bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-154-5p-MCP1 Axis Regulates Allergic Inflammation by Mediating Cellular Interactions
Authors: Kim Misun , Jo Hyein , Kwon Yoojung , Jeong Myeong Seon , Jung Hyun Suk , Kim Youngmi , Jeoung Dooil
Published: May 2021

In a previous study, we have demonstrated that p62, a selective receptor of autophagy, can regulate allergic inflammation. In the present study, microRNA array analysis showed that miR-154-5p was increased by antigen (DNP-HSA) in a p62-dependent manner in rat basophilic leukemia cells (RBL2H3). NF-kB directly increased the expression of miR-154-5p. miR-154-5p mediated in vivo allergic reactions, including passive cutaneous anaphylaxis and passive systemic anaphylaxis. Cytokine array analysis showed that antigen stimulation increased the expression of MCP1 in RBL2H3 cells in an miR-154-5p-dependent manner. Reactive oxygen species (ROS)-ERK-NF-kB signaling increased the expression of MCP1 in antigen-stimulated RBL2H3 cells. Recombinant MCP1 protein induced molecular features of allergic reactions both in vitro and in vivo. Anaphylaxis-promoted tumorigenic potential has been known to be accompanied by cellular interactions involving mast cells, and macrophages, and cancer cells. Our experiments employing culture medium, co-cultures, and recombinant MCP1 protein showed that miR-154 and MCP1 mediated these cellular interactions. MiR-154-5p and MCP1 were found to be present in exosomes of RBL2H3 cells. Exosomes from PSA-activated BALB/C mouse induced molecular features of passive cutaneous anaphylaxis in an miR-154-5p-dependent manner. Exosomes from antigen-stimulated RBL2H3 cells enhanced both tumorigenic and metastatic potentials of B16F1 melanoma cells in an miR-154-5p-dependent manner. Exosomes regulated both ROS level and ROS mediated cellular interactions during allergic inflammation. Our results indicate that the miR-154-5p-MCP1 axis might serve as a valuable target for the development of anti-allergy therapeutics.
Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy
Authors: Bertolini Thais B. , Shirley Jamie L. , Zolotukhin Irene , Li Xin , Kaisho Tsuneyasu , Xiao Weidong , Kumar Sandeep R. P. , Herzog Roland W.
Published: May 2021

Adeno associated viral (AAV) vectors have emerged as a preferred platform for in vivo gene replacement therapy and represent one of the most promising strategies to treat monogenetic disorders such as hemophilia. However, immune responses to gene transfer have hampered human gene therapy in clinical trials. Over the past decade, it has become clear that innate immune recognition provides signals for the induction of antigen-specific responses against vector or transgene product. In particular, TLR9 recognition of the vector’s DNA genome in plasmacytoid dendritic cells (pDCs) has been identified as a key factor. Data from clinical trials and pre-clinical studies implement CpG motifs in the vector genome as drivers of immune responses, especially of CD8+ T cell activation. Here, we demonstrate that cross-priming of AAV capsid-specific CD8+ T cells depends on XCR1+ dendritic cells (which are likely the main cross-presenting cell that cooperates with pDCs to activate CD8+ T cells) and can be minimized by the elimination of CpG motifs in the vector genome. Further, a CpG-depleted vector expressing human coagulation factor IX showed markedly reduced (albeit not entirely eliminated) CD8+ T cell infiltration upon intramuscular gene transfer in hemophilia B mice when compared to conventional CpG+ vector (comprised of native sequences), resulting in better preservation of transduced muscle fibers. Therefore, this deimmunization strategy is helpful in reducing the potential for CD8+ T cell responses to capsid or transgene product. However, CpG depletion had minimal effects on antibody responses against capsid or transgene product, which appear to be largely independent of CpG motifs.
Prognosis and Characterization of Immune Microenvironment in Acute Myeloid Leukemia Through Identification of an Autophagy-Related Signature
Authors: Fu Denggang , Zhang Biyu , Wu Shiyong , Zhang Yinghua , Xie Jingwu , Ning Wangbin , Jiang Hua
Published: May 2021

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies that has an unfavorable outcome and a high rate of relapse. Autophagy plays a vital role in the development of and therapeutic responses to leukemia. This study identifies a potential autophagy-related signature to monitor the prognoses of patients of AML. Transcriptomic profiles of AML patients (GSE37642) with the relevant clinical information were downloaded from Gene Expression Omnibus (GEO) as the training set while TCGA-AML and GSE12417 were used as validation cohorts. Univariate regression analyses and multivariate stepwise Cox regression analysis were respectively applied to identify the autophagy-related signature. The univariate Cox regression analysis identified 32 autophagy-related genes (ARGs) that were significantly associated with the overall survival (OS) of the patients, and were mainly rich in signaling pathways for autophagy, p53, AMPK, and TNF. A prognostic signature that comprised eight ARGs (BAG3, CALCOCO2, CAMKK2, CANX, DAPK1, P4HB, TSC2, and ULK1) and had good predictive capacity was established by LASSO–Cox stepwise regression analysis. High-risk patients were found to have significantly shorter OS than patients in low-risk group. The signature can be used as an independent prognostic predictor after adjusting for clinicopathological parameters, and was validated on two external AML sets. Differentially expressed genes analyzed in two groups were involved in inflammatory and immune signaling pathways. An analysis of tumor-infiltrating immune cells confirmed that high-risk patients had a strong immunosuppressive microenvironment. Potential druggable OS-related ARGs were then investigated through protein–drug interactions. This study provides a systematic analysis of ARGs and develops an OS-related prognostic predictor for AML patients. Further work is needed to verify its clinical utility and identify the underlying molecular mechanisms in AML.
Immunogenic Cell Death-Based Cancer Vaccines
Authors: Jin Ming-Zhu , Wang Xi-Peng
Published: May 2021

