bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of Project Organisations of the Japanese Construction Industry Focusing on the Modularity of Components
Authors: Yoshida Satoshi
Published: March 2022

Currently, technologies related to the construction industry have increased in their complexities and garnered important advancements. However, the pandemic upset the entire structure of industries, including the construction industry. Hence, a precise prescription is required for a right future direction of the construction industry. This study aims to provide a method for understanding the fundamental characteristics of the building industry via industrial analysis. In this article, the “Architecture concept” is adopted as an academic tool of consideration and is carried out a practical analysis on the building industry to provide a novel perspective. Previous studies analyzed several industries in this “architectural concept.” However, the analysis based on this concept has not progressed significantly for the building industry. Because this concept was created focusing on architecture, it has a high affinity with the building industry. Therefore, with the cooperation of multiple experts, we categorized the building components and modularization of the production process according to the selected indicators; then, we investigated the trends of the entire Japanese building industry. By analyzing the results of this survey, one can understand the basic correlation between the physical modularity of components and the independence of the design information creation process. This study contributes to providing the method to understanding the fundamental characteristics of the building industry and provides to presents the possibility of inter-industry and inter-regional comparisons from this perspective.
Optimize the Preparation of Novel Pyrite Tailings Based Non-sintered Ceramsite by Plackett-Burman Design Combined With Response Surface Method for Phosphorus Removal
Authors: Chen Ruihuan , Pan Zhenlin , Chu Shuyi , Xiao Jibo , Weng Rengui , Ouyang Da , Yang Yunlong , Wu Xiangting , Huang Zhida
Published: March 2022

The large amount of untreated pyrite tailings has caused serious environmental problems, and the recycling of pyrite tailings is considered as an attractive strategy. Here, we reported a novel non-sintered ceramsite prepared with pyrite tailings (PTNC) as the main active raw material for phosphorus control, and the dosage effect of ingredients on total phosphorus (TP) removal ability was investigated. The results from Plackett-Burman Design (PBD) suggested the dosages of dehydrated sludge, sodium bicarbonate, and cement were the factors which significantly affect the TP removal ability. The Box-Behnken Design (BBD) based response surface methodology was further employed, and it indicated the interactions between different factors, and the optimized recipe for PTNC was 84.5 g (pyrite tailings), 10 g (cement), 1 g (calcined lime), 1 g (anhydrous gypsum), 3 g (dehydrated sludge), and 0.5 g (sodium bicarbonate). The optimized PTNC was characterized and which presented much higher specific area (7.21 m2/g) than the standard limitation (0.5 m2/g), as well as a lower wear rate (2.08%) rather than 6%. Additionally, the leaching metal concentrations of PTNC were far below the limitation of Chinese National Standard. The adsorption behavior of TP on PTNC was subsequently investigated with batch and dynamic experiments. It was found that the calculated max adsorption amount (qmax) was about 7 mg/g, and PTNC was able to offer a stable TP removal ability under different hydraulic retention time (HRT). The adsorption mechanism was discussed by model fitting analysis combined with XRD and SEM characterization, and cobalt phosphide sulfide was observed as the newly formed substance through the adsorption process, which suggested the existing of both physical and chemical adsorption effect. Our research not only offered an economic preparation method of ceramsite, but also broadened the recycling pathway of pyrite tailings.
HDL Composition, Heart Failure, and Its Comorbidities
Authors: Diab Ahmed , Valenzuela Ripoll Carla , Guo Zhen , Javaheri Ali
Published: March 2022

Although research on high-density lipoprotein (HDL) has historically focused on atherosclerotic coronary disease, there exists untapped potential of HDL biology for the treatment of heart failure. Anti-oxidant, anti-inflammatory, and endothelial protective properties of HDL could impact heart failure pathogenesis. HDL-associated proteins such as apolipoprotein A-I and M may have significant therapeutic effects on the myocardium, in part by modulating signal transduction pathways and sphingosine-1-phosphate biology. Furthermore, because heart failure is a complex syndrome characterized by multiple comorbidities, there are complex interactions between heart failure, its comorbidities, and lipoprotein homeostatic mechanisms. In this review, we will discuss the effects of heart failure and associated comorbidities on HDL, explore potential cardioprotective properties of HDL, and review novel HDL therapeutic targets in heart failure.
Sepsis Prediction for the General Ward Setting
Authors: Yu Sean C. , Gupta Aditi , Betthauser Kevin D. , Lyons Patrick G. , Lai Albert M. , Kollef Marin H. , Payne Philip R. O. , Michelson Andrew P.
Published: March 2022

Objective

To develop and evaluate a sepsis prediction model for the general ward setting and extend the evaluation through a novel pseudo-prospective trial design.

Design

Retrospective analysis of data extracted from electronic health records (EHR).

Setting

Single, tertiary-care academic medical center in St. Louis, MO, USA.

Patients

Adult, non-surgical inpatients admitted between January 1, 2012 and June 1, 2019.

Interventions

None.

Measurements and Main Results

Of the 70,034 included patient encounters, 3.1% were septic based on the Sepsis-3 criteria. Features were generated from the EHR data and were used to develop a machine learning model to predict sepsis 6-h ahead of onset. The best performing model had an Area Under the Receiver Operating Characteristic curve (AUROC or c-statistic) of 0.862 ± 0.011 and Area Under the Precision-Recall Curve (AUPRC) of 0.294 ± 0.021 compared to that of Logistic Regression (0.857 ± 0.008 and 0.256 ± 0.024) and NEWS 2 (0.699 ± 0.012 and 0.092 ± 0.009). In the pseudo-prospective trial, 388 (69.7%) septic patients were alerted on with a specificity of 81.4%. Within 24 h of crossing the alert threshold, 20.9% had a sepsis-related event occur.

