bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpretation of laws as form of law implementation
Authors: Kostytsky V. V.
Published: August 2021

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Techniques of the teleological method of interpretation of legal norms
Authors: Malyshev B. V.
Published: August 2021

This article considers subjective and objective approaches to the teleological method of interpretation of legal norms.

Upon generalization of the thoughts presented in legal literature, the following list of techniques of the teleologicalmethod of interpretation of legal norms was made: 1) consideration of dialectics of the purpose and means of its achievement; 2) drawing conclusion on the purpose of the norm based on the purpose of another norm; 3) a conclusion on the purpose of the norm with regard to the general direction of the legal regulation of specific relations; 4) taking into account the link between the purpose of the norm and the goals of the more general nature (the general purpose of the normative legal act, the relationship of the norms of the special part with the purposes of the norms of the general part or for the purpose of the institution of law), in so doing goals of higher value and legal force are contained in the forms of law that have the higher legal force; 5) conclusion on the purpose of the norm in accordance with the content of the Constitution; 6) genetic reception of teleological interpretation (study of the purpose of a similar rule of law, which has expired); 7) in the case of an ambiguous understanding of a rule of law, you should choose the option that best meets its purpose.

Keywords: norm of law, purpose of the norm of law, teleology of law, teleological (purposive) way of interpretation of norms of law.
Therapeutic Options for Chronic Rhinosinusitis in N-ERD Patients
Authors: van der Lans Rik J. L. , Fokkens Wytske J. , Reitsma Sietze
Published: August 2021

Patients with non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) often suffer from chronic rhinosinusitis (CRS) with nasal polyps, a form of primary diffuse Type 2 CRS. Although this disease is also seen in NSAID-tolerant patients, CRS in N-ERD often is more severe and more treatment resistant; local nasal therapy (nasal corticosteroids) and endoscopic sinus surgery are employed like in NSAID-tolerant patients, but with limited and/or short-lived effects. This mini-review gives an overview of the current additional treatment options for CRS in N-ERD. As such diets, aspirin therapy after desensitization, antileukotriene therapy and biologicals are discussed based on the current body of literature. Selecting the right treatment strategy depends on shared-decision making, local availability and cooperation between ENT-surgeons, allergists, and pulmonologists.
Fexofenadine Protects Against Intervertebral Disc Degeneration Through TNF Signaling
Authors: Liu Kaiwen , Wei Jianlu , Li Guohua , Liu Ronghan , Zhao Dawang , Zhang Yuanqiang , Shi Jie , Xie Qing , Cheng Lei
Published: August 2021

Objective: Fexofenadine (FFD) is an antihistamine drug with an anti-inflammatory effect. The intervertebral disc (IVD) degeneration process is involved in inflammation in which tumor necrosis factor-α (TNF-α) plays an important role. This study aims to investigate the role of FFD in the pathological process of IVD degeneration.

Methods: Safranin O staining was used for the measurement of cartilageous tissue in the disc. Hematoxylin-Eosin (H&E) staining was used to determine the disc construction. A rat needle puncture model was taken advantage of to examine the role of FFD in disc degeneration in vivo. Western Blotting assay, immunochemistry, and immunoflurence staining were used for the determination of inflammatory molecules. ELISA assay was performed to detect the release of inflammatory cytokines. A real-time PCR assay was analyzed to determine the transcriptional expressions of molecules.

Results: Elevated TNF-α resulted in inflammatory disc degeneration, while FFD protected against TNF-α-induced IVD degeneration. Mechanism study found FFD exhibited a disc protective effect through at least two pathways. (a) FFD inhibited TNF-α-mediated extracellular matrix (ECM) degradation and (b) FFD rescued TNF-α induced inflammation in disc degeneration. Furthermore, the present study found that FFD suppressed TNF-α mediated disc degeneration via the cPLA2/NF-κB signaling pathway.

Conclusions: FFD provided another alternative for treating disc degeneration through a novel mechanism. Additionally, FFD may also be a potential target for the treatment of other inflammatory-related diseases, including IVD degeneration.
CircITGA7 Suppresses Gastric Cancer Progression Through miR-1471/MTDH Axis
Authors: Jin Haifeng , Wu Zheng , Tan Bibo , Liu Zhen , Zhang Binqian
Published: August 2021

