bluuebunny/crossref_metadata_2025_split huggingface dataset:
Family-based GWAS for dental class I malocclusion and clefts
Authors: Bezamat Mariana , Carver Chelsea E. , Vieira Alexandre R. 
Published: June 2024

Abstract
Background
Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts.

Methods
Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion.

Results
In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate.

Conclusions
These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.
Improved liver disease prediction from clinical data through an evaluation of ensemble learning approaches
Authors: Ganie Shahid Mohammad , Dutta Pramanik Pijush Kanti , Zhao Zhongming 
Published: June 2024

Abstract
Purpose
Liver disease causes two million deaths annually, accounting for 4% of all deaths globally. Prediction or early detection of the disease via machine learning algorithms on large clinical data have become promising and potentially powerful, but such methods often have some limitations due to the complexity of the data. In this regard, ensemble learning has shown promising results. There is an urgent need to evaluate different algorithms and then suggest a robust ensemble algorithm in liver disease prediction.

Method
Three ensemble approaches with nine algorithms are evaluated on a large dataset of liver patients comprising 30,691 samples with 11 features. Various preprocessing procedures are utilized to feed the proposed model with better quality data, in addition to the appropriate tuning of hyperparameters and selection of features.

Results
The models’ performances with each algorithm are extensively evaluated with several positive and negative performance metrics along with runtime. Gradient boosting is found to have the overall best performance with 98.80% accuracy and 98.50% precision, recall and F1-score for each.

Conclusions
The proposed model with gradient boosting bettered in most metrics compared with several recent similar works, suggesting its efficacy in predicting liver disease. It can be further applied to predict other diseases with the commonality of predicate indicators.
The effect of the preceptorship training program on the participation of clinical nurses in training nursing internship students: a quasi-experimental study
Authors: Mashayekh Razieh , Ebadi Abbas , Nehrir Batool , Moayed Malihe Sadat 
Published: June 2024

Abstract
Introduction
Clinical education is a fundamental part of nursing professional education. One method of education is the implementation of the preceptorship program, in which clinical nurses are responsible for educating nursing students. The present study aimed to determine the effectiveness of the preceptorship training program for the participation of clinical nurses in the education of nursing students.

Methods
This quasi-experimental study was conducted in 2023 at the teaching hospital in Tehran, Iran. The sample consisted of 66 nurses from a teaching hospital selected using the accessible method and randomly were put into two groups. The workshop addressed the educational needs of preceptors and students, their readiness for their role, and strategies to effectively support students. Prior to the study, the nurses’ level of participation was assessed utilizing a valid IMSOC questionnaire that gauged their involvement in guiding nursing students. The participation rate was reassessed after one month using the same questionnaire. The data were analyzed using SPSS version 19.

Findings
The two groups were homogeneous in terms of demographic characteristics. The average score for nurses’ participation in the education of students before the intervention was 101.84 ± 15.42 in the test group and 107.24 ± 10.53 in the control group; these two groups were not significantly different (P = 0.10). After the intervention, the scores reached 118.90 ± 15.11 in the test group and 106.21 ± 11.96 in the control group, indicating a significant difference (P < 0.001). A comparison of the nurses’ participation scores in the test group indicated a significant difference from the pretest to the posttest, with the improvement in all nurses’s participation scores (P < 0.001). However, in the control group, this difference was not significant (P = 0.41).

Conclusion
The preceptorship training program is effective in light of increasing the participation of clinical nurses in the education of nursing students. This program can improve various aspects, such as motivation, satisfaction, commitment, implementation, and obstacle removal. Considering the importance of clinical training for nursing students and the essential role of preceptors, it is recommended that managers and health trustees in all university hospitals implement a preceptorship training program to increase the participation of clinical nurses in the education of nursing students.
The glycosylation deficiency of flavivirus NS1 attenuates virus replication through interfering with the formation of viral replication compartments
Authors: Huang Shuhan , Shi Pan-Deng , Fan Xiao-Xuan , Yang Yang , Qin Cheng-Feng , Zhao Hui , Shi Lei , Ci Yali 
Published: June 2024

Abstract
Background
Flavivirus is a challenge all over the world. The replication of flavivirus takes place within membranous replication compartments (RCs) derived from endoplasmic reticulum (ER). Flavivirus NS1 proteins have been proven essential for the formation of viral RCs by remodeling the ER. The glycosylation of flavivirus NS1 proteins is important for viral replication, yet the underlying mechanism remains unclear.

Methods
HeLa cells were used to visualize the ER remodeling effects induced by NS1 expression. ZIKV replicon luciferase assay was performed with BHK-21 cells. rZIKV was generated from BHK-21 cells and the plaque assay was done with Vero Cells. Liposome co-floating assay was performed with purified NS1 proteins from 293T cells.

Results
We found that the glycosylation of flavivirus NS1 contributes to its ER remodeling activity. Glycosylation deficiency of NS1, either through N-glycosylation sites mutations or tunicamycin treatment, compromises its ER remodeling activity and interferes with viral RCs formation. Disruption of NS1 glycosylation results in abnormal aggregation of NS1, rather than reducing its membrane-binding activity. Consequently, deficiency in NS1 glycosylation impairs virus replication.

