bluuebunny/crossref_metadata_2025 huggingface dataset:
Sphingolipids in thyroid eye disease
Authors: Gulbins Anne , Görtz Gina-Eva , Gulbins Erich , Eckstein Anja
Published: April 2023

Graves’ disease (GD) is caused by an autoimmune formation of autoantibodies and autoreactive T-cells against the thyroid stimulating hormone receptor (TSHR). The autoimmune reaction does not only lead to overstimulation of the thyroid gland, but very often also to an immune reaction against antigens within the orbital tissue leading to thyroid eye disease, which is characterized by activation of orbital fibroblasts, orbital generation of adipocytes and myofibroblasts and increased hyaluronan production in the orbit. Thyroid eye disease is the most common extra-thyroidal manifestation of the autoimmune Graves’ disease. Several studies indicate an important role of sphingolipids, in particular the acid sphingomyelinase/ceramide system and sphingosine 1-phosphate in thyroid eye disease. Here, we discuss how the biophysical properties of sphingolipids contribute to cell signaling, in particular in the context of thyroid eye disease. We further review the role of the acid sphingomyelinase/ceramide system in autoimmune diseases and its function in T lymphocytes to provide some novel hypotheses for the pathogenesis of thyroid eye disease and potentially allowing the development of novel treatments.
Identification and characterization of bone/cartilage-associated signatures in common fibrotic skin diseases
Authors: Wu Ting , Jin Yifan , Chen Fangqi , Xuan Xiuyun , Cao Juanmei , Liang Yan , Wang Yuqing , Zhan Jinshan , Zhao Mengjie , Huang Changzheng
Published: April 2023

Background: Fibrotic skin diseases are characterized by excessive accumulation of the extracellular matrix (ECM) and activation of fibroblasts, leading to a global healthcare burden. However, effective treatments of fibrotic skin diseases remain limited, and their pathological mechanisms require further investigation. This study aims to investigate the common biomarkers and therapeutic targets in two major fibrotic skin diseases, namely, keloid and systemic sclerosis (SSc), by bioinformatics analysis.

Methods: The keloid (GSE92566) and SSc (GSE95065) datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, followed by functional enrichment analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We then constructed a protein–protein interaction (PPI) network for the identification of hub genes. We explored the possibility of further functional enrichment analysis of hub genes on the Metascape, GeneMANIA, and TissueNexus platforms. Transcription factor (TF)–hub gene and miRNA–hub gene networks were established using NetworkAnalyst. We fixed GSE90051 and GSE76855 as the external validation datasets. Student’s t-test and receiver operating characteristic (ROC) curve were used for candidate hub gene validation. Hub gene expression was assessed in vitro by quantitative real-time PCR.

Results: A total of 157 overlapping DEGs (ODEGs) were retrieved from the GSE92566 and GSE95065 datasets, and five hub genes (COL11A1, COL5A2, ASPN, COL10A1, and COMP) were identified and validated. Functional studies revealed that hub genes were predominantly enriched in bone/cartilage-related and collagen-related processes. FOXC1 and miR-335-5p were predicted to be master regulators at both transcriptional and post‐transcriptional levels.

Conclusion: COL11A1, COL5A2, ASPN, COL10A1, and COMP may help understand the pathological mechanism of the major fibrotic skin diseases; moreover, FOXC1 and miR-355-5p could build a regulatory network in keloid and SSc.
A systematic review of genetic ancestry as a risk factor for incidence of non-small cell lung cancer in the US
Authors: James Breanna A. , Williams Jennie L. , Nemesure Barbara
Published: April 2023

Background: Non-Small Cell Lung Cancer (NSCLC), the leading cause of cancer-related death in the United States, is the most diagnosed form of lung cancer. While lung cancer incidence has steadily declined over the last decade, disparities in incidence and mortality rates persist among African American (AA), Caucasian American (CA), and Hispanic American (HA) populations. Researchers continue to explore how genetic ancestry may influence differential outcomes in lung cancer risk and development. The purpose of this evaluation is to highlight experimental research that investigates the differential impact of genetic mutations and ancestry on NSCLC incidence.

Methods: This systematic review was conducted using PubMed and Google Scholar search engines. The following key search terms were used to select articles published between 2011 and 2022: “African/European/Latin American Ancestry NSCLC”; “Racial Disparities NSCLC”; “Genetic Mutations NSCLC”; “NSCLC Biomarkers”; “African Americans/Hispanic Americans/Caucasian Americans NSCLC incidence.” Systematic reviews, meta-analyses, and studies outside of the US were excluded. A total of 195 articles were initially identified and after excluding 156 which did not meet eligibility criteria, 38 were included in this investigation.

Results: Studies included in this analysis focused on racial/ethnic disparities in the following common genetic mutations observed in NSCLC: KRAS, EGFR, TP53, PIK3CA, ALK Translocations, ROS-1 Rearrangements, STK11, MET, and BRAF. Results across studies varied with respect to absolute differential expression. No significant differences in frequencies of specific genetic mutational profiles were noted between racial/ethnic groups. However, for HAs, lower mutational frequencies in KRAS and STK11 genes were observed. In genetic ancestry level analyses, multiple studies suggest that African ancestry is associated with a higher frequency of EGFR mutations. Conversely, Latin ancestry is associated with TP53 mutations. At the genomic level, several novel predisposing variants associated with African ancestry and increased risk of NSCLC were discovered. Family history among all racial/ethnic groups was also considered a risk factor for NSCLC.

