bluuebunny/crossref_metadata_2025 huggingface dataset:
Ikzf2 Regulates the Development of ICOS+ Th Cells to Mediate Immune Response in the Spleen of S. japonicum-Infected C57BL/6 Mice
Authors: Xie Shihao , Wei Haixia , Peng Anping , Xie Anqi , Li Jiajie , Fang Chao , Shi Feihu , Yang Quan , Huang He , Xie Hongyan , Pan Xingfei , Tian Xu , Huang Jun
Published: August 2021

Background

Th cells (helper T cells) have multiple functions in Schistosoma japonicum (S. japonicum) infection. Inducible co-stimulator (ICOS) is induced and expressed in activated T lymphocytes, which enhances the development of B cells and antibody production through the ICOS/ICOSL pathway. It remains unclear about the role and possible regulating mechanism of ICOS+ Th cells in the spleen of S. japonicum-infected C57BL/6 mice.

Methods

C57BL/6 mice were infected with cercariae of S. japonicum through the abdomen. The expression of ICOS, activation markers, and the cytokine production on CD4+ ICOS+ Th cells were detected by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR). Moreover, the differentially expressed gene data of ICOS+ and ICOS− Th cells from the spleen of infected mice were obtained by mRNA sequencing. Besides, Western blot and chromatin immunoprecipitation (ChIP) were used to explore the role of Ikzf2 on ICOS expression.

Results

After S. japonicum infection, the expression of ICOS molecules gradually increased in splenic lymphocytes, especially in Th cells (P < 0.01). Compared with ICOS− Th cells, more ICOS+ Th cells expressed CD69, CD25, CXCR5, and CD40L (P < 0.05), while less of them expressed CD62L (P < 0.05). Also, ICOS+ Th cells expressed more cytokines, such as IFN-γ, IL-4, IL-10, IL-2, and IL-21 (P < 0.05). RNA sequencing results showed that many transcription factors were increased significantly in ICOS+ Th cells, especially Ikzf2 (P < 0.05). And then, the expression of Ikzf2 was verified to be significantly increased and mainly located in the nuclear of ICOS+ Th cells. Finally, ChIP experiments and dual-luciferase reporter assay confirmed that Ikzf2 could directly bind to the ICOS promoter in Th cells.

Conclusion

In this study, ICOS+ Th cells were found to play an important role in S. japonicum infection to induce immune response in the spleen of C57BL/6 mice. Additionally, Ikzf2 was found to be one important transcription factor that could regulate the expression of ICOS in the spleen of S. japonicum-infected C57BL/6 mice.
RAPID: A Rep-Seq Dataset Analysis Platform With an Integrated Antibody Database
Authors: Zhang Yanfang , Chen Tianjian , Zeng Huikun , Yang Xiujia , Xu Qingxian , Zhang Yanxia , Chen Yuan , Wang Minhui , Zhu Yan , Lan Chunhong , Wang Qilong , Tang Haipei , Zhang Yan , Wang Chengrui , Xie Wenxi , Ma Cuiyu , Guan Junjie , Guo Shixin , Chen Sen , Yang Wei , Wei Lai , Ren Jian , Yu Xueqing , Zhang Zhenhai
Published: August 2021

The antibody repertoire is a critical component of the adaptive immune system and is believed to reflect an individual’s immune history and current immune status. Delineating the antibody repertoire has advanced our understanding of humoral immunity, facilitated antibody discovery, and showed great potential for improving the diagnosis and treatment of disease. However, no tool to date has effectively integrated big Rep-seq data and prior knowledge of functional antibodies to elucidate the remarkably diverse antibody repertoire. We developed a Rep-seq dataset Analysis Platform with an Integrated antibody Database (RAPID; https://rapid.zzhlab.org/), a free and web-based tool that allows researchers to process and analyse Rep-seq datasets. RAPID consolidates 521 WHO-recognized therapeutic antibodies, 88,059 antigen- or disease-specific antibodies, and 306 million clones extracted from 2,449 human IGH Rep-seq datasets generated from individuals with 29 different health conditions. RAPID also integrates a standardized Rep-seq dataset analysis pipeline to enable users to upload and analyse their datasets. In the process, users can also select set of existing repertoires for comparison. RAPID automatically annotates clones based on integrated therapeutic and known antibodies, and users can easily query antibodies or repertoires based on sequence or optional keywords. With its powerful analysis functions and rich set of antibody and antibody repertoire information, RAPID will benefit researchers in adaptive immune studies.
Gut Bacterial Characteristics of Patients With Type 2 Diabetes Mellitus and the Application Potential
Authors: Que Yanyan , Cao Man , He Jianquan , Zhang Qiang , Chen Qiongyun , Yan Changsheng , Lin Aiqiang , Yang Luxi , Wu Zezhen , Zhu Dan , Chen Fengwu , Chen Zhangran , Xiao Chuanxing , Hou Kaijian , Zhang Bangzhou
Published: August 2021

