bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory Cytokine Neutralizing Antibody Treatment Could Recover Increased Follicular Helper and Follicular Regulatory T Cells in Murine Models of Arthritis
Authors: Zeng Xingyue , Li Meng , Zheng Mohan , Liu Tianci , Kang Rui , Xu Lijuan , Xu Qinzhu , Lu Songsong , Song Ying , Liu Chen 
Published: September 2021

Abstract
Objective. We aimed to illustrate the changes of follicular helper (TFH) and follicular regulatory (TFR) cells in rheumatoid arthritis using the collagen-induced arthritis (CIA) model and clarity the impact of anti-inflammatory treatment on TFH and TFR cells.Methods. We established 10-week-old CIA model and used flow cytometry to analyze the changes of TFH and TFR cells in peripheral blood and spleen at different time points (5w, 7w, 10w,13w). The expression of TIGIT, CD226, ICOS and PD-1 characterizing the functions of TFH and TFR were also analyzed. The function of spleen TFH and TFR cells from CIA was further analyzed. The effects of anti-inflammatory antibody treatments on the subpopulation and function changes of TFH and TFR were also analyzed in CIA mice.Results. The levels of TFH and TFR were significantly increased in spleen and peripheral blood of CIA mice. After treatment, TFH and TFR cells decreased significantly. TIGIT+ and TIGIT+CD226-TFH cells in CIA mouse spleen were elevated and PD-1 and ICOS expression on TFH and TFR cells in the spleen were also significantly increased. The ability of TFH to secrete IL-21 and help B cells, and TFR to secrete IL-10 and inhibit TFH were both enhanced in CIA mouse spleen. After antibody treatment, cell subsets and functions were significantly recovered.Conclusion. In the pathogenesis of rheumatoid arthritis, TFH and TFR cells in the germinal center increases and their functions are enhanced. After the treatment by inflammatory factor antibodies, TFH and TFR subsets and their functions can be significantly recovered.
Significance of a Tumor Microenvironment-Mediated P65-miR-30a-5p-BCL2L11 Amplification Loop in Multiple Myeloma
Authors: Xie Ling , Shi Xiuying , Huang Hongming , Ju Shaoqing , Wang Xudong 
Published: September 2021

Abstract
Despite significant progress in the treatment of myeloma, multiple myeloma (MM) remains an incurable hematological malignancy due to cell adhesion-mediated drug resistance (CAM-DR) phenotype. However, data on the molecular mechanisms underlying the CAM-DR remains scanty. Here, we identified a miRNA-mRNA regulatory network in myeloma cells that are directly adherent to bone marrow stromal cells (BMSCs). Our data showed that the BMSCs up-regulated miR-30a-5p and down-regulated BCL2L11 at both mRNA and protein level in the myeloma cells. Besides, luciferase reporter genes demonstrated direct interaction between miR-30a-5p and BCL2L11 gene. Moreover, the BMSCs activated NF-ΚB signaling pathway in myeloma cells and the NF-κB P65 was shown to directly bind the miR-30a-5p promoter region. Moreover, suppression of the miR-30a-5p or upregulation of the BCL2L11 promoted apoptosis of the myeloma cells independent of the BMSCs, thus suggesting clinical significance of miR-30a-5p inhibitor and PLBCL2L11 plasmid in CAM-DR. Together, our data demonstrated the role of P65-miR-30a-5p-BCL2L11 loop in CAM-DR myeloma cells. These findings give new insights into the role of tumor microenvironment in the treatment of patients with myeloma.
RNA-Sequencing And Mass-Spectrometry Proteomic Time-Series Analysis of T-Cell Differentiation Identified Multiple Splice Variants Models That Predicted Validated Protein Biomarkers In Inflammatory Diseases
Authors: Magnusson Rasmus , Rundquist Olof , Kim Min Jung , Hellberg Sandra , Na Chan Hyun , Benson Mikael , Gomez-Cabrero David , Kockum Ingrid , Tegnér Jesper , Piehl Fredrik , Jagodic Maja , Mellergård Johan , Altafini Claudio , Ernerudh Jan , Jenmalm Maria C. , Nestor Colm E. , Kim Min-Sik , Gustafsson Mika 
Published: September 2021

