bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and validation of metabolism-related hub genes in idiopathic pulmonary fibrosis
Authors: Zeng Youjie , Huang Jun , Guo Ren , Cao Si , Yang Heng , Ouyang Wen 
Published: February 2023

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal and irreversible interstitial lung disease. The specific mechanisms involved in the pathogenesis of IPF are not fully understood, while metabolic dysregulation has recently been demonstrated to contribute to IPF. This study aims to identify key metabolism-related genes involved in the progression of IPF, providing new insights into the pathogenesis of IPF.Methods: We downloaded four datasets (GSE32537, GSE110147, GSE150910, and GSE92592) from the Gene Expression Omnibus (GEO) database and identified differentially expressed metabolism-related genes (DEMRGs) in lung tissues of IPF by comprehensive analysis. Then, we performed GO, KEGG, and Reactome enrichment analyses of the DEMRGs. Subsequently, key DEMRGs were identified by machine-learning algorithms. Next, miRNAs regulating these key DEMRGs were predicted by integrating the GSE32538 (IPF miRNA dataset) and the miRWalk database. The Cytoscape software was used to visualize miRNA-mRNA regulatory networks. In addition, the relative levels of immune cells were assessed by the CIBERSORT algorithm, and the correlation of key DEMRGs with immune cells was calculated. Finally, the mRNA expression of the key DEMRGs was validated in two external independent datasets and an in vivo experiment.Results: A total of 101 DEMRGs (51 upregulated and 50 downregulated) were identified. Six key DEMRGs (ENPP3, ENTPD1, GPX3, PDE7B, PNMT, and POLR3H) were further identified using two machine-learning algorithms (LASSO and SVM-RFE). In the lung tissue of IPF patients, the expression levels of ENPP3, ENTPD1, and PDE7B were upregulated, and the expression levels of GPX3, PNMT, and POLR3H were downregulated. In addition, the miRNA-mRNA regulatory network of key DEMRGs was constructed. Then, the expression levels of key DEMRGs were validated in two independent external datasets (GSE53845 and GSE213001). Finally, we verified the key DEMRGs in the lung tissue of bleomycin-induced pulmonary fibrosis mice by qRT-PCR.Conclusion: Our study identified key metabolism-related genes that are differentially expressed in the lung tissue of IPF patients. Our study emphasizes the critical role of metabolic dysregulation in IPF, offers potential therapeutic targets, and provides new insights for future studies.
Molecular dynamics and minigene assay of new splicing variant c.4298-20T>A of COL4A5 gene that cause Alport syndrome
Authors: Liang Lei , Wu Haotian , Cai Zeyu , Zhao Jianrong 
Published: February 2023

Introduction: Alport syndrome (AS; OMIM#308940) is a progressive hereditary kidney disease characterized by hearing loss and ocular abnormalities. According to the mode of inheritance, AS has three subtypes: X-linked (XL; OMIM#301050), autosomal recessive (AR; OMIM#203780), and autosomal dominant (AD; OMIM#104200). XLAS is caused by a pathogenic variant in COL4A5 (OMIM*303630) gene encoding type IV collagen (Col-IV) α5 chain, while ADAS and ARAS are consequences of a variant in COL4A3 (OMIM*120070) and COL4A4 (OMIM*120131) genes that encode Col-IV α3 and α4 chains, respectively. Usually, diagnosis of AS requires hereditary or pathological examinations. Splicing variants are hard to be determined as pathogenic or non-pathogenic based on the results of gene sequencing.Methods: This study focused on a splicing variant in COL4A5 gene, termed NM_000495.5: c.4298–20T&gt;A, and to analyzed its authenticity and damaged α5 chain. In vitro minigene splicing assay was applied to investigate the effect of splicing variant, c.4298–20T&gt;A, on COL4A5 mRNA synthesis. Molecular dynamics method was used to predict the capability of the responsible α5(IV) to form a triple helix.Results: The intron 46 of COL4A5 mRNA retained 18 bp, resulting in insertion of six amino acids behind the amino acid at position 1,433 of α5(IV). The predicted protein effect of this variant: p. (Pro1432_Gly1433insAspTyrPheValGluIle). As a consequence, the stability of α5(IV) secondary structure was impaired, probably leading to the unusual configuration of α345(IV).Discussion: Normally, splicing variant in COL4A5 gene can lead to phenotypes of XLAS, and the effect is associated with the extent of splicing. The patient reported here carried a c.4298–20T&gt;A splicing variant in COL4A5 gene, and AS was highly suspected based on the pathology results. However, the patient did not manifest any ocular or ear abnormalities. We therefore present the c.4298–20T&gt;A splicing variant in COL4A5 gene as likely-pathogenic splicing variant that leads to XLAS with mild phenotypes.
Comparison of the salt resistance of Solanum lycopersicum x Solanum chilense hybrids and their parents
Authors: Bigot Servane , Leclef Claire , Rosales Camila , Martínez Juan-Pablo , Lutts Stanley , Quinet Muriel 
Published: February 2023

