bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Six-Gene SLC Family Signature With Prognostic Value in Patients With Lung Adenocarcinoma
Authors: Zhu Jing , Mou Yong , Ye Shenglan , Hu Hongling , Wang Rujuan , Yang Qing , Hu Yi
Published: December 2021

Given the importance of solute carrier (SLC) proteins in maintaining cellular metabolic homeostasis and that their dysregulation contributes to cancer progression, here we constructed a robust SLC family signature for lung adenocarcinoma (LUAD) patient stratification. Transcriptomic profiles and relevant clinical information of LUAD patients were downloaded from the TCGA and GEO databases. SLC family genes differentially expressed between LUAD tissues and adjacent normal tissues were identified using limma in R. Of these, prognosis-related SLC family genes were further screened out and used to construct a novel SLC family-based signature in the training cohort. The accuracy of the prognostic signature was assessed in the testing cohort, the entire cohort, and the external GSE72094 cohort. Correlations between the prognostic signature and the tumor immune microenvironment and immune cell infiltrates were further explored. We found that seventy percent of SLC family genes (279/397) were differentially expressed between LUAC tissues and adjacent normal. Twenty-six genes with p-values < 0.05 in univariate Cox regression analysis and Kaplan-Meier survival analysis were regarded as prognosis-related SLC family genes, six of which were used to construct a prognostic signature for patient classification into high- and low-risk groups. Kaplan-Meier survival analysis in all internal and external cohorts revealed a better overall survival for patients in the low-risk group than those in the high-risk group. Univariate and multivariate Cox regression analyses indicated that the derived risk score was an independent prognostic factor for LUAD patients. Moreover, a nomogram based on the six-gene signature and clinicopathological factors was developed for clinical application. High-risk patients had lower stromal, immune, and ESTIMATE scores and higher tumor purities than those in the low-risk group. The proportions of infiltrating naive CD4 T cells, activated memory CD4 T cells, M0 macrophages, resting dendritic cells, resting mast cells, activated mast cells, and eosinophils were significantly different between the high- and low-risk prognostic groups. In all, the six-gene SLC family signature is of satisfactory accuracy and generalizability for predicting overall survival in patients with LUAD. Furthermore, this prognostics signature is related to tumor immune status and distinct immune cell infiltrates in the tumor microenvironment.
Establishment of a Dihydrofolate Reductase Gene Knock-In Zebrafish Strain to Aid Preliminary Analysis of Congenital Heart Disease Mechanisms
Authors: Gong Ke , Xie Ting , Yang Yifeng , Luo Yong , Deng Yun , Chen Kun , Tan Zhiping , Guo Hui , Xie Li
Published: December 2021

Background: The dihydrofolate reductase (DHFR) gene is imperative in development, therefore it is essential to explore its effects on heart development. Thus, here a dhfr zebrafish knock-in (KI) strain was constructed.

Methods: CRISPR/Cas9 technology was used to establish the dhfr KI zebrafish strain. This strain was hybridized with TgG fluorescent strain zebrafish to observe the phenotypes of heart shape, size, and circularization direction. Wild-type (WT) and KI zebrafish were then dissected and histologically stained to observe pathological changes. Western blot analysis was used to verify the increased expressions of zebrafish genes after KI. Hybridization experiments were used to confirm the presence of abnormal gonadal dysplasia.

Results: The zebrafish dhfr KI strain was successfully constructed through CRISPR/Cas9 technology. At 6 days post fertilization (dpf), microscopic examinations of KI (homozygous) specimens revealed pericardial effusions, heart compressions, and curled tails. Compared with WT, the Hematoxylin and Eosin (H&E) tissue sections of KI-homozygous zebrafish showed defects such as reduced atria and ventricles. Western blot analysis indicated that the expression of the DHFR protein increased in both heterozygotes and homozygotes of dhfr KI zebrafish. Hybridization experiments revealed that dhfr KI may affect gonadal function.

Conclusion: The DHFR gene plays an important regulatory role in the process of heart development, and copy number variations (CNVs) of this gene may constitute a new pathogenic mechanism of congenital heart disease (CHD).
Liraglutide Inhibits Osteoclastogenesis and Improves Bone Loss by Downregulating Trem2 in Female Type 1 Diabetic Mice: Findings From Transcriptomics
Authors: Yu Jie , Shi Yan-Chuan , Ping Fan , Li Wei , Zhang Hua-Bing , He Shu-Li , Zhao Yuan , Xu Ling-Ling , Li Yu-Xiu
Published: December 2021

Background

The mechanisms of bone fragility in type 1 diabetes (T1D) are not fully understood. Whether glucagon-like peptide-1 receptor (GLP-1R) agonists could improve bone quality in T1D context also remains elusive.

Aims

We aimed to explore the possible mechanisms of bone loss in T1D and clarify whether liraglutide has effects on bone quality of T1D mice using transcriptomics.

Methods

Female streptozotocin-induced diabetic C57BL/6J mice were randomly divided into four groups and received the following treatments daily for 8 weeks: saline as controls, insulin, liraglutide, and liraglutide combined with insulin. These groups were also compared with non-STZ-treated normal glucose tolerance (NGT) group. Trunk blood and bone tissues were collected for analysis. Three tibia from each of the NGT, saline-treated, and liraglutide-treated groups were randomly selected for transcriptomics.

