bluuebunny/crossref_metadata_2025_split huggingface dataset:
EBF1 and PAX5 control pro-B cell expansion via opposing regulation of the Myc gene
Authors: Somasundaram Rajesh , Jensen Christina T. , Tingvall-Gustafsson Johanna , Åhsberg Josefine , Okuyama Kazuki , Prasad Mahadesh , Hagman James R. , Wang Xun , Soneji Shamit , Strid Tobias , Ungerbäck Jonas , Sigvardsson Mikael 
Published: February 2021

Abstract
Genes encoding B lineage–restricted transcription factors are frequently mutated in B-lymphoid leukemias, suggesting a close link between normal and malignant B-cell development. One of these transcription factors is early B-cell factor 1 (EBF1), a protein of critical importance for lineage specification and survival of B-lymphoid progenitors. Here, we report that impaired EBF1 function in mouse B-cell progenitors results in reduced expression of Myc. Ectopic expression of MYC partially rescued B-cell expansion in the absence of EBF1 both in vivo and in vitro. Using chromosome conformation analysis in combination with ATAC-sequencing, chromatin immunoprecipitation–sequencing, and reporter gene assays, six EBF1-responsive enhancer elements were identified within the Myc locus. CRISPR-Cas9–mediated targeting of EBF1-binding sites identified one element of key importance for Myc expression and pro-B cell expansion. These data provide evidence that Myc is a direct target of EBF1. Furthermore, chromatin immunoprecipitation–sequencing analysis revealed that several regulatory elements in the Myc locus are targets of PAX5. However, ectopic expression of PAX5 in EBF1-deficient cells inhibits the cell cycle and reduces Myc expression, suggesting that EBF1 and PAX5 act in an opposing manner to regulate Myc levels. This hypothesis is further substantiated by the finding that Pax5 inactivation reduces requirements for EBF1 in pro–B-cell expansion. The binding of EBF1 and PAX5 to regulatory elements in the human MYC gene in a B-cell acute lymphoblastic leukemia cell line indicates that the EBF1:PAX5:MYC regulatory loop is conserved and may control both normal and malignant B-cell development.
P-selectin deficiency promotes liver senescence in sickle cell disease mice
Authors: Vats Ravi , Kaminski Tomasz W. , Ju Eun-Mi , Brozska Tomasz , Tutuncuoglu Egemen , Tejero Jesús , Novelli Enrico M. , Sundd Prithu , Pradhan-Sundd Tirthadipa 
Published: February 2021

Abstract
Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vasoocclusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vasoocclusive events in patients with SCD; however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin–deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin–deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance of investigating the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in patients with SCD.
ZAP-70 constitutively regulates gene expression and protein synthesis in chronic lymphocytic leukemia
Authors: Chen Jingyu , Sathiaseelan Vijitha , Moore Andrew , Tan Shengjiang , Chilamakuri Chandra Sekkar Reddy , Roamio Franklin Valar Nila , Shahsavari Arash , Jakwerth Constanze A. , Hake Sandra B. , Warren Alan J. , Mohorianu Irina , D’Santos Clive , Ringshausen Ingo 
Published: February 2021

Abstract
The expression of ZAP-70 in a subset of chronic lymphocytic leukemia (CLL) patients strongly correlates with a more aggressive clinical course, although the exact underlying mechanisms remain elusive. The ability of ZAP-70 to enhance B-cell receptor (BCR) signaling, independently of its kinase function, is considered to contribute. We used RNA-sequencing and proteomic analyses of primary cells differing only in their expression of ZAP-70 to further define how ZAP-70 increases the aggressiveness of CLL. We identified that ZAP-70 is directly required for cell survival in the absence of an overt BCR signal, which can compensate for ZAP-70 deficiency as an antiapoptotic signal. In addition, the expression of ZAP-70 regulates the transcription of factors regulating the recruitment and activation of T cells, such as CCL3, CCL4, and IL4I1. Quantitative mass spectrometry of double–cross-linked ZAP-70 complexes further demonstrated constitutive and direct protein-protein interactions between ZAP-70 and BCR-signaling components. Unexpectedly, ZAP-70 also binds to ribosomal proteins, which is not dependent on, but is further increased by, BCR stimulation. Importantly, decreased expression of ZAP-70 significantly reduced MYC expression and global protein synthesis, providing evidence that ZAP-70 contributes to translational dysregulation in CLL. In conclusion, ZAP-70 constitutively promotes cell survival, microenvironment interactions, and protein synthesis in CLL cells, likely to improve cellular fitness and to further drive disease progression.
CHARTS: a web application for characterizing and comparing tumor subpopulations in publicly available single-cell RNA-seq data sets
Authors: Bernstein Matthew N. , Ni Zijian , Collins Michael , Burkard Mark E. , Kendziorski Christina , Stewart Ron 
Published: February 2021

Abstract
Background
Single-cell RNA-seq (scRNA-seq) enables the profiling of genome-wide gene expression at the single-cell level and in so doing facilitates insight into and information about cellular heterogeneity within a tissue. This is especially important in cancer, where tumor and tumor microenvironment heterogeneity directly impact development, maintenance, and progression of disease. While publicly available scRNA-seq cancer data sets offer unprecedented opportunity to better understand the mechanisms underlying tumor progression, metastasis, drug resistance, and immune evasion, much of the available information has been underutilized, in part, due to the lack of tools available for aggregating and analysing these data.

