bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Validation of the Pyroptosis-Related Molecular Subtypes of Lung Adenocarcinoma by Bioinformatics and Machine Learning
Authors: Liu Le-Ping , Lu Lu , Zhao Qiang-Qiang , Kou Qin-Jie , Jiang Zhen-Zhen , Gui Rong , Luo Yan-Wei , Zhao Qin-Yu
Published: November 2021

Lung cancer remains the leading cause of cancer death globally, with lung adenocarcinoma (LUAD) being its most prevalent subtype. Due to the heterogeneity of LUAD, patients given the same treatment regimen may have different responses and clinical outcomes. Therefore, identifying new subtypes of LUAD is important for predicting prognosis and providing personalized treatment for patients. Pyroptosis-related genes play an essential role in anticancer, but there is limited research investigating pyroptosis in LUAD. In this study, 33 pyroptosis gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. By bioinformatics and machine learning analyses, we identified novel subtypes of LUAD based on 10 pyroptosis-related genes and further validated them in the GEO dataset, with machine learning models performing up to an AUC of 1 for classifying in GEO. A web-based tool was established for clinicians to use our clustering model (http://www.aimedicallab.com/tool/aiml-subphe-luad.html). LUAD patients were clustered into 3 subtypes (A, B, and C), and survival analysis showed that B had the best survival outcome and C had the worst survival outcome. The relationships between pyroptosis gene expression and clinical characteristics were further analyzed in the three molecular subtypes. Immune profiling revealed significant differences in immune cell infiltration among the three molecular subtypes. GO enrichment and KEGG pathway analyses were performed based on the differential genes of the three subtypes, indicating that differentially expressed genes (DEGs) were involved in multiple cellular and biological functions, including RNA catabolic process, mRNA catabolic process, and pathways of neurodegeneration-multiple diseases. Finally, we developed an 8-gene prognostic model that accurately predicted 1-, 3-, and 5-year overall survival. In conclusion, pyroptosis-related genes may play a critical role in LUAD, and provide new insights into the underlying mechanisms of LUAD.
Septin Remodeling During Mammalian Cytokinesis
Authors: Russo Giulia , Krauss Michael
Published: November 2021

Cytokinesis mediates the final separation of a mother cell into two daughter cells. Septins are recruited to the cleavage furrow at an early stage. During cytokinetic progression the septin cytoskeleton is constantly rearranged, ultimately leading to a concentration of septins within the intercellular bridge (ICB), and to the formation of two rings adjacent to the midbody that aid ESCRT-dependent abscission. The molecular mechanisms underlying this behavior are poorly understood. Based on observations that septins can associate with actin, microtubules and associated motors, we review here established roles of septins in mammalian cytokinesis, and discuss, how septins may support cytokinetic progression by exerting their functions at particular sites. Finally, we discuss how this might be assisted by phosphoinositide-metabolizing enzymes.
The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines
Authors: Morais Pedro , Adachi Hironori , Yu Yi-Tao
Published: November 2021

The current COVID-19 pandemic is a massive source of global disruption, having led so far to two hundred and fifty million COVID-19 cases and almost five million deaths worldwide. It was recognized in the beginning that only an effective vaccine could lead to a way out of the pandemic, and therefore the race for the COVID-19 vaccine started immediately, boosted by the availability of the viral sequence data. Two novel vaccine platforms, based on mRNA technology, were developed in 2020 by Pfizer-BioNTech and Moderna Therapeutics (comirnaty® and spikevax®, respectively), and were the first ones presenting efficacies higher than 90%. Both consisted of N1-methyl-pseudouridine-modified mRNA encoding the SARS-COVID-19 Spike protein and were delivered with a lipid nanoparticle (LNP) formulation. Because the delivery problem of ribonucleic acids had been known for decades, the success of LNPs was quickly hailed by many as the unsung hero of COVID-19 mRNA vaccines. However, the clinical trial efficacy results of the Curevac mRNA vaccine (CVnCoV) suggested that the delivery system was not the only key to the success. CVnCoV consisted of an unmodified mRNA (encoding the same spike protein as Moderna and Pfizer-BioNTech’s mRNA vaccines) and was formulated with the same LNP as Pfizer-BioNTech’s vaccine (Acuitas ALC-0315). However, its efficacy was only 48%. This striking difference in efficacy could be attributed to the presence of a critical RNA modification (N1-methyl-pseudouridine) in the Pfizer-BioNTech and Moderna’s mRNA vaccines (but not in CVnCoV). Here we highlight the features of N1-methyl-pseudouridine and its contributions to mRNA vaccines.
An Automated Aerosol Collection and Extraction System to Characterize Electronic Cigarette Aerosols
Authors: Son Yeongkwon , Khlystov Andrey
Published: November 2021