In recent years, there have been reports about the involvement of circular RNAs (circRNAs) in the pathogenesis of gastric cancer (GC), but the molecular mechanism in cell proliferation, invasion, and migration is still unclear. Based on The Cancer Genome Atlas (TCGA) database, we analyzed differentially expressed circRNAs between GC and non-tumor tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were used to clarify the functional role in GC. Here, we showed that circITGA7 was lowly expressed in GC tissues based on the TCGA database. In vitro, silencing the expression of circITGA7 increased cell proliferation and metastasis, whereas overexpression did the opposite. Mechanistically, miR-1471 has circITGA7 as a sponge, and miR-1471 has metadherin (MTDH) as a target gene. Consequently, functional analysis showed that the tumor suppressor effect of circITGA7 was the result of regulating the miR-1471/MTDH axis. Overall, the circITGA7/miR-1471/MTDH signaling pathway may play a crucial role in GC, providing a new potential mechanism involved in GC progression.
Blood–Brain Barrier, Cell Junctions, and Tumor Microenvironment in Brain Metastases, the Biological Prospects and Dilemma in Therapies
Authors: Guan Zhiyuan , Lan Hongyu , Cai Xin , Zhang Yichi , Liang Annan , Li Jin
Published: August 2021

Brain metastasis is the most commonly seen brain malignancy, frequently originating from lung cancer, breast cancer, and melanoma. Brain tumor has its unique cell types, anatomical structures, metabolic constraints, and immune environment, which namely the tumor microenvironment (TME). It has been discovered that the tumor microenvironment can regulate the progression, metastasis of primary tumors, and response to the treatment through the particular cellular and non-cellular components. Brain metastasis tumor cells that penetrate the brain–blood barrier and blood–cerebrospinal fluid barrier to alter the function of cell junctions would lead to different tumor microenvironments. Emerging evidence implies that these tumor microenvironment components would be involved in mechanisms of immune activation, tumor hypoxia, antiangiogenesis, etc. Researchers have applied various therapeutic strategies to inhibit brain metastasis, such as the combination of brain radiotherapy, immune checkpoint inhibitors, and monoclonal antibodies. Unfortunately, they hardly access effective treatment. Meanwhile, most clinical trials of target therapy patients with brain metastasis are always excluded. In this review, we summarized the clinical treatment of brain metastasis in recent years, as well as their influence and mechanisms underlying the differences between the composition of tumor microenvironments in the primary tumor and brain metastasis. We also look forward into the feasibility and superiority of tumor microenvironment-targeted therapies in the future, which may help to improve the strategy of brain metastasis treatment.
Characterization of Emerging Pathogens Carrying blaKPC-2 Gene in IncP-6 Plasmids Isolated From Urban Sewage in Argentina
Authors: Ghiglione Barbara , Haim María Sol , Penzotti Pedro , Brunetti Florencia , D´Amico González Gabriela , Di Conza José , Figueroa-Espinosa Roque , Nuñez Lidia , Razzolini María Tereza Pepe , Fuga Bruna , Esposito Fernanda , Vander Horden Maximiliano , Lincopan Nilton , Gutkind Gabriel , Power Pablo , Dropa Milena
Published: August 2021

Untreated wastewater is a reservoir for multidrug-resistant bacteria, but its role in the spread of antibiotic resistance in the human population remains poorly investigated. In this study, we isolated a KPC-2-producing ST2787 Klebsiella quasipneumoniae subsp. quasipneumoniae (WW14A), recovered from raw sewage at a wastewater treatment plant in Argentina in 2018 and determined its complete genome sequence. Strain WW14A was resistant to all β-lactams, ciprofloxacin and amikacin. A core genome phylogenetic analysis indicated that WW14A was closely related to a GES-5-producing Taiwanese strain isolated from hospital wastewater in 2015 and it was clearly distinct from strains isolated recently in Argentina and Brazil. Interestingly, blaKPC-2 was harbored by a recently described IncP-6 broad-spectrum plasmid which was sporadically reported worldwide and had never been reported before in Argentina. We investigated the presence of the IncP-6 replicon in isolates obtained from the same sampling and found a novel non-typable/IncP-6 hybrid plasmid in a newly assigned ST1407 Enterobacter asburiae (WW19C) also harboring blaKPC-2. Nanopore sequencing and hybrid assembly of strains WW14A and WW19C revealed that both IncP-6 plasmids shared 72% of coverage (~20 kb), with 99.99% of sequence similarity and each one also presented uniquely combined regions that were derived from other plasmids recently reported in different countries of South America, Asia, and Europe. The region harboring the carbapenem resistance gene (~11 kb) in both plasmids contained a Tn3 transposon disrupted by a Tn3-ISApu-flanked element and the core sequence was composed by ΔISKpn6/blaKPC-2/ΔblaTEM-1/ISKpn27. Both strains also carried genes conferring resistance to heavy metals (e.g., arsenic, mercury, lead, cadmium, copper), pesticides (e.g., glyphosate), disinfectants, and several virulence-related genes, posing a potential pathogenic risk in the case of infections. This is the first study documenting blaKPC-2 associated with IncP-6 plasmids in K. quasipneumoniae and Enterobacter cloacae complex from wastewater in Argentina and highlights the circulation of IncP-6 plasmids as potential reservoirs of blaKPC-2 in the environment.
U-Shaped Relationship of Low-Density Lipoprotein Cholesterol With Risk of Severe COVID-19 From a Multicenter Pooled Analysis
Authors: Gong Jiao , Chen Yaqiong , Jie Yusheng , Tan Mingkai , Jiang Zhaofang , Yuan Lianxiong , Cao Jing , Li Ganwen , Chong Yutian , Qu Jiuxin , Shi Yaling , Hu Bo
Published: August 2021

