bluuebunny/crossref_metadata_2025 huggingface dataset:
A Hybrid Forecasting Model Based on CNN and Informer for Short-Term Wind Power
Authors: Wang Hai-Kun , Song Ke , Cheng Yi
Published: January 2022

Wind power prediction reduces the uncertainty of an entire energy system, which is very important for balancing energy supply and demand. To improve the prediction accuracy, an average wind power prediction method based on a convolutional neural network and a model named Informer is proposed. The original data features comprise only one time scale, which has a minimal amount of time information and trends. A 2-D convolutional neural network was employed to extract additional time features and trend information. To improve the accuracy of long sequence input prediction, Informer is applied to predict the average wind power. The proposed model was trained and tested based on a dataset of a real wind farm in a region of China. The evaluation metrics included MAE, MSE, RMSE, and MAPE. Many experimental results show that the proposed methods achieve good performance and effectively improve the average wind power prediction accuracy.
Emerging Roles for LGR4 in Organ Development, Energy Metabolism and Carcinogenesis
Authors: Yang Linlin , Wang Jing , Gong Xiaodi , Fan Qiong , Yang Xiaoming , Cui Yunxia , Gao Xiaoyan , Li Lijuan , Sun Xiao , Li Yuhong , Wang Yudong
Published: January 2022

The leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) belonging to G protein-coupled receptors (GPCRs) family, had various regulatory roles at multiple cellular types and numerous targeting sites, and aberrant LGR4 signaling played crucial roles in diseases and carcinogenesis. On the basis of these facts, LGR4 may become an appealing therapeutic target for the treatment of diseases and tumors. However, a comprehensive investigation of its functions and applications was still lacking. Hence, this paper provided an overview of the molecular characteristics and signaling mechanisms of LGR4, its involvement in multiple organ development and participation in the modulation of immunology related diseases, metabolic diseases, and oxidative stress damage along with cancer progression. Given that GPCRs accounted for almost a third of current clinical drug targets, the in-depth understanding of the sophisticated connections of LGR4 and its ligands would not only enrich their regulatory networks, but also shed new light on designing novel molecular targeted drugs and small molecule blockers for revolutionizing the treatment of various diseases and tumors.
Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC
Authors: Lie Marie Udnesseter , Pedersen Linda Margareth , Heuch Ingrid , Winsvold Bendik , Gjerstad Johannes , Hasvik Eivind , Nygaard Øystein Petter , Grotle Margreth , Matre Dagfinn , Zwart John-Anker , Nilsen Kristian Bernhard
Published: January 2022

In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; SOX5, CCDC26/GSDMC and DCC. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (n = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.
Comparative Transcriptome Analysis in Taraxacum koksaghyz to Identify Genes that Determine Root Volume and Root Length
Authors: Wieghaus Annika , Roelfs Kai-Uwe , Twyman Richard M. , Prüfer Dirk , Schulze Gronover Christian
Published: January 2022

The Russian dandelion (Taraxacum koksaghyz, family Asteraceae) produces large amounts of natural rubber in the laticifers of its roots. This species has been proposed as an alternative source of natural rubber to augment or partly replace the rubber tree (Hevea brasiliensis) but domestication would require genetic improvement to increase rubber yields and agronomic optimization to facilitate harvesting and processing. Optimization has focused thus far on the size and shape of the roots, the primary storage organ for natural rubber and inulin. However, the corresponding genetic factors are poorly understood. Here we describe the comparative transcriptomic analysis of root tissues fromT. koksaghyzplant sets featuring different root sizes and shapes, aiming to identify differentially expressed genes correlating with root length or root diameter in the upper root and root tip. The resulting datasets revealed multiple candidate genes for each trait and root part, including a glucan endo-1,3-β-d-glucosidase, an allene oxide synthase 3, and a TIFY10A/JAZ1 homolog. These three genes were tested by qRT-PCR in outdoor-grown plants with diverse root morphology, and the expression of two genes correlated with the appropriate root morphotype, confirming the effectiveness of our method. We evaluated the candidate genes to gain insight into their potential functions in root development. Such candidate genes could be suitable for marker-assisted breeding programs in the future.
LncRNA–miRNA–mRNA Networks of Gastrointestinal Cancers Representing Common and Specific LncRNAs and mRNAs
Authors: Dastsooz Hassan , Alizadeh Ahad , Habibzadeh Parham , Nariman Ali , Hosseini Asieh , Mansoori Yaser , Haghi-Aminjan Hamed
Published: January 2022