Type 2 diabetes mellitus (T2DM) is a complex disorder comprehensively influenced by genetic and environmental risk, and research increasingly has indicated the role of microbial dysbiosis in T2DM pathogenesis. However, studies comparing the microbiome characteristics between T2DM and healthy controls have reported inconsistent results. To further identify and describe the characteristics of the intestinal flora of T2DM patients, we performed a systematic review and meta-analysis of stool microbial profiles to discern and describe microbial dysbiosis in T2DM and to explore heterogeneity among 7 studies (600 T2DM cases, 543 controls, 1143 samples in total). Using a random effects model and a fixed effects model, we observed significant differences in beta diversity, but not alpha diversity, between individuals with T2DM and controls. We identified various operational taxonomic unit (OTUs) and bacterial genera with significant odds ratios for T2DM. The T2DM signatures derived from a single study by stepwise feature selection could be applied in other studies. By training on multiple studies, we improved the detection accuracy and disease specificity for T2DM. We also discuss the relationship between T2DM-enriched or T2DM-depleted genera and probiotics and provide new ideas for diabetes prevention and improvement.
Towards Winter Seasonal Predictability of the North West European Shelf Seas
Authors: Tinker Jonathan , Hermanson Leon
Published: August 2021

We investigate the winter predictability of the North West European shelf seas (NWS), using the Met Office seasonal forecasting system GloSea5 and the Copernicus NWS reanalysis. We assess GloSea5’s representation of NWS climatological winter and its skill at forecasting winter conditions on the NWS. We quantify NWS winter persistence and compare this to the forecast skill. GloSea5 simulates the winter climatology adequately. We find important errors in the residual circulation (particularly in the Irish Sea) that introduce temperature and salinity biases in the Irish Sea, English Channel, and southern North Sea. The GloSea5 winter skill is significant for SST across most of the NWS but is lower in the southern North Sea. Salinity skill is not significant in the regions affected by the circulation errors. There is considerable NWS winter temperature and salinity persistence. GloSea5 exhibits significant predictive skill above this over ∼20% of the NWS, but for most of the NWS this is not the case. Dynamical downscaling is one method to improve the GloSea5 simulation of the NWS and its circulation, which may reduce biases and increase predictive skill. We investigate this approach with a pair of case studies, comparing the winters of 2010/2011 and 2011/2012 (with contrasting temperature and salinity anomalies, and NAO state). While 2 years are insufficient to assess skill, the differences in the simulations are evaluated, and their implications for the NWS winter predictability are considered. The NWS circulation is improved (where it was poor in the GloSea5), allowing more realistic advective pathways for salinity (and temperature) and enhancing their climatological spatial distributions. However, as the GloSea5 SST anomaly is already well simulated, downscaling does not substantially improve this – in other seasons or for other variables, downscaling may add more value. We show that persistence of early winter values provides some predictive skill for the NWS winter SST, and that the GloSea5 system adds modestly to this skill in certain regions. Such information will allow prospective end-users to consider how seasonal forecasts might be useful for their sector, providing the foundation on which marine environmental seasonal forecasts service and community may be developed for the NWS.
The Variability in Cytocompatibility and Bone Conduction Based on Different Pore Size and Porosity of n-HA/PA66 Composite Scaffolds
Authors: Liu Yiming , Zhang Rui , Liu Sirui , Sun Jingjing , Zhang Xue , Kang Peng , Zhang Ruipu , Yang Yanyu , Li Rui
Published: August 2021

As porous materials, nano-hydroxyapatite/polyamide 66 (n-HA/PA66) composite scaffolds with both desirable bioactivity and good mechanical properties showed great potential to reconstruct the bone defect. Moreover, the pore size and porosity played a key role in the scaffold architecture and cell or bone ingrowth. To investigate the cytocompatibility of different pore size and porosity of n-HA/PA66 composite scaffolds on differentiation and cytocompatibility of osteogenically induced bone marrow-derived mesenchymal stem cells (BMSCs) and bone conduction in repairing the calvarial critical size defect of Sprague-Dawley rats in vivo, we evaluated three kinds of n-HA/PA66 composite scaffolds according to the pore size and porosity in this study (group A: mean pore size was 214 ± 107.3 μm, and more than 70% were arranged in 100–300 μm; group B: material mean pore size was 375 ± 132.2 μm, and about 60% were distributed in 300–500 μm; group C: mean pore size was 533 ± 169.4 μm, and more than 60% were in 400–700 μm). Osteogenically induced BMSCs were seeded in the three types of n-HA/PA66 material and cultured in vitro, and the variability on cell adhesion, growth, proliferation, osteogenic differentiation was analyzed using scanning electron microscopy alkaline phosphatase (ALP) and collagen type I (COL I) immunohistochemical staining, as well as quantitative real-time PCR (qRT-PCR) analysis on the osteogenesis-related gene expression (alkaline phosphatase, COL I), was done. Three group matrices/BMSC composites were implanted into the cranial defect of Sprague-Dawley rats. The differentiations of osteogenesis in vivo were then evaluated by histological and qRT-PCR analysis on mRNA levels of OPG and RANKL after 4 and 8 weeks, respectively. The in vitro and in vivo results showed that the group B n-HA/PA66 scaffold was more suitable for osteogenically induced BMSC proliferation, differentiation in vitro, and bone conduction in vivo than groups A and C, indicating that the porous n-HA/PA66 matrices with a mean pore size of 375 ± 132.2 μm and porosity 77 ± 2.9% have better cell biocompatibility and bone conduction.
Reversible Superwetting Transition Between Superhydrophilicity and Superhydrophobicity on a Copper Sheet, and Its Corrosion Performance
Authors: Li Hong , Chen Tiange , Lu Yanfeng , Fu Xinyu , Chu Xingwen , Liu Qinzhuang , Zhang Jinfeng
Published: August 2021