Electronic cigarette (e-cigarette) market increased by 122% during 2014–2020 and is expected to continue growing rapidly. Despite their popularity, e-cigarettes are known to emit dangerous levels of toxic compounds (e.g., carbonyls), but a lack of accurate and efficient testing methods is hindering the characterization of e-cigarette aerosols emitted by a wide variety of e-cigarette devices, e-liquids, and use patterns. The aim of this study is to fill this gap by developing an automated E-cigarette Aerosol Collection and Extraction System (E-ACES) consisting of a vaping machine and a collection/extraction system. The puffing system was designed to mimic e-cigarette use patterns (i.e., power output and puff topography) by means of a variable power-supply and a flow control system. The sampling system collects e-cigarette aerosols using a combination of glass wool and a continuously wetted denuder. After the collection stage, the system is automatically washed with absorbing and extracting liquids (e.g., methanol, an acetaldehyde-DNPH solution). The entire system is controlled by a computer. E-ACES performance was evaluated against conventional methods during measurements of nicotine and carbonyl emissions from a tank type e-cigarette. Nicotine levels measured using glass fiber filters and E-ACES were not significantly different: 201.2 ± 6.2 and 212.5 ± 17 μg/puff (p = 0.377), respectively. Differences in formaldehyde and acetaldehyde levels between filter-DNPH cartridges and the E-ACES were 14% (p = 0.057) and 13% (p = 0.380), respectively. The E-ACES showed reproducible nicotine and carbonyl testing results for the selected e-cigarette vaping conditions.
Room-Temperature Phosphorescent Co-Crystal Showing Direct White Light and Photo-Electric Conversion
Authors: Yang Xiao-Gang , Qin Wen-Jing , Zhang Ji-Rui , Tian Xu-Ke , Fan Xin , Ma Lu-Fang , Yan Dongpeng
Published: November 2021

The development of molecular crystalline materials with efficient room-temperature phosphorescence has been obtained much attention due to their fascinating photophysical properties and potential applications in the fields of data storage, bioimaging and photodynamic therapy. Herein, a new co-crystal complex [(DCPA) (AD)2] (DCPA = 9,10-di (4-carboxyphenyl)anthracene; AD = acridine) has been synthesized by a facile solvothermal process. Crystal structure analysis reveals that the co-crystal possesses orderly and alternant arrangement of DCPA donors and AD acceptors at molecular level. Fixed by strong hydrogen bonds, the DCPA molecule displays seriously twisty spatial conformation. Density functional theory (DFT) calculations show well separation of HOMO and LUMO for this co-crystal system, suggesting the efficient triplet excitons generation. Photoluminescence measurements show intensive cyan fluorescence (58.20 ns) and direct white phosphorescence (325 µs) emission at room-temperature. The transient current density–time curve reveals a typical switching electric response under the irradiation of simulated light, reveal that the [(DCPA) (AD)2] co-crystal has a high photoelectric response performance.
A LysR-Type Transcriptional Regulator Controls Multiple Phenotypes in Acinetobacter baumannii
Authors: Tierney Aimee R. P. , Chin Chui Yoke , Weiss David S. , Rather Philip N.
Published: November 2021

Acinetobacter baumannii is a multidrug-resistant, Gram-negative nosocomial pathogen that exhibits phenotypic heterogeneity resulting in virulent opaque (VIR-O) and avirulent translucent (AV-T) colony variants. Each variant has a distinct gene expression profile resulting in multiple phenotypic differences. Cells interconvert between the VIR-O and AV-T variants at high frequency under laboratory conditions, suggesting that the genetic mechanism underlying the phenotypic switch could be manipulated to attenuate virulence. Therefore, our group has focused on identifying and characterizing genes that regulate this switch, which led to the investigation of ABUW_1132 (1132), a highly conserved gene predicted to encode a LysR-type transcriptional regulator. ABUW_1132 was shown to be a global regulator as the expression of 74 genes was altered ≥ 2-fold in an 1132 deletion mutant. The 1132 deletion also resulted in a 16-fold decrease in VIR-O to AV-T switching, loss of 3-OH-C12-HSL secretion, and reduced surface-associated motility. Further, the deletion of 1132 in the AV-T background caused elevated capsule production, which increased colony opacity and altered the typical avirulent phenotype of translucent cells. These findings distinguish 1132 as a global regulatory gene and advance our understanding of A. baumannii’s opacity-virulence switch.
Clinical Analysis of Risk Factors for Mortality in Type A Acute Aortic Dissection: A Single Study From China
Authors: Yuan Hongliang , Sun Zhenxing , Zhang Yongxing , Wu Wenqian , Liu Manwei , Yang Yali , Wang Jing , Lv Qing , Zhang Li , Li Yuman , Xie Mingxing
Published: November 2021

Objective: Acute type A aortic dissection (ATAAD) is a fatal condition that requires emergency surgery. The aim of the present study was to determine pre- and intra-operative risk factors for in-hospital mortality in patients with ATAAD.

Methods: Consecutive 313 patients with ATAAD who underwent emergency surgery at our hospital from February 2012 to February 2017 were enrolled in our study. Univariate and multivariate logistic regression analysis were performed to identify the pre-operative and intra-operative risk factors for in-hospital mortality.

Results: Of the 313 patients, 32 patients (10.2%) died. Compared with survivors, non-survivors had higher heart rate, serum potassium level and EuroSCORE II, and higher incidence of moderate to severe pericardial effusion, supra-aortic vessels involvement, myocardial ischemia and lower-extremity ischemia. As for surgery-related factors, the duration of surgery and cardiopulmonary bypass time were longer in non-survivors than survivors. In addition, non-survivors were more likely to undergo coronary-artery bypass graft compared with survivors. On multivariate analysis, elevated plasma potassium level (OR: 43.0, 95% CI: 3.8–51.5, p < 0.001), high incidence of supra-aortic vessels involvement (OR: 4.4, 95% CI: 1.5–7.0, p = 0.008) and lower-extremity ischemia (OR: 4.9, 95% CI: 1.6–6.9; p = 0.009), and longer duration of surgery (OR 6.0, 95% CI: 1.8–18.7, p = 0.000) and cardiopulmonary bypass time (OR: 3.7, 95% CI: 1.3–9.3, p = 0.001) were independently predictive of higher mortality in patients with ATAAD.

