bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship Between Social Motivation in Children With Autism Spectrum Disorder and Their Parents
Authors: Uljarević Mirko , Frazier Thomas W. , Jo Booil , Phillips Jennifer M. , Billingham Wesley , Cooper Matthew N. , Hardan Antonio Y.
Published: May 2021

Impairment in social motivation (SM) has been suggested as a key mechanism underlying social communication deficits observed in autism spectrum disorder (ASD). However, the factors accounting for variability in SM remain poorly described and understood. The current study aimed to characterize the relationship between parental and proband SM. Data from 2,759 children with ASD (Mage= 9.03 years, SDage= 3.57, 375 females) and their parents from the Simons Simplex Collection (SSC) project was included in this study. Parental and proband SM was assessed using previously identified item sets from the Social Responsiveness Scale (SRS). Children who had parents with low SM scores (less impairments) showed significantly lower impairments in SM compared to children who had either one or both parents with elevated SM scores. No parent-of-origin effect was identified. No significant interactions were found involving proband sex or intellectual disability (ID) status (presence/absence of ID) with paternal or maternal SM. This study establishes that low SM in children with ASD may be driven, in part, by lower SM in one or both parents. Future investigations should utilize larger family pedigrees, including simplex and multiplex families, evaluate other measures of SM, and include other related, yet distinct constructs, such as social inhibition and anhedonia. This will help to gain finer-grained insights into the factors and mechanisms accounting for individual differences in sociability among typically developing children as well as those with, or at risk, for developing ASD.
NPY Released From GABA Neurons of the Dentate Gyrus Specially Reduces Contextual Fear Without Affecting Cued or Trace Fear
Authors: Comeras Lucas B. , Hörmer Noa , Mohan Bethuraj Pradeepa , Tasan Ramon O.
Published: May 2021

Disproportionate, maladapted, and generalized fear are essential hallmarks of posttraumatic stress disorder (PTSD), which develops upon severe trauma in a subset of exposed individuals. Among the brain areas that are processing fear memories, the hippocampal formation exerts a central role linking emotional-affective with cognitive aspects. In the hippocampus, neuronal excitability is constrained by multiple GABAergic interneurons with highly specialized functions and an extensive repertoire of co-released neuromodulators. Neuropeptide Y (NPY) is one of these co-transmitters that significantly affects hippocampal signaling, with ample evidence supporting its fundamental role in emotional, cognitive, and metabolic circuitries. Here we investigated the role of NPY in relation to GABA, both released from the same interneurons of the dorsal dentate gyrus (DG), in different aspects of fear conditioning. We demonstrated that activation of dentate GABA neurons specifically during fear recall reduced cue-related as well as trace-related freezing behavior, whereas inhibition of the same neurons had no significant effects. Interestingly, concomitant overexpression of NPY in these neurons did not further modify fear recall, neither under baseline conditions nor upon chemogenetic stimulation. However, potentially increased co-release of NPY substantially reduced contextual fear, promoted extinction learning, and long-term suppression of fear in a foreground context–conditioning paradigm. Importantly, NPY in the dorsal DG was not only expressed in somatostatin neurons, but also in parvalbumin-positive basket cells and axoaxonic cells, indicating intense feedback and feedforward modulation of hippocampal signaling and precise curtailing of neuronal engrams. Thus, these findings suggest that co-release of NPY from specific interneuron populations of the dorsal DG modifies dedicated aspects of hippocampal processing by sharpening the activation of neural engrams and the consecutive fear response. Since inappropriate and generalized fear is the major impediment in the treatment of PTSD patients, the dentate NPY system may be a suitable access point to ameliorate PTSD symptoms and improve the inherent disease course.
Combination of Metformin, Sodium Oxamate and Doxorubicin Induces Apoptosis and Autophagy in Colorectal Cancer Cells via Downregulation HIF-1α
Authors: Coronel-Hernández Jossimar , Salgado-García Rebeca , Cantú-De León David , Jacobo-Herrera Nadia , Millan-Catalan Oliver , Delgado-Waldo Izamary , Campos-Parra Alma D. , Rodríguez-Morales Miguel , Delgado-Buenrostro Norma L. , Pérez-Plasencia Carlos
Published: May 2021

Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide in both sexes. Current therapies include surgery, chemotherapy, and targeted therapy; however, prolonged exposure to chemical agents induces toxicity in patients and drug resistance. So, we implemented a therapeutic strategy based on the combination of doxorubicin, metformin, and sodium oxamate called triple therapy (Tt). We found that Tt significantly reduced proliferation by inhibiting the mTOR/AKT pathway and promoted apoptosis and autophagy in CRC derived cells compared with doxorubicin. Several autophagy genes were assessed by western blot; ULK1, ATG4, and LC3 II were overexpressed by Tt. Interestingly, ULK1 was the only one autophagy-related protein gradually overexpressed during Tt administration. Thus, we assumed that there was a post-transcriptional mechanism mediating by microRNAs that regulate UKL1 expression during autophagy activation. Through bioinformatics approaches, we ascertained that ULK1 could be targeted by mir-26a, which is overexpressed in advanced stages of CRC. In vitro experiments revealed that overexpression of mir-26a decreased significantly ULK1, mRNA, and protein expression. Contrariwise, the Tt recovered ULK1 expression by mir-26a decrease. Due to triple therapy repressed mir-26a expression, we hypothesized this drug combination could be involved in mir-26a transcription regulation. Consequently, we analyzed the mir-26a promoter sequence and found two HIF-1α transcription factor recognition sites. We developed two different HIF-1α stabilization models. Both showed mir-26a overexpression and ULK1 reduction in hypoxic conditions. Immunoprecipitation experiments were performed and HIF-1α enrichment was observed in mir-26a promoter. Surprisingly, Tt diminished HIF-1α detection and restored ULK1 mRNA expression. These results reveal an important regulation mechanism controlled by the signaling that activates HIF-1α and that in turn regulates mir-26a transcription.
Prognostic Significance of Systemic Immune-Inflammation Index in Patients With Diffuse Large B-Cell Lymphoma
Authors: Wang Zanzan , Zhang Jiawei , Luo Shuna , Zhao Xiaoying
Published: May 2021

Objective

The systemic immune-inflammation index (SII) based on neutrophil, platelet and lymphocyte counts, is a prognostic biomarker in some solid cancers. However, the prognostic value of SII has not yet been validated. This study was to evaluate the role of SII in predicting survival for patients with diffuse large B cell lymphoma (DLBCL).

Methods

We retrospectively investigated 224 patients with DLBCL between August 2005 and October 2018. Kaplan–Meier analysis and Cox proportional hazard models were used to assess the prognostic value of SII.

Results

In the ROC curve analysis, SII had the highest AUC and was more accurate as a prognostic factor. Patients with higher SII tended to have higher level of LDH, more advanced stage, poor PS, and high IPI score compared with low SII group. In univariate analyses, SII, PLR and NLR were all prognostic for progression-free survival and overall survival. Moreover, only SII, older age, HBSAg-positive and IPI were the independent prognostic factors for patients in multivariate analysis. The nomogram based on SII, older age, HBSAg status and IPI showed accurate prognostic ability for predicting 3-years and 5-years survival rates (c-index, 0.791) compared to the IPI alone (c-index, 0.716).

Conclusion

SII was a powerful tool for predicting outcome in patients with DLBCL. It might assist the separation of high-risk patients among patients with the same IPI.
Preoperative Prediction of Meningioma Consistency via Machine Learning-Based Radiomics
Authors: Zhai Yixuan , Song Dixiang , Yang Fengdong , Wang Yiming , Jia Xin , Wei Shuxin , Mao Wenbin , Xue Yake , Wei Xinting
Published: May 2021

Objectives

The aim of this study was to establish and validate a radiomics nomogram for predicting meningiomas consistency, which could facilitate individualized operation schemes-making.

