bluuebunny/crossref_metadata_2025 huggingface dataset:
New Possible Earthquake Precursor and Initial Area for Satellite Monitoring
Authors: Vasilev Atanas , Tsekov Milen , Petsinski Petar , Gerilowski Konstantin , Slabakova Violeta , Trukhchev Dimitar , Botev Emil , Dimitrov Orlin , Dobrev Nikolai , Parlichev Dimitar
Published: February 2021

We propose a new possible earthquake precursor, a coastal water jet originating from shallow water gas seeps and colored by sediments, lifted from increased gas seeps emissions, preceding some earthquakes with offshore epicenters along the Bulgarian Black Sea coast and M ≥ 3. The new possible earthquake precursor is site specific and may be observed in shallow coastal water regions where active faults are accompanied by hydrocarbon gas seeps. We point out to a region where it can be easily detected by direct observation and satellite remote sensing, Zelenka methane seeps (ZMS), near the Bulgarian Black Sea coast. The ZMS activation is related to the tectonic stress and fracturing preceding and accompanying the earthquakes in the Shabla-Kaliakra-Balchik region along the northern part of the Bulgarian Black Sea coast. We also propose an earthquake forecasting experiment, based on the following four hypotheses: 1) The change of the methane emission of shallow horizons is related to crustal strain changes preceding earthquakes in the region; 2) extreme change of the activity of underwater methane seepages appears immediately before nearby earthquakes; 3) shallow water methane seepages activity can be monitored by remote sensing; 4) satellites can register effects from an extreme increase in their emissions. The proposed earthquake forecasting experiment is based on the monitoring of methane seepages activity in the ZMS area by direct observation and remote sensing which may provide indication for preparatory earthquake activity preceding offshore earthquakes in the region.
Gastrointestinal Helminth Infection Improves Insulin Sensitivity, Decreases Systemic Inflammation, and Alters the Composition of Gut Microbiota in Distinct Mouse Models of Type 2 Diabetes
Authors: Khudhair Zainab , Alhallaf Rafid , Eichenberger Ramon M. , Whan Jen , Kupz Andreas , Field Matt , Krause Lutz , Wilson David T. , Daly Norelle L. , Giacomin Paul , Sotillo Javier , Loukas Alex
Published: February 2021

Type 2 diabetes (T2D) is a major health problem and is considered one of the top 10 diseases leading to death globally. T2D has been widely associated with systemic and local inflammatory responses and with alterations in the gut microbiota. Microorganisms, including parasitic worms and gut microbes have exquisitely co-evolved with their hosts to establish an immunological interaction that is essential for the formation and maintenance of a balanced immune system, including suppression of excessive inflammation. Herein we show that both prophylactic and therapeutic infection of mice with the parasitic hookworm-like nematode, Nippostrongylus brasiliensis, significantly reduced fasting blood glucose, oral glucose tolerance and body weight gain in two different diet-induced mouse models of T2D. Helminth infection was associated with elevated type 2 immune responses including increased eosinophil numbers in the mesenteric lymph nodes, liver and adipose tissues, as well as increased expression of IL-4 and alternatively activated macrophage marker genes in adipose tissue, liver and gut. N. brasiliensis infection was also associated with significant compositional changes in the gut microbiota at both the phylum and order levels. Our findings show that N. brasiliensis infection drives changes in local and systemic immune cell populations, and that these changes are associated with a reduction in systemic and local inflammation and compositional changes in the gut microbiota which cumulatively might be responsible for the improved insulin sensitivity observed in infected mice. Our findings indicate that carefully controlled therapeutic hookworm infection in humans could be a novel approach for treating metabolic syndrome and thereby preventing T2D.
Cigarette Smoke-Induced Lymphoid Neogenesis in COPD Involves IL-17/RANKL Pathway
Authors: Xiong Jing , Zhou Lu , Tian Jieyu , Yang Xia , Li Yunsong , Jin Rong , Le Yanqing , Rao Yafei , Sun Yongchang
Published: February 2021

IL-17 is critical in lung lymphoid neogenesis in COPD, but the cellular and molecular mechanisms remain to be elucidated. Receptor activator of nuclear factor-κB ligand (RANKL) functions in lymphoid follicle formation in other organs, whether it is involved in IL-17A–dependent lymphoid neogenesis in COPD is unknown. To elucidate the expression and functional role of IL-17A/RANKL pathway in COPD. We first quantified and localized RANKL, its receptor RANK and IL-17A in lungs of patients with COPD, smokers and non-smokers. Next, IL-17A−/− and wild-type (WT) mice were exposed to air or cigarette smoke (CS) for 24 weeks, and lung lymphoid follicles and RANKL-RANK expression were measured. Lastly, we studied the in vitro biological function of RANKL pertaining to lymphoid neogenesis. We found that the expressions of RANKL-RANK and IL-17A, together with lymphoid follicles, were increased in lung tissues from patients with COPD. In WT mice exposed to CS, RANKL-RANK expressions were prominent in lung lymphoid follicles, which were absent in IL-17A−/− mice exposed to CS. In the lymphoid follicles, RANKL+ cells were identified mostly as B cells and RANK was localized in dendritic cells (DCs). In vitro IL-17A increased the expressions of RANKL in B cells and RANK in DCs, which in turn responded to RANKL stimulation by upregulation of CXCL13. Altogether, these results suggest that B lymphocyte RANKL pathway is involved in IL-17A–dependent lymphoid neogenesis in COPD.
In-Depth Analysis of the Impact of Different Serum-Free Media on the Production of Clinical Grade Dendritic Cells for Cancer Immunotherapy
Authors: Calmeiro João , Mendes Luís , Duarte Iola F. , Leitão Catarina , Tavares Adriana R. , Ferreira Daniel Alexandre , Gomes Célia , Serra João , Falcão Amílcar , Cruz Maria Teresa , Carrascal Mylène A. , Neves Bruno Miguel
Published: February 2021

