bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Impact of Left Ventricular Ejection Fraction in Patients With Moderate Aortic Regurgitation: Potential Implications for Treatment Decision-Making
Authors: Zhao Qinghao , Zhang Bin , Ye Yunqing , Li Zhe , Liu Qingrong , Zhao Rui , Zhao Zhenyan , Wang Weiwei , Yu Zikai , Zhang Haitong , Duan Zhenya , Wang Bincheng , Lv Junxing , Guo Shuai , Zhao Yanyan , Gao Runlin , Xu Haiyan , Wu Yongjian
Published: January 2022

Background:

The prognostic impact and optimal treatment of left ventricular systolic dysfunction in patients with moderate aortic regurgitation (AR) remain unknown. We aimed to assess the prognostic value of left ventricular ejection fraction (LVEF) in patients with moderate AR and explore the potential benefits of aortic valve intervention (AVI).

Methods:

In total, 1,211 consecutive patients with moderate AR (jet width, 25–64% of LV outflow tract; vena contracta, 0.3–0.6 cm; regurgitant volume, 30–59 mL/beat; regurgitant fraction, 30–49%; effective regurgitation orifice, 0.10–0.29 cm2) prospectively registered between April and June 2018 at 46 academic hospitals were included. The primary outcome was a composite of death or hospitalization for heart failure (HHF). The optimal LVEF threshold for predicting the primary outcome was determined through the penalized spline shape and maximally selected rank statistics.

Results:

During the 2-year follow-up, 125 deaths or HHF occurred. In the penalized splines, the relative hazard of death or HHF monotonically increased with decreasing LVEF. In the multivariate analysis, LVEF ≤55% was identified as the best threshold for independently predicting death or HHF under medical treatment (adjusted hazard ratio [HR]: 2.18; 95% confidence interval [CI] 1.38–3.42; P = 0.001), with substantial incremental values (integrated discrimination improvement index = 0.018, P = 0.030; net reclassification improvement index = 0.225, P = 0.006; likelihood ratio test P < 0.001). Among patients with LVEF 35–55%, AVI within 6 months of diagnosis was associated with a reduced risk of death or HHF compared with medical treatment alone (adjusted HR: 0.15; 95% CI: 0.04–0.50; P = 0.002), whereas this benefit was markedly attenuated when LVEF was ≤35% (adjusted HR: 0.65; 95% CI: 0.21–1.97; P = 0.441, P-interaction = 0.010) or >55% (adjusted HR: 0.40; 95% CI: 0.14–1.15; P = 0.089, P-interaction = 0.723).

Conclusions:

LVEF is an independent and incremental prognostic factor in patients with moderate AR, with LVEF ≤55% being a robust marker of poor prognosis. Patients with LVEF 35–55% may benefit from early surgical correction of moderate AR. Further studies are warranted to validate our findings in a randomized setting.

Registration:

China Valvular Heart Disease Study (China-VHD study, NCT03484806); clinicaltrials.gov/ct2/show/NCT03484806.
Equilibration Times of Dissolved Inorganic Carbon During pH Transitions
Authors: Sade Ziv , Hegyi Shahar , Halevy Itay
Published: January 2022

Equilibration times of dissolved inorganic carbon (DIC) depend on conversion reactions between CO2(aq) and the dissociation products of carbonic acid [S = (H2CO3) + (HCO3−) + (CO32−)]. Here, we develop analytical equations and a numerical model to calculate chemical equilibration times of DIC during pH transitions in buffered and unbuffered solutions. We approximate the equilibration degree of the DIC reservoir by the smaller of the CO2(aq) and S pools at the new pH, since the smaller pool is always farther from equilibrium during the chemical evolution. Both the amount of DIC converted and the rate of conversion differ between a pH increase and decrease, leading to distinct equilibration times for these general cases. Alkalinity perturbations in unbuffered solutions initially drive pH overshoots (increase or decrease) relative to the new equilibrium pH. The increased rates of DIC conversion associated with the pH overshoot yield shorter equilibration times compared to buffered solutions. Salinity has opposing effects on buffered and unbuffered solutions, decreasing and increasing equilibration times, respectively.
The Association Between Parents’ Growth Mindset and Children’s Persistence and Academic Skills
Authors: Song Yuchen , Barger Michael M , Bub Kristen L.
Published: January 2022

Parents’ educational beliefs are thought to guide children’s early development in school. The present study explored the association between parent’s growth mindset and elementary school-aged children’s self-reported persistence, as well as teacher-reported reading and math skills in 102 dyads. Findings showed that children self-reported greater persistence when their parents held more growth mindset. Teachers also rated students as more capable readers when their parents endorsed a growth, rather than fixed, mindset. Additional analysis indicated that although the effect of parents’ growth mindset on children’s reading skills became non-significant once SES was controlled, the positive association between parents’ mindset and children’s persistence was unaffected by SES. Our study provides evidence about the intergenerational association of motivational tendencies at an early age, even when children may not be able to develop a coherent system of motivational beliefs of their own.
Pilot-Scale Pelleting Tests on High-Moisture Pine, Switchgrass, and Their Blends: Impact on Pellet Physical Properties, Chemical Composition, and Heating Values
Authors: Tumuluru Jaya Shankar , Rajan Kalavathy , Hamilton Choo , Pope Conner , Rials Timothy G. , McCord Jessica , Labbé Nicole , André Nicolas O.
Published: January 2022

