bluuebunny/crossref_metadata_2025 huggingface dataset:
Counterfactual Explanation of Brain Activity Classifiers Using Image-To-Image Transfer by Generative Adversarial Network
Authors: Matsui Teppei , Taki Masato , Pham Trung Quang , Chikazoe Junichi , Jimura Koji
Published: March 2022

Deep neural networks (DNNs) can accurately decode task-related information from brain activations. However, because of the non-linearity of DNNs, it is generally difficult to explain how and why they assign certain behavioral tasks to given brain activations, either correctly or incorrectly. One of the promising approaches for explaining such a black-box system is counterfactual explanation. In this framework, the behavior of a black-box system is explained by comparing real data and realistic synthetic data that are specifically generated such that the black-box system outputs an unreal outcome. The explanation of the system's decision can be explained by directly comparing the real and synthetic data. Recently, by taking advantage of advances in DNN-based image-to-image translation, several studies successfully applied counterfactual explanation to image domains. In principle, the same approach could be used in functional magnetic resonance imaging (fMRI) data. Because fMRI datasets often contain multiple classes (e.g., multiple behavioral tasks), the image-to-image transformation applicable to counterfactual explanation needs to learn mapping among multiple classes simultaneously. Recently, a new generative neural network (StarGAN) that enables image-to-image transformation among multiple classes has been developed. By adapting StarGAN with some modifications, here, we introduce a novel generative DNN (counterfactual activation generator, CAG) that can provide counterfactual explanations for DNN-based classifiers of brain activations. Importantly, CAG can simultaneously handle image transformation among all the seven classes in a publicly available fMRI dataset. Thus, CAG could provide a counterfactual explanation of DNN-based multiclass classifiers of brain activations. Furthermore, iterative applications of CAG were able to enhance and extract subtle spatial brain activity patterns that affected the classifier's decisions. Together, these results demonstrate that the counterfactual explanation based on image-to-image transformation would be a promising approach to understand and extend the current application of DNNs in fMRI analyses.
Spontaneous State Detection Using Time-Frequency and Time-Domain Features Extracted From Stereo-Electroencephalography Traces
Authors: Ye Huanpeng , Fan Zhen , Li Guangye , Wu Zehan , Hu Jie , Sheng Xinjun , Chen Liang , Zhu Xiangyang
Published: March 2022

As a minimally invasive recording technique, stereo-electroencephalography (SEEG) measures intracranial signals directly by inserting depth electrodes shafts into the human brain, and thus can capture neural activities in both cortical layers and subcortical structures. Despite gradually increasing SEEG-based brain-computer interface (BCI) studies, the features utilized were usually confined to the amplitude of the event-related potential (ERP) or band power, and the decoding capabilities of other time-frequency and time-domain features have not been demonstrated for SEEG recordings yet. In this study, we aimed to verify the validity of time-domain and time-frequency features of SEEG, where classification performances served as evaluating indicators. To do this, using SEEG signals under intermittent auditory stimuli, we extracted features including the average amplitude, root mean square, slope of linear regression, and line-length from the ERP trace and three traces of band power activities (high-gamma, beta, and alpha). These features were used to detect the active state (including activations to two types of names) against the idle state. Results suggested that valid time-domain and time-frequency features distributed across multiple regions, including the temporal lobe, parietal lobe, and deeper structures such as the insula. Among all feature types, the average amplitude, root mean square, and line-length extracted from high-gamma (60–140 Hz) power and the line-length extracted from ERP were the most informative. Using a hidden Markov model (HMM), we could precisely detect the onset and the end of the active state with a sensitivity of 95.7 ± 1.3% and a precision of 91.7 ± 1.6%. The valid features derived from high-gamma power and ERP in this work provided new insights into the feature selection procedure for further SEEG-based BCI applications.
Association of the Protein-Quality-Control Protein Ubiquilin-1 With Alzheimer’s Disease Both in vitro and in vivo
Authors: Zhang Can , Inamdar Shivangi M. , Swaminathan Swathi , Marenda Daniel R. , Saunders Aleister J.
Published: March 2022

Alzheimer’s disease (AD) belongs to a class of diseases characterized by progressive accumulation and aggregation of pathogenic proteins, particularly Aβ proteins. Genetic analysis has identified UBQLN1 as an AD candidate gene. Ubiquilin-1 levels reduce with AD progression, suggesting a potential loss-of-function mechanism. The ubiquilin-1 protein is involved in protein quality control (PQC), which plays essential roles in cellular growth and normal cell function. Ubiquilin-1 regulates γ-secretase by increasing endoproteolysis of PS1, a key γ-secretase component. Presently, the effects of ubiquilin-1 on cellular physiology as well as Aβ-related events require further investigation. Here, we investigated the effects of ubiquilin-1 on cellular growth and viability in association with APP (amyloid-β protein precursor), APP processing-related β-secretase (BACE1, BACE) and γ-secretase using cell and animal-based models. We showed that loss-of-function in Drosophila ubqn suppresses human APP and human BACE phenotypes in wing veins and altered cell number and tissue compartment size in the wing. Additionally, we performed cell-based studies and showed that silencing UBQLN1 reduced cell viability and increased caspase-3 activity. Overexpression of UBQLN1 significantly reduced Aβ levels. Furthermore, pharmacological inhibition of γ-secretase increased ubiquilin-1 protein levels, suggesting a mechanism that regulates ubiquilin-1 levels which may associate with reduced Aβ reduction by inhibiting γ-secretase. Collectively, our results support not only a loss-of-function mechanism of ubiquilin-1 in association with AD, but also support the significance of targeting ubiquilin-1-mediated PQC as a potential therapeutic strategy for AD.
An Anodic Phase Can Facilitate Rather Than Weaken a Cathodic Phase to Activate Neurons in Biphasic-Pulse Axonal Stimulations
Authors: Zheng Lvpiao , Feng Zhouyan , Xu Yipeng , Yuan Yue , Hu Yifan
Published: March 2022

