bluuebunny/crossref_metadata_2025 huggingface dataset:
Can Emission Trading Scheme Improve Carbon Emission Performance? Evidence From China
Authors: Zheng Yuhua , Sun Xiaoyang , Zhang Chenyu , Wang Daojuan , Mao Ju
Published: September 2021

This paper explores the effect of China’s emission trading scheme (ETS) pilot policy implemented during 2013-2014 on carbon emission performance. Adopting the Difference-in-Difference (DID) model, we find that: 1) China’s ETS pilot policy can significantly improve the carbon emission performance of listed companies in the pilot provinces. 2) The heterogeneity analysis shows that the carbon emission performance of listed companies in the eastern coastal pilot areas has improved significantly, which is not significant in the central and western pilot areas. 3) We find that China’s ETS pilot policy can significantly improve innovation capabilities of listed companies, suggesting that innovation is a channel for the impact of the China’s ETS pilot policy on carbon emission performance in the pilot provinces. Overall, our study shows that ETS pilot policy has played a governance role in China and improved carbon emission performance. We further highlight some important policy implications with respect to helping companies save energy and reduce emissions, and promoting the further improvement of China’s ETS pilot policy.
Graph Representation Forecasting of Patient's Medical Conditions: Toward a Digital Twin
Authors: Barbiero Pietro , Viñas Torné Ramon , Lió Pietro
Published: September 2021

Objective: Modern medicine needs to shift from a wait and react, curative discipline to a preventative, interdisciplinary science aiming at providing personalized, systemic, and precise treatment plans to patients. To this purpose, we propose a “digital twin” of patients modeling the human body as a whole and providing a panoramic view over individuals' conditions.

Methods: We propose a general framework that composes advanced artificial intelligence (AI) approaches and integrates mathematical modeling in order to provide a panoramic view over current and future pathophysiological conditions. Our modular architecture is based on a graph neural network (GNN) forecasting clinically relevant endpoints (such as blood pressure) and a generative adversarial network (GAN) providing a proof of concept of transcriptomic integrability.

Results: We tested our digital twin model on two simulated clinical case studies combining information at organ, tissue, and cellular level. We provided a panoramic overview over current and future patient's conditions by monitoring and forecasting clinically relevant endpoints representing the evolution of patient's vital parameters using the GNN model. We showed how to use the GAN to generate multi-tissue expression data for blood and lung to find associations between cytokines conditioned on the expression of genes in the renin–angiotensin pathway. Our approach was to detect inflammatory cytokines, which are known to have effects on blood pressure and have previously been associated with SARS-CoV-2 infection (e.g., CXCR6, XCL1, and others).

Significance: The graph representation of a computational patient has potential to solve important technological challenges in integrating multiscale computational modeling with AI. We believe that this work represents a step forward toward next-generation devices for precision and predictive medicine.
Identification of Circular RNAs Associated With Chemoresistance in Colorectal Cancer
Authors: Yao Fei , Xiang Xiaochen , Zhou Chuanren , Huang Qiyou , Huang Xiaoying , Xie Zhufu , Wang Qiang , Wu Qingming
Published: September 2021

Chemoresistance is a major clinical obstacle for the treatment of colorectal cancer (CRC). Circular RNAs (circRNAs) are a new type of non-coding RNA that participated in the development of chemoresistance. However, the profiles and effects of circRNAs in 5-fluorouracil (5-Fu) and cisplatin resistance of CRC are still unclear and need to be elucidated. In the present study, the profiles of circRNAs in CRC chemoresistant (HCT8/5-Fu and HCT8/DDP) and chemosensitive (HCT8) cell lines were identified via RNA-sequencing. In total, 48 and 90 differentially expressed (DE)-circRNAs were detected in HCT8/5-Fu and HCT8/DDP cell lines, respectively. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted on the host genes of DE-circRNAs; the results showed that the most significant enrichment pathways in HCT8/5-Fu and HCT8/DDP cell lines were base excision repair and Hippo signaling pathway, respectively. In addition, 11 common DE-circRNAs in the two drug-resistant cell lines (two are upregulated and nine are downregulated) were screened and verified by quantitative real-time PCR; hsacirc_023607 and hsacirc_007420 were found to be the circRNAs with the highest upregulation and downregulation fold changes. However, functional studies showed hsacirc_023607 has no effect on CRC chemoresistance. Therefore, the regulatory networks of targeted miRNAs related to 5-Fu or cisplatin resistance were predicted and constructed, in which hsacirc_002482 was identified as a hub gene, and its overexpression could suppress HCT8/5-Fu and HCT8/DDP cell proliferation and promote cell apoptosis, and enhance cell chemosensitivity. Taken together, these results of the study suggested that hsacirc_002482 may play important roles in chemoresistance of CRC.
Whole Transcriptome Analysis Revealed a Stress Response to Deep Underground Environment Conditions in Chinese Hamster V79 Lung Fibroblast Cells
Authors: Duan Liju , Jiang Hongying , Liu Jifeng , Liu Yilin , Ma Tengfei , Xie Yike , Wang Ling , Cheng Juan , Zou Jian , Wu Jiang , Liu Shixi , Gao Mingzhong , Li Weimin , Xie Heping
Published: September 2021

Background: Prior studies have shown that the proliferation of V79 lung fibroblast cells could be inhibited by low background radiation (LBR) in deep underground laboratory (DUGL). In the current study, we revealed further molecular changes by performing whole transcriptome analysis on the expression profiles of long non-coding RNA (lncRNA), messenger RNA (mRNA), circular RNA (circRNA) and microRNA (miRNA) in V79 cells cultured for two days in a DUGL.