Dendritic cell (DC)-based antitumor vaccines have proven to be a safe approach, but often fail to generate robust results between trials. Translation to the clinic has been hindered in part by the lack of standard operation procedures for vaccines production, namely the definition of optimal culture conditions during ex-vivo DC differentiation. Here we sought to compare the ability of three clinical grade serum-free media, DendriMACS, AIM-V, and X-VIVO 15, alongside with fetal bovine serum-supplemented Roswell Park Memorial Institute Medium (RPMI), to support the differentiation of monocyte-derived DCs (Mo-DCs). Under these different culture conditions, phenotype, cell metabolomic profiles, response to maturation stimuli, cytokines production, allogenic T cell stimulatory capacity, as well as priming of antigen-specific CD8+ T cells and activation of autologous natural killer (NK) cells were analyzed. Immature Mo-DCs differentiated in AIM-V or X-VIVO 15 presented lower levels of CD1c, CD1a, and higher expression of CD11c, when compared to cells obtained with DendriMACS. Upon stimulation, only AIM-V or X-VIVO 15 DCs acquired a full mature phenotype, which supports their enhanced capacity to polarize T helper cell type 1 subset, to prime antigen-specific CD8+ T cells and to activate NK cells. CD8+ T cells and NK cells resulting from co-culture with AIM-V or X-VIVO 15 DCs also showed superior cytolytic activity. 1H nuclear magnetic resonance-based metabolomic analysis revealed that superior DC immunostimulatory capacities correlate with an enhanced catabolism of amino acids and glucose. Overall, our data highlight the impact of critically defining the culture medium used in the production of DCs for clinical application in cancer immunotherapy. Moreover, the manipulation of metabolic state during differentiation could be envisaged as a strategy to enhance desired cell characteristics.
Toxoplasma Infection Induces Sustained Up-Regulation of Complement Factor B and C5a Receptor in the Mouse Brain via Microglial Activation: Implication for the Alternative Complement Pathway Activation and Anaphylatoxin Signaling in Cerebral Toxoplasmosis
Authors: Shinjyo Noriko , Hikosaka Kenji , Kido Yasutoshi , Yoshida Hiroki , Norose Kazumi
Published: February 2021

Toxoplasma gondiiis a neurotropic protozoan parasite, which is linked to neurological manifestations in immunocompromised individuals as well as severe neurodevelopmental sequelae in congenital toxoplasmosis. While the complement system is the first line of host defense that plays a significant role in the prevention of parasite dissemination,Toxoplasmaartfully evades complement-mediated clearanceviarecruiting complement regulatory proteins to their surface. On the other hand, the details ofToxoplasmaand the complement system interaction in the brain parenchyma remain elusive. In this study, infection-induced changes in the mRNA levels of complement components were analyzed by quantitative PCR using a murineToxoplasmainfection modelin vivoand primary glial cellsin vitro. In addition to the core components C3 and C1q, anaphylatoxin C3a and C5a receptors (C3aR and C5aR1), as well as alternative complement pathway components properdin (CFP) and factor B (CFB), were significantly upregulated 2 weeks after inoculation. Two months post-infection, CFB, C3, C3aR, and C5aR1 expression remained higher than in controls, while CFP upregulation was transient. Furthermore,Toxoplasmainfection induced significant increase in CFP, CFB, C3, and C5aR1 in mixed glial culture, which was abrogated when microglial activation was inhibited by pre-treatment with minocycline. This study sheds new light on the roles for the complement system in the brain parenchyma duringToxoplasmainfection, which may lead to the development of novel therapeutic approaches toToxoplasmainfection-induced neurological disorders.
Notch Signaling in B Cell Immune Responses
Authors: Garis Matthew , Garrett-Sinha Lee Ann
Published: February 2021

The Notch signaling pathway is highly evolutionarily conserved, dictating cell fate decisions and influencing the survival and growth of progenitor cells that give rise to the cells of the immune system. The roles of Notch signaling in hematopoietic stem cell maintenance and in specification of T lineage cells have been well-described. Notch signaling also plays important roles in B cells. In particular, it is required for specification of marginal zone type B cells, but Notch signaling is also important in other stages of B cell development and activation. This review will focus on established and new roles of Notch signaling during B lymphocyte lineage commitment and describe the function of Notch within mature B cells involved in immune responses.
C-Terminal Amination of a Cationic Anti-Inflammatory Peptide Improves Bioavailability and Inhibitory Activity Against LPS-Induced Inflammation
Authors: Zhang Lulu , Wei Xubiao , Zhang Rijun , Koci Matthew , Si Dayong , Ahmad Baseer , Guo Henan , Hou Yanfei
Published: February 2021