Low-density lipoprotein cholesterol (LDL-C) is a well-known risk factor for coronary heart disease but protects against infection and sepsis. We aimed to disclose the exact association between LDL-C and severe 2019 novel coronavirus disease (COVID-19). Baseline data were retrospectively collected for 601 non-severe COVID-19 patients from two centers in Guangzhou and one center in Shenzhen, and patients on admission were medically observed for at least 15 days to determine the final outcome, including the non-severe group (n = 460) and the severe group (severe and critical cases) (n = 141). Among 601 cases, 76 (12.65%) received lipid-lowering therapy; the proportion of patients taking lipid-lowering drugs in the severe group was higher than that in the non-severe group (22.7 vs. 9.6%). We found a U-shaped association between LDL-C level and risk of severe COVID-19 using restricted cubic splines. Using univariate logistic regression analysis, odds ratios for severe COVID-19 for patients with LDL-C ≤1.6 mmol/L (61.9 mg/dL) and above 3.4 mmol/L (131.4 mg/dL) were 2.29 (95% confidence interval 1.12–4.68; p = 0.023) and 2.02 (1.04–3.94; p = 0.039), respectively, compared to those with LDL-C of 2.81–3.40 mmol/L (108.6–131.4 mg/dL); following multifactorial adjustment, odds ratios were 2.61 (1.07–6.37; p = 0.035) and 2.36 (1.09–5.14; p = 0.030). Similar results were yielded using 0.3 and 0.5 mmol/L categories of LDL-C and sensitivity analyses. Both low and high LDL-C levels were significantly associated with higher risk of severe COVID-19. Although our findings do not necessarily imply causality, they suggest that clinicians should pay more attention to lipid-lowering therapy in COVID-19 patients to improve clinical prognosis.
Surgical Risk Factors for Ischemic Stroke Following Coronary Artery Bypass Grafting. A Multi-Factor Multimodel Analysis
Authors: Gelsomino Sandro , Tetta Cecilia , Matteucci Francesco , del Pace Stefano , Parise Orlando , Prifti Edvin , Dokollari Aleksander , Parise Gianmarco , Micali Linda Renata , La Meir Mark , Bonacchi Massimo
Published: August 2021

Graphical Abstract

Factors increasing post CABG incidence of ischemic stroke (red) and those which were not significant at the multi-model multifactorial analysis that analyzed all technical factors alone or in different combinations (green).
The Role of the VEGF Family in Coronary Heart Disease
Authors: Zhou Yan , Zhu Xueping , Cui Hanming , Shi Jingjing , Yuan Guozhen , Shi Shuai , Hu Yuanhui
Published: August 2021

The vascular endothelial growth factor (VEGF) family, the regulator of blood and lymphatic vessels, is mostly investigated in the tumor and ophthalmic field. However, the functions it enjoys can also interfere with the development of atherosclerosis (AS) and further diseases like coronary heart disease (CHD). The source, regulating mechanisms including upregulation and downregulation, target cells/tissues, and known functions about VEGF-A, VEGF-B, VEGF-C, and VEGF-D are covered in the review. VEGF-A can regulate angiogenesis, vascular permeability, and inflammation by binding with VEGFR-1 and VEGFR-2. VEGF-B can regulate angiogenesis, redox, and apoptosis by binding with VEGFR-1. VEGF-C can regulate inflammation, lymphangiogenesis, angiogenesis, apoptosis, and fibrogenesis by binding with VEGFR-2 and VEGFR-3. VEGF-D can regulate lymphangiogenesis, angiogenesis, fibrogenesis, and apoptosis by binding with VEGFR-2 and VEGFR-3. These functions present great potential of applying the VEGF family for treating CHD. For instance, angiogenesis can compensate for hypoxia and ischemia by growing novel blood vessels. Lymphangiogenesis can degrade inflammation by providing exits for accumulated inflammatory cytokines. Anti-apoptosis can protect myocardium from impairment after myocardial infarction (MI). Fibrogenesis can promote myocardial fibrosis after MI to benefit cardiac recovery. In addition, all these factors have been confirmed to keep a link with lipid metabolism, the research about which is still in the early stage and exact mechanisms are relatively obscure. Because few reviews have been published about the summarized role of the VEGF family for treating CHD, the aim of this review article is to present an overview of the available evidence supporting it and give hints for further research.
Ultrasound-Guided Thermal Ablation of Bethesda IV Thyroid Nodules: A Pilot Study
Authors: Li Xinyang , Lan Yu , Li Nan , Yan Lin , Xiao Jing , Zhang Mingbo , Luo Yukun
Published: August 2021

Objective

The purpose of our study was to evaluate the effectiveness of thermal ablation (TA) for Bethesda IV thyroid nodules, and to compare TA and surgery in terms of treatment outcomes, complications, and costs.