Methods

A total of 172 patients was enrolled in the study (train cohort: 120 cases, test cohort: 52 cases). Tumor consistency was classified as soft or firm according to Zada’s consistency grading system. Radiomics features were extracted from multiparametric MRI. Variance selection and LASSO regression were used for feature selection. Then, radiomics models were constructed by five classifiers, and the area under curve (AUC) was used to evaluate the performance of each classifiers. A radiomics nomogram was developed using the best classifier. The performance of this nomogram was assessed by AUC, calibration and discrimination.

Results

A total of 3840 radiomics features were extracted from each patient, of which 3719 radiomics features were stable features. 28 features were selected to construct the radiomics nomogram. Logistic regression classifier had the highest prediction efficacy. Radiomics nomogram was constructed using logistic regression in the train cohort. The nomogram showed a good sensitivity and specificity with AUCs of 0.861 and 0.960 in train and test cohorts, respectively. Moreover, the calibration graph of the nomogram showed a favorable calibration in both train and test cohorts.

Conclusions

The presented radiomics nomogram, as a non-invasive prediction tool, could predict meningiomas consistency preoperatively with favorable accuracy, and facilitated the determination of individualized operation schemes.
Bioinformatics, Molecular Docking and Experiments In Vitro Analyze the Prognostic Value of CXC Chemokines in Breast Cancer
Authors: Wang Fei , Yuan Chong , Wu He-Zhen , Liu Bo , Yang Yan-Fang
Published: May 2021

The increasing incidence and mortality rate of Breast cancer (BC) make it a major public health problem around the world. CXC chemokines can mediate the migration of immune cells and regulate apoptosis in tumor. However, the expression and prognostic value of them in BC and their targeted drugs have not been clarified. Therefore, in this study, ONCOMINE, GEPIA2.0, UALCAN, Venny2.1.0, cBioPortal, STRING, Gene MANIA, Pathway Commons, DAVID6.8, Omicshare, Cytoscape3.6.1, TIMER2.0, Drug Bank, TCMSP, RSCBPDB, PubChem, pkCSM, Chem Draw, AutoDockTools-1.5.6 and PyMOL were utilized for analysis. The expression of CXCL1-3, CXCL9-13 between BC and normal tissues was significantly different in all the three databases. And the expression of CXCL1-2, CXCL12-13 was correlated with the stages of BC. But only CXCL1-3 were prone to mutation, and negatively correlated with survival and prognosis of BC patients. Taken together, CXCL1-2 might be therapeutic targets and biomarkers for BC patients. In addition, both of them were associated with immune infiltration. The results of molecular docking showed that Quercetin was most likely to be developed as drugs that interacted directly with CXCL1-2. And GLU29 of CXCL1, ASP-1, PRO-96, TRP-47 and LEU-45 of CXCL2 were the most potential sites, which provided valuable reference for further study of pharmacodynamics and mechanism. In addition, the inhibitory effect of Quercetin on proliferation and promoting apoptosis of BC related cell lines were confirmed in vitro. Western blot and Real-Time PCR confirmed that it increased the expression of CXCL1-2 in MDA-MB-231 and MCF-7 cells.
Rationale and Clinical Implications of Fluorescein-Guided Supramarginal Resection in Newly Diagnosed High-Grade Glioma
Authors: Wang Linda M. , Banu Matei A. , Canoll Peter , Bruce Jeffrey N.
Published: May 2021