Conclusion: Results from racially and ethnically diverse studies can elucidate driving factors that may increase susceptibility and subsequent lung cancer risk across different racial/ethnic groups. Identification of biomarkers that can be used as diagnostic, prognostic, and therapeutic tools may help improve lung cancer survival among high-risk populations.
In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model
Authors: Gerogianni Alexandra , Bal Melissa , Mohlin Camilla , Woodruff Trent M. , Lambris John D. , Mollnes Tom E. , Sjöström Dick J. , Nilsson Per H.
Published: April 2023

Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility.
Antagonizing FcαR1 (CD89) as treatment in IgA-mediated chronic inflammation and autoimmunity
Authors: van Delft Myrthe A. M. , Aleyd Esil , Mast Richard van der , de Jong Niels , Boon Louis , Simons Peter J. , van Egmond Marjolein
Published: April 2023

Introduction

Immunoglobulin A (IgA) is mostly considered as a non-inflammatory regulator at mucosal areas. However, previous work of our group showed that IgA can also be involved in disease pathology, because it provides a potent stimulus to activate neutrophils after crosslinking of surface CD89 (FcaRI), resulting in chronic inflammation and tissue damage. IgA (auto)antibodies and neutrophils are key players in various diseases, including blistering skin diseases and rheumatoid arthritis. Therefore, we generated an array of anti-CD89 monoclonal antibodies (mAbs) for therapeutic targeting of CD89. The biological activity of newly developed anti-human CD89 mAbs and their potential therapeutic capacity were investigated.

Methods

Human neutrophils were isolated from heparinized healthy donor blood. The ability of anti-CD89 mAbs to bind human neutrophils was investigated by flow cytometry. Furthermore, the capacity of these anti-CD89 mAbs to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and migration was studied. To this end, neutrophils were pre-incubated with/without anti-CD89 mAbs after which they were stimulated with IgA-coated beads. The amount of phagocytosed beads, NET release and migrated neutrophils were subsequently analysed. In parallel, chemoattractant leukotriene B4 and lactoferrin (as a measure for degranulation) release were determined. Finally, the therapeutic potential of our prototypic anti-CD89 mAb clone 10E7 was in vivo tested in anti-mouse collagen XVII human IgA-treated transgenic CD89 mice, a preclinical model for autoimmune linear IgA bullous disease (LABD).

Results

Our results show that all generated anti-CD89 mAbs bound surface CD89 on neutrophils. Although these anti-CD89 mAbs bind to different epitopes on EC1 of CD89, they all have the capacity to inhibit IgA-mediated phagocytosis, neutrophil extracellular trap (NET) release and neutrophil migration. Moreover, IgA mediated leukotriene B4 and lactoferrin release are decreased in supernatant from anti-CD89 mAbs-treated neutrophils. Finally, anti-CD89 mAb clone 10E7, that was selected based on its selective binding profile on tissue micro arrays, reduced anti-mouse collagen XVII hIgA-induced neutrophil influx in an in vivo linear IgA bullous disease (LABD) mice model.

Conclusion

This study clearly indicates that our newly developed anti-CD89 mAbs inhibited IgA-induced neutrophil activation and reduced anti-autoantigen IgA-induced neutrophil influx in vivo, supporting further clinical development for the treatment of LABD.
Immune-related pulmonary toxicities of checkpoint inhibitors in non-small cell lung cancer: Diagnosis, mechanism, and treatment strategies
Authors: Guo Xinyu , Chen Shi , Wang Xueyan , Liu Xiaowei
Published: April 2023

Immune checkpoint inhibitors (ICI) therapy based on programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) has changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC) and improved the survival expectancy of patients. However, it also leads to immune-related adverse events (iRAEs), which result in multiple organ damage. Among them, the most common one with the highest mortality in NSCLC patients treated with ICI is checkpoint inhibitor pneumonitis (CIP). The respiratory signs of CIP are highly coincident and overlap with those in primary lung cancer, which causes difficulties in detecting, diagnosing, managing, and treating. In clinical management, patients with serious CIP should receive immunosuppressive treatment and even discontinue immunotherapy, which impairs the clinical benefits of ICIs and potentially results in tumor recrudesce. Therefore, accurate diagnosis, detailedly dissecting the pathogenesis, and developing reasonable treatment strategies for CIP are essential to prolong patient survival and expand the application of ICI. Herein, we first summarized the diagnosis strategies of CIP in NSCLC, including the classical radiology examination and the rising serological test, pathology test, and artificial intelligence aids. Then, we dissected the potential pathogenic mechanisms of CIP, including disordered T cell subsets, the increase of autoantibodies, cross-antigens reactivity, and the potential role of other immune cells. Moreover, we explored therapeutic approaches beyond first-line steroid therapy and future direction based on targeted signaling pathways. Finally, we discussed the current impediments, future trends, and challenges in fighting ICI-related pneumonitis.
Endothelial dysfunction and immunothrombosis in sepsis
Authors: Maneta Eleni , Aivalioti Evmorfia , Tual-Chalot Simon , Emini Veseli Besa , Gatsiou Aikaterini , Stamatelopoulos Kimon , Stellos Konstantinos
Published: April 2023