Dense copper oxide nanoribbons arrays are prepared on a copper sheet by using a low-temperature hydrothermal method. The wettability of the surface modified by stearic acid is superhydrophobic, and the water contact angle is 153.6°. It is demonstrated that the reversible transition from superhydrophilicity to superhydrophobicity is successfully achieved by heat treatment and re-modification, and the whole process can be accomplished in 170 s. Potentiodynamic polarization curves and Nyquist curves show that these superhydrophobic surfaces have good corrosion resistance and superior durability.
From Single Batch to Mass Production–Automated Platform Design Concept for a Phase II Clinical Trial Tissue Engineered Cartilage Product
Authors: Haeusner Sebastian , Herbst Laura , Bittorf Patrick , Schwarz Thomas , Henze Chris , Mauermann Marc , Ochs Jelena , Schmitt Robert , Blache Ulrich , Wixmerten Anke , Miot Sylvie , Martin Ivan , Pullig Oliver
Published: August 2021

Advanced Therapy Medicinal Products (ATMP) provide promising treatment options particularly for unmet clinical needs, such as progressive and chronic diseases where currently no satisfying treatment exists. Especially from the ATMP subclass of Tissue Engineered Products (TEPs), only a few have yet been translated from an academic setting to clinic and beyond. A reason for low numbers of TEPs in current clinical trials and one main key hurdle for TEPs is the cost and labor-intensive manufacturing process. Manual production steps require experienced personnel, are challenging to standardize and to scale up. Automated manufacturing has the potential to overcome these challenges, toward an increasing cost-effectiveness. One major obstacle for automation is the control and risk prevention of cross contaminations, especially when handling parallel production lines of different patient material. These critical steps necessitate validated effective and efficient cleaning procedures in an automated system. In this perspective, possible technologies, concepts and solutions to existing ATMP manufacturing hurdles are discussed on the example of a late clinical phase II trial TEP. In compliance to Good Manufacturing Practice (GMP) guidelines, we propose a dual arm robot based isolator approach. Our novel concept enables complete process automation for adherent cell culture, and the translation of all manual process steps with standard laboratory equipment. Moreover, we discuss novel solutions for automated cleaning, without the need for human intervention. Consequently, our automation concept offers the unique chance to scale up production while becoming more cost-effective, which will ultimately increase TEP availability to a broader number of patients.
Predictive Biomarkers of Intensive Care Unit and Mechanical Ventilation Duration in Critically-Ill Coronavirus Disease 2019 Patients
Authors: Taleb Sara , Yassine Hadi M. , Benslimane Fatiha M. , Smatti Maria K. , Schuchardt Sven , Albagha Omar , Al-Thani Asmaa A. , Ait Hssain Ali , Diboun Ilhame , Elrayess Mohamed A.
Published: August 2021

Introduction: Detection of early metabolic changes in critically-ill coronavirus disease 2019 (COVID-19) patients under invasive mechanical ventilation (IMV) at the intensive care unit (ICU) could predict recovery patterns and help in disease management.

Methods: Targeted metabolomics of serum samples from 39 COVID-19 patients under IMV in ICU was performed within 48 h of intubation and a week later. A generalized linear model (GLM) was used to identify, at both time points, metabolites and clinical traits that predict the length of stay (LOS) at ICU (short ≤ 14 days/long >14 days) as well as the duration under IMV. All models were initially trained on a set of randomly selected individuals and validated on the remaining individuals in the cohort. Further validation in recently published metabolomics data of COVID-19 severity was performed.

Results: A model based on hypoxanthine and betaine measured at first time point was best at predicting whether a patient is likely to experience a short or long stay at ICU [area under curve (AUC) = 0.92]. A further model based on kynurenine, 3-methylhistidine, ornithine, p-cresol sulfate, and C24.0 sphingomyelin, measured 1 week later, accurately predicted the duration of IMV (Pearson correlation = 0.94). Both predictive models outperformed Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and differentiated COVID-19 severity in published data.

Conclusion: This study has identified specific metabolites that can predict in advance LOS and IMV, which could help in the management of COVID-19 cases at ICU.
FPGA-Based High-Performance Phonocardiography System for Extraction of Cardiac Sound Components Using Inverse Delayed Neuron Model
Authors: Anumukonda Madhubabu , Lakkamraju Prasadraju , Chowdhury Shubhajit Roy
Published: August 2021

The study focuses on the extraction of cardiac sound components using a multi-channel micro-electromechanical system (MEMS) microphone-based phonocardiography system. The proposed multi-channel phonocardiography system classifies the cardiac sound components using artificial neural networks (ANNs) and synaptic weights that are calculated using the inverse delayed (ID) function model of the neuron. The proposed ANN model was simulated in MATLABRand implemented in a field-programmable gate array (FPGA). The proposed system examined both abnormal and normal samples collected from 30 patients. Experimental results revealed a good sensitivity of 99.1% and an accuracy of 0.9.
Functional Identification of the Xanthomonas oryzae pv. oryzae Type I-C CRISPR-Cas System and Its Potential in Gene Editing Application
Authors: Liu Qibing , Wang Siwei , Long Juying , Chen Zhuoyue , Yang Bing , Lin Fei
Published: August 2021