Methods: Whole transcriptome analysis including lncRNA, mRNAs, circ RNA and miRNA was performed in V79 cells cultured for two days in DUGL and above ground laboratory (AGL), respectively. The differentially expressed (DE) lncRNA, mRNA, circRNA, and miRNA in V79 cells were identified by the comparison between DUGL and AGL groups. Quantitative real-time polymerase chain reaction(qRT-PCR)was conducted to verify the selected RNA sequencings. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was analyzed for the DE mRNAs which enabled to predict target genes of lncRNA and host genes of circRNA.

Results: With |log2(Fold-change)| ≥ 1.0 and p < 0.05, a total of 1257 mRNAs (353 mRNAs up-regulated, 904 mRNAs down-regulated), 866 lncRNAs (145 lncRNAs up-regulated, 721 lncRNAs down-regulated), and 474 circRNAs (247 circRNAs up-regulated, 227 circRNAs down-regulated) were significantly altered between the two groups. There was no significant difference in miRNA between the two groups. The altered RNA profiles were mainly discovered in lncRNAs, mRNAs and circRNAs. DE RNAs were involved in many pathways including ECM-RI, PI3K-Akt signaling, RNA transport and the cell cycle under the LBR stress of the deep underground environment.

Conclusion: Taken together, these results suggest that the LBR in the DUGL could induce transcriptional repression, thus reducing metabolic process and reprogramming the overall gene expression profile in V79 cells.
Integrated Analysis of Liver Transcriptome, miRNA, and Proteome of Chinese Indigenous Breed Ningxiang Pig in Three Developmental Stages Uncovers Significant miRNA–mRNA–Protein Networks in Lipid Metabolism
Authors: Li Biao , Yang Jinzeng , Gong Yan , Xiao Yu , Zeng Qinghua , Xu Kang , Duan Yehui , He Jianhua , He Jun , Ma Haiming
Published: September 2021

Liver is an important metabolic organ of mammals. During each transitional period of life, liver metabolism is programmed by a complex molecular regulatory system for multiple physiological functions, many pathways of which are regulated by hormones and cytokines, nuclear receptors, and transcription factors. To gain a comprehensive and unbiased molecular understanding of liver growth and development in Ningxiang pigs, we analyzed the mRNA, microRNA (miRNA), and proteomes of the livers of Ningxiang pigs during lactation, nursery, and fattening periods. A total of 22,411 genes (19,653 known mRNAs and 2758 novel mRNAs), 1122 miRNAs (384 known miRNAs and 738 novel miRNAs), and 1123 unique proteins with medium and high abundance were identified by high-throughput sequencing and mass spectrometry. We show that the differences in transcriptional, post-transcriptional, or protein levels were readily identified by comparing different time periods, providing evidence that functional changes that may occur during liver development are widespread. In addition, we found many overlapping differentially expressed genes (DEGs)/differentially expressed miRNAs (DEMs)/differentially expressed proteins (DEPs) related to glycolipid metabolism in any group comparison. These overlapping DEGs/DEMs/DGPs may play an important role in functional transformation during liver development. Short Time-series Expression Miner (STEM) analysis revealed multiple expression patterns of mRNA, miRNA, and protein in the liver. Furthermore, several diverse key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including immune defense, glycolipid metabolism, protein transport and uptake, and cell proliferation and development, were identified by combined analysis of DEGs and DGPs. A number of predicted miRNA–mRNA–protein pairs were found and validated by qRT-PCR and parallel reaction monitoring (PRM) assays. The results provide new and important information about the genetic breeding of Ningxiang pigs, which represents a foundation for further understanding the molecular regulatory mechanisms of dynamic development of liver tissue, functional transformation, and lipid metabolism.
Analysis of Genomic Copy Number Variation in Miscarriages During Early and Middle Pregnancy
Authors: Wu Heming , Huang Qingyan , Zhang Xia , Yu Zhikang , Zhong Zhixiong
Published: September 2021