Conclusions: Supra-aortic vessels involvement, lower-extremity ischemia and elevated plasma potassium level are independent predictors of mortality in patients with ATAAD. A significant decrease in duration of surgery and cardiopulmonary bypass time is helpful to improve survival of patients.
Ideal Cardiovascular Health Metrics Modify the Association Between Exposure to Chinese Famine in Fetal and Cardiovascular Disease: A Prospective Cohort Study
Authors: Ding Xiong , Li Jinfeng , Wu Ying , Yang Peng , Zhao Dandan , Yuan Xiaojie , Chen Shuohua , Luo Xiaoyan , Li Yun , Wu Shouling
Published: November 2021

Background: No study has explored the modification effect of ideal cardiovascular health metrics (ICVHMs) on the association between famine exposure and risk of cardiovascular disease (CVD) so far. We aim to examine the effect of ICVHMs on the association between exposure to famine early in life and the risk of CVD in adulthood.

Methods: A total of 61,527 participants free of CVD were included in this study from the Kailuan Study. All participants were divided into three groups, included nonexposed, fetal-exposed, and childhood-exposed groups. Cox regression was used to estimate the effect of famine exposure and ICVHMs on CVD risk.

Results: After a median of 13.0 (12.7–13.2) years follow-up, 4,814 incident CVD cases were identified. Compared with nonexposed participants, the CVD risk increased in participants with fetal famine exposure (hazard ratio [HR]: 1.21; 95% CI: 1.07–1.37), but not in childhood famine-exposed participants. After stratifying by the number of ICVHMs, the increased CVD risk associated with fetal famine exposure was only observed in participants with less ICVHMs ( ≤ 2) (HR: 1.30; 95% CI: 1.11–1.52, P for interaction=0.008), but disappeared in those with three or more ICVHMs. The modified effect of ICVHMs was sex specific (P for sex interaction = 0.031).

Conclusions: Exposing to famine in the fetal period could increase the risk of CVD in late life; however, ICVHMs might modify the effect of famine exposure on CVD risk, especially in men.
Extra-Pulmonary Vein Triggers at de novo and the Repeat Atrial Fibrillation Catheter Ablation
Authors: Kim Daehoon , Hwang Taehyun , Kim Min , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam
Published: November 2021

Background: Extra-pulmonary vein triggers can play a significant role in atrial fibrillation recurrence after catheter ablation. We explored the characteristics of the extra-pulmonary vein (PV) triggers in de novo and repeat atrial fibrillation (AF) catheter ablation (AFCA).

Methods: We included 2,118 patients who underwent a de novo AFCA (women 27.6%, 59.2 ± 10.9 years old, paroxysmal AF 65.9%) and 227 of them conducted repeat procedures. All included patients underwent isoproterenol provocation tests at the end of the procedure, and then we analyzed extra-PV triggers-related factors.

Results: Extra-PV triggers were documented in 11.7% of patients undergoing de novo AFCA (1.22 ± 0.46 foci per patient) and 28.6% undergoing repeat AFCA (1.49 ± 0.73 foci per patient). Older age and higher LA volume index in de novo procedures and women, diabetes, and higher parasympathetic nerve activity (heart rate variability) in repeat-AFCA were independently associated with the existence of extra-PV triggers. The septum (19.9%), coronary sinus (14.7%), and superior vena cava (11.2%) were common extra-PV foci. Among 46 patients who were newly found to have mappable extra-PV triggers upon repeat procedures, 15 (32.6%) matched with the previous focal or empirical extra-PV ablation sites. The rate of AF recurrence was significantly higher in patients with extra-PV triggers than in those without after de novo (HR 1.91, 95% CI 1.54–2.38, p < 0.001) and repeat procedures (HR 2.68, 95% CI 1.63–4.42, p < 0.001).

Conclusions: Extra-PV triggers were commonly found in AF patients with significant remodeling and previous empirical extra-PV ablation. The existence of extra-PV triggers was independently associated with poorer rhythm outcomes after the de novo and repeat AFCA.
Temporal Trends in Diagnosis, Treatments, and Outcomes in Patients With Bicuspid Aortic Valve
Authors: Kim Kyu , Kim Dae-Young , Seo Jiwon , Cho Iksung , Hong Geu-Ru , Ha Jong-Won , Shim Chi Young
Published: November 2021

Background: The population is aging and advances in multimodal imaging and transcatheter valve intervention have been prominent in the past two decades. This study investigated temporal trends in demographic characteristics, use of multimodal imaging, treatments, and outcomes in patients with bicuspid aortic valve (BAV).

