bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering a 500 million year old history and evidence of pseudogenization for TLR15
Authors: Neves Fabiana , Muñoz-Mérida Antonio , Machado André M. , Almeida Tereza , Gaigher Arnaud , Esteves Pedro J. , Castro L. Filipe C. , Veríssimo Ana 
Published: December 2022

IntroductionToll like receptors (TLRs) are at the front line of pathogen recognition and host immune response. Many TLR genes have been described to date with some being found across metazoans while others are restricted to specific lineages. A cryptic member of the TLR gene family, TLR15, has a unique phylogenetic distribution. Initially described in extant species of birds and reptiles, an ortholog has been reported for cartilaginous fish.MethodsHere, we significantly expanded the evolutionary analysis of TLR15 gene evolution, taking advantage of large genomic and transcriptomic resources available from different lineages of vertebrates. Additionally, we objectively search for TLR15 in lobe-finned and ray-finned fish, as well as in cartilaginous fish and jawless vertebrates.Results and discussionWe confirm the presence of TLR15 in early branching jawed vertebrates – the cartilaginous fish, as well as in basal Sarcopterygii – in lungfish. However, within cartilaginous fish, the gene is present in Holocephalans (all three families) but not in Elasmobranchs (its sister-lineage). Holocephalans have long TLR15 protein sequences that disrupt the typical TLR structure, and some species display a pseudogene sequence due to the presence of frameshift mutations and early stop codons. Additionally, TLR15 has low expression levels in holocephalans when compared with other TLR genes. In turn, lungfish also have long TLR15 protein sequences but the protein structure is not compromised. Finally, TLR15 presents several sites under negative selection. Overall, these results suggest that TLR15 is an ancient TLR gene and is experiencing ongoing pseudogenization in early-branching vertebrates.
Low vitamin D concentrations and BMI are causal factors for primary biliary cholangitis: A mendelian randomization study
Authors: Xu Honglin , Wu Ziyan , Feng Futai , Li Yongzhe , Zhang Shulan 
Published: December 2022

BackgroundsObservational studies have identified associations between smoking, alcohol use, body mass index (BMI), and the levels of vitamin D with primary biliary cholangitis (PBC). However, there was a lack of randomization control studies to estimate the causal relationship. This study was to investigate the causal estimates for the effects of those risk factors on PBC.MethodsThe genetic instrument variants were extracted from genome-wide association studies in European ancestry. Two-sample mendelian randomization (MR) and multivariable mendelian randomization were used to determine genetically causal estimates. Primary analyses consisted of random-effects and fix-mode inverse-variance-weighted methods, followed by secondary sensitivity analyses to verify the results.ResultsOur study showed that BMI was a causal factor for PBC (OR 1.35; 95% CI=1.03-1.77; p=0.029). In addition, we found that serum vitamin D levels had a protective effect on PBC after adjusting for BMI (OR 0.51; 95% CI=0.32-0.84; p=0.007). However, we failed to identify evidence supporting that genetic causal effect of smoking and alcohol intake were associated with PBC in European countries.ConclusionOur results enriched findings from previous epidemiology studies and provided evidence from MR that serum vitamin D concentrations and BMI were independent causal factors for PBC, suggesting that ensuing vitamin D sufficiency and healthy lifestyles might be a cost-effective measure for early intervention for PBC.
Study of epirubicin sustained–release chemoablation in tumor suppression and tumor microenvironment remodeling
Authors: Meng Liangliang , Wang Zhenjun , Hou Zhonghui , Wang Hufei , Zhang Xiao , Zhang Xiaobo , He Xiaofeng , Zhang Xin , Qin Boyu , Li Jing , Zhang Zhongliang , Xue Xiaodong , Wei Yingtian 
Published: December 2022