Method

This study was approved by the local ethics committee. From January 2017 to December 2019, 30 patients elected TA and 31 patients elected surgery for treatment of Bethesda IV thyroid nodules. Demographics information and conventional ultrasound before treatment for each patient was obtained. For the TA group, the ablation extent was 3 mm beyond the edge of the tumor to prevent marginal residual and recurrence. Patients were followed up at 1, 3, and 6 months after intervention, and every 6 months thereafter. Postoperative complications, operation time, hospitalization time, blood loss, and incision length were recorded.

Results

In the TA group, the volume reduction ratio (VRR) was 94.63 ± 8.99% (range:76%-100%) at the final follow-up. The mean follow-up time was 16.4 ± 5.2months (range:12–24 months). No recurrences, no metastatic lymph node, and no distant metastases were detected during follow-up. The TA group had fewer complications, shorter operation time, smaller incision length, less blood loss, shorter hospitalization time, and lower treatment costs compared to the surgery group (all P<0.001).

Conclusions

TA is technically feasible for the complete destruction of Bethesda IV thyroid nodules, and also safe and effective during the follow-up period, with high VRR and low complication rates, especially in patients who were ineligible for or refused surgery.
First Description of a Satellite DNA in Manatees’ Centromeric Regions
Authors: Valeri Mirela Pelizaro , Dias Guilherme Borges , do Espírito Santo Alice Alves , Moreira Camila Nascimento , Yonenaga-Yassuda Yatiyo , Sommer Iara Braga , Kuhn Gustavo C. S. , Svartman Marta
Published: August 2021

Trichechus manatus and Trichechus inunguis are the two Sirenia species that occur in the Americas. Despite their increasing extinction risk, many aspects of their biology remain understudied, including the repetitive DNA fraction of their genomes. Here we used the sequenced genome of T. manatus and TAREAN to identify satellite DNAs (satDNAs) in this species. We report the first description of TMAsat, a satDNA comprising ~0.87% of the genome, with ~684bp monomers and centromeric localization. In T. inunguis, TMAsat showed similar monomer length, chromosome localization and conserved CENP-B box-like motifs as in T. manatus. We also detected this satDNA in the Dugong dugon and in the now extinct Hydrodamalis gigas genomes. The neighbor-joining tree shows that TMAsat sequences from T. manatus, T. inunguis, D. dugon, and H. gigas lack species-specific clusters, which disagrees with the predictions of concerted evolution. We detected a divergent TMAsat-like homologous sequence in elephants and hyraxes, but not in other mammals, suggesting this sequence was already present in the common ancestor of Paenungulata, and later became a satDNA in the Sirenians. This is the first description of a centromeric satDNA in manatees and will facilitate the inclusion of Sirenia in future studies of centromeres and satDNA biology.
Fine-Scale Genetic Structure and Natural Selection Signatures of Southwestern Hans Inferred From Patterns of Genome-Wide Allele, Haplotype, and Haplogroup Lineages
Authors: Wang Mengge , Yuan Didi , Zou Xing , Wang Zheng , Yeh Hui-Yuan , Liu Jing , Wei Lan-Hai , Wang Chuan-Chao , Zhu Bofeng , Liu Chao , He Guanglin
Published: August 2021