The purpose of this study was to explore the copy number variations (CNVs) associated with miscarriage during early and middle pregnancy and provide useful genetic guidance for pregnancy and prenatal diagnosis. A total of 505 fetal specimens were collected and CNV sequencing (CNV-seq) analysis was performed to determine the types and clinical significance of CNVs, and relevant medical records were collected. The chromosomal abnormality rate was 54.3% (274/505), among which the numerical chromosomal abnormality rate was 40.0% (202/505) and structural chromosomal abnormality rate was 14.3% (72/505). Chromosomal monosomy mainly occurred on sex chromosomes, and chromosomal trisomy mainly occurred on chromosomes 16, 22, 21, 15, 13, and 9. The incidence of numerical chromosomal abnormalities in ≥35 year-old age pregnant women was significantly higher than <35 year-old age group. The highest incidence of pathogenic CNV (pCNV) was found in fetuses at ≤6 weeks of pregnancy (5.26%), and the incidence of variants of unknown significance (VOUS) CNVs decreased gradually with the increase of gestational age. The rate of chromosomal abnormalities of fetuses in early pregnancy (59.5%) was higher than that of fetuses in middle pregnancy (27.2%) (p < 0.001). There were 168 genes in VOUS + pCNV regions. 41 functions and 12 pathways (p < 0.05) were enriched of these genes by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Some meaningful genetic etiology information such as genes and pathways has been obtained, it may provide useful genetic guidance for pregnancy and prenatal diagnosis.
Identification of Mutation Landscape and Immune Cell Component for Liver Hepatocellular Carcinoma Highlights Potential Therapeutic Targets and Prognostic Markers
Authors: Wang Hengzhen , Jiang Wenjing , Wang Haijun , Wei Zheng , Li Hali , Yan Haichao , Han Peng
Published: September 2021

Liver hepatocellular carcinoma (LIHC) is a primary malignancy, and there is a lack of effective treatment for advanced patients. Although numerous studies exist to reveal the carcinogenic mechanism of LIHC, few studies have integrated multi-omics data to systematically analyze pathogenesis and reveal potential therapeutic targets. Here, we integrated genomic variation data and RNA-seq profiles obtained by high-throughput sequencing to define high- and low-genomic instability samples. The mutational landscape was reported, and the advanced patients of LIHC were characterized by high-genomic instability. We found that the tumor microenvironment underwent metabolic reprograming driven by mutations accumulate to satisfy tumor proliferation and invasion. Further, the co-expression network identifies three mutant long non-coding RNAs as potential therapeutic targets, which can promote tumor progression by participating in specific carcinogenic mechanisms. Then, five potential prognostic markers (RP11-502I4.3, SPINK5, CHRM3, SLC5A12, and RP11-467L13.7) were identified by examining the association of genes and patient survival. By characterizing the immune landscape of LIHC, loss of immunogenicity was revealed as a key factor of immune checkpoint suppression. Macrophages were found to be significantly associated with patient risk scores, and high levels of macrophages accelerated patient mortality. In summary, the mutation-driven mechanism and immune landscape of LIHC revealed by this study will serve precision medicine.
CAL-1 as Cellular Model System to Study CCR7-Guided Human Dendritic Cell Migration
Authors: Uetz-von Allmen Edith , Samson Guerric P. B. , Purvanov Vladimir , Maeda Takahiro , Legler Daniel F.
Published: September 2021

Dendritic cells (DCs) are potent and versatile professional antigen-presenting cells and central for the induction of adaptive immunity. The ability to migrate and transport peripherally acquired antigens to draining lymph nodes for subsequent cognate T cell priming is a key feature of DCs. Consequently, DC-based immunotherapies are used to elicit tumor-antigen specific T cell responses in cancer patients. Understanding chemokine-guided DC migration is critical to explore DCs as cellular vaccines for immunotherapeutic approaches. Currently, research is hampered by the lack of appropriate human cellular model systems to effectively study spatio-temporal signaling and CCR7-driven migration of human DCs. Here, we report that the previously established human neoplastic cell line CAL-1 expresses the human DC surface antigens CD11c and HLA-DR together with co-stimulatory molecules. Importantly, if exposed for three days to GM-CSF, CAL-1 cells induce the endogenous expression of the chemokine receptor CCR7 upon encountering the clinically approved TLR7/8 agonist Resiquimod R848 and readily migrate along chemokine gradients. Further, we demonstrate that CAL-1 cells can be genetically modified to express fluorescent (GFP)-tagged reporter proteins to study and visualize signaling or can be gene-edited using CRISPR/Cas9. Hence, we herein present the human CAL-1 cell line as versatile and valuable cellular model system to effectively study human DC migration and signaling.
CXCL5 Downregulation in Villous Tissue Is Correlated With Recurrent Spontaneous Abortion
Authors: Zhang Sainan , Ding Jinli , Wang Jiayu , Yin Tailang , Zhang Yan , Yang Jing
Published: September 2021