IntroductionAlthough intratumoral chemoablation can obtain an impressive therapeutic effect, there is still incomplete ablation and tumor recurrence in some patients. This could be due to the short retention time of the drug in the tumor, the limited distribution of intratumoral drugs, and, beyond that, the immunotolerance caused by the tumor microenvironment (TME). There is still an urgent need to find an optimal drug sustained-release carrier and figure out the impact of regional injection to TME.MethodsIn this study, we supposed to use polyethylene glycol (PEG) hydrogel as a drug carrier to improve the retention time of the drug to extend the exposure of tumor cells and investigate the feasibility of combination local Epirubicin injection with anti-PD-L1. ResultsThe results revealed obvious tumor suppression based on the tumor volume and the inhibition time of tumor growth in the A549 lung cancer mouse model after local injection. Furthermore, the enhanced antitumor effects of the combination of systematic anti- programmed death ligand 1 (PD-L1) therapy with local chemoablation (EPI-GEL/PD-L1) for abscopal tumor reduction in the 4T1 breast model were also observed. Flow cytometry analysis of the tumor and blood samples showed significant variations in the proportions of PD-L1+ and CD3+CD8+PD-1+ cells before and after anti-PD-L1 therapy. On day 4 after local injection of the EPI gel, the expression of PD-L1 in abscopal tumors was upregulated, while the expression of PD-L1 in bilateral tumors in mice was significantly reduced after anti-PD-L1 treatment. The proportion of CD3+CD8+PD-1+ cells in the tumor and circulating blood in the EPI-GEL/PD-L1 group was decreased compared with that in the EPI-GEL (single injection of epirubicin) group.DiscussionThe combination of local injection of the chemoablation agent with anti-PD-L1 monoclonal antibody (mAb) therapy may strengthen the antitumor activity, and the use of PEG hydrogel as the drug carrier can extend the retention time of the chemoablation agent around the tumor, maintaining a long-term tumor-killing activity.
Immune dysfunctions affecting bone marrow Vγ9Vδ2 T cells in multiple myeloma: Role of immune checkpoints and disease status
Authors: Giannotta Claudia , Castella Barbara , Tripoli Ezio , Grimaldi Daniele , Avonto Ilaria , D’Agostino Mattia , Larocca Alessandra , Kopecka Joanna , Grasso Mariella , Riganti Chiara , Massaia Massimo 
Published: December 2022

IntroductionBone marrow (BM) Vγ9Vδ2 T cells are intrinsically predisposed to sense the immune fitness of the tumor microenvironment (TME) in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).MethodsIn this work, we have used BM Vγ9Vδ2 T cells to interrogate the role of the immune checkpoint/immune checkpoint-ligand (ICP/ICP-L) network in the immune suppressive TME of MM patients.ResultsPD-1+ BM MM Vγ9Vδ2 T cells combine phenotypic, functional, and TCR-associated alterations consistent with chronic exhaustion and immune senescence. When challenged by zoledronic acid (ZA) as a surrogate assay to interrogate the reactivity to their natural ligands, BM MM Vγ9Vδ2 T cells further up-regulate PD-1 and TIM-3 and worsen TCR-associated alterations. BM MM Vγ9Vδ2 T cells up-regulate TIM-3 after stimulation with ZA in combination with αPD-1, whereas PD-1 is not up-regulated after ZA stimulation with αTIM-3, indicating a hierarchical regulation of inducible ICP expression. Dual αPD-1/αTIM-3 blockade improves the immune functions of BM Vγ9Vδ2 T cells in MM at diagnosis (MM-dia), whereas single PD-1 blockade is sufficient to rescue BM Vγ9Vδ2 T cells in MM in remission (MM-rem). By contrast, ZA stimulation induces LAG-3 up-regulation in BM Vγ9Vδ2 T cells from MM in relapse (MM-rel) and dual PD-1/LAG-3 blockade is the most effective combination in this setting.DiscussionThese data indicate that: 1) inappropriate immune interventions can exacerbate Vγ9Vδ2 T-cell dysfunction 2) ICP blockade should be tailored to the disease status to get the most of its beneficial effect.
Systematic analysis of brain and skull ischemic injury expression profiles reveals associations of the tumor immune microenvironment and cell death with ischemic stroke
Authors: Zhang Chao , Wang Lisi , Guo Yunmiao , Feng Wei 
Published: December 2022

BackgroundPrevious studies have shown that stroke is a potential first sign of neoplasia, but the relationship between stroke and cancer remains unclear. As a complex brain disease, ischemic stroke involves cell death and immunity. Thus, it is necessary to investigate the association of the tumor immune microenvironment and cell death with ischemic stroke.MethodsWe established a photothrombosis-induced ischemic injury model in mouse brain and skull. Subsequently, we sequenced the whole transcriptome of the injured mouse brain and skull and analyzed the expression profiles. To investigate the association of stroke with cell death and cancer, we systematically performed gene set enrichment analysis in pan-cell death (i.e., apoptosis, cuproptosis, ferroptosis, necroptosis, and pyroptosis) and the cancer hallmark pathways. The time-dependent immune cell abundance variations after ischemic injury were estimated. Furthermore, pan-cancer genomic and prognostic analyses of the ischemic injury-related gene sets were also performed.ResultsIn this study, we found that there exist temporal and spatial differences in the gene expression patterns of both the brain and skull with ischemic injury. The skull ischemic injury-induced changes in the brain transcriptome were particularly great, but could recover in a short period, while the skull transcriptome variation resulting from brain ischemic injury was long-lasting. In addition, the expression of the genes related to ischemic injury was also associated with pan-cell death and the cancer hallmark pathways. The changes in the abundance of immune cells indicate that brain ischemic injury may disrupt the immune microenvironment for a longer time, while the skull can balance the stability of the immune microenvironment better. Moreover, the brain ischemic injury-related gene sets were highly correlated with a variety of tumors, particularly glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM), which carry a greater mortality risk after stroke.ConclusionThis systematic analysis not only helps in the understanding of the changes in the gene expression profiles of both the brain and skull with ischemic injury but also reveals the association of the tumor immune microenvironment and cell death with ischemic stroke.
Precision-cut rat placental slices as a model to study sex-dependent inflammatory response to LPS and Poly I:C
Authors: Anandam Kasin Yadunandam , Abad Cilia , Synova Tetiana , Vinas-Noguera Mireia , Bolboli Bahareh , Vokral Ivan , Karahoda Rona , Staud Frantisek 
Published: December 2022