IntroductionSoil salinization is a major global problem. Tomato (Solanum lycopersicum) is one of the main crops produced in the world and is cultivated in areas affected by salinity. However, it is considered as a glycophyte species and is sensitive to salt stress. Solanum chilense is a wild tomato native to the Atacama Desert and is therefore adapted to harsh environmental conditions, including salinity. It is considered as a promising source of genes for tomato improvement. However, the physiology of abiotic stress resistance remains largely unknown in S. chilense and no studies have investigated the resistance of S. lycopersicum x S. chilense interspecific hybrids and the potential value of their use in harsh environments.MethodsIn this study, we compared the salt (0 vs. 100 mM NaCl) resistance of S. lycopersicum, S. chilense and their hybrids at vegetative and reproductive stages.ResultsOverall, hybrids showed an intermediate behavior between their parents and a higher salt resistance than S. lycopersicum. Their physiological behavior toward salt stress was sometimes closed to S. lycopersicum and sometimes closed to S. chilense. Their sodium accumulation was intermediate between parents, with a sodium concentration closer to S. lycopersicum than S. chilense in roots, but with an aerial concentration closer to S. chilense than to S. lycopersicum. In inflorescences and fruits, the sodium concentration of hybrids was closer to S. lycopersicum than to S. chilense. Despite a decrease in instantaneous transpiration, the photosynthetic nitrogen use efficiency of hybrids was not decreased by salt stress: our results suggest a greater tolerance to the osmotic phase of salt stress in hybrids compared to the parents. Regarding the reproductive stage, inflorescence production and fruit quality were not affected by salt in hybrids.DiscussionThis study highlights the potential use of hybrids in improving tomato for salt stress resistance.
Allergic adverse events following immunization: Data from post-marketing surveillance in Apulia region (South of Italy)
Authors: Stefanizzi Pasquale , Ferorelli Davide , Scazzi Francesco Livio , Di Lorenzo Antonio , Martinelli Andrea , Trinchera Chiara , Moscara Lorenza , Miniello Enrico , Di Bona Danilo , Tafuri Silvio 
Published: February 2023

IntroductionAmong adverse events following immunization (AEFIs), allergic reactions elicit the most concern, as they are often unpredictable and can be life-threatening. Their estimates range from one in 1,000,000 to one in 50,000 vaccine doses. This report describes allergic events following immunization reported from 2020 to 2021 in Puglia, a region in the South-East of Italy with around 4 million inhabitants. Its main objective is to describe the allergic safety profile of currently employed vaccines.Materials and methodsThis is a retrospective observational study. The study period spanned from January 2020 to December 2021, and the whole Apulian population was included in the study. Information regarding AEFIs reported in Puglia during the study period was gathered from the Italian Drug Authority’s pharmacovigilance database (National Pharmacovigilance Network, RNF). The overall number of vaccine doses administered was extrapolated by the Apulian online immunization database (GIAVA). Reporting rates were calculated as AEFIs reported during a certain time span/number of vaccine doses administered during the same period.Results10,834,913 vaccine doses were administered during the study period and 95 reports of allergic AEFIs were submitted to the RNF (reporting rate 0.88/100,000 doses). 27.4% of the reported events (26/95) were classified as serious (reporting rate 0.24/100,000 doses). 68 out of 95 (71.6%) adverse events were at least partially resolved by the time of reporting and none of them resulted in the subject’s death.ConclusionsAllergic reactions following vaccination were rare events, thus confirming the favourable risks/benefits ratio for currently marketed vaccines.
Resolvin D1 improves allograft osteointegration and directly enhances osteoblasts differentiation
Authors: Pinto Noy , Klein Yehuda , David Eilon , Polak David , Steinberg Daniel , Mizrahi Gilad , Khoury Yasmin , Barenholz Yechezkel , Chaushu Stella 
Published: February 2023

