bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Anti-14-3-3 Zeta Autoantibody as a Biomarker for Predicting Hepatocarcinogenesis
Authors: Wang Ting , Huang Xue-ying , Zheng Su-jun , Liu Ye-ying , Chen Si-si , Ren Feng , Lu Jun , Duan Zhong-ping , Liu Mei
Published: October 2021

Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Alpha-fetoprotein (AFP) is still the only serum biomarker widely used in clinical settings. However, approximately 40% of HCC patients exhibit normal AFP levels, including very early HCC and AFP-negative HCC; for these patients, serum AFP is not applicable as a biomarker of early detection. Thus, there is an urgent need to identify novel biomarkers for patients for whom disease cannot be diagnosed early. In this study, we screened and identified novel proteins in AFP-negative HCC and evaluated the feasibility of using autoantibodies to those protein to predict hepatocarcinogenesis. First, we screened and identified differentially expressed proteins between AFP-negative HCC tissue and adjacent non-tumor liver tissue using SWATH-MS proteome technology. In total, 2,506 proteins were identified with a global false discovery rate of 1%, of which 592 proteins were expressed differentially with 175 upregulated and 417 downregulated (adjusted p-value <0.05, fold-change FC ≥1.5 or ≤0.67) between the tumor and matched benign samples, including 14-3-3 zeta protein. For further serological verification, autoantibodies against 14-3-3 zeta in serum were evaluated using enzyme-linked immunosorbent, Western blotting, and indirect immunofluorescence assays. Five serial serum samples from one patient with AFP-negative HCC showed anti-14-3-3 zeta autoantibody in sera 9 months before the diagnosis of HCC, which gradually increased with an increase in the size of the nodule. Based on these findings, we detected the prevalence of serum anti-14-3-3 zeta autoantibody in liver cirrhosis (LC) patients, which is commonly considered a premalignant liver disease of HCC. We found that the prevalence of autoantibodies against 14-3-3 zeta protein was 16.1% (15/93) in LC patient sera, which was significantly higher than that in patients with chronic hepatitis (0/75, p = 0.000) and normal human sera (1/60, 1.7%, p = 0.01). Therefore, we suggest that anti-14-3-3 zeta autoantibody might be a biomarker for predicting hepatocarcinogenesis. Further follow-up and research of patients with positive autoantibodies will be continued to confirm the relationship between anti-14-3-3 zeta autoantibody and hepatocarcinogenesis.
Transcriptomic Analysis Identified Two Subtypes of Brain Tumor Characterized by Distinct Immune Infiltration and Prognosis
Authors: Shen Xilin , Wang Xiaoli , Shen Hongru , Feng Mengyao , Wu Dan , Yang Yichen , Li Yang , Yang Meng , Ji Wei , Wang Wei , Zhang Qiang , Song Fangfang , Liu Ben , Chen Kexin , Li Xiangchun
Published: October 2021

Background

Brain tumor ranks as the most devastating cancer type. The complex tumor immune microenvironment prevents brain tumor from receiving therapeutic benefits. The purpose of this study was to stratify brain tumors based on their distinct immune infiltration signatures to facilitate better clinical decision making and prognosis prediction.

Methods

We developed a deep learning model to characterize immune infiltration from transcriptome. The developed model was applied to distill expression signatures of transcriptome of brain tumor samples. We performed molecular subtyping with the extracted expression signatures to unveil brain tumor subtypes. Computational methods, including gene set enrichment analysis, Kaplan-Meier survival and multivariate Cox regression analyses, were employed.

Results

We identified two distinctive subtypes (i.e. C1/2) of brain tumor featured by distinct immune infiltration signatures. The C1 subtype is characterized by protective immune infiltration signatures, including high infiltration of CD8+ T cells and activation of CX3CL1. The C2 subtype has an extensive infiltration of tumor-associated macrophages and microglia, and was enriched with immune suppressive, wound-healing, and angiogenic signatures. The C1 subtype had significantly better prognosis as compared with C2 (Log-rank test, HR: 2.5, 95% CI: 2.2 – 2.7; P = 8.2e-78). This difference remained statistically significant (multivariate Cox model, HR: 2.2, 95% CI: 1.7 – 2.9; P = 3.7e-10) by taking into account age, gender, recurrent/secondary status at sampling time, tumor grade, histology, radio-chemotherapy, IDH mutation, MGMT methylation, and co-deletion of 1p and 19q. This finding was validated in six datasets. The C2 subtype of glioblastoma patients with IDH mutation has poor survival analogous to those without IDH mutation (Log-rank test, adjusted P = 0.8), while C1 has favorable prognosis as compared with glioblastoma of C2 subtype with IDH mutation (Log-rank test, adjusted P = 1.2e-3) or without IDH mutation (Log-rank test, adjusted P = 1.3e-6).