The evolutionary and admixture history of Han Chinese have been widely discussed via traditional autosomal and uniparental genetic markers [e.g., short tandem repeats, low-density single nucleotide polymorphisms). However, their fine-scale genetic landscapes (admixture scenarios and natural selection signatures) based on the high-density allele/haplotype sharing patterns have not been deeply characterized. Here, we collected and generated genome-wide data of 50 Han Chinese individuals from four populations in Guizhou Province, one of the most ethnolinguistically diverse regions, and merged it with over 3,000 publicly available modern and ancient Eurasians to describe the genetic origin and population admixture history of Guizhou Hans and their neighbors. PCA and ADMIXTURE results showed that the studied four populations were homogeneous and grouped closely to central East Asians. Genetic homogeneity within Guizhou populations was further confirmed via the observed strong genetic affinity with inland Hmong-Mien people through the observed genetic clade in Fst and outgroup f3/f4-statistics. qpGraph-based phylogenies and f4-based demographic models illuminated that Guizhou Hans were well fitted via the admixture of ancient Yellow River Millet farmers related to Lajia people and southern Yangtze River farmers related to Hanben people. Further ChromoPainter-based chromosome painting profiles and GLOBETROTTER-based admixture signatures confirmed the two best source matches for southwestern Hans, respectively, from northern Shaanxi Hans and southern indigenes with variable mixture proportions in the historical period. Further three-way admixture models revealed larger genetic contributions from coastal southern East Asians into Guizhou Hans compared with the proposed inland ancient source from mainland Southeast Asia. We also identified candidate loci (e.g., MTUS2, NOTCH4, EDAR, ADH1B, and ABCG2) with strong natural selection signatures in Guizhou Hans via iHS, nSL, and ihh, which were associated with the susceptibility of the multiple complex diseases, morphology formation, alcohol and lipid metabolism. Generally, we provided a case and ideal strategy to reconstruct the detailed demographic evolutionary history of Guizhou Hans, which provided new insights into the fine-scale genomic formation of one ethnolinguistically specific targeted population from the comprehensive perspectives of the shared unlinked alleles, linked haplotypes, and paternal and maternal lineages.
Comparative Transcriptome Analysis to Identify Candidate Genes for FaRCg1 Conferring Resistance Against Colletotrichum gloeosporioides in Cultivated Strawberry (Fragaria × ananassa)
Authors: Chandra Saket , Oh Youngjae , Han Hyeondae , Salinas Natalia , Anciro Ashlee , Whitaker Vance M. , Chacon Jose Guillermo , Fernandez Gina , Lee Seonghee
Published: August 2021

Colletotrichum crown rot (CCR) caused by Colletotrichum gloeosporioides is a serious threat to the cultivated strawberry (Fragaria × ananassa). Our previous study reported that a major locus, FaRCg1, increases resistance. However, the genomic structure of FaRCg1 and potential candidate genes associated with the resistance remained unknown. Here, we performed comparative transcriptome analyses of resistant ‘Florida Elyana’ and susceptible ‘Strawberry Festival’ after infection and identified candidate genes potentially involved in resistance. In ‘Florida Elyana’, 6,099 genes were differentially expressed in response to C. gloeosporioides. Gene ontology analysis showed that the most upregulated genes were functionally associated with signaling pathways of plant defense responses. Three genes in the genomic region of FaRCg1 were highly upregulated: a von Willebrand Factor A domain-containing protein, a subtilisin-like protease, and a TIFY 11A-like protein. Subgenome-specific markers developed for the candidate genes were tested with a diverse panel of 219 accessions from University of Florida and North Carolina State University breeding programs. Significant and positive associations were found between the high-resolution melting (HRM) marker genotypes and CCR phenotypes. These newly developed subgenome-specific functional markers for FaRCg1 can facilitate development of resistant varieties through marker-assisted selection.
Biomarkers and Immune Repertoire Metrics Identified by Peripheral Blood Transcriptomic Sequencing Reveal the Pathogenesis of COVID-19
Authors: Liu Yang , Wu Yankang , Liu Bing , Zhang Youpeng , San Dan , Chen Yu , Zhou Yu , Yu Long , Zeng Haihong , Zhou Yun , Zhou Fuxiang , Yang Heng , Yin Lei , Huang Yafei
Published: August 2021

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global crisis; however, our current understanding of the host immune response to SARS-CoV-2 infection remains limited. Herein, we performed RNA sequencing using peripheral blood from acute and convalescent patients and interrogated the dynamic changes of adaptive immune response to SARS-CoV-2 infection over time. Our results revealed numerous alterations in these cohorts in terms of gene expression profiles and the features of immune repertoire. Moreover, a machine learning method was developed and resulted in the identification of five independent biomarkers and a collection of biomarkers that could accurately differentiate and predict the development of COVID-19. Interestingly, the increased expression of one of these biomarkers, UCHL1, a molecule related to nervous system damage, was associated with the clustering of severe symptoms. Importantly, analyses on immune repertoire metrics revealed the distinct kinetics of T-cell and B-cell responses to SARS-CoV-2 infection, with B-cell response plateaued in the acute phase and declined thereafter, whereas T-cell response can be maintained for up to 6 months post-infection onset and T-cell clonality was positively correlated with the serum level of anti-SARS-CoV-2 IgG. Together, the significantly altered genes or biomarkers, as well as the abnormally high levels of B-cell response in acute infection, may contribute to the pathogenesis of COVID-19 through mediating inflammation and immune responses, whereas prolonged T-cell response in the convalescents might help these patients in preventing reinfection. Thus, our findings could provide insight into the underlying molecular mechanism of host immune response to COVID-19 and facilitate the development of novel therapeutic strategies and effective vaccines.
Current Desensitization Strategies in Heart Transplantation
Authors: Habal Marlena V.
Published: August 2021

Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.
The Role of Hemoglobin Subunit Delta in the Immunopathy of Multiple Sclerosis: Mitochondria Matters
Authors: Derakhshani Afshin , Safarpour Hossein , Abdoli Shadbad Mahdi , Hemmat Nima , Leone Patrizia , Asadzadeh Zahra , Pashazadeh Mehrdad , Baradaran Behzad , Racanelli Vito
Published: August 2021

Background

Although the exact pathophysiology of MS has not been identified, mitochondrial stress can be one of the culprits in MS development. Herein, we have applied microarray analysis, single-cell sequencing analysis, and ex vivo study to elucidate the role of mitochondrial stress in PBMCs of MS patients.