In this study, we evaluated the pelleting characteristics of southern yellow pine (SYP), switchgrass (SG), and their blends for thermochemical conversion processes, such as pyrolysis and gasification. Using a pilot-scale ring-die pellet mill, we specifically assessed the impact of blend moisture, length-to-diameter (L/D) ratio in the pellet die, and ratio of pine to SG on the physico-chemical properties of the resulting pellets. We found that an increase in pine content by 25–50% marginally affected the bulk density; however, it also led to an increase in calorific value by 7% and a decrease in ash content by 72%. A moisture content of 25% (wet basis) and an L/D ratio of 5 resulted in poor pellet durability at <90% and bulk density values of <500 kg/m3, but increasing the L/D ratio to 9 and lowering the moisture content to 20% (w.b.) improved the pellet durability to >90% and the bulk density to >500 kg/m3. Blends with ≥50% pine content resulted in lower energy consumption, while a lower L/D ratio resulted in higher pelleting energy. Based on these findings, we successfully demonstrated the high-moisture pelleting of 2.5 ton of pine top residues blended with SG at 60:40 and 50:50 ratios. The quality of the pellets was monitored off-line and at-line by near infrared (NIR) spectroscopy. Multivariate models constructed by combining the NIR data and the pelleting process variables could successfully predict the pine content (R2 = 0.99), higher heating value (R2 = 0.98), ash (R2 = 0.95), durability (R2 = 0.94), and bulk density (R2 = 0.86) of the pellets. Thus, we established how blending and densification of SYP and SG biomass could improve feedstock specifications and that NIR spectroscopy can effectively monitor the pellet properties during the high-moisture pelleting process.
Research on Dynamic Response of Slopes With Weak Interlayers Under Mining Blasting Vibration
Authors: Zhang Xiaochao , Yang Qingwen , Pei Xiangjun , Du Ruifeng
Published: January 2022

As blasting technology starts to be used in a wide range of areas, blast loading has led to an increasing number of geological disasters such as slope deformation, collapses, and soil slippage. Slopes with weak interlayers are more likely to be deformed and damaged under the influence of blast loading. It is of great importance to study the evolution for the deformation of slopes with weak interlayers during blasting excavation. This study constructed a slope model with a weak interlayer to investigate the influence of different factors of blasting, including explosive charge, blast radius, blast origin, and multi-hole blasting, on the internal dynamic response. The deformation mechanism of slopes with weak interlayers under the influence of blast loading was analyzed. Test results show that each layer of the model had a different displacement response (uncoordinated dynamic response) to blasting with various factors. Explosive energy and the pattern of dynamic response of each layer varied depending on different settings of blasting factors such as explosive charge, blast radius, blast origin, and detonation initiation method. When the explosive energy produced under the influence of various factors was small, the change in the uncoordinated dynamic response between layers was significant, and the change gradually became less significant as the explosive energy increased. Therefore, this study has proposed the concept of critical explosive energy, and it is speculated that when the explosive energy produced with various factors is less than critical explosive energy, the dynamic response is mainly affected by the internal structure of the slope (property difference induced geologic layers). In other words, the uncoordinated motion of material’s particles in each layer is caused by different limitations and the degree of movement of the particles, which leads to the uncoordinated dynamic response and uncoordinated deformation of each layer. If the explosive energy is greater than the critical value, the dynamic response of each layer is mainly affected by the explosive energy. The differences in the internal structure of the slope are negligible, and the incoordination of dynamic responses between layers gradually weakens and tends to synchronize.
Cheating Promotes Coexistence in a Two-Species One-Substrate Culture Model
Authors: Xenophontos Constantinos , Harpole W. Stanley , Küsel Kirsten , Clark Adam Thomas
Published: January 2022

