bluuebunny/crossref_metadata_2025 huggingface dataset:
Noncanonical Nf-κB Activation by Icariin-Triggered CEBP-β/G-CSF Axis Confers Neuroprotection in Ischemic Optic Neuropathy
Authors: Desai Tushar Dnyaneshwar , Wen Yao-Tseng , Rayalu Jayasimha Daddam , Tsai Rong Kung
Published: May 2021

BackgroundAn ischemic insult at the optic nerve is followed by detrimental neuroinflammation that results in the loss of the retinal ganglion cells (RGCs) and vision. NF-κB is the key transcription factor of inflammatory cytokines in response to neuroinflammatory events. Icariin, an anti-inflammatory drug, is involved in the regulation of NF-κB activation. However, the protective mechanisms of icariin-induced NF-κB activation remain little known. Here, the protective mechanisms of icariin-induced NF-κB activation were investigated in experimental optic nerve ischemia. MethodsThe GOLD bio-informatics tool was used to select target drug based on CEBP-β binding affinity. The neuroprotective effects of target drug, Icariin, were assessed by measuring the flash visual electrode potentials, density of fluorogold-labeled cells, and TUNEL-positive cells in ganglion cell layer. The processes affecting RGC death were probed using optical coherence tomography, immunohistochemistry and immunoblotting techniques. ResultsThe simulation analysis and in vivo test demonstrated that the binding complex of icariin and CEBP-β significantly induced endogenous G-CSF expression. A single intravitreal injection of poly(lactic-co-glycolic acid) (PLGA)-icariin preserved visual function and RGC density after optic nerve infarct. The optic nerve edema, RGC apoptosis, and macrophage infiltration were inhibited by treatment with PLGA-icariin. The endogenous G-CSF expression switched the canonical NF-kB activation to the noncanonical NF-kB activation by promoting an alternative phosphorylation reaction of IKK-β. The noncanonical NF-κB activation further promoted the M2 microglia/macrophage polarization and AKT1 activation, which prevented the neuroinflammation and RGC apoptosis Granulocyte colony-stimulating factor. ConclusionOur study concluded that the protective mechanism of icariin is a G-CSF-induced non-canonical NF-kB activation, which may provide a potential therapeutic strategy for a patient with neuroinflammation diseases.
Degradable mesoporous semimetal antimony nanospheres for near-infrared II multimodal theranostics
Authors: Chen Yu , Yu Zhongzheng , Ren Yaguang , Zheng Kai , Wang Meng , Wu Qiang , Zhou Feifan , Liu Chengbo , Liu Liwei , Song Jun , Qu Junle
Published: May 2021

Metallic and semimetallic mesoporous frameworks are of great importance owing to their unique properties and broad applications. However, semimetallic mesoporous structures cannot be obtained by the traditional template-mediated strategies due to the inevitable hydrolytic reaction of semimetal compounds. Therefore, it is yet challenging to fabricate mesoporous semimetal nanostructures, not even mention controlling their pore sizes. Thus, we have developed a facile and robust selective etching route to synthesize monodispersed mesoporous antimony nanospheres (MSbNSs). This is the first report of semimetallic mesoporous structure to the best of our knowledge. The pore sizes of MSbNSs are tunable by carefully controlling the partial oxidation of Sb nuclei and the selective etching of the as-formed Sb2O3. MSbNSs showed a wide absorption from visible to second near-infrared (NIR-II) region. Moreover, PEGylated MSbNSs were degradable and the degradation mechanism was further explained. The NIR-II photothermal performance of MSbNSs was excellent with a high photothermal conversion efficiency of ~44% and intensive NIR-II photoacoustic signal. MSbNSs showed great potential as multifunctional nanomedicines for NIR-II photoacoustic imaging guided synergistic photothermal/chemo therapy in vivo. Our novel selective etching process would contribute to the development of various semimetallic mesoporous structures and efficient multimodal nanoplatforms for theranostics.
A Novel Prognostic Index for Sporadic Burkitt Lymphoma in Adult Patients: A Real-Word Multicenter Study
Authors: Chen Mei-ting , Pan Fei , Zhang Wei , Lv Hui-juan , Chen Yong-chang , Wang Zhao , Hong Huang-ming , Fang Xiao-jie , Wang Ya-wen , Pan Tao , Zou Li-qun , Guo Hong-qiang , Xie Ke , Chen Li-min , Li Xiao-qian , Yao Yu-yi , Chen Ze-geng , Weng Hua-wei , Li Xu-dong , Shen Yuan-yuan , Zhou Hui , Xue Hong-wei , Zhang Hui-lai , Huang He , Lin Tong-yu
Published: May 2021