Sepsis is a life-threatening clinical syndrome characterized by multiorgan dysfunction caused by a dysregulated or over-reactive host response to infection. During sepsis, the coagulation cascade is triggered by activated cells of the innate immune system, such as neutrophils and monocytes, resulting in clot formation mainly in the microcirculation, a process known as immunothrombosis. Although this process aims to protect the host through inhibition of the pathogen’s dissemination and survival, endothelial dysfunction and microthrombotic complications can rapidly lead to multiple organ dysfunction. The development of treatments targeting endothelial innate immune responses and immunothrombosis could be of great significance for reducing morbidity and mortality in patients with sepsis. Medications modifying cell-specific immune responses or inhibiting platelet–endothelial interaction or platelet activation have been proposed. Herein, we discuss the underlying mechanisms of organ-specific endothelial dysfunction and immunothrombosis in sepsis and its complications, while highlighting the recent advances in the development of new therapeutic approaches aiming at improving the short- or long-term prognosis in sepsis.
Whole transcriptome analysis reveals that immune infiltration- lncRNAs are related to cellular apoptosis in liver transplantation
Authors: Wu Shile , Cheng Chao , Zhu Wenjun , Yang Jinyu , He Bei-bei , Li Song , Wang Xinsheng , Guo Hao , Chen Dong , Guo Ya-min
Published: April 2023

Introduction

In most instances, liver transplantation (LT) is the only available treatment for end‐stage liver diseases. However, LT could also induce serious liver diseases or injury, and the underlying mechanisms of LT-induced complications remain largely unknown, especially the mechanisms of the dysfunction of the immune system mediated by long noncoding RNAs (lncRNAs).

Methods

In this study, we globally analyzed the proportion of immune cells by using the transcriptome sequencing data (RNA-seq) of needle-core liver biopsies from pre- and post-transplantation recipients. Dysregulated lncRNAs were found to be correlated with the altered fractions of immune cells. We finally explored the potential targets of dysregulated lncRNAs and analyzed their functions in LT.

Results

We found that in the samples, some immune cells changed significantly after LT, including CD4 T cells, NK cells and mast cells. The proportion of macrophages in different polarization states also changed significantly, with M0 macrophages increasing and M2 macrophages decreasing. Through weighted gene co-expression network analysis (WGCNA), 7 gene expression modules related to LT were identified. These modules were related to changes in the proportion of different immune cells. The functions of these modules represent the response modes of different functional genes after LT. Among these modules, MEtan and MEyellow modules were primarily enriched in apoptosis and inflammatory pathways. Twelve immunity-related lncRNAs were identified for the first time, and the regulatory network co-changing with immune cells was also identified. The co-expressed genes of these lncRNAs were highly enriched in apoptosis-related pathways. Many apoptosis-related genes were found to be up-regulated after LT.

Discussion

In summary, we speculated that the expression and regulation of these apoptotic genes may be related to the changes in the proportion of immune cells. Some of these lncRNAs and apoptosis-related genes have been reported to be related to cell proliferation and apoptosis. They are also potential biomarkers or therapeutic targets.
Abundance and distribution of microplastics in tropical estuarine mangrove areas around Penang, Malaysia
Authors: Tan Evonne , Mohd Zanuri Norlaila Binti
Published: April 2023

Introduction

This study reports the abundance and distribution of microplastics in tropical estuarine mangrove areas in Penang, Malaysia.

Methods

Samples were collected by using a neuston net and Ponar grab at four study sites (Seberang Perai, Kuala Muda, Penaga and Balik Pulau).

Results and Discussion

A total of 8775 pieces were collected from the four sites, with abundance in coastal surface water, coastal bottom sediment, and estuarine sediment ranging between 201 ± 21.214 - 1407 ± 124.265 pcs/L, 255 ± 22.368 - 350 ± 25.892 pcs/kg, and 430 ± 7.234 - 4000 ± 29.174 pcs/kg respectively. Seberang Perai was found with the highest microplastics abundance in all compartments while fragment is the dominant morphology throughout all study sites. Stereomicroscopic analysis showed that microplastics are of numerous colours and irregular in shape while Field Emission Scanning Electron Microscope (FESEM) observed severe surficial weathering. Polyethylene is the most common identified polymer type via Fourier Transform Infrared Spectroscopy (FTIR) analysis and inorganic chemical compounds such as dimethylmercury were detected which pose a threat to organisms and the environment. The overall outcome suggests that human activities play a significant role in microplastic input into the estuarine environment and that the dominant polymer type in respective study site are closely related to the nature of human activities. This baseline study presents fundamental knowledge on microplastic pollution in the estuarine environment of Penang and encourages similar research to be conducted in the future for pollution control and management.
Characterizing seabed sediments at contrasting offshore renewable energy sites
Authors: Amjadian Pegah , Neill Simon P. , Martí Barclay Vicky
Published: April 2023