Recurrent spontaneous abortion (RSA) affects 5% of childbearing-age women worldwide. Inadequate trophoblast invasion is one of the main reasons for the development of RSA; however, the underlying molecular mechanisms for RSA have not been fully understood, and further explanation is urgently needed. C-X-C motif chemokine ligand 5 (CXCL5) is reported to contribute to the invasion of cancer cells, and its aberrant expression is associated with the cellular process of tumor pathology. Considering the high behavioral similarity between trophoblast cells and cancer cells, we hypothesized that CXCL5 may influence trophoblast invasion, and its expression levels in villous tissue may be correlated with RSA. In this study, we firstly investigated the CXCL5 expression in placental villous tissues of 15 RSA patients and 13 control patients, and the results showed that CXCL5 levels were significantly lower in villous tissue from RSA patients than those of the controls. Further in vitro experiments presented that recombinant human CXCL5 can enhance trophoblast migration, invasion, and epithelial-to-mesenchymal transition (EMT) process. We also demonstrated that CXCL5 exerted these effects on trophoblast cells through PI3K/AKT/ERK1/2 signaling pathway. In conclusion, these data indicate that CXCL5 downregulation in human villous tissue is correlated with RSA. Additionally, we found that estrogen, progesterone, human chorionic gonadotropin, and decidual stromal cells can regulate CXCL5 and chemokine receptor 2 (CXCR2) expression of trophoblast in a cell manner.
Mice Plasmacytoid Dendritic Cells Were Activated by Lipopolysaccharides Through Toll-Like Receptor 4/Myeloid Differentiation Factor 2
Authors: Zhang Wei , An Eun-Koung , Hwang Juyoung , Jin Jun-O
Published: September 2021

Plasmacytoid dendritic cells (pDCs) are known to respond to viral infections. However, the activation of pDCs by bacterial components such as lipopolysaccharides (LPS) has not been well studied. Here, we found that pDCs, conventional dendritic cells (cDCs), and B cells express high levels of toll-like receptor 4 (TLR4), a receptor for LPS. Moreover, LPS could effectively bind to not only cDCs but also pDCs and B cells. Intraperitoneal administration of LPS promoted activation of splenic pDCs and cDCs. LPS treatment led to upregulation of interferon regulatory factor 7 (IRF7) and induced production of interferon-alpha (IFN-α) in splenic pDCs. Furthermore, LPS-dependent upregulation of co-stimulatory molecules in pDCs did not require the assistance of other immune cells, such as cDCs. However, the production levels of IFN-α were decreased in cDC-depleted splenocytes, indicating that cDCs may contribute to the enhancement of IFN-α production in pDCs. Finally, we showed that activation of pDCs by LPS requires the TLR4 and myeloid differentiation factor 2 (MD2) signaling pathways. Thus, these results demonstrate that the gram-negative component LPS can directly stimulate pDCs via TLR4/MD2 stimulation in mice.
Dynamics of Polarized Macrophages and Activated CD8+ Cells in Heart Tissue of Atlantic Salmon Infected With Piscine Orthoreovirus-1
Authors: Malik Muhammad Salman , Nyman Ingvild Berg , Wessel Øystein , Dahle Maria K. , Rimstad Espen
Published: September 2021

Piscine orthoreovirus (PRV-1) infection causes heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon (Salmo salar). The virus is also associated with focal melanized changes in white skeletal muscle where PRV-1 infection of macrophages appears to be important. In this study, we studied the macrophage polarization into M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes during experimentally induced HSMI. The immune response in heart with HSMI lesions was characterized by CD8+ and MHC-I expressing cells and not by polarized macrophages. Fluorescent in situ hybridization (FISH) assays revealed localization of PRV-1 in a few M1 macrophages in both heart and skeletal muscle. M2 type macrophages were widely scattered in the heart and were more abundant in heart compared to the skeletal muscle. However, the M2 macrophages did not co-stain for PRV-1. There was a strong cellular immune response to the infection in the heart compared to that of the skeletal muscle, seen as increased MHC-I expression, partly in cells also containing PRV-1 RNA, and a high number of cytotoxic CD8+ granzyme producing cells that targeted PRV-1. In skeletal muscle, MHC-I expressing cells and CD8+ cells were dispersed between myocytes, but these cells did not stain for PRV-1. Gene expression analysis by RT-qPCR complied with the FISH results and confirmed a drop in level of PRV-1 following the cell mediated immune response. Overall, the results indicated that M1 macrophages do not contribute to the initial development of HSMI. However, large numbers of M2 macrophages reside in the heart and may contribute to the subsequent fast recovery following clearance of PRV-1 infection.
Intravascular Crawling of Patrolling Monocytes: A Lèvy-Like Motility for Unique Search Functions?
Authors: Moreno-Cañadas Rocío , Luque-Martín Laura , Arroyo Alicia G.
Published: September 2021

Patrolling monocytes (PMo) are the organism’s preeminent intravascular guardians by their continuous search of damaged endothelial cells and harmful microparticles for their removal and to restore homeostasis. This surveillance is accomplished by PMo crawling on the apical side of the endothelium through regulated interactions of integrins and chemokine receptors with their endothelial ligands. We propose that the search mode governs the intravascular motility of PMo in vivo in a similar way to T cells looking for antigen in tissues. Signs of damage to the luminal side of the endothelium (local death, oxidized LDL, amyloid deposits, tumor cells, pathogens, abnormal red cells, etc.) will change the diffusive random towards a Lèvy-like crawling enhancing their recognition and clearance by PMo damage receptors as the integrin αMβ2 and CD36. This new perspective can help identify new actors to promote unique PMo intravascular actions aimed at maintaining endothelial fitness and combating harmful microparticles involved in diseases as lung metastasis, Alzheimer’s angiopathy, vaso-occlusive disorders, and sepsis.
Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth
Authors: van Dorsten Rebecca T. , Wagh Kshitij , Moore Penny L. , Morris Lynn
Published: September 2021

Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC50 and IC80 data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC80 titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC80 titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.
To React or Not to React: The Dilemma of Fish Immune Systems Facing Myxozoan Infections
Authors: Holzer Astrid S. , Piazzon M. Carla , Barrett Damien , Bartholomew Jerri L. , Sitjà-Bobadilla Ariadna
Published: September 2021

Myxozoans are microscopic, metazoan, obligate parasites, belonging to the phylum Cnidaria. In contrast to the free-living lifestyle of most members of this taxon, myxozoans have complex life cycles alternating between vertebrate and invertebrate hosts. Vertebrate hosts are primarily fish, although they are also reported from amphibians, reptiles, trematodes, mollusks, birds and mammals. Invertebrate hosts include annelids and bryozoans. Most myxozoans are not overtly pathogenic to fish hosts, but some are responsible for severe economic losses in fisheries and aquaculture. In both scenarios, the interaction between the parasite and the host immune system is key to explain such different outcomes of this relationship. Innate immune responses contribute to the resistance of certain fish strains and species, and the absence or low levels of some innate and regulatory factors explain the high pathogenicity of some infections. In many cases, immune evasion explains the absence of a host response and allows the parasite to proliferate covertly during the first stages of the infection. In some infections, the lack of an appropriate regulatory response results in an excessive inflammatory response, causing immunopathological consequences that are worse than inflicted by the parasite itself. This review will update the available information about the immune responses against Myxozoa, with special focus on T and B lymphocyte and immunoglobulin responses, how these immune effectors are modulated by different biotic and abiotic factors, and on the mechanisms of immune evasion targeting specific immune effectors. The current and future design of control strategies for myxozoan diseases is based on understanding this myxozoan-fish interaction, and immune-based strategies such as improvement of innate and specific factors through diets and additives, host genetic selection, passive immunization and vaccination, are starting to be considered.
SPINK7 Recognizes Fungi and Initiates Hemocyte-Mediated Immune Defense Against Fungal Infections
Authors: Dong Zhaoming , An Lingna , Lu Mengyao , Tang Muya , Chen Haiqin , Huang Xuan , Hou Yong , Shen Guanwang , Zhang Xiaolu , Zhang Yan , Xia Qingyou , Zhao Ping
Published: September 2021

Serine protease inhibitors of Kazal-type (SPINKs) were widely identified in vertebrates and invertebrates, and played regulatory roles in digestion, coagulation, and fibrinolysis. In this study, we reported the important role of SPINK7 in regulating immune defense of silkworm, Bombyx mori. SPINK7 contains three Kazal domains and has 6 conserved cysteine residues in each domain. Quantitative real-time PCR analyses revealed that SPINK7 was exclusively expressed in hemocytes and was upregulated after infection with two fungi, Saccharomyces cerevisiae and Candida albicans. Enzyme activity inhibition test showed that SPINK7 significantly inhibited the activity of proteinase K from C. albicans. Additionally, SPINK7 inhibited the growth of three fungal spores, including S. cerevisiae, C. albicans, and Beauveria bassiana. The pathogen-associated molecular patterns (PAMP) binding assays suggested that SPINK7 could bind to β-D-glucan and agglutinate B. bassiana and C. albicans. In vitro assays were performed using SPINK7-coated agarose beads, and indicated that SPINK7 promoted encapsulation and melanization of agarose beads by B. mori hemocytes. Furthermore, co-localization studies using immunofluorescence revealed that SPINK7 induced hemocytes to aggregate and entrap the fungi spores of B. bassiana and C. albicans. Our study revealed that SPINK7 could recognize fungal PAMP and induce the aggregation, melanization, and encapsulation of hemocytes, and provided valuable clues for understanding the innate immunity and cellular immunity in insects.
The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes
Authors: Sharp Robert C. , Brown Matthew E. , Shapiro Melanie R. , Posgai Amanda L. , Brusko Todd M.
Published: September 2021

Background

The pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic β-cells. Interactions between risk variants and environmental factors result in significant heterogeneity in clinical presentation among those who develop T1D. Although genetic risk is dominated by the human leukocyte antigen (HLA) class II and insulin (INS) gene loci, nearly 150 additional risk variants are significantly associated with the disease, including polymorphisms in immune checkpoint molecules, such as SIRPG.