Results

Compared with NGT mice, saline-treated T1D mice manifested markedly hyperglycemia and weight loss, and micro-CT revealed significantly lower bone mineral density (BMD) and deficient microarchitectures in tibias. Eight weeks of treatment with liraglutide alone or combined with insulin rescued the decreased BMD and partly corrected the compromised trabecular microarchitectures. Transcriptomics analysis showed there were 789 differentially expressed genes mainly mapped to osteoclastogenesis and inflammation pathways. The RT-qPCR verified that the gene expression of Trem2, Nfatc1, Trap, and Ctsk were significantly increased in the tibia of T1D compared with those in the NGT group. Liraglutide treatment alone or combined with insulin could effectively suppress osteoclastogenesis by downregulating the gene expression of Trem2, Nfatc1, Ctsk, and Trap.

Conclusions

Taken together, increased osteoclastogenesis with upregulated expression of Trem2 played an important role in bone loss of T1D mice. Liraglutide provided protective effects on bone loss in T1D mice by suppressing osteoclastogenesis.
Research on Combined Electricity and Heating System Scheduling Method Considering Multi-Source Ring Heating Network
Authors: Ye Jing , Zhao Danyang , Zhang Lei , Li Zhenghua , Zhang Tao
Published: December 2021

Heating network constraint is one of the important factors that affect the scale of electro-thermal coupling scheduling. This paper first establishes an electrothermal coupling scheduling model considering the multi-source ring heating network pipe structure and then proposes a method of simplifying a multi-source cyclic heating network topology approximation. Second, the electrothermal coupling scheduling system is coordinated and solved. Finally, Through the simulation example results, the annular heating network topological approximate equivalent can simplify the model complexity of the original heating network while also retaining the thermal dynamic characteristics of the initial multi-source ring heating network. This study will greatly improve the efficiency of solving the electrothermal coupling system.
Pine Forest Management and Disturbance in Northern Poland: Combining High-Resolution 100-Year-Old Paleoecological and Remote Sensing Data
Authors: Łuców Dominika , Lamentowicz Mariusz , Kołaczek Piotr , Łokas Edyta , Marcisz Katarzyna , Obremska Milena , Theuerkauf Martin , Tyszkowski Sebastian , Słowiński Michał
Published: December 2021

Global warming has compelled to strengthen the resilience of European forests. Due to repeated droughts and heatwaves, weakened trees become vulnerable to insect outbreaks, pathogen invasions, and strong winds. This study combines high-resolution analysis of a 100-year-old high-resolution peat archive synthesized from the Martwe peatland in Poland with remote sensing data. We present the first REVEALS based vegetation reconstruction in a tornado-hit area from Poland on the background of previous forest management in monocultural even-aged stands – Tuchola Pinewoods. During the 20th century, the pine monocultures surrounding the peatland were affected by clear-cutting and insect outbreaks. In 2012, a tornado, destroyed ca. 550 ha of pine forest around the peatland. The palynological record reflects these major events of the past 100 years as well as changes in forest practices. Our study showed the strong relationships between the decrease of Pinus sylvestris (Scots pine) in palynological record as well as planting patterns after the tornado. Moreover, past forestry practices [such as domination of Pinus sylvestris, the collapse of Picea abies (Norway spruce), low share of Betula spec. (birch) due to Pinus sylvestris promotion and probable also to a lesser by removal of Betula as a “forest weed,” and low plant coverage of tree species due to clear-cutting and cutting after insect outbreaks] were well identified in the proxy record. In monocultures managed over decades, the reconstruction of vegetation may be challenging due to changes in the age composition of the Pinus sylvestris stands. We found that through historical, remote sensing, and paleoecological data, the dynamics of disturbances such as insect outbreaks and tornadoes, as well as the changing perceptions of local society about forests, can be determined.
Integration of Transcriptome and Methylome Analyses Provides Insight Into the Pathway of Floral Scent Biosynthesis in Prunus mume
Authors: Yuan Xi , Ma Kaifeng , Zhang Man , Wang Jia , Zhang Qixiang
Published: December 2021

DNA methylation is a common epigenetic modification involved in regulating many biological processes. However, the epigenetic mechanisms involved in the formation of floral scent have rarely been reported within a famous traditional ornamental plant Prunus mume emitting pleasant fragrance in China. By combining whole-genome bisulfite sequencing and RNA-seq, we determined the global change in DNA methylation and expression levels of genes involved in the biosynthesis of floral scent in four different flowering stages of P. mume. During flowering, the methylation status in the “CHH” sequence context (with H representing A, T, or C) in the promoter regions of genes showed the most significant change. Enrichment analysis showed that the differentially methylated genes (DMGs) were widely involved in eight pathways known to be related to floral scent biosynthesis. As the key biosynthesis pathway of the dominant volatile fragrance of P. mume, the phenylpropane biosynthesis pathway contained the most differentially expressed genes (DEGs) and DMGs. We detected 97 DMGs participated in the most biosynthetic steps of the phenylpropane biosynthesis pathway. Furthermore, among the previously identified genes encoding key enzymes in the biosynthesis of the floral scent of P. mume, 47 candidate genes showed an expression pattern matching the release of floral fragrances and 22 of them were differentially methylated during flowering. Some of these DMGs may or have already been proven to play an important role in biosynthesis of the key floral scent components of P. mume, such as PmCFAT1a/1c, PmBEAT36/37, PmPAL2, PmPAAS3, PmBAR8/9/10, and PmCNL1/3/5/6/14/17/20. In conclusion, our results for the first time revealed that DNA methylation is widely involved in the biosynthesis of floral scent and may play critical roles in regulating the floral scent biosynthesis of P. mume. This study provided insights into floral scent metabolism for molecular breeding.
A Novel Competing Endogenous RNA Network Associated With the Pathogenesis of Graves’ Ophthalmopathy
Authors: Yue Zifan , Mou Pei , Chen Sainan , Tong Fei , Wei Ruili
Published: December 2021