Gastrointestinal (GI) cancers are responsible for approximately half of cancer-related deaths, highlighting the need for the identification of distinct and common features in their clinicopathological characteristics. Long ncRNA (lncRNAs), which are involved in competitive endogenous RNA (ceRNA) networks with critical roles in biological processes, constitute a substantial number of non-coding RNAs. Therefore, our study aimed to investigate the similarities and differences in the ceRNA networks of The Cancer Genome Atlas (TCGA)-GI cancers. We performed a comprehensive bioinformatics analysis of ceRNA networks for TCGA-GI cancers in terms of the deferential mRNA, lncRNA, and miRNA expression levels, ceRNA networks, overall survival analysis, correlation analysis, pathological cancer stages, and gene set enrichment analysis. Our study revealed several common and distinct mRNAs and lncRNAs with prognostic values in these networks. It was specifically noteworthy that MAGI2-AS3 lncRNA was found to be shared in almost all GI cancers. Moreover, the most common shared mRNAs between GI cancers were MEIS1, PPP1R3C, ADAMTSL3, RIPOR2, and MYLK. For each cancer ceRNA network, we found that the expression level of a number of lncRNAs and mRNAs was specific. Furthermore, our study provided compelling evidence that several genes, most notably KDELC1, can act as novel proto-oncogenes in cancers. This, in turn, can highlight their role as new prognostic and therapeutic targets. Moreover, we found cell cycle and extracellular matrix structural constituent as the top shared KEGG and molecular function, respectively, among GI cancers. Our study revealed several known lncRNAs and known and unknown mRNAs in GI cancers with diagnostic and prognostic values.
Immunoglobulin Classification Based on FC* and GC* Features
Authors: Wan Hao , Zhang Jina , Ding Yijie , Wang Hetian , Tian Geng
Published: January 2022

Immunoglobulins have a pivotal role in disease regulation. Therefore, it is vital to accurately identify immunoglobulins to develop new drugs and research related diseases. Compared with utilizing high-dimension features to identify immunoglobulins, this research aimed to examine a method to classify immunoglobulins and non-immunoglobulins using two features, FC* and GC*. Classification of 228 samples (109 immunoglobulin samples and 119 non-immunoglobulin samples) revealed that the overall accuracy was 80.7% in 10-fold cross-validation using the J48 classifier implemented in Weka software. The FC* feature identified in this study was found in the immunoglobulin subtype domain, which demonstrated that this extracted feature could represent functional and structural properties of immunoglobulins for forecasting.
Cytokines in the Immune Microenvironment Change the Glycosylation of IgG by Regulating Intracellular Glycosyltransferases
Authors: Cao Yedi , Song Zhijing , Guo Zhendong , Zhao Xue , Gong Yan , Zhao Keli , Qu Chenxue , Huang Youyuan , Li Yan , Gao Ying , Zhang Junqing , Guo Xiaohui
Published: January 2022

Background

Changes in IgG glycosylation, as a novel pathological feature, are observed in various autoimmune diseases (AIDs). The glycosylation patterns of IgG play a critical role in regulating the biological function and stability of IgG involved in the pathophysiology of many AIDs. However, the intracellular regulatory mechanisms underlying the effects of disturbances in various cytokines on IgG glycosylation are poorly understood. Thus, we investigated the regulatory effects of elevated cytokines in AIDs on intracellular IgG glycosylation within B cells.

Methods

First, we established a controlled primary culture system in vitro to differentiate human CD19+ B cells into antibody-secreting cells (ASCs). Then, the IgG concentrations in the supernatants were measured by enzyme-linked immunoassay (ELISA) under IFN-γ, TNF-α, IL-21, IL-17A, BAFF, or APRIL stimulation. Next, the glycosylation levels of IgG under different stimuli were compared via a lectin microarray. The fine carbohydrate structures of IgG were confirmed by matrix-assisted laser desorption/ionization-quadrupole ion trap-time of flight-mass spectrometry (MALDI-TOF-MS). Finally, the expression of glycosyltransferases and glycosidases in B cells under stimulation with several cytokines was detected by real-time PCR and western blotting.

Results

We found that cytokines significantly promoted IgG production in vitro and led to considerably different IgG glycan patterns. Specifically, the results of lectin microarray showed the galactose level of IgG was increased by IFN-γ stimulation (p<0.05), and the sialylation of IgG was increased by IL-21 and IL-17A (p<0.05). The MALDI-TOF-MS data showed that the frequency of agalactosylation was decreased by IFN-γ with the increased frequency of mono-galactosylation and decreased frequency of digalactosylation, accompanied by upregulation of β-1,4-galactosyltransferase 1. Both frequencies of mono-sialylated and disialylated N-glycans were increased by IL-21 and IL-17A with decreased frequency of asialylation, and the expression of β-galactoside α-2,6-sialyltransferase 1 was upregulated by IL-21 and IL-17A.

Conclusion

Abnormally elevated cytokines in the microenvironment regulates IgG glycan patterns by regulating intracellular glycosyltransferases in human B cells.
Induction of TLR4/TLR2 Interaction and Heterodimer Formation by Low Endotoxic Atypical LPS
Authors: Francisco Sara , Billod Jean-Marc , Merino Javier , Punzón Carmen , Gallego Alicia , Arranz Alicia , Martin-Santamaria Sonsoles , Fresno Manuel
Published: January 2022

The Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex is considered the major receptor of the innate immune system to recognize lipopolysaccharides (LPSs). However, some atypical LPSs with different lipid A and core saccharide moiety structures and compositions than the well-studied enterobacterial LPSs can induce a TLR2-dependent response in innate immune cells. Ochrobactrum intermedium, an opportunistic pathogen, presents an atypical LPS. In this study, we found that O. intermedium LPS exhibits a weak inflammatory activity compared to Escherichia coli LPS and, more importantly, is a specific TLR4/TLR2 agonist, able to signal through both receptors. Molecular docking analysis of O. intermedium LPS predicts a favorable formation of a TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by fluorescence resonance energy transfer (FRET) in cells. Interestingly, the core saccharide plays an important role in this interaction. This study reveals for the first time TLR4/TLR2 heterodimerization that is induced by atypical LPS and may help to escape from recognition by the innate immune system.
Progressive Retinal and Optic Nerve Damage in a Mouse Model of Spontaneous Opticospinal Encephalomyelitis
Authors: Petrikowski Laura , Reinehr Sabrina , Haupeltshofer Steffen , Deppe Leonie , Graz Florian , Kleiter Ingo , Dick H. Burkhard , Gold Ralf , Faissner Simon , Joachim Stephanie C.
Published: January 2022

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) are antibody mediated CNS disorders mostly affecting the optic nerve and spinal cord with potential severe impact on the visual pathway. Here, we investigated inflammation and degeneration of the visual system in a spontaneous encephalomyelitis animal model. We used double-transgenic (2D2/Th) mice which develop a spontaneous opticospinal encephalomyelitis (OSE). Retinal morphology and its function were evaluated via spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG) in 6- and 8-week-old mice. Immunohistochemistry of retina and optic nerve and examination of the retina via RT-qPCR were performed using markers for inflammation, immune cells and the complement pathway. OSE mice showed clinical signs of encephalomyelitis with an incidence of 75% at day 38. A progressive retinal thinning was detected in OSE mice via SD-OCT. An impairment in photoreceptor signal transmission occurred. This was accompanied by cellular infiltration and demyelination of optic nerves. The number of microglia/macrophages was increased in OSE optic nerves and retinas. Analysis of the retina revealed a reduced retinal ganglion cell number and downregulated Pou4f1 mRNA expression in OSE retinas. RT-qPCR revealed an elevation of microglia markers and the cytokines Tnfa and Tgfb. We also documented an upregulation of the complement system via the classical pathway. In summary, we describe characteristics of inflammation and degeneration of the visual system in a spontaneous encephalomyelitis model, characterized by coinciding inflammatory and degenerative mechanisms in both retina and optic nerve with involvement of the complement system.
Concurrent Infection With the Filarial Helminth Litomosoides sigmodontis Attenuates or Worsens Influenza A Virus Pathogenesis in a Stage-Dependent Manner
Authors: Hardisty Gareth R. , Knipper Johanna A. , Fulton Alison , Hopkins John , Dutia Bernadette M. , Taylor Matthew D.
Published: January 2022

Filarial helminths infect approximately 120 million people worldwide initiating a type 2 immune response in the host. Influenza A viruses stimulate a virulent type 1 pro-inflammatory immune response that in some individuals can cause uncontrolled immunopathology and fatality. Although coinfection with filariasis and influenza is a common occurrence, the impact of filarial infection on respiratory viral infection is unknown. The aim of this study was to determine the impact of pre-existing filarial infection on concurrent infection with influenza A virus. A murine model of co-infection was established using the filarial helminth Litomosoides sigmodontis and the H1N1 (A/WSN/33) influenza A virus (IAV). Co-infection was performed at 3 different stages of L. sigmodontis infection (larval, juvenile adult, and patency), and the impact of co-infection was determined by IAV induced weight loss and clinical signs, quantification of viral titres, and helminth counts. Significant alterations of IAV pathogenesis, dependent upon stage of infection, was observed on co-infection with L. sigmodontis. Larval stage L. sigmodontis infection alleviated clinical signs of IAV co-infection, whilst more established juvenile adult infection also significantly delayed weight loss. Viral titres remained unaltered at either infection stage. In contrast, patent L. sigmdodontis infection led to a reversal of age-related resistance to IAV infection, significantly increasing weight loss and clinical signs of infection as well as increasing IAV titre. These data demonstrate that the progression of influenza infection can be ameliorated or worsened by pre-existing filarial infection, with the outcome dependent upon the stage of filarial infection.
Sympathetic Denervation Ameliorates Renal Fibrosis via Inhibition of Cellular Senescence
Authors: Li Qian , Deng Yuanjun , Liu Lele , Zhang Chunjiang , Cai Yang , Zhang Tianjing , Han Min , Xu Gang
Published: January 2022

Objective

Continuous overactivation of the renal sympathetic nerve is considered to be an important cause of renal fibrosis. Accumulated senescent cells in the damaged kidney have metabolic activities and secrete amounts of proinflammatory factors as part of the SASP (the senescence-associated secretory phenotype), which induce chronic inflammation and fibrosis. It is still unclear whether renal sympathetic nerves affect renal inflammation and fibrosis by regulating cellular senescence. Therefore, we hypothesize that sympathetic activation in the injured kidney induces cellular senescence, which contributes to progressive renal inflammation and fibrosis.

