bluuebunny/crossref_metadata_2025 huggingface dataset:
WT1: The Hinge Between Anemia Correction and Cancer Development in Chronic Kidney Disease
Authors: Lee Wen-Chin , Chiu Chien-Hua , Chu Tian-Huei , Chien Yu-Shu
Published: April 2022

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) emerge as promising agents to treat anemia in chronic kidney disease (CKD) but the major concern is their correlated risk of cancer development and progression. The Wilms’ tumor gene, WT1, is transcriptionally regulated by HIF and is known to play a crucial role in tumorigenesis and invasiveness of certain types of cancers. From the mechanism of action of HIF–PHIs, to cancer hypoxia and the biological significance of WT1, this review will discuss the link between HIF, WT1, anemia correction, and cancer. We aimed to reveal the research gaps and offer a focused strategy to monitor the development and progression of specific types of cancer when using HIF–PHIs to treat anemia in CKD patients. In addition, to facilitate the long-term use of HIF–PHIs in anemic CKD patients, we will discuss the strategy of WT1 inhibition to reduce the development and progression of cancer.
New Insights in CaVβ Subunits: Role in the Regulation of Gene Expression and Cellular Homeostasis
Authors: Vergnol Amélie , Traoré Massiré , Pietri-Rouxel France , Falcone Sestina
Published: April 2022

The voltage-gated calcium channels (CaVs or VGCCs) are fundamental regulators of intracellular calcium homeostasis. When electrical activity induces their activation, the influx of calcium that they mediate or their interaction with intracellular players leads to changes in intracellular Ca2+ levels which regulate many processes such as contraction, secretion and gene expression, depending on the cell type. The essential component of the pore channel is the CaVα1 subunit. However, the fine-tuning of Ca2+-dependent signals is guaranteed by the modulatory role of the auxiliary subunits β, α2δ, and γ of the CaVs. In particular, four different CaVβ proteins (CaVβ1, CaVβ2, CaVβ3, and CaVβ4) are encoded by four different genes in mammalians, each of them displaying several splice variants. Some of these isoforms have been described in regulating CaVα1 docking and stability at the membrane and controlling the channel complex’s conformational changes. In addition, emerging evidences have highlighted other properties of the CaVβ subunits, independently of α1 and non-correlated to its channel or voltage sensing functions. This review summarizes the recent findings reporting novel roles of the auxiliary CaVβ subunits and in particular their direct or indirect implication in regulating gene expression in different cellular contexts.
SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone
Authors: Gomarasca Marta , Lombardi Giovanni , Maroni Paola
Published: April 2022

Post-translational modifications comprise series of enzymatically-driven chemical modifications, virtually involving the entire cell proteome, that affect the fate of a target protein and, in turn, cell activity. Different classes of modifications can be established ranging from phosphorylation, glycosylation, ubiquitination, acetylation, methylation, lipidation and their inverse reactions. Among these, SUMOylation and NEDDylation are ubiquitin-like multi-enzymatic processes that determine the bound of SUMOs and NEDD8 labels, respectively, on defined amino acidic residues of a specific protein and regulate protein function. As fate-determinants of several effectors and mediators, SUMOylation and NEDDylation play relevant roles in many aspects of tumor cell biology. Bone represents a preferential site of metastasis for solid tumors (e.g., breast and prostate cancers) and the primary site of primitive tumors (e.g., osteosarcoma, chondrosarcoma). Deregulation of SUMOylation and NEDDylation affects different aspects of neoplastic transformation and evolution such as epithelial-mesenchymal transition, adaptation to hypoxia, expression and action of tumor suppressors and oncogenic mediators, and drug resistance. Thereby, they represent potential therapeutic targets. This narrative review aims at describing the involvement and regulation of SUMOylation and NEDDylation in tumor biology, with a specific focus on primary and secondary bone tumors, and to summarize and highlight their potentiality in diagnostics and therapeutic strategies.
Establishment of a Transient and Stable Transfection System for Babesia duncani Using a Homologous Recombination Strategy
Authors: Wang Sen , Li Dongfang , Chen Fangwei , Jiang Weijun , Luo Wanxin , Zhu Guan , Zhao Junlong , He Lan
Published: April 2022

Genetic modification provides an invaluable molecular tool to dissect the biology and pathogenesis of pathogens. However, no report is available about the genetic modification of Babesia duncani, a pathogen responsible for human babesiosis that is widespread in North America, suggesting the necessity to develop a genetic manipulation method to improve the strategies for studying and understanding the biology of protozoan pathogens. The establishment of a genetic modification method requires promoters, selectable markers, and reporter genes. Here, the double-copy gene elongation factor-1α (ef-1α) and its promoters were amplified by conventional PCR and confirmed by sequencing. We established a transient transfection system by using the ef-1αB promoter and the reporter gene mCherry and achieved stable transfection through homologous recombination to integrate the selection marker hDHFR-eGFP into the parasite genome. The potential of this genetic modification method was tested by knocking out the thioredoxin peroxidase-1 (TPX-1) gene, and under the drug pressure of 5 nM WR99210, 96.3% of the parasites were observed to express green fluorescence protein (eGFP) by flow cytometry at day 7 post-transfection. Additionally, the clone line of the TPX-1 knockout parasite was successfully obtained by the limiting dilution method. This study provided a transfection method for B. duncani, which may facilitate gene function research and vaccine development of B. duncani.
A Review on Bismuth Oxyhalide (BiOX, X=Cl, Br, I) Based Photocatalysts for Wastewater Remediation
Authors: Lv Xincong , Lam Frank Leung Yuk , Hu Xijun
Published: April 2022