Background: Growing evidence has recently revealed the characteristics of long noncoding (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-mRNA networks in numerous human diseases. However, a scientific lncRNA/circRNA-miRNA-mRNA network related to Graves’ ophthalmopathy (GO) remains lacking.

Materials and methods: The expression levels of RNAs in GO patients were measured through high-throughput sequencing technology, and the results were proven by quantitative real-time PCR (qPCR). We constructed a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and identified hub genes by the Cytoscape plug-in CytoHubba. Then, the miRNAs related to differentially expressed lncRNAs/circRNAs and mRNAs were predicted through seed sequence matching analysis. Correlation coefficient analysis was performed on the interesting RNAs to construct a novel competing endogenous RNA (ceRNA) network.

Results: In total, 361 mRNAs, 355 circRNAs, and 242 lncRNAs were differentially expressed in GO patients compared with control patients, 166 pairs were identified, and ceRNA networks were constructed. The qPCR results showed that 4 mRNAs (THBS2, CHRM3, CXCL1, FPR2) and 2 lncRNAs (LINC01820:13, ENST00000499452) were differentially expressed between the GO patients and control patients.

Conclusion: An innovative lncRNA/circRNA-miRNA-mRNA ceRNA network between GO patients and control patients was constructed, and two important ceRNA pathways were identified, the LINC01820:13-hsa-miR-27b-3p-FPR2 ceRNA pathway and the ENST00000499452-hsa-miR-27a-3p-CXCL1 pathway, which probably affect the autoimmune response and inflammation in GO patients.
Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia
Authors: Zhang Yuxiang , Li Peng , Liu Nachuan , Jing Tao , Ji Zhiyong , Yang Chao , Zhao Liangyu , Tian Ruhui , Chen Huixing , Huang Yuhua , Zhi Erlei , Ou Ningjing , Bai Haowei , Zhou Yuchuan , Li Zheng , Yao Chencheng
Published: December 2021

Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for the majority of NOA remain unknown. FANCM is a member of Fanconi Anemia (FA) core complex, whose defects are associated with cell hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. It was reported that variants in FANCM (MIM: 609644) might cause azoospermia or oligospermia. However, there is still a lack of evidence to explain the association between different FANCM variants and male infertility phenotypes. Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G > T:p. V555F), and a homozygous variant in FANCM (c. 1972C > T:p. R658X) in a sporadic case with NOA, respectively. H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA. Collectively, our study expands the knowledge of variants in FANCM, and provides a new insight to understand the genetic etiology of NOA.
smplot: An R Package for Easy and Elegant Data Visualization
Authors: Min Seung Hyun , Zhou Jiawei
Published: December 2021

R, a programming language, is an attractive tool for data visualization because it is free and open source. However, learning R can be intimidating and cumbersome for many. In this report, we introduce an R package called “smplot” for easy and elegant data visualization. The R package “smplot” generates graphs with defaults that are visually pleasing and informative. Although it requires basic knowledge of R and ggplot2, it significantly simplifies the process of plotting a bar graph, a violin plot, a correlation plot, a slope chart, a Bland-Altman plot and a raincloud plot. The aesthetics of the plots generated from the package are elegant, highly customisable and adhere to important practices of data visualization. The functions from smplot can be used in a modular fashion, thereby allowing the user to further customise the aesthetics. Thesmplotpackage is open source under the MIT license and available on Github (https://github.com/smin95/smplot), where updates will be posted. All the example figures in this report are reproducible and the codes and data are provided for the reader in a separate online guide (https://smin95.github.io/dataviz/).
Epigenetic Regulation in Pathology of Atherosclerosis: A Novel Perspective
Authors: Tang Haishuang , Zeng Zhangwei , Shang Chenghao , Li Qiang , Liu Jianmin
Published: December 2021

Atherosclerosis, characterized by atherosclerotic plaques, is a complex pathological process that involves different cell types and can be seen as a chronic inflammatory disease. In the advanced stage, the ruptured atherosclerotic plaque can induce deadly accidents including ischemic stroke and myocardial infarction. Epigenetics regulation, including DNA methylation, histone modification, and non-coding RNA modification. maintains cellular identity via affecting the cellular transcriptome. The epigenetic modification process, mediating by epigenetic enzymes, is dynamic under various stimuli, which can be reversely altered. Recently, numerous studies have evidenced the close relationship between atherosclerosis and epigenetic regulations in atherosclerosis, providing us with a novel perspective in researching mechanisms and finding novel therapeutic targets of this serious disease. Here, we critically review the recent discoveries between epigenetic regulation mechanisms in atherosclerosis.
FcγR Genetic Variation and HIV-1 Vaccine Efficacy: Context And Considerations
Authors: Lassaunière Ria , Tiemessen Caroline T.
Published: December 2021