Background: Adult sporadic Burkitt lymphoma (BL) is a rare but highly aggressive subtype of lymphoma which lacks its own unique prognostic model. Systemic inflammatory biomarkers have been confirmed as prognostic markers in several types of malignancy. Our objective was to explore the predictive value of pretreatment inflammatory biomarkers and establish a novel, clinically applicable prognostic index for adult patients with sporadic BL. Methods: We surveyed retrospectively 336 adult patients with newly diagnosed sporadic BL at 8 Chinese medical centers and divided into training cohort (n=229) and validation cohort (n=107). The pretreatment inflammatory biomarkers were calculated for optimal cut-off value. The association between serum biomarkers and overall survival (OS) was analyzed by Kaplan–Meier curves and Cox proportional models.Results and Conclusions: Univariate and multivariate analyses revealed that platelets<254×109/L, albumin<40g/L, lactate dehydrogenase≥334U/L independently predicted unfavorable OS. We used these data as the basis for the prognostic index, in which patients were stratified into Group 1 (no or one risk factor), Group 2 (two risk factors), or Group 3 (three risk factors), which were associated with 5-year OS rates of 88.1%, 72.4%, and 45%, respectively. In the subgroup analysis for high-risk patients, our prognostic model results showed that high-risk patients with no more than one adverse factor presented a 5-year survival rate of 85.9%, but patients with three adverse factors had a 5-year survival rate of 43.0%. Harrell’s concordance index (C-index) of the risk group score was 0.768. Therefore, the new prognostic model could be used to develop risk-adapted treatment approaches for adult sporadic BL.
Trends In Healthcare Visits And Antimicrobial Prescriptions For Acute Infectious Diarrhea In Individuals Aged 65 Years Or Younger In Japan From 2013 to 2018 Based On Administrative Claims Database: A Retrospective Observational Study
Authors: Ono Akane , Aoyagi Kensuke , Muraki Yuichi , Asai Yusuke , Tsuzuki Shinya , Koizumi Ryuji , Azuma Toshiaki , Kusama Yoshiki , Ohmagari Norio
Published: May 2021

Background: The inappropriate use of antimicrobials for acute infectious diarrhea is widespread and leads to the problem of antimicrobial resistance. To improve the use of antimicrobials, it is first necessary to understand the actual situation of diarrheal disease and to identify potential targets for intervention. This study aimed to investigate the recent epidemiological characteristics of and antimicrobial prescriptions for acute infectious diarrhea in Japan.Methods: This was a retrospective observational study of outpatients aged 0–65 years, separated into children (age 0–17 years) and adults (age 18–65 years), diagnosed with acute infectious diarrhea, using the administrative claims database of the Japan Medical Data Center from 2013 to 2018. We evaluated the number of eligible visits/number of database registrants (defined as the visit rate). The analysis of the antimicrobial prescription rate was restricted to otherwise healthy individuals diagnosed with acute infectious diarrhea alone by excluding patients with multiple disease diagnoses and with medical backgrounds of chronic bowel diseases or immunocompromised conditions. We further classified them by diagnosis of bacterial or nonbacterial acute infectious diarrhea.Results: The total number of eligible visits for acute infectious diarrhea was 2,600,065. The visit rate, calculated based on the number of eligible visits by database registrants, was higher in children (boys, 0.264; girls, 0.229) than in adults (men, 0.070; women, 0.079), with peaks in early summer and winter. The peaks for visits in adults lagged those of children. In total, 482,484 visits were analyzed to determine the antimicrobial prescription rate; 456,655 (94.6%) were diagnosed with nonbacterial acute infectious diarrhea. Compared with children (boys, 0.305; girls, 0.304), the antimicrobial prescription rate was higher in adults, and there were differences between sexes in adults (men, 0.465; women, 0.408). Fosfomycin and fluoroquinolone were most frequently used for nonbacterial acute infectious diarrhea in children (44.1%) and adults (50.3%), respectively.Conclusions: These results revealed overprescription of antimicrobials for acute infectious diarrhea in this administrative claims database in Japan and contribute to the development of antimicrobial stewardship strategies and the identification of targets for efficiently reducing inappropriate antimicrobial use.
The Positive Feedback Loop of NHE1-ERK Phosphorylation Mediated by BRAFV600E Mutation Contributes to Tumorigenesis and Development of Glioblastoma
Authors: Li Yuhui , Li Dan , Liu Yankun , Wang Shuqing , Sun Mingyang , Zhang Zhongyuan , Zheng Xuan , Li Jingwu , Li Yufeng
Published: May 2021

The occurrence rate of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation V600E (BRAFV600E) in glioblastoma multiforme (GBM) is more than 50%. Na/H exchanger 1 (NHE1), a main pH regulator affecting cell microenvironment, is hyper-expressed in GBM. However, the relationship between BRAFV600E signal pathway and NHE1 in GMB cells remains unclear. This study found that NHE1 was a downstream target of BRAFV600E and an upstream factor of extracellular signal-regulated kinase (ERK). In addition, there was a positive feedback loop between NHE1-ERK phosphorylation under regulation of BRAFV600E mutation contributing to the proliferation and invasion of GBM cells. Moreover, the proliferation and invasion abilities of BRAFV600E-mutant and BRAF wild type GBM cells were all suppressed by the NHE1 inhibitor, BRAFV600E inhibitor and combination of them. The inhibitory effect of combination of the two inhibitors was better than each single drug both in vitro and in vivo. Combination of BRAFV600E and NHE1 inhibitors could be considered as a new therapeutic regimen for GBM, especially for GBM with BRAFV600E.
How Costly is the First Prenatal Clinic Visit? Analysis of Out-of-Pocket Expenditure in Rural Sri Lanka - A Country With Free Maternal Health Care
Authors: Gunarathne Sajaan Praveena , Wickramasinghe Nuwan Darshana , Agampodi Thilini Chanchala , Prasanna Indika Ruwan , Agampodi Suneth Buddhika
Published: May 2021