Solar energy transformation over semiconductor-based photocatalysis is an ideal solution to environmental problems and future sustainability. Layered bismuth oxyhalides (BiOX, X = Cl, Br or I) are very attractive and promising photocatalysts in the environment fields. This review summarizes recent advances on the design of BiOX to enhance energy converting efficiency. Especially, the emerging techniques to enhance the photocatalytic behaviors of BiOX are discussed, including non-metal/metal doping, heterojunction engineering, carbon interfacing, coupling with noble metals, defect engineering, and morphology tuning. The application of BiOX composites in wastewater remediation is also reviewed in terms of organic photocatalytic oxidation and heavy metal ion photocatalytic reduction. Finally, the future chances and challenges of BiOX photocatalysts for practical application are summarized. In all, this review well underlies the innovative preparation of BiOX products for environment-related purposes.
Related Risk Factors and Treatment Management of Psoriatic Arthritis Complicated With Cardiovascular Disease
Authors: Zheng Zhoulan , Guo Qianyu , Ma Dan , Wang Xuexue , Zhang Chengqiang , Wang Haiyao , Zhang Liyun , Zhang Gailian
Published: April 2022

Psoriatic arthritis (PsA) is a chronic autoimmune inflammatory joint disease related to psoriasis (PsO). The risk of PsA patients with cardiovascular disease (CVD) is significantly higher than that of the general population. At present, the relevant mechanism is not clear, chronic inflammation and traditional cardiovascular risk factors are the most important factors for the increased risk of CVD in PsA patients. Early assessment of the risk of PsA patients with CVD, and active control of the disease activity of PsA patients and intervention of traditional cardiovascular risk factors can delay the progression of CVD risk. This article reviews the epidemiology and pathogenesis between PsA and CVD, and reviews the latest developments in the risk assessment and management of CVD in PsA patients.
High Specificity Wearable Device With Photoplethysmography and Six-Lead Electrocardiography for Atrial Fibrillation Detection Challenged by Frequent Premature Contractions: DoubleCheck-AF
Authors: Bacevicius Justinas , Abramikas Zygimantas , Dvinelis Ernestas , Audzijoniene Deimile , Petrylaite Marija , Marinskiene Julija , Staigyte Justina , Karuzas Albinas , Juknevicius Vytautas , Jakaite Rusne , Basyte-Bacevice Viktorija , Bileisiene Neringa , Solosenko Andrius , Sokas Daivaras , Petrenas Andrius , Butkuviene Monika , Paliakaite Birute , Daukantas Saulius , Rapalis Andrius , Marinskis Germanas , Jasiunas Eugenijus , Darma Angeliki , Marozas Vaidotas , Aidietis Audrius
Published: April 2022

Background

Consumer smartwatches have gained attention as mobile health (mHealth) tools able to detect atrial fibrillation (AF) using photoplethysmography (PPG) or a short strip of electrocardiogram (ECG). PPG has limited accuracy due to the movement artifacts, whereas ECG cannot be used continuously, is usually displayed as a single-lead signal and is limited in asymptomatic cases.

Objective

DoubleCheck-AF is a validation study of a wrist-worn device dedicated to providing both continuous PPG-based rhythm monitoring and instant 6-lead ECG with no wires. We evaluated its ability to differentiate between AF and sinus rhythm (SR) with particular emphasis on the challenge of frequent premature beats.

Methods and Results

We performed a prospective, non-randomized study of 344 participants including 121 patients in AF. To challenge the specificity of the device two control groups were selected: 95 patients in stable SR and 128 patients in SR with frequent premature ventricular or atrial contractions (PVCs/PACs). All ECG tracings were labeled by two independent diagnosis-blinded cardiologists as “AF,” “SR” or “Cannot be concluded.” In case of disagreement, a third cardiologist was consulted. A simultaneously recorded ECG of Holter monitor served as a reference. It revealed a high burden of ectopy in the corresponding control group: 6.2 PVCs/PACs per minute, bigeminy/trigeminy episodes in 24.2% (31/128) and runs of ≥3 beats in 9.4% (12/128) of patients. AF detection with PPG-based algorithm, ECG of the wearable and combination of both yielded sensitivity and specificity of 94.2 and 96.9%; 99.2 and 99.1%; 94.2 and 99.6%, respectively. All seven false-positive PPG-based cases were from the frequent PVCs/PACs group compared to none from the stable SR group (P < 0.001). In the majority of these cases (6/7) cardiologists were able to correct the diagnosis to SR with the help of the ECG of the device (P = 0.012).