Conclusions

A machine learning model capable of predicting sepsis in the general ward setting was developed using the EHR data. The pseudo-prospective trial provided a more realistic estimation of implemented performance and demonstrated a 29.1% Positive Predictive Value (PPV) for sepsis-related intervention or outcome within 48 h.
Randomized Clinical Trial: Probiotics Alleviated Oral-Gut Microbiota Dysbiosis and Thyroid Hormone Withdrawal-Related Complications in Thyroid Cancer Patients Before Radioiodine Therapy Following Thyroidectomy
Authors: Lin Baiqiang , Zhao Fuya , Liu Yang , Wu Xin , Feng Jing , Jin Xiangren , Yan Wei , Guo Xiao , Shi Shang , Li Zhiyong , Liu Lujia , Chen Hongye , Wang Haoran , Wang Shuang , Lu Yu , Wei Yunwei
Published: March 2022

Background

Thyroid hormone withdrawal (THW) in postoperative thyroid cancer patients who need always accompanied by complications (e.g., dyslipidemia and constipation). At present, there are no effective and safe means to alleviate these complications.

Purpose

We aimed to assess the oral-gut microbiota profiles in THW patients then investigate whether probiotics could alleviating alleviate THW related complications and investigate whether these therapeutic effects were associated with the oral-gut microbiota state.

Methods

Fifty eligible thyroid carcinoma patients undergoing thyroidectomy were randomly assigned to receive probiotics or placebo during THW. Complications were assessed through validated questionnaires and plasma lipid indicators. The complex probiotics preparation was composed of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus.

Results

Probiotics alleviated lack of energy, constipation, weight gain, and dry mouth and decreased the levels of fecal/serum LPS and plasma lipid indicators (total cholesterol, triglycerides, low-density lipoprotein, and apolipoprotein A) (P < 0.05). Gut and oral microbial diversity were significantly decreased after THW, while an increased microbial dysbiosis index (MDI) was observed. Probiotics distinctly restored the gut and oral microbial diversity. Increased Holdemanella, Enterococcus, and Coprococcus_2, while decreased Fusobacterium, Eubacterium_ruminantium_group, Ruminococcus_1, and Parasutterella in the gut were found after probiotics intervention. Lack of energy, constipation, weight gain, and dyslipidemia were seen to be related to the above microbiota. In addition, probiotics reduced oral Prevotella_9, Haemophilus, Fusobacterium, and Lautropia, which were positively correlated with the occurrence of dry mouth.

Conclusion

Probiotics reduce the incidence of complications in patients after THW, which may be related to modifying the oral and gut microbiota.

Clinical Trial Registration

[https://clinicaltrials.gov/], identifier America Clinical Trial Registry NCT03574051.
Optimal Dispatching Strategy of Active Distribution Network for Promoting Local Consumption of Renewable Energy
Authors: Xie Hua , Wang Wei , Wang Weixing , Tian Lulu
Published: March 2022

Large-scale renewable energy sources (RESs) have been integrated into the active distribution network (ADN). For promoting the local consumption of RESs within ADN, an optimal dispatching strategy was proposed with two-stage hierarchical energy management framework. On the spatial boundary, a two-layer energy management framework was designed with the local optimization layer and the global optimization layer. The local optimization layer was for optimal power flow in the branch feeder with the objective functions of minimizing operation costs and maximizing the consumption of RESs. The global optimization layer was for optimal power flow in the main feeder with the objective functions of minimizing power loss and the voltage deviation of nodes. On the time scale, two-stage optimal dispatching models were established, including the day-ahead optimal models and intra-day optimal models. The day-ahead optimal models identified the operation status of the controllable units, and then the intra-day optimal models were updated with the ultra-short-term forecast results. A risk indicator was introduced to quantify the uncertainty of RES, and a non-dominated sorting genetic algorithm with elite strategy was adopted to solve the multi-objective nonlinear programming problem. An actual project in northern China was used as the testing system. The results of case studies verify that the proposed strategy can effectively realize the maximum local consumption of RESs and support the economic operation of ADN.
Residue Monitoring of Propiconazole in the Rice–Crab Co-Culture Field and its Toxicity and Bioaccumulation to Eriocheir sinensis
Authors: Yu Lina , Li Changsheng , Zhang Yuting , Guo Xuanjun , Cao Niannian , Guo Shuxin , Wu Sijia , Li Xuefeng , Pang Sen
Published: March 2022

Rice–crab co-culture is a high-benefit eco-breeding pattern that has been extensively developed in many regions of China. However, little attention has been paid to the safety of pesticides used to control rice pests in the crab–rice co-culture system. This study monitored the actual residue levels of propiconazole in water and soil of rice–crab co-culture fields and evaluated the acute toxicity, subchronic toxicity, and bioaccumulation of propiconazole to Eriocheir sinensis. We observed that the residue level of propiconazole in paddy soil was higher than that in paddy water within 42-day field monitoring. Propiconazole demonstrated a low acute toxicity (96 h-LC50 > 100 mg/L) to E. sinensis and exhibited no obvious adverse impact on the growth of E. sinensis after exposure to 500 μg/L, which was 10 times the actual residual concentration of propiconazole in the crab–rice co-culture field. The highest bioaccumulation of propiconazole was obtained from gills, followed by the hepatopancreas and meat. These results will contribute to the guidance of scientific utilization of pesticides in the crab–rice co-culture field.
Bioinformatics Analysis Reveals Cell Cycle-Related Gene Upregulation in Ascending Aortic Tissues From Murine Models
Authors: Zhang Xiaoping , Yang Zuozhen , Li Xiaoyan , Liu Xuxia , Wang Xipeng , Qiu Tao , Wang Yueli , Li Tongxun , Li Qingle
Published: March 2022