Methods and Results: A total of 1,497 patients (male 71.7%, 57 ± 14 years old) first diagnosed with BAV between January 2003 and December 2020, in a single tertiary center were divided into three groups according to year of diagnosis: group 1 (2003–2008, n = 269), group 2 (2009–2014, n = 594), and group 3 (2015–2020, n = 634). The patients' demographic characteristics, comorbidities, BAV morphology, BAV function, BAV-related disease, use of multimodal diagnostic imaging, treatment modality for BAV, and clinical outcomes were compared among the three groups. The ages at diagnosis and at the time of surgery/intervention increased considerably from group 1 to 3. The patients' comorbidity index also increased progressively. The proportion of non-dysfunctional BAV and significant AS increased, while that of significant AR decreased. The frequency of infective endocarditis as an initial presentation significantly decreased over time. Additionally, the use of multimodal imaging increased markedly in the most recent group. The results also indicated increasing trends in the use of bioprosthetic valves and transcatheter aortic valve replacement. Overall and cardiovascular survival rates improved from group 1 to 3 (log rank p < 0.001).

Conclusions: For the past two decades, remarkable temporal changes have occurred in patient characteristics, use of multimodal diagnostic imaging, choice of treatment modality, and clinical outcomes in patients with BAV.
Evolution of a Fault-Controlled, Deep-Water Sub-Basin, Tabernas, SE Spain
Authors: Baudouy Lucie , Haughton Peter D. W. , Walsh John J.
Published: November 2021

The Neogene Tabernas Basin, SE Spain, provides important evidence at outcrop for the interplay between tectonic deformation of the sea floor, slope instability and turbidity current behaviour. Dextral-oblique strike-slip faults and associated folds propagated along the basin axis to deform the palaeo-sea floor, creating structurally-controlled depressions in which turbidity currents were trapped and ponded. EW-trending syn-depositional faults define a narrow sub-basin that subsided asymmetrically as a negative flower structure. The sub-basin contains an expanded succession (>300 m of ponded turbidite sheets, debrites and slumps) along its northern margin flanked by the principal fault strand defined by a wide zone of sheared and calcite-veined marl. A narrower fault zone with a smaller displacement marks the southern margin of the sub-basin and the fill close to it is thin with internal discordances, evidence of local failure and southward thinning of sandstone sheets. Both northern and southern faults ‘died’ at the same stratigraphic level and were overstepped by basin floor turbidites showing evidence of weaker and longer-range topographic confinement. As turbidites healed and aggraded out of the sub-basin to progressively onlap the southern margin of the basin, major gravity failures occurred emplacing thick (>100 m) mass-transport complexes. The first initially reworked the southern part of the sub-basin fill together with the early onlap wedge, the second remobilised the onlap wedge, and the third records failure of the upper part of the slope well above the wedge. The first two were toe-confined failures, the third and furthest travelled was confined by basin axis topography. All three failures are lateral to or directly overlain by ‘megabed’ sheets on the basin floor, implying either a common trigger (earthquakes) or slope instability following reflection of large volume flows. Tabernas turbidites highlight the role of basin tectonics (as opposed to up-dip supply and sea level fluctuations) in directly impacting on deep-water processes and stratigraphy. Small deep-water transtensional sub-basins opened up along long transfer faults accommodating regional extension.
The BAHD Gene Family in Cacao (Theobroma cacao, Malvaceae): Genome-Wide Identification and Expression Analysis
Authors: Abdullah  , Faraji Sahar , Heidari Parviz , Poczai Péter
Published: November 2021

The benzyl alcohol O-acetyl transferase, anthocyanin O-hydroxycinnamoyl transferase, N-hydroxycinnamoyl anthranilate benzoyl transferase, and deacetylvindoline 4-O-acetyltransferase (BAHD) enzymes play a critical role in regulating plant metabolites and affecting cell stability. In the present study, members of the BAHD gene family were recognized in the genome of Theobroma cacao and characterized using various bioinformatics tools. We found 27 non-redundant putative tcBAHD genes in cacao for the first time. Our findings indicate that tcBAHD genes are diverse based on sequence structure, physiochemical properties, and function. When analyzed with BAHDs of Gossypium raimondii and Corchorus capsularis clustered into four main groups. According to phylogenetic analysis, BAHD genes probably evolved drastically after their divergence. The divergence time of duplication events with purifying selection pressure was predicted to range from 1.82 to 15.50 MYA. Pocket analysis revealed that serine amino acid is more common in the binding site than other residuals, reflecting its key role in regulating the activity of tcBAHDs. Furthermore, cis-acting elements related to the responsiveness of stress and hormone, particularly ABA and MeJA, were frequently observed in the promoter region of tcBAHD genes. RNA-seq analysis further illustrated that tcBAHD13 and tcBAHD26 are involved in response to Phytophthora megakarya fungi. In conclusion, it is likely that evolutionary processes, such as duplication events, have caused high diversity in the structure and function of tcBAHD genes.
Do Growth-Limiting Temperatures at the High-Elevation Treeline Require an Adaptation of Phloem Formation and Anatomy?
Authors: Schröter Dennis Marko , Oberhuber Walter
Published: November 2021