Receptors for the crystallisable fragment (Fc) of immunoglobulin (Ig) G, Fcγ receptors (FcγRs), link the humoral and cellular arms of the immune response, providing a diverse armamentarium of antimicrobial effector functions. Findings from HIV-1 vaccine efficacy trials highlight the need for further study of Fc-FcR interactions in understanding what may constitute vaccine-induced protective immunity. These include host genetic correlates identified within the low affinity Fcγ-receptor locus in three HIV-1 efficacy trials – VAX004, RV144, and HVTN 505. This perspective summarizes our present knowledge of FcγR genetics in the context of findings from HIV-1 efficacy trials, and draws on genetic variation described in other contexts, such as mother-to-child HIV-1 transmission and HIV-1 disease progression, to explore the potential contribution ofFcγRvariability in modulating different HIV-1 vaccine efficacy outcomes. Appreciating the complexity and the importance of the collective contribution of variation within theFCGRgene locus is important for understanding the role of FcγRs in protection against HIV-1 acquisition.
The Role of Helper T Cells in Psoriasis
Authors: Hu Peng , Wang Mengyao , Gao Hu , Zheng Ai , Li Jinhui , Mu Dezhi , Tong Jiyu
Published: December 2021

Psoriasis is a complex, chronic relapsing and inflammatory skin disorder with a prevalence of approximately 2% in the general population worldwide. Psoriasis can be triggered by infections, physical injury and certain drugs. The most common type of psoriasis is psoriasis vulgaris, which primarily features dry, well-demarcated, raised red lesions with adherent silvery scales on the skin and joints. Over the past few decades, scientific research has helped us reveal that innate and adaptive immune cells contribute to the chronic inflammatory pathological process of psoriasis. In particular, dysfunctional helper T cells (Th1, Th17, Th22, and Treg cells) are indispensable factors in psoriasis development. When stimulated by certain triggers, antigen-presenting cells (APCs) can release pro-inflammatory factors (IL-23, IFN-α and IL-12), which further activate naive T cells and polarize them into distinct helper T cell subsets that produce numerous cytokines, such as TNF, IFN-γ, IL-17 and IL-22, which act on keratinocytes to amplify psoriatic inflammation. In this review, we describe the function of helper T cells in psoriasis and summarize currently targeted anti-psoriatic therapies.
Combination of Ablation and Immunotherapy for Hepatocellular Carcinoma: Where We Are and Where to Go
Authors: Wang Kunpeng , Wang Cong , Jiang Hao , Zhang Yaqiong , Lin Weidong , Mo Jinggang , Jin Chong
Published: December 2021

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is increasing in incidence. Local ablative therapy plays a leading role in HCC treatment. Radiofrequency (RFA) is one of the first-line therapies for early local ablation. Other local ablation techniques (e.g., microwave ablation, cryoablation, irreversible electroporation, phototherapy.) have been extensively explored in clinical trials or cell/animal studies but have not yet been established as a standard treatment or applied clinically. On the one hand, single treatment may not meet the needs. On the other hand, ablative therapy can stimulate local and systemic immune effects. The combination strategy of immunotherapy and ablation is reasonable. In this review, we briefly summarized the current status and progress of ablation and immunotherapy for HCC. The immune effects of local ablation and the strategies of combination therapy, especially synergistic strategies based on biomedical materials, were discussed. This review is hoped to provide references for future researches on ablative immunotherapy to arrive to a promising new era of HCC treatment.
Case Report: Glucocorticoid Effect Observation in a Ureteral Urothelial Cancer Patient With ICI-Associated Myocarditis and Multiple Organ Injuries
Authors: Hu Xiajun , Wei Yumiao , Shuai Xinxin
Published: December 2021

Immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAEs) are becoming important safety issues worthy of attention despite the exciting therapeutic prospects. The growing development of new ICIs also brings new cases of irAEs, raising more challenges to clinicians. Cardiac injury is rare but life-threatening among diverse organ injuries, and effective interventions are critical for patients. Here, we report a novel programmed cell death protein-1 (PD-1) inhibitor tislelizumab-associated severe myocarditis and myositis accompanied by liver and kidney damage in a ureteral urothelial cancer patient, who was firstly treated by cardiologists because of cardiac symptoms. Due to the lack of experience about ICI-associated irAEs, an initial low-dose (0.5 mg/kg/day) and short-term methylprednisolone therapy was used and found to be ineffective and risky to the patient; then, steroid therapy was modulated to a higher dose (1.5 mg/kg/day) with prolonged time course, and improvement of patient symptoms and laboratory markers were observed quickly and persistently. The patient did not show adverse events under this steroid dosage. This case reports a rare tislelizumab-related myocarditis and multiple organ injuries, which provides valuable experience to cardiologists like us. Early recognition of ICI-associated myocarditis and sufficient dosage and time course of glucocorticoid therapy are critical for severe cases. High-quality clinical evidence about the precise diagnosis and therapy in ICI-associated myocarditis and other organ injuries are necessary to guide our clinical works.
Computational Prediction of Biomarkers, Pathways, and New Target Drugs in the Pathogenesis of Immune-Based Diseases Regarding Kidney Transplantation Rejection
Authors: Alfaro Rafael , Martínez-Banaclocha Helios , Llorente Santiago , Jimenez-Coll Victor , Galián José Antonio , Botella Carmen , Moya-Quiles María Rosa , Parrado Antonio , Muro-Perez Manuel , Minguela Alfredo , Legaz Isabel , Muro Manuel
Published: December 2021