Electrical pulses have been promisingly utilized in neural stimulations to treat various diseases. Usually, charge-balanced biphasic pulses are applied in the clinic to eliminate the possible side effects caused by charge accumulations. Because of its reversal action to the preceding cathodic phase, the subsequent anodic phase has been commonly considered to lower the activation efficiency of biphasic pulses. However, an anodic pulse itself can also activate axons with its “virtual cathode” effect. Therefore, we hypothesized that the anodic phase of a biphasic pulse could facilitate neuronal activation in some circumstances. To verify the hypothesis, we compared the activation efficiencies of cathodic pulse, biphasic pulse, and anodic pulse applied in both monopolar and bipolar modes in the axonal stimulation of alveus in rat hippocampal CA1 region in vivo. The antidromically evoked population spikes (APS) were recorded and used to evaluate the amount of integrated firing of pyramidal neurons induced by pulse stimulations. We also used a computational model to investigate the pulse effects on axons at various distances from the stimulation electrode. The experimental results showed that, with a small pulse intensity, a cathodic pulse recruited more neurons to fire than a biphasic pulse. However, the situation was reversed with an increased pulse intensity. In addition, setting an inter-phase gap of 100 μs was able to increase the activation efficiency of a biphasic pulse to exceed a cathodic pulse even with a relatively small pulse intensity. Furthermore, the latency of APS evoked by a cathodic pulse was always longer than that of APS evoked by a biphasic pulse, indicating different initial sites of the neuronal firing evoked by the different types of pulses. The computational results of axon modeling showed that the subsequent anodic phase was able to relieve the hyperpolarization block in the flanking regions generated by the preceding cathodic phase, thereby increasing rather than decreasing the activation efficiency of a biphasic pulse with a relatively great intensity. These results of both rat experiments and computational modeling firstly reveal a facilitation rather than an attenuation effect of the anodic phase on biphasic-pulse stimulations, which provides important information for designing electrical stimulations for neural therapies.
Ramadan Diurnal Intermittent Fasting Is Associated With Attenuated FTO Gene Expression in Subjects With Overweight and Obesity: A Prospective Cohort Study
Authors: Madkour Mohamed I. , Malhab Lara J. Bou , Abdel-Rahman Wael M. , Abdelrahim Dana N. , Saber-Ayad Maha , Faris MoezAlIslam E.
Published: March 2022

Aim and Background

A growing body of evidence supports the impact of intermittent fasting (IF) on normalizing body weight and that the interaction between body genes and environmental factors shapes human susceptibility to developing obesity. FTO gene is one of these genes with metabolic effects related to energy metabolism and body fat deposition. This research examined the changes in FTO gene expression upon Ramadan intermittent fasting (RIF) in a group of metabolically healthy subjects with overweight and obesity.

Methods

Sixty-three (63) subjects were recruited, of which 57 (17 males and 40 females, mean age 38.4 ± 11.2 years) subjects with overweight and obesity (BMI = 29.89 ± 5.02 kg/m2were recruited and monitored before and at the end of Ramadan month), and 6 healthy subjects with normal BMI (21.4 ± 2.20 kg/m2) recruited only to standardize the reference for normal levels of FTO gene expression. In the two-time points, anthropometric, biochemical, and dietary assessments were undertaken, and FTO gene expression tests were performed using RNA extracted from the whole blood sample.

Results

In contrast to normal BMI subjects, the relative gene expressions in overweight/obese were significantly decreased at the end of Ramadan (−32.30%, 95% CI–0.052 −0.981) in comparison with the pre-fasting state. Significant reductions were found in body weight, BMI, fat mass, body fat percent, hip circumference, LDL, IL-6, TNF-α (P<0.001), and in waist circumference (P<0.05), whilst HDL and IL-10 significantly increased (P<0.001) at the end of Ramadan in comparison with the pre-fasting levels. Binary logistic regression analysis for genetic expressions showed no significant association between high-energy intake, waist circumference, or obesity and FTO gene expression.

Conclusions

RIF is associated with the downregulation of the FTO gene expression in subjects with obesity, and this may explain, at least in part, its favorable metabolic effects. Hence, RIF presumably may entail a protective impact against body weight gain and its adverse metabolic-related derangements in subjects with obesity.
Neoadjuvant and Adjuvant Treatments Compared to Concurrent Chemoradiotherapy for Patients With Locally Advanced Cervical Cancer: A Bayesian Network Meta-Analysis
Authors: Qiao Yunfeng , Li Huijun , Peng Bing
Published: March 2022

Aim

This study aimed to identify the most effective treatment mode for locally advanced cervical cancer (LACC) by adopting a network meta-analysis (NMA).

Methods

Randomized controlled trials about treatments were retrieved from PubMed, Medline and Embase. Odds ratios (OR) of overall survival (OS) and progression-free survival (PFS) were calculated by synthesizing direct and indirect evidence to rank the efficacy of nine treatments. Consistency was assessed by node-splitting method. Begg’s test was performed to evaluate publication bias. The surface under cumulative ranking curve (SUCRA) was also used in this NMA.

Results

A total of 24 eligible randomized controlled trials with 6,636 patients were included in our NMA. These trials compared a total of nine different regimens: radiotherapy (RT) alone, surgery, RT plus adjuvant chemotherapy (CT), concurrent chemoradiotherapy (CCRT), neoadjuvant CT plus CCRT, CCRT plus adjuvant CT, neoadjuvant CT, RT, CCRT plus surgery. Among those therapeutic modalities, we found that the two interventions with the highest SUCRA for OS and PFS were CCRT and CCRT plus adjuvant CT, respectively. ORs and 95% confidence interval (CI) for the two best strategies were CCRT versus CCRT plus adjuvant CT (OR, 0.84; 95% CI, 0.53–1.31) for OS, CCRT plus adjuvant CT versus CCRT (OR, 0.60; 95% CI, 0.38–0.96) for PFS.

Conclusions

This NMA supported that CCRT and CCRT plus adjuvant CT are likely to be the most optimal treatments in terms of both OS and PFS for LACC. Future studies should focus on comparing CCRT and CCRT plus adjuvant CT in the treatment of LACC.

Systematic Review Registration

PROSPERO, CRD42019147920.
Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening
Authors: Hou Jue , He Zongsheng , Liu Tian , Chen Dongfeng , Wang Bin , Wen Qinglian , Zheng Xi
Published: March 2022

Molecular targeted therapy has revolutionized the landscape of cancer treatment due to better therapeutic responses and less systemic toxicity. However, therapeutic resistance is a major challenge in clinical settings that hinders continuous clinical benefits for cancer patients. In this regard, unraveling the mechanisms of drug resistance may identify new druggable genetic alterations for molecularly targeted therapies, thus contributing to improved therapeutic efficacies. The recent rapid development of novel methodologies including CRISPR-Cas9 screening technology and patient-derived models provides powerful tools to dissect the underlying mechanisms of resistance to targeted cancer therapies. In this review, we updated therapeutic targets undergoing preclinical and clinical evaluation for various cancer types. More importantly, we provided comprehensive elaboration of high throughput CRISPR-Cas9 screening in deciphering potential mechanisms of unresponsiveness to molecularly targeted therapies, which will shed light on the discovery of novel opportunities for designing next-generation anti-cancer drugs.
Disulfiram Transcends ALDH Inhibitory Activity When Targeting Ovarian Cancer Tumor-Initiating Cells
Authors: Caminear Michael W. , Harrington Brittney S. , Kamdar Rahul D. , Kruhlak Michael J. , Annunziata Christina M.
Published: March 2022

Epithelial ovarian cancer (EOC) is a global health burden and remains the fifth leading cause of cancer related death in women worldwide with the poorest five-year survival rate of the gynecological malignancies. EOC recurrence is considered to be driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs). We previously showed that disulfiram, an ALDH inhibitor, effectively targeted TICs compared to adherent EOC cells in terms of viability, spheroid formation, oxidative stress and also prevented relapse in an in vivo model of EOC. In this study we sought to determine whether specific targeting of ALDH isoenzyme ALDH1A1 would provide similar benefit to broader pathway inhibition by disulfiram. NCT-505 and NCT-506 are isoenzyme-specific ALDH1A1 inhibitors whose activity was compared to the effects of disulfiram. Following treatment with both the NCTs and disulfiram, the viability of TICs versus adherent cells, sphere formation, and cell death in our in vitro relapse model were measured and compared in EOC cell lines. We found that disulfiram decreased the viability of TICs significantly more effectively versus adherent cells, while no consistent trend was observed when the cells were treated with the NCTs. Disulfiram also affected the expression of proteins associated with NFκB signaling. Comparison of disulfiram to the direct targeting of ALDH1A1 with the NCTs suggests that the broader cellular effects of disulfiram are more suitable as a therapeutic to eradicate TICs from tumors and prevent EOC relapse. In addition to providing insight into a fitting treatment for TICs, the comparison of disulfiram to NCT-505 and -506 has increased our understanding of the mechanism of action of disulfiram. Further elucidation of the mechanism of disulfiram has the potential to reveal additional targets to treat EOC TICs and prevent disease recurrence.
MicroRNA-138 Abates Fibroblast Motility With Effect on Invasion of Adjacent Cancer Cells
Authors: Rajthala Saroj , Parajuli Himalaya , Dongre Harsh Nitin , Ljøkjel Borghild , Hoven Kristin Marie , Kvalheim Arild , Lybak Stein , Neppelberg Evelyn , Sapkota Dipak , Johannessen Anne Christine , Costea Daniela-Elena
Published: March 2022

Background

Recent studies have shown aberrant expression of micro-RNAs in cancer-associated fibroblasts (CAFs). This study aimed to investigate miR-138 dysregulation in CAFs in oral squamous cell carcinoma (OSCC) and its effects on their phenotype and invasion of adjacent OSCC cells.

Methods

Expression of miR-138 was first investigated in OSCC lesions (n = 53) and OSCC-derived CAFs (n = 15). MiR-138 mimics and inhibitors were used to functionally investigate the role of miR-138 on CAF phenotype and the resulting change in their ability to support OSCC invasion.