Conclusions

We identified two distinctive subtypes of brain tumor with different immune infiltration signatures, which might be helpful as an independent prognosticator for brain tumor.
Identification and Validation of m6A-Related lncRNA Signature as Potential Predictive Biomarkers in Breast Cancer
Authors: Lv Wenchang , Wang Yichen , Zhao Chongru , Tan Yufang , Xiong Mingchen , Yi Yi , He Xiao , Ren Yuping , Wu Yiping , Zhang Qi
Published: October 2021

The metastasis and poor prognosis are still regarded as the main challenge in the clinical treatment of breast cancer (BC). Both N6-methyladenosine (m6A) modification and lncRNAs play vital roles in the carcinogenesis and evolvement of BC. Considering the unknown association of m6A and lncRNAs in BC, this study therefore aims to discern m6A-related lncRNAs and explore their prognostic value in BC patients. Firstly, a total of 6 m6A-related lncRNAs were screened from TCGA database and accordingly constructed a prognostic-predicting model. The BC patients were then divided into high-risk and low-risk groups dependent on the median cutoff of risk score based on this model. Then, the predictive value of this model was validated by the analyses of cox regression, Kaplan-Meier curve, ROC curve, and the biological differences in the two groups were validated by PCA, KEGG, GSEA, immune status as well as in vitro assay. Finally, we accordingly constructed a risk prognostic model based on the 6 identified m6A-related lncRNAs, including Z68871.1, AL122010.1, OTUD6B-AS1, AC090948.3, AL138724.1, EGOT. Interestingly, the BC patients were divided into the low-risk and high-risk groups with different prognoses according to the risk score. Notably, the risk score of the model was an excellent independent prognostic factor. In the clinical sample validation, m6A regulatory proteins were differentially expressed in patients with different risks, and the markers of tumor-associated macrophages and m6A regulators were co-localized in high-risk BC tissues. This well-validated risk assessment tool based on the repertoire of these m6A-related genes and m6A-related lncRNAs, is of highly prognosis-predicting ability, and might provide a supplemental screening method for precisely judging BC prognosis.
Measurement of Circulating Tumor Cells to Track Hepatocellular Carcinoma Progression After Liver Transplantation-Case Report
Authors: Deng Yuan , Sun Lei , Liang Heng , Cui Bojing , Cui Caimei , Zhao Dan , Wan Arabella , Wan Guohui
Published: October 2021

Management of patients with hepatocellular carcinoma (HCC) largely relies on surgery and other systemic therapies. However, the poor diagnosis of cancer recurrence or metastasis can lead to a high frequency of treatment failure. Thus, factors that can predict disease status and prognosis of patients need to be identified. Circulating tumor cells (CTCs) are known to accurately predict survival of patients. Here, we report a case in which CTCs successfully predicted the progression of metastatic colon polyps after interventional therapy for HCC. A 48-year-old man was diagnosed with HCC with moderate differentiation in 2016 and subsequently underwent orthotopic liver transplantation. Discharge medications were continued with immunosuppressants (tacrolimus) and antiviral drugs (Titin). In 2018, a colon polyp, a type of tubular adenoma, was detected and surgically removed. However, in 2020, the same tubular adenoma recurred. During cancer progression, CTC counts were measured to monitor the status of metastasis, and a positive correlation was noted between the dynamic change in CTC counts and cancer response (metastasis or recurrence). When diagnosing the metastatic adenoma, the number of cytokeratin-positive CTCs was significantly increased; however, it dropped to zero after the polyp was surgically removed. The same change in CTC counts was observed during the second recurrence of the adenoma, and a subgroup of CTCs, cell surface vimentin-positive CTCs, was significantly increased. The CTC count dropped to an undetectable level after the surgery for the first time. In summary, we presented a clinical case in which CTC counts could predict disease progression during HCC metastasis. Thus, CTC counts should be measured after liver transplantation in patients with HCC for diagnosis and clinical decision-making as it is effective in monitoring cancer progression.
Inhibition of Bromodomain and Extra Terminal (BET) Domain Activity Modulates the IL-23R/IL-17 Axis and Suppresses Acute Graft-Versus-Host Disease
Authors: Snyder Katiri J. , Choe Hannah K. , Gao Yandi , Sell Natalie E. , Braunreiter Kara M. , Zitzer Nina C. , Neidemire-Colley Lotus , Kalyan Sonu , Dorrance Adrienne M. , Keller Andrea , Mihaylova Maria M. , Singh Satishkumar , Sehgal Lalit , Bollag Gideon , Ma Yan , Powell Ben , Devine Steven M. , Ranganathan Parvathi
Published: October 2021

Acute graft-versus-host disease (GVHD) is the leading cause of non-relapse mortality following allogeneic hematopoietic cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Bromodomain and extra-terminal domain (BET) proteins influence inflammatory gene transcription, and therefore represent a potential target to mitigate inflammation central to acute GVHD pathogenesis. Using potent and selective BET inhibitors Plexxikon-51107 and -2853 (PLX51107 and PLX2853), we show that BET inhibition significantly improves survival and reduces disease progression in murine models of acute GVHD without sacrificing the beneficial graft-versus-leukemia response. BET inhibition reduces T cell alloreactive proliferation, decreases inflammatory cytokine production, and impairs dendritic cell maturation both in vitro and in vivo. RNA sequencing studies in human T cells revealed that BET inhibition impacts inflammatory IL-17 and IL-12 gene expression signatures, and Chromatin Immunoprecipitation (ChIP)-sequencing revealed that BRD4 binds directly to the IL-23R gene locus. BET inhibition results in decreased IL-23R expression and function as demonstrated by decreased phosphorylation of STAT3 in response to IL-23 stimulation in human T cells in vitro as well as in mouse donor T cells in vivo. Furthermore, PLX2853 significantly reduced IL-23R+ and pathogenic CD4+ IFNγ+ IL-17+ double positive T cell infiltration in gastrointestinal tissues in an acute GVHD murine model. Our findings identify a role for BET proteins in regulating the IL-23R/STAT3/IL-17 pathway. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.
Association of Ethnicity With Multisystem Inflammatory Syndrome in Children Related to SARS-CoV-2 Infection: An International Case-Referent Study
Authors: Middelburg Judith G. , Crijnen Thomas E. M. , D'Antiga Lorenzo , Verdoni Lucio , Chikermane Ashish , Garg Padma , Acharyya Bhaswati C. , Pruccoli Giulia , Schnapp Aviad , Rauf Abdul , Middelburg Rutger A.
Published: October 2021

