bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease
Authors: de Boer Esther C. W. , van Mourik Anouk G. , Jongerius Ilse
Published: December 2020

The complement system is an important part of the innate immune system, providing a strong defense against pathogens and removing apoptotic cells and immune complexes. Due to its strength, it is important that healthy human cells are protected against damage induced by the complement system. To be protected from complement, each cell type relies on a specific combination of both soluble and membrane-bound regulators. Their importance is indicated by the amount of pathologies associated with abnormalities in these complement regulators. Here, we will discuss the current knowledge on complement regulatory protein polymorphisms and expression levels together with their link to disease. These diseases often result in red blood cell destruction or occur in the eye, kidney or brain, which are tissues known for aberrant complement activity or regulation. In addition, complement regulators have also been associated with different types of cancer, although their mechanisms here have not been elucidated yet. In most of these pathologies, treatments are limited and do not prevent the complement system from attacking host cells, but rather fight the consequences of the complement-mediated damage, using for example blood transfusions in anemic patients. Currently only few drugs targeting the complement system are used in the clinic. With further demand for therapeutics rising linked to the wide range of complement-mediated disease we should broaden our horizon towards treatments that can actually protect the host cells against complement. Here, we will discuss the latest insights on how complement regulators can benefit therapeutics. Such therapeutics are currently being developed extensively, and can be categorized into full-length complement regulators, engineered complement system regulators and antibodies targeting complement regulators. In conclusion, this review provides an overview of the complement regulatory proteins and their links to disease, together with their potential in the development of novel therapeutics.
Resistance to Experimental Visceral Leishmaniasis in Mice Infected With Leishmania infantum Requires Batf3
Authors: Soto Manuel , Ramírez Laura , Solana José Carlos , Cook Emma C. L. , Hernández-García Elena , Charro-Zanca Sara , Redondo-Urzainqui Ana , Reguera Rosa M. , Balaña-Fouce Rafael , Iborra Salvador
Published: December 2020

Unveiling the protective immune response to visceral leishmaniasis is critical for a rational design of vaccines aimed at reducing the impact caused by this fatal, if left untreated, vector-borne disease. In this study we sought to determine the role of the basic leucine zipper transcription factor ATF-like 3 (Batf3) in the evolution of infection with Leishmania infantum, the causative agent of human visceral leishmaniasis in the Mediterranean Basin and Latin America. For that, Batf3-deficient mice in C57BL/6 background were infected with an L. infantum strain expressing the luciferase gene. Bioluminescent imaging, as well as in vitro parasite titration, demonstrated that Batf3-deficient mice were unable to control hepatic parasitosis as opposed to wild-type C57BL/6 mice. The impaired microbicide capacities of L. infantum-infected macrophages from Batf3-deficient mice mainly correlated with a reduction of parasite-specific IFN-γ production. Our results reinforce the implication of Batf3 in the generation of type 1 immunity against infectious diseases.
Perturbations to Homeostasis in Experimental Models Revealed Innate Pathways Driving Food Allergy
Authors: Bruton Kelly , Koenig Joshua F. E. , Phelps Allyssa , Jordana Manel
Published: December 2020

While type 2 immunity has been conventionally viewed as beneficial against helminths, venoms, and poisons, and harmful in allergy, contemporary research has uncovered its critical role in the maintenance of homeostasis. The initiation of a type 2 immune response involves an intricate crosstalk between structural and immune cells. Structural cells react to physical and chemical tissue perturbations by secreting alarmins, which signal the innate immune system to restore homeostasis. This pathway acts autonomously in the context of sterile injury and in the presence of foreign antigen initiates an adaptive Th2 response that is beneficial in the context of venoms, toxins, and helminths, but not food allergens. The investigation of the triggers and mechanisms underlying food allergic sensitization in humans is elusive because sensitization is a silent process. Therefore, the central construct driving food allergy modeling is based on introducing perturbations of tissue homeostasis along with an allergen which will result in an immunological and clinical phenotype that is consistent with that observed in humans. The collective evidence from multiple models has revealed the pre-eminent role of innate cells and molecules in the elicitation of allergic sensitization. We posit that, with the expanding use of technologies capable of producing formidable datasets, models of food allergy will continue to have an indispensable role to delineate mechanisms and establish causal relationships.
The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology
Authors: Rutsch Andrina , Kantsjö Johan B. , Ronchi Francesca
Published: December 2020

The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.
Schistosomiasis Pulmonary Arterial Hypertension
Authors: Sibomana Jean Pierre , Campeche Aloma , Carvalho-Filho Roberto J. , Correa Ricardo Amorim , Duani Helena , Pacheco Guimaraes Virginia , Hilton Joan F. , Kassa Biruk , Kumar Rahul , Lee Michael H. , Loureiro Camila M. C. , Mazimba Sula , Mickael Claudia , Oliveira Rudolf K. F. , Ota-Arakaki Jaquelina S. , Rezende Camila Farnese , Silva Luciana C. S. , Sinkala Edford , Ahmed Hanan Yusuf , Graham Brian B.
Published: December 2020

Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.
Relief of Cadmium-Induced Intestinal Motility Disorder in Mice by Lactobacillus plantarum CCFM8610
Authors: Liu Yang , Wu Jiangping , Xiao Yue , Liu Qing , Yu Leilei , Tian Fengwei , Zhao Jianxin , Zhang Hao , Chen Wei , Zhai Qixiao
Published: December 2020

Cadmium (Cd) is a toxic metal inducing a range of adverse effects on organs including liver and kidneys. However, the underlying molecular mechanisms of Cd-induced intestinal toxicity through dietary intake is poorly studied. This study evaluated the toxic effects of Cd on intestinal physiology and confirmed the effectiveness of the protective mechanism of the probiotic Lactobacillus plantarum CCFM8610 against chronic Cd toxicity. After treatment with Cd, the HT-29 cell line was subjected to iTRAQ analysis, which revealed that changes in the proteomic profiles after Cd exposure were related to pathways involved in the stress response and carbohydrate metabolism. The results of an animal trial also indicated that 10 weeks of Cd exposure decreased the fecal water content and contractile response of colonic muscle strips in mice, and delayed the excretion time of the first black feces. L. plantarum CCFM8610 treatment provided protective effects against these Cd-induced intestinal motility dysfunctions by recovering the levels of neurotransmitters, including substance P, acetyl cholinesterase, vasoactive intestinal peptide, 5-hydroxytryptamine, calcitonin gene-related peptide, and nitric oxide, and suppressing the cellular stress response in mice (e.g., the inhibition of mitogen-activated protein kinase pathways). The administration of this probiotic was also observed to reduce Cd levels in the tissues and blood of the mice. Our results suggest a newly identified protective mechanism of probiotics against Cd toxicity that involves the recovery of intestinal motility and increase in fecal cadmium excretion.
The 23S Ribosomal RNA From Pyrococcus furiosus Is Circularly Permuted
Authors: Birkedal Ulf , Beckert Bertrand , Wilson Daniel N. , Nielsen Henrik
Published: December 2020

Synthesis and assembly of ribosomal components are fundamental cellular processes and generally well-conserved within the main groups of organisms. Yet, provocative variations to the general schemes exist. We have discovered an unusual processing pathway of pre-rRNA in extreme thermophilic archaea exemplified byPyrococcus furiosus. The large subunit (LSU) rRNA is produced as a circularly permuted form through circularization followed by excision of Helix 98. As a consequence, the terminal domain VII that comprise the binding site for the signal recognition particle is appended to the 5´ end of the LSU rRNA that instead terminates in Domain VI carrying the Sarcin-Ricin Loop, the primary interaction site with the translational GTPases. To our knowledge, this is the first example of a true post-transcriptional circular permutation of a main functional molecule and the first example of rRNA fragmentation in archaea.
A Clinical Extensively-Drug Resistant (XDR) Escherichia coli and Role of Its β-Lactamase Genes
Authors: Wang Mingyu , Wang Wenjia , Niu Yu , Liu Ting , Li Ling , Zhang Mengge , Li Ziyun , Su Wenya , Liu Fangyue , Zhang Xuhua , Xu Hai
Published: December 2020

An extensively-drug resistant (XDR) Escherichia coli W60 was isolated from the urine sample of a patient. The genetic basis for its XDR phenotype was investigated, particularly the basis for its resistance toward β-lactam/BLI (β-Lactamase Inhibitor) combinations. Following determination of the XDR phenotype, third generation genomic sequencing was performed to identify genetic structures in E. coli W60. Further cloning analysis was performed to identify determinants of β-lactam/BLI combination resistance. It was found that E. coli W60 is resistant to nearly all of the tested antibiotics including all commonly used β-lactam/BLI combinations. Analysis of the genomic structures in E. coli W60 showed two novel transferable plasmids are responsible for the resistance phenotypes. Further genetic analysis showed blaNDM–5 leads to high resistance to β-lactam/BLI combinations, which was enhanced by co-expressing bleMBL. pECW602 harbors a truncated blaTEM that is not functional due to the loss of the N-terminal signal peptide coding region. Research performed in this work leads to several significant conclusions: the XDR phenotype of E. coli W60 can be attributed to the presence of transferable multidrug resistance plasmids; NDM-5 confers high resistance to β-lactam/BLI combinations; co-expression of bleMBL enhances resistance caused by NDM-5; the signal peptides of TEM type β-lactamases are essential for their secretion and function. Findings of this work show the danger of transferable multidrug resistance plasmids and metallo-β-lactamases, both of which should be given more attention in the analysis and treatment of multidrug resistant pathogens.
Autism Screening in Early Childhood: Discriminating Autism From Other Developmental Concerns
Authors: Brewer Neil , Young Robyn L. , Lucas Carmen A.
Published: December 2020

