bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis of single-cell transcriptomic and multilayer signaling networks in glioma reveal tumor progression stage
Authors: Atanaki Fereshteh Fallah , Mirsadeghi Leila , Manesh Mohsen Riahi , Kavousi Kaveh 
Published: November 2024

IntroductionTumor microenvironments (TMEs) encompass complex ecosystems of cancer cells, infiltrating immune cells, and diverse cell types. Intercellular and intracellular signals within the TME significantly influence cancer progression and therapeutic outcomes. Although computational tools are available to study TME interactions, explicitly modeling tumor progression across different cancer types remains a challenge.MethodsThis study introduces a comprehensive framework utilizing single-cell RNA sequencing (scRNA-seq) data within a multilayer network model, designed to investigate molecular changes across glioma progression stages. The heterogeneous, multilayered network model replicates the hierarchical structure of biological systems, from genetic building blocks to cellular functions and phenotypic manifestations.ResultsApplying this framework to glioma scRNA-seq data allowed complex network analysis of different cancer stages, revealing significant ligand‒receptor interactions and key ligand‒receptor-transcription factor (TF) axes, along with their associated biological pathways. Differential network analysis between grade III and grade IV glioma highlighted the most critical nodes and edges involved in interaction rewiring. Pathway enrichment analysis identified four essential genes—PDGFA (ligand), PDGFRA (receptor), CREB1 (TF), and PLAT (target gene)—involved in the Receptor Tyrosine Kinases (RTK) signaling pathway, which plays a pivotal role in glioma progression from grade III to grade IV.DiscussionThese genes emerged as significant features for machine learning in predicting glioma progression stages, achieving 87% accuracy and 93% AUC in a 3-year survival prediction through Kaplan-Meier analysis. This framework provides deeper insights into the cellular machinery of glioma, revealing key molecular relationships that may inform prognosis and therapeutic strategies.
Human CFTR deficient iPSC-macrophages reveal impaired functional and transcriptomic response upon Pseudomonas aeruginosa infection
Authors: Rodriguez Gonzalez Claudio , Basílio-Queirós Débora , Neehus Anna-Lena , Merkert Sylvia , Tschritter David , Ünal Sinem , Hegermann Jan , Mörgelin Matthias , Bustamante Jacinta , Nietert Manuel Manfred , Martin Ulrich , Tümmler Burkhard , Munder Antje , Lachmann Nico 
Published: November 2024

IntroductionCystic fibrosis (CF) is a hereditary autosomal recessive disease driven by deleterious variants of the CFTR gene, leading, among other symptoms, to increased lung infection susceptibility. Mucus accumulation in the CF lung is, as of yet, considered as one important factor contributing to its colonization by opportunistic pathogens such as Pseudomonas aeruginosa. However, in recent years evidence was provided that alveolar macrophages, which form the first line of defense against airborne pathogens, seem to be intrinsically defective with regard to bactericidal functionality in the CF lung. To assess the impact of CFTR deficiency in human macrophages only insufficient systems are available.MethodsTo address this problem and to evaluate the role of CFTR in human macrophages, we successfully differentiated human induced pluripotent stem cells (iPSC) from a CF p.Phe508del homozygous individual and a healthy donor into primitive macrophages (iMacΔF508 and iMacWT), respectively, and compared the bactericidal functionality in the relevant cell type.ResultsiMacΔF508 showed impaired P. aeruginosa clearance and intracellular killing capacity in comparison to iMacWT. Furthermore, iMacΔF508 exhibited a less acidic lysosomal pH, and upon P. aeruginosa infection, there were signs of mitochondrial fragmentation and autophagosome formation together with a hyperinflammatory phenotype and deficient type I interferon response.ConclusionIn summary, we present a defective phenotype in iMacΔF508 upon P. aeruginosa infection, which will constitute an ideal platform to further study the role of macrophages in the context of CF.
IGF2BP1 accelerates the aerobic glycolysis to boost its immune escape in hepatocellular carcinoma microenvironment
Authors: Ye Xuxing , Lin Junmei , Chen Yanping , Wang Xiaobo 
Published: November 2024