IntroductionAllografts are the most common bone grafts for repairing osseous defects. However, their use is associated with an increased risk for infections, donor disease transmission and osteointegration deficiency. Resolvin D1 (RvD1) is an endogenous lipid with a scientifically proven pivotal role in inflammation resolution and osteoclastogenesis inhibition. Yet, its biological relevance as a potential bone regenerative drug has been scarcely studied. Here, we aim to investigate the RvD1 effect on allograft osteointegration in the alveolar bone regeneration (ABR) murine model.MethodsABR model consisted of osseous defects that were generated by the extraction of the maxillary first molar in C57BL/6 mice. The sockets were filled with allograft and analyzed via RNA sequencing. Then they were locally injected with either RvD1 or saline via single or repeated administrations. The mice were sacrificed 2W after the procedure, and regenerated sites were analyzed using µCT and histology. First, MC3T3-E1 preosteoblasts were plated with IL-17 pro-inflammatory medium, and RANKL/OPG ratio was measured. Secondly, the MC3T3-E1 were cultured w/o RvD1, for 3W. Osteoblasts’ markers were evaluated in different days, using qRT-PCR and Alizarin Red staining for calcified matrix.ResultsIn vivo, neither allograft alone nor single RvD1 administration promote bone regeneration in comparison to the control of spontaneous healing and even triggered an elevation in NR1D1 and IL1RL1 expression, markers associated with inflammation and inhibition of bone cell differentiation. However, repeated RvD1 treatment increased bone content by 135.92% ± 45.98% compared to its specific control, repeated sham, and by 39.12% ± 26.3% when compared to the spontaneous healing control group (n=7/group). Histologically, repeated RvD1 reduced the number of TRAP-positive cells, and enhanced allograft osteointegration with new bone formation. In vitro, RvD1 rescued OPG expression and decreased RANKL/OPG ratio in IL-17 pro-inflammatory conditions. Furthermore, RvD1 increased the expression of RUNX2, OSX, BSP and OC/BGLAP2 and the mineralized extracellular matrix during MC3T3-E1 osteoblasts differentiation.ConclusionsRepeated administrations of RvD1 promote bone regeneration via a dual mechanism: directly, via enhancement of osteoblasts’ differentiation and indirectly, through reduction of osteoclastogenesis and RANKL/OPG ratio. This suggests that RvD1 may be a potential therapeutic bioagent for osseous regeneration following allograft implantation.
CircRNA_0075723 protects against pneumonia-induced sepsis through inhibiting macrophage pyroptosis by sponging miR-155-5p and regulating SHIP1 expression
Authors: Yang Dianyin , Zhao Dongyang , Ji Jinlu , Wang Chunxue , Liu Na , Bao Xiaowei , Liu Xiandong , Jiang Sen , Zhang Qianqian , Tang Lunxian 
Published: February 2023