Abstract
Background Profiling of mRNA expression is an important method to identify biomarkers but complicated by limited correlations between mRNA expression and protein abundance. We hypothesized that these correlations could be improved by mathematical models based on measuring splice variants and time delay in protein translation. Methods We characterized time-series of primary human naïve CD4+ T cells during early T-helper type 1 differentiation with RNA-sequencing and mass-spectrometry proteomics. We then performed computational time-series analysis in this system and in two other key human and murine immune cell types. Linear mathematical mixed time-delayed splice variant models were used to predict protein abundances, and the models were validated using out-of-sample predictions. Lastly, we re-analysed RNA-Seq datasets to evaluate biomarker discovery in five T-cell associated diseases, further validating the findings for multiple sclerosis (MS) and asthma.Results The new models significantly out-performing models not including the usage of multiple splice variants and time-delays, as shown in cross-validation tests. Our mathematical models provided more differentially expressed proteins between patients and controls in all five diseases. Moreover, analysis of these proteins in asthma and MS supported their relevance. One marker, sCD27, was clinically validated in MS using two independent cohorts, for treatment response and prognosis.Conclusion Our splice variant and time-delay models substantially improved the prediction of protein abundance from mRNA data in three immune cell-types. The models provided valuable biomarker candidates, which were validated in clinical studies of MS and asthma. We propose that our strategy is generally applicable for biomarker discovery.
A Computational Modeling of Invadopodia Protrusion Into an Extracellular Matrix Fiber Network
Authors: Kim Min-Cheol , Li Ran , Abeyaratne Rohan , Kamm Roger D. , Asada H. Harry 
Published: September 2021

Abstract
Invadopodia are dynamic actin-rich membrane protrusions that have been implicated in cancer cell invasion and metastasis. In addition, invasiveness of cancer cells is strongly correlated with invadopodia formation, which are observed during extravasation and colonization of metastatic cancer cells at secondary sites. However, quantitative understanding of the interaction of invadopodia with extracellular matrix (ECM) is lacking, and how invadopodia protrusion speed is associated with the frequency of protrusion-retraction cycles remains unknown. Here, we present a computational framework for the characterization of invadopodia protrusions which allows two way interactions between intracellular branched actin network and ECM fibers network. We have applied this approach to predicting the invasiveness of cancer cells by computationally knocking out actin-crosslinking molecules, such as α-actinin, filamin and fascin. The resulting simulations reveal distinct invadopodia dynamics with cycles of protrusion and retraction. Specifically, we found that 1) increasing accumulation of MT1-MMP at tips of invadopodia as the duration of protrusive phase is increased, and 2) the movement of nucleus toward the leading edge of the cell becomes unstable as duration of the retractile phase (or myosin turnover time) is longer than 1 min.
Significance of Platinum Distribution to Predicts Platinum Resistance in Ovarian Cancer After Platinum Treatment in Neoadjuvant Chemotherapy
Authors: Uno Kaname , Yoshikawa Nobuhisa , Tazaki Akira , Ohnuma Shoko , Kitami Kazuhisa , Iyoshi Shohei , Mogi Kazumasa , Yoshihara Masato , Koya Yoshihiro , Sugiyama Mai , Tamauchi Satoshi , Ikeda Yoshiki , Yokoi Akira , Kikkawa Fumitaka , Kato Masashi , Kajiyama Hiroaki 
Published: September 2021

Abstract
Most advanced ovarian cancer patients experience recurrence and develop resistance to platinum-based agents. However, the diagnosis of platinum resistance based on platinum-free interval is not always accurate and timely. In this study, we employed laser ablation inductively coupled plasma mass spectrometry to visualize platinum distribution in the tissues at the time of interval debulking surgery following neoadjuvant chemotherapy. Twenty seven patients with advanced high grade serous ovarian cancer were enrolled. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum through tumor and adjacent stroma. Type A was significantly correlated with worse prognosis (P = 0.031). Patients classified in type A and treated with platinum-based adjuvant chemotherapy after operation were significantly shorter period of recurrence after last platinum-based chemotherapy (P = 0.020) and diagnosed with “platinum-resistant recurrence”. Treatment with non-platinum-based chemotherapy after operation could be effective for the patients who were classified in type A. Our data indicate that the platinum resistance can be predicted prior to recurrence with platinum distribution. Thus, we will be able to select more appropriate adjuvant chemotherapy, which may possibly lead to improve patient’s prognosis.
A Toolkit to Rapidly Modify Root Systems Through Single Plant Selection
Authors: Rambla Charlotte , Meer Sarah Van Der , Voss-Fels Kai P. , Makhoul Manar , Obermeier Christian , Snowdon Rod , Ober Eric S. , Watt Michelle , Alahmad Samir , Hickey Lee T. 
Published: September 2021

Abstract
Background: The incorporation of root traits into elite germplasm is typically a slow process. Thus, innovative approaches are required to accelerate research and pre-breeding programs targeting root traits to improve yield stability in different environments and soil types. Marker-assisted selection (MAS) can help to speed up the process by selecting key genes or quantitative trait loci (QTL) associated with root traits. However, this approach is limited due to the complex genetic control of root traits and the limited number of well-characterised large effect QTL. Coupling MAS with phenotyping could increase the reliability of selection. Here we present a useful framework to rapidly modify root traits in elite germplasm. In this wheat exemplar, a single plant selection (SPS) approach combined three main elements: phenotypic selection (in this case for seminal root angle); MAS using KASP markers (targeting a root biomass QTL); and speed breeding to accelerate each cycle.Results: To develop a SPS approach that integrates non-destructive screening for seminal root angle and root biomass, two initial experiments were conducted. Firstly, we demonstrated that transplanting wheat seedlings from clear pots (for seminal root angle assessment) into sand pots (for root biomass assessment) did not impact the ability to differentiate genotypes with high and low root biomass. Secondly, we demonstrated that visual scores for root biomass were correlated with root dry weight (r = 0.73), indicating that single plants could be evaluated for root biomass in a non-destructive manner. To highlight the potential of the approach, we applied SPS in a backcrossing program which integrated MAS and speed breeding for the purpose of rapidly modifying the root system of elite bread wheat line Borlaug100. Bi-directional selection for root angle in segregating generations successfully shifted the mean root angle by 30o in the subsequent generation (P ≤ 0.05). Within 18 months, BC2F4:F5 introgression lines were developed that displayed a full range of root configurations, while retaining similar above-ground traits to the recurrent parent. Notably, the seminal root angle displayed by introgression lines varied more than 30° compared to the recurrent parent, resulting in lines with both narrow and wide root angles, and high and low root biomass phenotypes.Conclusion: The SPS approach enables researchers and plant breeders to rapidly manipulate root traits of future crop varieties, which could help improve productivity in the face of increasing environmental fluctuations. The newly developed elite wheat lines with modified root traits provide valuable materials to study the value of different root systems to support yield in different environments and soil types.
Dataset Size Sensitivity Analysis of Machine Learning Classifiers to Differentiate Molecular Markers of Pediatric Low-Grade Gliomas Based on MRI
Authors: Wagner Matthias W. , Namdar Khashayar , Alqabbani Abdullah , Hainc Nicolin , Figuereido Liana Nobre , Sheng Min , Shroff Manohar M , Bouffet Eric , Tabori Uri , Hawkins Cynthia , Zhang Michael , Yeom Kristen W. , Khalvati Farzad , Ertl-Wagner Birgit B. 
Published: September 2021

Abstract
Machine learning (ML) approaches can predict BRAF status of pediatric low-grade gliomas (pLGG) on pre-therapeutic brain MRI. The impact of training data sample size and type of ML model is not established. In this bi-institutional retrospective study, 251 pLGG FLAIR MRI datasets from 2 children’s hospitals were included. Radiomics features were extracted from tumor segmentations and five models (Random Forest, XGBoost, Neural Network (NN) 1 (100:20:2), NN2 (50:10:2), NN3 (50:20:10:2)) were tested to classify them. Classifiers were cross-validated on data from institution 1 and validated on data from institution 2. Starting with 10% of the training data, models were cross-validated using a 4-fold approach at every step with an additional 2.25% increase in sample size. Two-hundred-twenty patients (mean age 8.53 ± 4.94 years, 114 males, 67% BRAF fusion) were included in the training dataset, and 31 patients (mean age 7.97±6.20 years, 18 males, 77% BRAF fusion) in the independent test dataset. NN1 (100:20:2) yielded the highest area under the receiver operating characteristic curve (AUC). It predicted BRAF status with a mean AUC of 0.85, 95% CI [0.83, 0.87] using 60% of the training data and with mean AUC of 0.83, 95% CI [0.82, 0.84] on the independent validation data set.
Mean Brain Dose Remains Uninfluenced by Lesion Number for Gamma Knife Stereotactic Radiosurgery for Ten+ Metastases
Authors: Sachdev Sean , Sita Timothy L. , Gopalakrishnan Mahesh , Rooney Michael K. , Ho Alexander , Savoor Rohan , Sonabend Adam M. , Tate Matthew C. , Chandler James P. , Lesniak Maciej S. , Kruser Tim J. , Kalapurakal John A. 
Published: September 2021

Abstract
Purpose:Gamma Knife (GK) stereotactic radiosurgery (SRS) is increasingly used as an initial treatment for patients with ten or more brain metastases (BM). However, the clinical and dosimetric consequences of this practice are not well established.Methods: We performed a single institution, retrospective analysis of 30 patients who received GK SRS for ten or more BM in one session. We utilized MIM Software to contour the whole brain and accumulated the doses from all treated lesions to determine the mean dose delivered to the whole brain. Patient outcomes were determined from chart review. Results: Our cohort had a median number of 13 treated lesions (range 10 to 26 lesions) for a total of 427 treated lesions. The mean dose to the whole brain was determined to be 1.8 ± 0.91 Gy (range 0.70 to 3.8 Gy). Mean dose to the whole brain did not correlate with the number of treated lesions (Pearson r=0.23, p=0.21), but was closely associated with tumor volume (Pearson r=0.95, p<0.0001). There were no significant correlations between overall survival and number of lesions or aggregate tumor volume. Fourteen patients (47%) underwent additional SRS sessions and six patients (20%) underwent WBRT a median of 6.6 months (range 3.0-50 months) after SRS. Two patients (6.6%) developed grade 2 radionecrosis following SRS beyond earlier WBRT.Conclusion: The mean dose to the whole brain in patients treated with GK SRS for 10 or more BM remained low with an acceptable rate of radionecrosis. This strategy allowed the majority of patients to avoid subsequent WBRT.
Failure of salvage vemurafenib therapy for refractory multisystem Langerhans cell histiocytosis with BRAF-V600E mutation
Authors: Tang Xue , Wan Zhi , Guo Xia , Guo Ju 
Published: September 2021

Abstract
Background

Langerhans cell histiocytosis (LCH) has been defined as a disorder driven by misguided myeloid differentiation, with up to 50% of cases harboring the BRAF-V600E mutation. Salvage treatment with LCH refractory to vinblastine and steroid regimen is intractable. Vemurafenib is safe and effective in children with refractory BRAF-V600E-positive LCH, but the disease always reactivates with the withdrawal of vemurafenib.
Case presentation:

Here, we report the first case of BRAF-V600E positive LCH resistant to vemurafenib therapy but effectively salvaged by cytarabine-based chemotherapy.
Conclusions

Our case report shows that vemurafenib monotherapy might not be effective for every BRAF-V600E-positive refractory LCH, and cytarabine-based chemotherapy might still be a cost-effective therapeutic alternative. Keywords: Langerhans cell histiocytosis, BRAF-V600E mutation, Vemurafenib, Chemotherapy
Blood and Brain Transcriptome Analysis Reveals APOE Genotype-mediated and Immune-related Pathways Involved in Alzheimer Disease
Authors: Panitch Rebecca , Hu Junming , Xia Weiming , Bennett David A , Stein Thor D , Farrer Lindsay A , Jun Gyungah R. 
Published: September 2021

Abstract
Background: While Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for diagnosis and prediction of AD brain pathology. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier breakdown. Methods: We evaluated differential expression of previously established AD genes in brains from 344 pathologically confirmed AD cases and 232 controls and in blood from 112 pathologically confirmed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. Differential gene expression between AD cases and controls was analyzed in the blood and brain jointly using a multivariate approach in the total sample and within APOE genotype groups. Gene set enrichment analysis was performed within APOE genotype groups using the results from the combined blood and brain analyses to identify biologically important pathways. Gene co-expression networks in brain and blood samples were investigated using weighted correlation network analysis. Top ranked genes from networks and pathways were further evaluated with vascular injury traits. Results: We observed differentially expressed genes with P<0.05 in both brain and blood for established AD genes INPP5D (upregulated) and HLA-DQA1 (downregulated). PIGHP1 and FRAS1 were differentially expressed at the transcriptome-wide level (P<3.3x10 -6 ) within ε2/ε3 and ε3/ε4 groups, respectively. Gene-set enrichment analysis revealed 21 significant pathways (false discovery rate P<0.05) in at least one APOE genotype group. Ten pathways were significantly enriched in the ε3/ε4 group, and six of these were unique to these subjects. Four pathways were enriched for AD upregulated genes in the ε3/ε4 group and AD downregulated genes in ε4 lacking subjects. We identified a co-expressed gene network in brain that reproduced in blood and showed higher average expression in ε4 carriers. Twenty-three genes from pathway and network analyses were significantly associated at P<0.05 with at least one vascular injury trait. Conclusion: These results suggest that APOE genotype contributes to unique expression network profiles in both blood and brain. Several genes in these networks are associated with measures of vascular injury and potentially contribute to ε4’s effect on the blood brain barrier.
Chaotic Resonance in Izhikevich Neural Network Motifs Under Electromagnetic Induction
Authors: Wang Guowei , Yang Lijian , Zhan Xuan , Li Anbang , Jia Ya 
Published: September 2021

Abstract
Chaotic resonance (CR) is the response of a nonlinear system to weak signals enhanced by internal or external chaotic activity (such as the signal derived from Lorenz system). In this paper, the triple-neuron feed-forward loop (FFL) Izhikevich neural network motifs with eight types are constructed as the nonlinear systems, and the effects of EMI on CR phenomenon in FFL neuronal network motifs are studied. It is found that both the single Izhikevich neural model under electromagnetic induction (EMI) and its network motifs exhibit CR phenomenon depending on the chaotic current intensity. There exists an optimal chaotic current intensity ensuring the best detection of weak signal in single Izhikevich neuron or its network motifs via CR. The EMI can enhance the ability of neuron to detect weak signals. For T1-FFL and T2-FFL motifs, the adjustment of EMI parameters makes T2-FFL show a more obvious CR phenomenon than that for T1-FFL motifs, which is different from the impact of system parameters (e.g., the weak signal frequency, the coupling strength, and the time delay) on CR. Another interesting phenomenon is that the variation of CR with time delay exhibits quasi periodic characteristics. Our results showed that CR effect is a robust phenomenon which is observed in both single Izhikevich neuron and network motifs, which might help one understand how to improve the ability of weak signal detection and propagation in neuronal system.
Differences in the Flexion and Extension Phases during Kneeling Investigated by Kinematic and Contact Point Analyses: A Cross-sectional Study
Authors: Nakazoe Yusuke , Yonekura Akihiko , Takita Hiroyuki , Miyaji Takeshi , Okazaki Narihiro , Chiba Ko , Kidera Kenichi , Miyamoto Takashi , Tomita Masato , Gamada Kazuyoshi , Osaki Makoto 
Published: September 2021

Abstract
Background: Kneeling is necessary for certain religious and ceremonial occasions, crouching work, and gardening, which many people take part in worldwide. However, there have been few reports regarding kneeling activities. The purpose of this study was to clarify the kinematics of kneeling.Methods: The subjects were 15 healthy young males. Kneeling activity was analysed within a knee flexion angle from 100° to maximum flexion (maxflex, mean ± SD = 161.3 ± 3.2°). The kinematic and contact point (CP) analyses were performed using a 2D/3D registration method, in which a 3D bone model created from computed tomography images was matched to knee lateral fluoroscopic images and analysed on a personal computer.Results: In the kinematic analysis, the femur translated 37.5 mm posteriorly and rotated 19.8° externally relative to the tibia during the knee flexion phase. During the knee extension phase, the femur translated 36.4 mm anteriorly, which was almost the same amount as in the knee flexion phase. However, the femur rotated only 7.4° internally during the knee extension phase. In the CP analysis, the amount of anterior translation of the CP in the knee extension phase was greater in the medial CP and smaller in the lateral CP than that of posterior translation in the knee flexion phase.Conclusions: In kneeling, there was a difference in the rotational kinematics between the flexion phase and the extension phase. The kinematic difference between the flexion and extension phases may have some effect on the meniscus and articular cartilage.