Cheating in microbial communities is often regarded as a precursor to a “tragedy of the commons,” ultimately leading to over-exploitation by a few species and destabilization of the community. While current evidence suggests that cheaters are evolutionarily and ecologically abundant, they can also play important roles in communities, such as promoting cooperative behaviors of other species. We developed a closed culture model with two microbial species and a single, complex nutrient substrate (the metaphorical “common”). One of the organisms, an enzyme producer, degrades the substrate, releasing an essential and limiting resource that it can use both to grow and produce more enzymes, but at a cost. The second organism, a cheater, does not produce the enzyme but can access the diffused resource produced by the other species, allowing it to benefit from the public good without contributing to it. We investigated evolutionarily stable states of coexistence between the two organisms and described how enzyme production rates and resource diffusion influence organism abundances. Our model shows that, in the long-term evolutionary scale, monocultures of the producer species drive themselves extinct because selection always favors mutant invaders that invest less in enzyme production, ultimately driving down the release of resources. However, the presence of a cheater buffers this process by reducing the fitness advantage of lower enzyme production, thereby preventing runaway selection in the producer, and promoting coexistence. Resource diffusion rate controls cheater growth, preventing it from outcompeting the producer. These results show that competition from cheaters can force producers to maintain adequate enzyme production to sustain both itself and the cheater. This is similar to what is known in evolutionary game theory as a “snowdrift game” – a metaphor describing a snow shoveler and a cheater following in their clean tracks. We move further to show that cheating can stabilize communities and possibly be a precursor to cooperation, rather than extinction.
Seven-CpG DNA Methylation Age Determined by Single Nucleotide Primer Extension and Illumina’s Infinium MethylationEPIC Array Provide Highly Comparable Results
Authors: Vetter Valentin Max , Kalies Christian Humberto , Sommerer Yasmine , Bertram Lars , Demuth Ilja
Published: January 2022

DNA methylation age (DNAm age, epigenetic clock) is a novel and promising biomarker of aging. It is calculated from the methylation fraction of specific cytosine phosphate guanine sites (CpG sites) of genomic DNA. Several groups have proposed epigenetic clock algorithms and these differ mostly regarding the number and location of the CpG sites considered and the method used to assess the methylation status. Most epigenetic clocks are based on a large number of CpGs, e.g. as measured by DNAm microarrays. We have recently evaluated an epigenetic clock based on the methylation fraction of seven CpGs that were determined by methylation-sensitive single nucleotide primer extension (MS-SNuPE). This method is more cost-effective when compared to array-based technologies as only a few CpGs need to be examined. However, there is only little data on the correspondence in epigenetic age estimation using the 7-CpG clock and other algorithms. To bridge this gap, in this study we measured the 7-CpG DNAm age using two methods, via MS-SNuPE and via the MethylationEPIC array, in a sample of 1,058 participants of the Berlin Aging Study II (BASE-II), assessed as part of the GendAge study. On average, participants were 75.6 years old (SD: 3.7, age range: 64.9–90.0, 52.6% female). Agreement between methods was assessed by Bland-Altman plots. DNAm age was highly correlated between methods (Pearson’s r = 0.9) and Bland-Altman plots showed a difference of 3.1 years. DNAm age by the 7-CpG formula was 71.2 years (SD: 6.9 years, SNuPE) and 68.1 years (SD: 6.4 years, EPIC array). The mean of difference in methylation fraction between methods for the seven individual CpG sites was between 0.7 and 13 percent. To allow direct conversion of DNAm age obtained from both methods we developed an adjustment formula with a randomly selected training set of 529 participants using linear regression. After conversion of the Illumina data in a second and independent validation set, the adjusted DNAm age was 71.44 years (SD: 6.1 years, n = 529). In summary, we found the results of DNAm clocks to be highly comparable. Furthermore, we developed an adjustment formula that allows for direct conversion of DNAm age estimates between methods and enables one singular clock to be used in studies that employ either the Illumina or the SNuPE method.
Prediction of Two Molecular Subtypes of Gastric Cancer Based on Immune Signature
Authors: Wu Dan , Feng Mengyao , Shen Hongru , Shen Xilin , Hu Jiani , Liu Jilei , Yang Yichen , Li Yang , Yang Meng , Wang Wei , Zhang Qiang , Song Fangfang , Liu Ben , Chen Kexin , Li Xiangchun
Published: January 2022

Gastric cancer is the fifth most common type of human cancer and the third leading cause of cancer-related death. The purpose of this study is to investigate the immune infiltration signatures of gastric cancer and their relation to prognosis. We identified two distinct subtypes of gastric cancer (C1/C2) characterized by different immune infiltration signatures. C1 is featured by immune resting, epithelial–mesenchymal transition, and angiogenesis pathways, while C2 is featured by enrichment of the MYC target, oxidative phosphorylation, and E2F target pathways. The C2 subtype has a better prognosis than the C1 subtype (HR = 0.61, 95% CI: 0.44–0.85; log-rank test, p = 0.0029). The association of C1/C2 with prognosis remained statistically significant (HR = 0.62, 95% CI: 0.44–0.87; p = 0.006) after controlling for age, gender, and stage. The prognosis prediction of C1/C2 was verified in four independent cohorts (including an internal cohort). In summary, our study is helpful for better understanding of the association between immune infiltration and the prognosis of gastric cancer.
A Family Segregating Lethal Primary Coenzyme Q10 Deficiency Due to Two Novel COQ6 Variants
Authors: Wang Na , Zheng Youmin , Zhang Lingzi , Tian Xiong , Fang Yicheng , Qi Ming , Du Juping , Chen Shuaishuai , Chen Shiyong , Li Jun , Shen Bo , Wang Lizhen
Published: January 2022