Cancer immunotherapy has achieved great advancement in the past decades. Whereas, its response is largely limited in immunologically cold tumors, in an urgent need to be solve. In recent years, an increasing number of studies have shown that inducing immunogenic cell deaths (ICDs) is an attractive approach to activate antitumor immunity. Upon specific stress, cancer cells undergo ICDs and dying cancer cells release danger associated molecular patterns (DAMPs), produce neoantigens and trigger adaptive immunity. ICDs exert a cancer vaccine-like effect and Inducement of ICDs mimics process of cancer vaccination. In this review, we propose a concept of ICD-based cancer vaccines and summarize sources of ICD-based cancer vaccines and their challenges, which may broaden the understandings of ICD and cancer vaccines in cancer immunotherapy.
Preparation of Low-Dielectric-Constant Kaolin Clay Ceramics by Chemical Cleaning Method
Authors: Yang Xiaobing , Yang Weisen , Hu Jiapeng
Published: May 2021

Kaolin clay is an inexpensive and abundant material with potential for use as a low-dielectric-constant ceramic; however, the natural metallic oxides the clay contains hinder such applications. In this study, kaolin clay ceramics with excellent physical and dielectric properties were synthesized using kaolin clay as the raw material by chemical cleaning and sintering. Characterization of the resulting samples showed that the sulfuric acid treatment has a significant influence on the metallic oxide content and dielectric properties of the kaolin clay ceramics. When the kaolin clay raw material was treated with sulfuric acid three times, the dielectric constant decreased from 5.12 to 3.75 and the Vickers hardness increased from 946 to 1,214 kg/mm2 relative to the ceramic prepared from the untreated clay. Therefore, these ceramics exhibit significant potential for use in the microelectronics industry.
Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype
Authors: Gonzalez Acera Miguel , Patankar Jay V. , Diemand Leonard , Siegmund Britta , Neurath Markus F. , Wirtz Stefan , Becker Christoph
Published: May 2021

Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.
Involvement of RpoN in Regulating Motility, Biofilm, Resistance, and Spoilage Potential of Pseudomonas fluorescens
Authors: Liu Xiaoxiang , Ye Yifan , Zhu Yin , Wang Lifang , Yuan Leyang , Zhu Junli , Sun Aihua
Published: May 2021

Pseudomonas fluorescensis a typical spoiler of proteinaceous foods, and it is characterized by high spoilage activity. The sigma factor RpoN is a well-known regulator controlling nitrogen assimilation and virulence in many pathogens. However, its exact role in regulating the spoilage caused byP.fluorescensis unknown. Here, an in-frame deletion mutation ofrpoNwas constructed to investigate its global regulatory function through phenotypic and RNA-seq analysis. The results of phenotypic assays showed that therpoNmutant was deficient in swimming motility, biofilm formation, and resistance to heat and nine antibiotics, while the mutant increased the resistance to H2O2. Moreover, therpoNmutant markedly reduced extracellular protease and total volatile basic nitrogen (TVB-N) production in sterilized fish juice at 4°C; meanwhile, the juice with therpoNmutant showed significantly higher sensory scores than that with the wild-type strain. To identify RpoN-controlled genes, RNA-seq-dependent transcriptomics analysis of the wild-type strain and therpoNmutant was performed. A total of 1224 genes were significantly downregulated, and 474 genes were significantly upregulated by at least two folds at the RNA level in therpoNmutant compared with the wild-type strain, revealing the involvement of RpoN in several cellular processes, mainly flagellar mobility, adhesion, polysaccharide metabolism, resistance, and amino acid transport and metabolism; this may contribute to the swimming motility, biofilm formation, stress and antibiotic resistance, and spoilage activities ofP.fluorescens. Our results provide insights into the regulatory role of RpoN ofP.fluorescensin food spoilage, which can be valuable to ensure food quality and safety.
Optimisation of the Conversion and Extraction of Arctigenin From Fructus arctii Into Arctiin Using Fungi
Authors: Lu Zheng , He Bin , Chen Jie , Wu Li-Jun , Chen Xia-Bing , Ye Sheng-Qiang , Yang Wen-Hai , Shao Zhi-Yong , Jin Er-Guang , Wang Si-Jiu , Zhou Hong-Bo , Cao Ji-Yue
Published: May 2021