Conclusions

This is the first wearable combining PPG-based AF detection algorithm for screening of AF together with an instant 6-lead ECG with no wires for manual rhythm confirmation. The system maintained high specificity despite a remarkable amount of frequent single or multiple premature contractions.
Artificial Intelligence Uncovers Natural MMP Inhibitor Crocin as a Potential Treatment of Thoracic Aortic Aneurysm and Dissection
Authors: Qi Feiran , Liu Yan , Zhang Kunlin , Zhang Yanzhenzi , Xu Ke , Zhou Mei , Zhao Huinan , Zhu Shuolin , Chen Jianxin , Li Ping , Du Jie
Published: April 2022

Thoracic aortic aneurysm and dissection (TAAD) is a lethal cardiovascular condition without effective pharmaceutical therapy. Identifying novel drugs that target the key pathogenetic components is an urgent need. Bioinformatics analysis of pathological studies indicated “extracellular matrix organization” as the most significant functional pathway related to TAAD, in which matrix metallopeptidase (MMP) 2 and MMP9 ranked above other proteases. MMP1-14 were designated as the prototype molecules for docking against PubChem Compound Database using Surflex-Dock, and nine natural compounds were identified. Using a generic MMP activity assay and an aminopropionitrile (BAPN)-induced TAAD mouse model, we identified crocin as an effective MMP inhibitor, suppressing the occurrence and rupture of TAAD. Biolayer interferometry and AI/bioinformatics analyses indicated that crocin may inhibit MMP2 activity by direct binding. Possible binding sites were investigated. Overall, the integration of artificial intelligence and functional experiments identified crocin as an MMP inhibitor with strong therapeutic potential.
Developing a Three Dimensional (3D) Elastoplastic Constitutive Model for Soils Based on Unified Nonlinear Strength (UNS) Criterion
Authors: Wang Sui , Zhong Zuliang , Chen Bin , Liu Xinrong , Wu Bo
Published: April 2022

To achieve versatility, a unified nonlinear strength (UNS) criterion is put forward for capturing the complicated strength behaviors exhibited by geomaterials under three dimensional (3D) stress paths. The UNS criterion, widely covering meridian planes and octahedral planes, can serve for describing the nonlinear strength behaviors exhibited by soils, as well as confirm how the intermediate principal stress affects the strength of different materials. Based on UNS strength criterion, an elastoplastic constitutive model is presented, with the purpose of predicting the strength as well as deformation behavior exhibited by soils under 3D stress conditions. Besides, although the proposed model is extremely simple, it is fit for predicting the results of true triaxial tests in related literature with the help of the UNS criterion, and meanwhile can confirm how intermediate principal stress affects material strength and material deformation when the stresses are different.
Transition From Diencephalic Syndrome to Hypothalamic Obesity in Children With Suprasellar Low Grade Glioma: A Case Series
Authors: van Roessel Ichelle M. A. A. , Schouten-van Meeteren Antoinette Y. N. , Meijer Lisethe , Hoving Eelco W. , Bakker Boudewijn , van Santen Hanneke M.
Published: April 2022

Background

Children with suprasellar low grade glioma (LGG) frequently develop problems to maintain their body weight within the normal range, due to hypothalamic dysfunction. Hypothalamic damage may result in the diencephalic syndrome (DS), characterized by underweight or failure to thrive, but also in hypothalamic obesity (HO). Children with LGG presenting with DS at young age often develop HO later in life. The underlying pathophysiology for this change in body mass index (BMI) is not understood. Previous hypotheses have focused on the tumor or its treatment as the underlying cause. To better understand its etiology, we aimed to relate changes in BMI over time in children with suprasellar LGG presenting with DS to age, tumor progression, treatment, and endocrine function. We hypothesize that the development of HO in children with LGG presenting with DS is related to maturation status of the hypothalamus at time of injury and thus age.

Methods

In this retrospective case series, all cases diagnosed in the Netherlands with suprasellar located LGG, currently treated or followed, with a history of DS developing into HO were included.

Results

In total, 10 children were included. Median age at LGG diagnosis was 1.5 years (range 0.4–5.5), median BMI SDS was −2.64. The children developed overweight at a median age of 4.5 years (2.2–9.8). The median total difference in BMI SDS between underweight and obesity was +5.75 SDS (4.5–8.7). No association could be found between transition of DS to HO and onset of a pituitary disorder (present in 70.0%), surgery, chemotherapy, or tumor behavior. Two had developed central precocious puberty (CPP), both while having underweight or normal weight.