Low temperatures during the growing season restrict the growth of trees at high elevations and lead to the formation of the high-elevation treeline. To ensure the survival and growth of trees in such extreme locations, sufficient vascular transport capacity – enabled by vascular anatomical characteristics – is required. However, in contrast to the xylem, only little is known about the effects of low temperatures on the anatomy and formation of the phloem as important nutrient- and signal-conducting tissue. In this review, known findings of cold-induced changes in the anatomical and phenological properties of vascular tissues are used as starting points to discuss how low temperatures might affect phloem formation at the treeline and how this conductive tissue might adaptively respond to this growth-limiting environmental variable. Data currently available suggest that low temperatures lead to changes in the anatomy and phenological development of the phloem. In order to ensure the functionality of the phloem and thus the survival of trees at the high-elevation treeline, appropriate adaptations to the prevailing low temperatures are therefore to be expected and are discussed in this review.
Molecular Subclassification Based on Crosstalk Analysis Improves Prediction of Prognosis in Colorectal Cancer
Authors: Liu Xiaohua , Su Lili , Li Jingcong , Ou Guoping
Published: November 2021

The poor performance of single-gene lists for prognostic predictions in independent cohorts has limited their clinical use. Here, we employed a pathway-based approach using embedded biological features to identify reproducible prognostic markers as an alternative. We used pathway activity score, sure independence screening, and K-means clustering analyses to identify and cluster colorectal cancer patients into two distinct subgroups, G2 (aggressive) and G1 (moderate). The differences between these two groups with respect to survival, somatic mutation, pathway activity, and tumor-infiltration by immunocytes were compared. These comparisons revealed that the survival rates in the G2 subgroup were significantly reduced compared to that in the G1 subgroup; further, the mutational burden rates in several oncogenes, including KRAS, DCLK1, and EPHA5, were significantly higher in the G2 subgroup than in the G1 subgroup. The enhanced activity of the critical pathways such as MYC and epithelial-mesenchymal transition may also lead to the progression of colorectal cancer. Taken together, we established a novel prognostic classification system that offers meritorious insights into the hallmarks of colorectal cancer.
Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency
Authors: Lotz-Havla Amelie S. , Woidy Mathias , Guder Philipp , Schmiesing Jessica , Erdmann Ralf , Waterham Hans R. , Muntau Ania C. , Gersting Søren W.
Published: November 2021

Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this network into the cellular metabolism. Inborn peroxisomal disorders are autosomal or X-linked recessive diseases that affect peroxisomal biogenesis (PBD) and/or peroxisomal metabolism. Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. To investigate the phenotypic complexity of PEX26 deficiency, we performed a combined organelle protein interaction screen and network medicine approach and 1) analyzed whether PEX26 establishes interactions with other peroxisomal proteins, 2) deciphered the PEX26 interaction network, 3) determined how PEX26 is involved in further processes of peroxisomal biogenesis and metabolism, and 4) showed how variant-specific disruption of protein-protein interactions (edgetic perturbations) may contribute to phenotypic variability in PEX26 deficient patients. The discovery of 14 novel protein-protein interactions for PEX26 revealed a hub position of PEX26 inside the peroxisomal interactome. Analysis of edgetic perturbations of PEX26 variants revealed a strong correlation between the number of affected protein-protein interactions and the molecular phenotype of matrix protein import. The role of PEX26 in peroxisomal biogenesis was expanded encompassing matrix protein import, division and proliferation, and membrane assembly. Moreover, the PEX26 interaction network intersects with cellular lipid metabolism at different steps. The results of this study expand the knowledge about the function of PEX26 and refine genotype-phenotype correlations, which may contribute to our understanding of the underlying disease mechanism of PEX26 deficiency.
Mutational Effects of Mobile Introns on the Mitochondrial Genomes of Metschnikowia Yeasts
Authors: Thompson Scout R. L. , Lee Dong Kyung , Lachance Marc-André , Smith David Roy
Published: November 2021

It has been argued that DNA repair by homologous recombination in the context of endonuclease-mediated cleavage can cause mutations. To better understand this phenomenon, we examined homologous recombination following endonuclease cleavage in a native genomic context: the movement of self-splicing introns in the mitochondrial genomes of Metschnikowia yeasts. Self-splicing mitochondrial introns are mobile elements, which can copy and paste themselves at specific insertion sites in mitochondrial DNA using a homing endonuclease in conjunction with homologous recombination. Here, we explore the mutational effects of self-splicing introns by comparing sequence variation within the intron-rich cox1 and cob genes from 71 strains (belonging to 40 species) from the yeast genus Metschnikowia. We observed a higher density of single nucleotide polymorphisms around self-splicing-intron insertion sites. Given what is currently known about the movement of organelle introns, it is likely that their mutational effects result from the high binding affinity of endonucleases and their interference with repair machinery during homologous recombination (or, alternatively, via gene conversion occurring during the intron insertion process). These findings suggest that there are fitness costs to harbouring self-splicing, mobile introns and will help us better understand the risks associated with modern biotechnologies that use endonuclease-mediated homologous recombination, such as CRISPR-Cas9 gene editing.
Multi-Omics Data Analyses Identify B7-H3 as a Novel Prognostic Biomarker and Predict Response to Immune Checkpoint Blockade in Head and Neck Squamous Cell Carcinoma
Authors: Lin Wanzun , Xu Yanyan , Gao Jing , Zhang Haojiong , Sun Yun , Qiu Xianxin , Huang Qingting , Kong Lin , Lu Jiade J.
Published: November 2021