Conclusions
In summary, our results highlight the significance of NS1 glycosylation in flavivirus replication and elucidate the underlying mechanism. This provides a new strategy for combating flavivirus infections.
Development and validation of a nomogram for predicting cancer-specific survival in small-bowel adenocarcinoma patients using the SEER database
Authors: Xu Duogang , He Yulei , Liao Changkang , Tan Jing 
Published: June 2024

Abstract
Background
Small bowel adenocarcinoma (SBA) is a rare gastrointestinal malignancy forwhich survival is hampered by late diagnosis, complex responses to treatment, and poor prognosis. Accurate prognostic tools are crucial for optimizing treatment strategies and improving patient outcomes. This study aimed to develop and validate a nomogram based on the Surveillance, Epidemiology, and End Results (SEER) database to predict cancer-specific survival (CSS) in patients with SBA and compare it to traditional American Joint Committee on Cancer (AJCC) staging.

Methods
We analyzed data from 2,064 patients diagnosed with SBA between 2010 and 2020 from the SEER database. Patients were randomly assigned to training and validation cohorts (7:3 ratio). Kaplan‒Meier survival analysis, Cox multivariate regression, and nomograms were constructed for analysis of 3-year and 5-year CSS. The performance of the nomograms was evaluated using Harrell’s concordance index (C-index), the area under the receiver operating characteristic (ROC) curve, calibration curves, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).

Results
Multivariate Cox regression identified sex, age at diagnosis, marital status, tumor site, pathological grade, T stage, N stage, M stage, surgery, retrieval of regional lymph nodes (RORLN), and chemotherapy as independent covariates associated with CSS. In both the training and validation cohorts, the developed nomograms demonstrated superior performance to that of the AJCC staging system, with C-indices of 0.764 and 0.759, respectively. The area under the curve (AUC) values obtained by ROC analysis for 3-year and 5-year CSS prediction significantly surpassed those of the AJCC model. The nomograms were validated using calibration and decision curves, confirming their clinical utility and superior predictive accuracy. The NRI and IDI indicated the enhanced predictive capability of the nomogram model.

Conclusion
The SEER-based nomogram offers a significantly superior ability to predict CSS in SBA patients, supporting its potential application in clinical decision-making and personalized approaches to managing SBA to improve survival outcomes.
Altered glia-neuron communication in Alzheimer’s Disease affects WNT, p53, and NFkB Signaling determined by snRNA-seq
Authors: Soelter Tabea M. , Howton Timothy C. , Clark Amanda D. , Oza Vishal H. , Lasseigne Brittany N. 
Published: June 2024

Abstract
Background
Alzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.

Methods
Using public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.

Results
Cell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer’s disease risk genes APP and APOE across datasets. Most of the signaling mediators of these interactions were not significantly differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer’s disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity of NFIL3, an NFkB signaling-associated transcription factor.

Conclusions
Cell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.
Homotherapy for heteropathy: therapeutic effect of Butein in NLRP3-driven diseases
Authors: Liao Wenhao , Li Yuchen , Liu Jingwen , Mou Yu , Zhao Mei , Liu Juan , Zhang Tianxin , Sun Qin , Tang Jianyuan , Wang Zhilei 
Published: June 2024

Abstract
Background
Aberrant inflammatory responses drive the initiation and progression of various diseases, and hyperactivation of NLRP3 inflammasome is a key pathogenetic mechanism. Pharmacological inhibitors of NLRP3 represent a potential therapy for treating these diseases but are not yet clinically available. The natural product butein has excellent anti-inflammatory activity, but its potential mechanisms remain to be investigated. In this study, we aimed to evaluate the ability of butein to block NLRP3 inflammasome activation and the ameliorative effects of butein on NLRP3-driven diseases.

Methods
Lipopolysaccharide (LPS)-primed bone-marrow-derived macrophages were pretreated with butein and various inflammasome stimuli. Intracellular potassium levels, ASC oligomerization and reactive oxygen species production were also detected to evaluate the regulatory mechanisms of butein. Moreover, mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis were used to test whether butein has protective effects on these NLRP3-driven diseases.

Results
Butein blocks NLRP3 inflammasome activation in mouse macrophages by inhibiting ASC oligomerization, suppressing reactive oxygen species production, and upregulating the expression of the antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2). Importantly, in vivo experiments demonstrated that butein administration has a significant protective effect on the mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis.

Conclusion
Our study illustrates the connotation of homotherapy for heteropathy, i.e., the application of butein to broaden therapeutic approaches and treat multiple inflammatory diseases driven by NLRP3.
Progression of monoclonal gammopathy of undetermined significance to multiple myeloma is associated with enhanced translational quality control and overall loss of surface antigens
Authors: Ravn Berg Sigrid , Dikic Aida , Sharma Animesh , Hagen Lars , Vågbø Cathrine Broberg , Zatula Alexey , Misund Kristine , Waage Anders , Slupphaug Geir 
Published: June 2024

Abstract
Background
Despite significant advancements in treatment strategies, multiple myeloma remains incurable. Additionally, there is a distinct lack of reliable biomarkers that can guide initial treatment decisions and help determine suitable replacement or adjuvant therapies when relapse ensues due to acquired drug resistance.

