bluuebunny/crossref_metadata_2025 huggingface dataset:
Energy and Dynamics of Caveolae Trafficking
Authors: Matthaeus Claudia , Taraska Justin W.
Published: January 2021

Caveolae are 70–100 nm diameter plasma membrane invaginations found in abundance in adipocytes, endothelial cells, myocytes, and fibroblasts. Their bulb-shaped membrane domain is characterized and formed by specific lipid binding proteins including Caveolins, Cavins, Pacsin2, and EHD2. Likewise, an enrichment of cholesterol and other lipids makes caveolae a distinct membrane environment that supports proteins involved in cell-type specific signaling pathways. Their ability to detach from the plasma membrane and move through the cytosol has been shown to be important for lipid trafficking and metabolism. Here, we review recent concepts in caveolae trafficking and dynamics. Second, we discuss how ATP and GTP-regulated proteins including dynamin and EHD2 control caveolae behavior. Throughout, we summarize the potential physiological and cell biological roles of caveolae internalization and trafficking and highlight open questions in the field and future directions for study.
Secretory Vesicles Targeted to Plasma Membrane During Pollen Germination and Tube Growth
Authors: Ruan Huaqiang , Li Jiang , Wang Ting , Ren Haiyun
Published: January 2021

Pollen germination and pollen tube growth are important biological events in the sexual reproduction of higher plants, during which a large number of vesicle trafficking and membrane fusion events occur. When secretory vesicles are transported via the F-actin network in proximity to the apex of the pollen tube, the secretory vesicles are tethered and fused to the plasma membrane by tethering factors and SNARE proteins, respectively. The coupling and uncoupling between the vesicle membrane and plasma membrane are also regulated by dynamic cytoskeleton, proteins, and signaling molecules, including small G proteins, calcium, and PIP2. In this review, we focus on the current knowledge regarding secretory vesicle delivery, tethering, and fusion during pollen germination and tube growth and summarize the progress in research on how regulators and signaling molecules participate in the above processes.
Regulatory Role of the RNA N6-Methyladenosine Modification in Immunoregulatory Cells and Immune-Related Bone Homeostasis Associated With Rheumatoid Arthritis
Authors: Fan Danping , Xia Ya , Lu Cheng , Ye Qinbin , Xi Xiaoyu , Wang Qiong , Wang Zheng , Wang Chengyuan , Xiao Cheng
Published: January 2021

Rheumatoid arthritis (RA) is a systemic autoimmune disease for which the etiology has not been fully elucidated. Previous studies have shown that the development of RA has genetic and epigenetic components. As one of the most highly abundant RNA modifications, the N6-methyladenosine (m6A) modification is necessary for the biogenesis and functioning of RNA, and modification aberrancies are associated with various diseases. However, the specific functions of m6A in the cellular processes of RA remain unclear. Recent studies have revealed the relationship between m6A modification and immune cells associated with RA. Therefore, in this review, we focused on discussing the functions of m6A modification in the regulation of immune cells and immune-related bone homeostasis associated with RA. In addition, to gain a better understanding of the progress in this field of study and provide the proper direction and suggestions for further study, clinical application studies of m6A modification were also summarized.
Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease
Authors: Kuil Laura E. , Chauhan Rajendra K. , Cheng William W. , Hofstra Robert M. W. , Alves Maria M.
Published: January 2021

The Enteric Nervous System (ENS) is a large network of enteric neurons and glia that regulates various processes in the gastrointestinal tract including motility, local blood flow, mucosal transport and secretion. The ENS is derived from stem cells coming from the neural crest that migrate into and along the primitive gut. Defects in ENS establishment cause enteric neuropathies, including Hirschsprung disease (HSCR), which is characterized by an absence of enteric neural crest cells in the distal part of the colon. In this review, we discuss the use of zebrafish as a model organism to study the development of the ENS. The accessibility of the rapidly developing gut in zebrafish embryos and larvae, enablesin vivovisualization of ENS development, peristalsis and gut transit. These properties make the zebrafish a highly suitable model to bring new insights into ENS development, as well as in HSCR pathogenesis. Zebrafish have already proven fruitful in studying ENS functionality and in the validation of novel HSCR risk genes. With the rapid advancements in gene editing techniques and their unique properties, research using zebrafish as a disease model, will further increase our understanding on the genetics underlying HSCR, as well as possible treatment options for this disease.
RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation
Authors: Gao Qing-Yuan , Zhang Hai-Feng , Tao Jun , Chen Zhi-Teng , Liu Chi-Yu , Liu Wen-Hao , Wu Mao-Xiong , Yin Wen-Yao , Gao Guang-Hao , Xie Yong , Yang Ying , Liu Pin-Ming , Wang Jing-Feng , Chen Yang-Xin
Published: January 2021

Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related proteins were assessed in transforming growth factor beta 1 (TGF-β1)-activated CF, whereas the role of mitochondrial fission during this process was also elucidated, as were the underlying mechanisms. The interaction between mitochondrial fission and mitophagy, the main defense mechanism against mitochondrial impairment, was also explored. The results showed that the mitochondria in TGF-β1-treated CF were noticeably more fragmented than those of controls. The expression of several mitochondrial fission-related proteins was markedly upregulated, and the levels of fusion-related proteins were also altered, but to a lesser extent. Inhibiting mitochondrial fission resulted in a marked attenuation of TGF-β1-induced CF activation. The TGF-β1-induced increase in glycolysis was greatly suppressed in the presence of a mitochondrial inhibitor, whereas a glycolysis-specific antagonist exerted little additional antifibrotic effects. TGF-β1 treatment increased cellular levels of reactive oxygen species (ROS) and triggered mitophagy, but this effect was reversed following the application of ROS scavengers. For the signals mediating mitophagy, the expression of Pink1, but not Bnip3l/Nix or Fundc1, exhibited the most significant changes, which could be counteracted by treatment with a mitochondrial fission inhibitor. Pink1 knockdown suppressed CF activation and mitochondrial fission, which was accompanied by increased CF apoptosis. In conclusion, mitochondrial fission resulted in increased glycolysis and played a crucial role in CF activation. Moreover, mitochondrial fission promoted reactive oxygen species (ROS) production, leading to mitophagy and the consequent degradation of the impaired mitochondria, thus promoting CF survival and maintaining their activation.
Cullin3-TNFAIP1 E3 Ligase Controls Inflammatory Response in Hepatocellular Carcinoma Cells via Ubiquitination of RhoB
Authors: Liu Yue , Zhang Wenjuan , Wang Shiwen , Cai Lili , Jiang Yanyu , Pan Yongfu , Liang Yupei , Xian Jingrong , Jia Lijun , Li Lihui , Zhao Hu , Zhang Yanmei
Published: January 2021

Rho family GTPase RhoB is the critical signaling component controlling the inflammatory response elicited by pro-inflammatory cytokines. However, the underlying mechanisms of RhoB degradation in inflammatory response remain unclear. In this study, for the first time, we identified that TNFAIP1, an adaptor protein of Cullin3 E3 ubiquitin ligases, coordinated with Cullin3 to mediate RhoB degradation through ubiquitin proteasome system. In addition, we demonstrated that downregulation of TNFAIP1 induced the expression of pro-inflammatory cytokines IL-6 and IL-8 in TNFα-stimulated hepatocellular carcinoma cells through the activation of p38/JNK MAPK pathway via blocking RhoB degradation. Our findings revealed a novel mechanism of RhoB degradation and provided a potential strategy for anti-inflammatory intervention of tumors by targeting TNFAIP1-RhoB axis.
Telomere Dysfunction in Oocytes and Embryos From Obese Mice
Authors: Ge Juan , Li Congyang , Sun Hongzheng , Xin Yongan , Zhu Shuai , Liu Yuan , Tang Shoubin , Han Longsen , Huang Zhenyue , Wang Qiang
Published: January 2021

Maternal obesity impairs oocyte quality and embryo development. However, the potential molecular pathways remain to be explored. In the present study, we examined the effects of obesity on telomere status in oocytes and embryos obtained from mice fed with high-fat diet (HFD). Of note, telomere shortening was observed in both oocytes and early embryos from obese mice, as evidenced by the reduced expression of telomerase reverse transcriptase and activity of telomerase. Moreover, quantitative analysis of telomere dysfunction-induced foci (TIFs) revealed that maternal obesity induces the defective telomeres in oocytes and embryos. Meanwhile, the high frequency of aneuploidy was detected in HFD oocytes and embryos as compared to controls, accompanying with the increased incidence of apoptotic blastocysts. In conclusion, these results indicate that telomere dysfunction might be a molecular pathway mediating the effects of maternal obesity on oocyte quality and embryo development.
Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer
Authors: Sumei Sha , Xiangyun Kong , Fenrong Chen , Xueguang Sun , Sijun Hu , Bin Bai , Xiaolei Shi , Yongjiu Tu , Kaichun Wu , Qingchuan Zhao , Yongzhan Nie , Bin Xu
Published: January 2021

Background/Aims

The role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.

Materials

Bisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.

Results

The DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.

Conclusion

DHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.
Integrated Bioinformatical Analysis Identifies GIMAP4 as an Immune-Related Prognostic Biomarker Associated With Remodeling in Cervical Cancer Tumor Microenvironment
Authors: Xu Fangfang , Shen Jiacheng , Xu Shaohua
Published: January 2021