Results
We present CHARacterizing Tumor Subpopulations (CHARTS), a web application for exploring publicly available scRNA-seq cancer data sets in the NCBI’s Gene Expression Omnibus. More specifically, CHARTS enables the exploration of individual gene expression, cell type, malignancy-status, differentially expressed genes, and gene set enrichment results in subpopulations of cells across tumors and data sets. Along with the web application, we also make available the backend computational pipeline that was used to produce the analyses that are available for exploration in the web application.

Conclusion
CHARTS is an easy to use, comprehensive platform for exploring single-cell subpopulations within tumors across the ever-growing collection of public scRNA-seq cancer data sets. CHARTS is freely available at charts.morgridge.org.
Neural basis underlying the trait of attachment anxiety and avoidance revealed by the amplitude of low-frequency fluctuations and resting-state functional connectivity
Authors: Deng Min , Zhang Xing , Bi Xiaoyan , Gao Chunhai 
Published: February 2021

Abstract
Background
Attachment theory demonstrates that early attachment experience shapes internal working models with mental representations of self and close relationships, which affects personality traits and interpersonal relationships in adulthood. Although research has focused on brain structural and functional underpinnings to disentangle attachment styles in healthy individuals, little is known about the spontaneous brain activity associated with self-reported attachment anxiety and avoidance during the resting state.

Methods
One hundred and nineteen individuals participated in the study, completing the Experience in Close Relationship scale immediately after an 8-min fMRI scanning. We used the resting-state functional magnetic resonance imaging (rs-fMRI) signal of the amplitude of low-frequency fluctuation and resting-state functional connectivity to identify attachment-related regions and networks.

Results
Consequently, attachment anxiety is closely associated with the amplitude of low-frequency fluctuations in the right posterior cingulate cortex, over-estimating emotional intensity and exaggerating outcomes. Moreover, the functional connectivity between the posterior cingulate cortex and fusiform gyrus increases detection ability for potential threat or separation information, facilitating behavior motivation. The attachment avoidance is positively correlated with the amplitude of low-frequency fluctuation in the bilateral lingual gyrus and right postcentral and negatively correlated with the bilateral orbital frontal cortex and inferior temporal gyrus. Functional connection with attachment avoidance contains critical nodes in the medial temporal lobe memory system, frontal-parietal network, social cognition, and default mode network necessary to deactivate the attachment system and inhibit attachment-related behavior.

Conclusion and implications
These findings clarify the amplitude of low-frequency fluctuation and resting-state functional connectivity neural signature of attachment style, associated with attachment strategies in attachment anxiety and attachment avoidance individuals. These findings may improve our understanding of the pathophysiology of the attachment-related disorder.
Omic analysis of the endangered Taxaceae species Pseudotaxus chienii revealed the differences in taxol biosynthesis pathway between Pseudotaxus and Taxus yunnanensis trees
Authors: Yu Chunna , Zhang Chengchao , Xu Xinyun , Huang Jiefang , Chen Yueyue , Luo Xiujun , Wang Huizhong , Shen Chenjia 
Published: February 2021

Abstract
Background
Taxol is an efficient anticancer drug accumulated in Taxus species. Pseudotaxus chienii is an important member of Taxaceae, however, the level of six taxoids in P. chienii is largely unknown.

Results
High accumulation of 10-DAB, taxol, and 7-E-PTX suggested that P. chienii is a good taxol-yielding species for large-scale cultivation. By the omics approaches, a total of 3,387 metabolites and 61,146 unigenes were detected and annotated. Compared with a representative Taxus tree (Taxus yunnanensis), most of the differentially accumulated metabolites and differential expressed genes were assigned into 10 primary and secondary metabolism pathways. Comparative analyses revealed the variations in the precursors and intermediate products of taxol biosynthesis between P. chienii and T. yunnanensis. Taxusin-like metabolites highly accumulated in P. chienii, suggesting a wider value of P. chienii in pharmaceutical industry.