Lipopolysaccharide (LPS) has been implicated as a major cause of inflammation and an uncontrolled LPS response increases the risk of localized inflammation and sepsis. While some native peptides are helpful in the treatment of LPS-induced inflammation, the use of these peptides is limited due to their potential cytotoxicity and poor anti-inflammatory activity. Hybridization is an effective approach for overcoming this problem. In this study, a novel hybrid anti-inflammatory peptide that combines the active center of Cathelicidin 2 (CATH2) with thymopentin (TP5) was designed [CTP, CATH2 (1–13)-TP5]. CTP was found to have higher anti-inflammatory effects than its parental peptides through directly LPS neutralization. However, CTP scarcely inhibited the attachment of LPS to cell membranes or suppressed an established LPS-induced inflammation due to poor cellular uptake. The C-terminal amine modification of CTP (CTP-NH2) was then designed based on the hypothesis that C-terminal amidation can enhance the cell uptake by increasing the hydrophobicity of the peptide. Compared with CTP, CTP-NH2 showed enhanced anti-inflammatory activity and lower cytotoxicity. CTP-NH2 not only has strong LPS neutralizing activity, but also can significantly inhibit the LPS attachment and the intracellular inflammatory response. The intracellular anti-inflammatory effect of CTP-NH2 was associated with blocking of LPS binding to the Toll-like receptor 4-myeloid differentiation factor 2 complex and inhibiting the nuclear factor-kappa B pathway. In addition, the anti-inflammatory effect of CTP-NH2 was confirmed using a murine LPS-induced sepsis model. Collectively, these findings suggest that CTP-NH2 could be developed into a novel anti-inflammatory drug. This successful modification provides a design strategy to improve the cellular uptake and anti-inflammatory activity of peptide agents.
Crosstalk Between Staphylococcus aureus and Innate Immunity: Focus on Immunometabolism
Authors: Horn Christopher M. , Kielian Tammy
Published: February 2021

Staphylococcus aureusis a leading cause of bacterial infections globally in both healthcare and community settings. The success of this bacterium is the product of an expansive repertoire of virulence factors in combination with acquired antibiotic resistance and propensity for biofilm formation.S. aureusleverages these factors to adapt to and subvert the host immune response. With the burgeoning field of immunometabolism, it has become clear that the metabolic program of leukocytes dictates their inflammatory status and overall effectiveness in clearing an infection. The metabolic flexibility ofS. aureusoffers an inherent means by which the pathogen could manipulate the infection milieu to promote its survival. The exact metabolic pathways thatS. aureusinfluences in leukocytes are not entirely understood, and more work is needed to understand howS. aureusco-opts leukocyte metabolism to gain an advantage. In this review, we discuss the current knowledge concerning how metabolic biases dictate the pro- vs. anti-inflammatory attributes of various innate immune populations, howS. aureusmetabolism influences leukocyte activation, and compare this with other bacterial pathogens. A better understanding of the metabolic crosstalk betweenS. aureusand leukocytes may unveil novel therapeutic strategies to combat these devastating infections.
B Cell Dysregulation in Common Variable Immunodeficiency Interstitial Lung Disease
Authors: Matson Erik M. , Abyazi Miranda L. , Bell Kayla A. , Hayes Kevin M. , Maglione Paul J.
Published: February 2021

Common variable immunodeficiency (CVID) is the most frequently diagnosed primary antibody deficiency. About half of CVID patients develop chronic non-infectious complications thought to be due to intrinsic immune dysregulation, including autoimmunity, gastrointestinal disease, and interstitial lung disease (ILD). Multiple studies have found ILD to be a significant cause of morbidity and mortality in CVID. Yet, the precise mechanisms underlying this complication in CVID are poorly understood. CVID ILD is marked by profound pulmonary infiltration of both T and B cells as well as granulomatous inflammation in many cases. B cell depletive therapy, whether done as a monotherapy or in combination with another immunosuppressive agent, has become a standard of therapy for CVID ILD. However, CVID is a heterogeneous disorder, as is its lung pathology, and the precise patients that would benefit from B cell depletive therapy, when it should administered, and how long it should be repeated all remain gaps in our knowledge. Moreover, some have ILD recurrence after B cell depletive therapy and the relative importance of B cell biology remains incompletely defined. Developmental and functional abnormalities of B cell compartments observed in CVID ILD and related conditions suggest that imbalance of B cell signaling networks may promote lung disease. Included within these potential mechanisms of disease is B cell activating factor (BAFF), a cytokine that is upregulated by the interferon gamma (IFN-γ):STAT1 signaling axis to potently influence B cell activation and survival. B cell responses to BAFF are shaped by the divergent effects and expression patterns of its three receptors: BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA). Moreover, soluble forms of BAFF-R, TACI, and BCMA exist and may further influence the pathogenesis of ILD. Continued efforts to understand how dysregulated B cell biology promotes ILD development and progression will help close the gap in our understanding of how to best diagnose, define, and manage ILD in CVID.
Identifying Persistent Hot Spot Areas of Undersized Fish and Crustaceans in Southern European Waters: Implication for Fishery Management Under the Discard Ban Regulation
Authors: Milisenda Giacomo , Garofalo Germana , Fiorentino Fabio , Colloca Francesco , Maynou Francesc , Ligas Alessandro , Musumeci Claudia , Bentes Luís , Gonçalves Jorge M. S. , Erzini Karim , Russo Tommaso , D’Andrea Lorenzo , Vitale Sergio
Published: February 2021