Tumor microenvironment (TME) is emerging as an essential part of cervical cancer (CC) tumorigenesis and development, becoming a hotspot of research these years. However, comprehending the specific composition of TME is still facing enormous challenges, especially the immune and stromal components. In this study, we downloaded the RNA-seq profiles and somatic mutation data of 309 CC cases from The Cancer Genome Atlas (TCGA) database, which were analyzed by integrative bioinformatical methods. Initially, ESTIMATE computational method was employed to calculate the amount of immune and stromal components. Then, based on the high- and low-immunity cohorts, we recognized the differentially expressed genes (DEGs) as well as the differentially mutated genes (DMGs). Additionally, we conducted an intersection analysis of DEGs and DMGs, ultimately determining an immune-related prognostic signature, GTPase, IMAP Family Member 4 (GIMAP4). Moreover, sequential analyses demonstrated that GIMAP4 was a protective factor in CC, positively correlated with the overall survival (OS) and negatively with distant metastasis. Besides, we utilized the Gene Set Enrichment Analysis (GSEA) to explore the enrichment-pathways in high and low-expression cohorts of GIMAP4. The results indicated that the genes of the high-expression cohort had a high enrichment in immune-related biological processes and metabolic activities in the low one. Furthermore, CIBERSORT analysis was applied to evaluate the proportion of tumor-infiltrating immune cells (TICs), illustrating that several activated TICs were strongly associated with GIMAP4 expression, which suggested that GIMAP4 had the potential to be an indicator for the immune state in TME of CC. Hence, GIMAP4 contributed to predicting the CC patients’ clinical outcomes, such as survival rate, distant metastasis and immunotherapy response. Moreover, GIMAP4 could serve as a promising biomarker for TME remodeling, suggesting the possible underlying mechanisms of tumorigenesis and CC progression, which may provide different therapeutic perceptions of CC, and therefore improve treatment.
Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells
Authors: Sun Runzi , Wu Yixian , Zhou Huijun , Wu Yanshi , Yang Zhongzhou , Gu Yanzheng , Jiang Jingting , Lu Binfeng , Zhu Yibei
Published: January 2021

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.
Enhanced Plasmonic Resonance Characteristics of AgNRs–Gold Film Hybrid System
Authors: Yin Yanping , Zhu Jin , Wang Zaoji , Ma Guojun , Yuan Huining , Li Xiaolong
Published: January 2021

In recent years, the plasma gap resonance maintained by metal-film-coupled nanostructures has attracted extensive attention. This mainly originates from its flexible control of the spectral response and significantly enhanced field strength at the nanoparticle–film junction. In the present study, the tunability of local surface plasmon resonances (LSPRs) of nanorods coupled to a gold film is studied theoretically. To this end, the plasmonic resonances in the nanostructure of individual silver nanorod–gold film (AgNR-film) with different parameters are investigated. Obtained results show that the refractive index sensitivity (S) of nanostructures to the environment increases as the aspect ratio (Ar) of nanostructures increase. It is found that when the aspect ratio (Ar) is set to 3.5, the figure of merit (FOM) is the highest. Moreover, the variation in the gap distances of the nanorod monomer–gold film, electric field distribution of nanorods dimer, and the corresponding impact on the gold film are studied. It is concluded that the gap size of nanostructures has an exponential correlation with the resonance wavelength. Considering the remarkable influence of the gap size and the surrounding medium environment on the spectral shift of AgNR-film nanostructures, potential applications of the structure as a refractive index sensor and biomolecule measurement are proposed.
Computational Characterizations of the Interactions Between the Pontacyl Violet 6R and Exoribonuclease as a Potential Drug Target Against SARS-CoV-2
Authors: Munaweera Rangika , Hu Ying S.
Published: January 2021

We report a molecular-docking and virtual-screening-based identification and characterization of interactions of lead molecules with exoribonuclease (ExoN) enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From previously identified DEDDh/DEEDh subfamily nuclease inhibitors, our results revealed strong binding of pontacyl violet 6R (PV6R) at the catalytic active site of ExoN. The binding was found to be stabilized via two hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations further confirmed the stability of PV6R at the active site showing a shift in ligand to reach a more stabilized binding. Using PV6R as the lead molecule, we employed virtual screening to identify potential molecular candidates that form strong interactions at the ExoN active site. Our study paves ways for evaluating the ExoN as a novel drug target for antiviral treatment against SARS-CoV-2.
The Role of Intestinal Bacteria and Gut–Brain Axis in Hepatic Encephalopathy
Authors: Chen Zefeng , Ruan Jingsheng , Li Dinghua , Wang Min , Han Zhiwei , Qiu Wenxia , Wu Guobin
Published: January 2021

Hepatic encephalopathy (HE) is a neurological disorder that occurs in patients with liver insufficiency. However, its pathogenesis has not been fully elucidated. Pharmacotherapy is the main therapeutic option for HE. It targets the pathogenesis of HE by reducing ammonia levels, improving neurotransmitter signal transduction, and modulating intestinal microbiota. Compared to healthy individuals, the intestinal microbiota of patients with liver disease is significantly different and is associated with the occurrence of HE. Moreover, intestinal microbiota is closely associated with multiple links in the pathogenesis of HE, including the theory of ammonia intoxication, bile acid circulation, GABA-ergic tone hypothesis, and neuroinflammation, which contribute to cognitive and motor disorders in patients. Restoring the homeostasis of intestinal bacteria or providing specific probiotics has significant effects on neurological disorders in HE. Therefore, this review aims at elucidating the potential microbial mechanisms and metabolic effects in the progression of HE through the gut–brain axis and its potential role as a therapeutic target in HE.
Iron-Deficiency Anemia Results in Transcriptional and Metabolic Remodeling in the Heart Toward a Glycolytic Phenotype
Authors: Chung Yu Jin , Swietach Pawel , Curtis M. Kate , Ball Vicky , Robbins Peter A. , Lakhal-Littleton Samira
Published: January 2021