Due to the impacts of climate change, there is an urgent need to scale up existing, and develop novel, renewable energy technologies. Although there are many types of renewable energy technology, ocean renewable energy, including established offshore wind, and novel wave and tidal energy converters, offers many opportunities due to the abundance of the resource, availability of sea space, and (for tidal) predictability. However, the extraction of energy from the ocean environment will influence sediment dynamics and morphodynamics at various temporal and spatial scales. Detailed knowledge of seabed properties is also important for device installation, affecting foundation design and cabling. In this study, 36 seabed sediment samples were collected across a region of the Irish Sea extending from the west of Anglesey into Liverpool Bay up to a maximum distance of around 35 km offshore – a region where there are many existing and planned ocean renewable energy projects. Particle size analysis at quarter phi intervals was used to calculate the statistical properties of the seabed sediment samples, including Mean grain size, Sorting, Skewness and Kurtosis. These properties were compared against the outputs of wave (SWAN) and tidal (TELEMAC) models of the region to investigate the relationship between environmental variables and sediment characteristics, and to determine the impact and challenges of renewable energy technologies deployed in the region. Most of the sediments in the study area are medium sand, polymodal, very poorly sorted, coarse skewed, and very platykurtic. We found that mean water depth and peak current speed have the largest influence on Median grain size, and Sorting can be affected by tidal range, in addition to water depth and peak current speed. Moreover, minimal influence of wave climate was found on the sediments. A thorough discussion based on a literature review of the environmental issues of various energy converters (tidal energy converter (both individual and arrays), tidal barrage/lagoons, and wind turbines) was used to determine how devices in the study region, and at other sites throughout the world, would interact with sediment dynamics. We make recommendations on ways to minimize environmental impacts of ocean energy technologies.
Identification and genomic analyses of a novel endophytic actinobacterium Streptomyces endophytica sp. nov. with potential for biocontrol of yam anthracnose
Authors: Zhou Shuangqing , Zhou Yifan , Li Chengui , Wu Wenqiang , Xu Yun , Xia Wei , Huang Dongyi , Huang Xiaolong
Published: April 2023

Anthracnose disease caused by Colletotrichum gloeosporioides is one of the devastating diseases of yams (Dioscorea sp.) worldwide. In this study, we aimed to isolate endophytic actinobacteria from yam plants and to evaluate their potential for the control of yam anthracnose based on bioassays and genomic analyses. A total of 116 endophytic actinomycete strains were isolated from the surface-sterilized yam tissues from a yam orchard in Hainan Province, China. In total, 23 isolates showed antagonistic activity against C. gloeosporioides. An endophytic actinomycete, designated HNM0140T, which exhibited strong antifungal activities, multiple biocontrol, and plant growth-promoting (PGP) traits was subsequently selected to colonize in the tissue-cultured seedlings of yam and was tested for its in vivo biocontrol potential on yam anthracnose. The results showed that treatment with strain HNM0140T markedly reduced the severity and incidence of yam anthracnose under greenhouse conditions. Morphological and chemotaxonomic analyses showed that strain HNM0140T was assigned to the genus Streptomyces. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strain HNM0140T formed a separate cluster together with Streptomyces lydicus ATCC 25470T (99.45%), Streptomyces chattanoogensis NRRL ISP-5002T (99.45%), and Streptomyces kronopolitis NEAU-ML8T (98.97%). The phylogenomic tree also showed that strain HNM0140T stably clustered with Streptomyces lydicus ATCC 25470T. The ANI and dDDH between strain HNM0140T and its closest related-type species were well below the recommended thresholds for species demarcation. Hence, based on the phylogenetic, genomic, and phenotypic analyses, strain HNM0140T should represent a new streptomycete species named Streptomyces endophytica sp. nov. Genomic analysis revealed that strain HNM0140T harbored 18 putative BGCs for secondary metabolites, some PGP-related genes, and several genes coding for antifungal enzymes. The presented results indicated that strain HNM0140T was a promising biocontrol agent for yam anthracnose.
Gut microbiota alterations in critically Ill patients with carbapenem-resistant Enterobacteriaceae colonization: A clinical analysis
Authors: Baek Moon Seong , Kim Seungil , Kim Won-Young , Kweon Mi-Na , Huh Jin Won
Published: April 2023

Background

Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging concern for global health and are associated with high morbidity and mortality in critically ill patients. Risk factors for CRE acquisition include broad-spectrum antibiotic use and microbiota dysbiosis in critically ill patients. Therefore, we evaluated the alteration of the intestinal microbiota associated with CRE colonization in critically ill patients.

Methods

Fecal samples of 41 patients who were diagnosed with septic shock or respiratory failure were collected after their admission to the intensive care unit (ICU). The gut microbiota profile determined using 16S rRNA gene sequencing and quantitative measurement of fecal short-chain fatty acids were evaluated in CRE-positive (n = 9) and CRE negative (n = 32) patients. The analysis of bacterial metabolic abundance to identify an association between CRE acquisition and metabolic pathway was performed.

Results

CRE carriers showed a significantly increased proportion of the phyla Proteobacteria and decreased numbers of the phyla Bacteroidetes as compared to the CRE non-carriers. Linear discriminant analysis (LDA) with linear discriminant effect size showed that the genera Erwinia, Citrobacter, Klebsiella, Cronobacter, Kluyvera, Dysgomonas, Pantoea, and Alistipes had an upper 2 LDA score in CRE carriers. The alpha-diversity indices were significantly decreased in CRE carriers, and beta-diversity analysis demonstrated that the two groups were clustered significantly apart. Among short-chain fatty acids, the levels of isobutyric acid and valeric acid were significantly decreased in CRE carriers. Furthermore, the PICRUSt-predicted metabolic pathways revealed significant differences in five features, including ATP-binding cassette transporters, phosphotransferase systems, sphingolipid metabolism, other glycan degradation, and microbial metabolism, in diverse environments between the two groups.