IntroductionMaternal inflammation in pregnancy represents a major hallmark of several pregnancy complications and a significant risk factor for neurodevelopmental and neuropsychiatric disorders in the offspring. As the interface between the mother and the fetus, the placenta plays a crucial role in fetal development and programming. Moreover, studies have suggested that the placenta responds to an inflammatory environment in a sex-biased fashion. However, placenta-mediated immunoregulatory mechanisms are still poorly understood.MethodsTherefore, we have developed a model of ex vivo precision-cut placental slices from the rat term placenta to study acute inflammatory response. Rat placental slices with a precise thickness of 200 µm were generated separately from male and female placentas. Inflammation was stimulated by exposing the slices to various concentrations of LPS or Poly I:C for 4 and 18 hours.ResultsTreatment of placental slices with LPS significantly induced the expression and release of proinflammatory cytokines TNF-α, IL-6, and IL-1β. In contrast, Poly I:C treatment resulted in a less-pronounced inflammatory response. Interestingly, the female placenta showed higher sensitivity to LPS than male placenta. Anti-inflammatory agents, curcumin, 1α,25- dihydroxyvitamin D3, and progesterone attenuated the LPS-induced proinflammatory cytokine response at both mRNA and protein levels.DiscussionWe conclude that rat placental slices represent a novel alternative model to study the role of sexual dimorphism in the acute inflammatory response and immune activation in pregnancy.
Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma
Authors: Xu Jiahao , Hu Zhengang , Cao Hui , Zhang Hao , Luo Peng , Zhang Jian , Wang Xiaoyan , Cheng Quan , Li Jingbo 
Published: December 2022

BackgroundThe mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (FDX1), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of FDX1 in tumor biology remains obscure. A comprehensive pan-cancer analysis of FDX1 is needed.MethodsThirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell FDX1 expression, FDX1-related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed. FDX1 protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of FDX1 in KIRC was further explored by experiments in 786-O cell lines in vitro.ResultsFDX1 is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of FDX1 have been described in several tumors. Survival analysis showed that FDX1 was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of FDX1 expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that FDX1 may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased FDX1 expression in KIRC patients’ tumor tissues. Knockdown of FDX1 resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the FDX1-associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low-FDX1 groups in KIRC.ConclusionOur analysis showed that the central regulatory gene of cuproptosis, FDX1, has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.
“Nothing works without the doctor:” Physicians’ perception of clinical decision-making and artificial intelligence
Authors: Samhammer David , Roller Roland , Hummel Patrik , Osmanodja Bilgin , Burchardt Aljoscha , Mayrdorfer Manuel , Duettmann Wiebke , Dabrock Peter 
Published: December 2022

IntroductionArtificial intelligence–driven decision support systems (AI–DSS) have the potential to help physicians analyze data and facilitate the search for a correct diagnosis or suitable intervention. The potential of such systems is often emphasized. However, implementation in clinical practice deserves continuous attention. This article aims to shed light on the needs and challenges arising from the use of AI-DSS from physicians’ perspectives.MethodsThe basis for this study is a qualitative content analysis of expert interviews with experienced nephrologists after testing an AI-DSS in a straightforward usage scenario.ResultsThe results provide insights on the basics of clinical decision-making, expected challenges when using AI-DSS as well as a reflection on the test run.DiscussionWhile we can confirm the somewhat expectable demand for better explainability and control, other insights highlight the need to uphold classical strengths of the medical profession when using AI-DSS as well as the importance of broadening the view of AI-related challenges to the clinical environment, especially during treatment. Our results stress the necessity for adjusting AI-DSS to shared decision-making. We conclude that explainability must be context-specific while fostering meaningful interaction with the systems available.
A cautionary tale for health education initiatives in vulnerable populations: Improving nutrition in Haiti prisons
Authors: Mainous Arch G. , Bernard Jean , Auguste Stephanie , Louis Jacques R. , Dieufort Danove J. , Duverger Karine , Beau de Rochars Madsen , May John 
Published: December 2022