Iron deficiency is the most prevalent micronutrient disorder globally. When severe, iron deficiency leads to anemia, which can be deleterious to cardiac function. Given the central role of iron and oxygen in cardiac biology, multiple pathways are expected to be altered in iron-deficiency anemia, and identifying these requires an unbiased approach. To investigate these changes, gene expression and metabolism were studied in mice weaned onto an iron-deficient diet for 6 weeks. Whole-exome transcriptomics (RNAseq) identified over 1,500 differentially expressed genes (DEGs), of which 22% were upregulated and 78% were downregulated in the iron-deficient group, relative to control animals on an iron-adjusted diet. The major biological pathways affected were oxidative phosphorylation and pyruvate metabolism, as well as cardiac contraction and responses related to environmental stress. Cardiac metabolism was studied functionally using in vitro and in vivo methodologies. Spectrometric measurement of the activity of the four electron transport chain complexes in total cardiac lysates showed that the activities of Complexes I and IV were reduced in the hearts of iron-deficient animals. Pyruvate metabolism was assessed in vivo using hyperpolarized 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate. Hearts from iron-deficient and anemic animals showed significantly decreased flux through pyruvate dehydrogenase and increased lactic acid production, consistent with tissue hypoxia and induction of genes coding for glycolytic enzymes and H+-monocarboxylate transport-4. Our results show that iron-deficiency anemia results in a metabolic remodeling toward a glycolytic, lactic acid-producing phenotype, a hallmark of hypoxia.
Carbon Dioxide and Methane Flux Response and Recovery From Drought in a Hemiboreal Ombrotrophic Fen
Authors: Keane J. B , Toet S. , Ineson P. , Weslien P. , Stockdale J. E. , Klemedtsson L.
Published: January 2021

Globally peatlands store 500 Gt carbon (C), with northern blanket bogs accumulating 23 g C m−2 y−1 due to cool wet conditions. As a sink of carbon dioxide (CO2) peat bogs slow anthropogenic climate change, but warming climate increases the likelihood of drought which may reduce net ecosystem exchange (NEE) and increase soil respiration, tipping C sinks to sources. High water tables make bogs a globally important source of methane (CH4), another greenhouse gas (GHG) with a global warming potential (GWP) 34 times that of CO2. Warming may increase CH4 emissions, but drying may cause a reduction. Predicted species composition changes may also influence GHG balance, due to different traits such as erenchyma, e.g., Eriophorum vaginatum (eriophorum) and non-aerenchymatous species, e.g., Calluna vulgaris (heather). To understand how these ecosystems will respond to climate change, it is vital to measure GHG responses to drought at the species level. An automated chamber system, SkyLine2D, measured NEE and CH4 fluxes near-continuously from an ombrotrophic fen from August 2017 to September 2019. Four ecotypes were identified: sphagnum (Sphagnum spp), eriophorum, heather and water, hypothesizing that fluxes would significantly differ between ecotypes. The 2018 drought allowed comparison of fluxes between drought and non-drought years (May to September), and their recovery the following year. Methane emissions differed between ecotypes (p < 0.02), ordered high to low: eriophorum > sphagnum > water > heather, ranging from 23 to 8 mg CH4-C m−2 d−1. Daily NEE was similar between ecotypes (p > 0.7), but under 2018 drought conditions all ecotypes were greater sources of CO2 compared to 2019, losing 1.14 g and 0.24 g CO2-C m−2 d−1 respectively (p < 0.001). CH4 emissions were ca. 40% higher during 2018 than 2019, 17 mg compared to 12 mg CH4-C m−2 d−1 (p < 0.0001), and fluxes exhibited hysteresis with water table depth. A lag of 84–88 days was observed between rising water table and increased CH4 emissions. A significant interaction between ecotype and year showed fluxes from open water did not return to pre-drought levels. Our findings suggest that short-term drought may lead to a net increase in C emissions from northern wetlands.
Time-Scales of Inter-Eruptive Volcano Uplift Signals: Three Sisters Volcanic Center, Oregon (United States)
Authors: Rodríguez-Molina Sara , González Pablo J. , Charco María , Negredo Ana M. , Schmidt David A.
Published: January 2021