Fructus arctii is commonly used in Chinese medicine, and arctiin and arctigenin are its main active ingredients. Arctiin has low bioavailability in the human body and needs to be converted into arctigenin by intestinal microbes before it can be absorbed into the blood. Arctigenin has antiviral, anti-inflammatory, and anti-tumour effects and its development has important value. In this study, we used external microbial fermentation with Aspergillus awamori and Trichoderma reesei to process and convert arctiin from F. arctii powder into arctigenin, hence increasing its bioavailability. We developed a fermentation process by optimising the carbon and nitrogen source/ratio, fermentation time, pH, liquid volume, inoculation volume, and substrate solid-liquid ratio. This allowed for an arctiin conversion rate of 99.84%, and the dissolution rate of the final product was 95.74%, with a loss rate as low as 4.26%. After the fermentation of F. arctii powder, the average yield of arctigenin is 19.51 mg/g. Crude fermented F. arctii extract was purified by silica gel column chromatography, and we observed an arctigenin purity of 99.33%. Our technique effectively converts arctiin and extracts arctigenin from F. arctii and provides a solid basis for further development and industrialisation.
A Janus-Faced Bacterium: Host-Beneficial and -Detrimental Roles of Cutibacterium acnes
Authors: Brüggemann Holger , Salar-Vidal Llanos , Gollnick Harald P. M. , Lood Rolf
Published: May 2021

The bacterial species Cutibacterium acnes (formerly known as Propionibacterium acnes) is tightly associated with humans. It is the dominant bacterium in sebaceous regions of the human skin, where it preferentially colonizes the pilosebaceous unit. Multiple strains of C. acnes that belong to phylogenetically distinct types can co-exist. In this review we summarize and discuss the current knowledge of C. acnes regarding bacterial properties and traits that allow host colonization and play major roles in host-bacterium interactions and also regarding the host responses that C. acnes can trigger. These responses can have beneficial or detrimental consequences for the host. In the first part of the review, we highlight and critically review disease associations of C. acnes, in particular acne vulgaris, implant-associated infections and native infections. Here, we also analyse the current evidence for a direct or indirect role of a C. acnes-related dysbiosis in disease development or progression, i.e., reduced C. acnes strain diversity and/or the predominance of a certain phylotype. In the second part of the review, we highlight historical and recent findings demonstrating beneficial aspects of colonization by C. acnes such as colonization resistance, immune system interactions, and oxidant protection, and discuss the molecular mechanisms behind these effects. This new insight led to efforts in skin microbiota manipulation, such as the use of C. acnes strains as probiotic options to treat skin disorders.
Developmental Differences in Neocortex Neurogenesis and Maturation Between the Altricial Dwarf Rabbit and Precocial Guinea Pig
Authors: Kalusa Mirjam , Heinrich Maren D. , Sauerland Christine , Morawski Markus , Fietz Simone A.
Published: May 2021

Mammals are born on a precocial–altricial continuum. Altricial species produce helpless neonates with closed distant organs incapable of locomotion, whereas precocial species give birth to well-developed young that possess sophisticated sensory and locomotor capabilities. Previous studies suggest that distinct patterns of cortex development differ between precocial and altricial species. This study compares patterns of neocortex neurogenesis and maturation in the precocial guinea pig and altricial dwarf rabbit, both belonging to the taxon of Glires. We show that the principal order of neurodevelopmental events is preserved in the neocortex of both species. Moreover, we show that neurogenesis starts at a later postconceptional day and takes longer in absolute gestational days in the precocial than the altricial neocortex. Intriguingly, our data indicate that the dwarf rabbit neocortex contains a higher abundance of highly proliferative basal progenitors than the guinea pig, which might underlie its higher encephalization quotient, demonstrating that the amount of neuron production is determined by complex regulation of multiple factors. Furthermore, we show that the guinea pig neocortex exhibits a higher maturation status at birth, thus providing evidence for the notions that precocial species might have acquired the morphological machinery required to attain their high functional state at birth and that brain expansion in the precocial newborn is mainly due to prenatally initiating processes of gliogenesis and neuron differentiation instead of increased neurogenesis. Together, this study reveals important insights into the timing and cellular differences that regulate mammalian brain growth and maturation and provides a better understanding of the evolution of mammalian altriciality and presociality.
Deciphering in silico the Role of Mutated NaV1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3
Authors: Suleimanova Alina , Talanov Max , van den Maagdenberg Arn M. J. M. , Giniatullin Rashid
Published: May 2021