The recent establishment of the “landing obligation” under the reformed EU Common Fishery Policy has the twofold objective of reducing the excessive practice of discarding unwanted catch at sea and encouraging more selective and sustainable fisheries. Within this context, the awareness of the spatial distribution of potential unwanted catches is important for devising management measures aimed to decrease discards. This study analyzed the distribution of Hot Spot density areas of demersal fish and crustaceans below the Minimum Conservation Reference Size (MCRS) in four different southern European seas: continental Portuguese coast, Catalan Sea, South of Sicily, Liguria and northern Tyrrhenian Seas using both bottom trawl survey data and information on the spatial distribution of commercial fisheries. Critical areas for discarding were identified as zones where the highest densities of individuals below MCRS were consistently recorded throughout a series of years. Results clearly showed a patchy distribution of undersized individuals in each investigated area, highlighting the overlap between high density patches of both discards and fishing effort. The present findings provide a relevant knowledge for supporting the application of spatial-based management actions, such as the designation of Fisheries Restricted Areas (FRAs), in order to minimize the by-catch of undersized specimens and improve the sustainability of demersal fisheries.
Characteristics of Passive Films Formed on As-Cast Ti–6Al-4V in Hank’s Solution Before and After Transpassivation
Authors: Yi Guo , Liu Xinxin , Zheng Chuanbo , Zhang Hongyue , Xu Cheng , Cui Yu-Wei , Liu Shuan
Published: February 2021

In this work, the characteristics of passive films formed on as-cast Ti-6Al-4V before and after transpassivation by electrochemical methods will be studied. A simulated body fluid of Hank’s solution was used as the electrolyte in this work. According to the potentiodynamic polarization test, the passivation range, transpassive range, and repassivation range of as-cast Ti-6Al-4V were obtained. Afterward, the potentiostatic polarization was employed to passivate the Ti-6Al-4V in both passivation and repassivation ranges. Electrochemical impedance spectroscopy (EIS) was used to analyze the characteristics of formed passive films. Different electrochemical behavior of as-cast Ti–6Al-4V is found in passivation and repassivation ranges. The passivation current density of the sample in the repassivation range is significantly larger than that in the passivation range. Meanwhile, the growth rate of passive film in the repassivation range is also greater than that in the passivation range. Although the sample shows a higher charge transfer impedance in the repassivation range, metastable pitting corrosion is also observed, indicating the formation of the unstable passive film. Such results advance the understanding of as-cast Ti-6Al-4V polarized under different potentials for potential biomedical applications.
JAK Inhibitors and Modulation of B Cell Immune Responses in Rheumatoid Arthritis
Authors: Moura Rita A. , Fonseca João Eurico
Published: February 2021

Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disease that can lead to joint destruction, functional disability and substantial comorbidity due to the involvement of multiple organs and systems. B cells have several important roles in RA pathogenesis, namely through autoantibody production, antigen presentation, T cell activation, cytokine release and ectopic lymphoid neogenesis. The success of B cell depletion therapy with rituximab, a monoclonal antibody directed against CD20 expressed by B cells, has further supported B cell intervention in RA development. Despite the efficacy of synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs) in the treatment of RA, few patients reach sustained remission and refractory disease is a concern that needs critical evaluation and close monitoring. Janus kinase (JAK) inhibitors or JAKi are a new class of oral medications recently approved for the treatment of RA. JAK inhibitors suppress the activity of one or more of the JAK family of tyrosine kinases, thus interfering with the JAK-Signal Transducer and Activator of Transcription (STAT) signaling pathway. To date, there are five JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib) approved in the USA, Europe and/ or Japan for RA treatment. Evidence from the literature indicates that JAK inhibitors interfere with B cell functions. In this review, the main results obtained in clinical trials, pharmacokinetic,in vitroandin vivostudies concerning the effects of JAK inhibitors on B cell immune responses in RA are summarized.
Metagenomics Reveals That Intravenous Injection of Beta-Hydroxybutyric Acid (BHBA) Disturbs the Nasopharynx Microflora and Increases the Risk of Respiratory Diseases
Authors: Qi Jiancheng , Cai Dongjie , Cui Yaocheng , Tan Tianyu , Zou Huawei , Guo Wei , Xie Yue , Guo Hongrui , Chen Shi-Yi , Ma Xiaoping , Gou Liping , Cui Hengmin , Geng Yi , Zhang Ming , Ye Gang , Zhong Zhijun , Ren Zhihua , Hu Yanchun , Wang Ya , Deng Junliang , YU Shumin , Cao Suizhong , Wanapat Metha , Fang Jing , Wang Zhisheng , Zuo Zhicai
Published: February 2021

It is widely accepted that maintenance of microbial diversity is essential for the health of the respiratory tract; however, there are limited reports on the correlation between starvation and respiratory tract microbial diversity. In the present study, saline/β-hydroxybutyric acid (BHBA) intravenous injection after dietary restriction was used to imitate different degrees of starvation. A total of 13 healthy male yaks were imposed to different dietary restrictions and intravenous injections, and their nasopharyngeal microbiota profiles were obtained by metagenomic shotgun sequencing. In healthy yaks, the main dominant phyla were Proteobacteria (33.0%), Firmicutes (22.6%), Bacteroidetes (17.2%), and Actinobacteria (13.2%); the most dominated species was Clostridium botulinum (10.8%). It was found that 9 days of dietary restriction and 2 days of BHBA injection (imitating severe starvation) significantly decreased the microbial diversity and disturbed its structure and functional composition, which increased the risk of respiratory diseases. This study also implied that oral bacteria played an important role in maintaining nasopharynx microbial homeostasis. In this study, the correlation between starvation and nasopharynx microbial diversity and its potential mechanism was investigated for the first time, providing new ideas for the prevention of respiratory diseases.
Identification of Stress-Related Genes and a Comparative Analysis of the Amino Acid Compositions of Translated Coding Sequences Based on Draft Genome Sequences of Antarctic Yeasts
Authors: Baeza Marcelo , Zúñiga Sergio , Peragallo Vicente , Barahona Salvador , Alcaino Jennifer , Cifuentes Víctor
Published: February 2021

Microorganisms inhabiting cold environments have evolved strategies to tolerate and thrive in those extreme conditions, mainly the low temperature that slow down reaction rates. Among described molecular and metabolic adaptations to enable functioning in the cold, there is the synthesis of cold-active proteins/enzymes. In bacterial cold-active proteins, reduced proline content and highly flexible and larger catalytic active sites than mesophylls counterparts have been described. However, beyond the low temperature, microorganisms’ physiological requirements may differ according to their growth velocities, influencing their global protein compositions. This hypothesis was tested in this work using eight cold-adapted yeasts isolated from Antarctica, for which their growth parameters were measured and their draft genomes determined and bioinformatically analyzed. The optimal temperature for yeasts’ growth ranged from 10 to 22°C, and yeasts having similar or same optimal temperature for growth displayed significative different growth rates. The sizes of the draft genomes ranged from 10.7 (Tetracladiumsp.) to 30.7 Mb (Leucosporidium creatinivorum), and the GC contents from 37 (Candida sake) to 60% (L. creatinivorum). Putative genes related to various kinds of stress were identified and were especially numerous for oxidative and cold stress responses. The putative proteins were classified according to predicted cellular function and subcellular localization. The amino acid composition was compared among yeasts considering their optimal temperature for growth and growth rates. In several groups of predicted proteins, correlations were observed between their contents of flexible amino acids and both the yeasts’ optimal temperatures for growth and their growth rates. In general, the contents of flexible amino acids were higher in yeasts growing more rapidly as their optimal temperature for growth was lower. The contents of flexible amino acids became lower among yeasts with higher optimal temperatures for growth as their growth rates increased.
Attitudes Toward Epilepsy Among Parents of Children With Epilepsy in Southern China
Authors: Yang Haojun , Chi Yunfang , Zhu Ziqing , Huang Kailing , Xiang Lan , Xiao Bo , Tang Weiting , Feng Li
Published: February 2021

Purpose: To evaluate the attitudes toward epilepsy among parents of children with epilepsy (CWE) in China and identify some related factors for future interventions for parents to offer more social support for CWE.

Method: The Chinese Public Attitudes Toward Epilepsy (CPATE) scale was administered to 234 parents of CWE and 203 parents of normal children in Xiangya hospital during 2019–2020.

Results: The cumulative score of the parents of CWE (26.427 ± 6.688) was significantly lower than that of the normal children group (32.330 ± 7.234, p < 0.001). Subanalysis showed more positive attitudes among parents of CWE than the control group (p < 0.001) toward education (4.765 ± 1.985 vs. 6.621 ± 2.419), social life (6.556 ± 2.456 vs. 8.010 ± 2.683), marriage (9.586 ± 2.675 vs. 11.025 ± 2.900), and employment (3.876 ± 1.364 vs. 4.5123 ± 1.283). The attitudes toward epilepsy among parents of CWE with seizures in public (27.16 ± 6.66) or during sleep (27.10 ± 6.38) were more negative than those without (25.35 ± 6.62 and 25.08 ± 7.10, respectively) (p < 0.05). In addition, female and low income were negatively related to parents' attitudes toward epilepsy.