Current standard of care for glioblastoma is surgical resection followed by temozolomide chemotherapy and radiation. Recent studies have demonstrated that >95% extent of resection is associated with better outcomes, including prolonged progression-free and overall survival. The diffusely infiltrative pattern of growth in gliomas results in microscopic extension of tumor cells into surrounding brain parenchyma that makes complete resection unattainable. The historical goal of surgical management has therefore been maximal safe resection, traditionally guided by MRI and defined as removal of all contrast-enhancing tumor. Optimization of surgical resection has led to the concept of supramarginal resection, or removal beyond the contrast-enhancing region on MRI. This strategy of extending the cytoreductive goal targets a tumor region thought to be important in the recurrence or progression of disease as well as resistance to systemic and local treatment. This approach must be balanced against the risk of impacting eloquent regions of brain and causing permanent neurologic deficit, an important factor affecting overall survival. Over the years, fluorescent agents such as fluorescein sodium have been explored as a means of more reliably delineating the boundary between tumor core, tumor-infiltrated brain, and surrounding cortex. Here we examine the rationale behind extending resection into the infiltrative tumor margins, review the current literature surrounding the use of fluorescein in supramarginal resection of gliomas, discuss the experience of our own institution in utilizing fluorescein to maximize glioma extent of resection, and assess the clinical implications of this treatment strategy.
Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells
Authors: Yao Mengfei , Wu Yaqian , Cao Yanan , Liu Haijing , Ma Ningning , Chai Yijie , Zhang Shuang , Zhang Hong , Nong Lin , Liang Li , Zhang Bo
Published: May 2021

The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.
Prognostic Value of Tumor-Stroma Ratio in Rectal Cancer: A Systematic Review and Meta-analysis
Authors: Zhu Yuzhou , Jin Zechuan , Qian Yuran , Shen Yu , Wang Ziqiang
Published: May 2021

Background

Tumor-stroma ratio (TSR) is a promising new prognostic predictor for patients with rectal cancer (RC). Although several studies focused on this pathologic feature, results from those studies were still inconsistent.

Methods

This research aimed to estimate the prognostic values of TSR for RC. A search of PubMed, EMBASE, and Web of Science was carried out. A meta-analysis was performed on disease-free survival, cancer-specific survival, and overall survival in patients with RC.

Results

The literature search generated 1,072 possible studies, of which a total of 15 studies, involving a total of 5,408 patients, were eventually included in the meta-analysis. Thirteen of the 15 articles set the cutoff for the ratio of stroma at 50%, dividing patients into low-stroma and high-stroma groups. Low TSR (rich-stroma) was significantly associated with poorer survival outcome. (DFS: HR 1.54, 95% CI 1.32–1.79; OS: HR 1.52 95% CI 1.34–1.73; CSS: HR 2.05 95% CI 1.52–2.77).

Conclusion

Present data support TSR to be a risk predictor for poor prognosis in RC patients.
Screening of Chorioamnionitis Using Volatile Organic Compound Detection in Exhaled Breath: A Pre-clinical Proof of Concept Study
Authors: Ophelders Daan R. M. G. , Boots Agnes W. , Hütten Matthias C. , Al-Nasiry Salwan , Jellema Reint K. , Spiller Owen B. , van Schooten Frederik-Jan , Smolinska Agnieszka , Wolfs Tim G. A. M.
Published: May 2021

Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamical changes of organ injury after the onset of chorioamnionitis revealed novel therapeutic windows of opportunity. Importantly, successful development and implementation of therapies in clinical care is currently impeded by a lack of diagnostic tools for early (prenatal) detection and surveillance of intra-amniotic infections. In the current study we questioned whether an intra-amniotic infection could be accurately diagnosed by a specific volatile organic compound (VOC) profile in exhaled breath of pregnant sheep. For this purpose pregnant Texel ewes were inoculated intra-amniotically with Ureaplasma parvum and serial collections of exhaled breath were performed for 6 days. Ureaplasma parvum infection induced a distinct VOC-signature in expired breath of pregnant sheep that was significantly different between day 0 and 1 vs. day 5 and 6. Based on a profile of only 15 discriminatory volatiles, animals could correctly be classified as either infected (day 5 and 6) or not (day 0 and 1) with a sensitivity of 83% and a specificity of 71% and an area under the curve of 0.93. Chemical identification of these distinct VOCs revealed the presence of a lipid peroxidation marker nonanal and various hydrocarbons including n-undecane and n-dodecane. These data indicate that intra-amniotic infections can be detected by VOC analyses of exhaled breath and might provide insight into temporal dynamics of intra-amniotic infection and its underlying pathways. In particular, several of these volatiles are associated with enhanced oxidative stress and undecane and dodecane have been reported as predictive biomarker of spontaneous preterm birth in humans. Applying VOC analysis for the early detection of intra-amniotic infections will lead to appropriate surveillance of these high-risk pregnancies, thereby facilitating appropriate clinical course of action including early treatment of preventative measures for pre-maturity-associated morbidities.
Identification of Immunosuppressive Medication Nonadherence Factors Through a Combined Theory Model in Renal Transplant Recipients
Authors: Zhang Pengpeng , Zhu Xiao , Yan Jin , Liu Jia
Published: May 2021