The type I clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system is one of five adaptive immune systems and exists widely in bacteria and archaea. In this study, we showed that Xanthomonas oryzae pv. oryzae (Xoo) possesses a functional CRISPR system by engineering constructs mimicking its CRISPR cassette. CRISPR array analysis showed that the TTC at the 5′-end of the target sequence is a functional protospacer-adjacent motif (PAM) of CRISPR. Guide RNA (gRNA) deletion analysis identified a minimum of 27-bp spacer that was required to ensure successful self-target killing in PXO99A strain. Mutants with deletion of individual Cas genes were constructed to analyze the effects of Cas proteins on mature CRISPR RNA (crRNA), processing intermediates and DNA interference. Results showed that depleting each of the three genes, cas5d, csd1, and csd2 inactivated the pre-crRNA processing, whereas inactivation of cas3 impaired in processing pre-crRNA. Furthermore, the Xoo CRISPR/Cas system was functional in Pseudomonas syringae pv. tomato. Collectively, our results would contribute to the functional study of CRISPR/Cas system of Xoo, and also provide a new vision on the use of bacterial endogenous systems as a convenient tool for gene editing.
Nanostructured Antimicrobial Peptides: Crucial Steps of Overcoming the Bottleneck for Clinics
Authors: Yang Zhanyi , He Shiqi , Wu Hua , Yin Ting , Wang Lili , Shan Anshan
Published: August 2021

The security issue of human health is faced with dispiriting threats from multidrug-resistant bacteria infections induced by the abuse and misuse of antibiotics. Over decades, the antimicrobial peptides (AMPs) hold great promise as a viable alternative to treatment with antibiotics due to their peculiar antimicrobial mechanisms of action, broad-spectrum antimicrobial activity, lower drug residue, and ease of synthesis and modification. However, they universally express a series of disadvantages that hinder their potential application in the biomedical field (e.g., low bioavailability, poor protease resistance, and high cytotoxicity) and extremely waste the abundant resources of AMP database discovered over the decades. For all these reasons, the nanostructured antimicrobial peptides (Ns-AMPs), based on a variety of nanosystem modification, have made up for the deficiencies and pushed the development of novel AMP-based antimicrobial therapies. In this review, we provide an overview of the advantages of Ns-AMPs in improving therapeutic efficacy and biological stability, reducing side effects, and gaining the effect of organic targeting and drug controlled release. Then the different material categories of Ns-AMPs are described, including inorganic material nanosystems containing AMPs, organic material nanosystems containing AMPs, and self-assembled AMPs. Additionally, this review focuses on the Ns-AMPs for the effect of biological activities, with emphasis on antimicrobial activity, biosecurity, and biological stability. The “state-of-the-art” antimicrobial modes of Ns-AMPs, including controlled release of AMPs under a specific environment or intrinsic antimicrobial properties of Ns-AMPs, are also explicated. Finally, the perspectives and conclusions of the current research in this field are also summarized.
The Screening Accuracy of a Visually Based Montreal Cognitive Assessment Tool for Older Adult Hearing Aid Users
Authors: Utoomprurkporn Nattawan , Stott Joshua , Costafreda Sergi G. , North Courtney , Heatley Mary , Bamiou Doris Eva
Published: August 2021

Objectives

This research aims to validate a modified visually based Montreal Cognitive Assessment for hearing-aid users (MoCA-HA). This population should be the target of cognitive screening due to high risk of developing dementia.

Design

Case-control study.

Setting

The participants were recruited from referral hearing-aid center and memory clinic in central London, United Kingdom.

Participant

75 hearing-aid users were recruited. Of these, thirty were cognitively intact controls with hearing impairment (NC-HI); thirty had mild cognitive impairment with hearing impairment (MCI-HI); fifteen had dementia with hearing impairment (D-HI).

Measurements

The baseline characteristics and analysis of the MoCA-HA for the NC-HI were recorded. The MoCA-HA performance of the MCI-HI cohort and D-HI cohort were also studied.

Results

The cutpoint of <26 yields 93.3% sensitivity with 80% specificity in distinguishing MCI-HI from NC-HI. The specificity increased to 95.6% in screening for all cognitive impairment (MCI-HI and D-HI) from NC-HI.

Conclusion

The MoCA-HA has been validated with a cutpoint which is comparable to the traditional MoCA. This tool may help clinicians to early identify older adult hearing-aid users for appropriate cognitive evaluation.
Astrocyte Pannexin 1 Suppresses LPS-Induced Inflammatory Responses to Protect Neuronal SH-SY5Y Cells
Authors: Ling Zhuo-Min , Wang Qian , Ma Yu , Xue Peng , Gu Yun , Cao Mao-Hong , Wei Zhong-Ya
Published: August 2021

Reactive astrogliosis is a key hallmark of inflammatory responses in the pathogenesis of brain injury, including Parkinson’s disease (PD), but its role and regulatory mechanisms are not fully understood. Pannexin 1 (Panx 1) is a membrane channel that mediates substance release in many neurodegenerative diseases. However, the role of astrocyte Panx 1 in the regulation of PD-like neuroinflammation remains elusive. Here, we characterized the expression of Panx 1 in isolated primary astrocytes and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. The functions of Panx 1 in inflammatory cytokines expression and the viability of neuronal SH-SY5Y cells were examined in cultured cells treated with lipopolysaccharide (LPS) and 1-methyl-4-phenylpyridinium (MPP+). We found that Panx 1 expression was significantly increased under both LPS- and MPP+-treated conditions. Panx 1 downregulation suppressed LPS-induced pro-inflammatory cytokine expression but did not significantly affect MPP+-induced astrocyte apoptosis or inflammatory cytokine expression through treatment with the Panx 1 inhibitor carbenoxolone (CBX) and Panx 1 siRNA. Moreover, silencing Panx 1 in reactive astrocytes had a potentially protective effect on the viability of neuronal SH-SY5Y cells. Therefore, we propose that Panx 1 may serve as a key regulator in reactive astrocytes to intervene in the inflammatory response and maintain neuronal viability in the context of PD-like conditions.
Higher Serum Levels of Lactate Dehydrogenase Before Microsurgery Predict Poor Outcome of Aneurysmal Subarachnoid Hemorrhage
Authors: Zheng Shufa , Wang Haojie , Chen Guorong , Shangguan Huangcheng , Yu Lianghong , Lin Zhangya , Lin Yuanxiang , Yao Peisen , Kang Dezhi
Published: August 2021

Introduction: We explored whether higher preoperative serum levels of lactate dehydrogenase (LDH) predicted outcome 3 months after surgery in patients with aneurysmal subarachnoid hemorrhage (aSAH) treated using microsurgical clipping in our institution.