Conclusions: More active policy guidance and adequate social support should be given to parents of children with seizures in public or during sleep to instruct their children to form a positive perception about epilepsy, which is expected to have a positive impact on their social abilities in the future.
Error-Related Cognitive Control and Behavioral Adaptation Mechanisms in the Context of Motor Functioning and Anxiety
Authors: Topor Marta , Opitz Bertram , Leonard Hayley C.
Published: February 2021

Motor proficiency reflects the ability to perform precise and coordinated movements in different contexts. Previous research suggests that different profiles of motor proficiency may be associated with different cognitive functioning characteristics thus suggesting an interaction between cognitive and motor processes. The current study investigated this interaction in the general population of healthy adults with different profiles of motor proficiency by focusing on error-related cognitive control and behavioral adaptation mechanisms. In addition, the impact of these processes was assessed in terms of trait anxiety and worries. Forty healthy adults were divided into high and low motor proficiency groups based on an assessment of their motor skills. Using electroencephalography during a flanker task, error-related negativity (ERN) was measured as the neural indicator of cognitive control. Post-error slowing (PES) was measured to represent behavioral adaptation. Participants also completed an anxiety assessment questionnaire. Participants in the high motor proficiency group achieved better task accuracy and showed relatively enhanced cognitive control through increased ERN. Contrastingly, individuals in the lower motor proficiency group achieved poorer accuracy whilst showing some evidence of compensation through increased PES. Trait anxiety reflecting general worries was found to be correlated with motor functioning, but the study could not provide evidence that this was related to cognitive or behavioral control mechanisms. The interaction between cognitive and motor processes observed in this study is unique for healthy and sub-clinical populations and provides a baseline for the interpretation of similar investigations in individuals with motor disorders.
Effect of Repetitive Passive Movement Before Motor Skill Training on Corticospinal Excitability and Motor Learning Depend on BDNF Polymorphisms
Authors: Pham Manh Van , Miyaguchi Shota , Watanabe Hiraku , Saito Kei , Otsuru Naofumi , Onishi Hideaki
Published: February 2021

A decrease in cortical excitability tends to be easily followed by an increase induced by external stimuli via a mechanism aimed at restoring it; this phenomenon is called “homeostatic plasticity.” In recent years, although intervention methods aimed at promoting motor learning using this phenomenon have been studied, an optimal intervention method has not been established. In the present study, we examined whether subsequent motor learning can be promoted further by a repetitive passive movement, which reduces the excitability of the primary motor cortex (M1) before motor learning tasks. We also examined the relationship between motor learning and the brain-derived neurotrophic factor. Forty healthy subjects (Val/Val genotype, 17 subjects; Met carrier genotype, 23 subjects) participated. Subjects were divided into two groups of 20 individuals each. The first group was assigned to perform the motor learning task after an intervention consisting in the passive adduction–abduction movement of the right index finger at 5 Hz for 10 min (RPM condition), while the second group was assigned to perform the task without the passive movement (control condition). The motor learning task consisted in the visual tracking of the right index finger. The results showed that the corticospinal excitability was transiently reduced after the passive movement in the RPM condition, whereas it was increased to the level detected in the control condition after the motor learning task. Furthermore, the motor learning ability was decreased immediately after the passive movement; however, the motor performance finally improved to the level observed in the control condition. In individuals carrying the Val/Val genotype, higher motor learning was also found to be related to the more remarkable changes in corticospinal excitability caused by the RPM condition. This study revealed that the implementation of a passive movement before a motor learning tasks did not affect M1 excitatory changes and motor learning efficiency; in contrast, in subjects carrying the Val/Val polymorphism, the more significant excitatory changes in the M1 induced by the passive movement and motor learning task led to the improvement of motor learning efficiency. Our results also suggest that homeostatic plasticity occurring in the M1 is involved in this improvement.
No Impact of Cerebellar Anodal Transcranial Direct Current Stimulation at Three Different Timings on Motor Learning in a Sequential Finger-Tapping Task
Authors: Nguemeni Carine , Stiehl Annika , Hiew Shawn , Zeller Daniel
Published: February 2021

Background: Recently, attention has grown toward cerebellar neuromodulation in motor learning using transcranial direct current stimulation (tDCS). An important point of discussion regarding this modulation is the optimal timing of tDCS, as this parameter could significantly influence the outcome. Hence, this study aimed to investigate the effects of the timing of cerebellar anodal tDCS (ca-tDCS) on motor learning using a sequential finger-tapping task (FTT).

Methods: One hundred and twenty two healthy young, right-handed subjects (96 females) were randomized into four groups (Duringsham, Before, Duringreal, After). They performed 2 days of FTT with their non-dominant hand on a custom keyboard. The task consisted of 40 s of typing followed by 20 s rest. Each participant received ca-tDCS (2 mA, sponge electrodes of 25 cm2, 20 min) at the appropriate timing and performed 20 trials on the first day (T1, 20 min). On the following day, only 10 trials of FTT were performed without tDCS (T2, 10 min). Motor skill performance and retention were assessed.

Results: All participants showed a time-dependent increase in learning. Motor performance was not different between groups at the end of T1 (p = 0.59). ca-tDCS did not facilitate the retention of the motor skill in the FTT at T2 (p = 0.27). Thus, our findings indicate an absence of the effect of ca-tDCS on motor performance or retention of the FTT independently from the timing of stimulation.