Background: Immunosuppressive medication (IM) nonadherence is associated with poor transplant outcomes. Therefore, it is of great importance to identify predictive factors with IM nonadherence. We aimed to improve the predicted capacity of the theory of planned behavior (TPB) by adding health belief model’s (HBM) variables in renal transplant patients (RTPs).

Methods: This cross-sectional study distributed questionnaires to patients who had undergone renal transplant and follow-up regularly in the transplant center of Third Xiangya Hospital in China. The self-developed questionnaire collected data in three aspects: general data questionnaire, TPB, HBM-specific questionnaire, and Basel Assessment of Adherence to Immunosuppressive Medications scale.

Results: A total of 1,357 of 1,480 patients completed the survey, with a participation rate of 91.69% and IM nonadherence rate of 33.53%. The marital status, household income, preoperative drinking history, the time after transplantation, and religion showed independent predictive factors with IM nonadherence (p < 0.05). Strikingly, adding HBM variables to the TPB theory model significantly increased its prediction ability to IM nonadherence (52%). Also, HBM manifested the highest coefficient of effect (−0.620). Particularly, perceived barriers and perceived seriousness, the variables of the HBM model, played a vital influence on medication nonadherence (−0.284 and 0.256).

Conclusion: Our study here reveals the first investigation of the combined effects of the TPB and HBM model on IM nonadherence in Chinese RTPs, which could significantly improve the predictive ability of any single model. Meanwhile, future interventions should be conducted to both increase perceived seriousness and reduce perceived barriers for taking IM, which will effectively decrease IM nonadherence rates and improve transplant outcomes.
Psychoactive Effects of Lactobacillus johnsonii Against Restraint Stress-Induced Memory Dysfunction in Mice Through Modulating Intestinal Inflammation and permeability—a Study Based on the Gut–Brain Axis Hypothesis
Authors: Wang Hesong , He Shunhui , Xin Jinge , Zhang Tao , Sun Ning , Li Lianxin , Ni Xueqin , Zeng Dong , Ma Hailin , Bai Yang
Published: May 2021

Though the underlying mechanism remains elusive, a close relationship between psychological stress and intestinal inflammation has been widely accepted. Such a link is very important to set the basis for our understanding of the critical role of gut-brain axis (GBA) in homeostatic processes in health and disease. Probiotics that could confer benefits to mental health through GBA are referred to as “psychobiotics”. This study aimed to further determine whether a potential psychobiotic strain, Lactobacillus johnsonii BS15 could prevent memory dysfunction in mice induced by psychological stress through modulating the gut environment, including intestinal inflammation and permeability. Memory dysfunction in mice was induced by restraint stress (RS), one of the most commonly utilized models to mimic psychological stress. The mice were randomly categorized into three groups including no stress (NS), restraint stress (RS), and probiotic (RS-P) and administered with either phosphate buffered saline (NS and RS groups) or L. johnsonii BS15 (RS-P group) every day from day 1–28. From days 22–28, the mice in RS and RS-P groups were subjected to RS each day. Results revealed that BS15-pretreatment enhanced the performance of RS-induced mice during three different behavioral tests for memory ability and positively modulated the hypothalamic–pituitary–adrenal axis by attenuating the serum corticosterone level. In the hippocampus, L. johnsonii BS15 positively modulated the memory-related functional proteins related to synaptic plasticity, increased neurotransmitter levels, and prevented RS-induced oxidative stress and mitochondria-mediated apoptosis. In the intestines, L. johnsonii BS15 protected the RS-induced mice from damaged gut barrier by enhancing the mRNA levels of tight junction proteins and exerted beneficial effects on the anti-inflammatory cytokine levels reduced by RS. These findings provided more evidence to reveal the psychoactive effect of L. johnsonii BS15 against memory dysfunction in RS-induced mice by modulating intestinal inflammation and permeability.
Paeonol Induces Protective Autophagy in Retinal Photoreceptor Cells
Authors: Zhang Daowei , Wu Jiawen , Wu Jihong , Zhang Shenghai
Published: May 2021