Results

Expression of miR-138 showed marked heterogeneity in both OSCC tissues and cultured fibroblasts. Ectopic miR-138 expression reduced fibroblasts’ motility and collagen contraction ability and suppressed invasion of suprajacent OSCC cells, while its inhibition resulted in the opposite outcome. Transcript and protein examination after modulation of miR-138 expression showed changes in CAF phenotype-specific molecules, focal adhesion kinase axis, and TGFβ1 signaling pathway.

Conclusions

Despite its heterogeneous expression, miR-138 in OSCC-derived CAFs exhibits a tumor-suppressive function.
Advances in Photodynamic Therapy Based on Nanotechnology and Its Application in Skin Cancer
Authors: Zhang Ping , Han Ting , Xia Hui , Dong Lijie , Chen Liuqing , Lei Li
Published: March 2022

Comprehensive cancer treatments have been widely studied. Traditional treatment methods (e.g., radiotherapy, chemotherapy), despite ablating tumors, inevitably damage normal cells and cause serious complications. Photodynamic therapy (PDT), with its low rate of trauma, accurate targeting, synergism, repeatability, has displayed great advantages in the treatment of tumors. In recent years, nanotech-based PDT has provided a new modality for cancer treatment. Direct modification of PSs by nanotechnology or the delivery of PSs by nanocarriers can improve their targeting, specificity, and PDT efficacy for tumors. In this review, we strive to provide the reader with a comprehensive overview, on various aspects of the types, characteristics, and research progress of photosensitizers and nanomaterials used in PDT. And the application progress and relative limitations of nanotech-PDT in non-melanoma skin cancer and melanoma are also summarized.
Kidney Tumor Segmentation Based on FR2PAttU-Net Model
Authors: Sun Peng , Mo Zengnan , Hu Fangrong , Liu Fang , Mo Taiping , Zhang Yewei , Chen Zhencheng
Published: March 2022

The incidence rate of kidney tumors increases year by year, especially for some incidental small tumors. It is challenging for doctors to segment kidney tumors from kidney CT images. Therefore, this paper proposes a deep learning model based on FR2PAttU-Net to help doctors process many CT images quickly and efficiently and save medical resources. FR2PAttU-Net is not a new CNN structure but focuses on improving the segmentation effect of kidney tumors, even when the kidney tumors are not clear. Firstly, we use the R2Att network in the “U” structure of the original U-Net, add parallel convolution, and construct FR2PAttU-Net model, to increase the width of the model, improve the adaptability of the model to the features of different scales of the image, and avoid the failure of network deepening to learn valuable features. Then, we use the fuzzy set enhancement algorithm to enhance the input image and construct the FR2PAttU-Net model to make the image obtain more prominent features to adapt to the model. Finally, we used the KiTS19 data set and took the size of the kidney tumor as the category judgment standard to enhance the small sample data set to balance the sample data set. We tested the segmentation effect of the model at different convolution and depths, and we got scored a 0.948 kidney Dice and a 0.911 tumor Dice results in a 0.930 composite score, showing a good segmentation effect.
MD2 Is a Potential Biomarker Associated with Immune Cell Infiltration in Gliomas
Authors: Zhao Mengya , Li Xiaodong , Chen Yijun , Wang Shuzhen
Published: March 2022

Background

Glioma is the most common primary malignant tumor in the central nervous system. Myeloid differentiation protein 2 (MD2) acts as a coreceptor of toll-like receptor 4 (TLR4) to mediate innate immune response. However, the actual roles of MD2 in the regulation of progression and immune cell infiltration in gliomas remain largely unclear. This study aims to explore whether MD2 could be an independent prognostic factor through the mediation of immune cell infiltration in gliomas.

Methods

The mRNA expression and DNA methylation differential analyses of MD2 were performed using CGGA, TCGA and Rembrandt databases and survival analyses were performed using Kaplan-Meier plotter. Univariate and multivariate Cox regression was applied to analyze the prognostic value of MD2 and nomograms were constructed to evaluate the clinical value of MD2. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to analyze MD2-related signal pathways. Furthermore, correlations between MD2 and immune cell infiltration were calculated by TIMER and CIBERSOPT. The correlation between MD2 expression and the infiltrations of macrophages and neutrophils was experimentally verified by the knockdown of MD2 expression using small interfering RNA (siRNA) in glioma cells.

Results

We found that MD2 was overexpressed and associated with a poor prognosis in gliomas. Meanwhile, higher expression of MD2 could be a result of lower DNA methylation of MD2 gene in gliomas. In addition, univariate and multivariate Cox regression analysis indicated that MD2 could be an independent prognostic factor for gliomas. Further functional enrichment analysis revealed that the functions of MD2 were closely related to immune responses. Moreover, the expression level of MD2 was strongly correlated with the infiltration and polarization of pro-tumor phenotype of tumor-associated macrophages and tumor-associated neutrophils in gliomas.