Background

The diagnosis of graft rejection in kidney transplantation (KT) patients is made by evaluating the histological characteristics of biopsy samples. The evolution of omics sciences and bioinformatics techniques has contributed to the advancement in searching and predicting biomarkers, pathways, and new target drugs that allow a more precise and less invasive diagnosis. The aim was to search for differentially expressed genes (DEGs) in patients with/without antibody-mediated rejection (AMR) and find essential cells involved in AMR, new target drugs, protein-protein interactions (PPI), and know their functional and biological analysis.

Material and Methods

Four GEO databases of kidney biopsies of kidney transplantation with/without AMR were analyzed. The infiltrating leukocyte populations in the graft, new target drugs, protein-protein interactions (PPI), functional and biological analysis were studied by different bioinformatics tools.

Results

Our results show DEGs and the infiltrating leukocyte populations in the graft. There is an increase in the expression of genes related to different stages of the activation of the immune system, antigenic presentation such as antibody-mediated cytotoxicity, or leukocyte migration during AMR. The importance of the IRF/STAT1 pathways of response to IFN in controlling the expression of genes related to humoral rejection. The genes of this biological pathway were postulated as potential therapeutic targets and biomarkers of AMR. These biological processes correlated showed the infiltration of NK cells and monocytes towards the allograft. Besides the increase in dendritic cell maturation, it plays a central role in mediating the damage suffered by the graft during AMR. Computational approaches to the search for new therapeutic uses of approved target drugs also showed that imatinib might theoretically be helpful in KT for the prevention and/or treatment of AMR.

Conclusion

Our results suggest the importance of the IRF/STAT1 pathways in humoral kidney rejection. NK cells and monocytes in graft damage have an essential role during rejection, and imatinib improves KT outcomes. Our results will have to be validated for the potential use of overexpressed genes as rejection biomarkers that can be used as diagnostic and prognostic markers and as therapeutic targets to avoid graft rejection in patients undergoing kidney transplantation.
Impairment of Intestinal Barrier Function Induced by Early Weaning via Autophagy and Apoptosis Associated With Gut Microbiome and Metabolites
Authors: Tang Wenjie , Liu Jingliang , Ma Yanfei , Wei Yusen , Liu Jianxin , Wang Haifeng
Published: December 2021

Early weaning piglet is frequently accompanied by severe enteric inflammatory responses and microbiota dysbiosis. The links between the gut microbiome and the etiology of gut inflammation are not fully understood. The study is aimed to investigate the potential molecular mechanisms mediating inflammatory reactivity following early weaning, and to find whether these changes are correlated with gut microbiota and metabolite signatures by comparison between suckling piglets (SPs) and weaning piglets (WPs). Histopathology analysis showed a severe inflammatory response and the disruption of epithelial barrier function. Early weaning resulted in reduced autophagy indicated as the suppression of autophagic flux, whereas induced the TLR4/P38MAPK/IL-1β-mediated apoptotic pathway, as well as activation of the IL-1β precursor. The alpha-diversity and microbial composition were changed in WPs, such as the decreased abundances of Bifidobacterium, Bacteroides, Bacillus, Lactobacillus, and Ruminococcus. Microbial co-concurrence analysis revealed that early weaning significantly decreased network complexity, including network size, degree, average clustering coefficient and number of keystone species, as compared with the SP group. Differentially abundant metabolites were mainly associated with amino acid and purine metabolism. Strong correlations were detected between discrepant microbial taxa and multiple inflammatory parameters. In conclusion, we found that dysregulations of autophagy and apoptosis pathway were involved in colon inflammation during weaned period, which may result from gut microbiota dysbiosis. This study may provide possible intervention modalities for preventing or treating post-weaning infections through maintaining gut microbial ecosystem integrity.
Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment
Authors: Hwang Byeong-Oh , Park Se-Young , Cho Eunae Sandra , Zhang Xianglan , Lee Sun Kyoung , Ahn Hyung-Joon , Chun Kyung-Soo , Chung Won-Yoon , Song Na-Young
Published: December 2021

Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis. Notably, cancer patients often show thrombocytosis, a status of an increased platelet number in the bloodstream, as well as the platelet infiltration into the tumor stroma, which contributes to cancer promotion and progression. Thus, platelets function as one of the important stromal components in the TME, emerging as a promising chemotherapeutic target. However, the use of traditional antiplatelet agents, such as aspirin, has limitations mainly due to increased bleeding complications. This requires to implement new strategies to target platelets for anti-cancer effects. In oral squamous cell carcinoma (OSCC) patients, both high platelet counts and low tumor-stromal ratio (high stroma) are strongly correlated with increased metastasis and poor prognosis. OSCC tends to invade adjacent tissues and bones and spread to the lymph nodes for distant metastasis, which is a huge hurdle for OSCC treatment in spite of relatively easy access for visual examination of precancerous lesions in the oral cavity. Therefore, locoregional control of the primary tumor is crucial for OSCC treatment. Similar to thrombocytosis, higher expression of podoplanin (PDPN) has been suggested as a predictive marker for higher frequency of lymph node metastasis of OSCC. Cumulative evidence supports that platelets can directly interact with PDPN-expressing cancer cells via C-type lectin-like receptor 2 (CLEC2), contributing to cancer cell invasion and metastasis. Thus, the platelet CLEC2-PDPN axis could be a pinpoint target to inhibit interaction between platelets and OSCC, avoiding undesirable side effects. Here, we will review the role of platelets in cancer, particularly focusing on CLEC2-PDPN interaction, and will assess their potentials as therapeutic targets for OSCC treatment.
Evidence of Microplastic Size Impact on Mobility and Transport in the Marine Environment: A Review and Synthesis of Recent Research
Authors: Shamskhany Arefeh , Li Zhuoran , Patel Preet , Karimpour Shooka
Published: December 2021