Conclusion

Critically ill patients with CRE have a distinctive gut microbiota composition and community structure, altered short-chain fatty acid production and changes in the metabolic pathways. Further studies are needed to determine whether amino acids supplementation improves microbiota dysbiosis in patients with CRE.
Paraburkholderia tagetis sp. nov., a novel species isolated from roots of Tagetes patula enhances the growth and yield of Solanum lycopersicum L. (tomato)
Authors: Chhetri Geeta , Kim Inhyup , Kim Jiyoun , So Yoonseop , Park Sunho , Jung Yonghee , Seo Taegun
Published: April 2023

A multifunctional, Gram-stain-negative, aerobic, motile by flagella, short-rod shaped bacteria, designated strain RG36T was isolated from roots of marigold plant (Tagetes patula) sampled at Dongguk University, Republic of Korea. A 16S rRNA sequences indicated that the closest phylogenetic neighbors were Paraburkholderia acidiphila 7Q-K02T (99.0%) and Paraburkholderia sacchari IPT101T (98.9%) of the family Burkholderiaceae. The draft genome size was 8.52 Mb (63.7% GC). The genome contained 7,381 coding sequences. Digital DNA–DNA hybridization (dDDH) and average nucleotide identity (ANI) values of strain RG36T with its most closely related species were only 83.1–88.7 and 27.6–36.7%, respectively. Strain RG36T contained Q-8 as the major respiratory quinone and its main fatty acids (>10%) were C16:0, C17:0 cyclo, C19:0 cyclo ω8c, and summed feature 8 (comprising C18:1 ω7c and/or C18:1 ω6c). Strain RG36T accumulates polyhydroxybutyrates (PHB) and exhibits multiple plant growth-promoting properties including production of indole-3-acetic acid (IAA), siderophores, protease, phosphate solubilization, and harboring gene clusters for its multifunctional properties. A pot experiment was conducted to evaluate the effect of PGPR on the growth of Solanum lycopersicum L. (Tomato). Result also confirmed the ability of strain RG36T to promote tomato plant growth, especially it increases the yield of tomatoes. Structural assessment of the bioplastic by Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), and GC-MS spectroscopy, which confirmed the structure of the polymer as PHB. Our study revealed the potential of strain RG36T to promote the growth of tomato plant and fruit yield by stimulating the various phytohormones, which could be use as bio-fertilizers to reduce the use of chemical fertilizers and promotes sustainable agricultural production. The phenotypic, chemotaxonomic and phylogenetic data, and genome analysis showed that strain RG36T represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia tagetis sp. nov. is proposed. The type strain is RG36T (=KACC 22685T = TBRC 15696T).
Biomarker discovery in galactosemia: Metabolomics with UPLC/HRMS in dried blood spots
Authors: Alodaib Ahmad N. , Nimer Refat M. , Alhumaidy Rowan , Alhenaky Alaa , Abdel Jabar Mai , AlMalki Reem H. , Abdel Rahman Anas M.
Published: April 2023

Introduction:Galactosemia (GAL) is a genetic disorder that results in disturbances in galactose metabolism and can lead to life-threatening complications. However, the underlying pathophysiology of long-term complications in GAL remains poorly understood.

Methods: In this study, a metabolomics approach using ultra-performance liquid chromatography coupled with high-resolution mass spectrometry was used to investigate metabolomic changes in dried blood spots of 15 patients with GAL and 39 healthy individuals.

Results: The study found that 2,819 metabolites underwent significant changes in patients with GAL compared to the control group. 480 human endogenous metabolites were identified, of which 209 and 271 were upregulated and downregulated, respectively. PA (8:0/LTE4) and ganglioside GT1c (d18:0/20:0) metabolites showed the most significant difference between GAL and the healthy group, with an area under the curve of 1 and 0.995, respectively. Additionally, the study identified potential biomarkers for GAL, such as 17-alpha-estradiol-3-glucuronide and 16-alpha-hydroxy DHEA 3-sulfatediphosphate.

Conclusion: This metabolomics study deepened the understanding of the pathophysiology of GAL and presented potential biomarkers that might serve as prognostic biomarkers to monitor the progression or support the clinical diagnosis of GAL.
A simplified protocol for the generation of cortical brain organoids
Authors: Eigenhuis Kristel N. , Somsen Hedda B. , van der Kroeg Mark , Smeenk Hilde , Korporaal Anne L. , Kushner Steven A. , de Vrij Femke M. S. , van den Berg Debbie L. C.
Published: April 2023

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes.
Differential activation of spinal and parabrachial glial cells in a neuropathic pain model
Authors: Mussetto Valeria , Moen Aurora , Trofimova Lidia , Sandkühler Jürgen , Hogri Roni
Published: April 2023

The clinical burden faced by chronic pain patients is compounded by affective comorbidities, such as depression and anxiety disorders. Emerging evidence suggests that reactive glial cells in the spinal cord dorsal horn play a key role in the chronification of pain, while supraspinal glia are important for psychological aspects of chronic pain. The lateral parabrachial nucleus (LPBN) in the brainstem is a key node in the ascending pain system, and is crucial for the emotional dimension of pain. Yet, whether astrocytes and microglia in the LPBN are activated during chronic pain is unknown. Here, we evaluated the occurrence of glial activation in the LPBN of male Sprague–Dawley rats 1, 4, and 7 weeks after inducing a chronic constriction injury (CCI) of the sciatic nerve, a prevalent neuropathic pain model. CCI animals developed mechanical and thermal hypersensitivity that persisted for at least 4 weeks, and was mostly reversed after 7 weeks. Using immunohistochemical staining and confocal imaging, we found that CCI caused a strong increase in the expression of the astrocytic marker GFAP and the microglial marker Iba1 in the ipsilateral spinal dorsal horn, with peak expression observed 1 week post-injury. Moreover, morphology analysis revealed changes in microglial phenotype, indicative of microglia activation. In contrast, CCI did not induce any detectable changes in either astrocytes or microglia in the LPBN, at any time point. Thus, our results indicate that while neuropathic pain induces a robust glial reaction in the spinal dorsal horn, it fails to activate glial cells in the LPBN.
A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia
Authors: Wu Rui , Dou Weikang , Zhou Huimin , Shi Ming
Published: April 2023

Background

The etiology and pathogenesis of idiopathic dystonia remain obscure. Recent studies revealed that compound heterozygous mutations in collagen type VI alpha-3 gene COL6A3 may cause recessive isolated dystonia (DYT)-27. However, whether COL6A3 mutations are associated with Chinese patients with isolated dystonia is not yet reported.

Methods

In this study, 45 Chinese patients with isolated cervical dystonia were recruited, and their blood DNA samples were subjected to whole-exome sequencing. The potential causal variants of COL6A3 were identified based on the criteria of the American College of Medical Genetics and Genomics and by prediction software.

Results

Among 45 isolated cervical dystonia patients, 18 patients (10 female patients and eight male patients) were found to have seven potential causal variants in the COL6A3 gene. Among these variants, a compound heterozygous mutation was found in one patient. One allele had a c.1264G>A mutation in exon 4 that resulted in an amino acid substitution of methionine for valine at codon 422 (p.Val422Met) and the other a c.8965+9G>A mutation involving a splicing change in exon 40. In addition, other five missense variants, including c.958G>A (p.Ala320Thr), c.1478T>C (p.Val493Ala), c.1597C>T (p.Arg533Cys), c.1762G>A (p.Asp588Asn), and c.4912G>A (p.Ala1638Thr), were identified as well.

Conclusion

We identified a novel deleterious compound heterozygous mutation as well as five missense variants in the COL6A3 gene of Chinese patients with cervical dystonia. These findings may expand the spectrum of the COL6A3 genotype in isolated dystonia.
Trajectories of interleukin 10 and heart fatty acid-binding protein levels in traumatic brain injury patients with or without extracranial injuries
Authors: Niiranen Toni J. U. , Chiollaz Anne-Cécile , Takala Riikka S. K. , Voutilainen Miko , Tenovuo Olli , Newcombe Virginia F. J. , Maanpää Henna-Riikka , Tallus Jussi , Mohammadian Mehrbod , Hossain Iftakher , van Gils Mark , Menon David K. , Hutchinson Peter J. , Sanchez Jean-Charles , Posti Jussi P.
Published: April 2023

Background

Interleukin 10 (IL-10) and heart fatty acid-binding protein (H-FABP) have gained interest as diagnostic biomarkers of traumatic brain injury (TBI), but factors affecting their blood levels in patients with moderate-to-severe TBI are largely unknown.

Objective

To investigate the trajectories of IL-10 and H-FABP between TBI patients with and without extracranial injuries (ECI); to investigate if there is a correlation between the levels of IL-10 and H-FABP with the levels of inflammation/infection markers C-reactive protein (CRP) and leukocytes; and to investigate if there is a correlation between the admission level of H-FABP with admission levels of cardiac injury markers, troponin (TnT), creatine kinase (CK), and creatine kinase MB isoenzyme mass (CK-MBm).

Materials and methods

The admission levels of IL-10, H-FABP, CRP, and leukocytes were measured within 24 h post-TBI and on days 1, 2, 3, and 7 after TBI. The admission levels of TnT, CK, and CK-MBm were measured within 24 h post-TBI.

Results

There was a significant difference in the concentration of H-FABP between TBI patients with and without ECI on day 0 (48.2 ± 20.5 and 12.4 ± 14.7 ng/ml, p = 0.02, respectively). There was no significant difference in the levels of IL-10 between these groups at any timepoints. There was a statistically significant positive correlation between IL-10 and CRP on days 2 (R = 0.43, p < 0.01) and 7 (R = 0.46, p = 0.03) after injury, and a negative correlation between H-FABP and CRP on day 0 (R = -0.45, p = 0.01). The levels of IL-10 or H-FABP did not correlate with leukocyte counts at any timepoint. The admission levels of H-FABP correlated with CK (R = 0.70, p < 0.001) and CK-MBm (R = 0.61, p < 0.001), but not with TnT.

Conclusion

Inflammatory reactions during the early days after a TBI do not significantly confound the use of IL-10 and H-FABP as TBI biomarkers. Extracranial injuries and cardiac sources may influence the levels of H-FABP in patients with moderate-to-severe TBI.
Phytochemical composition and antioxidant activities of some wild edible plants locally consumed by rural communities in northern Uganda
Authors: Nyero Alfred , Anywar Godwin Upoki , Achaye Innocent , Malinga Geoffrey Maxwell
Published: April 2023

Background

Acalypha rhomboidea, Asystacia gangetica, Crassocephalum sacrobasis, Crotalaria ochroleuca, Heterosis rotundifolia, Hibiscus cannabinus, Hibiscus sp., Hibiscus surratensis, Ipomoea eriocarpa, Maerua angolensis, Senna obtusifolia and Vigna membranacea are among the common wild edible plants in the Acholi sub-region, northern Uganda. This study evaluated the phytochemical constituents and antioxidant potential of the plants.

Methods

Fresh leaves collected from each plant species were air-dried under shade. The phytochemical contents of the ethanol and petroleum ether extracts were determined using standard protocols. The antioxidant content of the methanolic extracts was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay.

Results

Preliminary phytochemical analyses indicated the presence of tannins, reducing compounds, alkaloids, flavonoids, flavons aglycones, flavanosides, anthracenosides, anthocyanosides, volatile oils, coumarins, steroid glycosides, sterols and triterpenes. However, the extracts did not contain any emodols and saponins. The results of the quantitative phytochemical analysis showed that the contents of different phytochemicals detected varied significantly (p < 0.05) among the selected plants. The amount of tannins in mg/g (gallic acid equivalent) of dry weight varied from 3.90 ± 0.16 in C. ochroleuca to 10.41 ± 0.78 in I. eriocarpa, total flavonoids in RE, mg/g dry matter from 4.07 ± 0.11 in I. eriocarpa to 14.94 ± 0.08 in S. obtusifolia. Total alkaloids in mg/100 g ranged from 1.59 ± 0.30 in I. eriocarpa to 6.37 ± 0.24 in Hibiscus sp. Total phenolic content in GAE, mg/g dry matter ranged from 13.39 ± 0.26 in A. rhomboidea to 64.25 ± 0.54 in I. eriocarpa. The in vitro antioxidant assays revealed substantial free radical scavenging activity in all the plants. Antioxidant activity expressed as IC50 (ppm) ranged from 13.39 for A. rhomboidea to 64.84 for I. eriocarpa, compared to 12.82 for ascorbic acid standard. The total phenolic compounds and total tannins had significant and positive correlations with DPPH free radical scavenging activity.

Conclusion

The findings of this study provide evidence that the species are good natural sources of phytochemicals and antioxidants, whose regular consumption could provide human health benefits by protecting against oxidative stress related diseases. Further research is needed on the structural characterization of the phytochemicals, profiling the plant extracts with high antioxidant activity and determining the antimicrobial activities.
Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy
Authors: Zhang Wei , Zheng Xiaoqiang
Published: April 2023

In addition to the rapid development of immune checkpoint inhibitors, there has also been a surge in the development of self-assembly immunotherapy drugs. Based on the immune target, traditional tumor immunotherapy drugs are classified into five categories, namely immune checkpoint inhibitors, direct immune modulators, adoptive cell therapy, oncolytic viruses, and cancer vaccines. Additionally, the emergence of self-assembled drugs with improved precision and environmental sensitivity offers a promising innovation approach to tumor immunotherapy. Despite rapid advances in tumor immunotherapy drug development, all candidate drugs require preclinical evaluation for safety and efficacy, and conventional evaluations are primarily conducted using two-dimensional cell lines and animal models, an approach that may be unsuitable for immunotherapy drugs. The patient-derived xenograft and organoids models, however, maintain the heterogeneity and immunity of the pathological tumor heterogeneity.
Severe cutaneous adverse reactions to drugs: A real-world pharmacovigilance study using the FDA Adverse Event Reporting System database
Authors: Li Dongxuan , Gou Jinghui , Zhu Jun , Zhang Tongyan , Liu Feng , Zhang Daojun , Dai Liyang , Li Wenjun , Liu Qinglong , Qin Chunmeng , Du Qian , Liu Songqing
Published: April 2023

Background: Sound drug safety information is important to optimize patient management, but the widely recognized comprehensive landscape of culprit-drugs that cause severe cutaneous adverse reactions (SCARs) is currently lacking.

Objective: The main aim of the study is to provide a comprehensive landscape of culprit-drugs for SCARs to guide clinical practice.

Methods: We analyzed reports associated with SCARs in the FDA Adverse Event Reporting System database between 1 January 2004 and 31 December 2021 and compiled a list of drugs with potentially serious skin toxicity. According to this list, we summarized the reporting proportions of different drugs and drug classes and conducted disproportionality analysis for all the drugs. In addition, the risk characteristic of SCARs due to different drugs and drug classes was summarized by the positive–negative distribution based on the results of the disproportionality analysis.