Primary coenzyme Q10 deficiency-6 (COQ10D6), as a rare autosomal recessive disease caused by COQ6 mutations, is characterized by progressive infantile-onset nephrotic syndrome resulting in end-stage renal failure and sensorineural hearing loss. Here, we report two Chinese siblings with COQ10D6 who primarily presented with severe metabolic acidosis, proteinuria, hypoalbuminemia, growth retardation, and muscle hypotonia and died in early infancy. Using whole-exome sequencing and Sanger sequencing, we identified two rare recessive nonsense mutations in the COQ6 gene segregating with disease in affected family members: c.249C > G (p.Tyr83Ter) and c.1381C > T (p.Gln461Ter), resulting in two truncated protein products. Both mutations are located in a highly conserved area and are predicted to be pathogenic. Indeed, the death of our patients in early infancy indicates the pathogenicity of the p.Tyr83Ter and p.Gln461Ter variants and highlights the significance of the two variants for COQ6 enzyme function, which is necessary for the biosynthesis of coenzyme Q10. In conclusion, we discovered a novel compound heterozygous pathogenic variant of the COQ6 gene as a cause of severe COQ10D6 in the two siblings. Based on the clinical history and genetic characteristics of the patients, our cases expand the genotypic spectrum of COQ10D6 and highlight the heterogeneity and severity of clinical features associated with COQ6 mutations. For patients with clinical manifestations suggestive of COQ10D6, early testing for COQ6 mutations is beneficial for disease diagnosis and therapeutic interventions as well as disease prevention in future generations.
Emerging Role of Exosomal Long Non-coding RNAs in Spaceflight-Associated Risks in Astronauts
Authors: Bisserier Malik , Saffran Nathaniel , Brojakowska Agnieszka , Sebastian Aimy , Evans Angela Clare , Coleman Matthew A. , Walsh Kenneth , Mills Paul J. , Garikipati Venkata Naga Srikanth , Arakelyan Arsen , Hadri Lahouaria , Goukassian David A.
Published: January 2022

During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts’ health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998–2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log2 fold change, with molecular, cellular, and clinical implications.
Genome-Wide Diversity of MADS-Box Genes in Bread Wheat is Associated with its Rapid Global Adaptability
Authors: Raza Qasim , Riaz Awais , Atif Rana Muhammad , Hussain Babar , Rana Iqrar Ahmad , Ali Zulfiqar , Budak Hikmet , Alaraidh Ibrahim A.
Published: January 2022

MADS-box gene family members play multifarious roles in regulating the growth and development of crop plants and hold enormous promise for bolstering grain yield potential under changing global environments. Bread wheat (Triticum aestivum L.) is a key stable food crop around the globe. Until now, the available information concerning MADS-box genes in the wheat genome has been insufficient. Here, a comprehensive genome-wide analysis identified 300 high confidence MADS-box genes from the publicly available reference genome of wheat. Comparative phylogenetic analyses with Arabidopsis and rice MADS-box genes classified the wheat genes into 16 distinct subfamilies. Gene duplications were mainly identified in subfamilies containing unbalanced homeologs, pointing towards a potential mechanism for gene family expansion. Moreover, a more rapid evolution was inferred for M-type genes, as compared with MIKC-type genes, indicating their significance in understanding the evolutionary history of the wheat genome. We speculate that subfamily-specific distal telomeric duplications in unbalanced homeologs facilitate the rapid adaptation of wheat to changing environments. Furthermore, our in-silico expression data strongly proposed MADS-box genes as active guardians of plants against pathogen insurgency and harsh environmental conditions. In conclusion, we provide an entire complement of MADS-box genes identified in the wheat genome that could accelerate functional genomics efforts and possibly facilitate bridging gaps between genotype-to-phenotype relationships through fine-tuning of agronomically important traits.
Neutrophil Extracellular Traps Caused by Gut Leakage Trigger the Autoimmune Response in Nonobese Diabetic Mice
Authors: You Qi , Shen Yiming , Wu Yiling , Li Yuyan , Liu Chang , Huang Fengjie , Gu Harvest F. , Wu Jie
Published: January 2022