Methods: Patients with aSAH treated at our institution between 2010 and 2018 were enrolled. The following parameters were recorded: age, sex, smoking and drinking history, medical history, Hunt–Hess and Fisher grades, aneurysm location, aneurysm size, surgical treatment, delayed cerebral ischemia (DCI), intracranial infection, hydrocephalus, pneumonia, and preoperative serum LDH levels within 24 h of aSAH. We investigated whether preoperative serum LDH levels were associated with Hunt–Hess grade, Fisher grade, and functional neurological outcome.

Results: In total, 2,054 patients with aSAH were enrolled, 874 of whom were treated using microsurgical clipping. The average serum LDH level (U/L) was significantly lower in the good outcome group (180.096 ± 50.237) than in the poor outcome group (227.554 ± 83.002; p < 0.001). After propensity score matching, the average serum LDH level (U/L) was still lower in the good outcome group (205.356 ± 76.785) than in the poor outcome group (227.119 ± 86.469; p = 0.029). The area under the receiver operating characteristic (ROC) curve was 0.702 (95% confidence interval [CI]: 0.650–0.754; p < 0.001). Based on the ROC curve, the optimal cutoff value for serum LDH levels as a predictor of poor 3-month outcome (modified Rankin Scale score > 2) was 201.5 U/L. The results revealed that Hunt–Hess grade, Fisher grade, DCI, pneumonia, and serum LDH (>201.5 U/L) were significantly associated with poor outcome. After propensity score matching, serum LDH levels > 201.5 U/L were still considered an independent risk factor for poor outcome (odds ratio: 2.426, 95% CI = 1.378–4.271, p = 0.002). Serum LDH levels were associated with Hunt–Hess and Fisher grades and were correlated with functional neurological outcomes (p < 0.001).

Conclusions: Our findings showed that higher preoperative serum levels of LDH correlated with Hunt–Hess grade, Fisher grade, and neurological functional outcome, and predicted the outcome of aSAH treated by microsurgical clipping at 3 months, which was involved in the related mechanisms of early brain injury and showed its potential clinical significance in patients with aSAH.
Co-registration Comparison of On-Scalp Magnetoencephalography and Magnetic Resonance Imaging
Authors: Cao Fuzhi , An Nan , Xu Weinan , Wang Wenli , Yang Yanfei , Xiang Min , Gao Yang , Ning Xiaolin
Published: August 2021

Magnetoencephalography (MEG) can non-invasively measure the electromagnetic activity of the brain. A new type of MEG, on-scalp MEG, has attracted the attention of researchers recently. Compared to the conventional SQUID-MEG, on-scalp MEG constructed with optically pumped magnetometers is wearable and has a high signal-to-noise ratio. While the co-registration between MEG and magnetic resonance imaging (MRI) significantly influences the source localization accuracy, co-registration error requires assessment, and quantification. Recent studies have evaluated the co-registration error of on-scalp MEG mainly based on the surface fit error or the repeatability error of different measurements, which do not reflect the true co-registration error. In this study, a three-dimensional-printed reference phantom was constructed to provide the ground truth of MEG sensor locations and orientations relative to MRI. The co-registration performances of commonly used three devices—electromagnetic digitization system, structured-light scanner, and laser scanner—were compared and quantified by the indices of final co-registration errors in the reference phantom and human experiments. Furthermore, the influence of the co-registration error on the performance of source localization was analyzed via simulations. The laser scanner had the best co-registration accuracy (rotation error of 0.23° and translation error of 0.76 mm based on the phantom experiment), whereas the structured-light scanner had the best cost performance. The results of this study provide recommendations and precautions for researchers regarding selecting and using an appropriate device for the co-registration of on-scalp MEG and MRI.
Visual Impairments Are Associated With Retinal Microvascular Density in Patients With Parkinson’s Disease
Authors: Zhou Min , Wu Lei , Hu Qinyuan , Wang Congyao , Ye Jiacheng , Chen Tingting , Wan Pengxia
Published: August 2021

Objective

This study aimed to evaluate retinal microvascular density in patients with Parkinson’s disease (PD) and its correlation with visual impairment.

Methods

This cross-sectional study included 24 eyes of 24 patients with PD and 23 eyes of 23 healthy controls. All participants underwent ophthalmic examination, visual evoked potential (VEP) test, 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25), and optical coherence tomography angiography (OCTA) examination. The correlation between retinal microvascular density and visual parameter was evaluated using Spearman correlation analysis, and the area under receiver operating characteristic curve (AUROC) was calculated.