Conclusion

The shift from DS to HO in children with hypothalamic LGG may be associated with age and not to tumor behavior, treatment characteristics or pituitary function. The development of CPP in these children seems not to be related to obesity. Our findings may indicate that the clinical picture of hypothalamic dysfunction reflects the maturation state of the hypothalamus at time of lesioning. Future prospective studies are needed to better understand underlying causative mechanisms of the morbid changes in body weight.
Perspective on the Recent Measurements of Reduced Nitrogen Compounds in the Atmosphere
Authors: Lee S.-H.
Published: April 2022

Reduced-nitrogen compounds (RNC), such as ammonia and amines, play important roles in atmospheric aerosol nucleation, secondary organic aerosol (SOA), and cloud formation processes. Fast measurements of ammonia and amines are made with a chemical ionization mass spectrometer (CIMS). Clusters containing RNC are measured with an atmospheric pressure interface time of flight mass spectrometer (APi-TOF) or chemical ionization APi-TOF (CI-APi-TOF). Aerosol-phase amines can be detected with a single particle mass spectrometer at real-time, or with offline chemical analytical methods using filter samples. However, the application of these instruments in real atmospheric measurements is still very limited. This perspective article highlights recent measurements of RNC in the atmosphere and discusses their implications in new particle formation (NPF).
Identification of Co-Existing Mutations and Gene Expression Trends Associated With K13-Mediated Artemisinin Resistance in Plasmodium falciparum
Authors: Rawat Mukul , Kanyal Abhishek , Choubey Deepak , Deshmukh Bhagyashree , Malhotra Rashim , Mamatharani DV , Rao Anjani Gopal , Karmodiya Krishanpal
Published: April 2022

Plasmodium falciparum infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has become even more challenging to control and eliminate the disease. Multiomics studies of the parasite have started to provide a glimpse into the confounding genetics and mechanisms of artemisinin resistance and identified mutations in Kelch13 (K13) as a molecular marker of resistance. Over the years, thousands of genomes and transcriptomes of artemisinin-resistant/sensitive isolates have been documented, supplementing the search for new genes/pathways to target artemisinin-resistant isolates. This meta-analysis seeks to recap the genetic landscape and the transcriptional deregulation that demarcate artemisinin resistance in the field. To explore the genetic territory of artemisinin resistance, we use genomic single-nucleotide polymorphism (SNP) datasets from 2,517 isolates from 15 countries from the MalariaGEN Network (The Pf3K project, pilot data release 4, 2015) to dissect the prevalence, geographical distribution, and co-existing patterns of genetic markers associated with/enabling artemisinin resistance. We have identified several mutations which co-exist with the established markers of artemisinin resistance. Interestingly, K13-resistant parasites harbor α-ß hydrolase and putative HECT domain–containing protein genes with the maximum number of SNPs. We have also explored the multiple, publicly available transcriptomic datasets to identify genes from key biological pathways whose consistent deregulation may be contributing to the biology of resistant parasites. Surprisingly, glycolytic and pentose phosphate pathways were consistently downregulated in artemisinin-resistant parasites. Thus, this meta-analysis highlights the genetic and transcriptomic features of resistant parasites to propel further exploratory studies in the community to tackle artemisinin resistance.
Genetic Variants of Glycogen Metabolism Genes Were Associated With Liver PDFF Without Increasing NAFLD Risk
Authors: Yang Liu , Sun Zewen , Li Jiuling , Pan Xingchen , Wen Jianping , Yang Jianli , Wang Qing , Chen Peng
Published: April 2022

Background/Aims: The storage amount of liver glycogen could affect the liver fibrosis assessment made by MRI-based methods. However, it remained unclear whether glycogen amount could bias the estimation of liver fat content by proton density fat fraction. In this study, we aimed to investigate whether glycogen metabolism gene variants could contribute to the bias of PDFF by genetic association.

Methods: We conducted an association study of the glycogen metabolism genes based on the PDFF data of 11,129 participants in the UK Biobank. The effect of the SNPs in these genes on non-alcoholic fatty liver disease was estimated by a meta-analysis of the available NAFLD case-control studies.

Results: We identified significant associations of the SNPs near the genes encoding glycogen phosphorylase (PYGM and PYGL) and synthase (GYS2) with PDFF (FDR-corrected p value < 0.05). The genes encoding the regulatory proteins of glycogenolysis (PHKB, CALM2/3), glucose transporter (SLC2A1), and glucose kinase (GCK) were also associated with PDFF. The SNP rs5402 of SLC2A2 and rs547066 of PYGM were associated with NAFLD (p < 0.05) with others being insignificant. Except for the PYGM gene, the PDFF-associated SNPs showed no associations with NAFLD. In addition, the burden tests of rare variants in these genes were not significant after FDR correction.

Conclusion: Liver glycogen metabolism genes associated with PDFF were not associated with NAFLD, which implicated a potential bias effect of glycogen storage on the quantification of liver fat content by PDFF.
Identification and Validation of Chromobox Family Members as Potential Prognostic Biomarkers and Therapeutic Targets for Human Esophageal Cancer
Authors: Fang Xuefen , Wang Junjun , Chen Jiabing , Zhuang Mingkai , Huang Tingxuan , Chen Zhixin , Huang Yuehong , Zheng Biyun , Wang Xiaozhong
Published: April 2022

Background: Chromobox family proteins (CBXs) are vital components of epigenetic regulation complexes and transcriptionally inhibit target genes by modifying the chromatin. Accumulating evidence indicates that CBXs are involved in the initiation and progression of multiple malignancies. However, the expression, function, and clinical relevance such as the prognostic and diagnostic values of different CBXs in esophageal carcinoma (ESCA) are still unclear.