IntroductionPrisons in low-income countries have barriers to providing adequate nutrition to the incarcerated. This perspective discusses a quality improvement program with health education to improve nutrition provided to men in two prisons in Haiti.MethodsIncarcerated men in the National Penitentiary in Port Au Prince and the prison in Mirebalais were the focus of the program. A culturally competent educational intervention was delivered to the prison cooks. Program evaluation included a baseline and a follow-up assessment in 2021 and 2022 in both prisons. Calories, body composition, and nutrition were assessed at both time points.ResultsAmong 1,060 men assessed in the baseline time period, the mean number of calories per day was 571. Further, 62.5% had a vitamin C intake insufficient to prevent scurvy and 91.6% had vitamin B1 insufficient to prevent beriberi. In the follow-up period, caloric intake decreased to a mean of 454 per day (p &lt; 0.001). The proportion of incarcerated men who had insufficient vitamin C and vitamin B1 to prevent disease increased in the follow-up period.DiscussionThe caloric and nutritional intake of incarcerated men in Haitian prisons is poor and is getting worse. The educational intervention with the cooks was not successful due to civil and political strife in the low-income country of Haiti. Standard interventions to improve nutrition need to consider the social context for accessing food.
Comprehensive molecular analyses of an autoimmune-related gene predictive model and immune infiltrations using machine learning methods in moyamoya disease
Authors: Li Shifu , Han Ying , Zhang Qian , Tang Dong , Li Jian , Weng Ling 
Published: December 2022

Background: Growing evidence suggests the links between moyamoya disease (MMD) and autoimmune diseases. However, the molecular mechanism from genetic perspective remains unclear. This study aims to clarify the potential roles of autoimmune-related genes (ARGs) in the pathogenesis of MMD.Methods: Two transcription profiles (GSE157628 and GSE141025) of MMD were downloaded from GEO databases. ARGs were obtained from the Gene and Autoimmune Disease Association Database (GAAD) and DisGeNET databases. Differentially expressed ARGs (DEARGs) were identified using “limma” R packages. GO, KEGG, GSVA, and GSEA analyses were conducted to elucidate the underlying molecular function. There machine learning methods (LASSO logistic regression, random forest (RF), support vector machine-recursive feature elimination (SVM-RFE)) were used to screen out important genes. An artificial neural network was applied to construct an autoimmune-related signature predictive model of MMD. The immune characteristics, including immune cell infiltration, immune responses, and HLA gene expression in MMD, were explored using ssGSEA. The miRNA-gene regulatory network and the potential therapeutic drugs for hub genes were predicted.Results: A total of 260 DEARGs were identified in GSE157628 dataset. These genes were involved in immune-related pathways, infectious diseases, and autoimmune diseases. We identified six diagnostic genes by overlapping the three machine learning algorithms: CD38, PTPN11, NOTCH1, TLR7, KAT2B, and ISG15. A predictive neural network model was constructed based on the six genes and presented with great diagnostic ability with area under the curve (AUC) = 1 in the GSE157628 dataset and further validated by GSE141025 dataset. Immune infiltration analysis showed that the abundance of eosinophils, natural killer T (NKT) cells, Th2 cells were significant different between MMD and controls. The expression levels of HLA-A, HLA-B, HLA-C, HLA-DMA, HLA-DRB6, HLA-F, and HLA-G were significantly upregulated in MMD. Four miRNAs (mir-26a-5p, mir-1343-3p, mir-129-2-3p, and mir-124-3p) were identified because of their interaction at least with four hub DEARGs.Conclusion: Machine learning was used to develop a reliable predictive model for the diagnosis of MMD based on ARGs. The uncovered immune infiltration and gene-miRNA and gene-drugs regulatory network may provide new insight into the pathogenesis and treatment of MMD.
Different subtypes of motor cortex pyramidal tract neurons projects to red and pontine nuclei
Authors: Lopez-Virgen Veronica , Olivares-Moreno Rafael , de Lafuente Victor , Concha Luis , Rojas-Piloni Gerardo 
Published: December 2022

IntroductionPyramidal tract neurons (PTNs) are fundamental elements for motor control. However, it is largely unknown if PTNs are segregated into different subtypes with distinct characteristics.MethodsUsing anatomical and electrophysiological tools, we analyzed in mice motor cortex PTNs projecting to red and pontine midbrain nuclei, which are important hubs connecting cerebral cortex and cerebellum playing a critical role in the regulation of movement.ResultsWe reveal that the vast majority of M1 neurons projecting to the red and pontine nuclei constitutes different populations. Corticopontine neurons have higher conduction velocities and morphologically, a most homogeneous dendritic and spine distributions along cortical layers.DiscussionThe results indicate that cortical neurons projecting to the red and pontine nuclei constitute distinct anatomical and functional pathways which may contribute differently to sensorimotor integration.