Background: It has been suggested that children and infants can develop multisystem inflammatory syndrome in children (MIS-C) in response to a SARS-CoV-2 infection and that Black children are overrepresented among cases. The aim of the current study was to quantify the association between Black, Asian, or other non-White genetic background and COVID-19-related MIS-C in children and infants.

Methods: Eight different research groups contributed cases of MIS-C, potentially related to SARS-CoV-2 infection. Several sensitivity analyses were performed, including additional data available from the literature. Analyses were stratified by geographical region.

Results: Seventy-three cases from nine distinct geographical regions were included in the primary analyses. In comparison to White children, the relative risk for developing MIS-C after SARS-CoV-2 infection was 15 [95% confidence interval (CI): 7.1 to 32] for Black children, 11 (CI: 2.2 to 57) for Asian, and 1.6 (CI: 0.58 to 4.2) for other ethnic background.

Conclusion: Pediatricians should be aware of the fact that the risk of COVID-19-related MIS-C is severely increased in Black children.
Association Between Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism and Childhood Idiopathic Nephrotic Syndrome: A Meta-Analysis
Authors: Ying Daojing , Jiang Mengjie , Rong Liping , Zhuang Hongjie , Chen Lizhi , Xu Yuanyuan , Jiang Xiaoyun
Published: October 2021

Background: Studies have identified that MIF -173 G>C gene polymorphism is associated with idiopathic nephrotic syndrome (INS) susceptibility and steroid resistance, but the results remain inconclusive.

Methods: We searched PubMed, Embase, and Web of Science for relevant studies published before 31 March 2021. Pooled data were reported as odds ratio (OR) with 95% confidence interval (CI). Noteworthiness of significant OR was estimated by the false positive report probability (FPRP) test. Trial sequential analysis (TSA) was used to control type I and type II errors.

Results: We selected seven case-control studies that included 1,026 INS children (362 were steroid-resistant NS and 564 were steroid-sensitive NS) and 870 controls. The results showed that MIF -173 G>C polymorphism was significantly associated with INS susceptibility in allelic, heterozygous and dominant genetic models (C vs. G: OR = 1.325, 95% CI: 1.011-1.738; GC vs. GG: OR = 1.540, 95% CI: 1.249-1.899; CC + GC vs. GG: OR = 1.507, 95% CI: 1.231-1.845), and FPRP test and TSA indicated that the associations were true in heterozygous and dominant models. The pooled results also revealed that MIF -173 G>C polymorphism was significantly associated with steroid resistance in allelic, homozygous and recessive models (C vs. G: OR = 1.707, 95% CI: 1.013-2.876; CC vs. GG: OR = 4.789, 95% CI: 2.109-10.877; CC vs. GC + GG: OR = 4.188, 95% CI: 1.831-9.578), but FPRP test indicated that all these associations were not noteworthy. Furthermore, TSA revealed that the non-significant associations between MIF -173 G>C polymorphism and steroid resistance in heterozygous and dominant models were potential false negative.

Conclusions: This meta-analysis could draw a firm conclusion that MIF -173 G>C polymorphism was significantly associated with increased INS risk in heterozygous and dominant genetic models. MIF -173 G>C polymorphism was not likely to affect steroid responsiveness, but more studies were needed to confirm.
Study on Binocular Accommodative Function in Children With Different Types of Intermittent Exotropia
Authors: Li Dan , Li Kun-Ling , Wang Jing , Du Lin-Lin , Li Li
Published: October 2021

Objective: This study aims to investigate the monocular and binocular accommodative amplitude (AMP) and accommodative function (AF) in children with different types of intermittent exotropia (IXT).

Methods: A total of 40 children with IXT were enrolled in the study. Monocular and binocular AMP and AF were measured using the modified approach method and the ±2D flip method, and the differences between the fixing and non-fixing eyes of non-strabismic children and children with different types of IXT were compared.

Results: The AMP of the fixing eyes of children with IXT was lower than that of their non-fixing eyes (p = 0.007). Conversely, the AF was higher in the fixing eyes than in the non-fixing eyes (p < 0.001). The AMPs of each group of children with IXT were lower than those of the control group, while the AMP of the group with convergence insufficiency was lower than that of the other two groups with IXT. In addition, the AF of the group with convergence insufficiency was lower than that of the group with basic exotropia and the control group (p < 0.05).

Conclusion: There is a difference in accommodation between the fixing and non-fixing eyes of children with IXT, and the degree of variation depends on the type of IXT. Moreover, the binocular accommodative function of children with IXT is lower than that of non-strabismic children.
Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome
Authors: Mehboob Riffat , Kurdi Maher , Ahmad Mursleen , Gilani Syed Amir , Khalid Sidra , Nasief Hisham , Mirdad Abeer , Malibary Husam , Hakamy Sahar , Hassan Amber , Alaifan Meshari , Bamaga Ahmed , Shahzad Syed Adnan
Published: October 2021

Background:Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches.