Methods

Renal denervation was performed 2 days before the UUO (unilateral ureteral obstruction) and UIRI (unilateral ischemia-reperfusion injury) models. The effects of renal denervation on renal fibrosis and cellular senescence were observed. In vitro, cellular senescence was induced in renal proximal tubular epithelial cell lines (TKPTS cells) by treatment with norepinephrine (NE). The selective α2A-adrenergic receptor (α2A-AR) antagonists BRL44408 and β-arrestin2 siRNA, were administered to inhibit NE-induced cellular senescence. A significantly altered pathway was identified through immunoblotting, immunofluorescence, immunocytochemistry, and functional assays involved in mitochondrial function.

Results

Renal fibrosis and cellular senescence were significantly increased in UUO and UIRI models, which were partially reversed by renal denervation. In vitro, NE induced epithelial cells secreting proinflammatory cytokines and promoted cell senescence by activating α2A-AR. Importantly, the effects of NE during cellular senescence were blocked by α2A-AR selective antagonist and β-arrestin2 (downstream of α2A-AR) siRNA.

Conclusion

Renal sympathetic activation and cellular senescence are important neurometabolic and neuroimmune mechanisms in the development of renal fibrosis. Renal sympathetic neurotransmitter NE acting on the α2A-AR of epithelial cells promotes cellular senescence through the downstream β-arrestin2 signaling, which is a potential preventive target for renal fibrosis.
Neutrophils Culture in Collagen Gel System
Authors: Li Ru , Wang Ziqing , Huang Junhao , He Sixiao , Peng Yanmei , Wan Yong , Ma Qiang
Published: January 2022

Neutrophils (Neu) migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis, including the intestinal epithelia injuries and immune responses. Although their important roles in these diseases, they are challenging to study due to their short life span and the inability to cryopreserve or expand themin vitro. Moreover, the standard cell culturing on plastic plates (two-dimensional (2D) cultures) does not represent the actual microenvironment where cells reside in tissues. In this study, we developed a new three-dimensional (3D) culture system for human and mouse peripheral blood Neu, which is made of hydrogel. The Neu showed much better cell integrity and less cell debris in the 3D culture system compared to that in 2D culture system. Moreover, the 3D culture system was more suitable for the observation of neutrophil extracellular traps (NETs) stimulated by the classical stimulation phorbol ester (PMA), and other damage associated molecular patterns (DAMPs) such as Lipopolysaccharide (LPS)/ATP, interleukin-1 β (IL-1β) and tumor necrosis factor α (TNFα) than the 2D culture system. Moreover, NETs phenomenon in 3D culture system is similar to thatin vivo. In addition, the 3D culture system was evaluated to co-culturing Neu and other parenchymal cells, such as colon mucosal epithelial cell lines. In conclusion, the 3D culture system could maintain better properties of Neu than that in 2D culture system and it may reduce the gap betweenin vitroanin vivoexperimentations.
IL-13 Genetic Susceptibility to Bullous Pemphigoid: A Potential Target for Treatment and a Prognostic Marker
Authors: Wang Yiman , Mao Xuming , Liu Yangchun , Yang Yuyan , Jin Hongzhong , Li Li
Published: January 2022

Background

Bullous pemphigoid (BP) is a senile chronic autoimmune bullous skin disease with a high relapse rate, which significantly impairs patients’ quality of life and contributes to disease mortality. This observational case-control study explores the gene polymorphisms of cytokines and their clinical significance in Chinese patients with BP.

Methods

IL-1α (rs1800587), IL-1β (rs16944, rs1143627, rs1143634), IL-4 (rs2243250), IL-6 (rs1800795), IL-10 (rs1800896, rs1800871, rs1800872), IL-13 (rs1800925, rs20541), TNF-α (rs1799964, rs1800630, rs1799724, rs361525), IFN-γ (rs1799964, rs1800630, rs361525, rs1800629, rs4248160, rs1800750), and TGF-β1 (rs2317130, rs1800469, rs4803457) genes were genotyped in the healthy controls and BP patients, respectively. Expression of these cytokines in serum was measured. Medical profiles of patients, including baseline characteristics and prognosis, were statistically analyzed.

Results

We found that IL-1 β and IL-13 concentrations were higher in the BP patients’ sera compared to those in the controls. For IL-13, significant differences were found in the nucleotide ratio/genotype/haploid frequency/haplotype, respectively. IL-13 (rs20541, rs1800925) is related to gender, and the IL-13 genotype was significantly associated with recurrence.