Conclusion: The present results suggest that the outcome of ca-tDCS is highly dependent on the task and stimulation parameters. Future studies need to establish a clear basis for the successful and reproducible clinical application of ca-tDCS.
High-Throughput Analysis of Water-Soluble Forms of Choline and Related Metabolites in Human Milk by UPLC-MS/MS and Its Application
Authors: Hampel Daniela , Shahab-Ferdows Setareh , Nguyen Ngoc , Kac Gilberto , Allen Lindsay H.
Published: February 2021

Choline and related metabolites are key factors in many metabolic processes, and insufficient supply can adversely affect reproduction and fetal development. Choline status is mainly regulated by intake, and human milk is the only choline source for exclusively breastfed infants. Further, maternal status, genotype, and phenotype, as well as infant outcomes, have been related to milk choline concentrations. In order to enable the rapid assessment of choline intake for exclusively breastfed infants and to further investigate the associations between milk choline and maternal and infant status and other outcomes, we have developed a simplified method for the simultaneous analysis of human milk choline, glycerophosphocholine, phosphocholine, and the less abundant related metabolites betaine, carnitine, creatinine, dimethylglycine (DMG), methionine, and trimethylamine N-oxide (TMAO) using ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). These analytes have milk concentrations ranging over 3 orders of magnitude. Unlike other recently described LC-based methods, our approach does not require an ion-pairing reagent or high concentrations of solvent modifiers for successful analyte separation and thus avoid signal loss and potential permanent contamination. Milk samples (10 μl) were diluted (1:80) in water : methanol (1:4, v:v) and filtered prior to analysis with an optimized gradient of 0.1% propionic acidaq and acetonitrile, allowing efficient separation and removal of contaminants. Recovery rates ranged from 108.0 to 130.9% (inter-day variation: 3.3–9.6%), and matrix effects (MEs) from 54.1 to 114.3%. MEs were greater for carnitine, creatinine, and TMAO at lower dilution (1:40, p < 0.035 for all), indicating concentration-dependent ion suppression. Milk from Brazilian women (2–8, 28–50, and 88–119 days postpartum, ntotal = 53) revealed increasing concentration throughout lactation for glycerophosphocholine, DMG, and methionine, while carnitine decreased. Choline and phosphocholine were negatively correlated consistently at all three collection time intervals. The method is suitable for rapid analysis of human milk water-soluble forms of choline as well as previously not captured related metabolites with minimal sample volumes and preparation.
Population Pharmacokinetics and Exposure–Safety Relationship of Paclitaxel Liposome in Patients With Non-small Cell Lung Cancer
Authors: Zhou Haiyan , Yan Jiaqing , Chen Wei , Yang Jun , Liu Min , Zhang Yuan , Shen Xin , Ma Yinglin , Hu Xingsheng , Wang Yan , Du Kehe , Li Guohui
Published: February 2021

Purpose

Paclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure–safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).

Methods

Data from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.

Results

The PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m–2, the estimated clearance of total plasma paclitaxel was 21.55 L h–1. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure–safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.

Conclusion

This PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure–safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.
ClC-5 Downregulation Induces Osteosarcoma Cell Apoptosis by Promoting Bax and tBid Complex Formation
Authors: Peng Fei , Cai Weisong , Li Jianping , Li Haohuan
Published: February 2021

Osteosarcoma is the most common malignant bone tumor. Chloride (Cl−) channels-mediated Cl− movement plays an important role in regulating the functions of various cancer cells, but its role in osteosarcoma remains unclear. In this study, we found that ClC-5 was increased in osteosarcoma tissues compared with normal bone tissues. Patients with high ClC-5 expression showed poor overall survival relative to those patients with low ClC-5 expression. Higher ClC-5 expression and lower intracellular Cl− concentration ([Cl−]i) were observed in osteosarcoma cells compared with normal osteoblasts. Lowering [Cl−]i increased the viability of osteosarcoma cells, which was markedly blocked by ClC-5 downregulation. Knockdown of ClC-5 significantly induced osteosarcoma cell apoptosis and increased the release of cytochrome c from mitochondria to cytosol, concomitantly with cleavage of caspase-9, caspase-3, and PARP. The effect of ClC-5 downregulation on osteosarcoma cell apoptosis and viability was abolished by caspase-3 and caspase-9 inhibitors, but not caspase-8 inhibitor. Furthermore, ClC-5 inhibition promoted Bax translocation from cytosol to mitochondria. Immunoprecipitation showed that ClC-5 interacted with Bax and ClC-5 downregulation enhanced Bax and tBid complex formation. Collectively, we demonstrate that ClC-5 downregulation induces osteosarcoma cell apoptosis via mitochondria-dependent apoptotic pathway activation by promoting Bax and tBid association and subsequent Bax translocation.
An E2F1/DDX11/EZH2 Positive Feedback Loop Promotes Cell Proliferation in Hepatocellular Carcinoma
Authors: Su Shu-Guang , Li Qiu-Li , Zhang Mei-Fang , Zhang Peng-Wei , Shen Huimin , Zhang Chris Zhiyi
Published: February 2021