B7 homolog 3 (B7-H3) is a recently found superfamily B7 molecule and therefore has significant involvement in immunological regulation. However, the relationships of B7-H3 expression with the tumor microenvironment (TME), response to immunotherapy, and prognosis in head and neck squamous cell carcinoma (HNSCC) are still unknown. In the present analysis, we determined B7-H3 as a novel biomarker that predicts the prognosis and response to immunotherapy in HNSCC. B7-H3 expression is enhanced in HNSCC compared to normal sample and is stably expressed in HNSCC cell line. Besides, high B7-H3 expression is correlated with a dismal prognosis and resistance to immunotherapy and contributes to an immunosuppressive microenvironment. Moreover, single-cell RNA sequencing (scRNA-seq) analysis shows that B7-H3 is mainly expressed in the stromal as well as malignant cells. In conclusion, the study provides insight in understanding the prognostic value of B7-H3 in HNSCC and highlights its involvement in promoting the immunosuppressive microenvironment, which presents an attractive strategy for antibody-based immunotherapy.
Inhibitor of Differentiation-2 Protein Ameliorates DSS-Induced Ulcerative Colitis by Inhibiting NF-κB Activation in Neutrophils
Authors: Ren Jie , Yan Dong , Wang Yichun , Zhang Jiaojiao , Li Min , Xiong Wancheng , Jing Xueqian , Li Puze , Zhao Weidong , Xiong Xiwen , Wu Minna , Zhong Genshen
Published: November 2021

The loss of inhibitor of differentiation-2 (ID2) could lead to the development of colitis in mice, supplementation with exogenous ID2 protein might be a potential strategy to ameliorate colitis. In this study, the effects of ID2 protein supplementation on Dextran sodium sulfate (DSS)-induced colitis were investigated. Firstly, we confirmed that the expression of ID2 was reduced in the colon tissues of DSS-induced colitis mice and patients with ulcerative colitis (UC). Then, we constructed a recombinant plasmid containing the human Id2 gene and expressed it in Escherichia coli (E. coli) successfully. After purification and identification, purified hID2 could ameliorate DSS-induced colitis efficiently in mice by improving disease symptoms, decreasing the levels of proinflammatory cytokines in colon tissues, maintaining the integrity of intestinal barrier and reducing the infiltration of neutrophils and macrophages in the colon. Further study showed that hID2 could be endocytosed efficiently by neutrophils and macrophages, and hID2 lost its protection function against colitis when neutrophils were depleted with an anti-Gr-1 antibody. hID2 decreased the mRNA levels of IL-6, IL-1β and TNF-α in lipopolysaccharides (LPS)-stimulated neutrophils and efficiently inhibited the activation of NF-κB signalling pathway in neutrophils. Interestingly, hID2 showed a synergistic role in inhibition of NF-κB activation with pyrrolidine dithiocarbamic acid (PDTC), an inhibitor of NF-κB activation. Therefore, this study demonstrated the potential use of hID2 to treat UC, and hID2 protein might be a promising anti-inflammatory agent that targets the NF-κB signalling pathway in neutrophils.
Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives
Authors: Wu Zhenyu , Li Patrick , Tian Yuzi , Ouyang Wenlu , Ho Jessie Wai-Yan , Alam Hasan B. , Li Yongqing
Published: November 2021

Peptidylarginine deiminases (PADs) are a group of enzymes that catalyze post-translational modifications of proteins by converting arginine residues into citrullines. Among the five members of the PAD family, PAD2 and PAD4 are the most frequently studied because of their abundant expression in immune cells. An increasing number of studies have identified PAD2 as an essential factor in the pathogenesis of many diseases. The successes of preclinical research targeting PAD2 highlights the therapeutic potential of PAD2 inhibition, particularly in sepsis and autoimmune diseases. However, the underlying mechanisms by which PAD2 mediates host immunity remain largely unknown. In this review, we will discuss the role of PAD2 in different types of cell death signaling pathways and the related immune disorders contrasted with functions of PAD4, providing novel therapeutic strategies for PAD2-associated pathology.
Dynamic Interaction Between Mucosal Immunity and Microbiota Drives Nose and Pharynx Homeostasis of Common Carp (Cyprinus carpio) After SVCV Infection
Authors: Wu Zheng-Ben , Meng Kai-Feng , Ding Li-Guo , Wu Sha , Han Guang-Kun , Zhai Xue , Sun Ru-Han , Yu Yong-yao , Ji Wei , Xu Zhen
Published: November 2021

The crosstalk between the immune system and microbiota drives an amazingly complex mutualistic symbiosis. In mammals, the upper respiratory tract acts as a gateway for pathogen invasion, and the dynamic interaction between microbiota and mucosal immunity on its surface can effectively prevent disease development. However, the relationship between virus-mediated mucosal immune responses and microbes in lower vertebrates remains uncharacterized. In this study, we successfully constructed an infection model by intraperitoneally injecting common carp (Cyprinus carpio) with spring viremia of carp virus (SVCV). In addition to the detection of the SVCV in the nose and pharynx of common carp, we also identified obvious histopathological changes following viral infection. Moreover, numerous immune-related genes were significantly upregulated in the nose and pharynx at the peak of SVCV infection, after which the expression levels decreased to levels similar to those of the control group. Transcriptome sequencing results revealed that pathways associated with bacterial infection in the Toll-like receptor pathway and the Nod-like receptor pathway were activated in addition to the virus-related Rig-I-like receptor pathway after SVCV infection, suggesting that viral infection may be followed by opportunistic bacterial infection in these mucosal tissues. Using 16S rRNA gene sequencing, we further identified an upward trend in pathogenic bacteria on the mucosal surface of the nose and pharynx 4 days after SVCV infection, after which these tissues eventually reached new homeostasis. Taken together, our results suggest that the dynamic interaction between mucosal immunity and microbiota promotes the host to a new ecological state.
Quantifying Soundscapes in the Ross Sea, Antarctica Using Long-Term Autonomous Hydroacoustic Monitoring Systems
Authors: Yun Sukyoung , Lee Won Sang , Dziak Robert P. , Roche Lauren , Matsumoto Haruyoshi , Lau Tai-Kwan , Sremba Angela , Mellinger David K. , Haxel Joseph H. , Kang Seung-Goo , Hong Jong Kuk , Park Yongcheol
Published: November 2021