Familial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene that encodes the α1 subunit of voltage-gated NaV1.1 sodium channels. The high level of expression of NaV1.1 channels in peripheral trigeminal neurons may lead to abnormal nociceptive signaling thus contributing to migraine pain. NaV1.1 dysfunction is relevant also for other neurological disorders, foremost epilepsy and stroke that are comorbid with migraine. Here we used computer modeling to test the functional role of FHM3-mutated NaV1.1 channels in mechanisms of trigeminal pain. The activation of Aδ-fibers was studied for two algogens, ATP and 5-HT, operating through P2X3 and 5-HT3 receptors, respectively, at trigeminal nerve terminals. In WT Aδ-fibers of meningeal afferents, NaV1.1 channels efficiently participate in spike generation induced by ATP and 5-HT supported by NaV1.6 channels. Of the various FHM3 mutations tested, the L263V missense mutation, with a longer activation state and lower activation voltage, resulted in the most pronounced spiking activity. In contrast, mutations that result in a loss of NaV1.1 function largely reduced firing of trigeminal nerve fibers. The combined activation of P2X3 and 5-HT3 receptors and branching of nerve fibers resulted in very prolonged and high-frequency spiking activity in the mutants compared to WT. We identified, in silico, key determinants of long-lasting nociceptive activity in FHM3-mutated Aδ-fibers that naturally express P2X3 and 5-HT3 receptors and suggest mutant-specific correction options. Modeled trigeminal nerve firing was significantly higher for FHM3 mutations, compared to WT, suggesting that pronounced nociceptive signaling may contribute to migraine pain.
Transparent Touch: Insights From Model Systems on Epidermal Control of Somatosensory Innervation
Authors: Yin Chang , Peterman Eric , Rasmussen Jeffrey P. , Parrish Jay Z.
Published: May 2021

Somatosensory neurons (SSNs) densely innervate our largest organ, the skin, and shape our experience of the world, mediating responses to sensory stimuli including touch, pressure, and temperature. Historically, epidermal contributions to somatosensation, including roles in shaping innervation patterns and responses to sensory stimuli, have been understudied. However, recent work demonstrates that epidermal signals dictate patterns of SSN skin innervation through a variety of mechanisms including targeting afferents to the epidermis, providing instructive cues for branching morphogenesis, growth control and structural stability of neurites, and facilitating neurite-neurite interactions. Here, we focus onstudies conducted in worms (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio): prominent model systems in which anatomical and genetic analyses have defined fundamental principles by which epidermal cells govern SSN development.
Localization and Identification of Brain Microstructural Abnormalities in Paediatric Concussion
Authors: Stillo David , Danielli Ethan , Ho Rachelle A. , DeMatteo Carol , Hall Geoffrey B. , Bock Nicholas A. , Connolly John F. , Noseworthy Michael D.
Published: May 2021

In the United States, approximately 2.53 million people sustain a concussion each year. Relative to adults, youth show greater cognitive deficits following concussion and a longer recovery. An accurate and reliable imaging method is needed to determine injury severity and symptom resolution. The primary objective of this study was to characterize concussions with diffusion tensor imaging (DTI). This was performed through a normative Z-scoring analysis of DTI metrics, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), to quantify patient-specific injuries and identify commonly damaged brain regions in paediatric concussion patients relative to healthy controls. It was hypothesized that personalizing the detection analysis through normative Z-scoring would provide an understanding of trauma-induced microstructural damage. Concussion patients were volunteers recruited from the Emergency Department of the McMaster Children’s Hospital with a recent concussion (n = 26), 9 males and 17 females, mean age 14.22 ± 2.64, while healthy paediatric brain DTI datasets (25 males and 24 females, mean age 13.52 ± 1.03) were obtained from an MRI data repository. Significant abnormalities were commonly found in the longitudinal fasciculus, fronto-occipital fasciculus, and corticospinal tract, while unique abnormalities were localized in a number of other areas reflecting the individuality of each child’s injury. Total injury burden, determined by the number of regions containing outliers per DTI metric per patient, was used as the metric to quantify the overall injury severity of each patient. The primary outcome of this analysis found that younger patients experienced a significantly greater injury burden when measured using fractional anisotropy (p < 0.001). These results show that DTI was able to detect microstructural changes caused by concussion, on a per-person basis, and has the potential to be a useful tool for improving diagnostic accuracy and prognosis of a concussion.
Building an Open Source Classifier for the Neonatal EEG Background: A Systematic Feature-Based Approach From Expert Scoring to Clinical Visualization
Authors: Montazeri Saeed , Pinchefsky Elana , Tse Ilse , Marchi Viviana , Kohonen Jukka , Kauppila Minna , Airaksinen Manu , Tapani Karoliina , Nevalainen Päivi , Hahn Cecil , Tam Emily W. Y. , Stevenson Nathan J. , Vanhatalo Sampsa
Published: May 2021

Neonatal brain monitoring in the neonatal intensive care units (NICU) requires a continuous review of the spontaneous cortical activity, i.e., the electroencephalograph (EEG) background activity. This needs development of bedside methods for an automated assessment of the EEG background activity. In this paper, we present development of the key components of a neonatal EEG background classifier, starting from the visual background scoring to classifier design, and finally to possible bedside visualization of the classifier results. A dataset with 13,200 5-minute EEG epochs (8–16 channels) from 27 infants with birth asphyxia was used for classifier training after scoring by two independent experts. We tested three classifier designs based on 98 computational features, and their performance was assessed with respect to scoring system, pre- and post-processing of labels and outputs, choice of channels, and visualization in monitor displays. The optimal solution achieved an overall classification accuracy of 97% with a range across subjects of 81–100%. We identified a set of 23 features that make the classifier highly robust to the choice of channels and missing data due to artefact rejection. Our results showed that an automated bedside classifier of EEG background is achievable, and we publish the full classifier algorithm to allow further clinical replication and validation studies.
Methylprednisolone Induces Neuro-Protective Effects via the Inhibition of A1 Astrocyte Activation in Traumatic Spinal Cord Injury Mouse Models
Authors: Zou Hong-jun , Guo Shi-Wu , Zhu Lin , Xu Xu , Liu Jin-bo
Published: May 2021