Conclusions

BP is associated with IL-13 gene polymorphism and IL-13 concentration is elevated in blood circulation in patients with BP. Our results support that IL-13 is relevant in the pathogenesis of BP, suggesting that IL-13 could potentially represent a promising target for BP therapy and a prognostic marker.
Assessment of Exploitation Intensity of Commercial Species and Associated Benthic Communities, in Chilean Marine Management Areas of North Patagonia
Authors: Hamame Madeleine , Ortiz Paula
Published: January 2022

The Aysén region of Chile (North Patagonia), has had limited studies on the effectiveness of management and exploitation areas of benthic resources, and performance relative to open access areas in this region has never been evaluated. We evaluated seven management areas (MAs) and five open access areas (OAAs) between 43.9°S and 45.2°S for exploitation intensity of three commercial species (Concholepas concholepas, Loxechinus albus, and Ameghinomya antiqua) together with characterization of the benthic community. Indicators based on size, density and weight were used to evaluate exploitation intensity of commercial species. Associated benthic communities were evaluated considering density, species composition, and community structure. We found a high species richness and a community structure with low variability between MAs and OAAs. Low densities and small sizes classes of C. concholepas in most of the areas indicated high exploitation intensity in both MAs and OAAs. In this context, a permanent ban to harvest C. concholepas within OAAs may need to be reevaluated since with no enforcement and monitoring, the exploitation status of this species remains unclear in these areas. L. albus in most areas were absent in the harvestable sizes, which could be indicating high exploitation intensity in both regimes. High densities and small sizes of C. concholepas and L. albus in some MAs, indicated a potential recruitment zones which bears further investigation. A. antiqua, showed better conditions than other commercial species evaluated, with no significant differences in densities and size-based indicators when comparing OAAs and MAs. Benthic communities were dominated numerically by the Echinoidea class in both MAs and OAAs, with L. albus, Arbacia dufresnii and Pseudechinus magellanicus being the dominant species. High densities of sea urchins co-occurring with low coverage of macroalgae found in MAs-Gala could indicate that a sea urchin barren was dominant during the study period. On the other hand, high densities of Cosmasterias lurida, a predatory sea star, in conjunction with low densities of C. concholepas in most of the studied areas suggested that a shift in predator roles is occurring. No differences were estimated in terms of fisheries indicators and benthic community structure across the two management regimes, suggesting the poor performance of MAs in Aysén region. Our data also support the need to improve monitoring of MAs especially with respect to associated benthic community incorporating a broader spatial scale.
Evaluation of Polymorphisms in Toll-Like Receptor Genes as Biomarkers of the Response to Treatment of Erythema Nodosum Leprosum
Authors: Maciel-Fiuza Miriãn Ferrão , Costa Perpétua do Socorro Silva , Kowalski Thayne Woycinck , Schuler-Faccini Lavínia , Bonamigo Renan Rangel , Vetoratto Rodrigo , Eidt Letícia Maria , de Moraes Paulo Cezar , Silveira Maria Irismar da Silva , Camargo Luis Marcelo Aranha , Callegari-Jacques Sidia Maria , Castro Stela Maris de Jezus , Vianna Fernanda Sales Luiz
Published: January 2022

Erythema nodosum leprosum (ENL) is an inflammatory complication caused by a dysregulated immune response to Mycobacterium leprae. Some Toll-like receptors (TLRs) have been identified as capable of recognizing antigens from M. leprae, triggering a wide antimicrobial and inflammatory response. Genetic polymorphisms in these receptors could influence in the appearance of ENL as well as in its treatment. Thus, the objective of this work was to evaluate the association of genetic variants of TLRs genes with the response to treatment of ENL with thalidomide and prednisone. A total of 162 ENL patients were recruited from different regions of Brazil and clinical information was collected from their medical records. Genomic DNA was isolated from blood and saliva samples and genetic variants in TLR1 (rs4833095), TLR2 (rs3804099), TLR4 (rs1927914), and TLR6 (rs5743810) genes were genotyped by TaqMan real-time PCR system. In order to evaluate the variants' association with the dose of the medications used during the treatment, we applied the Generalized Estimating Equations (GEE) analysis. In the present sample, 123 (75.9%) patients were men and 86 (53.1%) were in treatment for leprosy during the ENL episode. We found an association between polymorphisms in TLR1/rs4833095, TLR2/rs3804099, TLR4/rs1927914, and TLR6/rs5783810 with the dose variation of thalidomide in a time-dependent manner, i.e., the association with the genetic variant and the dose of the drug was different depending on the moment of the treatment evaluated. In addition, we identified that the association of polymorphisms in TLR1/rs4833095, TLR2/rs3804099, and TLR6/rs5783810 with the dose variation of prednisone also were time-dependent. Despite these associations, in all the interactions found, the influence of genetic variants on dose variation was not clinically relevant for therapeutic changes. The results obtained in this study show that TLRs polymorphism might play a role in the response to ENL treatment, however, in this context, they could not be considered as useful biomarkers in the clinical setting due small differences in medication doses. A larger sample size with patients with a more genetic profile is fundamental in order to estimate the association of genetic variants with the treatment of ENL and their clinical significance.
Pediatric Open Globe Injury in Central China
Authors: Chen Hongling , Zhang Xianliang , Han Junjun , Jin Xuemin
Published: January 2022

Purpose

To describe the characteristics, managements, and outcomes of pediatric open globe injury (OGI) in central China.

Methods

Retrospective chart review of pediatric diagnosis in patients with OGI between 2017 and 2020 at Henan Eye Hospital. Four hundred and one eyes of the patients younger than 17 years were included in this study. Open globe injury was classified according to the Birmingham Eye Trauma Terminology system (BETT). Age, sex, history, cause, month of trauma, treatment received, and outcomes were recorded. Visual acuity was documented according to standard visual acuity chart (decimals).