Increased formation of neutrophil extracellular traps (NETs) is associated with gut leakage in type 1 diabetes (T1D). To explore the mechanism of how enteropathy exacerbated by NETs triggers pancreatic autoimmunity in T1D, we carried out a correlation analysis for NET formation with gut barrier functions and autoimmunity in nonobese diabetic (NOD) mice. Inducing chronic colitis or knocking out of peptidyl arginine deiminase type 4 (PAD4) in NOD mice were used to further study the effect of NET formation on the progression of T1D. Microbial alterations in Deferribacteres and Proteobacteria, along with the loss of gut barrier function, were found to be associated with increased endotoxin and abnormal formation of NETs in NOD mice. Both DSS-induced colitis and knockout of PAD4 in NOD mice indicated that PAD4-dependent NET formation was involved in the aggravation of gut barrier dysfunction, the production of autoantibodies, and the activation of enteric autoimmune T cells, which then migrated to pancreatic lymph nodes (PLNs) and caused self-damage. The current study thus provides evidence that PAD4-dependent NET formation is engaged in leaky gut triggering pancreatic autoimmunity and suggests that either degradation of NETs or inhibition of NET formation may be helpful for innovative therapeutic interventions in T1D.
Immunological Classification of Pancreatic Carcinomas to Identify Immune Index and Provide a Strategy for Patient Stratification
Authors: Chen Yi , Chen Didi , Wang Qiang , Xu Yajing , Huang Xiaowei , Haglund Felix , Su Huafang
Published: January 2022

Background

Cancer immunotherapy has produced significant positive clinical effects in a variety of tumor types. However, pancreatic ductal adenocarcinoma (PDAC) is widely considered to be a “cold” cancer with poor immunogenicity. Our aim is to determine the detailed immune features of PDAC to seek new treatment strategies.

Methods

The immune cell abundance of PDAC patients was evaluated with the single-sample gene set enrichment analysis (ssGSEA) using 119 immune gene signatures. Based on these data, patients were classified into different immune subtypes (ISs) according to immune gene signatures. We analyzed their response patterns to immunotherapy in the datasets, then established an immune index to reflect the different degrees of immune infiltration through linear discriminant analysis (LDA). Finally, potential prognostic markers associated with the immune index were identified based on weighted correlation network analysis (WGCNA) that was functionally validated in vitro.

Results

Three ISs were identified in PDAC, of which IS3 had the best prognosis across all three cohorts. The different expressions of immune profiles among the three ISs indicated a distinct responsiveness to immunotherapies in PDAC subtypes. By calculating the immune index, we found that the IS3 represented higher immune infiltration, while IS1 represented lower immune infiltration. Among the investigated signatures, we identified ZNF185, FANCG, and CSTF2 as risk factors associated with immune index that could potentially facilitate diagnosis and could be therapeutic target markers in PDAC patients.

Conclusions

Our findings identified immunologic subtypes of PDAC with distinct prognostic implications, which allowed us to establish an immune index to represent the immune infiltration in each subtype. These results show the importance of continuing investigation of immunotherapy and will allow clinical workers to personalized treatment more effectively in PDAC patients.
PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer
Authors: Hu Rui , Zhou Bingqian , Chen Zheyi , Chen Shiyu , Chen Ningdai , Shen Lisong , Xiao Haibo , Zheng Yingxia
Published: January 2022

Protein arginine transferase 5 (PRMT5) has been implicated as an important modulator of tumorigenesis as it promotes tumor cell proliferation, invasion, and metastasis. Studies have largely focused on PRMT5 regulating intrinsic changes in tumors; however, the effects of PRMT5 on the tumor microenvironment and particularly immune cells are largely unknown. Here we found that targeting PRMT5 by genetic or pharmacological inhibition reduced lung tumor progression in immunocompromised mice; however, the effects were weakened in immunocompetent mice. PRMT5 inhibition not only decreased tumor cell survival but also increased the tumor cell expression of CD274 in vitro and in vivo, which activated the PD1/PD-L1 axis and eliminated CD8+T cell antitumor immunity. Mechanistically, PRMT5 regulated CD274 gene expression through symmetric dimethylation of histone H4R3, increased deposition of H3R4me2s on CD274 promoter loci, and inhibition of CD274 gene expression. Targeting PRMT5 reduced this inhibitory effect and promoted CD274 expression in lung cancer. However, PRMT5 inhibitors represent a double-edged sword as they may selectively kill cancer cells but may also disrupt the antitumor immune response. The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment.
Characterization of Leptin Receptor+ Stromal Cells in Lymph Node
Authors: Jiang Liwei , Yilmaz Mine , Uehara Mayuko , Cavazzoni Cecilia B. , Kasinath Vivek , Zhao Jing , Naini Said Movahedi , Li Xiaofei , Banouni Naima , Fiorina Paolo , Shin Su Ryon , Tullius Stefan G. , Bromberg Jonathan S. , Sage Peter T. , Abdi Reza
Published: January 2022

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.
Single-Cell Transcriptome Analysis of Chronic Antibody-Mediated Rejection After Renal Transplantation
Authors: Kong Fanhua , Ye Shaojun , Zhong Zibiao , Zhou Xin , Zhou Wei , Liu Zhongzhong , Lan Jianan , Xiong Yan , Ye Qifa
Published: January 2022