Methods: We applied Oncomine, TCGA, GEO, GEPIA, UALCAN, Kaplan–Meier plotter, cBioPortal, Metascape, and TIMER to investigate the roles of CBX family members in ESCA. Additionally, quantitative real-time PCR (RT-PCR), western blot, and immunofluorescence were used to verify the expression of CBX family members in ESCA clinical samples.

Results: Compared with normal tissues, the mRNA expression levels of CBX1/3/8 were significantly increased in ESCA, whereas CBX7 mRNA expression was reduced in both the TCGA cohort and GEO cohort. In the TCGA cohort, ROC curves suggested that CBX1/2/3/4/8 had great diagnostic value in ESCA, and the AUCs were above 0.9. Furthermore, upregulation of CBX1/3/8 and downregulation of CBX7 were closely related to the clinicopathological parameters in ESCA patients, such as tumor grades, tumor nodal metastasis status, and TP53 mutation status. The survival analysis indicated that higher CBX1/3/8 mRNA expressions and lower CBX7 expression suggested an unfavorable prognosis in ESCA. High genetic change rate (52%) of CBXs was found in ESCA patients. Functions and pathways of mutations in CBXs and their 50 frequently altered neighbor genes in ESCA patients were investigated; the results showed that DNA repair and DNA replication were correlated to CBX alterations. Moreover, we found a significant correlation between the expression level of CBX family members and the infiltration of immune cells in ESCA. Finally, we verified the expression of CBX family members in clinical samples and found the results were consistent with the databases.

Conclusion: Our study implied that CBX1/3/7/8 are potential targets of precision therapy for ESCA patients and new biomarkers for the prognosis.
Sleeping With the Enemy? The Current Knowledge of Piscine Orthoreovirus (PRV) Immune Response Elicited to Counteract Infection
Authors: Vallejos-Vidal Eva , Reyes-López Felipe E. , Sandino Ana María , Imarai Mónica
Published: April 2022

Piscine orthoreovirus (PRV) is a virus in the genus Orthoreovirus of the Reoviridae family, first described in 2010 associated with Heart and Skeletal Muscle Inflammation (HSMI) in Atlantic salmon (Salmo salar). Three phases of PRV infection have been described, the early entry and dissemination, the acute dissemination phase, and the persistence phase. Depending on the PRV genotype and the host, infection can last for life. Mechanisms of immune response to PRV infection have been just beginning to be studied and the knowledge in this matter is here revised. PRV induces a classical antiviral immune response in experimental infection of salmonid erythrocytes, including transcriptional upregulation ofifn-α,rig-i,mx, andpkr. In addition, transcript upregulation oftcra, tcrb, cd2, il-2, cd4-1, ifn-γ, il-12, and il-18has been observed in Atlantic salmon infected with PRV, indicating that PRV elicited a Th1 type response probably as a host defense strategy. The high expression levels ofcd8a,cd8b, andgranzyme-Ain PRV-infected fish suggest a positive modulatory effect on the CTL-mediated immune response. This is consistent with PRV-dependent upregulation of the genes involved in antigen presentation, including MHC class I, transporters, and proteasome components. We also review the potential immune mechanisms associated with the persistence phenotype of PRV-infected fish and its consequence for the development of a secondary infection. In this scenario, the application of a vaccination strategy is an urgent and challenging task due to the emergence of this viral infection that threatens salmon farming.
Large-Scale Single-Cell and Bulk Sequencing Analyses Reveal the Prognostic Value and Immune Aspects of CD147 in Pan-Cancer
Authors: Zhang Jingwei , Wang Zeyu , Zhang Xun , Dai Ziyu , Zhi-Peng Wen , Yu Jing , Peng Yun , Wu Wantao , Zhang Nan , Luo Peng , Zhang Jian , Liu Zaoqu , Feng Songshan , Zhang Hao , Cheng Quan
Published: April 2022