Thoracic aortic aneurysm and dissection (TAAD) is a high-risk aortic disease. Mouse models are usually used to explore the pathological progression of TAAD. In our studies, we performed bioinformatics analysis on a microarray dataset (GSE36778) and verified experiments to define the integrated hub genes of TAAD in three different mouse models. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein–protein interaction (PPI) network analyses, and histological and quantitative reverse transcription-PCR (qRT–PCR) experiments were used in our study. First, differentially expressed genes (DEGs) were identified, and twelve common differentially expressed genes were found. Second, genes related to the cell cycle and inflammation were enriched by using GO and PPI. We focused on filtering and validating eighteen hub genes that were upregulated. Then, expression data from human ascending aortic tissues in the GSE153434 dataset were also used to verify our findings. These results indicated that cell cycle-related genes participate in the pathological mechanism of TAAD and provide new insight into the molecular mechanisms of TAAD.
The Expression Pattern of Ferroptosis-Related Genes in Colon Adenocarcinoma: Highly Correlated to Tumor Microenvironment Characteristics
Authors: Liu Jie , Li Hui , Zhao Shen , Lin Rongbo , Yu Jiaqing , Fan Nanfeng
Published: March 2022

In the latest literatures, ferroptosis caused by T cells in cancerous cells provided new insights of improving curative effect of the PD-1/PD-L1 antibody. The microenvironment on which tumor cells develop and survive was also emphasized as its crucial role in tumor occurrence, development, metastasis and immune escape. Thus, the interaction of ferroptosis related genes and tumor microenvironment (TME) was urgently be detected in a comprehensive perspective. We comprehensively evaluated the transcriptional feature of ferroptosis related genes in colon adenocarcinoma (COAD), and systematically associated these ferroptosis subtypes with DNA damage repair (DDR) and TME characteristics. We found two unique patterns of ferroptosis characterized by distinct biological pathways activation. We also demonstrated that FRG score constructed based on ferroptosis subtypes has a significant correlation with prognosis of colon cancer and could act as an independent prognostic biomarker for predicting patients’ survival. The higher immune infiltrating level, immune functional pathways activation was observed in the high FRG score group. Furthermore, these results were verified by an independent external GEO cohort. This work revealed ferroptosis was highly associated with TME complexity and diversity. A novel ferroptosis subtypes related gene scoring system can be used for prognostic prediction in COAD. Targeting ferroptosis may be a therapeutic alternative for COAD.
Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3β-Mediated Keap1/Nrf2/HO-1 Signalling Pathway
Authors: Feng Senling , Zhou Yongheng , Huang Hongliang , Lin Ying , Zeng Yifeng , Han Shanshan , Huang Kaikai , Liu Quanzhi , Zhu Wenting , Yuan Zhongwen , Liang Baoying
Published: March 2022

Melanoma is an aggressive malignant skin tumour with an increasing global incidence. However, current treatments have limitations owing to the acquired tumour drug resistance. Ferroptosis is a recently discovered form of programmed cell death characterised by iron accumulation and lipid peroxidation and plays a critical role in tumour growth inhibition. Recently, ferroptosis inducers have been regarded as a promising therapeutic strategy to overcome apoptosis resistance in tumour cells. In this study, we reported that nobiletin, a natural product isolated from citrus peel, and exhibited antitumour activity by inducing ferroptosis in melanoma cells. Subsequently, we further explored the potential mechanism of nobiletin-induced ferroptosis, and found that the expression level of glycogen synthase kinase 3β (GSK3β) in the skin tissue of patients with melanoma was significantly reduced compared to that in the skin of normal tissue. Additionally, nobiletin increased GSK3β expression in melanoma cells. Moreover, the level of Kelch-like Ech-associated protein-1 (Keap1) was increased, while the level of nuclear factor erythroid 2-related factor 2 (Nrf2), and haem oxygenase-1 (HO-1) was decreased in nobiletin-treated melanoma cells, suggesting that the antioxidant defence system was downregulated. Furthermore, knockdown of GSK3β significantly reduced nobiletin-induced ferroptosis and upregulated the Keap1/Nrf2/HO-1 signalling pathway, while the opposite was observed in cells overexpressing GSK3β. In addition, molecular docking assay results indicated that nobiletin showed strong binding affinities for GSK3β, Keap1, Nrf2, and HO-1. Taken together, our results demonstrated that nobiletin could induce ferroptosis by regulating the GSK3β-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.
Differential H. pylori-Induced MAPK Responses Regulate Lewis Antigen Expression and Colonization Density on Gastric Epithelial Cells Between Children and Adults
Authors: Yang Yao-Jong , Lu Chia-Ling , Sheu Bor-Shyang
Published: March 2022