Deployment of long-term, continuously recording passive-acoustic sensors in the ocean can provide insights into sound sources related to ocean dynamics, air–sea interactions, and biologic and human activities, all which contribute to shaping ocean soundscapes. In the polar regions, the changing ocean climate likely contributes to seasonal and long-term variation in cryogenic sounds, adding to the complexity of these soundscapes. The Korea Polar Research Institute and the U.S. National Oceanic and Atmospheric Administration have jointly operated two arrays of autonomous underwater hydrophones in the Southern Ocean, one in the Terra Nova Bay Polynya (TNBP) during December 2015–January 2019 and the other in the Balleny Islands (BI) region during January 2015–March 2016, to monitor changes in ocean soundscapes. In the BI region, we found distinct seasonal variations in the cryogenic signals that were attributed to collisions and thermal/mechanical fracturing of the surface sea ice. This is consistent with sea-ice patterns due to annual freeze–thaw cycles, which are not clearly observed in TNBP, where frequent blowing out of sea ice by katabatic winds and icequakes from nearby ice shelves generate strong noise even in austral winters. Another advantage of passive acoustic recordings is that they provide opportunities to measure biodiversity from classifying spectral characteristics of marine mammals: we identified 1. Leopard seals (Hydrurga leptonyx; 200–400 Hz), most abundant in the BI region and TNBP in December; 2. Antarctic blue whales (Balaenoptera musculus; distinctive vocalization at 18 and 27 Hz), strong signals in austral winter and fall in the BI region and TNBP; 3. Fin whales (B. physalus; fundamental frequency in the 15–28 Hz and overtones at 80 and 90 Hz), maximum presence in the BI region during the austral summer and spring months; 4. Antarctic minke whales (B. bonaerensis; 100–200 Hz), strongest signals from June to August in the BI region; 5. Humpback whales in TNBP; 6. Unidentified whales (long-duration downsweeping from 75 to 62 Hz), detected in TNBP. Long-term soundscape monitoring can help understand the spatiotemporal changes in the Southern Ocean and cryosphere and provide a means of assessing the status and trends of biodiversity in the Ross Sea Region Marine Protected Area.
Soft-Sediment Communities of the Northern Indian River Lagoon, FL, United States
Authors: Lunt Jessica , Freeman Christopher J. , Janiak Dean S. , Bayliss Katrina , Stephens Michelle , Galimany Eve , Paul Valerie J.
Published: November 2021

Understanding the structure and function of infaunal communities is useful in determining the biodiversity and ecosystem function of shallow estuaries. We conducted a survey of infaunal communities within three separate water basins [Mosquito Lagoon (ML), Indian River (IR), and Banana River (BR)] in the larger Northern Indian River Lagoon, FL, United States to establish a database of infaunal community structure and function. Twenty-seven sites were sampled quarterly from 2014 to 2016. Analysis of all samples determined that basin, season, and sediment composition were the primary drivers of macrobenthic community composition. Diversity was highest in the ML, and lower in spring compared to other seasons. The occurrence of a brown tide (Aureoumbra lagunensis) in 2016 allowed a comparison of winter and spring communities before (2015) and during (2016) a bloom event. Community composition and diversity at the BR sites were the most affected by the bloom event with the lowest diversity and abundances during the bloom. Diversity in the IR was also lower during the bloom, while the ML was unaffected by the bloom. Species of all feeding groups were affected by the bloom, with lower abundances found in all groups. In addition, to determine the overall trophic diversity of infaunal communities, we collected infaunal organisms from two of the quarterly sampled sites for isotope analyses. Values of δ13C and δ15N from infaunal tissue were compared to those of potential food sources at each site. Substantial interspecific variation in isotope values of infaunal organisms within a site suggests the presence of diverse nutritional modes that include suspension and deposit feeding and predation. Together, these data suggest that infaunal communities contribute to benthic pelagic coupling and nutrient cycling within the estuarine communities, but the overall function of these communities may be tightly linked to their species composition.
Serum Sex Hormone Binding Globulin Concentration as a Predictor of Ovarian Response During Controlled Ovarian Hyperstimulation
Authors: Zhai Junyu , Li Shang , Zhu Yinci , Sun Yun , Chen Zi-Jiang , Du Yanzhi
Published: November 2021

Purpose: Serum concentrations of sex hormone binding globulin (SHBG), a glycated homodimeric plasma transport protein, correlate positively with the total number of follicles in women with infertility. However, the relationship between serum SHBG concentrations and the ovarian response during controlled ovarian hyperstimulation (COH) and whether this relationship differs between women with and without polycystic ovary syndrome (PCOS) remains unclear.