Methods

For this purpose, we analyzed the GSE21942 and GSE138266 datasets to identify the DEGs and hub genes in the PBMCS of MS patients and describe the expression of shared genes in the different immune cells. The GO pathway analysis of DEGs and turquoise module genes were conducted to shed light on their biological significance. To validate the obtained results, the gene expression of HBD, as the most remarkable DEG in the PBMCS of affected patients, was measured in the PBMCS of healthy donors, treatment-naïve MS patients, and MS patients treated with GA, fingolimod, DMF, and IFNβ-1α.

Results

Based on WGCNA and DEGs analysis, HBD, HBM, SLC4A1, LILRA5, SLC25A37, SELENBP1, ALYREF, SNRNP40, and HINT3 are the identified common genes in the PMBCS. Using single-cell sequencing analysis on PBMCS, we have characterized various cell populations in MS and illustrated the common gene expression on the different immune cells. Furthermore, GO pathway analysis of DEGs, and turquoise module genes have indicated that these genes are involved in immune responses, myeloid cell activation, leukocyte activation, oxygen carrier activity, and replication fork processing bicarbonate transport pathways. Our ex vivo investigation has shown that HBD expression in the treatment-naïve RRMS patients is significantly increased compared to healthy donors. Of interest, immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α have significantly decreased HBD expression.

Conclusion

HBD is one of the remarkably up-regulated genes in the PBMCS of MS patients. HBD is substantially up-regulated in treatment-naïve MS patients, and immunomodulatory therapies with fingolimod, DMF, and IFNβ-1α can remarkably down-regulate HBD expression. Based on the currently available evidence, the cytoprotective nature of HBD against oxidative stress can be the underlying reason for HBD up-regulation in MS. Nevertheless, further investigations are needed to shed light on the molecular mechanisms of HBD in the oxidative stress of MS patients.
Validation of a Triplex Pharmacokinetic Assay for Simultaneous Quantitation of HIV-1 Broadly Neutralizing Antibodies PGT121, PGDM1400, and VRC07-523-LS
Authors: Wesley Martina S. , Chiong Kelvin T. , Seaton Kelly E. , Arocena Christine A. , Sawant Sheetal , Hare Jonathan , Hernandez Kasey , Rojas Michelle , Heptinstall Jack , Beaumont David , Crisafi Katherine , Nkolola Joseph , Barouch Dan H. , Sarzotti-Kelsoe Marcella , Tomaras Georgia D. , Yates Nicole L.
Published: August 2021

The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection.
Traumatic Brain Injury Induces cGAS Activation and Type I Interferon Signaling in Aged Mice
Authors: Barrett James P. , Knoblach Susan M. , Bhattacharya Surajit , Gordish-Dressman Heather , Stoica Bogdan A. , Loane David J.
Published: August 2021

Aging adversely affects inflammatory processes in the brain, which has important implications in the progression of neurodegenerative disease. Following traumatic brain injury (TBI), aged animals exhibit worsened neurological function and exacerbated microglial-associated neuroinflammation. Type I Interferons (IFN-I) contribute to the development of TBI neuropathology. Further, the Cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway, a key inducer of IFN-I responses, has been implicated in neuroinflammatory activity in several age-related neurodegenerative diseases. Here, we set out to investigate the effects of TBI on cGAS/STING activation, IFN-I signaling and neuroinflammation in young and aged C57Bl/6 male mice. Using a controlled cortical impact model, we evaluated transcriptomic changes in the injured cortex at 24 hours post-injury, and confirmed activation of key neuroinflammatory pathways in biochemical studies. TBI induced changes were highly enriched for transcripts that were involved in inflammatory responses to stress and host defense. Deeper analysis revealed that TBI increased expression of IFN-I related genes (e.g. Ifnb1, Irf7, Ifi204, Isg15) and IFN-I signaling in the injured cortex of aged compared to young mice. There was also a significant age-related increase in the activation of the DNA-recognition pathway, cGAS, which is a key mechanism to propagate IFN-I responses. Finally, enhanced IFN-I signaling in the aged TBI brain was confirmed by increased phosphorylation of STAT1, an important IFN-I effector molecule. This age-related activation of cGAS and IFN-I signaling may prove to be a mechanistic link between microglial-associated neuroinflammation and neurodegeneration in the aged TBI brain.
Cyprinus carpio TRIF Participates in the Innate Immune Response by Inducing NF-κB and IFN Activation and Promoting Apoptosis
Authors: Liu Rongrong , Liu Xiaoye , Song Meijiao , Qi Yue , Li Hua , Yang Guiwen , Shan Shijuan
Published: August 2021