Methods
To define specific proteins and pathways involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM), we have applied super-SILAC quantitative proteomic analysis to CD138 + plasma cells from 9 individuals with MGUS and 37 with MM.

Results
Unsupervised hierarchical clustering defined three groups: MGUS, MM, and MM with an MGUS-like proteome profile (ML) that may represent a group that has recently transformed to MM. Statistical analysis identified 866 differentially expressed proteins between MM and MGUS, and 189 between MM and ML, 177 of which were common between MGUS and ML. Progression from MGUS to MM is accompanied by upregulated EIF2 signaling, DNA repair, and proteins involved in translational quality control, whereas integrin- and actin cytoskeletal signaling and cell surface markers are downregulated.

Conclusion
Compared to the premalignant plasma cells in MGUS, malignant MM cells apparently have mobilized several pathways that collectively contribute to ensure translational fidelity and to avoid proteotoxic stress, especially in the ER. The overall reduced expression of immunoglobulins and surface antigens contribute to this and may additionally mediate evasion from recognition by the immune apparatus. Our analyses identified a range of novel biomarkers with potential prognostic and therapeutic value, which will undergo further evaluation to determine their clinical significance.
Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer
Authors: Li Jie-pin , Liu Yuan-jie , Li Yang , Yin Yi , Ye Qian-wen , Lu Zhi-hua , Dong Yu-wei , Zhou Jin-yong , Zou Xi , Chen Yu-gen 
Published: June 2024

AbstractCellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial–mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.
Graphical Abstract
Developing a comprehensive abortion prevention program for couples based on I-change model: study protocol for a mixed method research
Authors: Dolatabadi Zari , Moridi Maryam , Farnam Farnaz , Damghanian Maryam 
Published: June 2024

Abstract
Background
In countries where abortion laws are stringent, induced abortions are prevalent. The limited availability of abortion services within these regions amplifies the likelihood of maternal complications and mortality. Induced abortions represent a significant public health concern in Iran and are characterized by a multitude of intricate factors that remain largely unexplored. Gaps in knowledge persist pertaining to the influences driving induced abortion within the Iranian context. To adequately address the issue of induced abortion, it is imperative to discern the determinants that shape the decision-making process. The primary objective of this study was to design an intervention program focused on mitigating the occurrence of induced abortion within couples, with an emphasis on identifying the key factors that contribute to this phenomenon.

Methods
This study comprises three phases. In the first phase, a qualitative approach based on the I-change model will be employed to identify the factors influencing induced abortion. The second phase involves a systematic review to identify the determinants of induced abortion and strategies to prevent induced abortion. In the third phase, the outcomes of the qualitative approach and systematic review will be shared with experts and specialists using the Delphi method to categorize and prioritize strategies. Subsequently, based on the final consensus, a comprehensive program will be developed to prevent induced abortion.

Discussion
This study introduces an I-change model-based program for the prevention of induced abortion. The prevention of induced abortion holds great significance in mitigating maternal morbidity and mortality, curtailing healthcare expenses, and fostering population growth rates. The research findings will be disseminated via reputable peer-reviewed journals and communicated to the academic and medical communities. This dissemination aims to provide valuable insights that can contribute to the advancement of induced abortion and abortion prevention programs.
Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression
Authors: Coleman Michael F. , Cotul Eylem Kulkoyluoglu , Pfeil Alexander J. , Devericks Emily N. , Safdar Muhammad H. , Monteiro Marvis , Chen Hao , Ho Alyssa N. , Attaar Numair , Malian Hannah M. , Kiesel Violet A. , Ramos Alexis , Smith Matthew , Panchal Heena , Mailloux Adam , Teegarden Dorothy , Hursting Stephen D. , Wendt Michael K. 
Published: June 2024

Abstract
Background
Metabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to regulate breast cancer progression are not fully understood. We identify hypoxia-mediated suppression of pyruvate carboxylase (PC), and subsequent induction of lactate production, as a metabolic regulator of immunosuppression.

Methods
We used qPCR, immunoblot, and reporter assays to characterize repression of PC in hypoxic primary tumors. Steady state metabolomics were used to identify changes in metabolite pools upon PC depletion. In vivo tumor growth and metastasis assays were used to evaluate the impact of PC manipulation and pharmacologic inhibition of lactate transporters. Immunohistochemistry, flow cytometry, and global gene expression analyzes of tumor tissue were employed to characterize the impact of PC depletion on tumor immunity.

Results
PC is essential for metastatic colonization of the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This effect was only observed in immune competent animals, supporting the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments, we demonstrate that hypoxia potently downregulated PC. In the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors.

Conclusions
We present a dimorphic role for PC in primary mammary tumors vs. pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immunity.

Graphical abstract