Marine Microplastics (MPs) exhibit a wide range of properties due to their variable origins and the weathering processes to which they are exposed. MP’s versatile properties are connected to their dispersal, accumulation, and deposition in the marine environment. MP transport and dispersion are often explained by analogy with sediments. For natural sediments, one of the key features linked to transport and marine morphology is particle size. There is, however, no size classification defined for MP particles and MPs constitute all plastic particles sized smaller than the threshold of 5 mm. In this study, based on existing knowledge in hydrodynamics and natural sediment transport, the impact of MP size on turbulent entrainment, particle settling, and resuspension is described. Moreover, by analyzing several quantitative studies that have provided size distribution, size-selective accumulation of MPs in various regions of the marine environment is reported on. The preferential presence of MPs based on their size in different marine compartments is discussed based on the governing hydrodynamic parameters. Furthermore, the linkage between polymer properties and MP shape and size is explored. Despite the evident connection between hydrodynamic transport and MP size presented, classification of MP size presents challenges. MP size, shape, and density appear simultaneously in the definition of many hydrodynamic parameters described in this study. Unlike mineral sediments that possess a narrow range of density and shape, plastics are manufactured in a wide variety of densities and marine MPs are versatile in shape. Classification for MP size should incorporate particle variability in terms of polymer density and shape.
Connections to the Deep: Deep Vertical Migrations, an Important Part of the Life Cycle of Apherusa glacialis, an Arctic Ice-Associated Amphipod
Authors: Drivdal Magnus , Kunisch Erin H. , Bluhm Bodil A. , Gradinger Rolf , Falk-Petersen Stig , Berge Jørgen
Published: December 2021

Arctic sea ice contains a substantial amount of living biota of which part is lost through melt and export out of the Arctic Ocean every year. It is unclear how populations can be maintained within the Arctic Ocean. A representative ice inhabitant, the amphipodApherusa glacialiswas previously assumed to spend its entire life in the sea ice habitat, hence being dependent on sea ice to complete its life cycle. However, several recent studies report pelagic occurrences and suggest that seasonal vertical migrations might be an adaptive life history trait enabling a viable population size in the Arctic Ocean. In this study we use a particle-tracking model to investigate to what extent vertical migration might affect the species’ retention in the Arctic Ocean and the sea ice habitat. The modeled trajectories ofA. glacialiswere calculated based on ice drift and ocean currents from a coupled ocean – sea ice model covering the Arctic Ocean. We test two scenarios: (1) trajectories ofA. glacialisthat stay attached to the ice or follow the surface currents if they melt out of the ice and (2) trajectories ofA. glacialisthat undertake a seasonal vertical migration to drift with the currents at depth for parts of the year. In the multi-year model simulations it is assumed that after an initial period of 2 yearsA. glacialisthat are located outside sea-ice cover each spring will perish while those located within the ice-covered region will reproduce. The model results show that a seasonal vertical migration both increases the total number of individuals and leads to a population distribution within the Arctic Ocean more in line with previous findings than the results from the non-migratingA. glacialis. Our results support the hypothesis that a seasonal migration may be an adaptive life history strategy in this species.
A Theoretical Perspective on Strategies for Modeling High Performance Nonlinear Optical Materials
Authors: Bano Rehana , Asghar Maria , Ayub Khurshid , Mahmood Tariq , Iqbal Javed , Tabassum Sobia , Zakaria Rozalina , Gilani Mazhar Amjad
Published: December 2021

Nonlinear optical (NLO) materials have spanned a large area of science and technology owning to their potential applications in optoelectronics. The invention of the first Ruby laser has sparked a fresh interest in the area of nonlinear optics. The computational designing and experimental synthesis of organic and inorganic NLO materials with higher order nonlinearities come into vogue in the field of materials science. To date, several strategies including metal ligand framework, push pull mechanism, diradical character, and so on have been devised to enhance the NLO response of materials. In addition, introduction of diffuse excess electrons is an efficient approach to design noncentrosymmetric materials for nonlinear optics. The current review highlights a systematic array of different computational studies (covering the last decade of intensive research work) for the theoretical designing of NLO materials. In the present review, theoretical designing from the simplest NLO material to the complex alkali, alkaline earth, transition, and superalkali doped nanomaterials is summarized. The emergence of excess electrons strategy has played a pivotal role in enhancing the NLO properties especially hyperpolarizabilities. We expect that this review will provide a better understanding of the NLO responses of nanoclusters, paving the way for the advancement of hi-tech NLO materials to meet the real challenges in optoelectronics.
The Impact of the COVID-19 Pandemic on Avoidance of Health Care, Symptom Severity, and Mental Well-Being in Patients With Coronary Artery Disease
Authors: Maehl Nathalie , Bleckwenn Markus , Riedel-Heller Steffi G. , Mehlhorn Sebastian , Lippmann Stefan , Deutsch Tobias , Schrimpf Anne
Published: December 2021