TRIF, an important adaptor downstream of Toll-like receptor signaling, plays a critical role in the innate immune response. In this study, the full-length coding sequence of TRIF from common carp (Cyprinus carpio L.) was cloned and characterized. Bioinformatics analysis showed that common carp TRIF exhibited a conserved TIR domain and had the closest relationship with grass carp TRIF. Expression analysis revealed that TRIF was constitutively expressed in the examined tissues of common carp, with the highest expression in the spleen and the lowest expression in the head kidney, and could be upregulated under Aeromonas hydrophila and poly(I:C) stimulation in vivo and under poly(I:C), LPS, PGN, flagellin, and Pam3CSK4 stimulation in vitro. Laser confocal microscopy showed that common carp TRIF colocalized with the Golgi apparatus. A luciferase reporter assay showed that carp TRIF elicited the activity of ifn-1 and nf-κb through the C-terminal domain. Additionally, crystal violet staining and qPCR assays revealed that carp TRIF inhibited the replication of SVCV in epithelioma papulosum cyprini (EPC) cells. Then, the signaling downstream of carp TRIF was investigated. Coimmunoprecipitation and Western blotting analysis demonstrated that carp TRIF interacted with TBK1 and augmented the expression of TRAF6 and phosphorylation of TBK1. Overexpression of carp TRIF significantly enhanced the expression of interferon-stimulated genes and inflammatory cytokines. Furthermore, flow cytometric (FCM) analysis suggested that carp TRIF induced apoptosis through the activation of caspase-8. In summary, our study indicated that TRIF plays an essential role in the innate immune responses of common carp against bacterial and viral infection.
The Molecular Mechanism of Multiple Organ Dysfunction and Targeted Intervention of COVID-19 Based on Time-Order Transcriptomic Analysis
Authors: Zou Miao , Su Xiaoyun , Wang Luoying , Yi Xingcheng , Qiu Yue , Yin Xirui , Zhou Xuan , Niu Xinhui , Wang Liuli , Su Manman
Published: August 2021

Coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus that has spread rapidly around the world, leading to high mortality because of multiple organ dysfunction; however, its underlying molecular mechanism is unknown. To determine the molecular mechanism of multiple organ dysfunction, a bioinformatics analysis method based on a time-order gene co-expression network (TO-GCN) was performed. First, gene expression profiles were downloaded from the gene expression omnibus database (GSE161200), and a TO-GCN was constructed using the breadth-first search (BFS) algorithm to infer the pattern of changes in the different organs over time. Second, Gene Ontology enrichment analysis was used to analyze the main biological processes related to COVID-19. The initial gene modules for the immune response of different organs were defined as the research object. The STRING database was used to construct a protein–protein interaction network of immune genes in different organs. The PageRank algorithm was used to identify five hub genes in each organ. Finally, the Comparative Toxicogenomics Database played an important role in exploring the potential compounds that target the hub genes. The results showed that there were two types of biological processes: the body’s stress response and cell-mediated immune response involving the lung, trachea, and olfactory bulb (olf) after being infected by COVID-19. However, a unique biological process related to the stress response is the regulation of neuronal signals in the brain. The stress response was heterogeneous among different organs. In the lung, the regulation of DNA morphology, angiogenesis, and mitochondrial-related energy metabolism are specific biological processes related to the stress response. In particular, an effect on tracheal stress response was made by the regulation of protein metabolism and rRNA metabolism-related biological processes, as biological processes. In the olf, the distinctive stress responses consist of neural signal transmission and brain behavior. In addition, myeloid leukocyte activation and myeloid leukocyte-mediated immunity in response to COVID-19 can lead to a cytokine storm. Immune genes such asSRC,RHOA,CD40LG,CSF1,TNFRSF1A,FCER1G,ICAM1,LAT,LCN2,PLAU,CXCL10,ICAM1,CD40,IRF7, andB2Mwere predicted to be the hub genes in the cytokine storm. Furthermore, we inferred that resveratrol, acetaminophen, dexamethasone, estradiol, statins, curcumin, and other compounds are potential target drugs in the treatment of COVID-19.
The Cancer Epitope Database and Analysis Resource: A Blueprint for the Establishment of a New Bioinformatics Resource for Use by the Cancer Immunology Community
Authors: Koşaloğlu-Yalçın Zeynep , Blazeska Nina , Carter Hannah , Nielsen Morten , Cohen Ezra , Kufe Donald , Conejo-Garcia Jose , Robbins Paul , Schoenberger Stephen P. , Peters Bjoern , Sette Alessandro
Published: August 2021