Methods:This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis.

Results:After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, “hsa-miR-133a-3p” was found to be prevalent in the targeted genes.

Conclusions:Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.
The Genetic Etiology Diagnosis of Fetal Growth Restriction Using Single-Nucleotide Polymorphism-Based Chromosomal Microarray Analysis
Authors: Chen Yu'e , Xie Yingjun , Jiang Yuying , Luo Qi , Shi Lijing , Zeng Shuhong , Zhuang Jianlong , Lyu Guorong
Published: October 2021

Background: An increase in pathogenic copy number variants (pCNVs) has been recognized to associate with fetal growth restriction (FGR). Here, we aim to explore the application value of chromosomal microarray analysis (CMA) in prenatal diagnosis of FGR.

Methods: Prenatal ultrasound was applied to identify FGR. A total of 149 pregnant women with FGR were enrolled in our study. All subjects underwent karyotype analysis and CMA to reveal the chromosomal abnormalities.

Results: In this study, all subjects were successfully detected by karyotype and CMA analyses. Of these subjects, the chromosomal abnormalities detection rate was 5.37% (8/149) for karyotyping and 13.42% (20/149) for CMA, respectively. Among them, an 8.05% (12/149) incremental yield of CMA over karyotype analysis was observed (p = 0.004). In addition, a significant difference of pCNV detection rate was observed between the groups with different high-risk factors (p = 0.005). The FGR with structural anomalies group showed the highest pCNV detection rate (33.33%), followed by the FGR with non-structural anomalies group (8.77%) and the isolated FGR group (8.06%).

Conclusion: In conclusion, CMA technology showed an effective application value in etiology diagnosis of FGR. We believe that CMA should be recommended as first-line detection technology for prenatal diagnosis in FGR.
Outcomes and Prognostic Factors for Survival of Neonates With Necrotizing Enterocolitis
Authors: Siahaan Elena Sophia Elekta Dilean , Adriansyah Wahyudhy , Sasmita Andika Purba , Fauzi Aditya Rifqi , Dwihantoro Andi , Gunadi
Published: October 2021

Background: Due to the survival of preterm neonates being continually improved, the modifiable prognostic factors of necrotizing enterocolitis (NEC) are essential to be investigated and considered in making a suitable treatment to decrease the prevalence and effect of NEC. Many prognostic factors have been associated with the survival of neonates with NEC; however, the studies show conflicting results. Moreover, the study from developing countries regarding NEC outcomes is minimal. Here, we aimed to determine the survival of neonates with NEC and associate it with the prognostic factors.

Methods: A retrospective study was conducted using medical records of neonates with NEC at our institution from January 2014 to December 2019.

Results: Fifty-two neonates with NEC were involved with the overall survival of 44.2%. Log-rank analysis showed that NEC staging and birth weight were significantly associated with the survival of neonates with NEC with a p-value of 0.010 and 0.002, respectively, while sex, APGAR score, platelet count, and type of treatment were not (p = 0.068, 0.752, 0.087, and 0.343, respectively). Multivariate analysis revealed that sex and NEC staging were strongly associated with the survival of neonates with NEC with a p-value of 0.018 [HR = 3.10 (95% CI = 1.21–7.93)] and 0.019 [HR = 0.44 (0.22–0.87)], respectively.

Conclusions: Our study shows that sex and NEC staging might affect the survival of neonates with NEC. It implies that NEC staging should be closely monitored and intervened as early as necessary to prevent further morbidity and mortality.
Multicentric Carpo-Tarsal Osteolysis Syndrome Mimicking Juvenile Idiopathic Arthritis: Two Case Reports and Review of the Literature
Authors: Wu Junfeng , Wang Li , Xu Ye , Zhang Zhiyong , Yan Xin , An Yunfei , Zhang Yu , Tang Xuemei
Published: October 2021

Multicentric carpo-tarsal osteolysis syndrome (MCTO) is a rare skeletal disorder commonly caused by MAF bZIP transcription factor B (MAFB) mutation. Clinically, it is characterized by aggressive osteolysis, which mainly affects the carpal tarsal bones, and is frequently associated with progressive nephropathy. Since the painful swelling and motion limitation on the wrists and/or ankles of MCTO mimics those of juvenile idiopathic arthritis (JIA), very often, MCTO is misdiagnosed as JIA. Here, we report two MCTO patients initially diagnosed with JIA but showed no response to treatment: P1, with a medical history of more than 10 years, was presented with a typical triad of arthritis-osteolysis-nephropathy; while P2 showed oligoarthritis. Gene tests were then taken and revealed a novel mutation, p.P63Q, and a previously reported conversion, p.S54L, in the MAFB gene. We also summarized the clinical and genetic features of a cohort containing 49 genetically confirmed MCTO patients. All 51 gene-confirmed MCTO cases (49 identified from the literature plus two patients identified herein) developed the disease during childhood. The median delay in diagnosis was 3.83 years (0–35 years). All cases presented bony lesions, and two-thirds had secondary renal lesions (32/48; three unknown), half of which (16/32) progressed into renal failure. Almost two-thirds (34/51), 75% (38/51), and 71% (36/51) of patients had no record of eye problems, facial abnormalities, and other manifestations. Most were misdiagnosed as JIA but didn't respond to treatment. Based on our experience, we suggest that clinicians should comprehensively evaluate the involvement of multiple systems in JIA patients, especially the kidney and eyes. And for JIA patients who underwent more than 3-month treatment with Bio-DMARD, genetic tests are recommended when they show little/no clinical and imaging changes, their high disease activity remains, and their disease activity remission is <50%, especially when combined with a triad of arthritis-osteolysis-nephropathy.
Schisandrin B Antagonizes Cardiotoxicity Induced by Pirarubicin by Inhibiting Mitochondrial Permeability Transition Pore (mPTP) Opening and Decreasing Cardiomyocyte Apoptosis
Authors: Shi Hongwei , Tang Heng , Ai Wen , Zeng Qingfu , Yang Hong , Zhu Fengqing , Wei Yunjie , Feng Rui , Wen Li , Pu Peng , He Quan
Published: October 2021