Conclusions
In our study, the occurrence of taxoids in P. chienii was determined. The differential expression of key genes involved in the taxol biosynthesis pathway is the major cause of the differential accumulation of taxoids. Moreover, identification of a number of differentially expressed transcription factors provided more candidate regulators of taxol biosynthesis. Our study may help to reveal the differences between Pseudotaxus and Taxus trees, and promote resource utilization of the endangered and rarely studied P. chienii.
General anaesthesia related mortality in a limited resource settings region: a retrospective study in two teaching hospitals of Butembo
Authors: Blaise Pascal Furaha Nzanzu , Malisawa Agnes , Barratt-Due Andreas , Namboya Felix , Pollach Gregor 
Published: February 2021

AbstractBackgroundGeneral anaesthesia (GA) in developing countries is still a high-risk practice, especially in Africa, accompanied with high morbidity and mortality. No study has yet been conducted in Butembo in the Democratic Republic of the Congo to determine the mortality related to GA practice. The main objective of this study was to assess mortality related to GA in Butembo.MethodsThis was a retrospective descriptive and analytic study of patients who underwent surgery under GA in the 2 main teaching hospitals of Butembo from January 2011 to December 2015. Data were collected from patients files, anaesthesia registries and were analysed with SPSS 26.ResultsFrom a total of 921 patients, 539 (58.5%) were male and 382 (41.5%) female patients. A total of 83 (9.0%) patients died representing an overall perioperative mortality rate of 90 per 1000. Out of the 83 deaths, 38 occurred within 24 h representing GA related mortality of 41 per 1000. There was a global drop in mortality from 2011 to 2015. The risk factors of death were: being a neonate or a senior adult, emergency operation, ASA physical status > 2 and a single deranged vital sign preoperatively, presenting any complication during GA, anaesthesia duration > 120 minutes as well as visceral surgeries/laparotomies. Ketamine was the most employed anaesthetic.ConclusionGA related mortality is very high in Butembo. Improved GA services and outcomes can be obtained by training more anaesthesia providers, proper patients monitoring, improved infrastructure, better equipment and drugs procurement and considering regional anaesthesia whenever possible.
Combined effect of menopause and cardiovascular risk factors on death and cardiovascular disease: a cohort study
Authors: Li Yan , Zhao Dong , Wang Miao , Sun Jia-yi , Liu Jun , Qi Yue , Hao Yong-chen , Deng Qiu-ju , Liu Jue , Liu Jing , Liu Min 
Published: February 2021

AbstractBackgroundObservational studies suggest that early menopause is associated with increased risk of death and cardiovascular disease (CVD); however, the results of these studies have been inconsistently. We aimed to assess the association of menopause with death and CVD and whether this association was modified by cardiovascular risk factors.MethodsThe study population was women age 35–64 years living in two communities of Beijing who were enrolled in the Chinese Multi-provincial Cohort Study in 1992. Participants were followed until first cardiovascular event, death, or the end of follow-up (2018). Self-reported age at menopause was recorded. Multivariate Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of death and CVD after adjusting for baseline covariates of age, family history of CVD, and white blood cell count, as well as time-varying covariates of menopause, use of oral estrogen, and conventional risk factors. Additionally, we assessed the combined effect of age at menopause and risk factors on the primary endpoint.ResultsOf 2104 eligible women, 124 died and 196 had a first CVD event (33 fatal CVD and 163 non-fatal CVD). Compared with women who experienced menopause at age 50–51 years, the risk of death was higher in women with menopause at age 45–49 years (HR 1.99, 95% CI 1.24–3.21;P = 0.005), and the risk of ischemic stroke was higher in women with menopause at age < 45 years (HR 2.16, 95% CI 1.04–4.51;P = 0.04) and at age 45–49 years (HR 2.05, 95% CI 1.15–3.63;P = 0.01). Women who had menopause before age 50 years and at least one elevated risk factor at baseline had a higher risk of death (HR 11.10, 95% CI 1.51–81.41;P = 0.02), CVD (HR 3.98, 95% CI 1.58–10.01;P = 0.003), ischemic CVD (HR 4.53, 95% CI 1.63–12.62;P = 0.004), coronary heart disease (HR 8.63, 95% CI 1.15–64.50;P = 0.04), and stroke (HR 2.92, 95% CI 1.03–8.29;P = 0.04) than those with menopause at age 50–51 years and optimal levels of all risk factors.ConclusionsEarlier menopause may predict death and ischemic stroke. Furthermore, there is a combined effect of earlier menopause and elevated risk factors on death and CVD.
Prognostic value of neutrophil- lymphocyte count ratio (NLCR) among adult ICU patients in comparison to APACHE II score and conventional inflammatory markers: a multi center retrospective cohort study
Authors: Zhou Tao , Zheng Nan , Li Xiang , Zhu Dongmei , Han Yi 
Published: February 2021

Abstract
Background
Neutrophil-lymphocyte count ratio (NLCR) has been reported as better indicator of bacteremia than procalcitonin (PCT), and more precise predictor of mortality than C-reactive protein (CRP) under various medical conditions. However, large controversy remains upon this topic. To address the discrepancy, our group has compared the efficiency of NLCR with conventional inflammatory markers in predicting the prognosis of critical illness.