Helicobacter pyloricauses gastrointestinal diseases, the manifestations of diseases are more serious in adults than in children. Lewis antigen expressions on the gastric epithelium serves as receptors targeted byH. pylori. Moreover, the MAPK signaling pathway involves glycoprotein synthesis of Lewis antigens. We aimed to investigate whether differences inH. pylori-induced MAPK responses mediate gastric Lewis antigens expression and colonization density differently in children and adults. We used human stomach fetal epithelium (HSFE) and SV40-immortalized human normal gastric epithelial (GES-1) cell lines to mimic primary gastric epithelium of children and adults, respectively.H. pyloricolonization intensity and Lewis antigens were significantly higher in GES-1 than in HSFE cells, whereas IL-8 and IL-6 levels were significantly higher in HSFE than in GES-1 cells after infection. c-Jun N-terminal kinase (JNK) siRNA and inhibitor (SP600125) experiments showed that Lewis antigen expression andH. pyloricolonization were reduced in GES-1 cells but increased in HSFE cells. Furthermore, p-p38 intensity was significantly higher in the superficial epithelium of the children than in the adults with/withoutH. pyloriinfection. The overexpression of p38 in GES-1 cells downregulatedH. pylori-induced JNK activity mimickingH. pyloriinfection in children. In conclusion, a higher p38 expression in gastric epithelium counteracting JNK activity in children may contribute to lower Lewis antigen expression and colonization density than in adults afterH. pyloriinfection.
GPC2 Is a Potential Diagnostic, Immunological, and Prognostic Biomarker in Pan-Cancer
Authors: Chen Guoming , Luo Dongqiang , Zhong Nan , Li Danyun , Zheng Jiyuan , Liao Hui , Li Zhuoyao , Lin Xiaoxiao , Chen Qiqi , Zhang Cheng , Lu Yuanjun , Chan Yau-Tuen , Ren Qing , Wang Ning , Feng Yibin
Published: March 2022

Background

Glypican 2 (GPC2), a member of glypican (GPC) family genes, produces proteoglycan with a glycosylphosphatidylinositol anchor. It has shown its ascending significance in multiple cancers such as neuroblastoma, malignant brain tumor, and small-cell lung cancer. However, no systematic pan-cancer analysis has been conducted to explore its function in diagnosis, prognosis, and immunological prediction.

Methods

By comprehensive use of datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genotype-Tissue Expression Project (GTEx), cBioPortal, Human Protein Atlas (HPA), UALCAN, StarBase, and Comparative Toxicogenomics Database (CTD), we adopted bioinformatics methods to excavate the potential carcinogenesis of GPC2, including dissecting the correlation between GPC2 and prognosis, gene mutation, immune cell infiltration, and DNA methylation of different tumors, and constructed the competing endogenous RNA (ceRNA) networks of GPC2 as well as explored the interaction of GPC2 with chemicals and genes.

Results

The results indicated that GPC2 was highly expressed in most cancers, except in pancreatic adenocarcinoma, which presented at a quite low level. Furthermore, GPC2 showed the early diagnostic value in 16 kinds of tumors and was positively or negatively associated with the prognosis of different tumors. It also verified that GPC2 was a gene associated with most immune-infiltrating cells in pan-cancer, especially in thymoma. Moreover, the correlation with GPC2 expression varied depending on the type of immune-related genes. Additionally, GPC2 gene expression has a correlation with DNA methylation in 20 types of cancers.

Conclusion

Through pan-cancer analysis, we discovered and verified that GPC2 might be useful in cancer detection for the first time. The expression level of GPC2 in a variety of tumors is significantly different from that of normal tissues. In addition, the performance of GPC2 in tumorigenesis and tumor immunity also confirms our conjecture. At the same time, it has high specificity and sensitivity in the detection of cancers. Therefore, GPC2 can be used as an auxiliary indicator for early tumor diagnosis and a prognostic marker for many types of tumors.
Multidimensional Evaluation of Brown Shrimp Trawling Fisheries on the Amazon Continental Shelf
Authors: Araújo Janayna Galvão , Mello Filho Adauto dos Santos , Peixoto Ualerson Iran , Bentes Bianca , Santos Marcos Antonio Souza dos , Dutka-Gianelli Jynessa , Isaac Victoria
Published: March 2022

Brown shrimp (Penaeus subtilis) trawling in the northern coastal waters of Brazil is an industrial fishing activity with a share in the international market and an important resource in the fishery market. Due to the scarcity of updated information on this practice and owing to its complexity, it is difficult to have a measurement of all dimensions of the development of this fishery, whether they are ecological, economic, or social-institutional. The present paper uses an assessment tool focused on data-poor fishery systems, the Fishery Performance Indicators (FPIs), to assess the multidimensional conditions of this fishery. The indicators were assessed between 2019 and 2020, and the metrics were based on public official data, scientific publications, in loco consultations with production agents, and databases of research projects. Results showed that the critical points of this activity are primarily related to the ecological indicator (1.75), which obtained a lower score compared to other fisheries assessed using the same methodology. This is due to its low selectivity, which results in high by-catch volumes and discards. The limited participation of productive chain actors also restrains the efficacy of management measures, which hampers successful resource management. This issue maximizes other setbacks throughout the productive chain, such as economic and social factors.
Orbital Apex Syndrome: A Case Series in a Tertiary Medical Center in Southern Taiwan
Authors: Lee Peng-Hsuan , Shao Shih-Chieh , Lee Wan-Ju Annabelle
Published: March 2022

Background

Orbital apex syndrome (OAS) is a rare ocular complication following by infection, inflammation, trauma, neoplasms, and vascularity. The epidemiological features of OAS remained limited, so this study aimed to present ophthalmic clinical features, determine the causes to evaluate the visual prognosis of orbital apex syndrome (OAS) patients in Taiwan.