CD147 plays an important role in promoting tumor proliferation and inhibiting cancer cell apoptosis in the tumor microenvironment. However, the mechanisms by which CD147 is involved in tumorigenesis remains unclear. This study systematically analyzed the prognostic value and immune characteristics of CD147 in 31 cancer types. The expression levels and mutant landscapes of CD147 in pan-cancer were explored. The Kaplan-Meier (KM) analysis was applied to analyze the prognostic value of CD147. The immune characteristics of CD147 in the tumor microenvironment were evaluated via TIMER 2.0 and R package (immunedeconv). We also explored the expression of CD147 on tumor cells and stromal cells through Gene Set Variation Analysis and single-cell sequencing analysis. The co-expression of CD147 and macrophage markers CD68 and CD163 in pan-cancer was detected using multiplex immunofluorescence staining on tissue microarrays. CD147 was found to be overexpressed in almost all cancer types, which was related to poor outcome. CD147 expression exhibited a strong association with immune infiltrates, immune checkpoint molecules, and neoantigen levels in the tumor microenvironment. In addition, CD147 was expressed on various cell types in the tumor microenvironment, including tumor cells, macrophages, T cells, monocytes, fibroblasts, etc. Furthermore, multiplex immunofluorescence revealed the co-expression pattern of CD147 and macrophage markers CD68 and CD163 in many tumor types. Finally, the immunotherapy response and sensitive small molecule drugs based on CD147 expression were predicted. In sum, CD147 has a significant relationship with the clinical outcome and immune infiltrates in multiple cancer types. Inhibiting the CD147-dependent signaling pathways might be a promising therapeutic strategy for tumor immunotherapy.
Long-Read RNA Sequencing Identifies Polyadenylation Elongation and Differential Transcript Usage of Host Transcripts During SARS-CoV-2 In Vitro Infection
Authors: Chang Jessie J.-Y. , Gleeson Josie , Rawlinson Daniel , De Paoli-Iseppi Ricardo , Zhou Chenxi , Mordant Francesca L. , Londrigan Sarah L. , Clark Michael B. , Subbarao Kanta , Stinear Timothy P. , Coin Lachlan J. M. , Pitt Miranda E.
Published: April 2022

Better methods to interrogate host-pathogen interactions during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections are imperative to help understand and prevent this disease. Here we implemented RNA-sequencing (RNA-seq) using Oxford Nanopore Technologies (ONT) long-reads to measure differential host gene expression, transcript polyadenylation and isoform usage within various epithelial cell lines permissive and non-permissive for SARS-CoV-2 infection. SARS-CoV-2-infected and mock-infected Vero (African green monkey kidney epithelial cells), Calu-3 (human lung adenocarcinoma epithelial cells), Caco-2 (human colorectal adenocarcinoma epithelial cells) and A549 (human lung carcinoma epithelial cells) were analyzed over time (0, 2, 24, 48 hours). Differential polyadenylation was found to occur in both infected Calu-3 and Vero cells during a late time point (48 hpi), with Gene Ontology (GO) terms such as viral transcription and translation shown to be significantly enriched in Calu-3 data. Poly(A) tails showed increased lengths in the majority of the differentially polyadenylated transcripts in Calu-3 and Vero cell lines (up to ~101 nt in mean poly(A) length, padj = 0.029). Of these genes, ribosomal protein genes such as RPS4X and RPS6 also showed downregulation in expression levels, suggesting the importance of ribosomal protein genes during infection. Furthermore, differential transcript usage was identified in Caco-2, Calu-3 and Vero cells, including transcripts of genes such as GSDMB and KPNA2, which have previously been implicated in SARS-CoV-2 infections. Overall, these results highlight the potential role of differential polyadenylation and transcript usage in host immune response or viral manipulation of host mechanisms during infection, and therefore, showcase the value of long-read sequencing in identifying less-explored host responses to disease.
Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19
Authors: Liu Zhaoli , Kilic Gizem , Li Wenchao , Bulut Ozlem , Gupta Manoj Kumar , Zhang Bowen , Qi Cancan , Peng He , Tsay Hsin-Chieh , Soon Chai Fen , Mekonnen Yonatan Ayalew , Ferreira Anaísa Valido , van der Made Caspar I. , van Cranenbroek Bram , Koenen Hans J. P. M. , Simonetti Elles , Diavatopoulos Dimitri , de Jonge Marien I. , Müller Lisa , Schaal Heiner , Ostermann Philipp N. , Cornberg Markus , Eiz-Vesper Britta , van de Veerdonk Frank , van Crevel Reinout , Joosten Leo A. B. , Domínguez-Andrés Jorge , Xu Cheng-Jian , Netea Mihai G. , Li Yang
Published: April 2022

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.
Immune Dysregulation in Monogenic Inborn Errors of Immunity in Oman: Over A Decade of Experience From a Single Tertiary Center
Authors: Al Farsi Tariq , Ahmed Khwater , Alshekaili Jalila , Al Kindi Mahmood , Cook Matthew , Al-Hosni Aliya , Ansari Zainab , Nasr Iman , Al Sukaiti Nashat
Published: April 2022

Background

Inborn errors of immunity (IEIs) are being recognized as an important cause of morbidity and mortality in communities with a high frequency of consanguinity, such as Oman, and thus recessively inherited conditions. Various monogenic causes of IEI have been recently discovered; however, the disease phenotype may be variable and does not always include infection at presentation, leading to a delay in diagnosis and a poor outcome. It is now well recognized that immune dysregulation manifestations are observed in a significant proportion of patients with IEI and occasionally precede infection.

Methods

Here, we retrospectively report the epidemiological, clinical, immunological, and molecular findings and outcomes from 239 patients with IEI who were diagnosed and managed at the Royal Hospital, Oman, from January 2010 to October 2021.

