCD27+NK subset has a previously unrecognized role in suppressing TH2 immunity and ILC2 activation in AD mice, suggesting that the function of TGF-β-producing NK subset is closely associated with the severity of AD in humans.
EOGT Correlated With Immune Infiltration: A Candidate Prognostic Biomarker for Hepatocellular Carcinoma
Authors: Shu Yang , He Lingling , Gao Meixin , Xiao Fan , Yang Junru , Wang Shiwei , Wei Herui , Zhang Fuyang , Wei Hongshan
Published: January 2022

Background

A preliminary study by our group revealed that the deficiency of EGF domain-specific O-linked N-acetylglucosamine transferase (EOGT) impaired regulatory T-cell differentiation in autoimmune hepatitis. Nevertheless, the prognostic value of EOGT in advanced hepatocellular carcinoma (HCC) and its relationship with immune infiltration remain obscured.

Methods

Initially, EOGT expression was evaluated by Oncomine, TIMER, GEO, and UALCAN databases. Besides, the prognostic potential of EOGT expression was analyzed using GEPIA, Kaplan–Meier plotter, CPTAC, Cox regression, and nomogram in HCC samples. Furthermore, we investigated the association between EOGT expression and tumor mutation burden, DNA methylation, and immune infiltration in addition to its possible mechanism via cBioPortal, TIMER, GEPIA, ESTIMATE, CIBERSORT, GSEA, STRING, and Cytoscape.

Results

The expression of EOGT in HCC was significantly higher than that in normal tissues. Additionally, elevated EOGT expression was correlated with advanced tumor staging and linked to poor overall survival and relapse-free survival, serving as a significant unfavorable prognostic indicator in HCC patients. Remarkably, our results revealed that high-EOGT expression subgroups with elevated TP53 or low CTNNB1 mutations have worse clinical outcomes than the others. Regarding immune infiltration, immunofluorescent staining showed that immune cells in HCC were positive for EOGT. Besides, elevated EOGT expression was linked to exhausted T cells and immune suppressor cells in HCC samples. More importantly, the proportion of CD8+ T cells was reduced in HCC samples with a high level of EOGT expression, but EOGT did not exhibit prognostic potential in HCC samples with increased CD8+ T cells.

Conclusions

EOGT may hold great potential as a novel biomarker to distinguish prognosis and immune profiles of HCC patients.
Cardiovascular Risk After SARS-CoV-2 Infection Is Mediated by IL18/IL18R1/HIF-1 Signaling Pathway Axis
Authors: Zhang Liwei , Li Mingxing , Wang Zhiwei , Sun Peng , Wei Shunbo , Zhang Cong , Wu Haoliang , Bai Hualong
Published: January 2022

Objectives

Currently, cardiovascular risk associated with COVID-19 has been brought to people’s attention, but the mechanism is not clear. The aim of this study is to elucidate the mechanisms based on multiple omics data.

Methodology

Weighted gene co-expression network analysis (WGCNA) was used to identify key pathways. Combination analysis with aneurysm and atherosclerosis related pathways, hypoxia induced factor-1 (HIF-1) signaling were identified as key pathways of the increased cardiovascular risk associated with COVID-19. ScMLnet algorithm based on scRNA-seq was used to explore the regulation of HIF-1 pathway by intercellular communication. Proteomic analysis was used to detect the regulatory mechanisms between IL18 and HIF-1 signaling pathway. Pseudo time locus analysis was used to study the regulation of HIF1 signaling pathway in macrophages and vascular smooth muscle cells (VSMC) phenotypic transformation. The Virtual Inference of protein-activity by Enriched Regulon (VIPER) analysis was used to study the activity of regulatory proteins. Epigenetic analysis based on methylation revealed epigenetic changes in PBMC after SARS-CoV-2 infection. Potential therapeutic compounds were explored by using Cmap algorithm.

Results

HIF-1 signaling pathway is a common key pathway for aneurysms, atherosclerosis and SARS-CoV-2 infection. Intercellular communication analysis showed that macrophage-derived interleukin-18 (IL-18) activates the HIF-1 signaling pathway through IL18R1. Proteomic analysis showed that IL18/IL18R1 promote NF-κB entry into the nucleus, and activated the HIF-1 signaling pathway. Macrophage-derived IL18 promoted the M1 polarization of macrophages and the syntactic phenotype transformation of VSMCs. MAP2K1 mediates the functional regulation of HIF-1 signaling pathway in various cell types. Epigenetic changes in PBMC after COVID-19 infection are characterized by activation of the type I interferon pathway. MEK inhibitors are the promising compounds for the treatment of HIF-1 overactivation.

Conclusions

The IL18/IL18R1/HIF1A axis is expected to be an therapeutic target for cardiovascular protection after SARS-CoV-2 infection. MEK inhibitors may be an choice for cardiovascular protection after SARS-COV-2 infection
N-Formyl Methionine Peptide-Mediated Neutrophil Activation in Systemic Sclerosis
Authors: Kuley Runa , Stultz Ryan D. , Duvvuri Bhargavi , Wang Ting , Fritzler Marvin J. , Hesselstrand Roger , Nelson J Lee , Lood Christian
Published: January 2022

Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are reported in systemic sclerosis (SSc) but its involvement in SSc pathogenesis is not clear. In the present study we assessed markers of neutrophil activation and NET formation in SSc patients in relation to markers of inflammation and disease phenotype. Factors promoting neutrophil activation in SSc remain largely unknown. Among the neutrophil activating factors, mitochondrial-derived N-formyl methionine (fMet) has been reported in several autoinflammatory conditions. The aim of the current study is to assess whether SSc patients have elevated levels of fMet and the role of fMet in neutrophil-mediated inflammation on SSc pathogenesis. Markers of neutrophil activation (calprotectin, NETs) and levels of fMet were analyzed in plasma from two SSc cohorts (n=80 and n=20, respectively) using ELISA. Neutrophil activation assays were performed in presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporin H. Elevated levels of calprotectin and NETs were observed in SSc patients as compared to healthy controls (p<0.0001) associating with SSc clinical disease characteristics. Further, SSc patients had elevated levels of circulating fMet as compared to healthy controls (p<0.0001). Consistent with a role for fMet-mediated neutrophil activation, fMet levels correlated with levels of calprotectin and NETs (r=0.34, p=0.002; r=0.29, p<0.01 respectively). Additionally, plasma samples from SSc patients with high levels of fMet induced de novo neutrophil activation through FPR1-dependent mechanisms. Our data for the first time implicates an important role for the mitochondrial component fMet in promoting neutrophil-mediated inflammation in SSc.
PP2A and Its Inhibitors in Helper T-Cell Differentiation and Autoimmunity
Authors: Khan Mohd Moin , Kalim Ubaid Ullah , Khan Meraj H. , Lahesmaa Riitta
Published: January 2022

Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric Ser/Thr phosphatase that regulates many cellular processes. The role of PP2A as a tumor suppressor has been extensively studied and reviewed. However, emerging evidence suggests PP2A constrains inflammatory responses and is important in autoimmune and neuroinflammatory diseases. Here, we reviewed the existing literature on the role of PP2A in T-cell differentiation and autoimmunity. We have also discussed the modulation of PP2A activity by endogenous inhibitors and its small-molecule activators as potential therapeutic approaches against autoimmunity.
Whole-Tissue Deconvolution and scRNAseq Analysis Identify Altered Endometrial Cellular Compositions and Functionality Associated With Endometriosis
Authors: Bunis Daniel G. , Wang Wanxin , Vallvé-Juanico Júlia , Houshdaran Sahar , Sen Sushmita , Ben Soltane Isam , Kosti Idit , Vo Kim Chi , Irwin Juan C. , Giudice Linda C. , Sirota Marina
Published: January 2022

The uterine lining (endometrium) exhibits a pro-inflammatory phenotype in women with endometriosis, resulting in pain, infertility, and poor pregnancy outcomes. The full complement of cell types contributing to this phenotype has yet to be identified, as most studies have focused on bulk tissue or select cell populations. Herein, through integrating whole-tissue deconvolution and single-cell RNAseq, we comprehensively characterized immune and nonimmune cell types in the endometrium of women with or without disease and their dynamic changes across the menstrual cycle. We designed metrics to evaluate specificity of deconvolution signatures that resulted in single-cell identification of 13 novel signatures for immune cell subtypes in healthy endometrium. Guided by statistical metrics, we identified contributions of endometrial epithelial, endothelial, plasmacytoid dendritic cells, classical dendritic cells, monocytes, macrophages, and granulocytes to the endometrial pro-inflammatory phenotype, underscoring roles for nonimmune as well as immune cells to the dysfunctionality of this tissue.
Cleavage-Mediated Regulation of Myd88 Signaling by Inflammasome-Activated Caspase-1
Authors: Avbelj Monika , Hafner-Bratkovič Iva , Lainšček Duško , Manček-Keber Mateja , Peternelj Tina Tinkara , Panter Gabriela , Treon Steven P. , Gole Boris , Potočnik Uroš , Jerala Roman
Published: January 2022

Coordination among multiple signaling pathways ensures an appropriate immune response, where a signaling pathway may impair or augment another signaling pathway. Here, we report a negative feedback regulation of signaling through the key innate immune mediator MyD88 by inflammasome-activated caspase-1. NLRP3 inflammasome activation impaired agonist- or infection-induced TLR signaling and cytokine production through the proteolytic cleavage of MyD88 by caspase-1. Site-specific mutagenesis was used to identify caspase-1 cleavage site within MyD88 intermediary segment. Different cleavage site location within MyD88 defined the functional consequences of MyD88 cleavage between mouse and human cells. LPS/monosodium urate–induced mouse inflammation model corroborated the physiological role of this mechanism of regulation, that could be reversed by chemical inhibition of NLRP3. While Toll/interleukin-1 receptor (TIR) domain released by MyD88 cleavage additionally contributed to the inhibition of signaling, Waldenström’s macroglobulinemia associated MyD88L265P mutation is able to evade the caspase-1-mediated inhibition of MyD88 signaling through the ability of its TIRL265P domain to recruit full length MyD88 and facilitate signaling. The characterization of this mechanism reveals an additional layer of innate immunity regulation.
Parasite-Probiotic Interactions in the Gut: Bacillus sp. and Enterococcus faecium Regulate Type-2 Inflammatory Responses and Modify the Gut Microbiota of Pigs During Helminth Infection
Authors: Myhill Laura J. , Stolzenbach Sophie , Mejer Helena , Krych Lukasz , Jakobsen Simon R. , Kot Witold , Skovgaard Kerstin , Canibe Nuria , Nejsum Peter , Nielsen Dennis S. , Thamsborg Stig M. , Williams Andrew R.
Published: January 2022

Dietary probiotics may enhance gut health by directly competing with pathogenic agents and through immunostimulatory effects. These properties are recognized in the context of bacterial and viral pathogens, but less is known about interactions with eukaryotic pathogens such as parasitic worms (helminths). In this study we investigated whether two probiotic mixtures (comprised of Bacillus amyloliquefaciens, B. subtilis, and Enterococcus faecium [BBE], or Lactobacillus rhamnosus LGG and Bifidobacterium animalis subspecies Lactis Bb12 [LB]) could modulate helminth infection kinetics as well as the gut microbiome and intestinal immune responses in pigs infected with the nodular worm Oesophagostomum dentatum. We observed that neither probiotic mixture influenced helminth infection levels. BBE, and to a lesser extent LB, changed the alpha- and beta-diversity indices of the colon and fecal microbiota, notably including an enrichment of fecal Bifidobacterium spp. by BBE. However, these effects were muted by concurrent O. dentatum infection. BBE (but not LB) significantly attenuated the O. dentatum-induced upregulation of genes involved in type-2 inflammation and restored normal lymphocyte ratios in the ileo-caecal lymph nodes that were altered by infection. Moreover, inflammatory cytokine release from blood mononuclear cells and intestinal lymphocytes was diminished by BBE. Collectively, our data suggest that selected probiotic mixtures can play a role in maintaining immune homeostasis during type 2-biased inflammation. In addition, potentially beneficial changes in the microbiome induced by dietary probiotics may be counteracted by helminths, highlighting the complex inter-relationships that potentially exist between probiotic bacteria and intestinal parasites.
NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease
Authors: Aukrust Sverre Grøver , Holte Kristine Bech , Opstad Trine B. , Seljeflot Ingebjørg , Berg Tore Julsrud , Helseth Ragnhild
Published: January 2022

Background

Neutrophil extracellular traps NETs have been linked to glucose and the pathogenesis of type 1 diabetes mellitus (T1DM). NETs also play a role in vascular inflammation and the development of coronary artery disease (CAD). The role of NETs in CAD progression in patients with long-term T1DM is unclear. We aimed to 1) investigate whether levels of circulating NETs markers were elevated in long-term T1DM subjects compared to controls, and 2) explore whether levels of NETs were related to the presence of CAD.

Material and Methods

102 patients with > 45 years of T1DM and 75 age-matched controls were enrolled in a cross-sectional study. Median age was 62 years. Computed tomography coronary angiography (CTCA) was performed in 148 subjects without established coronary heart disease. For the current study, CAD was defined as a coronary artery stenosis >50%. Double-stranded deoxyribonucleic acid (dsDNA) was measured by a nucleic acid stain, myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (H3Cit) and peptidylarginine deiminase 4 (PAD4) by ELISAs, while gene expression of PAD4 was measured in leukocytes from PAXgene tubes.

Results

Circulating MPO-DNA levels were significantly lower in patients with T1DM than in controls (0.17 vs 0.29 OD, p<0.001), while dsDNA, H3Cit, PAD4 and gene expression of PAD4 did not differ with respect to the presence of T1DM. There were no significant associations between NETs markers and HbA1c in the T1DM group. None of the NETs markers differed according to the presence of CAD in patients with T1DM. While all circulating NETs markers correlated significantly with circulating neutrophils in the control group (r=0.292-393, p<0.014), only H3Cit and PAD4 correlated with neutrophils in the T1DM group (r= 0.330-0.449, p ≤ 0.001).

Conclusions

In this cross-sectional study of patients with long-term T1DM and age-matched controls, circulating NETs levels were not consistently associated with the presence of T1DM or glycemic status, and did not differ according to the presence of CAD in patients with T1DM. Our results entail the possibility of altered neutrophil function and reduced NETosis in T1DM. This warrants further investigation.
Pregnancy-Related Attack in Neuromyelitis Optica Spectrum Disorder With AQP4-IgG: A Single-Center Study and Meta-Analysis
Authors: Deng Shuwen , Lei Qiang , Lu Wei
Published: January 2022

Objective

This study aimed to investigate the demographic characteristic of pregnancy-related attacks (PRAs) in neuromyelitis optica spectrum disorder (NMOSD). In addition, we investigated the predictors of PRAs as well as the effect of immunosuppressive (IS) therapy in patients with pregnancy-related NMOSD.

Method

We retrospectively analyzed data on clinical and diagnostic characteristics, therapeutic management, and pregnancy outcomes for PRAs in AQP4-IgG-positive NMOSD patients admitted to the Second Xiangya Hospital of Central South University. Moreover, we searched the literature (without any temporal restriction) to identify all such similar cohorts and performed a meta-analysis to evaluate the effectiveness and safety of IS therapy on NMOSD patients with PRAs.

Result

We collected clinical data on 117 women with AQP4 antibody-positive NMOSD; we ultimately included 33 patients (34 pregnancies). Ten patients were relapse-free during pregnancy, and 23 (69.7%) had PRA; attacks were most common during the first trimester of the postpartum period. Maintenance of IS treatment during pregnancy was found to greatly reduce PRAs in patients with NMOSD. PRAs were associated with a higher neutrophil-to-lymphocyte ratio (NLR) at relapse during pregnancy and shorter time interval between the last relapse and conception. The meta-analysis suggested that maintenance of IS treatment during pregnancy can significantly reduce the RR of NMOSD (95%CI=0.35-0.62; z=5.18, p<0.0001) and had no adverse effect on the miscarriage rate. However, the unhealthy newborn occurrence among those receiving IS treatment was 3.73 times higher than that of those not receiving treatment during pregnancy (95%CI=1.40–9.91; z=2.64, p=0.008).

Conclusion

Our study results demonstrates that pregnancy can induce the onset or relapse of attacks in NMOSD patients. The increased NLR value and disease activity may be a predictor for PRAs in patients with NMOSD. Moreover, administration of IS treatment during pregnancy can reduce the relapse rate. However, the dosage of drugs and risks of adverse effects to the fetus need to be considered. Future prospective studies with larger sample sizes are needed to confirm and extend our findings.
Duality of Interactions Between TGF-β and TNF-α During Tumor Formation
Authors: Liu Zhi-wei , Zhang Yi-ming , Zhang Li-ying , Zhou Ting , Li Yang-yang , Zhou Gu-cheng , Miao Zhi-ming , Shang Ming , He Jin-peng , Ding Nan- , Liu Yong-qi
Published: January 2022

The tumor microenvironment is essential for the formation and development of tumors. Cytokines in the microenvironment may affect the growth, metastasis and prognosis of tumors, and play different roles in different stages of tumors, of which transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α) are critical. The two have synergistic and antagonistic effect on tumor regulation. The inhibition of TGF-β can promote the formation rate of tumor, while TGF-β can promote the malignancy of tumor. TNF-α was initially determined to be a natural immune serum mediator that can induce tumor hemorrhagic necrosis, it has a wide range of biological activities and can be used clinically as a target to immune diseases as well as tumors. However, there are few reports on the interaction between the two in the tumor microenvironment. This paper combs the biological effect of the two in different aspects of different tumors. We summarized the changes and clinical medication rules of the two in different tissue cells, hoping to provide a new idea for the clinical application of the two cytokines.
PU.1 Regulates Cathepsin S Expression in Large Yellow Croaker (Larimichthys crocea) Macrophages
Authors: Zhang Xiang-Yang , Zhuo Xinyue , Cheng Jie , Wang Xiaohong , Liang Kexin , Chen Xinhua
Published: January 2022

Different morphologies have been detected in teleost macrophages. In this study, two macrophage cell lines were sub-cloned from a large yellow croaker head kidney cell line, LYCK. One type of sub-cloned cells was fusiform but the other was round, named LYC-FM and LYC-RM cells respectively, based on their morphologies. Both types showed the characteristics of macrophages, including expression of macrophage-specific marker genes, possession of phagocytic and bactericidal activities, and production of reactive oxygen species (ROS) and nitric oxide (NO). The transcription factor PU.1, crucial for the development of macrophages in mammals, was found to exist in two transcripts, PU.1a and PU.1b, in large yellow croaker, and constitutively expressed in LYC-FM and LYC-RM cells. The expression levels of PU.1a and PU.1b could be upregulated by recombinant large yellow croaker IFN-γ protein (rLcIFN-γ). Further studies showed that both PU.1a and PU.1b increased the expression of cathepsin S (CTSS) by binding to different E26−transformation−specific (Ets) motifs of the CTSS promoter. Additionally, we demonstrated that all three domains of PU.1a and PU.1b were essential for initiating CTSS expression by truncated mutation experiments. Our results therefore provide the first evidence that teleost PU.1 has a role in regulating the expression of CTSS.
Quantitative Test and Engineering Application of Wear Resistance of a Kind of Mine-Filled Composite Pipeline
Authors: Wang Yong , Yang Gang-feng , Ma Cheng-liang , Jia Quan-li , Jin Qin-guo
Published: January 2022

Wear resistance is one of the most important performance indicators of filling pipelines, but there are few studies on its quantitative test and life prediction. In this paper, an experimental device and its application method for testing the wear resistance of the pipeline are proposed, and the device is used to test the wear resistance of the self-developed lining composite pipeline, the traditional 16 Mn steel pipeline and the ordinary carbon structural steel pipeline. The results show that the wear resistance of the composite lining material is 12.35 times of that of 16 Mn steel and 7.32 times of that of ordinary carbon structural steel. The wear resistance mechanism is analyzed from the perspective of the material composition of the composite liner, mainly because the composite liner material uses fused alumina grain sand, silicon carbide and other extremely wear-resistant materials with high hardness as aggregate, and the aggregates are spherical or nearly spherical particles, with smooth surface and small friction resistance. Finally, through a comparison engineering application of a certain iron ore concentrate transportation. Compared with the traditional 16 Mn steel pipeline, the composite lined pipeline has been used for more than 5 years without any problems, while the traditional 16 Mn steel pipeline is worn through within 1 year. Engineering application shows that the composite lined pipeline has good wear resistance, and it also confirms the reliability of the detection method proposed in this paper.
Serum Uric Acid Might Be Positively Associated With Hypertension in Chinese Adults: An Analysis of the China Health and Nutrition Survey
Authors: Han Yingdong , Han Kaidi , Han Xinxin , Yin Yue , Di Hong , Wu Juan , Zhang Yun , Zeng Xuejun
Published: January 2022

Background: Previous studies have clarified the relationship between serum uric acid (SUA) and hypertension; most of previous studies suggest that elevated uric acid levels are associated with an increased risk of hypertension, while in China, there are relatively few studies to explore above association. The objective of this longitudinal study is to investigate the correlation of SUA and hypertension in Chinese adults with a nationwide large-scale sample.

Methods: Data from the China Health and Nutrition Survey 2009, 2011, and 2016 were used; a total of 8,469 participants (3,973 men and 4,496 women) were involved. This study was conducted separately by gender. Clinical characteristics of the participants among different uric acid groups are compared. The binary logistic regression analysis was conducted to examine the association between SUA and hypertension. Restricted cubic spline analysis with three knots of the SUA concentration were used to characterize the dose-response relationship. Additionally, we compared the incidence of hypertension in the different baseline uric acid groups during follow-up in 2011 and 2015.

Results: After the covariates were fully adjusted, we found that elevated uric acid levels were correlated with increased risk of hypertension in both males (p < 0.01) and females (p < 0.01). With 2-year or 6-year of follow-up, we found participants with higher baseline uric acid levels had a higher incidence of hypertension (p < 0.01). In stratified analysis by obesity, above relationship remained significant in nonobesity population (males: p < 0.05, females: p < 0.01) and became nonsignificant in obesity people. In stratified analysis by age, above positively correlation remained significant in middle-aged men (p < 0.05) and elderly women (p < 0.01). Restricted cubic spline revealed the dose-response relationship between SUA and hypertension; we also found that above relationship was much stronger in females.

Conclusion: This study suggests that elevated SUA levels might be positively associated with an increased risk of hypertension in general Chinese adults.
Robo2 and Gen1 Coregulate Ureteric Budding by Activating the MAPK/ERK Signaling Pathway in Mice
Authors: Li Yaxin , Yu Minghui , Tan Lihong , Xue Shanshan , Du Xuanjin , Wu Xiaohui , Xu Hong , Shen Qian
Published: January 2022

Congenital anomalies of the kidney and urinary tract (CAKUT) are some of the most common developmental defects and have a complicated etiology, indicating an interaction of (epi-) genetic and environmental factors. Single gene mutations and copy number variations (CNVs) do not explain most cases of CAKUT, and simultaneous contributions of more than one gene (di-, oligo-, or polygenic effects; i.e., complex genetics) may lead to the pathogenesis of CAKUT. Robo2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations leading to supernumerary kidneys. Gen1 is a candidate gene associated with CAKUT because of its important role in early metanephric development in mice. We established a mouse model with double disruption of Robo2 and Gen1 using a piggyBac transposon and found that double gene mutation led to significantly increased CAKUT phenotypes in Robo2PB/+Gen1PB/+ mouse offspring, especially a duplicated collecting system. Increased ectopic UB formation was observed in the Robo2PB/+Gen1PB/+ mice during the embryonic period. Robo2 and Gen1 exert synergistic effects on mouse kidney development, promoting cell proliferation by activating the GDNF/RET pathway and downstream MAPK/ERK signaling. Our findings provide a disease model for CAKUT as an oligogenic disorder.
An Endophytic Strain of Bacillus amyloliquefaciens Suppresses Fusarium oxysporum Infection of Chinese Wolfberry by Altering Its Rhizosphere Bacterial Community
Authors: Uwaremwe Constantine , Yue Liang , Wang Yun , Tian Yuan , Zhao Xia , Liu Yang , Zhou Qin , Zhang Yubao , Wang Ruoyu
Published: January 2022

Root rot disease is a serious infection leading to production loss of Chinese wolfberry (Lycium barbarum). This study tested the potential for two bacterial biological control agents, Bacillus amyloliquefaciens HSB1 and FZB42, against five fungal pathogens that frequently cause root rot in Chinese wolfberry. Both HSB1 and FZB42 were found to inhibit fungal mycelial growth, in vitro and in planta, as well as to promote the growth of wolfberry seedlings. In fact, a biocontrol experiment showed efficiency of 100% with at least one treatment involving each biocontrol strain against Fusarium oxysporum. Metagenomic sequencing was used to assess bacterial community shifts in the wolfberry rhizosphere upon introduction of each biocontrol strain. Results showed that HSB1 and FZB42 differentially altered the abundances of different taxa present and positively influenced various functions of inherent wolfberry rhizosphere bacteria. This study highlights the application of biocontrol method in the suppression of fungal pathogens that cause root rot disease in wolfberry, which is useful for agricultural extension agents and commercial growers.
RNA Granules in Antiviral Innate Immunity: A Kaposi’s Sarcoma-Associated Herpesvirus Journey
Authors: Sharma Nishi R. , Zheng Zhi-Ming
Published: January 2022

RNA granules are cytoplasmic, non-membranous ribonucleoprotein compartments that form ubiquitously and are often referred to as foci for post-transcriptional gene regulation. Recent research on RNA processing bodies (PB) and stress granules (SG) has shown wide implications of these cytoplasmic RNA granules and their components in suppression of RNA translation as host intracellular innate immunity against infecting viruses. Many RNA viruses either counteract or co-opt these RNA granules; however, many fundamental questions about DNA viruses with respect to their interaction with these two RNA granules remain elusive. Kaposi’s sarcoma-associated herpesvirus (KSHV), a tumor-causing DNA virus, exhibits two distinct phases of infection and encodes ∼90 viral gene products during the lytic phase of infection compared to only a few (∼5) during the latent phase. Thus, productive KSHV infection relies heavily on the host cell translational machinery, which often links to the formation of PB and SG. One major question is how KSHV counteracts the hostile environment of RNA granules for its productive infection. Recent studies demonstrated that KSHV copes with the translational suppression by cellular RNA granules, PB and SG, by expressing ORF57, a viral RNA-binding protein, during KSHV lytic infection. ORF57 interacts with Ago2 and GW182, two major components of PB, and prevents the scaffolding activity of GW182 at the initial stage of PB formation in the infected cells. ORF57 also interacts with protein kinase R (PKR) and PKR-activating protein (PACT) to block PKR dimerization and kinase activation, and thus inhibits eIF2α phosphorylation and SG formation. The homologous immediate-early regulatory protein ICP27 of herpes simplex virus type 1 (HSV-1), but not the EB2 protein of Epstein-Barr virus (EBV), shares this conserved inhibitory function with KSHV ORF57 on PB and SG. Through KSHV ORF57 studies, we have learned much about how a DNA virus in the infected cells is equipped to evade host antiviral immunity for its replication and productive infection. KSHV ORF57 would be an excellent viral target for development of anti-KSHV-specific therapy.
The Bacteroidetes Aequorivita sp. and Kaistella jeonii Produce Promiscuous Esterases With PET-Hydrolyzing Activity
Authors: Zhang Hongli , Perez-Garcia Pablo , Dierkes Robert F. , Applegate Violetta , Schumacher Julia , Chibani Cynthia Maria , Sternagel Stefanie , Preuss Lena , Weigert Sebastian , Schmeisser Christel , Danso Dominik , Pleiss Juergen , Almeida Alexandre , Höcker Birte , Hallam Steven J. , Schmitz Ruth A. , Smits Sander H. J. , Chow Jennifer , Streit Wolfgang R.
Published: January 2022

Certain members of the Actinobacteria and Proteobacteria are known to degrade polyethylene terephthalate (PET). Here, we describe the first functional PET-active enzymes from the Bacteroidetes phylum. Using a PETase-specific Hidden-Markov-Model- (HMM-) based search algorithm, we identified several PETase candidates from Flavobacteriaceae and Porphyromonadaceae. Among them, two promiscuous and cold-active esterases derived from Aequorivita sp. (PET27) and Kaistella jeonii (PET30) showed depolymerizing activity on polycaprolactone (PCL), amorphous PET foil and on the polyester polyurethane Impranil® DLN. PET27 is a 37.8 kDa enzyme that released an average of 174.4 nmol terephthalic acid (TPA) after 120 h at 30°C from a 7 mg PET foil platelet in a 200 μl reaction volume, 38-times more than PET30 (37.4 kDa) released under the same conditions. The crystal structure of PET30 without its C-terminal Por-domain (PET30ΔPorC) was solved at 2.1 Å and displays high structural similarity to the IsPETase. PET30 shows a Phe-Met-Tyr substrate binding motif, which seems to be a unique feature, as IsPETase, LCC and PET2 all contain Tyr-Met-Trp binding residues, while PET27 possesses a Phe-Met-Trp motif that is identical to Cut190. Microscopic analyses showed that K. jeonii cells are indeed able to bind on and colonize PET surfaces after a few days of incubation. Homologs of PET27 and PET30 were detected in metagenomes, predominantly aquatic habitats, encompassing a wide range of different global climate zones and suggesting a hitherto unknown influence of this bacterial phylum on man-made polymer degradation.
Cytoadherence Properties of Plasmodium knowlesi-Infected Erythrocytes
Authors: Lee Wenn-Chyau , Shahari Shahhaziq , Nguee Samantha Yee Teng , Lau Yee-Ling , Rénia Laurent
Published: January 2022

Plasmodium knowlesi is responsible for zoonotic malaria infections that are potentially fatal. While the severe pathology of falciparum malaria is associated with cytoadherence phenomena by Plasmodium falciparum-infected erythrocytes (IRBC), information regarding cytoadherence properties of P. knowlesi-IRBC remained scarce. Here, we characterized the cytoadherence properties of RBC infected with the laboratory-adapted P. knowlesi A1-H.1 strain. We found that late-stage IRBC formed rosettes in a human serum-dependent manner, and rosettes hampered IRBC phagocytosis. IRBC did not adhere much to unexposed (unstimulated) human endothelial cell lines derived from the brain (hCMEC/D3), lungs (HPMEC), and kidneys (HRGEC). However, after being “primed” with P. knowlesi culture supernatant, the IRBC-endothelial cytoadherence rate increased in HPMEC and HRGEC, but not in hCMEC/D3 cells. Both endothelial cytoadherence and rosetting phenomena were abrogated by treatment of P. knowlesi-IRBC with trypsin. We also found that different receptors were involved in IRBC cytoadherence to different types of endothelial cells. Although some of the host receptors were shared by both P. falciparum- and P. knowlesi-IRBC, the availability of glycoconjugates on the receptors might influence the capacity of P. knowlesi-IRBC to cytoadhere to these receptors.
Relationships Between Oral Microecosystem and Respiratory Diseases
Authors: Dong Jiajia , Li Wei , Wang Qi , Chen Jiahao , Zu Yue , Zhou Xuedong , Guo Qiang
Published: January 2022

Oral microecosystem is a very complicated ecosystem that is located in the mouth and comprises oral microbiome, diverse anatomic structures of oral cavity, saliva and interactions between oral microbiota and between oral microbiota and the host. More and more evidence from studies of epidemiology, microbiology and molecular biology is establishing a significant link between oral microecosystem and respiratory diseases. Microbiota settling down in oral microecosystem is known as the main source of lung microbiome and has been associated with the occurrence and development of respiratory diseases like pneumonia, chronic obstructive pulmonary disease, lung cancer, cystic fibrosis lung disease and asthma. In fact, it is not only indigenous oral microbes promote or directly cause respiratory infection and inflammation when inhaled into the lower respiratory tract, but also internal environment of oral microecosystem serves as a reservoir for opportunistic respiratory pathogens. Moreover, poor oral health and oral diseases caused by oral microecological dysbiosis (especially periodontal disease) are related with risk of multiple respiratory diseases. Here, we review the research status on the respiratory diseases related with oral microecosystem. Potential mechanisms on how respiratory pathogens colonize oral microecosystem and the role of indigenous oral microbes in pathogenesis of respiratory diseases are also summarized and analyzed. Given the importance of oral plaque control and oral health interventions in controlling or preventing respiratory infection and diseases, we also summarize the oral health management measures and attentions, not only for populations susceptible to respiratory infection like the elderly and hospitalized patients, but also for dentist or oral hygienists who undertake oral health care. In conclusion, the relationship between respiratory diseases and oral microecosystem has been established and supported by growing body of literature. However, etiological evidence on the role of oral microecosystem in the development of respiratory diseases is still insufficient. Further detailed studies focusing on specific mechanisms on how oral microecosystem participate in the pathogenesis of respiratory diseases could be helpful to prevent and treat respiratory diseases.
QSalignWeb: A Server to Predict and Analyze Protein Quaternary Structure
Authors: Dey Sucharita , Prilusky Jaime , Levy Emmanuel D.
Published: January 2022

The identification of physiologically relevant quaternary structures (QSs) in crystal lattices is challenging. To predict the physiological relevance of a particular QS, QSalign searches for homologous structures in which subunits interact in the same geometry. This approach proved accurate but was limited to structures already present in the Protein Data Bank (PDB). Here, we introduce a webserver (www.QSalign.org) allowing users to submit homo-oligomeric structures of their choice to the QSalign pipeline. Given a user-uploaded structure, the sequence is extracted and used to search homologs based on sequence similarity and PFAM domain architecture. If structural conservation is detected between a homolog and the user-uploaded QS, physiological relevance is inferred. The web server also generates alternative QSs with PISA and processes them the same way as the query submitted to widen the predictions. The result page also shows representative QSs in the protein family of the query, which is informative if no QS conservation was detected or if the protein appears monomeric. These representative QSs can also serve as a starting point for homology modeling.
The Impact of Oxidative Stress in Male Infertility
Authors: Mannucci Amanda , Argento Flavia Rita , Fini Eleonora , Coccia Maria Elisabetta , Taddei Niccolò , Becatti Matteo , Fiorillo Claudia
Published: January 2022

At present infertility is affecting about 15% of couples and male factor is responsible for almost 50% of infertility cases. Oxidative stress, due to enhanced Reactive Oxygen Species (ROS) production and/or decreased antioxidants, has been repeatedly suggested as a new emerging causative factor of this condition. However, the central roles exerted by ROS in sperm physiology cannot be neglected. On these bases, the present review is focused on illustrating both the role of ROS in male infertility and their main sources of production. Oxidative stress assessment, the clinical use of redox biomarkers and the treatment of oxidative stress-related male infertility are also discussed.
Everyday Functioning in a Community-Based Volunteer Population: Differences Between Participant- and Study Partner-Report
Authors: Verrijp Merike , Dubbelman Mark A. , Visser Leonie N. C. , Jutten Roos J. , Nijhuis Elke W. , Zwan Marissa D. , van Hout Hein P. J. , Scheltens Philip , van der Flier Wiesje M. , Sikkes Sietske A. M.
Published: January 2022

Introduction: Impaired awareness in dementia caused by Alzheimer’s disease and related disorders made study partner-report the preferred method of measuring interference in “instrumental activities of daily living” (IADL). However, with a shifting focus toward earlier disease stages and prevention, the question arises whether self-report might be equally or even more appropriate. The aim of this study was to investigate how participant- and study partner-report IADL perform in a community-based volunteer population without dementia and which factors relate to differences between participant- and study partner-report.

Methods: Participants (N = 3,288; 18–97 years, 70.4% females) and their study partners (N = 1,213; 18–88 years, 45.8% females) were recruited from the Dutch Brain Research Registry. IADL were measured using the Amsterdam IADL Questionnaire. The concordance between participant- and study partner-reported IADL difficulties was examined using intraclass correlation coefficient (ICC). Multinomial logistic regressions were used to investigate which demographic, cognitive, and psychosocial factors related to participant and study partner differences, by looking at the over- and underreport of IADL difficulties by the participant, relative to their study partner.

Results: Most A-IADL-Q scores represented no difficulties for both participants (87.9%) and study partners (89.4%). The concordance between participants and study partners was moderate (ICC = 0.55, 95% confidence interval [CI] = [0.51, 0.59]); 24.5% (N = 297) of participants overreported their IADL difficulties compared with study partners, and 17.8% (N = 216) underreported difficulties. The presence of depressive symptoms (odds ratio [OR] = 1.31, 95% CI = [1.12, 1.54]), as well as memory complaints (OR = 2.45, 95% CI = [1.80, 3.34]), increased the odds of participants overreporting their IADL difficulties. Higher IADL ratings decreased the odds of participant underreport (OR = 0.71, 95% CI = [0.67, 0.74]).

Conclusion: In this sample of community-based volunteers, most participants and study partners reported no major IADL difficulties. Differences between participant and study partner were, however, quite prevalent, with subjective factors indicative of increased report of IADL difficulties by the participant in particular. These findings suggest that self- and study partner-report measures may not be interchangeable, and that the level of awareness needs to be considered, even in cognitively healthy individuals.