Renal transplantation is currently the most effective treatment for end-stage renal disease. However, chronic antibody-mediated rejection (cABMR) remains a serious obstacle for the long-term survival of patients with renal transplantation and a problem to be solved. At present, the role and mechanism underlying immune factors such as T- and B- cell subsets in cABMR after renal transplantation remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood monocytes (PBMCs) from cABMR and control subjects was performed to define the transcriptomic landscape at single-cell resolution. A comprehensive scRNA-seq analysis was performed. The results indicated that most cell types in the cABMR patients exhibited an intense interferon response and release of proinflammatory cytokines. In addition, we found that the expression of MT-ND6, CXCL8, NFKBIA, NFKBIZ, and other genes were up-regulated in T- and B-cells and these genes were associated with pro-inflammatory response and immune regulation. Western blot and qRT-PCR experiments also confirmed the up-regulated expression of these genes in cABMR. GO and KEGG enrichment analyses indicated that the overexpressed genes in T- and B-cells were mainly enriched in inflammatory pathways, including the TNF, IL-17, and Toll-like receptor signaling pathways. Additionally, MAPK and NF-κB signaling pathways were also involved in the occurrence and development of cABMR. This is consistent with the experimental results of Western blot. Trajectory analysis assembled the T-cell subsets into three differentiation paths with distinctive phenotypic and functional prog rams. CD8 effector T cells and γδ T cells showed three different differentiation trajectories, while CD8_MAI T cells and naive T cells primarily had two differentiation trajectories. Cell-cell interaction analysis revealed strong T/B cells and neutrophils activation in cABMR. Thus, the study offers new insight into pathogenesis and may have implications for the identification of novel therapeutic targets for cABMR.
The Association of HLA-G Gene Polymorphism and Its Soluble Form With Male Infertility
Authors: Piekarska Karolina , Radwan Paweł , Tarnowska Agnieszka , Wiśniewski Andrzej , Krasiński Rafał , Radwan Michał , Wilczyński Jacek R. , Malinowski Andrzej , Nowak Izabela
Published: January 2022

Successful reproduction depends on many factors. Male factors contribute to infertility in approximately 50% of couples who fail to conceive. Seminal plasma consists of secretions from different accessory glands containing a mixture of various cytokines, chemokines, and growth factors, which together can induce a local immune response that might impact on a male’s as well as a female’s fertility. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The HLA-G gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of HLA-G polymorphisms and their impact on soluble HLA-G (sHLA-G) production. We tested the HLA-G polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in the promoter region; rs371194629: c.∗65_∗66insATTTGTTCATGCCT in the 3′ untranslated region. We tested two cohorts of men: 663 who participated in in vitro fertilization (test material was blood or sperm), and 320 fertile controls who possessed children born after natural conception (test material was blood). Since 50% of men visiting assisted reproductive clinics have abnormal semen parameters, we wondered if men with normal sperm parameters differ from those with abnormal parameters in terms of HLA-G polymorphism and secretion of sHLA-G into semen. We found that certain rs1632947-rs1233334-rs371194629 HLA-G haplotypes and diplotypes were associated with male infertility, while others were protective. Normozoospermic men with the A-C-del haplotype and A-C-del/A-C-del diplotype secreted the most sHLA-G into semen (574.1 IU/mL and 1047.0 IU/mL, respectively), while those with the G-C-ins haplotype and G-C-ins/G-C-ins diplotype – the least (80.8 IU/mL and 75.7 IU/mL, respectively). Men with the remaining haplotypes/diplotypes secreted sHLA-G at an intermediate level. However, only in one haplotype, namely G-C-ins, did we observe strong significant differences in the concentration of sHLA-G in the semen of men with teratozoospermia compared to men with normal sperm parameters (p = 0.009). In conclusion, fertile men differ in the profile of HLA-G polymorphism from men participating in IVF. Among all HLA-G haplotypes, the most unfavorable for male fertility is the G-C-ins haplotype, which determines the secretion of the lowest concentration of the soluble HLA-G molecule. This haplotype may reduce sperm parameters.
Integrating RNA-Seq With GWAS Reveals a Novel SNP in Immune-Related HLA-DQB1 Gene Associated With Occupational Pulmonary Fibrosis Risk: A Multi-Stage Study
Authors: Zhou Yan , Zhang Yingyi , Zhao Rui , Cheng Zhounan , Tang Minzhu , Qiu Anni , Dong Yang , Lu Yihua , Lian Yulong , Zhuang Xun , Tian Tian , Wang Wei , Chu Minjie
Published: January 2022

Objective

To evaluate the association between single-nucleotide polymorphisms (SNPs) in RNA-seq identified mRNAs and silicosis susceptibility.

Methods

A comprehensive RNA-seq was performed to screen for differently expressed mRNAs in the peripheral blood lymphocytes of eight subjects exposed to silica dust (four silicosis cases and four healthy controls). Following this, the SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility, were screened through silicosis-related genome-wide association studies (GWAS) (155 silicosis cases and 141 healthy controls), whereas functional expression quantitative trait locus (eQTL)-SNPs were identified using the GTEx database. Finally, the association between functional eQTL-SNPs and silicosis susceptibility (194 silicosis cases and 235 healthy controls) was validated.

Results

A total of 70 differentially expressed mRNAs (fold change > 2 or fold change < 0.5, P < 0.05) was obtained using RNA-seq. Furthermore, 476 SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility (P < 0.05) were obtained using GWAS, whereas subsequent six functional eQTL-SNPs were identified. The mutant A allele of rs9273410 in HLA-DQB1 indicated a potential increase in silicosis susceptibility in the validation stage (additive model: odds ratio (OR)= 1.31, 95% confidence interval (CI) = 0.99–1.74, P = 0.061), whereas the combination of GWAS and the validation results indicated that the mutant A allele of rs9273410 was associated with increased silicosis susceptibility (additive model: OR = 1.35, 95% CI =1.09–1.68, P = 0.006).

Conclusion

The mutant A allele of rs9273410 was associated with increased silicosis susceptibility by modulating the expression of HLA-DQB1.
Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55–IL6ST Gene Region in Immature Dendritic Cells
Authors: Mena Jorge , Alloza Iraide , Tulloch Navarro Raquel , Aldekoa Ane , Díez García Javier , Villanueva Etxebarria Ane , Lindskog Cecilia , Antigüedad Alfredo , Boyero Sabas , Mendibe-Bilbao María del Mar , Álvarez de Arcaya Amaya , Sánchez Menoyo José Luis , Midaglia Luciana , Villarrubia Noelia , Malhotra Sunny , Montalban Xavier , Villar Luisa María , Comabella Manuel , Vandenbroeck Koen
Published: January 2022

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.
Probing the Anti-Corrosion Behavior of X65 Steel Underwater FSW Joint in Simulated Seawater
Authors: Ma Gang , Gao Hui , Sun Chong , Gu Yanhong , Zhao Jie , Fang Zewei
Published: January 2022

To detect the corrosion resistance of a friction stud welding (FSW) joint in simulated seawater (a 3.5 wt% NaCl solution), the pulse electrochemical deposition method was used for electroplating Ni coating with different duty ratios (50%, 80%, and 100%) on the surface of FSW joint. The microstructure and surface structure of the coating were observed by micro-spectroscopy and other characterization methods. The corrosion behavior of the coating was analyzed by means of macroscopic electrochemical testing. The local corrosion law of joint surface and coating surface defects were innovatively explored by using micro-zone electrochemical scanning system. The coating characterization results showed that, as the duty ratio continues to increase, the coating surface becomes denser and smoother, and the corrosion products such as Fe2O3, Fe3O4, and FeOOH are generated. The results of macroscopic electrochemical experiment indicated that the coating with 100% duty ratio has the lowest corrosion current density and the maximum polarization resistance. The scanning vibrating electrode technique results showed that the corrosion current density in the defect area is higher than that in the coating area, and the maximum corrosion current density decreases with the increase of duty ratio. The localized electrochemical impedance spectroscopy results indicated that the localized impedance at the welded zone was the largest, and with the increase of the pulse duty ratio, the impedance diffusion in the defect area was decreasing.
Influence of Air Plasma Pretreatments on Mechanical Properties in Metal-Reinforced Laminated Wood
Authors: Dahle Sebastian , Srinivasa Kavyashree , Žigon Jure , Cheumani Yona Arnaud Maxime , Avramidis Georg , Viöl Wolfgang , Petrič Marko
Published: January 2022

The use of wood-based materials in building and construction is constantly increasing as environmental aspects and sustainability gain importance. For structural applications, however, there are many examples where hybrid material systems are needed to fulfil the specific mechanical requirements of the individual application. In particular, metal reinforcements are a common solution to enhance the mechanical properties of a wooden structural element. Metal-reinforced wood components further help to reduce cross-sectional sizes of load-bearing structures, improve the attachment of masonry or other materials, enhance the seismic safety and tremor dissipation capacity, as well as the durability of the structural elements in highly humid environments and under high permanent mechanical load. A critical factor to achieve these benefits, however, is the mechanical joint between the different material classes, namely the wood and metal parts. Currently, this joint is formed using epoxy or polyurethane (PU) adhesives, the former yielding highest mechanical strengths, whereas the latter presents a compromise between mechanical and economical constraints. Regarding sustainability and economic viability, the utilization of different adhesive systems would be preferable, whereas mechanical stabilities yielded for metal-wood joints do not permit for the use of other common adhesive systems in such structural applications. This study extends previous research on the use of non-thermal air plasma pretreatments for the formation of wood-metal joints. The plasma treatments of Norway spruce [Picea abies (L.) Karst.] wood and anodized (E6/EV1) aluminum AlMgSi0.5 (6060) F22 were optimized, using water contact angle measurements to determine the effect and homogeneity of plasma treatments. The adhesive bond strengths of plasma-pretreated and untreated specimens were tested with commercial 2-component epoxy, PU, melamine-urea formaldehyde (MUF), polyvinyl acetate (PVAc), and construction adhesive glue systems. The influence of plasma treatments on the mechanical performance of the compounds was evaluated for one selected glue system via bending strength tests. The impact of the hybrid interface between metal and wood was isolated for the tests by using five-layer laminates from three wood lamellae enclosing two aluminum plates, thereby excluding the influence of congeneric wood-wood bonds. The effect of the plasma treatments is discussed based on the chemical and physical modifications of the substrates and the respective interaction mechanisms with the glue systems.
Efficacy of Intravenous Lidocaine for Pain Relief in the Emergency Department: A Systematic Review and Meta-Analysis
Authors: Zhong Junfeng , Hu Junfeng , Mao Linling , Ye Gang , Qiu Kai , Zhao Yuhong , Hu Shuangyan
Published: January 2022