Conclusions

These findings have provided strong evidence that MD2 could be served as a valuable immune-related biomarker to diagnose and predict the progression of gliomas.
CircRNAs in Malignant Tumor Radiation: The New Frontier as Radiotherapy Biomarkers
Authors: Wu Xixi , Wu Junying , Wang Lingxia , Yang Wei , Wang Bo , Yang Huan
Published: March 2022

World Health Organization (WHO) data show that of the top 20 factors that threaten human life and health, cancer is at the forefront, and the therapeutic approaches for cancer consist of surgery, radiotherapy, chemotherapy and immunotherapy. For most highly metastatic and recurrent cancer, radiation therapy is an essential modality to mitigate tumor burden and improve patient survival. Despite the great accomplishments that have been made in clinical therapy, an inevitable challenge in effective treatment is radioresistance, the mechanisms of which have not yet been completely elucidated. In addition, radiosensitization methods based on molecular mechanisms and targets, and clinical applications are still inadequate. Evidence indicates that circular RNAs (circRNAs) are important components in altering tumor progression, and in influencing resistance and susceptibility to radiotherapy. This review summarizes the reasons for tumor radiotherapy resistance induced by circRNAs, and clarifies the molecular mechanisms and targets of action. Moreover, we determine the potential value of circRNAs as clinical indicators in radiotherapy, providing a theoretical basis for circRNAs-based strategies for cancer radiotherapy.
Treatment of Preschool Children With Autism Spectrum Disorder: A Trial to Evaluate a Learning Style Profile Intervention Program in China
Authors: Ma Chen-huan , Chen Ling-yan , Li Meng-fan , Wu Dan , Wang Sha-sha , Zhao Yan-jun , Shi Jian-li , Rydell Patrick J. , Chen Jin-jin , Wang Yu
Published: March 2022

Objective

To investigate whether the provision of learning style profile (LSP) training improves development in preschool children with autism spectrum disorder (ASD) in China and to describe the characteristics of children who benefit from the intervention.

Methods

Eighty-one children aged 36 to 72 months who were diagnosed with ASD for the first time were recruited for the intervention group. All of them received 24 weeks of LSP training, consisting of hospital- and home-based training. Twenty-one children with ASD of the same age in the control group had never received any intervention after diagnosis but underwent an assessment. Assessments were conducted at baseline and 24 weeks later. Differences in the developmental level and severity of ASD symptoms over time and between groups were analyzed by repeated standardized measures. Secondary analyses examined age effects among the 36– 48-, 48– 60-, and 60–72-month age groups.

Results

Within-group comparison of the intervention group revealed significant treatment effects after the intervention, according to: language, social and adaptive developmental quotients (DQs) of the China Developmental Scale; total Childhood Autism Rating Scale (CARS) score; and hyperactivity, peer problems, total difficulties, and prosocial behavior scores of the Strengths and Difficulties Questionnaire (SDQ). Similar gains were observed in gross and fine motor DQs of the China Developmental Scale and emotional symptoms and conduct problems scores of the SDQ; however, the differences between these pre- and postintervention scores did not reach statistical significance. Comparisons among the three age groups in the intervention groups demonstrated a significant age effect on adaptive DQs of the China Developmental Scale; total CARS score; hyperactivity, peer problems and total difficulties scores of the SDQ. Comparison between the intervention and control groups revealed significant treatment effects on language, social and adaptive DQs of the China Developmental Scale; total CARS score; and emotional symptoms, conduct problems, hyperactivity, peer problems, total difficulties, and prosocial behavior scores of the SDQ after the intervention. Similar gains were observed in gross and fine motor DQs of the China Developmental Scale, although differences between the two groups did not reach statistical significance.

Conclusion

Our findings suggest that LSP training can effectively improve social behavior and reduce the severity of ASD symptoms in children with ASD. Our data also highlight the importance of early intervention.
Effectiveness of Sodium Bicarbonate Infusion on Mortality in Critically Ill Children With Metabolic Acidosis
Authors: Wang Huabin , Liang Rui , Liang Tianqi , Chen Songyao , Zhang Yulong , Zhang Lidan , Chen Chun
Published: March 2022

Objective: Metabolic acidosis often occurs in the paediatric intensive care unit (PICU). Although sodium bicarbonate (SB) has been widely used in paediatrics, data on the effect of SB on children with metabolic acidosis in the PICU are scarce.

Methods: Patients with metabolic acidosis who were treated with SB within 48 h of PICU admission were screened. Multivariate logistic regression, subgroup analysis, and propensity score matching (PSM) were used to investigate the relationships between SB infusion and clinical outcomes.

Results: A total of 1,595 patients with metabolic acidosis were enrolled in this study. In the multivariate logistic regression model, SB infusion was not correlated with in-hospital mortality (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.47–1.63, p = 0.668), but was significantly correlated with hypernatraemia (OR 1.98, 95% CI 1.14–3.46, p = 0.016), hypokalaemia (OR 2.01, 95% CI 1.36–2.96, p < 0.001), and hypocalcaemia (OR 4.29, 95% CI 2.92–6.31, p < 0.001). In the pH value, lactate level, acute kidney injury level, age grouping, and anion gap level subgroups, the ORs for SB and in-hospital mortality were not statistically significant. After PSM, the results remained unchanged.

Conclusion: SB infusion does not reduce the in-hospital mortality of severely ill children with metabolic acidosis and increases the risk of hypernatraemia, hypokalaemia, and hypocalcaemia. More effort should be focused on eliminating the causes of metabolic acidosis rather than SB infusion.
Establishment and Characterization of Brain Cancer Primary Cell Cultures From Patients to Enable Phenotypic Screening for New Drugs
Authors: dePadua Michelle , Kulothungan Preethi , Lath Rahul , Prasad Ravikanti , Madamchetty Kranthi , Atmakuri Shravya , Ragamouni Sravanthi , Gandhari Mukesh , Khandrika Lakshmipathi , Jain Jugnu
Published: March 2022

Aim: Desmoplastic infantile ganglioglioma (DIG), is a rare tumor arising mainly during the first 2 years of life. Molecular characterization of these benign yet rapidly proliferating tumors has been limited to evaluating a few mutations in few genes. Our aim was to establish a live cell culture to enable the understanding of the cellular processes driving the non-malignant growth of these tumors.