Background: This study aimed to determine the magnitude of and factors associated with out-of-pocket expenditure (OOPE) during the first prenatal clinic visit among pregnant women in Anuradhapura district, Sri Lanka, which provides free maternal healthcare. Methods: The study design was a cross-sectional study, and the study setting was 22 Medical Officers of Health areas in Anuradhapura District, Sri Lanka. Data of 1,389 pregnant women were analyzed using descriptive statistics and non-parametric tests. Results: The mean OOPE of the first prenatal clinic visit was USD 8.12, which accounted for 2.9% and 4.5% of the household income and expenditure, respectively. Pregnant women who used only government-free health services had an OOPE of USD 3.49. A significant correlation was recorded between household expenditure (rs=0.095, p=0.002) and the number of pregnancies (rs=-0.155, p<0.001) with OOPE. Conclusion: Despite having free maternal services, the OOPE of the first prenatal clinic visit is high in rural Sri Lanka. One-fifth of pregnant women utilize private health services, and pregnant women who used only government-free maternal health services also spend a direct medical cost.
The Orbitofrontal Cortex Represents Advantageous Choice in the Iowa Gambling Task
Authors: Zha Rujing , Li Peng , Li Ying , Li Nan , Gao Meijun , Fan Yiyang , Aili Ruhuiya , Liu Ying , Zhang Xiaochu , Li Jun
Published: May 2021

A good-based model proposes that the orbitofrontal cortex (OFC) represents binary choice outcome, i.e., the chosen good. Previous studies have found that the OFC represents the binary choice outcome in decision-making tasks involving commodity type, cost, risk, and delay. Real-life decisions are often complex and involve uncertainty, rewards, and penalties; however, whether the OFC represents binary choice outcomes in a such decision-making situation, e.g., Iowa gambling task (IGT), remains unclear. Here, we propose that the OFC represents binary choice outcome, i.e., advantageous choice versus disadvantageous choice, in the IGT. We propose two hypotheses: first, the activity pattern in the human OFC represents an advantageous choice; and second, choice induces an OFC-related functional network. Using functional magnetic resonance imaging and advanced machine learning tools, we found that the OFC represented an advantageous choice in the IGT. The OFC representation of advantageous choice was related to decision-making performance. Choice modulated the functional connectivity between the OFC and the superior medial gyrus. In conclusion, the OFC represents an advantageous choice during the IGT. In the framework of a good-based model, the results extend the role of the OFC to complex decision-making when making a binary choice.
Capparis Spinosa Improves Non-Alcoholic Steatohepatitis Through Down-Regulating SREBP-1c and a PPARα-Independent Pathway in High-Fat Diet-Fed Rats
Authors: Akbari Rasoul , Yaghooti Hamid , Jalali Mohammad Taha , Khorsandi Laya Sadat , Mohammadtaghvaei Narges
Published: May 2021

Background: Non-alcoholic steatohepatitis (NASH) has become a global medical problem. Currently, there is no approved pharmacologic treatment for this condition. This study aimed to evaluate the ameliorative effects of Capparis spinosa (CS) on NASH in comparison to fenofibrate.Methods: An animal model of NASH was developed using a high-fat (HF) emulsion. Fatty liver rats were treated with aqueous extract of CS fruit or fenofibrate in parallel to the HF for six weeks. Animals were examined for weight gain, serum biochemistry, insulin sensitivity, hepatic triglyceride (TG) content, histopathological changes as well as gene expression of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), peroxisome proliferator-activated receptor α (PPARα) and Carnitine palmitoyltransferase I (CPT1) in liver.Results: Fasting blood sugar, insulin level, body and liver weight, activities of liver enzymes, hepatic triglyceride (TG) content as well as serum lipids were decreased following six weeks CS and fenofibrate treatments compared to the HF administration alone. Histopathological examinations also showed that liver steatosis, inflammation and hepatic fibrosis were markedly attenuated in response to CS and fenofibrate interventions. At the molecular level, CS treatment down-regulated SREBP1c, ACC and up-regulated CPT1 expression, but did not show a significant effect on PPARα. In contrast, fenofibrate treatment induced the expression of all studied genes in fatty liver rats.Conclusions: These findings indicated the favorable therapeutic effects of CS fruit extract on liver damages associated with NASH. The beneficial effects of CS on lipid accumulation and steatosis were comparable to those of fenofibrate.
Exploring Dynamic Metabolomics Data With Multiway Data Analysis: a Simulation Study
Authors: Li Lu , Hoefsloot Huub , Graaf Albert A. , Acar Evrim , Smilde Age K.
Published: May 2021

Background: Analysis of dynamic metabolomics data holds the promise to improve our understanding of underlying mechanisms in metabolism. For example, it may detect changes in metabolism due to the onset of a disease. Dynamic or time-resolved metabolomics data can be arranged as a three-way array with entries organized according to a subjects mode, a metabolites mode and a time mode. While such time-evolving multiway data sets are increasingly collected, revealing the underlying mechanisms and their dynamics from such data remains challenging. For such data, one of the complexities is the presence of a superposition of several sources of variation: induced variation (due to experimental conditions or inborn errors), individual variation, and measurement error. Multiway data analysis (also known as tensor factorizations) has been successfully used in data mining to find the underlying patterns in multiway data. In this paper, we study the use of multiway data analysis to reveal the underlying patterns and dynamics in time-resolved metabolomics data. Results: We focus on simulated data arising from different dynamic models of increasing complexity, i.e., a simple linear system, a yeast glycolysis model, and a human cholesterol model. We generate data with induced variation as well as individual variation. Systematic experiments are performed to demonstrate the advantages and limitations of multiway data analysis in analyzing such dynamic metabolomics data and their capacity to disentangle the different sources of variations. We choose to use simulations since we want to understand the capability of multiway data analysis methods which is facilitated by knowing the ground truth. Conclusion: Our numerical experiments demonstrate that despite the increasing complexity of the studied dynamic metabolic models, tensor factorization methods CANDECOMP/PARAFAC(CP) and Parallel Profiles with Linear Dependences (Paralind) can disentangle the sources of variations and thereby reveal the underlying mechanisms and their dynamics.
ADP/ATP Translocase 1 Protects Against an A-Synuclein-Associated Neuronal Cell Damage in Parkinson's Disease Model
Authors: Ding Wenyong , Qi Minghua , Ma Li , Xu Xuefei , Chen Yingfei , Zhang Wenli
Published: May 2021