Results

The estimated annual cumulative mean incidence of IEI was 25.5 per 100,000 Omani live births with a total prevalence of 15.5 per 100,000 Omani population. Both the high incidence and prevalence are attributed to the high rate of consanguinity (78.2%). Defects affecting cellular and humoral immunity including severe combined immunodeficiency (SCID), combined immunodeficiency (CID), and CID with syndromic features were the predominant defects in IEI (36%). Immune dysregulation was a prominent manifestation and occurred in approximately a third of all patients with IEI (32%), with a mean age of onset of 81 months and a mean diagnostic delay of 50.8 months. The largest percentage of patients who showed such clinical signs were in the category of diseases of immune dysregulation (41%), followed by predominantly antibody deficiency (18%). The overall mortality rate in our cohort was 25.1%, with higher death rates seen in CID including SCID and diseases of immune dysregulation.

Conclusion

Immune dysregulation is a frequent manifestation of Omani patients with IEI. Early detection through raising awareness of signs of IEI including those of immune dysregulation and implementation of newborn screening programs will result in early intervention and improved overall outcome.
Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma
Authors: Kollis Paris M. , Ebert Lisa M. , Toubia John , Bastow Cameron R. , Ormsby Rebecca J. , Poonnoose Santosh I. , Lenin Sakthi , Tea Melinda N. , Pitson Stuart M. , Gomez Guillermo A. , Brown Michael P. , Gargett Tessa
Published: April 2022

Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.
Dual Relationship Between Stromal Cells and Immune Cells in the Tumor Microenvironment
Authors: Mun Jeong-Yeon , Leem Sun-Hee , Lee Jun Ho , Kim Hyuk Soon
Published: April 2022

The tumor microenvironment (TME) plays a critical role in tumorigenesis and is comprised of different components, including tumor cells, stromal cells, and immune cells. Among them, the relationship between each mediator involved in the construction of the TME can be understood by focusing on the secreting or expressing factors from each cells. Therefore, understanding the various interactions between each cellular component of the TME is necessary for precise therapeutic approaches. In carcinoma, stromal cells are well known to influence extracellular matrix (ECM) formation and tumor progression through multiple mediators. Immune cells respond to tumor cells by causing cytotoxicity or inflammatory responses. However, they are involved in tumor escape through immunoregulatory mechanisms. In general, anti-cancer therapy has mainly been focused on cancer cells themselves or the interactions between cancer cells and specific cell components. However, cancer cells directly or indirectly influence other TME partners, and members such as stromal cells and immune cells also participate in TME organization through their mutual communication. In this review, we summarized the relationship between stromal cells and immune cells in the TME and discussed the positive and negative relationships from the point of view of tumor development for use in research applications and therapeutic strategies.
Transepithelial Secretion of Mucosal IgM Mediated by Polymeric Immunoglobulin Receptor of Flounder (Paralichthys olivaceus): In-Vivo and In-Vitro Evidence
Authors: Sheng Xiuzhen , Guo Yuan , Zhu Hui , Chai Baihui , Tang Xiaoqian , Xing Jing , Chi Heng , Zhan Wenbin
Published: April 2022

Secretory immunoglobulin (SIg) is crucial for mucosal surface defenses, but the transepithelial secretion of SIg mediated by polymeric immunoglobulin receptor (pIgR) is not clarified in fish. We previously found that flounder (Paralichthys olivaceus) pIgR (fpIgR) and secretory IgM (SIgM) increased in gut mucus post-vaccination. Here, the fpIgR-positive signal was mainly observed in the intestinal epithelium, whereas the IgM-positive signal was mainly distributed in the lamina propria, before immunization. IgM signals increased in the lamina propria and then in the epithelium after immunization with inactivated Vibrio anguillarum, and co-localization between IgM and fpIgR in the epithelium was determined, while the presence of EdU+IgM+ cells in the lamina propria identified the proliferative B cells, revealing that the secretion and transepithelial transport of SIgM locally occurred in the gut of flounder. Subsequently, we established an in-vitro model of transfected MDCK cells that stably expressed the fpIgR. After a recombinant eukaryotic expression plasmid (pCIneoEGFP-fpIgR) was constructed and transfected into MDCK cells, stable expression of the fpIgR in transfected MDCK-fpIgR cells was confirmed, and the tightness and integrity of the polarized cell monolayers grown on Transwells were evaluated. Afterward, the serum IgM of flounder was purified as a binding ligand and placed in the lower compartment of Transwells. An ~800-kDa protein band in the upper compartment was shown to be IgM- and fpIgR-positive, and IgM-positive fluorescence was seen in MDCK-fpIgR cells but not in MDCK-mock cells. Hence, the fpIgR helped polymeric IgM to pass across MDCK-fpIgR cells via transcytosis in a basolateral-to-apical fashion. These new findings provide a better understanding of the pathways shaping mucosal IgM responses and the local mucosal immune mechanisms in teleosts.
Case Report: Precision COVID-19 Immunization Strategy to Overcome Individual Fragility: A Case of Generalized Lipodystrophy Type 4
Authors: Zaffina Salvatore , Piano Mortari Eva , Di Prinzio Reparata Rosa , Cappa Marco , Novelli Antonio , Agolini Emanuele , Raponi Massimiliano , Dallapiccola Bruno , Locatelli Franco , Perno Carlo Federico , Carsetti Rita
Published: April 2022