IntroductionCircular RNAs (circRNAs) have been linked to regulate macrophage polarization and subsequent inflammation in sepsis. However, the underlying mechanism and the function of circRNAs in macrophage pyroptosis in pneumonia-induced sepsis are still unknown.MethodsIn this study, we screened the differentially expressed circRNAs among the healthy individuals, pneumonia patients without sepsis and pneumonia-induced sepsis patients in the plasma by RNA sequencing (RNA-seq). Then we evaluated macrophage pyroptosis in sepsis patients and in vitro LPS/nigericin activated THP-1 cells. The lentiviral recombinant vector for circ_0075723 overexpression (OE-circ_0075723) and circ_0075723 silence (sh-circ_0075723) were constructed and transfected into THP-1 cells to explore the potential mechanism of circ_0075723 involved in LPS/nigericin induced macrophage pyroptosis.ResultsWe found circ_0075723, a novel circRNA that was significantly downregulated in pneumonia-induced sepsis patients compared to pneumonia patients without sepsis and healthy individuals. Meanwhile, pneumonia-induced sepsis patients exhibited activation of NLRP3 inflammasome and production of the pyroptosis-associated pro-inflammatory cytokines IL-1β and IL-18. circ_0075723 inhibited macrophage pyroptosis via sponging miR-155-5p which promoted SHIP1 expression directly. Besides, we found that circ_0075723 in macrophages promoted VE-cadherin expression in endothelial cells through inhibiting the release of NLRP3 inflammasome-related cytokines, IL-1β and IL-18, and protects endothelial cell integrity.DiscussionOur findings propose a unique approach wherein circ_0075723 suppresses macrophage pyroptosis and inflammation in pneumonia-induced sepsis via sponging with miR-155-5p and promoting SHIP1 expression. These findings indicate that circRNAs could be used as possible potential diagnostic and therapeutic targets for pneumonia-induced sepsis.
Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells
Authors: Barbieri Laura , Veliça Pedro , Gameiro Paulo A. , Cunha Pedro P. , Foskolou Iosifina P. , Rullman Eric , Bargiela David , Johnson Randall S. , Rundqvist Helene 
Published: February 2023

IntroductionCD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in local tissues can result in significant exposure of cytotoxic T cells to the lactate metabolite. Lactate has been known to act as an immunosuppressor, at least in part due to its association with tissue acidosis.MethodsTo dissect the role of the lactate anion, independently of pH, we performed phenotypical and metabolic assays, high-throughput RNA sequencing, and mass spectrometry, on primary cultures of murine or human CD8+ T cells exposed to high doses of pH-neutral sodium lactate.ResultsThe lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and can displace glucose as a carbon source. Activation in the presence of sodium lactate significantly alters the CD8+ T cell transcriptome, including the expression key effector differentiation markers such as granzyme B and interferon-gamma.DiscussionOur studies reveal novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.
Unisexual infection with Schistosoma mansoni in mice has the potential to boost the immune response against eggs after challenge infection
Authors: Reinholdt Cindy , Winkelmann Franziska , Koslowski Nicole , Reisinger Emil C. , Sombetzki Martina 
Published: February 2023

IntroductionThe complexity of the Schistosoma spp. life cycle and their effective immune evasion strategies, makes vaccine development challenging. Unisexual infection models, that excludes any immunomodulatory effects of the parasite eggs, may contribute to a better understanding of complex immunological processes and identification of new targets for vaccine research. We have recently shown that long-term unisexual infection with schistosomes in mice results in an unpolarized Th1/Th2 response associated with an abnormally enlarged spleen and diffuse liver inflammation. Herein, we investigated whether (i) unisexual worms can mate after three months of single sex infection and (ii) thus the Th2 response induced by oviposition can reverse or heal the described systemic inflammation.MethodsTherefore, we infected 6–8 weeks old female C57BL/6j mice with 100 male or female cercariae and reinfected with the opposite sex for the same period after 12 weeks. At 24 weeks after initial infection, we histologically examined worm mating, as evidenced by the presence of parasite eggs, infection-related pathology associated with eggs, and characterization of fibrosis in the livers.ResultsSingle worms are able to mate months after unisexual infection and start oviposition. Egg deposition has been associated with a typical Th2 immune response in the liver after unisexual reinfection, accompanied by increased recruitment of CD4+ T cells. Hepatic collagen levels were significantly increased in the reinfected groups compared to the naive and unisexually infected group.DiscussionOur results indicate that the eggs are able to restore the Th1/Th2 immune balance of a previous unisexual infection. However, the organ damage caused by the unisexual worms does not subside, but rather provides the baseline for the emerging egg-triggered inflammation and fibrosis. Since single schistosomes can mate even several weeks after unisexual infection and then accumulate worm- and egg-related organ damage, infection status without positive egg detection is very important, especially in areas with low prevalence.
Comparison of the efficacy of the Epley maneuver and repeated Dix–Hallpike tests for eliminating positional nystagmus: A multicenter randomized study
Authors: Imai Takao , Uno Atsuhiko , Yamato Akiyuki , Takimoto Yasumitsu , Sato Go , Matsuda Kazunori , Takeda Noriaki , Nishiike Suetaka , Kawashima Kayoko , Iga Tomoko , Ueno Yuya , Ohta Yumi , Sato Takashi , Kamakura Takefumi , Shingai-Higashi Kayoko , Mikami Shinji , Kimura Naomiki , Nakajima Takashi , Tanaka Akihisa , Inohara Hidenori 
Published: February 2023