Hepatocellular carcinoma (HCC) accounts for one of the leading causes of cancer-related death, and is attributed to the dysregulation of genes involved in genome stability. DDX11, a DNA helicase, has been implicated in rare genetic disease and human cancers. Yet, its clinical value, biological function, and the underlying mechanism in HCC progression are not fully understood. Here, we show that DDX11 is upregulated in HCC and exhibits oncogenic activity via EZH2/p21 signaling. High expression of DDX11 is significantly correlated with poor outcomes of HCC patients in two independent cohorts. DDX11 overexpression increases HCC cell viabilities and colony formation, whereas DDX11 knockdown arrests cells at G1 phase without alteration of p53 expression. Ectopic expression of DDX11 reduces, while depletion of DDX11 induces the expression of p21. Treatment of p21 siRNA markedly attenuates the cell growth suppression caused by DDX11 silence. Further studies reveal that DDX11 interacts with EZH2 in HCC cells to protect it from ubiquitination-mediated protein degradation, consequently resulting in the downregulation of p21. In addition, E2F1 is identified as one of the upstream regulators of DDX11, and forms a positive feedback loop with EZH2 to upregulate DDX11 and facilitate cell proliferation. Collectively, our data suggest DDX11 as a promising prognostic factor and an oncogene in HCC via a E2F1/DDX11/EZH2 positive feedback loop.
Identification and Validation of an Autophagy-Related lncRNA Signature for Patients With Breast Cancer
Authors: Zhang Ruyue , Zhu Qingwen , Yin Detao , Yang Zhe , Guo Jinxiu , Zhang Jingmin , Zhou Yubing , Yu Jane J.
Published: February 2021

Background

Autophagy is a “self-feeding” phenomenon of cells, which is crucial in mammalian development. Long non-coding RNA (lncRNA) is a new regulatory factor for cell autophagy, which can regulate the process of autophagy to affect tumor progression. However, poor attention has been paid to the roles of autophagy-related lncRNAs in breast cancer.

Objective

This study aimed to construct an autophagy-related lncRNA signature that can effectively predict the prognosis of breast cancer patients and explore the potential functions of these lncRNAs.

Methods

The RNA sequencing (RNA-Seq) data of breast cancer patients was collected from The Cancer Genome Atlas (TCGA) database and the GSE20685 database. Multivariate Cox analysis was implemented to produce an autophagy-related lncRNA signature in the TCGA cohort. The signature was then validated in the GSE20685 cohort. The receiver operator characteristic (ROC) curve was performed to evaluate the predictive ability of the signature. Gene set enrichment analysis (GSEA) was used to explore the potential functions based on the signature. Finally, the study developed a nomogram and internal verification based on the autophagy-related lncRNAs.

Results

A signature composed of 9 autophagy-related lncRNAs was determined as a prognostic model, and 1,109 breast cancer patients were divided into high-risk group and low-risk group based on median risk score of the signature. Further analysis demonstrated that the over survival (OS) of breast cancer patients in the high-risk group was poorer than that in the low-risk group based on the prognostic signature. The area under the curve (AUC) of ROC curve verified the sensitivity and specificity of this signature. Additionally, we confirmed the signature is an independent factor and found it may be correlated to the progression of breast cancer. GSEA showed gene sets were notably enriched in carcinogenic activation pathways and autophagy-related pathways. The qRT-PCR identified 5 lncRNAs with significantly differential expression in breast cancer cells based on the 9 lncRNAs of the prognostic model, and the results were consistent with the tissues.

Conclusion

In summary, our signature has potential predictive value in the prognosis of breast cancer and these autophagy-related lncRNAs may play significant roles in the diagnosis and treatment of breast cancer.
MiR-21-5p Induces Pyroptosis in Colorectal Cancer via TGFBI
Authors: Jiang Rilei , Chen Xiaolei , Ge Shaohua , Wang Qin , Liu Yichang , Chen Haijun , Xu Jiatuo , Wu Jiang
Published: February 2021

Pyroptosis is a distinct form of programmed cell death in eukaryotic cells that has garnered increasing attention in cancer-related research. Moreover, although miR-21 has been reported as abnormally expressed in colorectal cancer, due to a lack of in-depth research on the transcriptional regulation mechanisms of miR-21, its clinical usage remains limited. Our study is the first, to our knowledge, to compare the clinical manifestations and laboratory phenotypes associated with miR-21-3p and miR-21-5p. Morphologically, the transfection of miR-21-3p or miR-21-5p inhibitors, as well as miR-21-5p mimics into HCT-116 and HT-29 cell lines, induced cell death. Surprisingly, overexpression of miR-21-5p induced cell death more strongly than its knockdown. Mechanistic studies of miR-21-5p overexpression revealed that various inflammatory factors including IL-1β and IL-18 were released, while pyroptosis-associated mRNAs were upregulated and proteins were activated. Moreover, miR-21-5p was found to act as a downstream factor to significantly and directly regulate transforming growth factor beta-induced (TGFB1). Specifically, miR-21-5p overexpression caused downregulation of TGFBI, which may have led to pyroptosis. Collectively, we revealed that miR-21-5p induces pyroptosis in colorectal cancer via TGFBI regulation, thereby providing important mechanistic insights into its antitumor effects and expanding its potential for clinical applications.