Methods

This was a retrospective study by reviewing the electronic medical records from National Cheng Kung University Hospital in Taiwan during 2017–2019. We included patients diagnosed with OAS to review their ocular symptoms and signs, visual acuity, ocular images, etiologies, treatment and visual prognosis.

Results

Twenty cases (mean age: 65.55 ± 13.06; male: 75%) with the diagnosis of OAS were included in this study. All patients presented as unilateral involvement, but the initial ocular presentations and etiologies varied. For example, blurred vision was reported in 80% of these patients, and tumor-related compression (55%) and infection (15%) were the most frequent causes for the OAS. After the follow-up, we found 35% of patients' visions declined or worsened to the blindness, 15% of patients' visions remained stable, 20% of patients' visions had mild improvement, and 35% of patients' visions were not measured because of debilitating clinical condition. We identified three OAS patients with mortality (15%), and all of them were attributed to the underlying malignancies.

Conclusion

The clinical magnifications and etiologies of OAS are heterogeneous in Taiwan. Our findings indicated the tumor-related compression is the most frequent causes of OAS in Taiwan, and it is also related to poor clinical outcomes.
Assessment of the Effects of the Synbiotic Combination of Bifidobacterium longum subsp. infantis CECT 7210 and Oligofructose-Enriched Inulin Against Digestive Bacterial Infections in a Piglet Model
Authors: Rodríguez-Sorrento Agustina , Castillejos Lorena , López-Colom Paola , Cifuentes-Orjuela Gloria , Moreno-Muñoz José A. , Martín-Orúe Susana M.
Published: March 2022

The use of bifidobacteria as probiotics has proven to be beneficial in gastroenteric infections. Furthermore, prebiotics such as inulin can enhance the survival and growth of these bacteria. Two trials were performed to evaluate the effects of the administration of Bifidobacterium longum subsp. infantis CECT 7210 and oligofructose-enriched inulin against Salmonella enterica serovar Typhimurium or enterotoxigenic Escherichia coli (ETEC) F4. A total of 72 (Salmonella trial) and 96 (ETEC F4 trial) weaned piglets were used in a 2 × 2 design (with or without synbiotic, inoculated or not with the pathogen). After adaptation, animals were orally inoculated. Performance and clinical signs were evaluated. On days 4 and 8 (Salmonella trial) and 3 and 7 (ETEC F4 trial) post-inoculation (PI), one animal per pen was euthanized. Blood, digestive content and tissue samples were collected and microbiological counts, fermentation products, serum inflammatory markers and ileum histomorphometry analysis were performed. Both challenges had an impact on faecal consistency (p < 0.001), including the faecal shedding of Salmonella and increased numbers of enterobacteria and coliforms. The synbiotic administration did not have any effect on pathogen loads but induced changes in the fermentation profile, such as increased valeric acid in both trials as well as decreased acetic acid, except for Salmonella-challenged animals. The effect on propionate varied among trials, increasing in challenged synbiotic-treated pigs and decreasing in non-challenged ones in the Salmonella trial (P interaction = 0.013), while the opposed occurred in the ETEC F4 trial (P interaction = 0.013). The administration of the synbiotic increased intraepithelial lymphocytes (IEL; p = 0.039) on day 8 PI in the Salmonella trial and a similar trend occurred in non-challenged pigs in the ETEC F4 trial (P interaction = 0.086). The results did not provide evidence of reduced pathogen load with the synbiotic, although a modulation in fermentative activity could be identified depending on the challenge. Consistent increases were found in IEL, suggesting that this synbiotic combination has some immunomodulatory properties.
Different Complement Activation Pathways Underly Cognitive Impairment and Type 2 Diabetes Mellitus Combined With Cognitive Impairment
Authors: Li Zhenxing , Zhang Weiwei , Gao Feng , Tang Qiqiang , Kang Dongmei , Shen Yong
Published: March 2022

Background

The immune response and the complement system are associated with cognitive impairment and diabetes mellitus, respectively. Activation of the complement system in these diseases occurs mainly through either the classical pathway or the alternative pathway. However, the specific complement proteins involved in the development of the type 2 diabetes mellitus (T2DM) and cognitive impairment are still unclear. Here, we investigated complement proteins in serum from patients with T2DM, cognitive impairment, or both T2DM and cognitive impairment.

Objective

To investigate the levels of serum immune complement proteins in patients with T2DM, cognitive impairment, or T2DM combined with cognitive impairment and the associations between these complement proteins and risk factors for T2DM or cognitive impairment.

Methods

Clinical markers were collected from blood samples of 264 participants. Luminex multiplex assays were used to detect serum complement proteins. All statistical analyses were performed using Prism or R studio.

Results

There was a difference in serum levels of the complement proteins C1q, C3, C3b, and FH between the three different groups. Hyperglycemia was significantly correlated with elevated C3b or reduced C3, C1q, and FH. In addition, hyperlipidemia was positively correlated with elevated levels of C3, C4, C1q, and FH proteins. There was an association between C1q, C3, C4, and FH and β-pancreas cell function, whereas only FH was associated with insulin resistance. Higher serum C1q was significantly associated with an increased risk of cognitive impairment.