Background and objectivesPatients with benign paroxysmal positional vertigo of the posterior canal (pc-BPPV) exhibit BPPV fatigue, where the positional nystagmus diminishes with the repeated performance of the Dix–Hallpike test (DHt). BPPV fatigue is thought to be caused by the disintegration of lumps of otoconial debris into smaller parts and can eliminate positional nystagmus within a few minutes [similar to the immediate effect of the Epley maneuver (EM)]. In this study, we aimed to show the non-inferiority of the repeated DHt to the EM for eliminating positional nystagmus after 1 week.MethodsThis multicenter, randomized controlled clinical trial was designed based on the CONSORT 2010 guidelines. Patients who had pc-BPPV were recruited and randomly allocated to Group A or Group B. Patients in Group A were treated using the EM, and patients in Group B were treated using repeated DHt. For both groups, head movements were repeated until the positional nystagmus had been eliminated (a maximum of three repetitions). After 1 week, the patients were examined to determine whether the positional nystagmus was still present. The groups were compared in terms of the percentage of patients whose positional nystagmus had been eliminated, with the non-inferiority margin set at 15%.ResultsData for a total of 180 patients were analyzed (90 patients per group). Positional nystagmus had been eliminated in 50.0% of the patients in Group A compared with 47.8% in Group B. The upper limit of the 95% confidence interval for the difference was 14.5%, which was lower than the non-inferiority margin.DiscussionThis study showed the non-inferiority of repeated DHt to the EM for eliminating positional nystagmus after 1 week in patients with pc-BPPV and that even the disintegration of otoconial debris alone has a therapeutic effect for pc-BPPV. Disintegrated otoconial debris disappears from the posterior canal because it can be dissolved in the endolymph or returned to the vestibule via activities of daily living.Classification of evidenceThis study provides Class II evidence of the non-inferiority of repeated DHt to the EM for eliminating positional nystagmus after 1 week.Registration numberUMIN000016421.
FMRI study of implicit emotional face processing in patients with MDD with melancholic subtype
Authors: Kustubayeva Almira , Eliassen James , Matthews Gerald , Nelson Erik 
Published: February 2023

IntroductionThe accurate perception of facial expressions plays a vital role in daily life, allowing us to select appropriate responses in social situations. Understanding the neuronal basis of altered emotional face processing in patients with major depressive disorder (MDD) may lead to the appropriate choice of individual interventions to help patients maintain social functioning during depressive episodes. Inconsistencies in neuroimaging studies of emotional face processing are caused by heterogeneity in neurovegetative symptoms of depressive subtypes. The aim of this study was to investigate brain activation differences during implicit perception of faces with negative and positive emotions between healthy participants and patients with melancholic subtype of MDD. The neurobiological correlates of sex differences of MDD patients were also examined.MethodsThirty patients diagnosed with MDD and 21 healthy volunteers were studied using fMRI while performing an emotional face perception task.ResultsComparing general face activation irrespective of emotional content, the intensity of BOLD signal was significantly decreased in the left thalamus, right supramarginal gyrus, right and left superior frontal gyrus, right middle frontal gyrus, and left fusiform gyrus in patients with melancholic depression compared to healthy participants. We observed only limited mood-congruence in response to faces of differing emotional valence. Brain activation in the middle temporal gyrus was significantly increased in response to fearful faces in comparison to happy faces in MDD patients. Elevated activation was observed in the right cingulate for happy and fearful faces, in precuneus for happy faces, and left posterior cingulate cortex for all faces in depressed women compared to men. The Inventory for Depressive Symptomatology (IDS) score was inversely correlated with activation in the left subgenual gyrus/left rectal gyrus for sad, neutral, and fearful faces in women in the MDD group. Patients with melancholic features performed similarly to controls during implicit emotional processing but showed reduced activation.Discussion and conclusionThis finding suggests that melancholic patients compensate for reduced brain activation when interpreting emotional content in order to perform similarly to controls. Overall, frontal hypoactivation in response to implicit emotional stimuli appeared to be the most robust feature of melancholic depression.