Background: Retinal photoreceptor (RP) cells are widely involved in retina-related diseases, and oxidative stress plays a critical role in retinal secondary damage. Herein, we investigated the effectiveness and potential mechanisms of autophagy of paeonol (Pae) in terms of oxidation resistance.

Methods: The animal model was induced by light damage (LD) in vivo, whereas the in vitro model was established by H2O2 stimulation. The effectiveness of Pae was evaluated by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunofluorescence, transmission electron microscopy, electroretinogram, and Western blot analysis in vivo, and the underlying mechanisms of Pae were assessed by Cell Counting Kit-8 assay, reactive oxygen species (ROS) assay, and Western blot analysis in 661W cells. We mainly evaluated the effects of Pae on apoptosis and autophagy.

Results: Increased apoptosis of the LD-induced and decreased autophagy of RPs were mitigated by Pae treatment. Pea, which increased the expression of mitochondrial functional protein cytochrome c, reversed the decreased cell viability and autophagy induced by oxidative stress in 661W cells. Experiments showed that autophagy was downregulated in PINK1/Parkin dependent and the BNIP3L/Nix dependent pathways under H2O2 stimulation and was upregulated by Pae treatment. Pae increased the cell viability and reduced ROS levels through autophagy.

Conclusion: Pretreatment with Pae preserved RP cells by enhancing autophagy, which protected retinal function.
Systemic Corticosteroid Administration in Coronavirus Disease 2019 Outcomes: An Umbrella Meta-Analysis Incorporating Both Mild and Pulmonary Fibrosis–Manifested Severe Disease
Authors: Cheng Bin , Ma Jinxiu , Yang Yani , Shao Tingting , Zhao Binghao , Zeng Linxiang
Published: May 2021

Background: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed. The real role of corticosteroid use in COVID-19 has long been of interest and is disputable.

Methods: We aimed to quantitatively reevaluate the efficacy of corticosteroids on COVID-19. Databases were searched for eligible meta-analyses/systematic reviews with available outcome data. For each association, we estimated the summary effect size with fixed- and random-effects models, 95% confidence intervals, and 95% prediction intervals. Heterogeneity, Egger’s test, evidence of small-study effects and excess significance bias, and subgroup analyses were rigorously evaluated.

Results: Intended outcomes of 12 eligible studies were mortality, clinical improvement, hospitalization, mechanical ventilation (MV), adverse events (AEs), intensive care unit (ICU) stay, hospital stay, virus clearance time (VCT), and negative conversion. Corticosteroid administration was associated with a 27% risk reduction in MV [hazard ratio (HR): 0.73 (0.64–0.83)] and a 20% reduction in mortality of critically ill/severe COVID-19 patients [HR: 0.80 (0.65–0.98)]. Interestingly, shorter ICU stays and, conversely, potentially longer hospital stays, a longer VCT, and a longer time to negative conversion were associated with corticosteroid use. There was no significant impact of different corticosteroid doses on mortality. Only one study showed slightly excess significant bias. Caution should be applied given the weak nature of the evidence, and it has been confirmed by sensitivity analyses too.