Early identification of autism, followed by appropriate intervention, has the potential to improve outcomes for autistic individuals. Numerous screening instruments have been developed for children under 3 years of age. Level 1 screeners are used in large-scale screening to detect at-risk children in the general population; Level 2 screeners are concerned with distinguishing children with signs of autism from those with other developmental problems. The focus here is evaluation of Level 2 screeners. However, given the contributions of Level 1 screeners and the necessity to understand how they might interface with Level 2 screeners, we briefly review Level 1 screeners and consider instrument characteristics and system variables that may constrain their effectiveness. The examination of Level 2 screeners focuses on five instruments associated with published evaluations in peer-reviewed journals. Key criteria encompass the traditional indices of test integrity such as test reliability (inter-rater, test-retest) and construct validity, including concurrent and predictive validity, sensitivity (SE), and specificity (SP). These evaluations reveal limitations, including inadequate sample sizes, reliability issues, and limited involvement of independent researchers. Also lacking are comparative test evaluations under standardized conditions, hindering interpretation of differences in discriminative performance across instruments. Practical considerations constraining the use of such instruments—such as the requirements for training in test administration and test administration time—are canvassed. Published Level 2 screener short forms are reviewed and, as a consequence of that evaluation, future directions for assessing the discriminative capacity of items and measures are suggested. Suggested priorities for future research include targeting large and diverse samples to permit robust appraisals of Level 2 items and scales across the 12–36 month age range, a greater focus on precise operationalization of items and response coding to enhance reliability, ongoing exploration of potentially discriminating items at the younger end of the targeted age range, and trying to unravel the complexities of developmental trajectories in autistic infants. Finally, we emphasize the importance of understanding how screening efficacy is dependent on clinicians' and researchers' ability not only to develop screening tests but also to negotiate the complex organizational systems within which screening procedures must be implemented.
Resting-State Static and Dynamic Functional Abnormalities in Active Professional Fighters With Repetitive Head Trauma and With Neuropsychological Impairments
Authors: Zhuang Xiaowei , Mishra Virendra , Nandy Rajesh , Yang Zhengshi , Sreenivasan Karthik , Bennett Lauren , Bernick Charles , Cordes Dietmar
Published: December 2020

Previous neuroimaging studies have identified structural brain abnormalities in active professional fighters with repetitive head trauma and correlated these changes with fighters' neuropsychological impairments. However, functional brain changes in these fighters derived using neuroimaging techniques remain unclear. In this study, both static and dynamic functional connectivity alterations were investigated (1) between healthy normal control subjects (NC) and fighters and (2) between non-impaired and impaired fighters. Resting-state fMRI data were collected on 35 NC and 133 active professional fighters, including 68 impaired fighters and 65 non-impaired fighters, from the Professional Fighters Brain Health Study at our center. Impaired fighters performed worse on processing speed (PSS) tasks with visual-attention and working-memory demands. The static functional connectivity (sFC) matrix was estimated for every pair of regions of interest (ROI) using a subject-specific parcellation. The dynamic functional connectivity (dFC) was estimated using a sliding-window method, where the variability of each ROI pair across all windows represented the temporal dynamics. A linear regression model was fitted for all 168 subjects, and different t-contrast vectors were used for between-group comparisons. An association analysis was further conducted to evaluate FC changes associated with PSS task performances without creating artificial impairment group-divisions in fighters. Following corrections for multiple comparisons using network-based statistics, our study identified significantly reduced long-range frontal-temporal, frontal-occipital, temporal-occipital, and parietal-occipital sFC strengths in fighters than in NCs, corroborating with previously observed structural damages in corresponding white matter tracts in subjects experiencing repetitive head trauma. In impaired fighters, significantly decreased sFC strengths were found among key regions involved in visual-attention, executive and cognitive process, as compared to non-impaired fighters. Association analysis further reveals similar sFC deficits to worse PSS task performances in all 133 fighters. With our choice of dFC indices, we were not able to observe any significant dFC changes beyond a trend-level increased temporal variability among similar regions with weaker sFC strengths in impaired fighters. Collectively, our functional brain findings supplement previously reported structural brain abnormalities in fighters and are important to comprehensively understand brain changes in fighters with repetitive head trauma.
Adaptive Memory: Independent Effects of Survival Processing and Reward Motivation on Memory
Authors: Forester Glen , Kroneisen Meike , Erdfelder Edgar , Kamp Siri-Maria
Published: December 2020

Humans preferentially remember information processed for their survival relevance, a memorial benefit known as the survival processing effect. Memory is also biased towards information associated with the prospect of reward. Given the adaptiveness of these effects, they may depend on similar mechanisms. We tested whether motivation drives both effects, with reward incentives that are known to boost extrinsic motivation and survival processing perhaps stimulating intrinsic motivation. Accordingly, we manipulated survival processing and reward incentive independently during an incidental-encoding task in which participants chose between pairs of words concerning their relevance for a scenario, and examined the effects on encoding event-related potentials (ERP) activity and later performance on a surprise recall test. We hypothesized that if survival processing fosters intrinsic motivation, it should reduce the beneficial effects of extrinsic motivation (reward incentive). In contrast to this prediction, we found that reward incentive and survival processing independently improved memory and that the P300, a measure of lower-level cognitive resource allocation, was increased by reward incentive independent of survival processing. Further, survival processing and reward incentive independently increased the frontal slow wave (FSW), a measure of higher-level elaboration. These findings suggest that while survival processing and reward incentive may both increase encoding elaboration, the memory-enhancing effect of survival processing does not depend on increased intrinsic motivation. Additionally, we replicated a recent finding whereby the survival processing effect generalizes to a choice-based encoding task and further showed that the beneficial effect of choice on memory likely does not interact with either survival processing or reward.
Prognostic Role of the Activated p-AKT Molecule in Various Hematologic Malignancies and Solid Tumors: A Meta-Analysis
Authors: Yao Zhen , Gao Guangyu , Yang Jiawen , Long Yuming , Wang Zhenzhen , Hu Wentao , Liu Yulong
Published: December 2020

Cancer is one of the main causes of human death worldwide. Recently, many studies have firmly established the causal relationship between oxidative stress and cancer initiation and progression. As a key protein in PI3K/Akt signaling pathway, p-AKT (phosphorylated Akt) participates in the process of oxidative stress and plays a prognostic role in various hematologic tumors and solid tumors. We conducted a comprehensive search of the PubMed, Embase and Cochrane libraries to identify studies published in the past decade involving cancer patients expressing p-AKT that reported overall survival (OS) during follow-up. In this study, 6,128 patients in total were evaluated from 29 enrolled articles, and we concluded that overexpression of p-AKT was closely related to worse OS in cancer patients with a hazard ratio (HR) of 2.33 (95% CI: 1.67–4.00). Furthermore, we conducted a subgroup analysis, and the results indicated that overexpression of p-AKT was associated with worse OS in hematological tumor (HR: 1.64, 95% CI: 1.41–1.92), and solid tumor (HR: 2.44, 95% CI: 1.61–5.26). High expression of p-AKT is related to poor prognosis of various hematologic tumors and solid tumors.
Cadherins, Selectins, and Integrins in CAM-DR in Leukemia
Authors: Kim Hye Na , Ruan Yongsheng , Ogana Heather , Kim Yong-Mi
Published: December 2020

The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. This phenomenon, called cell adhesion-mediated drug resistance (CAM-DR), has been demonstrated in many subsets of leukemia including B- and T-acute lymphoblastic leukemia (B- and T-ALL) and acute myeloid leukemia (AML). Cell adhesion molecules (CAMs) are surface molecules that allow cell–cell or cell–extracellular matrix (ECM) adhesion. CAMs not only recognize ligands for binding but also initiate the intracellular signaling pathways that are associated with cell proliferation, survival, and drug resistance upon binding to their ligands. Cadherins, selectins, and integrins are well-known cell adhesion molecules that allow binding to neighboring cells, ECM proteins, and soluble factors. The expression of cadherin, selectin, and integrin correlates with the increased drug resistance of leukemia cells. This paper will review the role of cadherins, selectins, and integrins in CAM-DR and the results of clinical trials targeting these molecules.
A Nomogram Based on Serum Biomarkers and Clinical Characteristics to Predict Survival in Patients With Non-Metastatic Nasopharyngeal Carcinoma
Authors: Li Qing-Jie , Mao Yan-Ping , Guo Rui , Huang Cheng-Long , Fang Xue-Liang , Ma Jun , Tang Ling-Long , Chen Lei
Published: December 2020

Objective

This study focused on developing an effective nomogram for improving prognostication for patients with primary nasopharyngeal carcinoma (NPC) restaged according to the eighth edition of the AJCC/UICC TNM staging system.

Methods

Based on data of 5,903 patients with non-metastatic NPC (primary cohort), we used Cox regression analysis to identify survival risk factors and created a nomogram. We used the nomogram to predict overall survival (OS), distant metastasis-free survival (DMFS) and disease-free survival (DFS) in the primary and independent validation (3,437 patients) cohorts. Moreover, we compared the prognostic accuracy between the 8th TNM system and the nomogram.

Results

The nomogram included gender, age, T stage, N stage, Epstein–Barr virus DNA, hemoglobin, C-reactive protein, lactate dehydrogenase, and radiotherapy with/without induction or concurrent chemotherapy. In the prediction of OS, DMFS and DFS, the nomogram had significantly higher concordance index (C-index) and area under ROC curve (AUC) than the TNM system alone. Calibration curves demonstrated satisfactory agreements between nomogram-predicted and observed survival. The stratification in different groups permitted remarkable differentiation among Kaplan–Meier curves for OS, DMFS, and DFS.

Conclusion

The nomogram led to a more precise prognostic prediction for NPC patients in comparison with the 8th TNM system. Therefore, it could facilitate individualized and personalized patients’ counseling and care.
Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review
Authors: Guo Yijia , Song Jun , Wang Yanru , Huang Letian , Sun Li , Zhao Jianzhu , Zhang Shuling , Jing Wei , Ma Jietao , Han Chengbo
Published: December 2020

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.
Peripheral Blood Lymphocyte Analysis in Oligo- and Polyarticular Juvenile Idiopathic Arthritis Patients Receiving Methotrexate or Adalimumab Therapy: A Cross-Sectional Study
Authors: Nagy Arnold , Mosdosi Bernadett , Simon Diana , Dergez Timea , Berki Timea
Published: December 2020

Juvenile idiopathic arthritis (JIA) is an umbrella term for seven distinct chronic immune-mediated diseases. Disease-modifying anti-rheumatic drugs (DMARD) are used to treat the underlying joint inflammation as well as extra-articular manifestations. Immunosuppression is a considerable side effect of the drugs. The main goal of this study was to investigate the effect of different JIA therapies on leukocyte subpopulations, which play a role in immune-defense. Three study groups were established. The first group consisted of JIA patients treated with methotrexate solely, the second one received a combination of methotrexate (MTX) and adalimumab (ADA). The control group was made up of the patients' healthy siblings. A total of 63 children were recruited. Fourty-one children with JIA and 22 healthy controls were included in the study. The absolute number of CD3+ T-cells was significantly elevated in patients treated with biological therapy compared to healthy controls (p2 = 0.017). In contrast, the number of CD56+ natural killer cells was significantly lower in children receiving biological therapy in comparison with healthy donors (p2 = 0.039). A significant alteration was also demonstrated between patients treated with MTX and MTX/ADA group concerning CD 19+ B-cells (p3 = 0.042). This is the first study that demonstrates significant alterations in the number of B-cells and T-cells with a relative decrease of NK-cell ratios in JIA patients receiving different DMARD therapy.

Clinical Trial Registration:NCT03833271. 21.01.2019.
Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes
Authors: Timmermann Viviane , McCulloch Andrew D.
Published: December 2020

A wide range of arrhythmogenic phenotypes have been associated with heterogeneous mechanical dyskinesis. Pro-arrhythmic effects are often associated with dysregulated intra-cellular calcium handling, especially via the development of intra- and inter-cellular calcium waves. Experimental evidence suggests that mechanical strain can contribute to the generation and maintenance of these calcium waves via a variety of mechano-electric coupling mechanisms. Most model studies of mechano-electric coupling mechanisms have been focused on mechano-sensitive ion channels, even though experimental studies have shown that intra- and inter-cellular calcium waves triggered by mechanical perturbations are likely to be more prevalent pro-arrhythmic mechanisms in the diseased heart. A one-dimensional strongly coupled computational model of electromechanics in rabbit ventricular cardiomyocytes showed that specific myocyte stretch sequences can modulate the susceptibility threshold for delayed after-depolarizations. In simulations of mechanically-triggered calcium waves in cardiomyocytes coupled to fibroblasts, susceptibility to calcium wave propagation was reduced as the current through the gap junction caused current drain from the myocytes. In 1D multi-cellular arrays coupled via gap junctions, mechanically-induced waves may contribute to synchronizing arrhythmogenic calcium waves and after-depolarizations.
Comparison of Left Ventricular Global Strain in Anterior and Non-anterior Wall Myocardial Infarction With CMR Tissue Tracking
Authors: Li Shuhao , Zhao Lei , Lu Aijia , Tian Jie , Gong Lianggeng , Ma Xiaohai
Published: December 2020

Left ventricular (LV) myocardial dysfunction occurs after myocardial infarction (MI) is associated with the location, infarct size, and transmurality degrees of MI. The myocardial strain is a sensitive index used for the quantification of myocardium dysfunction. This study used Tissue-Tracking to evaluate whether the different location of MI would result in different myocardial dysfunction. One hundred patients diagnosed with MI who underwent cardiovascular magnetic resonance examination were included. The tissue-tracking indices, LV global radial strain (GRS), global circumferential strain (GCS), global longitudinal strain (GLS), and the infarct size (IS,% of LV mass) were quantified. There were 42 cases of anterior wall MI (AWMI) and 58 cases of non-anterior wall MI (NAWMI). The GCS of AWMI was significantly lower than that of NAWMI (P = 0.036). In the same level of infarct size, the myocardial strain of AWMI was not significantly different from NAWMI group (P > 0.05). The GRS and GCS were significantly different between transmurality > 50% group with transmurality ≤ 50% group (P < 0.05). The present study demonstrated that LV MI is associated with reduced myocardial strain, and the infarct size and degrees of transmurality were both related to the decline of myocardial strain in patients with MI.
Modeling of the Transport and Exchange of a Gas Species in Lungs With an Asymmetric Branching Pattern. Application to Nitric Oxide
Authors: Buess Alexandra , Van Muylem Alain , Nonclercq Antoine , Haut Benoit
Published: December 2020

Over the years, various studies have been dedicated to the mathematical modeling of gas transport and exchange in the lungs. Indeed, the access to the distal region of the lungs with direct measurements is limited and, therefore, models are valuable tools to interpret clinical data and to give more insights into the phenomena taking place in the deepest part of the lungs. In this work, a new computational model of the transport and exchange of a gas species in the human lungs is proposed. It includes (i) a method to generate a lung geometry characterized by an asymmetric branching pattern, based on the values of several parameters that have to be given by the model user, and a method to possibly alter this geometry to mimic lung diseases, (ii) the calculation of the gas flow distribution in this geometry during inspiration or expiration (taking into account the increased resistance to the flow in airways where the flow is non-established), (iii) the evaluation of the exchange fluxes of the gaseous species of interest between the tissues composing the lungs and the lumen, and (iv) the computation of the concentration profile of the exchanged species in the lumen of the tracheobronchial tree. Even if the model is developed in a general framework, a particular attention is given to nitric oxide, as it is not only a gas species of clinical interest, but also a gas species that is both produced in the walls of the airways and consumed within the alveolar region of the lungs. First, the model is presented. Then, several features of the model, applied to lung geometry, gas flow and NO exchange and transport, are discussed, compared to existing works and notably used to give new insights into experimental data available in the literature, regarding diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease.
Novel Aspects of Nitrate Regulation in Arabidopsis
Authors: Fan Hongmei , Quan Shuxuan , Qi Shengdong , Xu Na , Wang Yong
Published: December 2020

Nitrogen (N) is one of the most essential macronutrients for plant growth and development. Nitrate (NO3–), the major form of N that plants uptake from the soil, acts as an important signaling molecule in addition to its nutritional function. Over the past decade, significant progress has been made in identifying new components involved in NO3– regulation and starting to unravel the NO3– regulatory network. Great reviews have been made recently by scientists on the key regulators in NO3– signaling, NO3– effects on plant development, and its crosstalk with phosphorus (P), potassium (K), hormones, and calcium signaling. However, several novel aspects of NO3– regulation have not been previously reviewed in detail. Here, we mainly focused on the recent advances of post-transcriptional regulation and non-coding RNA (ncRNAs) in NO3– signaling, and NO3– regulation on leaf senescence and the circadian clock. It will help us to extend the general picture of NO3– regulation and provide a basis for further exploration of NO3– regulatory network.
Identification of Rf9, a Gene Contributing to the Genetic Complexity of Fertility Restoration in Hybrid Wheat
Authors: Shahinnia Fahimeh , Geyer Manuel , Block Annette , Mohler Volker , Hartl Lorenz
Published: December 2020

Wheat (Triticum aestivum L.) is a self-pollinating crop whose hybrids offer the potential to provide a major boost in yield. Male sterility induced by the cytoplasm of Triticum timopheevii is a powerful method for hybrid seed production. Hybrids produced by this method are often partially sterile, and full fertility restoration is crucial for wheat production using hybrid cultivars. To identify the genetic loci controlling fertility restoration in wheat, we produced two cytoplasmic male-sterile (CMS) backcross (BC1) mapping populations. The restorer lines Gerek 79 and 71R1203 were used to pollinate the male-sterile winter wheat line CMS-Sperber. Seed set and numbers of sterile spikelets per spike were evaluated in 340 and 206 individuals of the populations derived from Gerek 79 and 71R1203, respectively. Genetic maps were constructed using 930 and 994 single nucleotide polymorphism (SNP) markers, spanning 2,160 and 2,328 cM over 21 linkage groups in the two populations, respectively. Twelve quantitative trait loci (QTL) controlled fertility restoration in both BC1 populations, including a novel restorer-of-fertility (Rf) locus flanked by the SNP markers IWB72413 and IWB1550 on chromosome 6AS. The locus was mapped as a qualitative trait in the BC1 Gerek 79 population and was designated Rf9. One hundred-nineteen putative candidate genes were predicted within the QTL region on chromosome 6AS. Among them were genes encoding mitochondrial transcription termination factor and pentatricopeptide repeat-containing proteins that are known to be associated with fertility restoration. This finding is a promising step to better understand the functions of genes for improving fertility restoration in hybrid wheat.
Root Silicon Addition Induces Fe Deficiency in Cucumber Plants, but Facilitates Their Recovery After Fe Resupply. A Comparison With Si Foliar Sprays
Authors: Hernández-Apaolaza Lourdes , Escribano Laura , Zamarreño Ángel Mª , García-Mina José Mª , Cano Carlos , Carrasco-Gil Sandra
Published: December 2020

Silicon has not been cataloged as an essential element for higher plants. However, it has shown beneficial effects on many crops, especially under abiotic and biotic stresses. Silicon fertilization was evaluated for the first time on plants exposed to fluctuations in an Fe regime (Fe sufficiency followed by Fe deficiency and, in turn, by Fe resupply). Root and foliar Si applications were compared using cucumber plants that were hydroponically grown in a growth chamber under different Fe nutritional statuses and Si applied either to the roots or to the shoots. The SPAD index, Fe, and Mn concentration, ROS, total phenolic compounds, MDA concentration, phytohormone balance, and cell cycle were determined. The results obtained showed that the addition of Si to the roots induced an Fe shortage in plants grown under optimal or deficient Fe nutritional conditions, but this was not observed when Si was applied to the leaves. Plant recovery following Fe resupply was more effective in the Si-treated plants than in the untreated plants. A relationship between the ROS concentration, hormonal balance, and cell cycle under different Fe regimes and in the presence or absence of Si was also studied. The contribution of Si to this signaling pathway appears to be related more to the induction of Fe deficiency, than to any direct biochemical or metabolic processes. However, these roles could not be completely ruled out because several hormone differences could only be explained by the addition of Si.
Proper Glyphosate Application at Post-anthesis Lowers Grain Moisture Content at Harvest and Reallocates Non-structural Carbohydrates in Maize
Authors: Zhao Linmao , Xie Liuyong , Huang Jingli , Su Yingchun , Zhang Chunqing
Published: December 2020

Glyphosate (GP)-based herbicides have been widely applied to crops for weed control and pre-harvest desiccation. The objective of this research was to evaluate the effects of pre-harvest GP application on maize or how it physiologically alters this crop. Here, we applied four GP treatment (Control, GP150, GP200, and GP250) on maize lines of Z58 and PH6WC belonging to different maturity groups at grain-filling stages form DAP30 to DAP45. GP application significantly decreased the grain moisture content at harvest by 22–35% for Z58 and by 15–41% for PH6WC. However, the responses of grain weight to glyphosate vary with inbred lines and application time. A high concentration of glyphosate (GP250) reduced the grain weight of Z58 and low concentrations (GP150 and GP200) did not affect, while the grain weight of PH6WC significantly decreased under glyphosate treatment. In summary, our results revealed that timely and appropriate GP application lowers grain moisture content without causing seed yield and quality loss. GP application adversely affected photosynthesis by promoting maturation and leaf senescence. Meanwhile, it also enhanced non-structural carbohydrate (soluble sugars and starch) remobilization from the vegetative organs to the grains. Hence, GP treatment coordinates plant senescence and assimilate remobilization. RNA sequencing revealed that glyphosate regulated the transcript levels of sugar signaling-related genes and induced assimilate repartitioning in grains. This work indicates the practical significance of GP application for maize seed production and harvest, which highlights the contributions of source-sink communication to maize yield in response to external stress or pre-harvest desiccant application.
Lectin Receptor-Like Kinases: The Sensor and Mediator at the Plant Cell Surface
Authors: Sun Yali , Qiao Zhenzhen , Muchero Wellington , Chen Jin-Gui
Published: December 2020

Lectin receptor-like kinases (LecRLKs), a plant-specific receptor-like kinase (RLK) sub-family, have been recently found to play crucial roles in plant development and responses to abiotic and biotic stresses. In this review, we first describe the classification and structures of Lectin RLKs. Then we focus on the analysis of functions of LecRLKs in various biological processes and discuss the status of LecRLKs from the ligands they recognize, substrate they target, signaling pathways they are involved in, to the overall regulation of growth-defense tradeoffs. LecRLKs and the signaling components they interact with constitute recognition and protection systems at the plant cell surface contributing to the detection of environmental changes monitoring plant fitness.
Neural Correlates of Mental Rotation in Preschoolers With High or Low Working Memory Capacity: An fNIRS Study
Authors: Yang Jinfeng , Wu Dandan , Luo Jiutong , Xie Sha , Chang Chunqi , Li Hui
Published: December 2020

This study explored the differentiated neural correlates of mental rotation (MR) in preschoolers with high and low working memory capacity using functional near-infrared spectroscopy (fNIRS). Altogether 38 Chinese preschoolers (M = 5.0 years, SD = 0.69 years) completed the Working Memory Capacity (WMC) test, the Mental Rotation (MR), and its Control tasks (without MR). They were divided into High-WMC (N1 = 9) and Low-WMC (N2 = 18) groups based on the WMC scores. The behavioral and fNIRS results indicated that: (1) there were no significant differences in MR task performance between the High-WMC (Mmr = 23.44, SD = 0.88) and Low-WMC group (Mmr = 23.67, SD = 0.59); (2) the Low-WMC group activated BA6, BA8, BA 9, and BA 44, whereas the High-WMC group activated BA8, BA10 and BA 44 during mental rotation; (3) significant differences were found in the activation of BA44 and BA9 between the High-WMC and Low-WMC groups during mental rotation; and (4) the High-WMC and Low-WMC groups differed significantly in the activation of BA 9 and BA10 during the control tasks, indicating that both areas might be responsible for the group differences in working memory.
Can Psychodynamically Oriented Early Prevention for “Children-at-Risk” in Urban Areas With High Social Problem Density Strengthen Their Developmental Potential? A Cluster Randomized Trial of Two Kindergarten-Based Prevention Programs
Authors: Fischmann Tamara , Asseburg Lorena K. , Green Jonathan , Hug Felicitas , Neubert Verena , Wan Ming , Leuzinger-Bohleber Marianne
Published: December 2020

Children who live on the margins of society are disadvantaged in achieving their developmental potential because of the lack of a necessary stable environment and nurturing care. Many early prevention programs aim at mitigating such effects, but often the evaluation of their long-term effect is missing. The aim of the study presented here was to evaluate such long-term effects in two prevention programs for children-at-risk growing up in deprived social environments focusing on child attachment representation as the primary outcome as well as on self-reflective capacities of teachers taking care of these children. The latter was a key component for promoting resilient behavior in children. Five hundred and twenty-six children aged 36 to 60 months at risk due to immigration status, low family socio-economic status and child behavior were examined in a cluster-randomized study comparing two preventions, the psychodynamic, attachment-based holistic approach EARLY STEPS (ES) with the classroom based FAUSTLOS (FA) for their efficacy. Primary outcome was the child attachment representation measured by the Manchester Child Attachment Story Task (MCAST). Secondary outcomes were derived from (a) the Caregiver-Teacher Report Form (C-TRF: problem behaviors, including anxiety/depressive symptoms, emotional-reactive and somatic problems, social withdrawal, aggressive behavior, and attention deficit), from (b) the Strength and Difficulties Questionnaire (SDQ, parent version: resilience and wellbeing) and (c) Self-Reflective Scales for teachers (SRS: self-reflective capacities of teachers). Compared to baseline, attachment and behavioral problems improved in both programs. ES led to more secure and more organized attachment representations (medium effect sizes). Aggressive behavior and externalizing problems were reduced in the FA group compared with ES, particularly in boys (medium effect sizes). Self-reflective capacities of the teachers increased only in the ES group. High correlation between children’s attachment type with the number of social risk factors and the increase of problematic social behavior strongly indicate that an increase in teachers’ self-reflective capacities helps to change children’s attachment patterns which thus strengthens the resilience of these children-at-risk [An ethical vote from LPPKJP 2009-02-25 was obtained and the trial registered; Clinical trial registration information: The trial was registered 14.02.2012 (DRKS00003500;https://www.drks.de)].
Negative Problems Orientation Questionnaire for Chinese Adolescents: Bifactor Model and Measurement Invariance
Authors: Xiao Huiwen , Lin Rongmao , Wu Qiaoling , Shen Saili , Yan Youwei
Published: December 2020

The Negative Problem Orientation Questionnaire (NPOQ) is a widely used tool for assessing negative problem orientation (NPO). However, its construct and measurement invariance has not been adequately tested in adolescents. The present study explored the possible construct of the NPOQ and its measurement invariance in a sample of 754 Chinese adolescents (51.6% girls, all 12–18 years old). The results supported a bifactor model of the NPOQ that consists of a general factor NPO and three domain-specific factors including perceived threat, self-inefficacy, and negative outcome expectancy. A multiple-group CFA indicated that the bifactor model showed strict invariance across gender and age. The general and domain factors showed unique variance in indexes of worry, depression, anxiety, and stress, which supported well incremental validity of them. This study confirms for a bifactor conceptualization of the NPOQ and its measurement invariance across gender and age in Chinese adolescents. Additionally, it is recommended that the total score should be used to assess NPO in Chinese adolescents.