Methods: Tumor tissue from a rare non-infantile 8-year-old female DIG patient was dissociated and digested using collagenase to establish live cultures. Both 2D monolayer and 3D neurospheres were successfully cultured and characterized for proliferative potential, intrinsic plasticity, presence of cancer stem cells and the expression of stem cell markers. Cells cultured as 3D were embedded as tissue blocks. Immunohistochemistry was performed in both tissue and 3D sections for markers including synaptophysin, vimentin, neurofilament and MIB-1. Mutation analysis by NGS was performed using a-100 gene panel.

Results: Using immunohistochemistry, the 3D cultures were shown to express markers as in the original DIG tumor tissue indicating that the spheroid cultures were able to maintain the heterogeneity found in the original tumor. Cells continued proliferating past passage 10 indicative of immortalization. Enrichment of cancer stem cells was observed in neurospheres by FACS using CD133 antibody and RT-PCR. Mutation analysis indicated the presence of germline mutations in three genes and somatic mutations in two other genes.

Conclusion: A spontaneous cell line-like cell culture with high percentage of stem cells has been established from a DIG tumor for the first time.
Long-Lasting Analgesia With Transdermal Fentanyl: A New Approach in Rat Neonatal Research
Authors: Dutriez-Casteloot Isabelle , Emmanuelli Virginie , Wiart Jean-François , Tavernier Annabelle , Besengez Capucine , Storme Laurent , Houfflin-Debarge Véronique
Published: March 2022

Background:With advances in neonatal care, management of prolonged pain in newborns is a daily concern. In addition to ethical considerations, pain in early life would have long-term effects and consequences. However, its treatment remains inadequate. It was therefore important to develop an experimental model of long-lasting analgesia for neonatal research.

Materials and Methods:Experiments were performed in six groups of rats with transdermal fentanyl 0, 3, 12, 50, 100, or 200 μg/kg/h from second postnatal day (P2) until weaning. Assessment of analgesia was carried out at P21, with behavioral scores (ranging from 0 to 3) using a 4% formalin test. Plasma levels of fentanyl were determined by UPLC/TQD at P22. Growth rate was investigated.

Results:Fentanyl 100 and 200 μg/kg/h reduced scores of formalin-evoked behavioral pain. They increased time spent in pain score 0 (8 min 55 s and 6 min 34 s versus 23 s in controls) as in low pain scores 1 and 2, and decreased time in the most severe pain score 3 (19 min 56 s and 17 min 39 s versus 44 min 15 s). Fentanylemia increased in a dose-dependent manner from 50 μg/kg/h (2.36 ± 0.64 ng/ml) to 200 μg/kg/h (8.66 ± 1.80 ng/ml). Concerning growth, no difference was observed except weaker growth from P17 to P22 with 200 μg/kg/h. Clinically, we noticed no visible side effect from 3 to 100 μg/kg/h. Concomitantly, 200 μg/kg/h was responsible for ophthalmological side effects with appearance of corneal bilateral clouding in 90% pups. No difference was observed between male and female rats.

Conclusion:Altogether, results indicate that transdermal fentanyl 100 μg/kg/h is an efficient therapeutic for long-lasting analgesia in lactating pups. This new model provides a useful tool for protection and welfare, and future opportunity for studying long-term health consequences of sustainable neonatal analgesia.
Strongylocentrotus nudus Eggs Polysaccharide Enhances Macrophage Phagocytosis Against E.coli Infection by TLR4/STAT3 Axis
Authors: Tian Xinlei , Guo Min , Zhang Xiaoya , Guo Lingfeng , Lan Nan , Cheng Yaojun , Han Yannan , Wang Mingxin , Peng Zhonglu , Zhou Changlin , Fan Hongye
Published: March 2022

Antibiotics resistance is one of the most significant public health threats globally. Strategies that strengthen host defenses to control pathogen infection has become a hot research field. Macrophages are part of early host defense mechanisms, and are activated via host pattern recognition receptors (PRRs), such as Toll-like receptor 4 (TLR4), which then facilitates phagocytosis and elimination of invading pathogens. However, few activators of PRRs have been approved for clinical use because of their toxic effects. This study aimed to investigate whether Strongylocentrotus nudus eggs polysaccharide (SEP), a non-toxic extract from seafood, contributes to host defense against bacterial infection. Results showed that SEP promoted bacterial clearance by enhancing phagocytosis by macrophages during E. coli infection in vitro, but was inhibited by TLR4 specific inhibitor TAK-242, STAT3 inhibitor Stattic or blockade of CD64. In addition, SEP protected mice from E. coli induced mortality, reduced pulmonary inflammation and inhibited dissemination of bacteria to organs, while TAK-242 retarded the protection of SEP. Overall, SEP strengthened innate host defense and improved the outcome in bacterial infection, suggesting that SEP could be used as a potential immunomodulator in host-directed therapies.
Elevated Serum Regulator of Calcineurin 2 is Associated With an Increased Risk of Non-Alcoholic Fatty Liver Disease
Authors: Fang Xia , Wang Hongya , Tan Xiaozhen , Ye Ting , Xu Yong , Fan Jiahao
Published: March 2022

Background: The promoting effect of the regulator of calcineurin 2 (RCAN2) in hepatic steatosis has been observed in animal studies. However, the association of RCAN2 with non-alcoholic fatty liver disease (NAFLD) in humans remains unclear. This study aimed to evaluate the expression of RCAN2 in the liver of mice with hepatic steatosis and in the serum of NAFLD patients and to explore the relationship between serum RCAN2 levels and NAFLD.