Objective: Pirarubicin (THP), one of the anthracycline anticancer drugs, is widely used in the treatment of various cancers, but its cardiotoxicity cannot be ignored. Schisandrin B (SchB) has the ability to upregulate cellular antioxidant defense mechanism and promote mitochondrial function and antioxidant status. However, it has not been reported whether it can resist THP-induced cardiotoxicity. The aim of this study was to investigate the effect of SchB on THP cardiotoxicity and its mechanism.

Methods: The rat model of cardiotoxicity induced by THP was established, and SchB treatment was performed at the same time. The changes of ECG, cardiac coefficient, and echocardiogram were observed. The changes of myocardial tissue morphology were observed by H&E staining. Apoptosis was detected by TUNEL. The levels of LDH, BNP, CK-MB, cTnT, SOD, and MDA in serum were measured to observe the heart damage and oxidative stress state of rats. The expression of cleaved-caspase 9, pro/cleaved-caspase 3, Bcl-2/Bax, and cytosol and mitochondrial Cyt C and Bax was evaluated by western blot. H9c2 cardiomyocytes were cocultured with THP, SchB, and mPTP inhibitor CsA to detect the production of ROS and verify the above signaling pathways. The opening of mPTP and mitochondrial swelling were detected by mPTP kit and purified mitochondrial swelling kit.

Results: After 8 weeks, a series of cardiotoxicity manifestations were observed in THP rats. These adverse effects can be effectively alleviated by SchB treatment. Further studies showed that SchB had strong antioxidant and antiapoptotic abilities in THP cardiotoxicity.

Conclusion: SchB has an obvious protective effect on THP-induced cardiotoxicity. The mechanism may be closely related to the protection of mitochondrial function, inhibition of mPTP opening, and alleviation of oxidative stress and apoptosis of cardiomyocytes.
Magnetic Structure in Successively Erupting Active Regions: Comparison of Flare-Ribbons With Quasi-Separatrix Layers
Authors: Vemareddy P.
Published: October 2021

This paper studies the magnetic topology of successively erupting active regions (ARs) 11,429 and 12,371. Employing vector magnetic field observations from Helioseismic and Magnetic Imager, the pre-eruptive magnetic structure is reconstructed by a model of non-linear force-free field (NLFFF). For all the five CMEs from these ARs, the pre-eruptive magnetic structure identifies an inverse-S sigmoid consistent with the coronal plasma tracers in EUV observations. In all the eruption cases, the quasi-separatrix layers (QSLs) of large Q values are continuously enclosing core field bipolar regions in which inverse-S shaped flare ribbons are observed. These QSLs essentially represent the large connectivity gradients between the domains of twisted core flux within the inner bipolar region and the surrounding potential like arcade. It is consistent with the observed field structure largely with the sheared arcade. The QSL maps in the chromosphere are compared with the flare-ribbons observed at the peak time of the flares. The flare ribbons are largely inverse-S shape morphology with their continuity of visibility is missing in the observations. For the CMEs in the AR 12371, the QSLs outline the flare ribbons as a combination of two inverse J-shape sections with their straight parts being separated. These QSLs are typical with the weakly twisted flux rope. Similarly, for the CMEs in the AR 11429, the QSLs are co-spatial with the flare ribbons both in the middle of the PIL and in the hook sections. In the frame work of standard model of eruptions, the observed flare ribbons are the characteristic of the pre-eruptive magnetic structure being sigmoid which is reproduced by the NLFFF model with a weakly twisted flux rope at the core.
The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle
Authors: Iyer Shama R. , Folker Eric S. , Lovering Richard M.
Published: October 2021

Intermediate filaments (IFs) are a primary structural component of the cytoskeleton extending throughout the muscle cell (myofiber). Mechanotransduction, the process by which mechanical force is translated into a biochemical signal to activate downstream cellular responses, is crucial to myofiber function. Mechanical forces also act on the nuclear cytoskeleton, which is integrated with the myofiber cytoskeleton by the linker of the nucleoskeleton and cytoskeleton (LINC) complexes. Thus, the nucleus serves as the endpoint for the transmission of force through the cell. The nuclear lamina, a dense meshwork of lamin IFs between the nuclear envelope and underlying chromatin, plays a crucial role in responding to mechanical input; myofibers constantly respond to mechanical perturbation via signaling pathways by activation of specific genes. The nucleus is the largest organelle in cells and a master regulator of cell homeostasis, thus an understanding of how it responds to its mechanical environment is of great interest. The importance of the cell nucleus is magnified in skeletal muscle cells due to their syncytial nature and the extreme mechanical environment that muscle contraction creates. In this review, we summarize the bidirectional link between the organization of the nucleoskeleton and the contractile features of skeletal muscle as they relate to muscle function.
The Second Wind in McArdle Patients: Fitness Matters
Authors: Salazar-Martínez Eduardo , Santalla Alfredo , Valenzuela Pedro L. , Nogales-Gadea Gisela , Pinós Tomàs , Morán María , Santos-Lozano Alejandro , Fiuza-Luces Carmen , Lucia Alejandro
Published: October 2021

Background: The “second wind” (SW) phenomenon—commonly referring to both an initial period of marked intolerance to dynamic exercise (e.g., brisk walking) that is not followed by perceived improvement and disappearance of previous tachycardia (i.e., the actual “SW”) until 6–10 min has elapsed—is an almost unique feature of McArdle disease that limits adherence to an active lifestyle. In this regard, an increase in the workload eliciting the SW could potentially translate into an improved patients’ exercise tolerance in daily life. We aimed to determine whether aerobic fitness and physical activity (PA) levels are correlated with the minimum workload eliciting the SW in McArdle patients—as well as with the corresponding heart rate value. We also compared the SW variables and aerobic fitness indicators in inactive vs. active patients.

Methods: Fifty-four McArdle patients (24 women, mean ± SD age 33 ± 12 years) performed 12-min constant-load and maximum ramp-like cycle-ergometer tests for SW detection and aerobic fitness [peak oxygen uptake (VO2peak) and workload and ventilatory threshold] determination, respectively. They were categorized as physically active/inactive during the prior 6 months (active = reporting ≥150 min/week or ≥75 min/week in moderate or vigorous-intensity aerobic PA, respectively) and were also asked on their self-report of the SW.

Results: Both peak and submaximal indicators of aerobic fitness obtained in the ramp tests were significantly correlated with the workload of the SW test, with a particularly strong correlation for the VO2peak and peak workload attained by the patients (both Pearson’s coefficients > 0.70). Twenty (seven women) and 24 patients (18 women) were categorized as physically active and inactive, respectively. Not only the aerobic fitness level [∼18–19% higher values of VO2peak (ml⋅kg–1⋅min–1)] but also the workload of the SW tests was significantly higher in active than in inactive patients. All the inactive patients reported that they experienced the SW during walking/brisk walking in daily life, whereas active patients only reported experiencing this phenomenon during more strenuous activities (very brisk walking/jogging and bicycling).

Conclusion: A higher aerobic fitness and an active lifestyle are associated with a higher workload eliciting the so-called SW phenomenon in patients with McArdle disease, which has a positive impact on their exercise tolerance during daily living.
Time Course and Role of Exercise-Induced Cytokines in Muscle Damage and Repair After a Marathon Race
Authors: de Sousa Cesar Augustus Zocoler , Sierra Ana Paula Renno , Martínez Galán Bryan Steve , Maciel Jaqueline Fernanda de Sousa , Manoel Richelieau , Barbeiro Hermes Vieira , Souza Heraldo Possolo de , Cury-Boaventura Maria Fernanda
Published: October 2021

Endurance exercise induces an increase in the expression of exercise-induced peptides that participate in the repair and regeneration of skeletal muscles. The present study aimed to evaluate the time course and role of exercise-induced cytokines in muscle damage and repair after a marathon race. Fifty-seven Brazilian male amateur marathon finishers, aged 30–55 years, participated in this study. The blood samples were collected 24 h before, immediately after, and 24 and 72 h after the São Paulo International Marathon. The leukogram and muscle damage markers were analyzed using routine automated methodology in the clinical laboratory. The plasma levels of the exercise-induced cytokines were determined using the Human Magnetic Bead Panel or enzyme-linked immunosorbent assays [decorin and growth differentiation factor 15 (GDF-15)]. A muscle damage was characterized by an increase in plasma myocellular proteins and immune changes (leukocytosis and neutrophilia). Running the marathon increased interleukin (IL)-6 (4-fold), IL-8 (1.5-fold), monocyte chemoattractant protein-1 (2.4-fold), tumor necrosis factor alpha (TNF-α) (1.5-fold), IL-10 (11-fold), decorin (1.9-fold), GDF-15 (1.8-fold), brain-derived neurotrophic factor (BDNF) (2.7-fold), follistatin (2-fold), and fibroblast growth factor (FGF-21) (3.4-fold) plasma levels. We also observed a reduction in musclin, myostatin, IL-15, and apelin levels immediately after the race (by 22–36%), 24 h (by 26–52%), and 72 h after the race (by 25–53%). The changes in BDNF levels were negatively correlated with the variations in troponin levels (r = −0.36). The variations in IL-6 concentrations were correlated with the changes in follistatin (r = 0.33) and FGF-21 (r = 0.31) levels after the race and with myostatin and irisin levels 72 h after the race. The changes in IL-8 and IL-10 levels had positive correlation with variation in musclin (p < 0.05). Regeneration of exercise-induced muscle damage involves the participation of classical inflammatory mediators, as well as GDF-15, BDNF, follistatin, decorin, and FGF-21, whose functions include myogenesis, mytophagia, satellite cell activation, and downregulation of protein degradation. The skeletal muscle damage markers were not associated to myokines response. However, BDNF had a negative correlation with a myocardial damage marker. The classical anti-inflammatory mediators (IL-10, IL-8, and IL-6) induced by exercise are associated to myokines response immediately after the race and in the recovery period and may affect the dynamics of muscle tissue repair.
Cross-Talks Between Macro- and Micronutrient Uptake and Signaling in Plants
Authors: Fan Xiaoning , Zhou Xiaoqin , Chen Hui , Tang Ming , Xie Xianan
Published: October 2021