Scope of Review

In this review, we summarize the literature related to the T1D-associated risk variants in SIRPG, which include a protein-coding variant (rs6043409, G>A; A263V) and an intronic polymorphism (rs2281808, C>T), and their potential impacts on the immunoregulatory signal regulatory protein (SIRP) family:CD47 signaling axis. We discuss how dysregulated expression or function of SIRPs and CD47 in antigen-presenting cells (APCs), T cells, natural killer (NK) cells, and pancreatic β-cells could potentially promote T1D development.

Major Conclusions

We propose a hypothesis, supported by emerging genetic and functional immune studies, which states a loss of proper SIRP:CD47 signaling may result in increased lymphocyte activation and cytotoxicity and enhanced β-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.
PET Imaging of Neuroinflammation in Alzheimer’s Disease
Authors: Zhou Rong , Ji Bin , Kong Yanyan , Qin Limei , Ren Wuwei , Guan Yihui , Ni Ruiqing
Published: September 2021

Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.
Short-Term Daily Prediction of Sea Ice Concentration Based on Deep Learning of Gradient Loss Function
Authors: Liu Quanhong , Zhang Ren , Wang Yangjun , Yan Hengqian , Hong Mei
Published: September 2021

The navigability potential of the Northeast Passage has gradually emerged with the melting of Arctic sea ice. For the purpose of navigation safety in the Arctic area, a reliable daily sea ice concentration (SIC) prediction result is required. As the mature application of deep learning technique in short-term prediction of other fields (atmosphere, ocean, and hurricane, etc.), a new model was proposed for daily SIC prediction by selecting multiple factors, adopting gradient loss function (Grad-loss) and incorporating an improved predictive recurrent neural network (PredRNN++). Three control experiments are designed to test the impact of these three improvements for model performance with multiple indicators. Results show that the proposed model has best prediction skill in our experiments by taking physical process and local SIC variation into consideration, which can continuously predict daily SIC for up to 9 days.
Non-valvular Atrial Fibrillation in CKD: Role of Vitamin K Antagonists and Direct Oral Anticoagulants. A Narrative Review
Authors: Cases Aleix , Gomez Pablo , Broseta Jose Jesus , Perez Bernat Elisa , Arjona Barrionuevo Juan de Dios , Portolés Jose Maria , Gorriz Jose Luis
Published: September 2021

Atrial fibrillation (AF) is the most common arrhythmia in chronic kidney disease (CKD), with a close bidirectional relationship between the two entities. The presence of CKD in AF increases the risk of thromboembolic events, mortality and bleeding. Vitamin K antagonists (VKA) have been the mainstay of treatment for the prevention of thromboembolic events in AF until recently, with confirmed benefits in AF patients with stage 3 CKD. However, the risk-benefit profile of VKA in patients with AF and stages 4–5 CKD is controversial due to the lack of evidence from randomized controlled trials. Treatment with VKA in CKD patients has been associated with conditions such as poorer anticoagulation quality, increased risk of bleeding, faster progression of vascular/valvular calcification and higher risk of calciphylaxis. Direct oral anticoagulants (DOACs) have shown equal or greater efficacy in stroke/systemic embolism prevention, and a better safety profile than VKA in post-hoc analysis of the pivotal randomized controlled trials in patients with non-valvular AF and stage 3 CKD, yet evidence of its risk-benefit profile in more advanced stages of CKD is scarce. Observational studies associate DOACs with a good safety/effectiveness profile compared to VKA in non-dialysis CKD patients. Further, DOACs have been associated with a lower risk of acute kidney injury and CKD development/progression than VKA. This narrative review summarizes the evidence of the efficacy and safety of warfarin and DOACs in patients with AF at different CKD stages, as well as their effects on renal function, vascular/valvular calcification and bone health.
Diverse Bacterial Resistance Genes Detected in Fecal Samples From Clinically Healthy Women and Infants in Australia—A Descriptive Pilot Study
Authors: Guernier-Cambert Vanina , Chamings Anthony , Collier Fiona , Alexandersen Soren
Published: September 2021

The gut microbiota is an immense reservoir of antimicrobial resistance genes (ARGs), the so-called “resistome.” In Australia, where antibiotic use is high and resistance rates in some common pathogens are increasing, very little is known about the human resistome. To assess the presence and diversity of ARGs in the gut of Australians from south-eastern Victoria, we investigated fecal samples from clinically healthy infants and pregnant women using non-targeted (shotgun metagenomics sequencing or SMS) and targeted sequencing (two Ion AmpliseqTM panels). All methods detected ARGs in all samples, with the detection overall of 64 unique genes conferring resistance to 12 classes of antibiotics. Predominant ARGs belonged to three classes of antibiotics that are the most frequently prescribed in Australia: tetracycline, β-lactams and MLSB (macrolide, lincosamide, streptogramin B). The three bacterial Orders commonly identified as carrying ARGs were Clostridiales, Bacteroidales, and Enterobacteriales. Our preliminary results indicate that ARGs are ubiquitously present and diverse among the gut microbiota of clinically healthy humans from south-eastern Victoria, Australia. The observed resistance pattern partly overlaps with antimicrobial usage in human medicine in Australia, but ARGs to tetracycline are more common than could be expected. Our current sample is small and limited to south-eastern Victoria, and more data on healthy individuals will be needed to better depict resistance patterns at the population level, which could guide population and/or environmental monitoring and surveillance of antibiotic resistance on various spatio-temporal scales in Australia. For future studies, we recommend using the Ion AmpliseqTM Antimicrobial Resistance Research panel, which is sensitive and user-friendly, or combining several methods to increase the detected diversity.
A Bacterial Quorum Sensing Molecule Elicits a General Stress Response in Saccharomyces cerevisiae
Authors: Delago Antonia , Gregor Rachel , Dubinsky Luba , Dandela Rambabu , Hendler Adi , Krief Pnina , Rayo Josep , Aharoni Amir , Meijler Michael M.
Published: September 2021