Methods: The mRNA and protein expression of RCAN2 were detected by quantitative real-time PCR (qRT-PCR) and Western blot. NAFLD was diagnosed by abdominal ultrasonography. Circulating RCAN2 levels were measured by ELISA kits. The relationship between serum RCAN2 levels and NAFLD was assessed.

Results: qRT-PCR and Western blot analysis showed that compared with the corresponding controls, the mRNA and protein expression of RCAN2 were significantly increased in the liver tissues of db/db and mice on a high-fat diet. Serum RCAN2 levels were markedly elevated in NAFLD patients compared with non-NAFLD subjects. Binary logistic regression analysis showed that serum RCAN2 levels were significantly associated with NAFLD. Receiver operation characteristic (ROC) curve analysis showed that serum RCAN2 might act as a predictive biomarker for NAFLD [area under the curve (AUC) = 0.663, 95% CI = 0.623–0.702], and the serum RCAN2/(AST/ALT) ratio displayed improved predictive accuracy (AUC = 0.816, 95% CI = 0.785–0.846).

Conclusion: Elevated serum RCAN2 levels were associated with an increased risk of NAFLD. Serum RCAN2, especially the serum RCAN2/(AST/ALT) ratio, might be a candidate diagnostic marker for NAFLD.
Investigation of Antiparasitic Activity of Two Marine Natural Products, Estradiol Benzoate, and Octyl Gallate, on Toxoplasma gondii In Vitro
Authors: Lu Daiqiang , Zhang Nian-Zhang , Yao Yinning , Wang Tingting , Hua Qianqian , Zheng Xiaozi , Cong Wei , Tan Feng
Published: March 2022

Toxoplasmosis, caused by Toxoplasma gondii, is a common disease worldwide and could be severe and even fatal in immunocompromised individuals and fetuses. Limitation in current available treatment options drives the need to develop novel therapeutics. This study assessed the anti-T. gondii potential of 103 marine natural products. A luminescence-based β-galactosidase activity assay was used to screen the marine natural products library. Afterward, those compounds that displayed over 70% parasite inhibition ratio were further chosen to assess their cytotoxicity. Compounds exhibiting low cytotoxicity (≥80% cell viability) were applied to evaluate the inhibition efficacy on discrete steps of the T. gondii lytic cycle, including invasion, intracellular growth, and egress abilities as well as the cell cycle. We found that both estradiol benzoate and octyl gallate caused >70% inhibition of tachyzoite growth with IC50 values of 4.41 ± 0.94 and 5.66 ± 0.35 μM, respectively, and displayed low cytotoxicity with TD50 values of 34.11 ± 2.86 and 26.4 ± 0.98 μM, respectively. Despite their defects in inhibition of invasion and egress of tachyzoite, the two compounds markedly inhibited the tachyzoite intracellular replication. Flow cytometric analyses further suggested that the anti-T. gondii activity of estradiol benzoate, rather than octyl gallate, may be linked to halting cell cycle progression of tachyzoite from G1 to S phase. Taken together, these findings suggest that both estradiol benzoate and octyl gallate are potential inhibitors for anti-T. gondii infection and support the further exploration of marine natural products as a thinkable source of alternative and active agents against T. gondii.
The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy
Authors: Ishikawa Makoto , Nakazawa Toru , Kunikata Hiroshi , Sato Kota , Yoshitomi Takeshi , Krishnan Kathiresan , Covey Douglas F. , Zorumski Charles F. , Izumi Yukitoshi
Published: March 2022

In an ex vivo rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABAA receptors and autophagy. We now examine whether its enantiomer (ent-AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in ex vivo and in vivo rat OHT models. Ex vivo rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An in vivo ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, ent-AlloP, picrotoxin (a GABAA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and ent-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABAA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). ent-AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and ent-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by ent-AlloP. In an rat in vivo OHT model, single intravitreal ent-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, ent-AlloP was more effective in activating autophagy than AlloP. We conclude that ent-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.
Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites
Authors: Wisedchaisri Goragot , Gamal El-Din Tamer M.
Published: March 2022

Voltage-gated ion channels are important drug targets because they play crucial physiological roles in both excitable and non-excitable cells. About 15% of clinical drugs used for treating human diseases target ion channels. However, most of these drugs do not provide sufficient specificity to a single subtype of the channels and their off-target side effects can be serious and sometimes fatal. Recent advancements in imaging techniques have enabled us for the first time to visualize unique and hidden parts of voltage-gated sodium channels in different structural conformations, and to develop drugs that further target a selected functional state in each channel subtype with the potential for high precision and low toxicity. In this review we describe the druggability of voltage-gated sodium channels in distinct functional states, which could potentially be used to selectively target the channels. We review classical drug receptors in the channels that have recently been structurally characterized by cryo-electron microscopy with natural neurotoxins and clinical drugs. We further examine recent drug discoveries for voltage-gated sodium channels and discuss opportunities to use distinct, state-dependent receptor sites in the voltage sensors as unique drug targets. Finally, we explore potential new receptor sites that are currently unknown for sodium channels but may be valuable for future drug discovery. The advancement presented here will help pave the way for drug development that selectively targets voltage-gated sodium channels.
Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway
Authors: Tian Xue , Chen Xu , Jiang Qianqian , Sun Qianbin , Liu Tiantian , Hong Yiqin , Zhang Yawen , Jiang Yanyan , Shao Mingyan , Yang Ran , Li Chun , Wang Qiyan , Wang Yong
Published: March 2022