Results

Parkinson’s disease patients had prolonged P100 latency (P = 0.041), worse vision-related quality of life (composite score and 3 of 12 subscales in NEI VFQ-25), and decreased vessel density (VD) in all sectors of 3-mm-diameter region (all P < 0.05) compared with healthy controls. There were no statistical differences in the ganglion cell-inner plexiform layer (GCIPL) thickness and retinal nerve fiber layer (RNFL) thickness between the two groups. A negative correlation was found between P100 latency and nasal and superior sectors of macular VD in a 3-mm-diameter region (r = −0.328, P = 0.030; r = −0.302, and P = 0.047, respectively). Macular VD in a 3-mm-diameter region showed diagnostic capacities to distinguish PD patients from healthy controls (AUROCs, ranging from 0.655 to 0.723).

Conclusion

This study demonstrated that decreased retinal microvascular density was correlated with visual impairment in PD patients. Retinal microvasculature change may occur earlier than visual decline and retinal structure change and has the potential to be a promising diagnostic marker for early PD.
Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling
Authors: Verdinez Jissele A. , Sebag Julien A.
Published: August 2021

Prokineticin receptors are GPCRs involved in several physiological processes including the regulation of energy homeostasis, nociception, and reproductive function. PKRs are inhibited by the endogenous accessory protein MRAP2 which prevents them from trafficking to the plasma membrane. Very little is known about the importance of post-translational modification of PKRs and their role in receptor trafficking and signaling. Here we identify 2 N-linked glycosylation sites within the N-terminal region of PKR2 and demonstrate that glycosylation of PKR2 at position 27 is important for its plasma membrane localization and signaling. Additionally, we show that glycosylation at position 7 results in a decrease in PKR2 signaling through Gαs without impairing Gαq/11 signaling.
Structural Alterations in a Rat Model of Short-Term Conductive Hearing Loss Are Associated With Reduced Resting State Functional Connectivity
Authors: Manno Francis A. M. , An Ziqi , Kumar Rachit , Wu Ed X. , He Jufang , Feng Yanqiu , Lau Condon
Published: August 2021

Conductive hearing loss (CHL) results in attenuation of air conducted sound reaching the inner ear. How a change in air conducted sound alters the auditory system resulting in cortical alterations is not well understood. Here, we have assessed structural and functional magnetic resonance imaging (MRI) in an adult (P60) rat model of short-term conductive hearing loss (1 week). Diffusion tensor imaging (DTI) revealed fractional anisotropy (FA) and axial diffusivity alterations after hearing loss that circumscribed the auditory cortex (AC). Tractography found the lateral lemniscus tract leading to the bilateral inferior colliculus (IC) was reduced. For baseline comparison, DTI and tractography alterations were not found for the somatosensory cortex. To determine functional connectivity changes due to hearing loss, seed-based analysis (SBA) and independent component analysis (ICA) were performed. Short term conductive hearing loss altered functional connectivity in the AC and IC, but not the somatosensory cortex. The results present an exploratory neuroimaging assessment of structural alterations coupled to a change in functional connectivity after conductive hearing loss. The results and implications for humans consist of structural-functional brain alterations following short term hearing loss in adults.
MRI-Radiomics Prediction for Cytokeratin 19-Positive Hepatocellular Carcinoma: A Multicenter Study
Authors: Yang Fan , Wan Yidong , Xu Lei , Wu Yichao , Shen Xiaoyong , Wang Jianguo , Lu Di , Shao Chuxiao , Zheng Shusen , Niu Tianye , Xu Xiao
Published: August 2021

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has poor prognosis. Cytokeratin (CK)19-positive (CK19+) HCC is especially aggressive; early identification of this subtype and timely intervention can potentially improve clinical outcomes. In the present study, we developed a preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI)-based radiomics model for noninvasive and accurate classification of CK19+ HCC. A multicenter and time-independent cohort of 257 patients were retrospectively enrolled (training cohort, n = 143; validation cohort A, n = 75; validation cohort B, n = 39). A total of 968 radiomics features were extracted from preoperative multisequence MR images. The maximum relevance minimum redundancy algorithm was applied for feature selection. Multiple logistic regression, support vector machine, random forest, and artificial neural network (ANN) algorithms were used to construct the radiomics model, and the area under the receiver operating characteristic (AUROC) curve was used to evaluate the diagnostic performance of corresponding classifiers. The incidence of CK19+ HCC was significantly higher in male patients. The ANN-derived combined classifier comprising 12 optimal radiomics features showed the best diagnostic performance, with AUROCs of 0.857, 0.726, and 0.790 in the training cohort and validation cohorts A and B, respectively. The combined model based on multisequence MRI radiomics features can be used for preoperative noninvasive and accurate classification of CK19+ HCC, so that personalized management strategies can be developed.
Development and Validation of a Nomogram for Predicting Prognosis to Immune Checkpoint Inhibitors Plus Chemotherapy in Patients With Non-Small Cell Lung Cancer
Authors: Zeng Hao , Huang Wei-wei , Liu Yu-jie , Huang Qin , Zhao Sheng-min , Li Ya-lun , Tian Pan-wen , Li Wei-min
Published: August 2021

Background

Immune checkpoint inhibitors (ICIs) plus chemotherapy improved the prognosis of patients with non-small cell lung cancer (NSCLC); however, reliable prognostic biomarkers are lacking. We explored factors associated with prognosis and developed a predictive model.

Methods

We retrospectively analyzed 130 consecutive stage IIIA–IVB NSCLC patients treated with ICIs combined with chemotherapy. Cox univariate and multivariate proportional hazards regression analyses were used to identify prognostic factors associated with progression-free survival (PFS). A nomogram was developed based on key factors in the training cohort (n = 86) and evaluated in the validation cohort (n = 44). According to the nomogram-based total point scores, we divided patients into low- and high-risk groups.