Bacteria assess their population density through a chemical communication mechanism termed quorum sensing, in order to coordinate group behavior. Most research on quorum sensing has focused primarily on its role as an intraspecies chemical signaling mechanism that enables the regulation of certain phenotypes through targeted gene expression. However, in recent years several seminal studies have revealed important phenomena in which quorum sensing molecules appear to serve additional roles as interspecies signals that may regulate microbial ecology. In this study, we asked whether the budding yeast Saccharomyces cerevisiae can sense chemical signals from prokaryotes. When exposed to a variety of quorum sensing molecules from different bacterial species and from Candida albicans we found that N-(3-oxododecanoyl)-L-homoserine lactone (C12) from the opportunistic human pathogen Pseudomonas aeruginosa induces a remarkable stress response in yeast. Microarray experiments confirmed and aided in interpreting these findings, showing a unique and specific expression pattern that differed significantly from the response to previously described stress factors. We further characterized this response and report preliminary findings on the molecular basis for the recognition of C12 by the yeast.
Detection of Bioavailable Cadmium by Double-Color Fluorescence Based on a Dual-Sensing Bioreporter System
Authors: Hui Chang-ye , Guo Yan , Wu Jian , Liu Lisa , Yang Xue-qin , Guo Xiang , Xie Ying , Yi Juan
Published: September 2021

Cadmium (Cd) is carcinogenic to humans and can accumulate in the liver, kidneys, and bones. There is widespread presence of cadmium in the environment as a consequence of anthropogenic activities. It is important to detect cadmium in the environment to prevent further exposure to humans. Previous whole-cell biosensor designs were focused on single-sensing constructs but have had difficulty in distinguishing cadmium from other metal ions such as lead (Pb) and mercury (Hg). We developed a dual-sensing bacterial bioreporter system to detect bioavailable cadmium by employing CadC and CadR as separate metal sensory elements and eGFP and mCherry as fluorescent reporters in one genetic construct. The capability of this dual-sensing biosensor was proved to simultaneously detect bioavailable cadmium and its toxic effects using two sets of sensing systems while still maintaining similar specificity and sensitivity of respective signal-sensing biosensors. The productions of double-color fluorescence were directly proportional to the exposure concentration of cadmium, thereby serving as an effective quantitative biosensor to detect bioavailable cadmium. This novel dual-sensing biosensor was then validated to respond to Cd(II) spiked in environmental water samples. This is the first report of the development of a novel dual-sensing, whole-cell biosensor for simultaneous detection of bioavailable cadmium. The application of two biosensing modules provides versatile biosensing signals and improved performance that can make a significant impact on monitoring high concentration of bioavailable Cd(II) in environmental water to reduce human exposure to the harmful effects of cadmium.
In vivo Emergence of Colistin and Tigecycline Resistance in Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae During Antibiotics Treatment
Authors: Chen Jiawei , Zeng Yu , Zhang Rong , Cai Jiachang
Published: September 2021

Three carbapenem-resistant Klebsiella pneumoniae (CRKP; strains KP-426, KP-C76, and KP-CT77) were isolated from a patient with severe burns during the treatment of colistin and tigecycline. Single-nucleotide polymorphism typing showed that three ST11 CRKP were clonally related. Three isolates harbored the same set of antimicrobial resistance genes. blaKPC-2, blaSHV-12, blaTEM-1, and rmtB genes were located on the same 128,928-bp IncFII/IncR plasmid. Tet(A), catA2, sul2, and dfrA14 genes were located on a plasmid with an unknown Inc-type. blaSHV-11, fosA, and aadA2 were chromosomal genes. An IS1 and an ISKpn14 were found in the promoter region of the mgrB gene of two colistin-resistant CRKP, K. pneumoniae KP-C76, and KP-CT77, respectively. A novel amino acid substitution, G300E, was identified in the type 1 Tet(A) variant of K. pneumoniae KP-CT77 which exhibited high-level tigecycline resistance compared to strains KP-426 and KP-C76 (MIC of 32, 4, and 4mg/l, respectively). Conjugation and cloning experiments confirmed that the mutated Tet(A) resulted in a 4-fold increase in tigecycline minimal inhibitory concentration (MIC) of Escherichia coli. Three CRKP belonged to the K64 serotype and possessed a similar IncHI1B/repB virulence plasmid carrying rmpA, rmpA2, and iucABCDiutA. The survival rates of Galleria Mellonella injected with K. pneumoniae KP-426, KP-C76, and KP-CT77 were 4.2, 20.8, and 8.3%, respectively. The emergence of colistin and tigecycline resistance in carbapenem-resistant hypervirulent K. pneumoniae posed a serious threat to clinical anti-infective therapy. The type 1 Tet(A) variant carrying G300E mutation, which conferred significantly elevated tigecycline MIC and was located on a conjugative plasmid, needs attention.
Soil Fungal Community in Grazed Inner Mongolian Grassland Adjacent to Coal-Mining Activity
Authors: Xie Linlin , Bi Yinli , Li Xianglei , Wang Kun , Christie Peter
Published: September 2021