A 48-year-old patient affected with congenital generalized lipodystrophy type 4 failed to respond to two doses of the BNT162b2 vaccine, consisting of lipid nanoparticle encapsulated mRNA. As the disease is caused by biallelic variants of CAVIN1, a molecule indispensable for lipid endocytosis and regulation, we complemented the vaccination cycle with a single dose of the Ad26.COV2 vaccine. Adenovirus-based vaccine entry is mediated by the interaction with adenovirus receptors and transport occurs in clathrin-coated pits. Ten days after Ad26.COV2 administration, S- and RBD-specific antibodies and high-affinity memory B cells increased significantly to values close to those observed in Health Care Worker controls.
Phylogenetic Structure of Synechococcus Assemblages and Its Environmental Determinants in the Bay and Strait Areas of a Continental Sea
Authors: Wang Ting , Chen Xi , Li Jialin , Qin Song
Published: April 2022

Marine Synechococcus, a significant contributor to primary production, shows high phylogenetic diversity. However, studies on its phylogenetic composition in the Bohai Sea, the largest continental sea in China, are lacking. We sequenced rpoC1 (encodes the RNA polymerase β’ subunit protein) in samples from the Laizhou Bay (LZB) and Bohai Strait (BS) in June and November using high-throughput sequencing to reveal the phylogenetic composition of Synechococcus assemblages in the bay and strait areas of the Bohai Sea. In total, 12 lineages representing Synechococcus subclusters S5.1, S5.2, and S5.3 were identified. Spatially, clade I was obligately dominant in BS. In contrast, the Synechococcus assemblage in LZB was more diverse, with clades VI and III being highly abundant. In addition, we detected strong variation in Synechococcus structure between June and November in the Bohai Sea. Clades II, III, XX, and miyav were only detected in November. Vertically, variation in Synechococcus assemblage was not apparent among the water layers probably due to the shallow water depth with intense water mixing. Results of redundancy analysis (RDA) and random forest (RF) analysis together highlighted the key role of silicate in the Synechococcus assemblage. Our results suggested that the Bohai Sea provides various niches for different Synechococcus clades, resulting in a special phylogenetic composition of the Synechococcus assemblage, compared with that in the adjacent shelf sea and other continental seas in the world.
Plasma Exosomal Proteomic Pattern of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis
Authors: Xie Yan , Yang Li , Cao Pengfei , Li Shen , Zhang Wentao , Dang Wei , Xin Shuyu , Jiang Mingjuan , Xin Yujie , Li Jing , Long Sijing , Wang Yiwei , Zhang Senmiao , Yang Yang , Lu Jianhong
Published: April 2022

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening syndrome, which is caused by EBV infection that is usually refractory to treatment and shows relapse. The development of new biomarkers for the early diagnosis and clinical treatment of EBV-HLH is urgently needed. Exosomes have been shown to mediate various biological processes and are ideal non-invasive biomarkers. Here, we present the differential plasma exosomal proteome of a patient with EBV-HLH before vs. during treatment and with that of his healthy twin brother. A tandem mass tag-labeled LC-MS technique was employed for proteomic detection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that differential proteomic profiles were related to virus infection, coagulopathy, nervous system dysfunction, imbalance of immune response, and abnormal liver function. The candidate biomarkers were first identified in the patient’s plasma exosomes at different treatment and follow-up time points. Then, 14 additional EBV-HLH exosome samples were used to verify six differentially expressed proteins. The upregulation of C-reactive protein, moesin, galectin three-binding protein, and heat shock cognate 71 kDa protein and the downregulation of plasminogen and fibronectin 1 could serve as potential biomarkers of EBV-HLH. This plasma exosomal proteomic analysis provides new insights into the diagnostic and therapeutic biomarkers of EBV-HLH.
Prevalence, Antibiotic-Resistance, and Growth Profile of Vibrio spp. Isolated From Fish and Shellfish in Subtropical-Arid Area
Authors: Abdalla Tarfa , Al-Rumaithi Hind , Osaili Tareq M. , Hasan Fayeza , Obaid Reyad S. , Abushelaibi Aisha , Ayyash Mutamed M.
Published: April 2022

The study aimed to determine the prevalence of different species of Vibrio spp. in fish and shellfish sold in subtropical-arid countries (United Arab Emirates). It also examined the antimicrobial resistance of the isolated species and their growth behavior upon in vitro environmental changes concerning temperature, pH, and salinity. The prevalence of Vibrio spp. in fish and shellfish samples, was 64.5 and 92%, respectively. However, Vibrio parahemolyticus were detected in a mere 7.5 and 13.0% of the samples, respectively. On the other hand, Vibrio mimicus was detected in 1.5 and 8.5% of the samples, respectively. None of the six antibiotics studied except for Sulfamethoxazole-trimethoprim were effective against fish Vibrio spp. isolates. On a similar note, three antibiotics, namely Penicillin, Daptomycin, and Vancomycin, were ineffective against the shellfish isolates. The growth of the microorganisms did not show any significant trend with changes in pH and salinity. The optimum temperature for Vibrio spp. growth was observed to be 37°C.