Conclusion: This umbrella study found benefits from corticosteroids on MV and especially the mortality of critically ill/severe patients with shorter ICU stays but prolonged hospital stays and VCT. The benefits and harms should be reevaluated and balanced before corticosteroids are cautiously prescribed in clinical practice.
Measurement of Dabigatran Concentration Using Finger Prick Dried Blood Spot Sample Collection
Authors: Lin Shin-Yi , Peng Yu-Fong , Huang Chih-Fen , Kuo Ching-Hua , Tang Sung-Chun , Jeng Jiann-Shing
Published: May 2021

Background and Purpose: Real-world laboratory monitoring of dabigatran activity is challenging. The purpose of the present study was to demonstrate the feasibility and accuracy of finger prick sampling with dried blood spot (fpDBS) cards in measuring the dabigatran concentration.

Material and Methods: Patients >20 years of age with atrial fibrillation and receiving dabigatran therapy for more than 7 days were included in the study. Peak and trough dabigatran concentrations were collected by simultaneous finger prick and venous puncture. The dabigatran concentration was measured by ultra-high performance liquid chromatography with tandem mass spectrometry. Our previously developed post-column infused internal standard (PCI-IS) method was applied to estimate the blood spot volume on fpDBS and to calibrate the drug concentration. Deming regression was used to analyze the correlation between dabigatran concentration on fpDBS cards and in plasma samples, followed by Bland–Altman analysis to compare the bias between two sampling techniques.

Results: A total of 33 patients were enrolled and contributed 66 plasma and 55 fpDBS dabigatran samples. The average patient age was 74.6 ± 7.9 years, mean creatinine clearance 58.1 ± 18.3 mL/min, and CHA2DS2-VASc score 3.5 ± 1.6 points. The dabigatran concentration ranged from 41.8–1421.7 ng/mL. The plasma and DBS dabigatran concentrations correlated well (r = 0.98), and the conversion factor for fpDBS to plasma dabigatran concentration was 1.28. The Bland–Altman analysis showed that 94.5% of the fpDBS-predicted concentration fell within 20% of bias.

Conclusions: The study showed that fpDBS measurement of dabigatran concentration is reliable and can be applied in clinical scenarios.
Uncovering the Roles of Clocks and Neural Transmission in the Resilience of Drosophila Circadian Network
Authors: Jaumouillé Edouard , Koch Rafael , Nagoshi Emi
Published: May 2021

Studies of circadian locomotor rhythms inDrosophila melanogastergave evidence to the preceding theoretical predictions on circadian rhythms. The molecular oscillator in flies, as in virtually all organisms, operates using transcriptional-translational feedback loops together with intricate post-transcriptional processes. Approximately150 pacemaker neurons, each equipped with a molecular oscillator, form a circuit that functions as the central pacemaker for locomotor rhythms. Input and output pathways to and from the pacemaker circuit are dissected to the level of individual neurons. Pacemaker neurons consist of functionally diverse subclasses, including those designated as the Morning/Master (M)-oscillator essential for driving free-running locomotor rhythms in constant darkness and the Evening (E)-oscillator that drives evening activity. However, accumulating evidence challenges this dual-oscillator model for the circadian circuit organization and propose the view that multiple oscillators are coordinated through network interactions. Here we attempt to provide further evidence to the revised model of the circadian network. We demonstrate that the disruption of molecular clocks or neural output of the M-oscillator during adulthood dampens free-running behavior surprisingly slowly, whereas the disruption of both functions results in an immediate arrhythmia. Therefore, clocks and neural communication of the M-oscillator act additively to sustain rhythmic locomotor output. This phenomenon also suggests that M-oscillator can be a pacemaker or a downstream path that passively receives rhythmic inputs from another pacemaker and convey output signals. Our results support the distributed network model and highlight the remarkable resilience of theDrosophilacircadian pacemaker circuit, which can alter its topology to maintain locomotor rhythms.
The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function
Authors: Nakada Emily M. , Sun Rui , Fujii Utako , Martin James G.
Published: May 2021

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.
Objectively Measured Physical Activity Is Associated With Body Composition and Metabolic Profiles of Pacific and New Zealand European Women With Different Metabolic Disease Risks
Authors: Slater Joanne , Kruger Rozanne , