bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Peripheral T Helper Cells Are Associated With Atrial Fibrillation in Patients With Rheumatoid Arthritis
Authors: Wang Xin , Fan Hongxuan , Wang Yongle , Yin Xufang , Liu Guangying , Gao Chong , Li Xiaofeng , Liang Bin
Published: October 2021

Patients with rheumatoid arthritis (RA) have a significantly high risk of atrial fibrillation (AF). This study aimed to compare the absolute and relative changes in peripheral T cells in patients with RA who were also affected with and without AF. To help make an early diagnosis and prevent the initiation and progression of AF, the changes in the lymphocyte subsets were assessed in RA patients with and without AF. A propensity score matching (PSM) system (1:3) was used to perform a matched case-control study with 40 RA-AF cases and 120 RA controls. Changes in the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-citrullinated peptide antibody (ACPA), and rheumatoid factor (RF) were examined. The percentage and absolute number of T, B, natural killer (NK), T helper (Th)1, Th2, Th17, and T-regulatory (Treg) cells in the peripheral blood of patients with and without RA-AF were determined using flow cytometry. Univariate and multivariate analyses were performed to determine the association between peripheral lymphocytes and RA-AF. Demographic data, ESR, CRP, ACPA, and the percentage, as well as the absolute value of B, NK, Th2, and Treg cells, showed no significant differences between the propensity score-matched groups of RA and RA-AF. Meanwhile, the absolute number and percentage of Th1 cells, the absolute number of Th17 cells, the ratio of Th1/Treg, Th17/Treg, and RF were significantly higher in patients with RA-AF than those in the control groups (P < 0.05). Univariate and multivariate logistic regression analyses also revealed that the percentage of Th1 cells, the absolute number of Th17 cells, and the ratio of Th1/Treg were associated with a significantly higher risk of AF. This PSM study demonstrated that the incidence of AF was higher in RA patients with Th cell immunological derangements.
A Validation Study Comparing Risk Prediction Models of IgA Nephropathy
Authors: Ouyang Yan , Zhao Zhanzheng , Li Guisen , Luo Huimin , Xu Feifei , Shao Leping , Chen Zijin , Yu Shuwen , Jin Yuanmeng , Xu Jing , Shi Manman , Hussain Hafiz Muhammad Jafar , Du Wen , Fang Zhengying , Pan Xiaoxia , Wang Weiming , Xie Jingyuan , Chen Nan
Published: October 2021

We aimed to validate three IgAN risk models proposed by an international collaborative study and another CKD risk model generated by an extended CKD cohort with our multicenter Chinese IgAN cohort. Biopsy-proven IgAN patients with an eGFR ≥15 ml/min/1.73 m2 at baseline and a minimum follow-up of 6 months were enrolled. The primary outcomes were a composite outcome (50% decline in eGFR or ESRD) and ESRD. The performance of those models was assessed using discrimination, calibration, and reclassification. A total of 2,300 eligible cases were enrolled. Of them, 288 (12.5%) patients reached composite outcome and 214 (9.3%) patients reached ESRD during a median follow-up period of 30 months. Using the composite outcome for analysis, the Clinical, Limited, Full, and CKD models had relatively good performance with similar C statistics (0.81, 0.81, 0.82, and 0.82, respectively). While using ESRD as the end point, the four prediction models had better performance (all C statistics > 0.9). Furthermore, subgroup analysis showed that the models containing clinical and pathological variables (Full model and Limited model) had better discriminatory abilities than the models including only clinical indicators (Clinical model and CKD model) in low-risk patients characterized by higher baseline eGFR (≥60 ml/min/1.73 m2). In conclusion, we validated recently reported IgAN and CKD risk models in our Chinese IgAN cohort. Compared to pure clinical models, adding pathological variables will increase performance in predicting ESRD in low-risk IgAN patients with baseline eGFR ≥60 ml/min/1.73 m2.
HIV-1-Specific CD11c+ CD8+ T Cells Display Low PD-1 Expression and Strong Anti-HIV-1 Activity
Authors: Guo An-Liang , Zhao Jin-Fang , Gao Lin , Huang Hui-Huang , Zhang Ji-Yuan , Zhang Chao , Song Jin-Wen , Xu Ruo-Nan , Fan Xing , Shi Ming , Jiao Yan-Mei , Wang Fu-Sheng
Published: October 2021

Exhaustion of HIV-1-specific CD8+ T cells prevents optimal control of HIV-1 infection. Identifying unconventional CD8+ T cell subsets to effectively control HIV-1 replication is vital. In this study, the role of CD11c+ CD8+ T cells during HIV-1 infection was evaluated. The frequencies of CD11c+ CD8+ T cells significantly increased and were negatively correlated with viral load in HIV-1-infected treatment-naïve patients. HIV-1-specific cells were enriched more in CD11c+ CD8+ T cells than in CD11c- CD8+ T cells, which could be induced by HIV-1-derived overlapping peptides, marking an HIV-1-specific CD8+ T cell population. This subset expressed higher levels of activating markers (CD38 and HLA-DR), cytotoxic markers (granzyme B, perforin, and CD107a), and cytokines (IL-2 and TNF-α), with lower levels of PD-1 compared to the CD11c- CD8+ T cell subset. In vitro analysis verified that CD11c+ CD8+ T cells displayed a stronger HIV-1-specific killing capacity than the CD11c- counterparts. These findings indicate that CD11c+ CD8+ T cells have potent immunotherapeutic efficacy in controlling HIV-1 infection.
Phylogeography and Diversity Among Populations of the Toxigenic Benthic Dinoflagellate Prorocentrum From Coastal Reef Systems in Mexico
Authors: Cembella Allan D. , Durán-Riveroll Lorena M. , Tarazona-Janampa Ulrike I. , Okolodkov Yuri B. , García-Sandoval Ricardo , Krock Bernd , Hörstmann Cora , John Uwe
Published: October 2021

The marine dinoflagellate genus Prorocentrum Ehrenberg comprises many species occupying primarily benthic or epiphytic habitats, particularly in tropical and sub-tropical waters. Despite concerted efforts to establish phylogenetic associations, there remain unresolved issues in defining morphospecies and membership in species complexes. The study described herein addressed the inter- and infraspecific relationships of members of the Prorocentrum lima and Prorocentrum hoffmannianum species complexes (PLSC and PHSC, respectively) by applying multivariate approaches in morphotaxonomy, molecular phylogenetics and chemodiversity to establish affinities among multiple clonal isolates. Morphotaxonomic analysis showed consistency with classical morphospecies descriptors, and high variability in cell size and dimensions, but did not challenge current species complex concepts. Phylogenetic analysis of ITS/5.8S rDNA sequences from isolates from the Gulf of California, Caribbean Sea, and Gulf of Mexico coasts compared with archived global GenBank sequences served to define five consistent clades with separation of the PLSC and PHSC. Secondary structure modeling of ITS2 rRNA variation based on compensatory base changes (CBC) was effective in resolving details of the respective species complexes and even indicated putative incipient or cryptic speciation due to potential hybridization barriers. This study represents the largest (n = 67 isolates) chemodiversity analysis of polyketide-derived toxins associated with diarrheic shellfish poisoning (DSP) from a benthic dinoflagellate genus. Relative composition of some analogs (OA, OA-D8, DTX1, DTX1a, and DTX1a-D8), including two new undescribed isomers, distinguished P. lima from P. hoffmannianum sensu lato, but without clear associations with substrate type or geographical origin. Although all P. lima and most (one exception) P. hoffmannianum were toxigenic, the total cell toxin content could not be linked at the species level. This research demonstrates that clonal chemodiversity in toxin composition cannot yet be effectively applied to define ecological niches or species interactions within local assemblages. Phylogenetic analysis of the ITS/5.8 rDNA, particularly when combined with secondary structure modeling, rather than only a comparison of LSU rDNA sequences, is a more powerful approach to identify cryptic speciation and to resolve species complexes within benthic dinoflagellate groups.
Thermomechanical Characterization of Carbon Black Reinforced Rubbers During Rapid Adiabatic Straining
Authors: Kyei-Manu William Amoako , Tunnicliffe Lewis B. , Plagge Jan , Herd Charles R. , Akutagawa Keizo , Pugno Nicola M. , Busfield James J. C.
Published: October 2021

The thermo-mechanical properties of carbon black reinforced natural and styrene butadiene rubbers are investigated under rapid adiabatic conditions. Eleven carbon black grades with varying surface area and structure properties at 40 parts per hundred (phr) loading are studied and the unreinforced equivalents are included for reference. The results show a strong correlation of the modulus, mechanical hysteresis, temperature rise and calculated crystallinity of the rubbers measured in tensile extension with strain amplification factors. This highlights the influence of matrix overstraining on microstructural deformations of the rubber upon extension. The strain amplification factors are calculated via the Guth-Gold equation directly from carbon black type and loading, allowing a correlation of the fundamental morphological properties of carbon black with thermal and mechanical properties of rubbers upon extension. Analysis of the thermal measurements of the rubber compounds upon extension and retraction and contrasting between crystallizing and non-crystallizing rubbers reveals that a substantial irreversible heat generation is present upon extension of the rubber compounds. These irreversible effects most likely originate from microstructural damage mechanisms which have been proposed to account for the Mullins Effect in particle reinforced rubbers.
Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions
Authors: Albalat Emmanuelle , Cavey Thibault , Leroyer Patricia , Ropert Martine , Balter Vincent , Loréal Olivier
Published: October 2021

Hereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of hemochromatosis patients and is sensitive to the amount of total iron removed by the phlebotomy treatment. The use of stable isotopes to unravel the pathological mechanisms of iron overload diseases is promising but hampered by the lack of data in organs involved in the iron metabolism. Here, we use Hfe−/− mice, a model of hereditary hemochromatosis, to study the impact of the knock-out on iron isotope compositions of erythrocytes, spleen and liver. Iron concentration increases in liver and red blood cells of Hfe−/− mice compared to controls. The iron stable isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of iron heavy isotopes in Hfe−/− mice. In contrast, no difference in the iron concentration nor isotope composition is observed in spleen of Hfe−/− and control mice. Our results in mice suggest that the observed increase of whole blood isotope composition in hemochromatosis human patients does not originate from, but is aggravated by, bloodletting. The subsequent rapid increase of whole blood iron isotope composition of treated hemochromatosis patients is rather due to the release of hepatic heavy isotope-enriched iron than augmented iron dietary absorption. Further research is required to uncover the iron light isotope component that needs to balance the accumulation of hepatic iron heavy isotope, and to better understand the iron isotope fractionation associated to metabolism dysregulation during hereditary hemochromatosis.
Broadening the Mutation Spectrum in GJA8 and CHMP4B: Novel Missense Variants and the Associated Phenotypes in Six Chinese Han Congenital Cataracts Families
Authors: Wang Xun , Wang Dongni , Wang Qiwei , Huang Weiming , Dongye Meimei , Zhang Xulin , Lin Duoru , Lin Zhuoling , Li Jing , Hu Weiling , Li Xiaoyan , Lin Xiaoshan , Zhong Qiuping , Chen Weirong , Lin Haotian
Published: October 2021

Purpose: To broaden the mutation and phenotype spectrum of the GJA8 and CHMP4B genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs).

Methods: Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins.

Results: Four heterozygous candidate variants in three different genes (CRYBB2, GJA8, and CHMP4B) were identified in affected individuals from the six families, including two novel missense variants (GJA8: c.64G > C/p. G22R, and CHMP4B: c.587C > G/p. S196C), one missense mutation (CRYBB2: c.562C > T/p. R188C), and one small deletion (GJA8: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the GJA8: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts.

Conclusion: This study further expands the mutation spectrum and genotype-phenotype correlation of CRYBB2, GJA8, and CHMP4B underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants.
The Influence of Analysis Mode Selection on Prediction Accuracy of Corneal Astigmatism Using Pentacam
Authors: Meng Jiaqi , Yu Jifeng , He Wenwen , Wei Ling , Lu Yi , Zhu Xiangjia
Published: October 2021

Purpose: To evaluate the influence of analysis mode selection on prediction accuracy of corneal astigmatism using Pentacam.

Methods: Fifty-nine eyes of 59 patients implanted with toric intraocular lenses (IOLs) were included in the retrospective study. Preoperative corneal astigmatism (total refractive power) measured with Pentacam was analyzed based on 2-, 3-, 4-, or 5-mm ring or zone mode either centered on corneal apex or pupil center. Actual corneal astigmatism was calculated based on residual astigmatism on the corneal plane, surgical-induced astigmatism, and effective toric power on the corneal plane. Prediction error, the difference between actual corneal astigmatism and measured astigmatism, was compared among different analysis modes. Influences of local topography on prediction error were also evaluated.

Results: Based on the zone mode, prediction error was lower when centered on corneal apex than on pupil center at different diameters, whereas based on the ring mode, this difference was only seen at 2-mm cornea (all P < 0.05). When centered on the corneal apex, the zone mode showed lower prediction error than the ring mode at 4- and 5-mm corneas (both P < 0.001), regardless of asymmetric or symmetric astigmatism. In symmetric bowtie, the zone mode showed lower prediction error than the ring mode at 2-mm cornea of the small bowtie, and 4- and 5-mm corneas of the large bowtie (all P < 0.05).

Conclusions: For toric IOL planning, the corneal apex may be a better reference center. At a cornea diameter ≥4 mm, the zone mode is more accurate than the ring mode. Local topography affects prediction accuracy in the symmetric bowtie.
Morphological and Functional Relationship Between OCTA and FA/ICGA Quantitative Features in AMD-Related Macular Neovascularization
Authors: Arrigo Alessandro , Aragona Emanuela , Bordato Alessandro , Amato Alessia , Borghesan Federico , Bandello Francesco , Battaglia Parodi Maurizio
Published: October 2021

Background: The aim was to study the relationship between quantitative information provided by optical coherence tomography (OCT) angiography (OCTA) and conventional angiography in macular neovascularization (MNV) secondary to age-related macular degeneration (AMD).

Methods: The research was designed as an interventional, prospective study. We included 66 eyes (66 patients) affected by naïve MNV. Multimodal imaging included structural OCT, OCTA, fluorescein angiography (FA), and indocyanine green angiography (ICGA). The follow-up lasted 1 year. Patients were treated by PRN anti-VEGF injections. Based on FA/ICGA examinations, we divided the patients into two categories: low vessel tortuosity (VT) (<8.40) and high VT (>8.40), correlating VT with the MNV area, leakage area, speckled fluorescence (SF) quadrants and MNV area/leakage area ratio.

Results: Mean baseline BCVA was 0.50 ± 0.61 LogMAR, improved to 0.31 ± 0.29 LogMAR after 1 year (p < 0.01), with a mean number of 7 ± 2 anti-VEGF injections. The patients revealed type-1 MNV in 36 eyes (55%), mixed type 1 and 2 MNV in 18 eyes (27%), and type-2 MNV in 12 eyes (18%). MNV eyes in high-VT MNV featured poorer BCVA, CMT, and OCTA parameters, higher SF quadrants, and less exudation, compared with low-VT MNV (p < 0.01). Moreover, 30% of high-VT MNV eyes developed outer retinal atrophy.

Conclusions: Low VT MNV turned out to be more exudative at the baseline but less damaging to the outer retinal structures, whereas high VT MNV proved to be less exudative but more prone to lead to atrophic changes and visual function deterioration. VT may be usefully applied to artificial intelligence-based models designed to characterize MNV secondary to AMD.
Transcriptional Response of Mycobacterium tuberculosis to Cigarette Smoke Condensate
Authors: Willemse Danicke , Moodley Chivonne , Mehra Smriti , Kaushal Deepak
Published: October 2021

Smoking is known to be an added risk factor for tuberculosis (TB), with nearly a quarter of the TB cases attributed to cigarette smokers in the 22 countries with the highest TB burden. Many studies have indicated a link between risk of active TB and cigarette smoke. Smoking is also known to significantly decrease TB cure and treatment completion rate and increase mortality rates. Cigarette smoke contains thousands of volatile compounds including carcinogens, toxins, reactive solids, and oxidants in both particulate and gaseous phase. Yet, to date, limited studies have analyzed the impact of cigarette smoke components on Mycobacterium tuberculosis (Mtb), the causative agent of TB. Here we report the impact of cigarette smoke condensate (CSC) on survival, mutation frequency, and gene expression of Mtb in vitro. We show that exposure of virulent Mtb to cigarette smoke increases the mutation frequency of the pathogen and strongly induces the expression of the regulon controlled by SigH—a global transcriptional regulator of oxidative stress. SigH has previously been shown to be required for Mtb to respond to oxidative stress, survival, and granuloma formation in vivo. A high-SigH expression phenotype is known to be associated with greater virulence of Mtb. In patients with pulmonary TB who smoke, these changes may therefore play an important, yet unexplored, role in the treatment efficacy by potentially enhancing the virulence of tubercle bacilli.
Biofilm Formation in Methicillin-Resistant Staphylococcus aureus Isolated in Cystic Fibrosis Patients Is Strain-Dependent and Differentially Influenced by Antibiotics
Authors: Boudet Agathe , Sorlin Pauline , Pouget Cassandra , Chiron Raphaël , Lavigne Jean-Philippe , Dunyach-Remy Catherine , Marchandin Hélène
Published: October 2021

Cystic fibrosis (CF) is a genetic disease with lung abnormalities making patients particularly predisposed to pulmonary infections. Staphylococcus aureus is the most frequently identified pathogen, and multidrug-resistant strains (MRSA, methicillin-resistant S. aureus) have been associated with more severe lung dysfunction leading to eradication recommendations. Diverse bacterial traits and adaptive skills, including biofilm formation, may, however, make antimicrobial therapy challenging. In this context, we compared the ability of a collection of genotyped MRSA isolates from CF patients to form biofilm with and without antibiotics (ceftaroline, ceftobiprole, linezolid, trimethoprim, and rifampicin). Our study used standardized approaches not previously applied to CF MRSA, the BioFilm Ring test® (BRT®), the Antibiofilmogram®, and the BioFlux™ 200 system which were adapted for use with the artificial sputum medium (ASM) mimicking conditions more relevant to the CF lung. We included 63 strains of 10 multilocus sequence types (STs) isolated from 35 CF patients, 16 of whom had chronic colonization. The BRT® showed that 27% of the strains isolated in 37% of the patients were strong biofilm producers. The Antibiofilmogram® performed on these strains showed that broad-spectrum cephalosporins had the lowest minimum biofilm inhibitory concentrations (bMIC) on a majority of strains. A focus on four chronically colonized patients with inclusion of successively isolated strains showed that ceftaroline, ceftobiprole, and/or linezolid bMICs may remain below the resistance thresholds over time. Studying the dynamics of biofilm formation by strains isolated 3years apart in one of these patients using BioFlux™ 200 showed that inhibition of biofilm formation was observed for up to 36h of exposure to bMIC and ceftaroline and ceftobiprole had a significantly greater effect than linezolid. This study has brought new insights into the behavior of CF MRSA which has been little studied for its ability to form biofilm. Biofilm formation is a common characteristic of prevalent MRSA clones in CF. Early biofilm formation was strain-dependent, even within a sample, and not only observed during chronic colonization. Ceftaroline and ceftobiprole showed a remarkable activity with a long-lasting inhibitory effect on biofilm formation and a conserved activity on certain strains adapted to the CF lung environment after years of colonization.
Mini Review: Advances in 2-Haloacid Dehalogenases
Authors: Wang Yayue , Xiang Qiao , Zhou Qingfeng , Xu Jingliang , Pei Dongli
Published: October 2021

The 2-haloacid dehalogenases (EC 3.8.1.X) are industrially important enzymes that catalyze the cleavage of carbon–halogen bonds in 2-haloalkanoic acids, releasing halogen ions and producing corresponding 2-hydroxyl acids. These enzymes are of particular interest in environmental remediation and environmentally friendly synthesis of optically pure chiral compounds due to their ability to degrade a wide range of halogenated compounds with astonishing efficiency for enantiomer resolution. The 2-haloacid dehalogenases have been extensively studied with regard to their biochemical characterization, protein crystal structures, and catalytic mechanisms. This paper comprehensively reviews the source of isolation, classification, protein structures, reaction mechanisms, biochemical properties, and application of 2-haloacid dehalogenases; current trends and avenues for further development have also been included.
Construction of a Novel Signature and Prediction of the Immune Landscape in Soft Tissue Sarcomas Based on N6-Methylandenosine-Related LncRNAs
Authors: Zhang Li , Tang Xianzhe , Wan Jia , Zhang Xianghong , Zheng Tao , Lin Zhengjun , Liu Tang
Published: October 2021

Background: N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) are critically involved in cancer development. However, the roles and clinical significance of m6A-related lncRNAs in soft tissue sarcomas (STS) are inconclusive, thereby warranting further investigations.

Methods: Transcriptome profiling data were extracted from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx). Consensus clustering was employed to divide patients into clusters and Kaplan–Meier analysis was used to explore the prognostic differences between the subgroups. Gene set enrichment analysis (GSEA) was conducted to identify the biological processes and signaling pathways associated with m6A-Related lncRNAs. Finally, patients were randomly divided into training and validation cohorts, and least absolute shrinkage and selection operator (LASSO) Cox regression was conducted to establish the m6A-related lncRNA-based risk signature.

Results: A total of 259 STS patients from TCGA-SARC dataset were enrolled in our study. Thirteen m6A-Related lncRNAs were identified to be closely related to the prognosis of STS patients. Patients were divided into two clusters, and patients in cluster 2 had a better overall survival (OS) than those in cluster 1. Patients in different clusters also showed differences in immune scores, infiltrating immune cells, and immune checkpoint expression. Patients were further classified into high-risk and low-risk subgroups according to risk scores, and high-risk patients were found to have a worse prognosis. The receiver operating characteristic (ROC) curve indicated that the risk signature displayed excellent performance at predicting the prognosis of patients with STS. Further, the risk signature was remarkably connected with the immune microenvironment and chemosensitivity in STS.

Conclusion: Our study demonstrated that m6A-related lncRNAs were significantly associated with prognosis and tumor immune microenvironment and could function as independent prognosis-specific predictors in STS, thereby providing novel insights into the roles of m6A-related lncRNAs in STS.
Application of Single-Cell Multi-Omics in Dissecting Cancer Cell Plasticity and Tumor Heterogeneity
Authors: Pan Deshen , Jia Deshui
Published: October 2021

Tumor heterogeneity, a hallmark of cancer, impairs the efficacy of cancer therapy and drives tumor progression. Exploring inter- and intra-tumoral heterogeneity not only provides insights into tumor development and progression, but also guides the design of personalized therapies. Previously, high-throughput sequencing techniques have been used to investigate the heterogeneity of tumor ecosystems. However, they could not provide a high-resolution landscape of cellular components in tumor ecosystem. Recently, advance in single-cell technologies has provided an unprecedented resolution to uncover the intra-tumoral heterogeneity by profiling the transcriptomes, genomes, proteomes and epigenomes of the cellular components and also their spatial distribution, which greatly accelerated the process of basic and translational cancer research. Importantly, it has been demonstrated that some cancer cells are able to transit between different states in order to adapt to the changing tumor microenvironment, which led to increased cellular plasticity and tumor heterogeneity. Understanding the molecular mechanisms driving cancer cell plasticity is critical for developing precision therapies. In this review, we summarize the recent progress in dissecting the cancer cell plasticity and tumor heterogeneity by use of single-cell multi-omics techniques.
Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer
Authors: He Xiao-Shun , Zou Sheng-Yi , Yao Jia-Lu , Yu Wangjianfei , Deng Zhi-Yong , Wang Jing-Ru , Gan Wen-Juan , Wan Shan , Yang Xiao-Qin , Wu Hua
Published: October 2021

Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance.

Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC.

Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression.

Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.
Measurement Method of Human Lower Limb Joint Range of Motion Through Human-Machine Interaction Based on Machine Vision
Authors: Wang Xusheng , Liu Guowei , Feng Yongfei , Li Wei , Niu Jianye , Gan Zhongxue
Published: October 2021

To provide stroke patients with good rehabilitation training, the rehabilitation robot should ensure that each joint of the limb of the patient does not exceed its joint range of motion. Based on the machine vision combined with an RGB-Depth (RGB-D) camera, a convenient and quick human-machine interaction method to measure the lower limb joint range of motion of the stroke patient is proposed. By analyzing the principle of the RGB-D camera, the transformation relationship between the camera coordinate system and the pixel coordinate system in the image is established. Through the markers on the human body and chair on the rehabilitation robot, an RGB-D camera is used to obtain their image data with relative position. The threshold segmentation method is used to process the image. Through the analysis of the image data with the least square method and the vector product method, the range of motion of the hip joint, knee joint in the sagittal plane, and hip joint in the coronal plane could be obtained. Finally, to verify the effectiveness of the proposed method for measuring the lower limb joint range of motion of human, the mechanical leg joint range of motion from a lower limb rehabilitation robot, which will be measured by the angular transducers and the RGB-D camera, was used as the control group and experiment group for comparison. The angle difference in the sagittal plane measured by the proposed detection method and angle sensor is relatively conservative, and the maximum measurement error is not more than 2.2 degrees. The angle difference in the coronal plane between the angle at the peak obtained by the designed detection system and the angle sensor is not more than 2.65 degrees. This paper provides an important and valuable reference for the future rehabilitation robot to set each joint range of motion limited in the safe workspace of the patient.
A Comparison Between Pressure Wire and Microcatheter Measurements for Evaluating the Cerebral Venous Pressure Gradient
Authors: Horev Anat , Lorber Dana , Vardi-Dvash Noa , Zlotnik Yair , Biederko Ron , Ifergane Gal , Shelef Ilan , Zvenigorodsky Vladislav , Horev Amir
Published: October 2021

Introduction: A pressure gradient of over 8 mm Hg across the stenosis (usually located in the transverse-sigmoid junction) is one of the criteria for cerebral venous stenting in idiopathic intracranial hypertension (IIH) patients. The possible inaccuracy of the traditional microcatheter-based pressure measurements has been discussed in previous studies. In the cardiology field, a dual-sensor pressure wire is routinely used for the evaluation of stenotic lesions. Using a pressure wire for cerebral vasculature was previously discussed in a small case series and case reports. In this study, we compared venous pressure measurements obtained using both a microcatheter and a pressure wire in patients who were candidates for stenting.

Methods: A retrospective study was conducted, comparing the two methods of pressure measurements in 26 patients with venous stenosis. Altogether, 120 measurements were performed using both methods. Demographic characteristics, medical history, procedural details, medications, indications for the procedure, and complications were collected from the patient charts.

Results: Based on an 8-mm Hg pressure gradient cutoff indication, 19 patients were found eligible to go through unilateral venous stenting based on catheter measurements alone. The wire results corroborated the catheter results in detecting all cases indicated for a stent. This finding implies a sensitivity equal to 100% for the wire measurements. There were no wire-related complications, demonstrating its safety.

Conclusions: We conclude that the pressure wire is as safe as the microcatheter and can identify cases requiring intervention. A larger-scale study is needed to assess the measurement accuracy of the pressure wire in brain vasculature.
Functional Connectivity Analysis in Motor-Imagery Brain Computer Interfaces
Authors: Leeuwis Nikki , Yoon Sue , Alimardani Maryam
Published: October 2021

Motor Imagery BCI systems have a high rate of users that are not capable of modulating their brain activity accurately enough to communicate with the system. Several studies have identified psychological, cognitive, and neurophysiological measures that might explain this MI-BCI inefficiency. Traditional research had focused on mu suppression in the sensorimotor area in order to classify imagery, but this does not reflect the true dynamics that underlie motor imagery. Functional connectivity reflects the interaction between brain regions during the MI task and resting-state network and is a promising tool in improving MI-BCI classification. In this study, 54 novice MI-BCI users were split into two groups based on their accuracy and their functional connectivity was compared in three network scales (Global, Large and Local scale) during the resting-state, left vs. right-hand motor imagery task, and the transition between the two phases. Our comparison of High and Low BCI performers showed that in the alpha band, functional connectivity in the right hemisphere was increased in High compared to Low aptitude MI-BCI users during motor imagery. These findings contribute to the existing literature that indeed connectivity might be a valuable feature in MI-BCI classification and in solving the MI-BCI inefficiency problem.
Automatic Seizure Classification Based on Domain-Invariant Deep Representation of EEG
Authors: Cao Xincheng , Yao Bin , Chen Binqiang , Sun Weifang , Tan Guowei
Published: October 2021

Accurate identification of the type of seizure is very important for the treatment plan and drug prescription of epileptic patients. Artificial intelligence has shown considerable potential in the fields of automated EEG analysis and seizure classification. However, the highly personalized representation of epileptic seizures in EEG has led to many research results that are not satisfactory in clinical applications. In order to improve the clinical adaptability of the algorithm, this paper proposes an adversarial learning-driven domain-invariant deep feature representation method, which enables the hybrid deep networks (HDN) to reliably identify seizure types. In the train phase, we first use the labeled multi-lead EEG short samples to train squeeze-and-excitation networks (SENet) to extract short-term features, and then use the compressed samples to train the long short-term memory networks (LSTM) to extract long-time features and construct a classifier. In the inference phase, we first adjust the feature mapping of LSTM through the adversarial learning between LSTM and clustering subnet so that the EEG of the target patient and the EEG in the database obey the same distribution in the deep feature space. Finally, we use the adjusted classifier to identify the type of seizure. Experiments were carried out based on the TUH EEG Seizure Corpus and CHB-MIT seizure database. The experimental results show that the proposed domain adaptive deep feature representation improves the classification accuracy of the hybrid deep model in the target set by 5%. It is of great significance for the clinical application of EEG automatic analysis equipment.
An Expanded Polyproline Domain Maintains Mutant Huntingtin Soluble in vivo and During Aging
Authors: Pigazzini Maria Lucia , Lawrenz Mandy , Margineanu Anca , Kaminski Schierle Gabriele S. , Kirstein Janine
Published: October 2021

Huntington’s disease is a dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat, encoding for the amino acid glutamine (Q), present in the first exon of the protein huntingtin. Over the threshold of Q39 HTT exon 1 (HTTEx1) tends to misfold and aggregate into large intracellular structures, but whether these end-stage aggregates or their on-pathway intermediates are responsible for cytotoxicity is still debated. HTTEx1 can be separated into three domains: an N-terminal 17 amino acid region, the polyglutamine (polyQ) expansion and a C-terminal proline rich domain (PRD). Alongside the expanded polyQ, these flanking domains influence the aggregation propensity of HTTEx1: with the N17 initiating and promoting aggregation, and the PRD modulating it. In this study we focus on the first 11 amino acids of the PRD, a stretch of pure prolines, which are an evolutionary recent addition to the expanding polyQ region. We hypothesize that this proline region is expanding alongside the polyQ to counteract its ability to misfold and cause toxicity, and that expanding this proline region would be overall beneficial. We generated HTTEx1 mutants lacking both flanking domains singularly, missing the first 11 prolines of the PRD, or with this stretch of prolines expanded. We then followed their aggregation landscape in vitro with a battery of biochemical assays, and in vivo in novel models of C. elegans expressing the HTTEx1 mutants pan-neuronally. Employing fluorescence lifetime imaging we could observe the aggregation propensity of all HTTEx1 mutants during aging and correlate this with toxicity via various phenotypic assays. We found that the presence of an expanded proline stretch is beneficial in maintaining HTTEx1 soluble over time, regardless of polyQ length. However, the expanded prolines were only advantageous in promoting the survival and fitness of an organism carrying a pathogenic stretch of Q48 but were extremely deleterious to the nematode expressing a physiological stretch of Q23. Our results reveal the unique importance of the prolines which have and still are evolving alongside expanding glutamines to promote the function of HTTEx1 and avoid pathology.
Deep Brain Stimulation Can Differentiate Subregions of the Human Subthalamic Nucleus Area by EEG Biomarkers
Authors: Sand Daniel , Arkadir David , Abu Snineh Muneer , Marmor Odeya , Israel Zvi , Bergman Hagai , Hassin-Baer Sharon , Israeli-Korn Simon , Peremen Ziv , Geva Amir B. , Eitan Renana
Published: October 2021

Introduction: Precise lead localization is crucial for an optimal clinical outcome of subthalamic nucleus (STN) deep brain stimulation (DBS) treatment in patients with Parkinson's disease (PD). Currently, anatomical measures, as well as invasive intraoperative electrophysiological recordings, are used to locate DBS electrodes. The objective of this study was to find an alternative electrophysiology tool for STN DBS lead localization.

Methods: Sixty-one postoperative electrophysiology recording sessions were obtained from 17 DBS-treated patients with PD. An intraoperative physiological method automatically detected STN borders and subregions. Postoperative EEG cortical activity was measured, while STN low frequency stimulation (LFS) was applied to different areas inside and outside the STN. Machine learning models were used to differentiate stimulation locations, based on EEG analysis of engineered features.

Results: A machine learning algorithm identified the top 25 evoked response potentials (ERPs), engineered features that can differentiate inside and outside STN stimulation locations as well as within STN stimulation locations. Evoked responses in the medial and ipsilateral fronto-central areas were found to be most significant for predicting the location of STN stimulation. Two-class linear support vector machine (SVM) predicted the inside (dorso-lateral region, DLR, and ventro-medial region, VMR) vs. outside [zona incerta, ZI, STN stimulation classification with an accuracy of 0.98 and 0.82 for ZI vs. VMR and ZI vs. DLR, respectively, and an accuracy of 0.77 for the within STN (DLR vs. VMR)]. Multiclass linear SVM predicted all areas with an accuracy of 0.82 for the outside and within STN stimulation locations (ZI vs. DLR vs. VMR).

Conclusions: Electroencephalogram biomarkers can use low-frequency STN stimulation to localize STN DBS electrodes to ZI, DLR, and VMR STN subregions. These models can be used for both intraoperative electrode localization and postoperative stimulation programming sessions, and have a potential to improve STN DBS clinical outcomes.
A Catalog of Natural Products Occurring in Watermelon—Citrullus lanatus
Authors: Sorokina Maria , McCaffrey Kira S. , Deaton Erin E. , Ma Guoying , Ordovás José M. , Perkins-Veazie Penelope M. , Steinbeck Christoph , Levi Amnon , Parnell Laurence D.
Published: October 2021

Graphical Abstract
The Saturation Effect of Body Mass Index on Bone Mineral Density for People Over 50 Years Old: A Cross-Sectional Study of the US Population
Authors: Ma Ming , Feng Zhiwei , Liu Xiaolong , Jia Gengxin , Geng Bin , Xia Yayi
Published: October 2021

Background: Previous studies had revealed that Body Mass Index (BMI) positively affected Bone Mineral Density (BMD). However, an excessively high BMI was detrimental to health, especially for the elderly. Moreover, it was elusive how much BMI was most beneficial for BMD in older adults to maintain.

Objective: To investigate whether there was a BMI saturation effect value that existed to maintain optimal BMD.

Methods: A cross-sectional study was conducted using the datasets of the National Health and Nutrition Examination Survey (NHANES) 2005–2006, 2007–2008, 2009–2010, 2013–2014, and 2017–2018. After adjusting for covariates, an analysis of the association between BMI and BMD in different femoral regions (Total femur, Femoral neck, Trochanter, Intertrochanter, and Ward's triangle) and lumbar spine regions (Total spine, L1, L2, L3, and L4) in the whole population was performed using the multivariate linear regression models, smoothing curve fitting, and saturation effects analysis models. Then, subgroup analyses were performed according to gender, age, and race.

Results: A total of 10,910 participants (5,654 males and 5,256 females) over 50 years were enrolled in this population-based study. Multivariate linear regression analyses in the population older than 50 years showed that BMI was positively associated with femoral BMD and lumbar spine BMD (P < 0.001, respectively). Smoothing curve fitting showed that the relationship between BMI and BMD was not simply linear and that a saturation value existed. The saturation effect analysis showed that the BMI saturation value was 26.13 (kg/m2) in the total femur, 26.82 (kg/m2) in the total spine, and showed site-specificity in L1 (31.90 kg/m2) and L2 (30.89 kg/m2). The saturation values were consistent with the whole participants in males, while there was high variability in the females. BMI saturation values remained present in subgroup analyses by age and race, showing specificity in some age (60–70 years old) groups and in some races.

Conclusions: Our study showed a saturation value association between BMI and BMD for people over 50 years old. Keeping the BMI in the slightly overweight value (around 26 kg/m2) might reduce other adverse effects while obtaining optimal BMD.
Identification of a Putative Enhancer RNA for EGFR in Hyper-Accessible Regions in Esophageal Squamous Cell Carcinoma Cells by Analysis of Chromatin Accessibility Landscapes
Authors: Choi Sangyong , Sathe Adwait , Mathé Ewy , Xing Chao , Pan Zui
Published: October 2021

Abnormal genetic and epigenetic modifications play a key role in esophageal cancer. By Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq), this study compared chromatin accessibility landscapes among two esophageal squamous cell carcinoma (ESCC) cell lines, KYSE-30 and KYSE-150, and a non-cancerous esophageal epithelial cell line, HET-1A. Data showed that hyper-accessible regions in ESCC cells contained genes related with cancer hallmarks, such as epidermal growth factor receptor (EGFR). Multi-omics analysis and digital-droplet PCR results demonstrated that several non-coding RNAs in EGFR upstream were upregulated in ESCC cells. Among them, one appeared to act as an enhancer RNA responsible for EGFR overexpression. Further motif analysis and pharmacological data suggested that AP-1 family transcription factors were able to bind the hyper-accessible regions and thus to regulate cancer cell proliferation and migration. This study discovered a putative enhancer RNA for EGFR gene and the reliance of ESCC on AP-1 transcription factor.