IntroductionEnergy metabolism abnormity emerges as a crucial factor that facilitates tumorigenesis by accelerating aerobic glycolysis. However, the function of N6-methyladenosine (m6A) on hepatocellular carcinoma (HCC) aerobic glycolysis and immune escape is still unclear. Here, this investigation was intended to elucidate the regulation of m6A ‘reader’ IGF2BP1 involved in HCC aerobic glycolysis and immune escape.MethodsThe aerobic glycolysis was tested by glucose uptake, lactate, ATP generation and ECAR. The CD8+ T cell-mediated killing effect was tested by cytotoxicity, IFN-γ and granzyme B. The molecular interaction was confirmed by luciferase reporter assay, immunoprecipitation assay and chromatin immunoprecipitation (ChIP)-PCR.ResultsElevated IGF2BP1 expression was associated with poor prognosis in HCC patients. Functionally, IGF2BP1 emerged as an oncogenic factor that accelerated HCC aerobic glycolysis (glucose uptake, lactate, ATP generation and ECAR) and oxaliplatin resistance. Meanwhile, IGF2BP1 repressed the activated CD8+ T cell-mediated killing effect (cytotoxicity, IFN-γ and granzyme B) and apoptosis of HCC cells, indicating a suppressed cytotoxic T-cell response. By recognizing and binding to the m6A-modified sites on c-Myc mRNA, IGF2BP1 enhanced the stability of c-Myc mRNA, consequently upregulating c-Myc expression. In addition, transcription factor c-Myc targeted the programmed death ligand 1 (PD-L1) promoter region to strengthen its transcription.DiscussionTaken together, this study illustrates IGF2BP1 as a potential therapeutic target in HCC, aiming to disrupt the interplay between aberrant metabolism and immune escape.
Protective effects of YCHD on the autoimmune hepatitis mice model induced by Ad-CYP2D6 through modulating the Th1/Treg ratio and intestinal flora
Authors: Wu Jiawen , Lyu Sixue , Guo Di , Yang Na , Liu Yang 
Published: November 2024

BackgroundAutoimmune hepatitis (AIH) is a chronic liver inflammatory disease mediated by autoimmune reactions, the pathogenesis of AIH is probably related to the imbalance of intestinal flora. Yinchenhao decoction (YCHD) has been used to relieve AIH. However, the mechanisms underpinning YCHD’s hepatoprotective effects with the gut microbito have not been fully revealed.ObjectiveTo explore the potential mechanism of YCHD in treating AIH based on changes in the intestinal flora and Th1/Treg ratio in the spleen and hepatic hilar lymph nodes.MethodsThe AIH mice model induced by the adenovirus vectors that overexpress human cytochrome P450 family 2 subfamily D member 6 (Ad-CYP2D6) was established (untreated group). One week after the Ad-CYP2D6 injection, the AIH model mice were treated by administering YCHD by gavage for 14 days (YCHD-treated group). The therapeutic efficacy of YCHD on AIH was evaluated by detecting the histopathological changes of the liver, serum transaminases (ALT and AST), inflammatory factors (TNF-α,IL-17 and IFN-γ), and autoantibodies (including LKM-1 and LC-1). The ratio of Th1 to Treg within the spleen and hepatic hilar lymph nodes of the mice was detected by flow cytometry. The changes in the species and abundance of intestinal flora and intestinal flora metabolites were analyzed via 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC/MS) to reveal the protective mechanism of YCHD on liver injury.ResultYCHD decreased the transaminase activity (AST and ALT), the content of autoantibodies (LC-1 and LKM-1), and the serum TNF-α, IL-12, and IL-17 levels in AIH mice. The degree of inflammatory infiltration in the YCHD-treated group was significantly less than that in the untreated group. YCHD can effectively reverse the abundance and diversity of intestinal flora in AIH mice and affect the release of short-chain fatty acids (SCFAs), especially butyric acid. Moreover, the flow cytometry results showed that YCHD could also decline the ratio of Th1/Treg, which probably be induced by SCFAs via the G protein-coupled receptor (GPR).ConclusionYCHD may affect the release of SCFAs by regulating the intestinal microbiota, thereby affecting the differentiation of Th1 and Treg, and achieving the effect of alleviating liver damage.
Addressing barriers to post-graduate research training in low resource settings: an innovative approach in an institution of higher learning in Kenya
Authors: Mwangi Eunice Muthoni , Iseme-Ondiek Rosebella Alungata , Riang'a Roselyter Monchari , Orwa James , Njenga Kennedy W. , Ngugi Anthony K. 
Published: November 2024