Background: ADP/ATP translocase 1 (ANT1) is involved in the exchange of cytosolic ADP and mitochondrial ATP, and its defection plays an important role in mitochondrial pathogenesis. To reveal an etiological implication of ANT1 for Parkinson’s disease (PD), a neurodegenerative disorder, a mouse model treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine and neuroblasma cell model induced by 1-methyl-4-pehny1-pyridine were utilized in this study. Results: The tissue-specific abundance in ANT1 in mouse brains was accessed using the analysis of Western blot and immunohistochemistry. Down-regulated soluble ANT1 was found to be correlated with PD, and ANT1 was associated with PD pathogenesis via forming protein aggregates with α-synuclein. This finding was confirmed at cellular level using neuroblasma cell models. Protein interaction assay, coupled with the analysis of LC-MS/MS, silver-stained SDS-PAGE and Western blot against anti-ANT1 antibody respectively, illustrated the interaction of ANT1 with α-synuclein using the expressed α-synuclein as a bite. Additionally, a significant increasing ROSs was detected in PD-like cells. Conclusions: his study indicated that ANT1 was a potentially causative factor of PD, and led to neuropathogenic injury via promoting the formation of protein aggregates with α-synuclein. This investigation potentially promotes an innovative understanding of ANT1 on the etiology of PD and provides valuable information on developing potential drug targets in PD treatment or reliable biomarkers in PD prognostication.
Potential of Enterococcus Faecium LM5.2 for Lipopeptide Biosurfactant Production and Its Effect on the Growth of Maize (Zea Mays L.)
Authors: Chaurasia Lalit K. , Tirwa Ranjan K. , Tamang Buddhiman
Published: May 2021

The lipopeptide biosurfactants' chemical characteristics from the lactic acid bacteria isolated from milk and milk products were studied and their effect on maize plant growth. The oil displacement test was performed as a primary screening method to select the BS producing bacteria. Enterococcus faecium LM5.2 had the maximum emulsification index of 45.1±3 and reduced the surface tension to 32.98 ± 0.23% among all the isolates. E. faecium LM5.2 efficiently produced 945.26 ± 4.62 mg/l biosurfactants within 48 hours in MRS broth under the optimum conditions. The confirmation of the identity of the isolate LM5.2 was done with physiochemical tests and 16S rRNA gene sequencing. The molecular phylogenetic relationship was evaluated by the Neighbour-Joining phylogenetic method. The biosurfactant was purified by TLC and identified as lipopeptide-like iturines and surfactins based on Rf values. Mass spectroscopy, NMR, and FTIR analysis also confirmed the biosurfactant's identity as the derivatives of iturin and surfactin. Both the biosurfactant and its producer bacterium were evaluated for their plant growth-promoting activity, and it was found that the biosurfactant and the bacterium could enhance plant growth. To the best of our knowledge, this is the first report of lipopeptide biosurfactant production from Enterococcus faecium. Moreover, the study also showed that the biosurfactant and biosurfactant producing E. faecium LM5.2 could be an eco-friendly plant growth-promoting agent.
Clinical Characteristics, Prognostic Factors, and Real-World Practice of Abnormal Liver Function Tests in Children with Acute Infectious Diseases: A Multicenter Study
Authors: Lee Kyung Jae , Yi Dae Yong , Lee Yoo Min , Choi So Yoon , Choi You Jin , Lee Yoon
Published: May 2021

Background Abnormal liver function tests (LFTs) are commonly seen in pediatric patients with acute infectious diseases; few studies and no definite clinical guidelines for these conditions are available. This study aimed to elucidate the causes and factors associated with prolongation of liver enzyme elevation. We also investigated actual real-world practices in Korea.Methods A retrospective study was performed on all patients younger than 18 years, who visited six tertiary teaching hospitals around Korea in 2018 for acute infectious diseases and showed alanine aminotransferase (ALT) levels above 60 IU/L. We categorized the infections that cause LFT elevation into six groups: respiratory infection, gastrointestinal infection, urinary tract infection, other febrile disease, Epstein-Barr virus infection, and cytomegalovirus infection. We collected data on the medical specialty of the attending physician who followed up the subject, follow-up duration, percentage of follow-up loss, and their investigation.ResultsA total of 613 patients were enrolled in this study, half of whom (50.7%) were younger than 12 months. The mean initial aspartate aminotransferase and ALT values were 171.2±274.1 and 194.9±316.1 IU/L (range 23~2881, 60~2949 IU/L), respectively; however, other LFTs were within the normal range. Respiratory infection was the most common diagnosis (45.0%), and rhinovirus was the most commonly identified pathogen (9.8%). The follow-up rate was higher with pediatric gastroenterologists (90.5%) and non-gastroenterology pediatricians (76.4%) than with pediatric residents and emergency doctors. Older age was related to better ALT recovery (odds ratio [OR] of age for month was 1.003, with 95% confidence interval [CI] 1.001-1.004, p=0.004), while the number of infection episodes (OR=0.626, 95% CI 0.505-0.777, p<0.001) was associated with poor ALT recovery. Abdominal sonography was the most commonly used diagnostic tool (36.9%), followed by the hepatotropic virus workup. The modalities of hepatitis workup were significantly differently applied by physicians based on their specialties and institutions.Conclusions An LFT abnormality after a systemic infection was common in respiratory infection and under the age of 1 year. Age, number of infections, and initial results of LFTs were related to ALT recovery time. Inter-physician, inter-institution, and inter-specialty variances were observed in real-world practice.
Potential Probiotic Lactobacillus Rhamnosus (MTCC-5897) Attenuates Escherichia Coli Induced Inflammatory Response in Intestinal Cells
Authors: Gupta Taruna , Kaur Harpreet , Kapila Suman , Kapila Rajeev
Published: May 2021