A classical inflation-eruption-deflation cycle of a volcano is useful to conceptualize the time-evolving deformation of volcanic systems. Such a model predicts accelerated uplift during pre-eruptive periods, followed by subsidence during the co-eruptive stage. Some volcanoes show puzzling persistent uplift signals with minor or no other geophysical or geochemical variations, which are difficult to interpret. Such temporal behaviors are usually observed in large calderas (e.g., Yellowstone, Long Valley, Campi Flegrei, Rabaul), but less commonly for stratovolcanoes. Volcano deformation needs to be better understood during inter-eruptive stages, to assess its value as a tool for forecasting eruptions and to understand the processes governing the unrest behavior. Here, we analyze inter-eruptive uplift signals at Three Sisters, a complex stratovolcano in Oregon (United States), which in recent decades shows persistent inter-eruptive uplift signals without associated eruptive activity. Using a Bayesian inversion method, we re-assessed the source characteristics (magmatic system geometry and location) and its uncertainties. Furthermore, we evaluate the most recent evolution of the surface deformation signals combining both GPS and InSAR data through a new non-subjective linear regularization inversion procedure to estimate the 26 years-long time-series. Our results constrain the onset of the Three Sisters volcano inflation to be between October 1998 and August 1999. In the absence of new magmatic inputs, we estimate a continuous uplift signal, at diminishing but detectable rates, to last for few decades. The observed uplift decay observed at Three Sisters is consistent with a viscoelastic response of the crust, with viscosity of ∼1018 Pa s around a magmatic source with a pressure change which increases in finite time to a constant value. Finally, we compare Three Sisters volcano time series with historical uplift at different volcanic systems. Proper modeling of scaled inflation time series indicates a unique and well-defined exponential decay in temporal behavior. Such evidence supports that this common temporal evolution of uplift rates could be a potential indicator of a rather reduced set of physical processes behind inter-eruptive uplift signals.
Debris Flow Modelling Using RAMMS Model in the Alpine Environment With Focus on the Model Parameters and Main Characteristics
Authors: Mikoš Matjaž , Bezak Nejc
Published: January 2021

Debris flows are among the natural hazards that can occur in mountainous areas and endanger people’s lives and cause large economic damage. Debris flow modelling is needed in multiple applications such as design of protection measures or preparation of debris flow risk maps. Many models are available that can be used for debris flow modelling. The Rapid Mass Movement Simulation (RAMMS) model with its debris flow module, (i.e. RAMMS-DF) is one of the most commonly used ones. This review provides a comprehensive overview of past debris flow modelling applications in an alpine environment with their main characteristics, including study location, debris flow magnitude, simulation resolution, and Voellmy-fluid friction model parameter ranges, (i.e. μ and ξ). A short overview of each study is provided. Based on the review conducted, it is clear that RAMMS parameter ranges are relatively wide. Furthermore, model calibration using debris-flow post-event survey field data is the essential step that should be done before applying the model. However, an overview of the parameters can help to limit the parameter ranges. Particularly when considering the similarity between relevant case studies conducted in similar environments. This is especially relevant should the model be applied for estimating debris-flow hazard for potential future events. This model has been used mostly in Europe, (i.e. Alpine region) for modelling small and extremely large debris flows.
Advances on circRNAs Contribute to Carcinogenesis and Progression in Papillary Thyroid Carcinoma
Authors: Xu Xiaoqin , Jing Jiexian
Published: January 2021

In view of the highly increased prevalence of papillary thyroid carcinoma (PTC) year by year, it is of great importance to explore new molecular targets for anticancer strategies. Emerging evidence indicates that circular RNAs (circRNAs), characterized by a closed-loop structure and high stability, play important roles in tumorigenesis and development of human cancer by regulating multiple complex biological processes, such as cellular proliferation, metastasis, and metabolism. A comprehensive understanding of the roles of circRNAs will facilitate the development of promising future therapeutic strategies for treating cancers, including PTC. In this paper, we review the profile of circRNA in PTC, its regulatory roles, and the pathological mechanism as well as their related clinical significance. In addition, challenges of this specific field are discussed.
Decreased Trabecular Bone Score in Patients With Active Endogenous Cushing’s Syndrome
Authors: Stachowska Barbara , Halupczok-Żyła Jowita , Kuliczkowska-Płaksej Justyna , Syrycka Joanna , Bolanowski Marek
Published: January 2021

Introduction

The impairment in bone microarchitecture and reduced bone quality are relevant mechanisms underlying the increased fracture risk in Cushing’s syndrome (CS). The trabecular bone score (TBS) is a relatively novel textural index of bone microarchitecture.

Purpose

The objective of the study was to compare TBS, bone mineral density (BMD), and fracture risk in patients with endogenous CS to controls. We have investigated the association of TBS with anthropometric parameters and 25(OH) vitamin D concentrations.

Materials and Methods

The study group comprised 19 consecutive patients with CS (14 women and 5 men; mean age 45.84 ± 13.15 years) and sex-, age-matched 36 controls (25 women and men; mean age 52.47 ± 8.98 years). Anthropometric parameters, biochemical and hormonal data were compared between groups. Lumbar spine (L1–L4) and femoral neck BMD (LS BMD, FN BMD) measurements were performed. TBS values were obtained from lumbar spine DXA images.

Results

TBS was significantly lower in patients with CS compared to controls (p = 0.0002). The 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture were significantly higher in the CS group than in controls (p = 0.03, p < 0.0001, respectively). All subjects from the CS group with fractures had low TBS value (degraded microarchitecture). TBS correlated negatively with the duration of disease in patients with CS (r = -0.590 p = 0.008).