Aims: Cardiac lipotoxicity is the common consequence of lipid metabolism disorders in cardiomyocytes during development of heart failure (HF). Adenosine 5′monophosphate-activated protein kinase (AMPK) acts as an energy sensor and has a beneficial effect in reducing lipotoxicity. Notoginsenoside R1 (NGR1) is extracted from the traditional Chinese medicine Panax notoginseng (Burkill) F.H.Chen (P. notoginseng) and has definite cardioprotective effects. However, whether NGR1 can attenuate HF by mitigating lipotoxicity has not been elucidated yet. This study aimed to explore whether NGR1 plays a protective role against HF by ameliorating cardiac lipotoxicity via the AMPK pathway.

Methods: In this study, HF mice model was established by left anterior descending (LAD) ligation. palmitic acid (PA) stimulated H9C2 cell model was applied to clarify the effects and potential mechanism of NGR1 on lipotoxicity. In vivo, NGR1 (7.14 mg/kg/days) and positive drug (simvastatin: 2.9 mg/kg/days) were orally administered for 14 days. Echocardiography was applied to assess heart functions. Lipid levels were measured by Enzyme-linked immunosorbent assay (ELISA) and key proteins in the AMPK pathway were detected by western blots. In vitro, NGR1 (40 μmol/L) or Compound C (an inhibitor of AMPK, 10 μmol/L) was co-cultured with PA stimulation for 24 h in H9C2 cells. CCK-8 assay was used to detect cell viability. Key lipotoxicity-related proteins were detected by western blots and the LipidTOX™ neutral lipid stains were used to assess lipid accumulation. In addition, Apoptosis was assessed by Hoechst/PI staining.

Results: NGR1 could significantly improve the cardiac function and myocardial injury in mice with HF and up-regulate the expression of p-AMPK. Impressively, NGR1 inhibited the synthesis of diacylglycerol (DAG) and ceramide and promoted fatty acid oxidation (FAO) in vivo. Moreover, NGR1 significantly promoted expression of CPT-1A, the key enzyme in FAO pathway, and down-regulated the expression of GPAT and SPT, which were the key enzymes catalyzing production of DAG and ceramide. In vitro experiments showed that NGR1 could significantly attenuate lipid accumulation in PA-induced H9C2 cells and the Hoechst/PI staining results showed that NGR1 ameliorated lipotoxicity-induced apoptosis in PA-stimulated H9C2 cell model. Furthermore, co-treatment with inhibitor of AMPK abrogated the protective effects of NGR1. The regulative effects of NGR1 on lipid metabolism were also reversed by AMPK inhibitor.

Conclusion: NGR1 could significantly improve the heart function of mice with HF and reduce cardiac lipotoxicity. The cardio-protective effects of NGR1 are mediated by the activation of AMPK pathway.
Phase Diversity-Based Fourier Ptychography for Varying Aberration Correction
Authors: Xiang Meng , Pan An , Liu Jinpeng , Xi Teli , Guo Xin , Liu Fei , Shao Xiaopeng
Published: March 2022

Fourier ptychography (FP) is geared toward high-resolution imaging with a large field of view efficiently. In the original illumination-based FP scheme, the aberrations in optical systems can be well reconstructed, which plays a prominent role in simple and compact optical arrangements. Unfortunately, the reconstruction strategy for recovering an optical system’s pupil function fails to carefully consider the nature of the field-dependent pupil function in the aperture-scanning FP scheme, which affects the quality of the reconstructed image to a certain extent. Based on this observation, we report a phase diversity-based FP (PDFP) scheme for varying aberration correction. We image USAF resolution target with the proposed PDFP scheme and demonstrate our ability to correct varying aberration and improve image quality. The reported approach allows aperture-scanning FP technology to use simpler optical systems for imaging and may facilitate the further development of FP in practical applications such as industrial inspection and long-distance imaging.
High Sensitivity and Label-Free Detection of the SARS-CoV-2 S1 Protein Using a Terahertz Meta-Biosensor
Authors: Niu Qiang , Zhang Ran , Yang Yuping
Published: March 2022

High sensitivity and quantitative detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S protein) is of great significance for the diagnosis and treatment of coronaviruses. Here, we utilized terahertz time-domain spectroscopy (THz-TDS) integrated with a metamaterial (MM)-based biosensor and biological modification technology to demonstrate a high accuracy and label-free detection of the SARS-CoV-2 S1 protein by comparing the changes of the dielectric environment before and after binding the S1 protein. To confirm the sensing characteristics observed in the experiments and provide a further insight into the sensing mechanisms, we performed numerical simulations through varying the thickness, quantity, position, and refractive index of analyte aggregates. The sensitivity increases with the increase of the number of gaps and the amount of analyte near the gaps, which convincingly proves that the frequency shift and sensing performance are strongly influenced by the field enhancement and near-field coupling at the gap area.