Probiotics are microbes having tremendous potential to prevent gastrointestinal disorders. In current investigation, immunomodulatory action of probiotic Lactobacillus rhamnosus (LR:MTCC-5897) was studied during exclusion, competition and displacement of Escherichia coli on intestinal epithelial (Caco-2) cells. The incubation of intestinal cells with E. coli, enhanced downstream signalling and activated nuclear factor kappa B (NF-κB). This significantly increased (p<0.01) the pro-inflammatory cytokines (IL-8, TNF-α and IFN-ϒ) expression. While, incubation of epithelial cells with L. rhamnosus during exclusion and competition with E. coli, counteracted these enhanced expressions. The immunomodulatory feature of L rhamnosus was also highlighted with increased (p<0.05) transcription of toll like receptor-2 (TLR-2) and single Ig IL-1-related receptor (SIGIRR) along with diminished expression of TLR-4. Likewise, attenuation (p<0.05) of E.coli-mediated enhanced nuclear translocation of NF-κB p-65 subunit by L. rhamnosus during exclusion was confirmed with western blotting. Thus, present finding establishes the prophylactic potential of L. rhamnosus against exclusion of E. coli in intestinal cells.
A Microservice Regression Testing Selection Approach Based on Belief Propagation
Authors: Chen Lizhe , Wu Ji , Yang Haiyan , Zhang Kui
Published: May 2021

Regression testing is required in each iteration of microservice systems. Regression testing selection, which reduces testing costs by selecting a subset from the original test cases, is one of the main techniques to optimize regression testing. Existing techniques mainly rely on the information retrieved from artifacts such as code files and system models. For microservice systems with service autonomy, development method diversity and a large amount of services, such artifacts are too difficultly obtained and costly processed to apply those approaches. This paper presents a regression testing selection approach called MRTS-BP, which needs the API gateway layer logs instead of code files and system models as inputs. By parsing the API gateway layer logs, our approach establishes the service dependency matrix, which in further is transformed into a directed graph with the services as nodes. Then, to find out which test cases are affected by service changes, an algorithm based on belief propagation is presented to compute the quantitative results of service-change propagation from the directed graph. Finally, the relationships between original test cases and service-change propagation results are established to select test cases with three strategies. To evaluate the efficiency of MRTS-BP, the empirical study based on four microservice systems is presented. A typical technique RTS-CFG is compared with MRTS-CFG and four experiments are setup to investigate four research questions. The results show that MRTS-BP can not only reduce the number of test cases by half compared with the retest-all strategy while ensuring the safety, but also save at least 20% testing time costs more than that of RTS-CFG. MRTS-BP is more practical than the techniques relying on the artifacts when the latter cannot be implemented due to the artifacts are difficult to obtain and process.
Link ER ion homeostasis maintained by an ER anion channel to ALS
Authors: Jia Yichang , Guo Liang , Mao Qionglei , He Ji , LIU Xiaoling , Piao Xuejiao , Luo Li , Hao Xiaoxu , Xiao Bailong , Fan Dongsheng , Gao Zhaobing
Published: May 2021

Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of CLCC1 (Chloride Channel CLIC Like 1) to ALS (amyotrophic lateral sclerosis). We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair the channel activity. CLCC1 unitary conductance is inhibited by luminal Ca2+ but facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2). We identified a conserved lysine 298 (K298) in CLCC1 intraluminal loop as the critical PIP2-sensing residue. CLCC1 maintains steady-state [Cl-]ER and morphology and regulates ER Ca2+ homeostasis including steady-state [Ca2+]ER and efficiency of internal Ca2+ release. ALS-associated mutant CLCC1 increase steady-state [Cl-]ER and impair ER Ca2+ homeostasis. Phenotypic comparisons of multiple Clcc1 mutant alleles, including ALS-associated mutations, reveal a CLCC1 dosage-dependence in severity of disease phenotypes in vivo. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress, misfolded protein accumulation, and characteristic ALS pathologies in the spinal cord. Thus, we argue that disruption of ER ion homeostasis maintained by CLCC1 underlies etiology of neurodegenerative diseases.
Hallux Rigidus: Prevalence and Risk Factors
Authors: Senga Yoshiyuki , Nishimura Akinobu , Ito Naoya , Kitaura Yukie , Sudo Akihiro
Published: May 2021