BackgroundNumerous barriers hinder health research training in Post-Graduate Medical Education Programs, especially in developing countries. Research training is pivotal for medical residency, providing essential knowledge and skills for dissertation completion, fostering evidence-based medical practice, and nurturing future independent clinical researchers. A holistic approach to research education is imperative to surmount these barriers. We describe here a dissertation-centric research curriculum, delivered longitudinally, an innovative strategy undertaken by Aga Khan University's Medical College in East Africa (AKU-MCEA) to deliver postgraduate research.MethodsA review of AKU-MCEA post-graduate research methods curriculum was conducted based on implementing Departments' experience, institutional policies, and residency program output.Program implementationThe Master of Medicine program requires a well-executed dissertation for graduation. Residents undergo structured research training across four modules, with interactive sessions and workshops supporting their research milestones. Protected time allows residents to develop and report on their dissertation work. Faculty receive specialized training in dissertation supervision to ensure residents benefit from expert guidance in producing high-quality research.OutcomesThis approach achieves a dissertation completion and graduation rate of 98–100%. Notably, 68.5% (n = 126) of those who graduated in 2013–2023 have published two or more papers (i.e., range 2–36) in their current portfolio, demonstrating a commitment to ongoing research endeavors even after graduation. Residents' research covers diverse themes and is disseminated through departmental presentations, university-wide Faculty Academic Rounds, peer-reviewed journals, conferences, and the Annual Early Career Researchers symposium.Lessons learntA comprehensive approach featuring a structured research curriculum, longitudinal delivery with predetermined milestones, dedicated supervision, financial and resource support, protected research time, ongoing faculty development in dissertation supervision, and clear institutional research policies accelerates dissertation completion and enhances effective research dissemination.
Mechanism of medical hemorrhoid gel in relieving pruritus ani via inhibiting the activation of JAK2/STAT3 pathway
Authors: Ai Zhongzhu , Yuan Dongfeng , Cai Jingyi , Dong Ruotong , Liu Wei , Zhou Daonian 
Published: November 2024

BackgroundPruritus ani (PA), a neurofunctional dermatosis, is one of the most common complications of hemorrhoids, which seriously affects the quality of life of patients. Medical hemorrhoid gel (MHG), a product mainly composed of herbal medicine, is widely used for treatment of PA clinically. This study aim to assess the alleviating effect and mechanism of MHG on PA based on rectal epidermis-spinal cord-brain axis using animal models.MethodsA chloroquine-induced mouse itching model and a croton oil preparation-induced rat hemorrhoid model were established to evaluate anti-PA effect of MHG. Scratching behaviors of mice were recorded, and histopathology of mice skin and rat ano-rectal tissues was observed through H&amp;E staining. Network pharmacology and western blotting were employed to explore potential mechanism of MHG.ResultsThe study indicated that MHG significantly alleviated chloroquine-induced skin itching and improved pathological injuries in mice skin and rat ano-rectal tissues. Network pharmacology suggested that MHG might regulate the JAK/STAT signaling pathway. Experimental findings showed that MHG significantly downregulated TRPV1 and TRPA1 in rectal tissue, c-Fos and GRPR in spinal cord tissue, and 5-HT1a protein in brain tissue, while upregulating TRPM8 protein in rectal tissue. Furthermore, MHG inhibited the activation of the JAK2/STAT3 signaling pathway in the rectal epidermis-spinal cord-brain axis.ConclusionMHG improves PA by inhibiting the transmission of itching signals in rectal epidermis-spinal cord-brain axis via the JAK2/STAT3 signaling pathway, providing experimental evidence for its clinical application.
Effects of sex and estrous cycle on extended-access oxycodone self-administration and cue-induced drug seeking behavior
Authors: Patel Bhumiben P. , Loweth Jessica A. 
Published: November 2024

IntroductionIncreasing evidence indicates that sex is a factor that impacts the abuse liability and relapse vulnerability of prescription opioids like oxycodone. However, while women are more likely than men to be prescribed and to use these drugs, the impact of sex and ovarian hormones on prescription opioid use and relapse vulnerability remains unclear. Accurately assessing these measures is complicated by the fact that chronic opioid exposure can lower ovarian hormone levels and cause cycle irregularities.MethodsAdult male and female Sprague–Dawley rats self-administered oxycodone (0.1 mg/kg/infusion) under extended-access conditions (6 h/day, 10 days) followed by forced abstinence. Separate groups of animals received cue-induced seeking tests in a drug-free state during early (1–2 days) or later periods of abstinence (43–45 days). To track estrous cycle stage, animals were regularly vaginally swabbed throughout the study.ResultsWe observed oxycodone-induced estrous cycle dysregulation in the majority (~60%) of the animals during both self-administration and the first month of abstinence. In animals whose cycles were not dysregulated, we found a reduction in oxycodone intake during estrus compared to all other cycle stages (non-estrus). We also found that males but not females showed a time-dependent intensification or incubation of cue-induced oxycodone craving over the first 6 weeks of abstinence. This sex difference was estrous cycle-dependent, driven by a selective reduction in drug seeking during estrus.DiscussionThese findings highlight the importance of tracking drug-induced estrous cyclicity and identify a clear impact of ovarian hormones on oxycodone taking and seeking behavior.
Neural speech tracking and auditory attention decoding in everyday life
Authors: Straetmans Lisa , Adiloglu Kamil , Debener Stefan 
Published: November 2024

IntroductionIn our complex world, the auditory system plays a crucial role in perceiving and processing our environment. Humans are able to segment and stream concurrent auditory objects, allowing them to focus on specific sounds, such as speech, and suppress irrelevant auditory objects. The attentional enhancement or suppression of sound processing is evident in neural data through a phenomenon called neural speech tracking. Previous studies have identified correlates of neural speech tracking in electroencephalography (EEG) data, but EEG measures are susceptible to motion artefacts, and the association between neural data and auditory objects is vulnerable to distraction.MethodsThe current study investigated EEG-based auditory attention decoding in realistic everyday scenarios. N=20 participants were exposed to the sound of a busy cafeteria or walked along busy and quiet streets while listening to one or two simultaneous speech streams. We also investigated the robustness of neural speech tracking estimates within subjects. Linear decoding models were used to determine the magnitude of neural speech tracking.ResultsThe results confirmed that neural speech tracking was strongest in single speaker scenarios. In dual speaker conditions, there was significantly stronger neural speech tracking for the attended speaker compared to the ignored speaker, even in complex environments such as a busy cafeteria or outdoor settings.DiscussionIn conclusion, EEG-based attention decoding is feasible in highly complex and realistic everyday conditions while humans behave naturally.
(+)-Borneol inhibits neuroinflammation and M1 phenotype polarization of microglia in epileptogenesis through the TLR4-NFκB signaling pathway
Authors: Li Shuo , Adamu Alhamdu , Ye Yucai , Gao Fankai , Mi Rulin , Xue Guofang , Wang Zhaojun 
Published: November 2024

ObjectiveTo investigate the effect of (+)-borneol on neuroinflammation and microglia phenotype polarization in epileptogenesis and its possible mechanism.MethodsBased on mouse models of status epilepticus (SE) induced by pilocarpine, and treated with 15 mg/kg (+)-borneol, western-blot was used to detect the expressions of NeuN, Iba-1, TLR4, p65 and p-p65 in the hippocampus. Immunofluorescence was used to detect the expression of apoptosis-related proteins Bax and Bcl-2. To explore the effect of (+)-borneol on microglia in vitro, we used the kainic acid-induced microglia model and the concentration of (+)-borneol was 25 μM according to CCK-8 results. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) in the supernatant of each group was detected by ELISA. The nitric oxide (NO) content in the supernatant was detected by Griess method. The expressions of Iba-1 and TLR4-NFκB signaling pathway-related proteins (TLR4, p65, p-p65) were detected by Western-Blot. Immunofluorescence was used to detect microglia’s M1 and M2 phenotype polarization and the expression of Iba-1 and TLR4.Results(+)-borneol reduced hippocampal neuronal injury, apoptosis, and microglia activation by inhibiting the TLR-NFκB signaling pathway in SE mice. TLR4 agonist LPS partially reversed the neuroprotective effect of (+)-borneol. In the KA-induced microglia model, (+)-borneol inhibited microglia activation, M1 phenotype polarization, and secretion of pro-inflammatory cytokines through the TLR4-NFκB signaling pathway. LPS treatment inhibited the therapeutic effects of (+)-borneol.Conclusion(+)-borneol inhibits microglial neuroinflammation and M1 phenotype polarization through TLR4-NFκB signaling pathway and reduces neuronal damage and apoptosis in SE mice. Therefore, (+)-borneol may be a potential drug for epilepsy modification therapy.
Epileptiform activity in brain organoids derived from patient with Glucose Transporter 1 Deficiency Syndrome
Authors: Müller Y. , Lengacher L. , Friscourt F. , Quairiaux C. , Stoppini L. , Magistretti P. J. , Lengacher S. , Finsterwald C. 
Published: November 2024