Conclusion

Serum levels of complement proteins were closely associated with hyperglycemia and hyperlipidemia. We found that classical complement pathway activation mainly occurred in the cognitive impairment only group, whereas the alternative pathway may reflect T2DM and T2DM with cognitive impairment.
The Effect of Schwann Cells/Schwann Cell-Like Cells on Cell Therapy for Peripheral Neuropathy
Authors: Wang Qian , Chen Fang-Yu , Ling Zhuo-Min , Su Wen-Feng , Zhao Ya-Yu , Chen Gang , Wei Zhong-Ya
Published: March 2022

Peripheral neuropathy is a common neurological issue that leads to sensory and motor disorders. Over time, the treatment for peripheral neuropathy has primarily focused on medications for specific symptoms and surgical techniques. Despite the different advantages of these treatments, functional recovery remains less than ideal. Schwann cells, as the primary glial cells in the peripheral nervous system, play crucial roles in physiological and pathological conditions by maintaining nerve structure and functions and secreting various signaling molecules and neurotrophic factors to support both axonal growth and myelination. In addition, stem cells, including mesenchymal stromal cells, skin precursor cells and neural stem cells, have the potential to differentiate into Schwann-like cells to perform similar functions as Schwann cells. Therefore, accumulating evidence indicates that Schwann cell transplantation plays a crucial role in the resolution of peripheral neuropathy. In this review, we summarize the literature regarding the use of Schwann cell/Schwann cell-like cell transplantation for different peripheral neuropathies and the potential role of promoting nerve repair and functional recovery. Finally, we discuss the limitations and challenges of Schwann cell/Schwann cell-like cell transplantation in future clinical applications. Together, these studies provide insights into the effect of Schwann cells/Schwann cell-like cells on cell therapy and uncover prospective therapeutic strategies for peripheral neuropathy.
Eucommia ulmoides Oliver-Tribulus terrestris L. Drug Pair Regulates Ferroptosis by Mediating the Neurovascular-Related Ligand-Receptor Interaction Pathway- A Potential Drug Pair for Treatment Hypertension and Prevention Ischemic Stroke
Authors: Zhang Qian , Yang Jie , Yang Chuanhua , Yang Xuesong , Chen Yongzhi
Published: March 2022

Background

In this study, we used the network pharmacology approach to explore the potential disease targets of the Eucommia ulmoides Oliver (EUO)-Tribulus terrestris L. (TT) drug pair in the treatment of hypertension-associated neurovascular lesions and IS via the ferroptosis pathway.

Methods

We used the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform to search for the key active compounds and targets of the drug pair. Based on the GeneCards database, the relevant targets for the drug pair were obtained. Then, we performed the molecular docking of the screened core active ingredients and proteins using the DAVID database and the R AutoDock Vina software. Based on the GSE22255 dataset, these screened target proteins were used to build random forest (RF) and support vector machine (SVM) models. Finally, a new IS nomogram prediction model was constructed and evaluated.

Results

There were 36 active compounds in the EUO-TT drug pair. CHRM1, NR3C1, ADRB2, and OPRD1 proteins of the neuroactive ligand-receptor interaction pathway interacted with the proteins related to the ferroptosis pathway. Molecular docking experiments identified 12 active ingredients of the drug pair that may tightly bind to those target proteins. We constructed a visual IS nomogram prediction model using four genes (CHRM1, NR3C1, ADRB2, and OPRD1). The calibration curve, DCA, and clinical impact curves all indicated that the nomogram model is clinically applicable and diagnostically capable. CHRM1, NR3C1, ADRB2, and OPRD1, the target genes of the four effective components of the EUO-TT drug pair, were considered as risk markers for IS.

Conclusions

The active ingredients of EUO-TT drug pair may act on proteins associated with the neuroactive ligand-receptor interaction pathway to regulate ferroptosis in vascular neurons cells, ultimately affecting the onset and progression of hypertension.
Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report
Authors: Lang-Orsini Melanie , Gonzalez-Perez Paloma
Published: March 2022

Mutations in nuclear-encoded genes that are involved in mitochondrial DNA replication and maintenance (e.g., POLG) have been associated with chronic progressive external ophthalmoplegia (CPEO) phenotype. These nuclear genome mutations may lead to multiple mitochondrial DNA deletions or mitochondrial DNA depletion. On the other hand, primary genetic defects of mitochondrial DNA (such as single large-scale deletion or point mutations) have also been associated with the CPEO phenotype. Chronic progressive external ophthalmoplegia (CPEO) may be a manifestation of specific syndromes that, when clinically recognized, prompt clinicians to investigate specific genetic defects. Thus, CPEO, as part of Kearns Sayre syndrome, suggests the presence of a large-scale deletion of mitochondrial DNA. However, in pure CPEO or CPEO plus phenotypes, it is more difficult to know whether causative genetic defects affect the nuclear or mitochondrial DNA. Here, we present a patient with a long-standing history of CPEO plus phenotype, in whom the sequencing of mitochondrial DNA from skeletal muscle was normal, and no other genetic defect was suspected at first. At the time of our evaluation, the presence of polyneuropathy and neuropathic pain prompted us to investigate nuclear genetic defects and, specifically, mutations in the POLG gene. Thus, the sequencing of the POLG gene revealed p.Thr251Ile and p.Pro587Leu mutations in one allele, and p.Ala467Thr mutation in another allele. Although one would expect that mutations in POLG lead to multiple mitochondrial DNA deletions or depletion (loss of copies), the absence of mitochondrial DNA abnormalities in tissue may be explained by heteroplasmy, a lack or no significant involvement of biopsied tissue, or a sampling bias. So, the absence of secondary mitochondrial DNA alterations should not discourage clinicians from further investigating mutations in nuclear-encoded genes. Lastly, mitochondrial point mutations and single mitochondrial DNA deletions very rarely cause CPEO associated with polyneuropathy and neuropathic pain, and POLG-related disease should be considered in this scenario, instead.
“GENYAL” Study to Childhood Obesity Prevention: Methodology and Preliminary Results
Authors: Marcos-Pasero Helena , Aguilar-Aguilar Elena , de la Iglesia Rocío , Espinosa-Salinas Isabel , Molina Susana , Colmenarejo Gonzalo , Martínez J. Alfredo , Ramírez de Molina Ana , Reglero Guillermo , Loria-Kohen Viviana
Published: March 2022