In nature, land plants as sessile organisms are faced with multiple nutrient stresses that often occur simultaneously in soil. Nitrogen (N), phosphorus (P), sulfur (S), zinc (Zn), and iron (Fe) are five of the essential nutrients that affect plant growth and health. Although these minerals are relatively inaccessible to plants due to their low solubility and relative immobilization, plants have adopted coping mechanisms for survival under multiple nutrient stress conditions. The double interactions between N, Pi, S, Zn, and Fe have long been recognized in plants at the physiological level. However, the molecular mechanisms and signaling pathways underlying these cross-talks in plants remain poorly understood. This review preliminarily examined recent progress and current knowledge of the biochemical and physiological interactions between macro- and micro-mineral nutrients in plants and aimed to focus on the cross-talks between N, Pi, S, Zn, and Fe uptake and homeostasis in plants. More importantly, we further reviewed current studies on the molecular mechanisms underlying the cross-talks between N, Pi, S, Zn, and Fe homeostasis to better understand how these nutrient interactions affect the mineral uptake and signaling in plants. This review serves as a basis for further studies on multiple nutrient stress signaling in plants. Overall, the development of an integrative study of multiple nutrient signaling cross-talks in plants will be of important biological significance and crucial to sustainable agriculture.
Identification of Candidate Genes for Self-Compatibility in Perennial Ryegrass (Lolium perenne L.)
Authors: Cropano Claudio , Manzanares Chloé , Yates Steven , Copetti Dario , Do Canto Javier , Lübberstedt Thomas , Koch Michael , Studer Bruno
Published: October 2021

Self-incompatibility (SI) is a genetic mechanism preventing self-pollination in ~40% of plant species. Two multiallelic loci, called S and Z, control the gametophytic SI system of the grass family (Poaceae), which contains all major forage grasses. Loci independent from S and Z have been reported to disrupt SI and lead to self-compatibility (SC). A locus causing SC in perennial ryegrass (Lolium perenne L.) was previously mapped on linkage group (LG) 5 in an F2 population segregating for SC. Using a subset of the same population (n = 68), we first performed low-resolution quantitative trait locus (QTL) mapping to exclude the presence of additional, previously undetected contributors to SC. The previously reported QTL on LG 5 explained 38.4% of the phenotypic variation, and no significant contribution from other genomic regions was found. This was verified by the presence of significantly distorted markers in the region overlapping with the QTL. Second, we fine mapped the QTL to 0.26 centimorgan (cM) using additional 2,056 plants and 23 novel sequence-based markers. Using Italian ryegrass (Lolium multiflorum Lam.) genome assembly as a reference, the markers flanking SC were estimated to span a ~3 Mb region encoding for 57 predicted genes. Among these, seven genes were proposed as relevant candidate genes based on their annotation and function described in previous studies. Our study is a step forward to identify SC genes in forage grasses and provides diagnostic markers for marker-assisted introgression of SC into elite germplasm.
10Boron Is Mobile in Cowpea Plants
Authors: Silva Sylvia Leticia Oliveira , Prado Renato de Mello , Abreu-Junior Cassio Hamilton , Silva Gilmara Pereira da , Silva Júnior Gabriel Barbosa da , Silva José Lucas Farias da
Published: October 2021

Cowpea [Vigna unguiculata (L.) Walp] is cultivated in tropical and subtropical regions worldwide, but its production is usually limited by boron (B) deficiency, which can be mitigated by applying B via foliar spraying. In plants with nutrient mobility, the residual effect of foliar fertilization increases, which might improve its efficiency. An experiment was carried out to evaluate the concentration and mobility of the B isotopic tracer (10B) in different organs of cowpea plants, after the application of this micronutrient in the growing media and also to leaves. Treatments were designed based on B fertilization as follows: without B in the growth media, with 10B applied via foliar spraying (10B-L), with B in the growth media (substrate) and 10B via foliar spraying (10B-L + B-S), and with 10B in the growth media (substrate) without foliar spraying (10B-S), and a control without fertilization. A redistribution of 10B was observed in new leaves when the element was supplied via foliar spraying, resulting in greater leaf area, dry mass and dry matter production of aerial parts, and also the whole plant. 10Boron was redistributed when applied via foliar spraying in cowpea plants, regardless of the plant's nutritional status, which in turn might increase internal B cycling.
Effects of Deficit Irrigation and Huanglongbing on Sweet Orange Trees
Authors: Silva Jefferson Rangel da , Boaretto Rodrigo Marcelli , Lavorenti Jéssica Aparecida Lara , dos Santos Bruna Castriani Ferreira , Coletta-Filho Helvecio Della , Mattos Dirceu
Published: October 2021