IntroductionGlucose Transporter 1-Deficiency Syndrome (GLUT1-DS) is a rare genetic disorder caused by mutations in the gene encoding for GLUT1 and characterized by impaired glucose uptake in the brain. This leads to brain hypometabolism and the development of symptoms that include epilepsy, motor dysfunctions and cognitive impairment. The development of patient-specific in vitro models is a valuable tool for understanding the pathophysiology of rare genetic disorders and testing new therapeutic interventions.MethodsIn this study, we generated brain organoids from induced pluripotent stem cells (iPSCs) derived either from a GLUT1-DS patient or a healthy individual. The functional organoids were analyzed for cellular composition, maturity, and electrophysiological activity using a custom-made microelectrode array (MEA) platform, which allowed for the detection of spikes, burst patterns, and epileptiform discharges.ResultsImmunostaining revealed a similar distribution of neurons and astrocytes in both healthy and GLUT1-DS brain organoids, though GLUT1-DS brain organoids exhibited reduced cellular density and smaller overall size. Electrophysiological recordings demonstrated functional spike profiles in both organoid types. Notably, our study demonstrates that brain organoids derived from a GLUT1-DS patient exhibit distinct epileptiform activity and heightened sensitivity to glucose deprivation, reflecting key features of the disorder.DiscussionThese findings validate the use of brain organoids as a model for studying GLUT1-DS and highlight their potential for testing novel therapeutic strategies aimed at improving glucose metabolism and managing epilepsy in patients.
The role of low-carbohydrate, high-fat diet in modulating autophagy and endoplasmic reticulum stress in aortic endothelial dysfunction of metabolic syndrome animal model
Authors: Eldakhakhny Basmah , Bima Abdulhadi , Alamoudi Aliaa A. , Alnami Abrar , Abo-Elkhair Salwa Mohamed , Sakr Hussein , Almoghrabi Yousef , Ghoneim Fatma Mohamed , Nagib Reham Mohamed , Elsamanoudy Ayman 
Published: November 2024

BackgroundEndothelial dysfunction (ED) is induced by insulin resistance, mediated by endoplasmic reticulum (ER) stress and disturbed autophagy. This study investigates the protective role of a low-carbohydrate, high-fat (LCHF) diet on ED, ER stress, and autophagy dysregulation in an experimental animal model of metabolic syndrome.MethodsForty male Sprague–Dawley rats were divided into four groups: a Control group (standard diet) and three Dexamethasone (DEX) treated groups. Group II continued the standard diet, Group III received an LCHF diet, and Group IV received a high-carbohydrate, low-fat (HCLF) diet. At the end of the experiment, aortic tissue samples were obtained and used for histological, immunohistochemical (Endothelin and PCNA, biochemical MDA, TCA, NO, 8-OH-dG, and Nrf2/ARE protein) and molecular (Endothelin, eNOS, Nrf-2 α, p62, LC3, BECN-1, PINK1, CHOP, BNIP3, PCNA) analysis.ResultsOxidative stress, autophagy markers, and ED markers are increased in the metabolic syndrome group. LCHF diet mitigates the adverse effects of DEX on endothelial dysfunction and oxidative stress, as evidenced by reduced BMI, HOMA-IR, and improved histological and molecular parameters.ConclusionOxidative stress, autophagy dysregulation, and ER stress play crucial roles in the pathogenesis of insulin resistance-induced endothelial dysfunction. An LCHF diet offers protective benefits against insulin resistance and related comorbidities, including endothelial dysfunction.