Objective

To compare the efficacy of intravenous (IV) lidocaine with standard analgesics (NSAIDS, opioids) for pain control due to any cause in the emergency department.

Methods

The electronic databases of PubMed, Embase, ScienceDirect, CENTRAL, and Google Scholar were explored from 1st January 2000 to 30th March 2021 and randomized controlled trials (RCTs) comparing IV lidocaine with a control group of standard analgesics were included.

Results

Twelve RCTs including 1,351 patients were included. The cause of pain included abdominal pain, renal or biliary colic, traumatic pain, radicular low back pain, critical limb ischemia, migraine, tension-type headache, and pain of unknown origin. On pooled analysis, we found no statistically significant difference in pain scores between IV lidocaine and control group at 15 min (MD: −0.24 95% CI: −1.08, 0.61 I2 = 81% p = 0.59), 30 min (MD: −0.24 95% CI: −1.03, 0.55 I2 = 86% p = 0.55), 45 min (MD: 0.31 95% CI: −0.66, 1.29 I2 = 66% p = 0.53), and 60 min (MD: 0.59 95% CI: −0.26, 1.44 I2 = 75% p = 0.18). There was no statistically significant difference in the need for rescue analgesics between the two groups (OR: 1.45 95% CI: 0.82, 2.56 I2 = 41% p = 0.20), but on subgroup analysis, the need for rescue analgesics was significantly higher with IV lidocaine in studies on abdominal pain but not for musculoskeletal pain. On meta-analysis, there was no statistically significant difference in the incidence of side-effects between the two study groups (OR: 1.09 95% CI: 0.59, 2.02 I2 = 48% p = 0.78).

Conclusion

IV lidocaine can be considered as an alternative analgesic for pain control in the ED. However, its efficacy may not be higher than standard analgesics. Further RCTs with a large sample size are needed to corroborate the current conclusions.
Non-alcoholic Fatty Liver Disease and Longitudinal Cognitive Changes in Middle-Aged and Elderly Adults
Authors: Liu Qi , Liu Chang , Hu Feifei , Deng Xuan , Zhang Yumei
Published: January 2022

Background and Purpose

Non-alcoholic fatty liver disease (NAFLD) and cognitive impairment are common aging-related disorders. This study aims to explore the changes of cognitive function in middle-aged and elderly population with NAFLD from a Jidong impairment cohort.

Methods

A total of 1,651 middle-aged and elderly participants (>40 years) without cognitive impairment were recruited into the current study in 2015 and were followed up until to 2019. Abdominal ultrasonography was used for diagnosis of NAFLD. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE). Cognitive impairment was defined as a score <18 for illiterates, a score <21 for primary school graduates, and a score <25 for junior school graduates or above. Multivariable regression analysis was performed to evaluate the association between NAFLD and the four-year cognitive changes.

Results

Out of 1,651 participants, 795 (48.2%) of them had NAFLD in 2015. Cognitive impairment occurred in 241 (14.6%) participants in 2019. Patients with NAFLD had higher 4-year incidence of cognitive impairment than non-NAFLD patients did (17.7 vs. 11.7%, p < 0.001). Multivariable linear regression analysis showed significant association of baseline NAFLD with lower MMSE score in 2019 (β = −0.36, p < 0.05). Multivariable logistic analysis found that the adjusted odds ratio (OR) with 95% confidence interval (CI) of baseline NAFLD was 1.45 (1.00–2.11) for cognitive impairment in 2019 (p = 0.05). We also identified effects of baseline NAFLD on subsequent cognitive impairment as modified by age (interaction p < 0.01) and carotid stenosis (interaction p = 0.05) but not by gender.

Conclusions

NAFLD is associated with cognitive decline, especially in middle-aged and with carotid stenosis population.