Results

In the training cohort, bone metastases (p = 0.017) and an increased derived neutrophil-to-lymphocyte ratio (p = 0.018) were significantly associated with poor PFS, while smoking (p = 0.007) and programmed death-ligand 1 (PD-L1) ≥50% (p = 0.001) were associated with improved PFS. A nomogram based on these factors was developed to predict PFS at 3, 6, and 12 months. The C-index of the nomogram to predict PFS was 0.725 (95% CI: 0.711–0.739) in the training cohort and 0.688 (95% CI: 0.665–0.711) in the validation cohort. The area under the curve (AUC) exhibited an acceptable discriminative ability, and calibration curves demonstrated a consistency between the actual results and predictions. In the training cohort, the median PFS (mPFS) was 12.3 and 5.7 months in the low- and high-risk groups, respectively (p < 0.001). In the validation cohort, the mPFS was 12.6 and 6.2 months in the low- and high-risk groups, respectively (p = 0.021).

Conclusions

A predictive nomogram was developed to help clinicians assess prognosis early for advanced NSCLC patients who received ICI plus chemotherapy.
DMF Activates NRF2 to Inhibit the Pro-Invasion Ability of TAMs in Breast Cancer
Authors: Li Ying , Jia Yaxu , Xu Yurong , Li Kan
Published: August 2021

Tumor-associated macrophages (TAMs) account for more than 50% of the cells in the tumor immune microenvironment of patients with breast cancer. A high TAM density is associated with a poor clinical prognosis. Targeting TAMs is a promising therapeutic strategy because they promote tumor growth, development, and metastasis. In this study, we found that dimethyl formamide (DMF) significantly inhibited the tumor invasion-promoting ability of TAMs in the co-culture system and further showed that DMF functioned by reducing reactive oxygen species (ROS) production in TAMs. The orthotopic 4T1 cell inoculation model and the spontaneous mouse mammary tumor virus-polyoma middle tumor-antigen tumor model were used to evaluate the antitumor effect of DMF. The results showed that DMF significantly inhibited tumor metastasis and increased T-cell infiltration into the tumor microenvironment. Mechanistically, NRF2 activation was necessary for DMF to exert its function, and DMF can play a role in breast cancer as an anticancer drug targeting TAMs.
The Role of Neutrophil Extracellular Traps in Cancer
Authors: Shao Bo-Zong , Yao Yi , Li Jin-Ping , Chai Ning-Li , Linghu En-Qiang
Published: August 2021

Neutrophils are vital components of innate and adaptive immunity. It is widely acknowledged that in various pathological conditions, neutrophils are activated and release condensed DNA strands, triggering the formation of neutrophil extracellular traps (NETs). NETs have been shown to be effective in fighting against microbial infections and modulating the pathogenesis and progression of diseases, including malignant tumors. This review describes the current knowledge on the biological characteristics of NETs. Additionally, the mechanisms of NETs in cancer are discussed, including the involvement of signaling pathways and the crosstalk between other cancer-related mechanisms, including inflammasomes and autophagy. Finally, based on previous and current studies, the roles of NET formation and the potential therapeutic targets and strategies related to NETs in several well-studied types of cancers, including breast, lung, colorectal, pancreatic, blood, neurological, and cutaneous cancers, are separately reviewed and discussed.
Family-Centered Care at Pediatric Cardiac Intensive Care Units in Germany and the Relationship With Parent and Infant Well-Being: A Study Protocol
Authors: Ferentzi Hannah , Rippe Ralph C. A. , Latour Jos M. , Schubert Stephan , Girch Alona , Jönebratt Stocker Michaela , Pfitzer Constanze , Photiadis Joachim , Sandica Eugen , Berger Felix , Schmitt Katharina R. L.
Published: August 2021

Rationale and Aim: Infants with Congenital Heart Disease (CHD) are at risk for neurodevelopmental delays, emotional, social and behavioral difficulties. Hospitalization early in life and associated stressors may contribute to these challenges. Family-centered Care (FCC) is a health care approach that is respectful of and responsive to the needs and values of a family and has shown to be effective in improving health outcomes of premature infants, as well as the mental well-being of their parents. However, there is limited empirical data available on FCC practices in pediatric cardiology and associations with parent and infant outcomes.

Methods and Analysis: In this cross-sectional study, we will explore FCC practices at two pediatric cardiac intensive care units in Germany, assess parent satisfaction with FCC, and investigate associations with parental mental well-being and parenting stress, as well as infant physical and mental well-being. We will collect data of 280 infants with CHD and their families. Data will be analyzed using multivariate statistics and multilevel modeling.

Implications and Dissemination: The study protocol was approved by the medical ethics committees of both partner sites and registered with the German registry for clinical trials (NR DRKS00023964). This study serves as a first step to investigate FCC practices in a pediatric cardiology setting, providing insight into the relationship between FCC and parent and infant outcomes in a population of infants with CHD. Results will be disseminated in peer-reviewed journals.
Oxytocin Attenuates Methamphetamine-Induced Apoptosis via Oxytocin Receptor in Rat Hippocampal Neurons
Authors: Li Chunli , Wang Haipeng , Wang Min , Chen Chunyun , Bai Fei , Ban Mengqi , Wu Chunfu
Published: August 2021

Methamphetamine (METH) is a highly neurotoxic psychoactive substance that can directly damage the central nervous system through prolonged use. Oxytocin (OT) has attracted much attention because of its neuroprotective effect. The purpose of this study was to investigate whether OT is neuroprotective against METH-induced damage in rat hippocampal neurons. Our results revealed that pre-incubation with OT significantly prevented the damage of METH to hippocampal neurons, including the decrease of mitochondrial membrane potential and the increase of ROS (reactive oxygen species). OT pre-incubation attenuated the up-regulation of Cleaved-Caspase-3 expression and the down-regulation of Bcl-2/Bax expression induced by METH. Pre-incubation with OT prevented the decrease in oxytocin receptor density and P-CREB (phosphorylation of cAMP-response element binding) expression induced by METH in rat hippocampal neurons. Moreover, Pre-incubation of atosiban (ATO) significantly prevented these changes. In conclusion, our study proved that pre-administration of OT could significantly attenuate hippocampal neuron apoptosis induced by METH. Oxytocin receptor activation is involved in the preventive effect of OT on METH-induced apoptosis in rat hippocampal neurons.
Quantitative Structure-Activity Relationship Modeling of the Amplex Ultrared Assay to Predict Thyroperoxidase Inhibitory Activity
Authors: Gadaleta Domenico , d’Alessandro Luca , Marzo Marco , Benfenati Emilio , Roncaglioni Alessandra
Published: August 2021

The thyroid system plays a major role in the regulation of several physiological processes. The dysregulation of the thyroid system caused by the interference of xenobiotics and contaminants may bring to pathologies like hyper- and hypothyroidism and it has been recently correlated with adverse outcomes leading to cancer, obesity, diabetes and neurodevelopmental disorders. Thyroid disruption can occur at several levels. For example, the inhibition of thyroperoxidase (TPO) enzyme, which catalyses the synthesis of thyroid hormones, may cause dysfunctions related to hypothyroidism. The inhibition of the TPO enzyme can occur as a consequence of prolonged exposure to chemical compounds, for this reason it is of utmost importance to identify alternative methods to evaluate the large amount of pollutants and other chemicals that may pose a potential hazard to the human health. In this work, quantitative structure-activity relationship (QSAR) models to predict the TPO inhibitory potential of chemicals are presented. Models are developed by means of several machine learning and data selection approaches, and are based on data obtained in vitro with the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay. Balancing methods and feature selection are applied during model development. Models are rigorously evaluated through internal and external validation. Based on validation results, two models based on Balanced Random Forest (BRF) and K-Nearest Neighbours (KNN) algorithms were selected for a further validation phase, that leads predictive performance (BA = 0.76–0.78 on external data) that is comparable with the reported experimental variability of the AUR-TPO assay (BA ∼0.70). Finally, a consensus between the two models was proposed (BA = 0.82). Based on the predictive performance, these models can be considered suitable for toxicity screening of environmental chemicals.
Naringenin Inhibits Platelet Activation and Arterial Thrombosis Through Inhibition of Phosphoinositide 3-Kinase and Cyclic Nucleotide Signaling
Authors: Huang Manting , Deng Minzhen , Nie Wenqiang , Zou Dezhi , Wu Huanlin , Xu Danping
Published: August 2021

Citrus flavanoids intake can reduce the risk of cardiovascular diseases. Naringenin, a natural predominant flavonoid abundant in citrus fruits, possesses protective effects against atherothrombotic diseases. As platelet activation plays central roles in atherothrombogenesis, we studied the effects of naringenin on platelet activation, signaling, thrombosis and hemostasis. Naringenin dose-dependently inhibited agonist-induced platelet aggregation in vitro, and exhibited more-potent efficacy on ADP-induced platelet aggregation. It also suppressed platelet aggregation stimulated by ADP ex vivo. Naringenin inhibited ADP-induced platelet α-granule secretion, fibrinogen binding, intracellular calcium mobilization and platelet adhesion on collagen-coated surface. Naringenin also inhibited platelet spreading on fibrinogen and clot retraction, processes mediated by outside-in integrin signaling. Mechanism studies indicated that naringenin suppressed PI3K-mediated signaling and phosphodiesterase activity in platelets, in addition to increasing cGMP levels and VASP phosphorylation at Ser239. Furthermore, naringenin-induced VASP phosphorylation and inhibition of platelet aggregation were reversed by a PKA inhibitor treatment. Interestingly, naringenin inhibited thrombus formation in the (FeCl3)-induced rat carotid arterial thrombus model, but not cause a prolonged bleeding time in mice. This study suggests that naringenin may represent a potential antiplatelet agent targeting PI3K and cyclic nucleotide signaling, with a low bleeding risk.
A Network View of Portfolio Optimization Using Fundamental Information
Authors: Yan Xiangzhen , Yang Hanchao , Yu Zhongyuan , Zhang Shuguang
Published: August 2021

This article proposes the use of a novel approach to portfolio optimization, referred to as “Fundamental Networks” (FN). FN is an effective and robust network-based fundamental-incorporated method, and can be served as an alternative to classical mean-variance framework models. As a proxy for a portfolio, a fundamental network is defined as a set of “interconnected” stocks, among which linkages are a measure of similarity of fundamental information and are referred to asset allocation directly. Two empirical models are provided in this paper as applications of Fundamental Networks. We find that Fundamental Networks efficient portfolios are in general more mean-variance efficient in out-of-sample performance than Markwotiz’s efficient portfolios. Specifically, portfolios set for profitability goals create excess return in a general/upward trending market; portfolios targeted for operating fitness perform better in a downward trending market, and can be considered as a defensive strategy in the event of a crisis.