The COVID-19 pandemic affected regular health care for patients with chronic diseases. However, the impact of the pandemic on primary care for patients with coronary artery disease (CAD) who are enrolled in a structured disease management program (DMP) in Germany is not clear. We investigated whether the pandemic affected primary care and health outcomes of DMP-CAD patients (n = 750) by using a questionnaire assessing patients' utilization of medical care, CAD symptoms, as well as health behavior and mental health since March 2020. We found that out of concern about getting infected with COVID-19, 9.1% of the patients did not consult a medical practitioner despite having CAD symptoms. Perceived own influence on infection risk was lower and anxiety was higher in these patients compared to symptomatic CAD patients who consulted a physician. Among the patients who reported chest pain lasting longer than 30 min, one third did not consult a medical practitioner subsequently. These patients were generally more worried about COVID-19. Patients with at least one worsening CAD symptom (chest pain, dyspnea, perspiration, or nausea without apparent reason) since the pandemic showed more depressive symptoms, higher anxiety scores, and were less likely to consult a doctor despite having CAD symptoms out of fear of infection. Our results provide evidence that the majority of patients received sufficient medical care during the COVID-19 pandemic in Germany. However, one in ten patients could be considered particularly at risk for medical undersupply and adverse health outcomes. The perceived infection risk with COVID-19 might have facilitated the decision not to consult a medical doctor.
Associations Between Physical Activity and Hypertension in Chinese Children: A Cross-Sectional Study From Chongqing
Authors: Wang Qianqian , Qu Ping , Chen Jingyu , Tang Xian , Hao Guang , Liang Xiaohua
Published: December 2021

Background: Childhood blood pressure is a marker for cardiovascular disease risk later in life. Few studies examined the association between physical activity (PA) and hypertension in Chinese children, and this study aimed to explore this relationship.

Methods: A cross-sectional study among pupils was conducted in Chongqing in 2014. In total, 15,203 children aged 6–12 years in Chongqing were included in this study. The duration of self-reported PA on school days and the weekend in pupils were collected with a standardized questionnaire.

Results: The results showed that, on school days, only 22.3% of boys and 17.8% of girls engaged in more than 60 min of PA per day; while on the weekend, only 38.5% of boys and 32.0% of girls engaged in at least 60 min of PA per day. There was no strong evidence for an association between PA and systolic or diastolic hypertension in boys. However, in girls, a weak negative association between PA on weekdays and hypertension was observed, and there was a significant interactive effect of PA and obesity on hypertension risk (Pfor interaction = 0.042). In obese children, PA was positively related to the risk of hypertension.

Conclusion: The overall level of PA among pupils in Chongqing was insufficient, and a weak negative relationship between PA and hypertension was found in girls.
Hypercalciuria in Postmenopausal Women With Reduced Bone Mineral Density Is Associated With Different Mineral Metabolic Profiles: Effects of Treatment With Thiazides and Anti-resorptives
Authors: Nicoli Federico , Dito Giorgia , Guabello Gregorio , Longhi Matteo , Corbetta Sabrina
Published: December 2021

Hypercalciuria may represent a challenge during the workup for osteoporosis management. The present study aimed: (1) to describe the phenotype associated with hypercalciuria in vitamin D-sufficient (serum 25 hydroxyvitamin D (25OHD) > 20 ng/ml) patients with osteopenia/osteoporosis; (2) to analyze the effects of thiazides and anti-resorptive drugs on urine calcium excretion (UCa), mineral metabolic markers, and bone mineral density. Seventy-seven postmenopausal women with hypercalciuria (Uca > 4.0 mg/kg body weight/24 h on two determinations) were retrospectively evaluated in a real-life setting. Median UCa was 5.39 (4.75–6.70) mg/kg/24 h. Kidney stones occurred in 32.9% of patients, who had median UCa similar to that of patients without kidney stones. Clustering analysis considering the three variables, such as serum calcium, phosphate, and parathormone (PTH), identified two main clusters of hypercalciuric patients. Cluster 1 (n = 13) included patients with a primary hyperparathyroidism-like profile, suggesting a certain degree of autonomous PTH secretion from parathyroid glands. Within cluster 2 (n = 61), two subgroups were recognized, cluster 2A (n = 18) that included patients with relatively increased PTH and normophosphatemia, and cluster 2B (n = 43) that included patients with the normal mineral profile. After a follow-up of 33.4 ± 19.6 months, 49 patients treated with thiazidic diuretics (TZD) were reevaluated; 20 patients were treated with hydrochlorothiazide (HCT; 12.5–37.5 mg/day), 29 with indapamide (IND; 1.50–3.75 mg/day). Any significant difference could be detected in all the parameters both basal and treated conditions between patients treated with HCT or IND. TZD induced a mean 39% reduction in UCa and 63.3% of patients obtained Uca < 4.0 mg/kg/24 h, independent of their mineral metabolic profile. Moreover, TZD induced a significant decrease in PTH levels. TZD-treated patients normalizing UCa experienced an increase in bone mineral densities when concomitantly treated with anti-resorptives, while any gain could be observed in TZD-treated patients with persistent hypercalciuria. Finally, multiple regression analysis showed that UCa reduction was at least in part related to denosumab treatment. In conclusion, in postmenopausal osteoporotic women, hypercalciuria is associated with kidney stones in about one-third of patients and with a wide range of impaired PTH secretion, determining a diagnostic challenge. TZD efficiently reduces UCa and normalization contributes to increasing anti-resorptives positive effect on bone mineral density.
Cardiovascular Autonomic Function Changes and Predictors During a 2-Year Physical Activity Program in Rheumatoid Arthritis: A PARA 2010 Substudy
Authors: Hupin David , Sarajlic Philip , Venkateshvaran Ashwin , Fridén Cecilia , Nordgren Birgitta , Opava Christina H. , Lundberg Ingrid E. , Bäck Magnus
Published: December 2021