Objective

This article describes the methodology and summarizes some preliminary results of the GENYAL study aiming to design and validate a predictive model, considering both environmental and genetic factors, that identifies children who would benefit most from actions aimed at reducing the risk of obesity and its complications.

Design

The study is a cluster randomized clinical trial with 5-year follow-up. The initial evaluation was carried out in 2017. The schools were randomly split into intervention (nutritional education) and control schools. Anthropometric measurements, social and health as well as dietary and physical activity data of schoolchildren and their families are annually collected. A total of 26 single nucleotide polymorphisms (SNPs) were assessed. Machine Learning models are being designed to predict obesity phenotypes after the 5-year follow-up.

Settings

Six schools in Madrid.

Participants

A total of 221 schoolchildren (6–8 years old).

Results

Collected results show that the prevalence of excess weight was 19.0, 25.4, and 32.2% (according to World Health Organization, International Obesity Task Force and Orbegozo Foundation criteria, respectively). Associations between the nutritional state of children with mother BMI [β = 0.21 (0.13–0.3),p(adjusted) <0.001], geographical location of the school [OR = 2.74 (1.24–6.22),p(adjusted) = 0.06], dairy servings per day [OR = 0.48 (0.29–0.75),p(adjusted) = 0.05] and 8 SNPs [rs1260326, rs780094, rs10913469, rs328, rs7647305, rs3101336, rs2568958, rs925946;p(not adjusted) <0.05] were found.

Conclusions

These baseline data support the evidence that environmental and genetic factors play a role in the development of childhood obesity. After 5-year follow-up, the GENYAL study pretends to validate the predictive model as a new strategy to fight against obesity.

Clinical Trial Registration

This study has been registered inClinicalTrials.govwith the identifier NCT03419520,https://clinicaltrials.gov/ct2/show/NCT03419520.
Increased Variation in Body Weight and Food Intake Is Related to Increased Dietary Fat but Not Increased Carbohydrate or Protein in Mice
Authors: Wu Yingga , Hu Sumei , Yang Dengbao , Li Li , Li Baoguo , Wang Lu , Li Min , Wang Guanlin , Li Jianbo , Xu Yanchao , Zhang Xueying , Niu Chaoqun , Speakman John R.
Published: March 2022

A variety of inbred mouse strains have been used for research in metabolic disorders. Despite being inbred, they display large inter-individual variability for many traits like food intake and body weight. However, the relationship between dietary macronutrients and inter-individual variation in body weight and food intake of different mouse strains is still unclear. We investigated the association between macronutrient content of the diet and variations in food intake, body composition, and glucose tolerance by exposing five different mouse strains (C57BL/6, BALB/c, C3H, DBA/2, and FVB) to 24 different diets with variable protein, fat, and carbohydrate contents. We found only increasing dietary fat, but not protein or carbohydrate had a significant association (positive) with variation in both food intake and body weight. The highest variation in both body weight and food intake occurred with 50% dietary fat. However, there were no significant relationships between the variation in fat and lean mass with dietary protein, fat, or carbohydrate levels. In addition, none of the dietary macronutrients had significant impacts on the variation in glucose tolerance ability in C57BL/6 mice. In conclusion, the variations in food intake and body weight changes increased with the elevation of dietary fat levels.
Computational Analysis of Cytokine Release Following Bispecific T-Cell Engager Therapy: Applications of a Logic-Based Model
Authors: Selvaggio Gianluca , Parolo Silvia , Bora Pranami , Leonardelli Lorena , Harrold John , Mehta Khamir , Rock Dan A. , Marchetti Luca
Published: March 2022

Bispecific T-cell engaging therapies harness the immune system to elicit an effective anticancer response. Modulating the immune activation avoiding potential adverse effects such as cytokine release syndrome (CRS) is a critical aspect to realizing the full potential of this therapy. The use of suitable exogenous intervention strategies to mitigate the CRS risk without compromising the antitumoral capability of bispecific antibody treatment is crucial. To this end, computational approaches can be instrumental to systematically exploring the effects of combining bispecific antibodies with CRS intervention strategies. Here, we employ a logical model to describe the action of bispecific antibodies and the complex interplay of various immune system components and use it to perform simulation experiments to improve the understanding of the factors affecting CRS. We performed a sensitivity analysis to identify the comedications that could ameliorate CRS without impairing tumor clearance. Our results agree with publicly available experimental data suggesting anti-TNF and anti-IL6 as possible co-treatments. Furthermore, we suggest anti-IFNγ as a suitable candidate for clinical studies.
Immune Checkpoint Inhibitor-Induced Hypophysitis and Patterns of Loss of Pituitary Function
Authors: Jessel Shlomit , Weiss Sarah A. , Austin Matthew , Mahajan Amit , Etts Katrina , Zhang Lin , Aizenbud Lilach , Perdigoto Ana Luisa , Hurwitz Michael , Sznol Mario , Herold Kevan C. , Kluger Harriet M.
Published: March 2022

Background

Immune checkpoint inhibitors (ICI) are clinically active across multiple tumor types but the associated immune-related adverse events (irAEs) lead to treatment delays or discontinuation and negatively impact quality-of-life. Hypophysitis is often a permanent irAE that may affect multiple pituitary hormonal axes. Here we comprehensively characterize our institution’s clinical experience with ICI-induced hypophysitis and the associated patterns of pituitary function loss.