Methods
We performed a multi-center retrospective cohort study involving 536 ICU patients with outcomes of survival, 28- and 7-day mortality. NLCR was compared with conventional inflammatory markers such as PCT, CRP, serum lactate (LAC), white blood cell, neutrophil and severity score APACHE II (Acute Physiology and Chronic Health Evaluation II) to evaluate the potential outcomes of critical illness. Then, receiver operating characteristics (ROC) curves were constructed to assess and compare each marker’s sensitivity and specificity respectively.

Results
NLCR values were not different between survival and mortality groups. Meanwhile, remarkable differences were observed upon APACHE II score, CRP, PCT and LAC levels between survival and death groups. ROC analysis revealed that NLCR was not competent to predict prognosis of critical illness. The AUROCs of conventional markers such as CRP, PCT, LAC and APACHE II score were more effective in predicting 28- and 7-day mortality.

Conclusions
NLCR is less reliable than conventional markers CRP, PCT, LAC and APACHE II score in assessing severity and in predicting outcomes of critical illness.
Spontaneous intracapsular hemorrhage of a giant hepatic cavernous hemangioma: a rare case report and literature review
Authors: Yang Yong-Guang , Chen Wei-Feng , Mai Wei-Heng , Li Xiao-Fang , Zhou Hong-Lian , Liu Li-Juan , Li Ming-Yi 
Published: February 2021

Abstract
Background
Hepatic cavernous hemangioma is the most common type of benign liver tumor. Although ruptures and hemorrhages of hepatic hemangioma are rare complications, they are associated with high mortality. Most practitioners only pay more attention to abdominal hemorrhages caused by the rupture of hepatic hemangiomas. However, spontaneous intracapsular hemorrhages can often be neglected and poorly understood.

Case presentation
A 65-year-old man was referred to our institution with right upper quadrant pain, which had occurred suddenly and without a history of recent trauma. The blood test results were normal. Magnetic resonance imaging (MRI) of the abdomen showed a cystic mass in the right liver lobe. Considering the possibility of hepatic cystadenoma with hemorrhage, the patient underwent a right hepatic lobectomy. The pathological findings unexpectedly revealed intratumoral hemorrhage of hepatic hemangioma. The patient recovered well and was discharged eight days after surgery.

Conclusions
Intracapsular hemorrhage of hepatic cavernous hemangioma is challenging to diagnose and has a high potential risk of rupture. MRI is beneficial for diagnosing subacute internal hemorrhage cases, and it is recommended to undergo surgery for patients with a definitive diagnosis.
V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) as a prognostic biomarker of poor outcomes in esophageal cancer patients
Authors: Kuerbanjiang Aihemaijiang , Maimaituerxun Maimaitiyiming , Zhang Yanjun , Li Yiliang , Cui Gang , Abuduhabaier Aibaidula , Aierken Abuduwaili , Miranbieke Buya , Anzaer Meilikezati , Maimaiti Yusufu 
Published: February 2021

Abstract
Background
Esophageal cancer is one of the most aggressive malignancies, and is associated with multiple genetic mutations. At present, the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) gene mutation has been observed in esophageal cancer and is associated with poor prognosis. This study aimed to investigate the protein expression of BRAF in esophageal cancer and determine its effect on patient outcomes.

Methods
We used immunohistochemistry to detect the expression of BRAF via tissue microarrays in esophageal cancer samples, the Kaplan–Meier method to perform survival analysis, and the Cox proportional hazards regression model to explore the risk factors of esophageal cancer. The role of BRAF in the proliferation, invasion, and metastasis of esophageal cancer was studied by clone formation, scratch test, Transwell invasion and migration test. The tumor-bearing model of BRAF inhibitor was established using TE-1 cells, and corresponding negative control was set up to observe the growth rate of the two models.

Results
The results revealed that BRAF overexpression was significantly correlated with Ki67 (P < 0.05). Survival analysis showed that BRAF overexpression contributed to a shorter overall survival (P = 0.014) in patients with esophageal cancer. Univariate and multivariate regression analyses demonstrated that BRAF was a prognostic factor for poor esophageal cancer outcomes (P < 0.05). Small interfering RNA knockdown of BRAF significantly reduced the cell clone formation rate compared to the control group. Transwell assay analysis showed that the migration and invasion of cells in the experimental group were significantly inhibited relative to the control group, and the inhibition rates of the small interfering RNA group were 67% and 60%, respectively. In the scratch test, the wound healing ability of the BRAF knockdown group was significantly weaker than that of the control group. There were significant differences in tumor growth volume and weight between the two groups in nude mice.

Conclusion
BRAF overexpression may serve as an effective predictive factor for poor prognosis.