Background: Chronic inflammation leads to autonomic dysfunction, which may contribute to the increased risk of cardiovascular diseases (CVD) in patients with rheumatoid arthritis (RA). Exercise is known to restore autonomic nervous system (ANS) activity and particularly its parasympathetic component. A practical clinical tool to assess autonomic function, and in particular parasympathetic tone, is heart rate recovery (HRR). The aim of this substudy from the prospective PARA 2010 study was to determine changes in HRR post-maximal exercise electrocardiogram (ECG) after a 2-year physical activity program and to determine the main predictive factors associated with effects on HRR in RA.

Methods: Twenty-five participants performed physiotherapist-guided aerobic and muscle-strengthening exercises for 1 year and were instructed to continue the unsupervised physical activity program autonomously in the next year. All participants were examined at baseline and at years 1 and 2 with a maximal exercise ECG on a cycle ergometer. HRR was measured at 1, 2, 3, 4, and 5 min following peak heart rate during exercise. Machine-learning algorithms with the elastic net linear regression models were performed to predict changes in HRR1 and HRR2 at 1 year and 2 years of the PARA program.

Results: Mean age was 60 years, range of 41–73 years (88% women). Both HRR1 and HRR2 increased significantly from baseline to year 1 with guided physical activity and decreased significantly from year 1 to year 2 with unsupervised physical activity. Blood pressure response to exercise, low BMI, and muscular strength were the best predictors of HRR1/HRR2 increase during the first year and HRR1/HRR2 decrease during the second year of the PARA program.

Conclusion: ANS activity in RA assessed by HRR was improved by guided physical activity, and machine learning allowed to identify predictors of the HRR response at the different time points. HRR could be a relevant marker of the effectiveness of physical activity recommended in patients with RA at high risk of CVD. Very inactive and/or high CVD risk RA patients may get substantial benefits from a physical activity program.
Emerging Fatal Ib/CC12 Hypervirulent Multiresistant Streptococcus agalactiae in Young Infants With Bloodstream Infection in China
Authors: Liu Jingxian , Chen Feng , Guan Hongyan , Yu Jiajia , Yu Jing , Zhao Jing , Liu Ying , Shen Lisong
Published: December 2021

Streptococcus agalactiae [also known as group B Streptococcus (GBS)] is a tremendous threat to young infants. Eighty pediatric GBS infection cases were enrolled from a teaching hospital in Shanghai between 2009 and 2020; among them, 72.5% (58/80) were diagnosed with bloodstream infection (BSI). Sequence types (STs) and serotypes of associated GBS strains were identified, and most of the Ib/clonal complex (CC)12 (86.7%, 13/15) strains caused BSIs, which was significantly higher than that of the genetically related clone Ib/CC10 (20%, 2/10; p < 0.05). Ib/CC12 BSI (30.8%) mortality was significantly higher than that of non-Ib/CC12 BSI (2.2%; p < 0.05). Virulence genes associated with adhesion, invasion, and immune evasion were detected using polymerase chain reaction. The fbsA and gbsPC1 positive rates of Ib/CC12 strains was higher than that of non-Ib/CC12 strains, whereas cpsIaJ, cpsJ, cpsI, and cpsG positive rates were lower than those of non-Ib/CC12 (p < 0.05). In in vitro studies, the Ib/CC12 strains had strong invasiveness in RAW264.7 cells, but less invasiveness in human umbilical vein endothelial cells, human brain microvascular endothelial cells, and human mammary epithelial cells when compared to other two clones. In the in vivo model, the Ib/CC12 GBS invaded the circulation system more rapidly after intraperitoneal injection, was more difficult to eradicate by phagocytes, and caused significantly higher mortality than Ib/CC10 and III/ST17 (p < 0.05). Genome analysis showed that the Ib/CC12 strains had two clustered regularly interspaced short palindromic repeat-Cas systems and carried more antibiotic resistant genes, which conferred resistance to macrolides, clindamycin, aminoglycosides, and tetracycline. The Ib/CC12 strains had 45 unique annotated genes compared to that of Ib/CC10, including the pathogen-related toxin/antitoxin system, PezA/T. In conclusion, Ib/CC12 is an emerging hypervirulent multiresistant GBS clone that causes invasive and fatal infections in pediatric patients. The prevention and control of Ib/CC12 GBS infection should be emphasized.