Methods

Patients with solid tumors, mostly melanoma and renal cell carcinoma (RCC), treated with ICI at Yale Cancer Center were prospectively enrolled from October 2016-May 2021. Demographics and clinical data were obtained from the medical record including type and timing of irAEs. Patients were included in this cohort if hypophysitis was diagnosed by pre-specified biochemical and clinical parameters.

Results

The overall incidence of hypophysitis was 69/490 (14%) in patients with melanoma (n=58, 84%), RCC (n=10,14%), and merkel cell carcinoma (n=1, 1%) who received ipilimumab plus nivolumab (77%; 53/69), anti-PD-(L)1 (17%; 12/69), or ipilimumab monotherapy (6%; 4/69). Of the 69 patients analyzed, median time to hypophysitis on combination ICI versus anti-PD-1 was 2.8 vs. 4.1 months. The incidence of hypophysitis in patients with melanoma was 25% (46/187) with ipilimumab plus nivolumab and 5% (7/129) with anti-PD-(L)1 compared to 9% (7/77) and 8% (3/37), respectively, in patients with RCC. Patients who developed hypophysitis on combination ICI had a higher rate of headache (p=0.05) and co-occurring irAEs (p=0.01) compared anti-PD-(L1)1 monotherapy. At a median follow-up of 2.2 years, 77% of patients were alive. Objective response rates to ICI in melanoma patients were higher than previously reported for unselected populations. Central hypothyroidism and hypogonadism were the most common pituitary axes affected after the adrenal axis. In select cases, there was evidence of spontaneous rebound in free testosterone levels after an initial decline.

Conclusions

We demonstrate a higher rate of ICI-induced hypophysitis than previously reported, which may be reflective of real-world practice due to increased awareness as experience with ICI has grown. In select cases, there was evidence of rebound in free testosterone and/or gonadotropins but not in adrenal axis hormones.
Spinal Cord Stimulation as an Alternative to Opioid for Axial Neck and Back Pain: A Case Series
Authors: Mullins Graeme Sampson , Burns Joanna Jane , Schneider Andre Perillier , El Helou Antonios
Published: March 2022

Introduction

Spinal cord stimulation is emerging as a minimally invasive technique for treatment of persistent spinal pain syndrome (PSPS).

Methods

We describe a case series of 25 individuals with PSPS who underwent implantation of a spinal cord stimulator device between 2017 and 2021.

Results

There was a significant reduction in mean visual analog scale pain scores in the immediate postoperative phase, (8.61 vs. 2.3, p < 0.001). There were twelve patients who consumed pre-operative opioid, and 75% showed reduction of use with a significantly lower average daily dose (66.8 vs. 26.9 meq/D, p < 0.05). There was a significant reduction in the Oswestry Disability Index during postoperative follow-up visits (p < 0.001). There were no major perioperative or long-term complications from the procedure in follow-up.

Conclusion

The analysis of this cohort suggests successful long-term treatment of a diverse set of patients with PSPS who underwent spinal cord stimulation (SCS) and had meaningful improvement in quality of life and reduction in opioid consumption.
Hippocampus RNA Sequencing of Pentylenetetrazole-Kindled Rats and Upon Treatment of Novel Chemical Q808
Authors: Li Xiang , Wang Qing , Zhang Dian-wen , Wu Di , Zhang Si-wei , Wei Zheng-ren , Chen Xia , Li Wei
Published: March 2022

The expression of genes altered in epilepsy remains incomplete, particularly in the hippocampus, which exhibits exquisite vulnerability to epilepsy. Q808 is an innovation chemical compound that has potent anti-convulsant effect. Exploring its mechanism can not only explore the pathogenesis of epilepsy but also provide a theoretical basis for its clinical application. The present study aimed to use RNA sequencing (RNA-seq) to reveal the gene transcriptomic profile of chronic pentylenetetrazole (PTZ)-kindled seizure rats and the difference of the PTZ model rat before and after treatment with Q808. Quantitative real-time PCR (qRT-PCR) was performed to validate the RNA-seq results. The protein level was estimated with Western blot. Hippocampal transcriptomic analysis showed that 289 differentially expressed genes (DEGs) were confirmed in the PTZ-kindled seizure group compared with the vehicle control. Gene cluster analysis identified most of the DEGs linked to neuronal apoptosis, neurogenesis, neuronal projections, and neurotransmitter regulation. After analysis across the three groups, 23 hub genes and 21 pathways were identified, and qRT-PCR analysis confirmed that most of the mRNA levels of hub genes were consistent with the RNA-seq results. Q808 treatment increased the level of ACE, a GABA-related protein. Our analysis showed the comprehensive compendium of genes and pathways differentially expressed for PTZ-kindled seizure rats and upon Q808 treatment in PTZ-kindled seizure, which may provide a theoretical basis to explore the mechanism and unique efficacy of Q808 and the pathophysiology of epilepsy in the future.