Results

Four hundred and one eyes of patients were included in the study. The mean age was 6.6 ± 3.4 years with the range from 8 months to 16 years. Open globe injuries (OGIs) occurred most frequently in the 2–8 year age and significant male predominance was noted (70.8%). The incidence of pediatric OGIs was lowest in summer months while it increased in the winter months. The most common type of pediatric OGI was penetration (89%). Scissors/knife accounted for 22%, followed by pen/pencil (15.2%), and wood/bamboo sticks (14.5%) of all the pediatric OGIs. Among the injuries, the most frequently involved is the zone I (76.1%). Initially, 70.8% of the eyes received primary debridement and wound closure without any additional intervention, while only one eye has no possibility of anatomical reconstruction when it received an evisceration. After the initial management, 198 eyes received subsequent operation, including 44 eyes that underwent cataract removal + intraocular lens (IOL) implantation, and 24 eyes underwent IOL implantation. Finally, over 6 months of follow-up, 129 eyes (32.2%) got visual acuity (VA) of 0.3–1.5 and, 63 eyes (15.7%) got VA of 0.01–0.25, while 11 eyes (2.7%) were eviscerated.

Conclusion

This study showed that pediatric OGIs in central China are most seen in 2–8-year age group with significant male predominance. Scissors/knife, pen/pencil, and wood/bamboo sticks accounted for over half of all cases. Pediatric OGIs often result in significant vision loss. In some severe cases (2.7%), evisceration was ultimately performed. We should call on the public to pay more attention to their children and build a safer environment for them.
Customized Color Settings of Digitally Assisted Vitreoretinal Surgery to Enable Use of Lower Dye Concentrations During Macular Surgery
Authors: Park Su Jin , Do Jae Rock , Shin Jae Pil , Park Dong Ho
Published: January 2022

Purpose

This study evaluated the color contrast ratio (CCR) of the internal limiting membrane (ILM) using different color settings of digitally assisted vitreoretinal surgery (DAVS) with different indocyanine green (ICG) concentrations.s

Methods

This is a prospective comparative observational study. Consecutive patients that underwent 25G vitrectomy and ILM peeling using a standard operating microscope (SOM) (25 eyes), DAVS Ver. 1.1 (12 eyes), or DAVS Ver. 1.3 (13 eyes) were enrolled. The SOM and DAVS Ver. 1.1 groups used 0.075% ICG, and the DAVS Ver. 1.3 group used 0.025% ICG. In DAVS Ver. 1.1, macular CCR was compared between four different presets in the red, green, and blue channels: Default (Red (R) 100%, Green (G) 100%, and Blue (B) 100%); Preset 1 (R 20%, G 100%, B 100%); Preset 2 (R 80%, G 80%, B 100%), and Preset 3 (R 85%, G 100%, B 90%). In DAVS Ver. 1.3, macular CCR was evaluated using two different customized settings that modified the hue and saturation: Customized Setting 1 (R 86, G 100, B 100%, Hue +2°, Saturation 90%, Gamma 1.2) and Customized Setting 2 (R 90, G 100, B 100%, Hue +20°, Saturation 100%, Gamma 0.9). All patients underwent ophthalmologic examinations including BCVA at baseline and at 12 months.

Results

In DAVS Ver. 1.1, macular CCR was highest in Preset 3 (P < 0.01). The CCR of Customized Setting 2 of DAVS Ver. 1.3 using 0.025% ICG did not differ from that of Preset 3 in DAVS Ver. 1.1 using 0.075% ICG. Furthermore, there was no significant difference in BCVA between the Customized Setting 2 of DAVS Ver. 1.3 with 0.025% ICG and the Preset 3 of DAVS Ver. 1.1 with 0.075% ICG groups at baseline and at 12 months (P > 0.05, respectively).

Conclusion

Customized DAVS settings enabled surgeons to use a 3-fold lower ICG concentration in ILM peeling.
Pathogenesis of Anti-melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis: A Concise Review With an Emphasis on Type I Interferon System
Authors: Hu Huifang , Yang Hang , Liu Yi , Yan Bing
Published: January 2022

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5+DM) is typically characterized by cutaneous manifestations, amyopathic or hypomyopathic muscle involvement, and a high incidence of rapid progressive interstitial lung disease (RP-ILD). However, the exact etiology and pathogenesis of this condition has yet to be fully elucidated. Melanoma differentiation-associated gene 5 (MDA5), as the autoantigen target, is a member of the retinoic acid-inducible gene-I (RIG-I) family. The MDA5 protein can function as a cytosolic sensor that recognizes viral double-strand RNA and then triggers the transcription of genes encoding type I interferon (IFN). Therefore, it was presumed that viruses might trigger the overproduction of type I IFN, thus contributing to the development of MDA5+DM. Emerging evidence provides further support to this hypothesis: the increased serum IFNα level was detected in the patients with MDA5+DM, and the type I IFN gene signature was upregulated in both the peripheral blood mononuclear cells (PBMCs) and the skin tissues from these patients. In particular, RNA sequencing revealed the over-expression of the type I IFN genes in blood vessels from MDA5+DM patients. In addition, Janus kinase (JAK) inhibitors achieved the promising therapeutic effects in cases with interstitial lung disease (ILD) associated with MDA5+DM. In this review, we discuss the role of the type I IFN system in the pathogenesis of MDA5+DM.
Transcriptome Analysis of Peripheral Blood Mononuclear Cells in Pulmonary Sarcoidosis
Authors: Yoshioka Keiichiro , Sato Hironori , Kawasaki Takeshi , Ishii Daisuke , Imamoto Takuro , Abe Mitsuhiro , Hasegawa Yoshinori , Ohara Osamu , Tatsumi Koichiro , Suzuki Takuji
Published: January 2022