Conclusions

The patients with active CS have altered bone microstructure as indicated by the decreased TBS and are at higher risk of hip and a major osteoporotic fractures. TBS seems to be a very important analytical tool facilitating fracture risk assessment in endogenous hypercortisolism.
The Skin Epilipidome in Stress, Aging, and Inflammation
Authors: Gruber Florian , Marchetti-Deschmann Martina , Kremslehner Christopher , Schosserer Markus
Published: January 2021

Lipids are highly diverse biomolecules crucial for the formation and function of cellular membranes, for metabolism, and for cellular signaling. In the mammalian skin, lipids additionally serve for the formation of the epidermal barrier and as surface lipids, together regulating permeability, physical properties, acidification and the antimicrobial defense. Recent advances in accuracy and specificity of mass spectrometry have allowed studying enzymatic and non-enzymatic modifications of lipids—the epilipidome—multiplying the known diversity of molecules in this class. As the skin is an organ that is frequently exposed to oxidative-, chemical- and thermal stress, and to injury and inflammation, it is an ideal organ to study epilipidome dynamics, their causes, and their biological consequences. Recent studies uncover loss or gain in biological function resulting from either specific modifications or the sum of the modifications of lipids. These studies suggest an important role for the epilipidome in stress responses and immune regulation in the skin. In this minireview we provide a short survey of the recent developments on causes and consequences of epilipidomic changes in the skin or in cell types that reside in the skin.
Threespine Stickleback in Lake Constance: The Ecology and Genomic Substrate of a Recent Invasion
Authors: Hudson Cameron M. , Lucek Kay , Marques David A. , Alexander Timothy J. , Moosmann Marvin , Spaak Piet , Seehausen Ole , Matthews Blake
Published: January 2021

Invasive species can be powerful models for studying contemporary evolution in natural environments. As invading organisms often encounter new habitats during colonization, they will experience novel selection pressures. Threespine stickleback (Gasterosteus aculeatuscomplex) have recently colonized large parts of Switzerland and are invasive in Lake Constance. Introduced to several watersheds roughly 150 years ago, they spread across the Swiss Plateau (400–800 m a.s.l.), bringing three divergent hitherto allopatric lineages into secondary contact. As stickleback have colonized a variety of different habitat types during this recent range expansion, the Swiss system is a useful model for studying contemporary evolution with and without secondary contact. For example, in the Lake Constance region there has been rapid phenotypic and genetic divergence between a lake population and some stream populations. There is considerable phenotypic variation within the lake population, with individuals foraging in and occupying littoral, offshore pelagic, and profundal waters, the latter of which is a very unusual habitat for stickleback. Furthermore, adults from the lake population can reach up to three times the size of adults from the surrounding stream populations, and are large by comparison to populations globally. Here, we review the historical origins of the threespine stickleback in Switzerland, and the ecomorphological variation and genomic basis of its invasion in Lake Constance. We also outline the potential ecological impacts of this invasion, and highlight the interest for contemporary evolution studies.
Genome Editing and Protoplast Regeneration to Study Plant–Pathogen Interactions in the Model Plant Nicotiana benthamiana
Authors: Hsu Chen-Tran , Lee Wen-Chi , Cheng Yu-Jung , Yuan Yu-Hsuan , Wu Fu-Hui , Lin Choun-Sea
Published: January 2021

Biotic diseases cause substantial agricultural losses annually, spurring research into plant pathogens and strategies to mitigate them. Nicotiana benthamiana is a commonly used model plant for studying plant–pathogen interactions because it is host to numerous plant pathogens and because many research tools are available for this species. The clustered regularly interspaced short palindromic repeats (CRISPR) system is one of several powerful tools available for targeted gene editing, a crucial strategy for analyzing gene function. Here, we demonstrate the use of various CRISPR-associated (Cas) proteins for gene editing of N. benthamiana protoplasts, including Staphylococcus aureus Cas9 (SaCas9), Streptococcus pyogenes Cas9 (SpCas9), Francisella novicida Cas12a (FnCas12a), and nCas9-activation-induced cytidine deaminase (nCas9-Target-AID). We successfully mutated Phytoene Desaturase (PDS) and Ethylene Receptor 1 (ETR1) and the disease-associated genes RNA-Dependent RNA Polymerase 6 (RDR6), and Suppressor of Gene Silencing 3 (SGS3), and confirmed that the mutated alleles were transmitted to progeny. sgs3 mutants showed the expected phenotype, including absence of trans-acting siRNA3 (TAS3) siRNA and abundant expression of the GFP reporter. Progeny of both sgs3 and rdr6 null mutants were sterile. Our analysis of the phenotypes of the regenerated progeny indicated that except for the predicted phenotypes, they grew normally, with no unexpected traits. These results confirmed the utility of gene editing followed by protoplast regeneration in N. benthamiana. We also developed a method for in vitro flowering and seed production in N. benthamiana, allowing the regenerants to produce progeny in vitro without environmental constraints.
Construction and Analysis of a ceRNA Network in Cardiac Fibroblast During Fibrosis Based on in vivo and in vitro Data
Authors: Gao Qing-Yuan , Zhang Hai-Feng , Chen Zhi-Teng , Li Yue-Wei , Wang Shao-Hua , Wen Zhu-Zhi , Xie Yong , Mai Jing-Ting , Wang Jing-Feng , Chen Yang-Xin
Published: January 2021

Aims

Activation of cardiac fibroblasts (CF) is crucial to cardiac fibrosis. We constructed a cardiac fibroblast-related competing endogenous RNA (ceRNA) network. Potential functions related to fibrosis of “hub genes” in this ceRNA network were explored.