Traumatic spinal cord injury (TSCI) leads to pathological changes such as inflammation, edema, and neuronal apoptosis. Methylprednisolone (MP) is a glucocorticoid that has a variety of beneficial effects, including decreasing inflammation and ischemic reaction, as well as inhibiting lipid peroxidation. However, the efficacy and mechanism of MP in TSCI therapy is yet to be deciphered. In the present study, MP significantly attenuated the apoptotic effects of H2O2 in neuronal cells. Western blot analysis demonstrated that the levels of apoptotic related proteins, Bax and cleaved caspase-3, were reduced while levels of anti-apoptotic Bcl-2 were increased. In vivo TUNEL assays further demonstrated that MP effectively protected neuronal cells from apoptosis after TSCI, and was consistent with in vitro studies. Furthermore, we demonstrated that MP could decrease expression levels of IBA1, Il-1α, TNFα, and C3 and suppress A1 neurotoxic reactive astrocyte activation in TSCI mouse models. Neurological function was evaluated using the Basso Mouse Scale (BMS) and Footprint Test. Results demonstrated that the neurological function of MP-treated injured mice was significantly increased. In conclusion, our study demonstrated that MP could attenuate astrocyte cell death, decrease microglia activation, suppress A1 astrocytes activation, and promote functional recovery after acute TSCI in mouse models.
Energy-Efficient Integrated Circuit Solutions Toward Miniaturized Closed-Loop Neural Interface Systems
Authors: Cho Jaeouk , Seong Geunchang , Chang Yonghee , Kim Chul
Published: May 2021

Miniaturized implantable devices play a crucial role in neural interfaces by monitoring and modulating neural activities on the peripheral and central nervous systems. Research efforts toward a compact wireless closed-loop system stimulating the nerve automatically according to the user's condition have been maintained. These systems have several advantages over open-loop stimulation systems such as reduction in both power consumption and side effects of continuous stimulation. Furthermore, a compact and wireless device consuming low energy alleviates foreign body reactions and risk of frequent surgical operations. Unfortunately, however, the miniaturized closed-loop neural interface system induces several hardware design challenges such as neural activity recording with severe stimulation artifact, real-time stimulation artifact removal, and energy-efficient wireless power delivery. Here, we will review recent approaches toward the miniaturized closed-loop neural interface system with integrated circuit (IC) techniques.
Knowledge Mapping of Dietary Factors of Metabolic Syndrome Research: Hotspots, Knowledge Structure, and Theme Trends
Authors: Cao Xia , Wu Qi-Jun , Chang Qing , Zhang Tie-Ning , Li Xiang-Sen , Chen Yun-Xiang , Zhao Yu-Hong
Published: May 2021

Background: The global incidence of metabolic syndrome (MetS) is continuously increasing, making it a potential worldwide public health concern. Research on dietary factors related to MetS has attracted considerable attention in the recent decades. However, the research hotspots, knowledge structure, and theme trends for the dietary factors associated with MetS remain unknown, and have not yet been systematically mapped. This study aimed to review the research status of diet as a risk factor for MetS through bibliometric methods. Bibliometric analysis was conducted using the Web of Science database. Research hotspots were identified using biclustering analysis with the gCLUTO software, and knowledge structure was explored via social network analysis using the Ucinet software. Theme trends were investigated using evolutionary analysis with the SciMAT software. In total, 1,305 papers were analyzed. The research output on the dietary factors associated with MetS increased steadily. The research scope was gradually expanding and diverse. Overall, eight research hot spots, four key dietary nodes, and four motor themes on the dietary factors associated with MetS were identified. Fatty acids, dietary fiber, and polyphenols have been the focus of research in this field over the years. Evolutionary analysis showed that fish oil and vitamin C were well-developed research foci recently. Prebiotics was recognized as an emerging theme with certain developmental potential. These findings provide a better understanding of the research status of the dietary factors associated with MetS and a reference for future investigations.
Palmitic Acid, but Not Lauric Acid, Induces Metabolic Inflammation, Mitochondrial Fragmentation, and a Drop in Mitochondrial Membrane Potential in Human Primary Myotubes
Authors: Sergi Domenico , Luscombe-Marsh Natalie , Naumovski Nenad , Abeywardena Mahinda , O'Callaghan Nathan
Published: May 2021