Background: Hallux rigidus (HR) is a common degenerative arthritis of the first metatarsophalangeal joint. However, the epidemiology and risk factors of this pathology have yet to be clarified.Methods: This cohort study estimated the prevalence of and clarified risk factors for radiographic HR in individuals over 50 years old.Results: The prevalence of HR was 26.7% (161/604). Rates of grade 0, 1, 2, and 3 HR according to the Hattrup and Johnson classification were 73.3% (443/604), 16.4% (99/604), 8.0% (48/604), and 2.3% (14/604), respectively. Overall ratio of symptomatic HR was 8.1%. Univariate analysis revealed knee osteoarthritis (KOA), gout attack (GA), and hallux valgus (HV) as significantly associated with HR. The same factors were confirmed as independent risk factors for HR in multivariate analysis. All parameters were significantly associated with HR. Odds ratios of KOA, HV, and GA for HR were 1.73, 3.98, and 3.86, respectively. The presence or absence of KOA was significantly associated with severity of HR.Conclusion: Our study revealed the prevalence of HR in the elderly (≥50 years) was 26.7%, and KOA, HV, and GA were independent risk factors for HR. KOA was associated with severity of HR.
Efficacy of Cetuximab and 4-PBA Combination Therapy in Human Oral Squamous Cell Carcinoma Cells
Authors: Noguchi Akira , Nishida Takeshi , Hatta Hideki , Takagi Kohji , Kakiuchi Toshiko , Tanaka Shinichi , Minamisaka Takashi , Nakajima Takahiko , Imura Johji
Published: May 2021

Background: Cetuximab is a powerful anti-neoplastic agent that can inhibit cell growth in oral squamous cell carcinomas (OSCCs). Unfortunately, there are cases with unfavorable outcomes. Because few studies have focused on the combined effects of cetuximab and histone deacetylase (HDAC) inhibitors, we aimed to evaluate the antitumor effect of cetuximab in combination with HDAC inhibitors in human OSCC cell lines, and investigate the mechanism of apoptosis enhancing activity thereof.Methods: We used human OSCC cell lines treated with cetuximab (500 mg/ml) and several HDAC inhibitors. The WST assay and ApoToxGlo™ Triplex Assay determined cell survival. We employed the TdT-mediated dUTP-biotin nick end labeling method to detect apoptosis. We used western blotting to examine the histone acetylation status, ER stress markers, and epidermal growth factor receptor (EGFR) signaling pathways.Results: Cetuximab in combination with 4-phenyl butyric acid (4-PBA) remarkably decreases cell growth in vitro. In addition, the combined treatment resulted in increased EGFR mRNA expression, and it promoted the activation of ERK. The combination treatment induced apoptosis at a significantly higher frequency than did either agent alone.Conclusions: The combination of cetuximab and 4-PBA is more effective against human OSCC cells than either agent alone, suggesting a potential clinical applicability of combination treatment in OSCC therapies.
Natural selection drives genome-wide evolution via chance genetic associations
Authors: Gompert Zachariah , Feder Jeffrey , Nosil Patrik
Published: May 2021

Understanding selection's impact on the genome is a major theme in biology. Functionally-neutral genetic regions can be affected indirectly by natural selection, via their statistical association with genes under direct selection. The genomic extent of such indirect selection, particularly across loci not physically linked to those under direct selection, remains poorly understood, as does the time scale at which indirect selection occurs. Here we use field experiments and genomic data to show that widespread statistical associations with genes known to affect fitness in stick insects, deer mice and stickleback fish cause many genetic loci across the genome to be impacted indirectly by selection. We then show that statistical associations with other, unknown causal variants make aspects of evolution more predictable in stick insects. Thus, natural selection combines with chance genetic associations to affect genome-wide evolution across linked and unlinked loci and even in modest-sized populations.
Intravitreal Injection of Mitochondrial DNA Induces Cell Damage and Retinal Dysfunction in Rats
Authors: Guo Yue , Gan Dekang , Hu Fangyuan , Cheng Yun , Yu Jian , Lei Boya , Shu Qinmeng , Gu Ruiping , Xu Gezhi
Published: May 2021

Background: Retinal neurodegeneration is induced by a variety of environmental insults and stresses, but the exact mechanisms are unclear. In the present study, we explored the involvement of cytosolic mitochondrial DNA (mtDNA), resulting in the cGAS-STING dependent inflammatory response and apoptosis in retinal damage in vivo.Methods: Retinal injury was induced by white light or intravitreal injection of lipopolysaccharide (LPS). After light- or LPS-induced injury, the amount of cytosolic mtDNA in the retina was detected by PCR. The mtDNA was isolated and used to transfect retinas in vivo. WB and real-time PCR were used to evaluated the activation of cGAS-STING pathway and the levels of apoptosis-associated protein at different times after mtDNA stimulation. Retinal cell apoptosis rate was detected by TUNEL staining. Full-field electroretinography (ERG) was used to assess the retinal function.Results: Light injury and the intravitreal injection of LPS both caused the leakage of mtDNA into the cytoplasm in retinal tissue. After the transfection of mtDNA in vivo, the levels of cGAS, STING, and IFN-β mRNAs and the protein levels of STING, phosph-TBK1, phospho-IRF3, and IFN-β were upregulated. mtDNA stimulation also induced the phosphorylation of caspase 3 and caspase 9. BAX and BAK were increased at both the mRNA and protein levels. The release of cytochrome c from the mitochondria to the cytosol was increased after mtDNA stimulation. The wave amplitudes on ERG decreased and retinal cell apoptosis was detected after mtDNA stimulation.Conclusion: Cytosolic mtDNA triggers an inflammatory response. It also promotes apoptosis and the dysfunction of the retina.
LRP4 mediated synaptic plasticity in the piriform cortex
Authors: Yan Min , Jing Hongyang , Xiong Mingtao , Lin Dong , Chen Peng , Chen Jiang , Liu Ziyang , Zhang Hang , Ren Dongyan , Fei Erkang , Lai Xinsheng , Zou Suqi , Wang Shunqi
Published: May 2021