Materials and Methods

The Gene Expression Omnibus database was searched for eligible datasets. Differentially expressed messenger (m)RNA (DE-mRNA) and long non-coding (lnc)RNA (DE-lncRNA) were identified. microRNA was predicted and validated. A predicted ceRNA network was constructed and visualized by Cytoscape, and ceRNA crosstalk was validated. A Single Gene Set Enrichment Analysis (SGSEA) was done, and the Comparative Toxicogenomics Database (CTD) was employed to analyze the most closely associated pathways and diseases of DE-mRNA in the ceRNA network. The functions of DE-mRNA and DE-lncRNA in the ceRNA network were validated by small interfering (si)RNA depletion.

Results

The GSE97358 and GSE116250 datasets (which described differentially expressed genes in human cardiac fibroblasts and failing ventricles, respectively) were used for analyses. Four-hundred-and-twenty DE-mRNA and 39 DE-lncRNA, and 369 DE-mRNA and 93 DE-lncRNA were identified, respectively, in the GSE97358 and GSE116250 datasets. Most of the genes were related to signal transduction, cytokine activity, and cell proliferation. Thirteen DE-mRNA with the same expression tendency were overlapped in the two datasets. Twenty-three candidate microRNAs were predicted and the expression of 11 were different. Only two DE-lncRNA were paired to any one of 11 microRNA. Finally, two mRNA [ADAM metallopeptidase domain 19, (ADAM19) and transforming growth factor beta induced, (TGFBI)], three microRNA (miR-9-5p, miR-124-3p, and miR-153-3p) and two lncRNA (LINC00511 and SNHG15) constituted our ceRNA network. siRNA against LINC00511 increased miR-124-3p and miR-9-5p expression, and decreased ADAM19 and TGFBI expression, whereas siRNA against SNHG15 increased miR-153-3p and decreased ADAM19 expression. ADAM19 and TGFBI were closely related to the TGF-β1 pathway and cardiac fibrosis, as shown by SGSEA and CTD, respectively. Depletion of two mRNA or two lncRNA could alleviate CF activation.

Conclusions

The CF-specific ceRNA network, including two lncRNA, three miRNA, and two mRNA, played a crucial role during cardiac fibrosis, which provided potential target genes in this field.
Gene Expression Changes and Associated Pathways Involved in the Progression of Prostate Cancer Advanced Stages
Authors: Pudova Elena A. , Krasnov George S. , Kobelyatskaya Anastasiya A. , Savvateeva Maria V. , Fedorova Maria S. , Pavlov Vladislav S. , Nyushko Kirill M. , Kaprin Andrey D. , Alekseev Boris Y. , Trofimov Dmitry Y. , Sukhikh Gennady T. , Snezhkina Anastasiya V. , Kudryavtseva Anna V.
Published: January 2021

Prostate cancer (PC) is one of the most common cancers among men worldwide, and advanced PCs, such as locally advanced PC (LAPC) and castration-resistant PC (CRPC), present the greatest challenges in clinical management. Current indicators have limited capacity to predict the disease course; therefore, better prognostic markers are greatly needed. In this study, we performed a bioinformatic analysis of The Cancer Genome Atlas (TCGA) datasets, including RNA-Seq data from the prostate adenocarcinoma (PRAD; n = 55) and West Coast Dream Team – metastatic CRPC (WCDT-MCRPC; n = 84) projects, to evaluate the transcriptome changes associated with progression-free survival (PFS) for LAPC and CRPC, respectively. We identified the genes whose expression was positively/negatively correlated with PFS. In LAPC, the genes with the most significant negative correlations were ZC2HC1A, SQLE, and KIF11, and the genes with the most significant positive correlations were SOD3, LRRC26, MIR22HG, MEG3, and MIR29B2CHG. In CRPC, the most significant positive correlations were found for BET1, CTAGE5, IFNGR1, and GIMAP6, and the most significant negative correlations were found for CLPB, PRPF19, ZNF610, MPST, and LINC02001. In addition, we performed a gene network interaction analysis using STRINGdb, which revealed a significant relationship between genes predominantly involved in the cell cycle and characterized by upregulated expression in early recurrence. Based on the results, we propose several genes that can be used as potential prognostic markers.
A Novel Prognostic Model of Early-Stage Lung Adenocarcinoma Integrating Methylation and Immune Biomarkers
Authors: Ren Jin , Yang Yun , Li Chuanyin , Xie Lu , Hu Ronggui , Qin Xiong , Zhang Menghuan
Published: January 2021