The chain length of saturated fatty acids may dictate their impact on inflammation and mitochondrial dysfunction, two pivotal players in the pathogenesis of insulin resistance. However, these paradigms have only been investigated in animal models and cell lines so far. Thus, the aim of this study was to compare the effect of palmitic (PA) (16:0) and lauric (LA) (12:0) acid on human primary myotubes mitochondrial health and metabolic inflammation. Human primary myotubes were challenged with either PA or LA (500 μM). After 24 h, the expression of interleukin 6 (IL-6) was assessed by quantitative polymerase chain reaction (PCR), whereas Western blot was used to quantify the abundance of the inhibitor of nuclear factor κB (IκBα), electron transport chain complex proteins and mitofusin-2 (MFN-2). Mitochondrial membrane potential and dynamics were evaluated using tetraethylbenzimidazolylcarbocyanine iodide (JC-1) and immunocytochemistry, respectively. PA, contrarily to LA, triggered an inflammatory response marked by the upregulation of IL-6 mRNA (11-fold; P < 0.01) and a decrease in IκBα (32%; P < 0.05). Furthermore, whereas PA and LA did not differently modulate the levels of mitochondrial electron transport chain complex proteins, PA induced mitochondrial fragmentation (37%; P < 0.001), decreased MFN-2 (38%; P < 0.05), and caused a drop in mitochondrial membrane potential (11%; P < 0.01) compared to control, with this effect being absent in LA-treated cells. Thus, LA, as opposed to PA, did not trigger pathogenetic mechanisms proposed to be linked with insulin resistance and therefore represents a healthier saturated fatty acid choice to potentially preserve skeletal muscle metabolic health.
Survival Analysis and Prediction Model for Pulmonary Sarcomatoid Carcinoma Based on SEER Database
Authors: Chen Mingjing , Yang Qiao , Xu Zihan , Luo Bangyu , Li Feng , Yu Yongxin , Sun Jianguo
Published: May 2021

Objective

This study aimed to investigate the incidence of the pulmonary sarcomatoid carcinoma (PSC), to compare the clinical characteristics and overall survival (OS) of patients with PSC and those with other non-small-cell lung cancer (oNSCLC), so as to analyze the factors affecting the OS of patients with PSC and construct a nomogram prediction model.

Methods

Data of patients with PSC and those with oNSCLC diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results database were collected. The age-adjusted incidence of PSC was calculated. The characteristics of patients with PSC and those with oNSCLC were compared, then the patients were matched 1:2 for further survival analysis. Patients with PSC were randomly divided into training set and testing set with a ratio of 7:3. The Cox proportional hazards model was used to identify the covariates associated with the OS. Significant covariates were used to construct the nomogram, and the C-index was calculated to measure the discrimination ability. The accuracy of the nomogram was compared with the tumor–node–metastasis (TNM) clinical stage, and the corresponding area under the curve was achieved.

Results

A total of 1049 patients with PSC were enrolled, the incidence of PSC was slowly decreased from 0.120/100,000 in 2004 to 0.092/100,000 in 2015. Before PSM, 793 PSC patients and 191356 oNSCLC patients were identified, the proportion of male, younger patients (<65 years), grade IV, TNM clinical stage IV was higher in the PSC. The patients with PSC had significantly poorer OS compared with those with oNSCLC. After PSM, PSC still had an extremely inferior prognosis. Age, sex, TNM clinical stage, chemotherapy, radiotherapy, and surgery were independent factors for OS. Next, a nomogram was established based on these factors, and the C-indexs were 0.775 and 0.790 for the training and testing set, respectively. Moreover, the nomogram model indicated a more comprehensive and accurate prediction than the TNM clinical stage.

Conclusions

The incidence of PSC was slowly decreased. PSC had a significantly poor prognosis compared with oNSCLC. The nomogram constructed in this study accurately predicted the prognosis of PSC, performed better than the TNM clinical stage.
The Landscape of Microbial Composition and Associated Factors in Pancreatic Ductal Adenocarcinoma Using RNA-Seq Data
Authors: Yu Dong , Wang Tengjiao , Liang Dong , Mei Yue , Zou Wenbin , Guo Shiwei
Published: May 2021

Recent research studies on interrogation of the tumor microbiome (including bacteria, viruses, and fungi) have yielded important insights into the role of microbes in carcinogenesis, therapeutic responses, and resistance. Once thought to be a sterile organ, a number of studies have showed the presence of microbes within this organ in PDAC status. A microbiome–pancreas axis for PDAC (pancreatic ductal adenocarcinoma) carcinogenesis is proposed. However, the microbial composition of localized PDAC tissue is still unclear. The associations between microbiome and PDAC reported in previous studies were detected in an indirect way, which mostly used samples from stool, oral saliva, and intestinal samples. This study integrated 582 samples derived from PDAC tissues across four datasets and presented a landscape of tumor microbiome at the genus level in PDAC based on remining of RNA-Seq data. On average, there are hundreds of genera distributed in the PDAC tissue, and dozens of core microbiota were identified by PDAC tissue. The pan-microbiome of PDAC tissue was also estimated, which might surpass 2,500 genera. In addition, sampling sites (stroma vs. epithelium) and tissue source (human tissue vs. PDX) were found to have great effects on the microbial composition of PDAC tissue, but not the traditional risk factors (sex and age). It is the first study to systematically focus on exploring the microbial composition of PDAC tissue and is helpful to have a deep understanding of tumor microbiome. The identified specific taxa might be potential biomarkers for follow-up research studies.
Aberrant Expression of PAFAH1B3 Affects Proliferation and Apoptosis in Osteosarcoma
Authors: Fan Jian , Yang Yi , Qian Ji-kui , Zhang Xin , Ji Jia-qing , Zhang Li , Li Shan-zhu , Yuan Feng
Published: May 2021