Background

Low-density lipoprotein receptor-related protein 4(LRP4) plays a critical role in the central nervous system (CNS), including hippocampal synaptic plasticity, maintenance of excitatory synaptic transmission, fear regulation, as well as long-term enhancement.
Results

In this study, we found that Lrp4 was highly expressed in the piriform cortex and located in the second layer of the piriform cortex. When the transmembrane domain (TMD) and the intracellular domain (ICD) were missing, the Lrp4ECD/ECD mice appeared to be smaller, and the brain’s weight decreased, compared with the control mice. Simultaneously, finding food was prolonged for Lrp4ECD/ECD mice in the buried food-seeking test. In the piriform cortex of Lrp4ECD/ECD mice, the spine density of layer Ⅱ increased, and the frequency of both miniature excitatory postsynaptic current (mEPSC) and spontaneous excitatory postsynaptic current (sEPSC) enhanced.
Conclusions

This study indicated that LRP4 mediated synaptic plasticity in the piriform cortex. Moreover, it also suggested that TMD and ICD of LRP4 are nonnegligible for the LRP4 function in the piriform cortex.
Male breast cancer and female breast cancer: A population-based study
Authors: Yao Nan , Shi Wenzai , Liu Tong , Siyin Sarah Tan , Wang Weiqi , Duan Ning , Xu Guoshuai , Qu Jun
Published: May 2021

Male breast cancer (MBC) is a rare disease. Due to limited information, MBC has always been understudied. We conducted a retrospective population-based cohort study by using the 2010–2014 Surveillance, Epidemiology, and End Results (SEER) program data. The clinical and biological features of female breast cancer (FBC) patients were compared with MBC patients. Survival curves were constructed with the Kaplan-Meier method. Multivariate Cox regression models and competitive risk models were separately built to identify factors associated with survival time in the MBC and FBC group. Our retrospective study showed that MBC patients suffered with higher TNM stages, higher grades, and more percent of hormone receptor–positive tumors, compared with FBC patients. In addition, the site of the primary breast cancer varied greatly different between genders. FBC patients demonstrated superior overall survival than MBC patients on Kaplan-Meier analysis. In multivariate COX analysis for FBC patients, older age, black race, higher T, N, M-stages, higher grades, estrogen receptor (ER)/progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative were associated with higher risk of death. MBC patients had similar independent prognostic factors, but PR and HER-2 status did not appear to independently influence survival. Interestingly, primary site location was an independent prognostic factor for both MBC patients and FBC patients, which should be considered by clinicians as a prognostic factor.
Target prediction of anti-chronic liver injury of Kangxian pill based on network pharmacology
Authors: Cao Min , Wang Yiyang , Liu Haizhao , Dong Xueqian , Dong Mengxue , Jin Yutong , Wang Jida , Jia Beitian , Bian Yuhong , Wang Li
Published: May 2021

BackgroundThe present study aimed to validate the protect effect of Kangxian pill (KXP) on chronic hepatic injury (CHI) and investigate its potential mechanism by network pharmacology-based prediction and experimental verification in vivo . MethodsThe effect of KXP in the treatment of carbon tetrachloride (CCL 4 )-induced CHI is investigated by calculating liver index, measuring AST and ALT levels and performing HE staining. Targets of active ingredients of KXP were predicted in TCSMP and targets of chronic liver injury were searched in DisGeNET, OMIM and GeneCards databases. We obtain some pivotal targets of KXP for the treatment of CHI by intersecting the targets of KXP and CHI. Subsequently, we performed gene ontology (GO) functional and pathways enrichment analyses, as well as conducted networks based on potential targets to determine the core targets and representative pathways.We further validated expressions of IL-6, IL-1β, TNF-α, Bax, Bcl2, PI3K, Akt, and pAkt according to the potential molecular mechanisms analyzed based on network pharmacology analysis.ResultsThe results showed that the levels of AST and ALT in serum decreased after treatment with KXP. HE staining also revealed that KXP could improve hepatocyte abnormality in vivo . A total of 81 potential targets of KXP in the treatment of CHI were identified through network pharmacology analysis. After integrating potential targets, function enrichment, representative pathways and networks, we identified PI3K, AKT1,BCL2, TNF-α, IL-1β, and IL-6 as potential targets, which may play a vital role in the KXP treatment. The experimental results also showed that KXP could down-regulate the mRNA and protein expression of IL-1β, IL-6, TNF-α and Bax, and up-regulate the PI3K and p-Akt protein expression i n vivo .ConclusionsOur results suggest that KXP could alleviate CHI through regulating inflammation and apoptosis and provide deep insight into the hepato-protective mechanisms.
Mast Cell Sensitization as a Plausible and Researchable Mechanism for Chemical Intolerance
Authors: Miller Claudia S. , Palmer Raymond F , Dempsey Tania T. , Ashford Nicholas A. , Afrin Lawrence B.
Published: May 2021

Background

Worldwide observations provide evidence for a two-stage disease process called Toxicant-Induced Loss of Tolerance (TILT), described in this journal in the first of two related papers. The disease process is initiated by a major exposure event, or a series of lower level exposures (Stage I, Initiation). Subsequently, affected individuals report that common chemical inhalants, foods, and drugs trigger multisystem symptoms (Stage II, Triggering). Given that foods and drugs also are comprised of chemicals, we refer to these intolerances simply as “chemical intolerance” (CI). In this second, companion paper we propose mast cell sensitization and mediator release as a plausible and researchable biological explanation for TILT.
Methods