Lung adenocarcinoma (LUAD) is caused by multiple biological factors. Therefore, it will be more meaningful to study the prognosis from the perspective of omics integration. Given the significance of epigenetic modification and immunity in tumorigenesis and development, we tried to combine aberrant methylation and tumor infiltration CD8 T cell-related genes to build a prognostic model, to explore the key biomarkers of early-stage LUAD. On the basis of RNA-seq and methylation microarray data downloaded from The Cancer Genome Atlas (TCGA), differentially expressed genes and aberrant methylated genes were calculated with “DEseq2” and “ChAMP” packages, respectively. A Chi-square test was performed to obtain methylation driver genes. Weighted correlation network analysis (WGCNA) was utilized to mine cancer biomarkers related to CD8 T cells. With the consequences of univariate Cox proportional hazards analysis and least absolute shrinkage and selection operator (LASSO) COX regression analysis, the prognostic index based on 17 methylation driver genes (ZNF677, FAM83A, TRIM58, CLDN6, NKD1, NFE2L3, FKBP5, ITGA5, ASCL2, SLC24A4, WNT3A, TMEM171, PTPRH, ITPKB, ITGA2, SLC6A17, and CCDC81) and four CD8 T cell-related genes (SPDL1, E2F7, TK1, and TYMS) was successfully established, which could make valuable predictions for the survival risk of patients with early-stage LUAD.
Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia
Authors: Bhattacharya Soumyaroop , Mereness Jared A. , Baran Andrea M. , Misra Ravi S. , Peterson Derick R. , Ryan Rita M. , Reynolds Anne Marie , Pryhuber Gloria S. , Mariani Thomas J.
Published: January 2021

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation ofTGFB, NRF2, HIPPO, andCD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved inTGFBsignaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.
Initiation of Post-Primary Tuberculosis of the Lungs: Exploring the Secret Role of Bone Marrow Derived Stem Cells
Authors: Pathak Lekhika , Das Bikul
Published: January 2021

Mycobacterium tuberculosis (Mtb), the causative organism of pulmonary tuberculosis (PTB) now infects more than half of the world population. The efficient transmission strategy of the pathogen includes first remaining dormant inside the infected host, next undergoing reactivation to cause post-primary tuberculosis of the lungs (PPTBL) and then transmit via aerosol to the community. In this review, we are exploring recent findings on the role of bone marrow (BM) stem cell niche in Mtb dormancy and reactivation that may underlie the mechanisms of PPTBL development. We suggest that pathogen’s interaction with the stem cell niche may be relevant in potential inflammation induced PPTBL reactivation, which need significant research attention for the future development of novel preventive and therapeutic strategies for PPTBL, especially in a post COVID-19 pandemic world. Finally, we put forward potential animal models to study the stem cell basis of Mtb dormancy and reactivation.
A Dimerization Site at SCR-17/18 in Factor H Clarifies a New Mechanism for Complement Regulatory Control
Authors: Dunne Orla M. , Gao Xin , Nan Ruodan , Gor Jayesh , Adamson Penelope J. , Gordon David L. , Moulin Martine , Haertlein Michael , Forsyth V. Trevor , Perkins Stephen J.
Published: January 2021

Complement Factor H (CFH), with 20 short complement regulator (SCR) domains, regulates the alternative pathway of complement in part through the interaction of its C-terminal SCR-19 and SCR-20 domains with host cell-bound C3b and anionic oligosaccharides. In solution, CFH forms small amounts of oligomers, with one of its self-association sites being in the SCR-16/20 domains. In order to correlate CFH function with dimer formation and the occurrence of rare disease-associated variants in SCR-16/20, we identified the dimerization site in SCR-16/20. For this, we expressed, inPichia pastoris, the five domains in SCR-16/20 and six fragments of this with one-three domains (SCR-19/20, SCR-18/20, SCR-17/18, SCR-16/18, SCR-17 and SCR-18). Size-exclusion chromatography suggested that SCR dimer formation occurred in several fragments. Dimer formation was clarified using analytical ultracentrifugation, where quantitativec(s)size distribution analyses showed that SCR-19/20 was monomeric, SCR-18/20 was slightly dimeric, SCR-16/20, SCR-16/18 and SCR-18 showed more dimer formation, and SCR-17 and SCR-17/18 were primarily dimeric with dissociation constants of ~5 µM. The combination of these results located the SCR-16/20 dimerization site at SCR-17 and SCR-18. X-ray solution scattering experiments and molecular modelling fits confirmed the dimer site to be at SCR-17/18, this dimer being a side-by-side association of the two domains. We propose that the self-association of CFH at SCR-17/18 enables higher concentrations of CFH to be achieved when SCR-19/20 are bound to host cell surfaces in order to protect these better during inflammation. Dimer formation at SCR-17/18 clarified the association of genetic variants throughout SCR-16/20 with renal disease.