Osteosarcoma is a major malignant tumor of bone and soft tissue, which is presenting with early metastasis and a high mortality rate. Platelet activating factor acetylhydrolase 1B3 (PAFAH1B3), a cancer-relevant molecular, was found to play a vital role in tumorigenesis and aggressiveness in several cancer types. However, the roles and the regulating mechanisms of PAFAH1B3 in osteosarcoma progression remain unclear. PAFAH1B3 expression was detected by immunohistochemistry in 83 osteosarcoma tissues and 44 paired adjacent normal bone tissues. In vitro, loss-of-function assay was performed to explore the role of PAFAH1B3 in osteosarcoma cells. Tumor xenograft growth assay was used to verify the effect of PAFAH1B3 knockdown on osteosarcoma growth in vivo. Chip assay was carried out to investigate the mechanism in osteosarcoma proliferation regulated by PAFAH1B3. PAFAH1B3 was overexpressed in osteosarcoma tissues and cell lines. Moreover, PAFAH1B3 knockdown inhibited osteosarcoma cell proliferation and promoted apoptosis in vitro, and also suppressed osteosarcoma growth in vivo. Furthermore, the proliferative effect of PAFAH1B3 in osteosarcoma was related to the regulation of the expression of EIF4EBP1, MYC, PTGS2 and RPS6KB1. This study demonstrated the biological function of PAFAH1B3 on osteosarcoma proliferation. This research suggested that PAFAH1B3 could be a novel therapeutic target for osteosarcoma patients.
CircKEAP1 Suppresses the Progression of Lung Adenocarcinoma via the miR-141-3p/KEAP1/NRF2 Axis
Authors: Wang Yanbo , Ren Fenghai , Sun Dawei , Liu Jing , Liu BenKun , He YunLong , Pang Sainan , Shi BoWen , Zhou FuCheng , Yao Lei , Lang YaoGuo , Xu ShiDong , Wang JunFeng
Published: May 2021

Background

Lung cancer is the leading cause of death from cancer, and lung adenocarcinoma (LUAD) is the most common form. Despite the great advances that has been made in the diagnosis and treatment for LUAD, the pathogenesis of LUAD remains unclear. In this study, we aimed to identify the function of circKEAP1 derived from the exon of KEAP1 in LUAD.

Methods

The expression profiles of circRNAs in LUAD tissues and adjacent non-tumor tissues were analyzed by Agilent Arraystar Human CircRNA microarray. The levels and prognostic values of circKEAP1 in tissues and cancer cell lines were determined by quantitative real-time PCR (qRT-PCR). Subsequently, the effects of circKEAP1 on tumor growth were investigated by functional experiments in vitro and in vivo. Mechanistically, the dual luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation experiments were performed to confirm the interaction between circKEAP1 and miR-141-3p in LUAD.

Results

We found circKEAP1 was significantly downregulated in LUAD tissues and repressed tumor growth both in vitro and in vivo. Mechanistically, circKEAP1 competitively binds to miR-141-3p and relive miR-141-3p repression for its host gene, which activated the KEAP1/NRF2 signal pathway, and finally suppresses the tumor progress. Our findings suggest that circKEAP1 inhibits LUAD progression through circKEAP1/miR-141-3p/KEAP1 axis and it may serve as a novel method for the treatment of LUAD.
Characteristics of Patients With Complex Limb Pain Evaluated Through an Interdisciplinary Approach Utilizing Magnetic Resonance Neurography
Authors: Johnson Emily M. , Yoon Daehyun , Biswal Sandip , Curtin Catherine , Fox Paige , Wilson Thomas J. , Carroll Ian , Lutz Amelie , Tawfik Vivianne L.
Published: May 2021

Patients with persistent complex limb pain represent a substantial diagnostic challenge. Physical exam, and tests such as nerve conduction, are often normal even though the patient suffers from severe pain. In 2015, we initiated a team-based approach to evaluate such patients. The approach included physicians from several specialties (Anesthesiology/Pain Medicine, Radiology, Plastic Surgery, Neurosurgery) combined with the use of advanced imaging with Magnetic Resonance Neurography (MRN). This preliminary case series discusses MRN findings identified in patients with previously difficult-to-diagnose peripheral limb pain and describes how this combination of approaches influenced our diagnosis and treatment plans. We extracted demographics, patient characteristics, presenting features, diagnostic tests performed, treatments provided, referral diagnosis and the diagnosis after interdisciplinary team evaluation from patient charts. We evaluated MRN and electrodiagnostic studies (EDX) ability to identify injured nerves. We compared abnormal findings from these diagnostics to patient reported outcome after ultrasound-guided nerve block. A total of 58 patients, 17 males and 41 females, were identified. The majority of patients presented with lower extremity pain (75%) and had prior surgery (43%). The most commonly identified abnormality on MRN was nerve signal alteration on fluid sensitive sequences, followed by caliber change and impingement. Comparing the outcome of diagnostic nerve blocks with abnormal nerve findings on MRN or EDX, we found that MRN had a sensitivity of 67% and specificity of 100% while for EDX it was 45 and 0%, respectively. After interdisciplinary discussion and imaging review, a more specific diagnosis was produced in 78% of evaluated cases opening up additional treatment pathways such as nerve-targeted surgery, which was performed in 36% cases. This descriptive case series demonstrates that a majority of patients evaluated by our team for complex limb pain were women with lower extremity pain resulting from surgery. In addition, an interdisciplinary team evaluation and the use of the moderately sensitive but highly specific MRN imaging modality resulted in a change in diagnosis for a majority of patients with complex limb pain. Future studies investigating patient outcomes after diagnosis change are currently underway based on the findings of this preliminary study.
Efficacy of Antimicrobial-Impregnated Catheters for Prevention of Bloodstream Infections in Pediatric Patients: A Meta-Analysis
Authors: Lai Li , Yue Xuan
Published: May 2021