Methods: The study cohort included 120 participants (60 non-PCOS and 60 PCOS) undergoing in vitro fertilization. Serum samples were collected from each participant every 2–3 days during the COH cycle. The concentrations of serum SHBG and other sex hormones were determined to investigate the relationship between serum SHBG concentrations and the ovarian response in women with and without PCOS.

Results: We found that the serum SHBG concentration was positively correlated with the ovarian response in non-PCOS patients but not in PCOS patients.

Conclusion: The serum SHBG concentration may be clinically useful as a predictor of the ovarian response during COH in patients without PCOS.
Factors Associated With Childhood Asthma and Wheeze in Chinese Preschool-Aged Children
Authors: Deng Xiangling , Yang Min , Wang Shunan , Wang Qiong , Pang Bo , Wang Kundi , Zhang Zhixin , Niu Wenquan
Published: November 2021

This study was prepared to identify and characterize potential factors associated with childhood asthma and wheeze in Chinese preschool-aged children. A comprehensive questionnaire was designed for children aged 3–6 years and their parents or guardians in Beijing and Tangshan from September to December 2020. The least absolute shrinkage and selection operator (LASSO) model was used to identify factors in a significant association with childhood asthma and wheeze, respectively. The LASSO model was internally validated using bootstrap resampling with 100 replications. A total of 9,529 questionnaires were certified as eligible for inclusion after stringent quality control. The prevalence of doctor-diagnosed childhood asthma and parent-reported wheeze was 2.8 and 6.2%, respectively. Factors simultaneously associated with childhood asthma and wheeze were children with a history of allergic rhinitis, hay fever, eczema, initial age of using antibiotics, body mass index category, and family history of asthma. Specifically, children's vitamin D supplement duration was significantly associated with childhood asthma, whereas the association with childhood wheeze was significant for intake frequency of night meals for children and their screen time. Modeling of significant factors in nomograms had decent prediction accuracies, with C-index reaching 0.728 and 0.707 for asthma and wheeze, respectively. In addition, internal validation was good, with bootstrap C-statistic of being 0.736 for asthma and 0.708 for wheeze. Taken together, our findings indicated that the development of asthma and wheeze among preschool-aged children was probably determined by the joint contribution of multiple factors including inherited, nutritional, unhealthy lifestyles, and history of allergic disease. Further validation in other groups is necessary.
CT-Based Radiomics Score Can Accurately Predict Esophageal Variceal Rebleeding in Cirrhotic Patients
Authors: Meng Dongxiao , Wei Yingnan , Feng Xiao , Kang Bing , Wang Ximing , Qi Jianni , Zhao Xinya , Zhu Qiang
Published: November 2021

Purpose: This study aimed to develop a radiomics score (Rad-score) extracted from liver and spleen CT images in cirrhotic patients to predict the probability of esophageal variceal rebleeding.

Methods: In total, 173 cirrhotic patients were enrolled in this retrospective study. A total of 2,264 radiomics features of the liver and spleen were extracted from CT images. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select features and generate the Rad-score. Then, the Rad-score was evaluated by the concordance index (C-index), calibration curves, and decision curve analysis (DCA). Kaplan–Meier analysis was used to assess the risk stratification ability of the Rad-score.

Results: Rad-scoreLiver, Rad-scoreSpleen, and Rad-scoreLiver−Spleen were independent risk factors for EV rebleeding. The Rad-scoreLiver−Spleen, which consisted of ten features, showed good discriminative performance, with C-indexes of 0.853 [95% confidence interval (CI), 0.776–0.904] and 0.822 (95% CI, 0.749–0.875) in the training and validation cohorts, respectively. The calibration curve showed that the predicted probability of rebleeding was very close to the actual probability. DCA verified the usefulness of the Rad-scoreLiver−Spleen in clinical practice. The Rad-scoreLiver−Spleen showed good performance in stratifying patients into high-, intermediate- and low-risk groups in both the training and validation cohorts. The C-index of the Rad-scoreLiver−Spleen in the hepatitis B virus (HBV) cohort was higher than that in the non-HBV cohort.

Conclusion: The radiomics score extracted from liver and spleen CT images can predict the risk of esophageal variceal rebleeding and stratify cirrhotic patients accordingly.
Infectious Agents and Bone Marrow Failure: A Causal or a Casual Connection?
Authors: Giudice Valentina , Risitano Antonio M. , Selleri Carmine
Published: November 2021

Acquired bone marrow failure (BMF) syndromes are considered immune-mediated disorders because hematological recovery after immunosuppressive therapies is the strongest indirect evidence of the involvement of immune cells in marrow failure development. Among pathophysiology hypotheses, immune derangement after chronic antigen exposure or cross-reactivity between viral particles and cellular components are the most accepted; however, epitopes against whom these lymphocytes are directed to remain unknown. In this study, we showed that BMF-associated immunodominant clones, namely the most represented T cells carrying an antigen-specific T-cell receptor (TCR) sequence in a random pool, were frequently associated with those described in various infectious diseases, such as cytomegalovirus (CMV) and Mycobacterium tuberculosis infection. We hypothesize that these pathogens might elicit an autoimmune response triggered by cross-reactivity between pathogen-related components and proteins or might be expanded as an unspecific response to a global immune dysregulation during BMF. However, those frequent intracellular pathogens might not only be passengers in marrow failure development, while playing a central role in starting the autoimmune response against hematopoietic stem cells.