Coal mining results in reduced soil quality and makes environments less stable. Soil fungi are suitable indicators of soil quality for monitoring purposes. Here, the objective was therefore to investigate the effects of grazing and mining on the composition of the soil fungal community at the periphery of an opencast coal-mine dump in the Shengli mining area, Xilingol League, Inner Mongolia. A total of 2,110 fungal operational taxonomic units were identified and subdivided into 81 orders and nine categories, based on trophic modes. The sensitive factor to mining was soil pH, and that to grazing were soil nitrate-nitrogen and alkaline phosphatase activity. According to the Pearson correlation and Mantel test, we propose interactions between grazing and coal-mining exist a co-effect and could regulate edaphic variables to alter the behavior of soil fungal community. Moreover, compared with coal-mining, grazing has a greater impact on it. The results provide a basis to further clarify soil fungal ecological functions, and may also contribute to the practice of soil remediation and environmental management in coal-mining areas.
Genomic and Epidemiological Analysis of SARS-CoV-2 Viruses in Sri Lanka
Authors: Jeewandara Chandima , Jayathilaka Deshni , Ranasinghe Diyanath , Hsu Nienyun Sharon , Ariyaratne Dinuka , Jayadas Tibutius Thanesh , Panambara Arachchige Deshan Madhusanka , Lindsey Benjamin B. , Gomes Laksiri , Parker Matthew D. , Wijewickrama Ananda , Karunaratne Malika , Ogg Graham S. , de Silva Thushan I. , Malavige Gathsaurie Neelika
Published: September 2021

Background: In order to understand the molecular epidemiology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Sri Lanka, since March 2020, we carried out genomic sequencing overlaid on available epidemiological data until April 2021.

Methods: Whole genome sequencing was carried out on diagnostic sputum or nasopharyngeal swabs from 373 patients with COVID-19. Molecular clock phylogenetic analysis was undertaken to further explore dominant lineages.

Results: The B.1.411 lineage was most prevalent, which was established in Sri Lanka and caused outbreaks throughout the country until March 2021. The estimated time of the most recent common ancestor (tMRCA) of this lineage was June 1, 2020 (with 95% lower and upper bounds March 30 to July 27) suggesting cryptic transmission may have occurred, prior to a large epidemic starting in October 2020. Returning travellers were identified with infections caused by lineage B.1.258, as well as the more transmissible B.1.1.7 lineage, which has replaced B.1.411 to fuel the ongoing large outbreak in the country.

Conclusions: The large outbreak that started in early October, is due to spread of a single virus lineage, B.1.411 until the end of March 2021, when B.1.1.7 emerged and became the dominant lineage.
Appendectomy Is Associated With Alteration of Human Gut Bacterial and Fungal Communities
Authors: Cai Shuntian , Fan Yanyun , Zhang Bangzhou , Lin Jinzhou , Yang Xiaoning , Liu Yunpeng , Liu Jingjing , Ren Jianlin , Xu Hongzhi
Published: September 2021

Recent research has revealed the importance of the appendix in regulating the intestinal microbiota and mucosal immunity. However, the changes that occur in human gut microbial communities after appendectomy have never been analyzed. We assessed the alterations in gut bacterial and fungal populations associated with a history of appendectomy. In this cross-sectional study, we investigated the association between appendectomy and the gut microbiome using 16S and ITS2 sequencing on fecal samples from 30 healthy individuals with prior appendectomy (HwA) and 30 healthy individuals without appendectomy (HwoA). Analysis showed that the gut bacterial composition of samples from HwA was less diverse than that of samples from HwoA and had a lower abundance of Roseburia, Barnesiella, Butyricicoccus, Odoribacter, and Butyricimonas species, most of which were short-chain fatty acids-producing microbes. The HwA subgroup analysis indicated a trend toward restoration of the HwoA bacterial microbiome over time after appendectomy. HwA had higher gut fungi composition and diversity than HwoA, even 5 years after appendectomy. Compared with those in samples from HwoA, the abundance correlation networks in samples from HwA displayed more complex fungal–fungal and fungal–bacterial community interactions. This study revealed a marked impact of appendectomy on gut bacteria and fungi, which was particularly durable for fungi.