Recent years have witnessed a dramatic rise in interest towards cancer epitopes in general and particularly neoepitopes, antigens that are encoded by somatic mutations that arise as a consequence of tumorigenesis. There is also an interest in the specific T cell and B cell receptors recognizing these epitopes, as they have therapeutic applications. They can also aid in basic studies to infer the specificity of T cells or B cells characterized in bulk and single-cell sequencing data. The resurgence of interest in T cell and B cell epitopes emphasizes the need to catalog all cancer epitope-related data linked to the biological, immunological, and clinical contexts, and most importantly, making this information freely available to the scientific community in a user-friendly format. In parallel, there is also a need to develop resources for epitope prediction and analysis tools that provide researchers access to predictive strategies and provide objective evaluations of their performance. For example, such tools should enable researchers to identify epitopes that can be effectively used for immunotherapy or in defining biomarkers to predict the outcome of checkpoint blockade therapies. We present here a detailed vision, blueprint, and work plan for the development of a new resource, the Cancer Epitope Database and Analysis Resource (CEDAR). CEDAR will provide a freely accessible, comprehensive collection of cancer epitope and receptor data curated from the literature and provide easily accessible epitope and T cell/B cell target prediction and analysis tools. The curated cancer epitope data will provide a transparent benchmark dataset that can be used to assess how well prediction tools perform and to develop new prediction tools relevant to the cancer research community.
Impact of Ship Traffic on the Characteristics of Shelf Sediments: An Anthropocene Prospective
Authors: Xue Chengfeng , Yang Yang , Zhao Peipei , Wei Dongyun , Gao Jianhua , Sun Peng , Huang Zhiyang , Jia Jianjun
Published: August 2021

Humans have been sailing across seas and oceans for thousands of years. However, the story of large ships capable of affecting coastal ecology and shelf sedimentary processes is only about 100 years old. Modern large seagoing vessels with a draft of 10–20 m can cause resuspension of seabed sediment, erosion of the channel slope and shoal, enhancement of seafloor sediment activity and thickening of the active layer, thereby having a significant impact on seabed topography and sedimentation processes. However, little is known about the effects of this anthropogenic agent on shelf sedimentation due to limited observational data. Here, two sediment cores were collected from a shipping lane used by vessels of 5,000- to 50,000-ton off the coast of China to analyze their sedimentary properties, with focus on both the grain size and elements. It was found that ship disturbance selectively modified the sedimentary record, with the fine-grained sediment becoming increasingly unstable. In addition, there was a reduction in grain size of sediment finer than 6.25 Φ, which decreased by 11% after the disturbance by ship. Biogenic elements that were closely related to the ecological environment were significantly altered, with Br/Cl, Si/Ti, and Ca/Ti ratios all becoming significantly smaller. This indicated that frequent disturbance caused by ships had reduced the productivity in the waters near the shipping lane. In terms of sensitivity to the effects of ship navigation, the sedimentation response was relatively rapid and began to emerge from the commencement of ship navigation, whereas the ecological response became evident later than the sedimentation response and only appeared after a significant growth in the maritime transportation of China. Following the comparison of the two sediment cores, we propose that the constant rate of supply (CRS- with ship disturbance)–constant initial concentration (CIC- without ship disturbance) dual dating model be used to establish a dating framework in waters frequently disturbed by ship. This type of anthropogenic sedimentary dynamic process and its sedimentary–ecological effects deserve attention on this era where there is a surge in shipping globally. Shipping lanes present an excellent area for quantitative studies on the impacts of human activity and defining the Anthropocene in the context of shipping.
Improve the Forming Ability of Al-Based Metallic Glass Under Ultrasonic Vibration at Room Temperature
Authors: Liang Xiong , Fan Caitao , Fu Jianan , Liu Zehang , Zhang Zhenxuan , Ren Shuai , Ruan Wenqing , Shi Hongyan
Published: August 2021

In this work, a rapid and controllable ultrasonic vibration method for forming Al-based metallic glass at room temperature is proposed. This method can dramatically improve the forming ability of Al-based metallic glasses, which are virtually brittle at room temperature and have almost no supercooled liquid region at high temperatures. Under ultrasonic vibration, Al-based metallic glasses exhibited obvious plastic flow, with a maximum deformation degree up to 58% and an average deformation degree up to 43%. It is worth mentioning that no crystalline peaks were found on the X-ray diffraction patterns after deformation under ultrasonic vibration, and the mechanical properties remained the same as the primary sample. The present results provide a new approach for the deformation and forming of Al-based metallic glasses, which can significantly broaden their applications.