Using the Quick Environmental Exposure and Sensitivity Inventory (QEESI), we compared patients diagnosed with mast cell activation syndrome (MCAS) (n = 147) to individuals who reported chemical intolerances following various exposures (n = 345), and to controls (n = 76). We compared QEESI scores using ANOVA across groups. Clinical scores for the MCAS patient group were used to predict CI status using logistic regression.
Results

As the likelihood of patients’ having CI increased, their likelihood of having MCAS similarly increased, to a near-perfect correspondence at the high ends of the QEESI and clinical MCAS scores. Symptom patterns were near-identical for CI and MCAS groups.
Conclusion

The close correspondence between QEESI scores for MCAS and TILT patients supports mast cell sensitization and mediator release as a plausible biological mechanism underlying both conditions, with implications for medicine, environmental health, and regulatory toxicology.
Atypical Processing Pattern of Gaze Cues in Dynamic Situations in Autism Spectrum Disorders
Authors: Liu Jia , Hu Jinsheng , Li Songze , Li Qi , Zhao Xiaoning , Liu Ying , Liu Shuqing
Published: May 2021

Psychological studies have generally shown that individuals with Autism Spectrum Disorder (ASD) have specificity in the processing of social information by using static or abstract images. Yet, a recent study showed that there was no differ in their use of the added social or non-social cues in dynamic interactive situations. To establish the cause of the inconsistent results, we explored the processing pattern of gaze cues in individuals with ASD by using chase detection paradigm and eye-tracking methodologies. In this study, unlike typical controls, participants with ASD showed no detection advantage under the oriented condition. The results suggested that individuals with ASD may utilize an atypical processing pattern in dynamic interactive situations.
Failure Analysis and Control Measures of Deep Roadway with Composite Roof: A Case Study
Authors: LI Yongliang , Yang Renshu , Fang Shizheng , Lin Hai , Lu Shaojie , Zhu Ye , Wang Maosheng
Published: May 2021

There is great variation in the lithology and lamination thickness of composite roof in coal-measure strata; thus, the roof is prone to delamination and falling, and it is difficult to control the surrounding rock when developing roadway in such rock strata. In deep mining, the stress environment of surrounding rock is complex, and the mechanical response of the rock mass is different from that of the shallow rock mass. For composite-roof roadway excavated in deep rock mass, the key to safe and efficient production of the mine is ensuring the stability of the roadway. The present paper obtains typical failure characteristics and deformation and failure mechanisms of composite-roof roadway with a buried depth of 650 m at Zhaozhuang Coal Mine (Shanxi Province, China). On the basis of determining a reasonable cross-section shape of the roadway and according to the failure characteristics of the composite roof in different regions, the roof is divided into an unstable layer, metastable layer, and stable layer. The controlled unstable layer and metastable layer are regarded as a small structure while the stable layer is regarded as a large structure. A superimposed coupling support technology of large and small structures with a multi-level prestressed bearing arch formed by strong rock bolts and highly prestressed cable bolts is put forward. The support technology provides good application results in the field. The study thus provides theoretical support and technical guidance for ground control under similar geological conditions.
Barriers and Facilitators to Modern Contraception Among Married Women in Conflict Affected Town of Mogadishu, Somalia
Authors: Gele Abdi , Shrestha Mary , Khalif Fathia , Qureshi Samera
Published: May 2021

Background - With a maternal mortality ratio of 692 per 100,000 live births and modern contraception prevalence of 1%, understanding factors hindering Somali women from using modern contraception is key to developing and implementing locally adopted public health responses. The purpose of this qualitative study is to explore barriers and facilitators to the use of modern contraception among married women in Mogadishu. Methods - We conducted a qualitative study using semi-structured, in-depth interviews with 21 married women aged >18 years, living in different neighborhoods in Mogadishu between July—December 2018. We recruited the participants using a convenience sampling method. We used thematic analysis and adapted ecological model as a framework for the synthesis.Results – The findings show that systemic, individual and socio-cultural barriers hinder women’s ability to access modern contraception. Barriers identified by this study include: Health communication messages and contraceptive information provided by health providers, prevalent religious fallacies among women and fear of permanent infertility upon modern contraception. Conclusion - Training health providers in the principles of modern contraception, in addition to the medical ethics that govern their responsibility to provide correct and relevant information to their patients, is vital for increasing modern contraception use among Somali women. The findings of this study may be used for designing public health interventions that promote acceptance and the use of modern contraception among both women and men in Somalia.
Composition Optimization, High-temperature Stability and Thermal Cycling Performance of Sc-doped Gd2Zr2O7 Thermal Barrier Coatings: Theoretical and Experimental Studies
Authors: Guo Lei , Li Bowen , Cheng Yuxian , Wang Lu
Published: May 2021

Sc was doped into Gd2Zr2O7 for expanding the potential for thermal barrier coating (TBC) applications. According to first-principles calculation, the solid solution mechanism of Sc in Gd2Zr2O7 lattice was revealed, i.e., Sc first occupies the lattice interstitial sites followed by substituting for Gd, and the interstitial Sc concentration is less than 11.11%. By considering the mechanical and thermophysical properties comprehensively, the optimum Sc doping content was determined to be 16.67%, and this composition was selected to produce TBCs by air plasma spraying with YSZ as a bottom ceramic coating (Gd-Sc/YSZ TBC). After sintering at 1400 ℃ for 100 h, Gd-Sc coatings remain phase and structural stability indicative of excellent sintering resistance. By thermal cycling tests, Gd-Sc TBCs fails due to the low toughness and the interface reaction between Gd-Sc and boding coatings, while Gd-Sc/YSZ TBCs exhibit much longer thermal cycling lifetime, and the failure mode is YSZ coating cracking.