This study addresses the interactive effects of deficit irrigation and huanglongbing (HLB) infection on the physiological, biochemical, and oxidative stress responses of sweet orange trees. We sought to answer: (i) What are the causes for the reduction in water uptake in HLB infected plants? (ii) Is the water status of plants negatively affected by HLB infection? (iii) What are the key physiological traits impaired in HLB-infected plants? and (iv) What conditions can mitigate both disease severity and physiological/biochemical impairments in HLB-infected plants? Two water management treatments were applied for 11 weeks to 1-year-old-trees that were either healthy (HLB–) or infected with HLB (+) and grown in 12-L pots. Half of the trees were fully irrigated (FI) to saturation, whereas half were deficit-irrigated (DI) using 40% of the water required to saturate the substrate. Our results demonstrated that: reduced water uptake capacity in HLB+ plants was associated with reduced root growth, leaf area, stomatal conductance, and transpiration. Leaf water potential was not negatively affected by HLB infection. HLB increased leaf respiration rates (ca. 41%) and starch synthesis, downregulated starch breakdown, blocked electron transport, improved oxidative stress, and reduced leaf photosynthesis (ca. 57%) and photorespiration (ca.57%). Deficit irrigation reduced both leaf respiration (ca. 45%) and accumulation of starch (ca.53%) by increasing maltose (ca. 20%), sucrose, glucose, and fructose contents in the leaves, decreasing bacterial population (ca. 9%) and triggering a series of protective measures against further impairments in the physiology and biochemistry of HLB-infected plants. Such results provide a more complete physiological and biochemical overview of HLB-infected plants and can guide future studies to screen genetic tolerance to HLB and improve management strategies under field orchard conditions.
Differential Association of Free, Conjugated, and Bound Forms of Polyamines and Transcript Abundance of Their Biosynthetic and Catabolic Genes During Drought/Salinity Stress in Tomato (Solanum lycopersicum L.) Leaves
Authors: Upadhyay Rakesh K. , Fatima Tahira , Handa Avtar K. , Mattoo Autar K.
Published: October 2021

Polyamines have been implicated in ameliorating the detrimental effects of drought and saline conditions on plant growth and development. The independent impact of these two abiotic stresses on polyamine (PA) biosynthesis, catabolism, and homeostasis, as well as on their transcript abundance in tomato leaves, is presented here. We show that the total levels of putrescine (PUT), spermidine (SPD), and spermine (SPM) increase up to 72 h during drought and up to 48 h during salinity stress before their precipitable drop thereafter. Thus, tomato plants maintain survivability to drought as well as salinity stress for up to 3 and 2 days, respectively. Independent multivariant analyses of drought and salinity stress kinetic data separately showed a closer association with levels of free, conjugated, and bound forms of SPD and SPM, but not with free or bound PUT. However, combined multivariant analyses showed a closer association of free SPD, conjugated SPD, and bound SPD with both stresses; SPD-bound and SPM conjugated with drought; and free SPM and conjugated PUT with salinity stress, respectively. PA biosynthesis genes,ARG1,SPDS1, andSAMDc3, segregated with drought andSPDS2with salinity stress. PA catabolic genesCuAO4-likeandPAO4were associated with drought and salinity stresses, respectively, suggesting differential involvement of PA biosynthesis and catabolic genes in drought and salinity stresses. Pearson correlation indicated mostly positive correlations between the levels of free, conjugated, and bound forms of PUT, SPD, and SPM under drought and salinity stress. However, negative correlations were mostly seen between the levels of various forms of the PAs and their biosynthesis/catabolic genes. Levels of different PA forms had a twofold higher negative correlation during drought as compared to salinity stress (66 vs. 32) and with transcript levels of PA biosynthesis and catabolic genes. Transcripts of light-harvesting chlorophyll a/b-binding genes were generally positively associated with different forms of PAs but negatively to carbon flow genes. Most of the PA biosynthesis genes were coordinately regulated under both stresses. Collectively, these results indicate that PAs are distinctly regulated under drought and salinity stress with different but specific homologs of PA biosynthesis and catabolic genes contributing to the accumulation of free, conjugated, and bound forms of PAs.
Plants and Microbes Mediate the Shift in Ecosystem Multifunctionality From Low to High Patterns Across Alpine Grasslands on the Tibetan Plateau
Authors: Wang Yi , Liu Miao , Chen Youchao , Zeng Tao , Lu Xuyang , Yang Bin , Wang Yafeng , Zhang Lin , Nie Xiaowei , Xiao Feipeng , Zhang Zhigang , Sun Jian
Published: October 2021

Both plant communities and soil microbes have been reported to be correlated with ecosystem multifunctionality (EMF) in terrestrial ecosystems. However, the process and mechanism of aboveground and belowground communities on different EMF patterns are not clear. In order to explore different response patterns and mechanisms of EMF, we divided EMF into low (<0) and high patterns (>0). We found that there were contrasting patterns of low and high EMF in the alpine grassland ecosystem on the Tibetan Plateau. Specifically, compared with low EMF, environmental factors showed higher sensitivity to high EMF. Soil properties are critical factors that mediate the impact of community functions on low EMF based on the change of partial correlation coefficients from 0 to 0.24. In addition, plant community functions and microbial biomass may mediate the shift of EMF from low to high patterns through the driving role of climate across the alpine grassland ecosystem. Our findings will be vital to clarify the mechanism for the stability properties of grassland communities and ecosystems under ongoing and future climate change.