Background

Sarcoidosis is a granulomatous systemic disease of unknown etiology. Mononuclear cells such as macrophages or lymphocytes in lung tissue and hilar or mediastinal lymph nodes have been recognized to play an essential role in granuloma formation in pulmonary sarcoidosis. Peripheral blood mononuclear cells (PBMCs) consist of several immunocompetent cells and have been shown to play a mechanistic role in the pathogenesis of sarcoidosis. However, the genetic modifications that occur in bulk PBMCs of sarcoidosis remain to be elucidated.

Purpose

This study aimed to explore the pathobiological markers of sarcoidosis in PBMCs by comparing the transcriptional signature of PBMCs from patients with pulmonary sarcoidosis with those of healthy controls by RNA sequencing.

Methods

PBMC samples were collected from subjects with pulmonary sarcoidosis with no steroid/immunosuppressant drugs (n= 8) and healthy controls (n= 11) from August 2020 to April 2021, and RNA sequencing was performed with the PBMC samples.

Results

Principal component analysis using RNA sequencing datasets comparing pulmonary sarcoidosis with healthy controls revealed that the two groups appeared to be differentiated, in which 270 differentially expressed genes were found in PBMCs between sarcoidosis and healthy controls. Enrichment analysis for gene ontology suggested that some biological processes related to the pathobiology of sarcoidosis, such as cellular response to interleukin (IL)-1 and IFN-γ, regulation of IL-6 production, IL-8 secretion, regulation of mononuclear cell migration, and response to lipopolysaccharide, were involved. Enrichment analysis of the KEGG pathway indicated the involvement of tumor necrosis factor (TNF), toll-like receptor signaling, IL-17 signaling pathways, phagosomes, and ribosomes. Most of the genes involved in TNF and IL-17 signaling pathways and phagosomes were upregulated, while most of the ribosome-related genes were downregulated.

Conclusion

The present study demonstrated that bulk gene expression patterns in PBMCs were different between patients with pulmonary sarcoidosis and healthy controls. The changes in the gene expression pattern of PBMCs could reflect the existence of sarcoidosis lesions and influence granuloma formation in sarcoidosis. These new findings are important to strengthen our understanding of the etiology and pathobiology of sarcoidosis and indicate a potential therapeutic target for sarcoidosis.
The Virulence Factor p25 of Beet Necrotic Yellow Vein Virus Interacts With Multiple Aux/IAA Proteins From Beta vulgaris: Implications for Rhizomania Development
Authors: Muellender Maximilian M. , Savenkov Eugene I. , Reichelt Michael , Varrelmann Mark , Liebe Sebastian
Published: January 2022

Rhizomania caused by Beet necrotic yellow vein virus (BNYVV) is characterized by excessive lateral root (LR) formation. Auxin-mediated degradation of Aux/IAA transcriptional repressors stimulates gene regulatory networks leading to LR organogenesis and involves several Aux/IAA proteins acting at distinctive stages of LR development. Previously, we showed that BNYVV p25 virulence factor interacts with BvIAA28, a transcriptional repressor acting at early stages of LR initiation. The evidence suggested that p25 inhibits BvIAA28 nuclear localization, thus, de-repressing transcriptional network leading to LR initiation. However, it was not clear whether p25 interacts with other Aux/IAA proteins. Here, by adopting bioinformatics, in vitro and in vivo protein interaction approaches we show that p25 interacts also with BvIAA2 and BvIAA6. Moreover, we confirmed that the BNYVV infection is, indeed, accompanied by an elevated auxin level in the infected LRs. Nevertheless, expression levels of BvIAA2 and BvIAA6 remained unchanged upon BNYVV infection. Mutational analysis indicated that interaction of p25 with either BvIAA2 or BvIAA6 requires full-length proteins as even single amino acid residue substitutions abolished the interactions. Compared to p25-BvIAA28 interaction that leads to redistribution of BvIAA28 into cytoplasm, both BvIAA2 and BvIAA6 remained confined into the nucleus regardless of the presence of p25 suggesting their stabilization though p25 interaction. Overexpression of p25-interacting partners (BvIAA2, BvIAA6 and BvIAA28) in Nicotiana benthamiana induced an auxin-insensitive phenotype characterized by plant dwarfism and dramatically reduced LR development. Thus, our work reveals a distinct class of transcriptional repressors targeted by p25.
Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects
Authors: Qin Wei , Li Yi-Heng , Tong Jing , Wu Jie , Zhao Dong , Li Hui-Jin , Xing Lu , He Chun-Xia , Zhou Xin , Li Peng-Quan , Meng Ge , Wu Shao-Ping , Cao Hui-Ling
Published: January 2022

Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development.
A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease
Authors: Hernández González Jorge E. , Eberle Raphael J. , Willbold Dieter , Coronado Mônika A.
Published: January 2022

The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CLpro), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature nonstructural proteins essential for the replication of the virus. Due to its essential role, numerous studies have been conducted so far, which have confirmed 3CLpro as an attractive drug target to combat Covid-19 and have reported a vast number of inhibitors and their co-crystal structures. Despite all the ongoing efforts, D-peptides, which possess key advantages over L-peptides as therapeutic agents, have not been explored as potential drug candidates against 3CLpro. The current work fills this gap by reporting an in silico approach for the discovery of D-peptides capable of inhibiting 3CLpro that involves structure-based virtual screening (SBVS) of an in-house library of D-tripeptides and D-tetrapeptides into the protease active site and subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations and molecular dynamics (MD) simulations. In vitro enzymatic assays conducted for the four top-scoring D-tetrapeptides at 20 μM showed that all of them caused 55–85% inhibition of 3CLpro activity, thus highlighting the suitability of the devised approach. Overall, our results present a promising computational strategy to identify D-peptides capable of inhibiting 3CLpro, with broader application in problems involving protein inhibition.
Construction and Comprehensive Analysis of a circRNA-miRNA-mRNA Regulatory Network to Reveal the Pathogenesis of Hepatocellular Carcinoma
Authors: Mo Meile , Liu Bihu , Luo Yihuan , Tan Jennifer Hui Juan , Zeng Xi , Zeng Xiaoyun , Huang Dongping , Li Changhua , Liu Shun , Qiu Xiaoqiang
Published: January 2022

Background: Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. However, the molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. We aimed to identify critical circRNAs and explore their potential regulatory network in HCC.

Methods: The robust rank aggregation (RRA) algorithm and weighted gene co-expression network analysis (WGCNA) were conducted to unearth the differentially expressed circRNAs (DEcircRNAs) in HCC. The expression levels of DEcircRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A circRNA-miRNA-mRNA regulatory network was constructed by computational biology, and protein-protein interaction (PPI) network, functional enrichment analysis, survival analysis, and infiltrating immune cells analysis were performed to uncover the potential regulatory mechanisms of the network.

Results: A total of 22 DEcircRNAs were screened out from four microarray datasets (GSE94508, GSE97332, GSE155949, and GSE164803) utilizing the RRA algorithm. Meanwhile, an HCC-related module containing 404 circRNAs was identified by WGCNA analysis. After intersection, only four circRNAs were recognized in both algorithms. Following qRT-PCR validation, three circRNAs (hsa_circRNA_091581, hsa_circRNA_066568, and hsa_circRNA_105031) were chosen for further analysis. As a result, a circRNA-miRNA-mRNA network containing three circRNAs, 17 miRNAs, and 222 mRNAs was established. Seven core genes (ESR1, BUB1, PRC1, LOX, CCT5, YWHAZ, and DDX39B) were determined from the PPI network of 222 mRNAs, and a circRNA-miRNA-hubgene network was also constructed. Functional enrichment analysis suggested that these seven hub genes were closely correlated with several cancer related pathways. Survival analysis revealed that the expression levels of the seven core genes were significantly associated with the prognosis of HCC patients. In addition, we also found that these seven hub genes were remarkably related to the infiltrating levels of immune cells.

Conclusion: Our research identified three pivotal HCC-related circRNAs and provided novel insights into the underlying mechanisms of the circRNA-miRNA-mRNA regulatory network in HCC.
The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice
Authors: Giacobbo Bruno Lima , Özalay Özgün , Mediavilla Tomas , Ericsson Madelene , Axelsson Jan , Rieckmann Anna , Sultan Fahad , Marcellino Daniel
Published: January 2022

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BPND), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BPND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.
Are You Sure: Preference and Ambivalence in Delay Discounting
Authors: Grunevski Sergej , Smith Aaron P. , Yi Richard
Published: January 2022

Delay discounting (DD) research has become ubiquitous due to its robust associations with clinical outcomes. Typical DD tasks involve multiple trials in which participants indicate preference between smaller, sooner and larger, later rewards. Scoring of these binary choice tasks has not considered trial-level ambivalence as a possible decision-making construct. The present study explored the extent to which trial-level ambivalence varied within-individual using an established assessment of DD (the Monetary Choice Questionnaire). Results indicate that degree of ambivalence peaks around the trials associated with the DD rate. Moreover, ambivalence is associated with a diminished impact of reward delay differences on choice, where greater delay differences decrease the odds of choosing the larger, later rewards. Taken together, we believe ambivalence to be a relevant construct for research on intertemporal decision making, and it may be particularly useful in the study of manipulations on individual rates of DD.