Results: A total of 77,789 reports in the FDA Adverse Event Reporting System database were considered SCAR-related, of which lamotrigine (6.2%) was the most reported single drug followed by acetaminophen (5.8%) and allopurinol (5.8%) and antibacterials (20.6%) was the most reported drug class followed by antiepileptics (16.7%) and antineoplastics (11.3%). A total of 1,219 drugs were reported as culprit-drugs causing SCARs in those reports, and the largest number of drugs belonged to antineoplastics. In disproportionality analysis, 776 drugs showed at least one positive pharmacovigilance signal. Drugs with the most positive signals were lamotrigine, acetaminophen, furosemide, and sulfamethoxazole/trimethoprim.

Conclusion: Our study provided a real-world overview of SCARs to drugs, and the investigation of SCAR positive–negative distribution across different drugs revealed its risk characteristics, which may help optimize patient management.
Licorice extract inhibits the cGAS-STING pathway and protects against non-alcoholic steatohepatitis
Authors: Luo Wei , Xu Guang , Song Zheng , Mu Wenqing , Wen Jincai , Hui Siwen , Zhao Jia , Zhan Xiaoyan , Bai Zhaofang , Xiao Xiaohe
Published: April 2023

Background: Inflammation and fibrosis are typical symptoms of non-alcoholic steatohepatitis (NASH), which is one of the most common chronic liver diseases. The cGAS-STING signaling pathway has been implicated in the progression of NASH, and targeting this pathway may represent a new therapeutic strategy. Licorice is a widely used herb with anti-inflammatory and liver-protective properties. In this study, we assessed the effect of licorice extract on the cGAS-STING pathway.

Methods: Bone marrow-derived macrophages (BMDMs) were treated with licorice extract and then stimulated with HT-DNA, 2'3'-cGAMP, or other agonists to activate the cGAS-STING pathway. Quantitative real-time PCR and western blot were conducted to analyze whether licorice extract could affect the cGAS-STING pathway. Methionine and choline-deficient diet (MCD) was used to induce NASH in mice, which were treated with licorice extract (500 mg/kg) by gavage and/or c-176 (15 mg/kg) by intraperitoneal injection every 2 days. After 6 weeks of treatment, histological analysis of liver tissue was performed, along with measurements of plasma biochemical parameters.

Results: Licorice extract inhibits cGAS-STING pathway activation. Mechanistically, it might function by inhibiting the oligomerization of STING. Treatment with licorice extract reduced inflammation and fibrosis in MCD diet-induced NASH mice models. Furthermore, we found that the therapeutic effect of combination treatment with licorice extract and C-176 (STING inhibitor) on the pathology and fibrosis of MCD diet-induced NASH models was similar to that of licorice extract or C-176 administered alone.

Conclusion: Licorice extract can inhibit the cGAS-STING pathway and improve hepatic inflammation and fibrosis in NASH mice models. It strongly suggests that licorice extract may be a candidate therapeutic for NASH.
MEPIRAPIM-derived synthetic cannabinoids inhibit T-type calcium channels with divergent effects on seizures in rodent models of epilepsy
Authors: Harman Thomas , Udoh Michael , McElroy Dan L. , Anderson Lyndsey L. , Kevin Richard C. , Banister Samuel D. , Ametovski Adam , Markham Jack , Bladen Chris , Doohan Peter T. , Greba Quentin , Laprairie Robert B. , Snutch Terrance P. , McGregor Iain S. , Howland John G. , Arnold Jonathon C.
Published: April 2023

Background: T-type Ca2+ channels (Cav3) represent emerging therapeutic targets for a range of neurological disorders, including epilepsy and pain. To aid the development and optimisation of new therapeutics, there is a need to identify novel chemical entities which act at these ion channels. A number of synthetic cannabinoid receptor agonists (SCRAs) have been found to exhibit activity at T-type channels, suggesting that cannabinoids may provide convenient chemical scaffolds on which to design novel Cav3 inhibitors. However, activity at cannabinoid type 1 (CB1) receptors can be problematic because of central and peripheral toxicities associated with potent SCRAs. The putative SCRA MEPIRAPIM and its analogues were recently identified as Cav3 inhibitors with only minimal activity at CB1 receptors, opening the possibility that this scaffold may be exploited to develop novel, selective Cav3 inhibitors. Here we present the pharmacological characterisation of SB2193 and SB2193F, two novel Cav3 inhibitors derived from MEPIRAPIM.

Methods: The potency of SB2193 and SB2193F was evaluated in vitro using a fluorometric Ca2+ flux assay and confirmed using whole-cell patch-clamp electrophysiology. In silico docking to the cryo-EM structure of Cav3.1 was also performed to elucidate structural insights into T-type channel inhibition. Next, in vivo pharmacokinetic parameters in mouse brain and plasma were determined using liquid chromatography-mass spectroscopy. Finally, anticonvulsant activity was assayed in established genetic and electrically-induced rodent seizure models.

Results: Both MEPIRAPIM derivatives produced potent inhibition of Cav3 channels and were brain penetrant, with SB2193 exhibiting a brain/plasma ratio of 2.7. SB2193 was further examined in mouse seizure models where it acutely protected against 6 Hz-induced seizures. However, SB2193 did not reduce spontaneous seizures in the Scn1a+/− mouse model of Dravet syndrome, nor absence seizures in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Surprisingly, SB2193 appeared to increase the incidence and duration of spike-and-wave discharges in GAERS animals over a 4 h recording period.

Conclusion: These results show that MEPIRAPIM analogues provide novel chemical scaffolds to advance Cav3 inhibitors against certain seizure types.