Background: Multiple Randomized controlled trials (RCTs) have evaluated the efficacy of antimicrobial-impregnated catheters to prevent catheter-related bloodstream infections (CRBSI). However, the RCTs showed contradictory results, the studies were limited in sample size and methodology quality. Thus, we conducted a meta-analysis to overcome these RCT limitations.

Methods: We designed a meta-analysis of RCTs comparing antimicrobial-impregnated and conventional catheters for the prevention of CRBSI. We conducted a detailed search of various databases for RCTs published before November 2019. We calculated mean differences (MDs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects model.

Results: We included five RCTs with a total of 2,294 patients. The incidence of CRBSI between the two groups was 0.50 (95% CI, 0.19–1.27), with evidence of heterogeneity (I2 = 55%). The difference was not statistically significant (p = 0.15). On subgroup analysis based on the age of the sample, there was no difference in the rate of CRBSI in the neonatal population [0.42 (95% CI, 0.08–2.27 I2 = 61% p = 0.31] as well as pediatric population [0.45 (95% CI, 0.12–1.67 I2 = 39% p = 0.23]. The summary OR on the incidence of catheter colonization between antimicrobial-impregnated and conventional catheters was 0.64 (95% CI, 0.17–2.35), with no evidence of heterogeneity (I2 = 0%) and a non-significant difference (p = 0.50).

Conclusions: To conclude, analysis of a limited number of heterogeneous studies mostly with a small sample indicates that the CRBSI and catheter colonization rates are similar between conventional and antimicrobial-impregnated catheters in the pediatric and neonatal population. There is an urgent need for large-scale RCTs focusing on different antimicrobial-impregnated catheters in these patients to further enhance current evidence.
Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation
Authors: Chen Yan , Ma Yuan , Feng Jin Jin , Wang Yi He , Li Tian Fang , Nurmi Katariina , Eklund Kari K. , Wen Jian Guo
Published: May 2021

NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1β (IL-1β), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1β was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1β upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNFα-induced IL-1β secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.
Targeting Signaling Pathway Networks in Several Malignant Tumors: Progresses and Challenges
Authors: He Hongdan , Shao Xiaoni , Li Yanan , Gihu Ribu , Xie Haochen , Zhou Junfu , Yan Hengxiu
Published: May 2021

Malignant tumors remain the health problem of highest concern among people worldwide due to its high mortality and recurrence. Lung, gastric, liver, colon, and breast cancers are among the top five malignant tumors in terms of morbidity and mortality. In cancer biology, aberrant signaling pathway regulation is a prevalent theme that drives the generation, metastasis, invasion, and other processes of all malignant tumors. The Wnt/β-catenin, PI3K/AKT/mTOR, Notch and NF-kB pathways are widely concerned and signal crosstalks exist in the five solid tumors. This review provides an innovative summary of the recent progress in research on these signaling pathways, the underlying mechanism of the molecules involved in these pathways, and the important role of some miRNAs in tumor-related signaling pathways. It also presents a brief review of the antitumor molecular drugs that target these signaling pathways. This review may provide a theoretical basis for the study of the molecular biological mechanism of malignant tumors and vital information for the development of new treatment strategies with a focus on efficacy and the reduction of side effects.
Platform Effects on Alternative Influencer Content: Understanding How Audiences and Channels Shape Misinformation Online
Authors: Hiaeshutter-Rice Dan , Chinn Sedona , Chen Kaiping
Published: May 2021

People are increasingly exposed to science and political information from social media. One consequence is that these sites play host to “alternative influencers,” who spread misinformation. However, content posted by alternative influencers on different social media platforms is unlikely to be homogenous. Our study uses computational methods to investigate how dimensions we refer to as audience and channel of social media platforms influence emotion and topics in content posted by “alternative influencers” on different platforms. Using COVID-19 as an example, we find that alternative influencers’ content contained more anger and fear words on Facebook and Twitter compared to YouTube. We also found that these actors discussed substantively different topics in their COVID-19 content on YouTube compared to Twitter and Facebook. With these findings, we discuss how the audience and channel of different social media platforms affect alternative influencers’ ability to spread misinformation online.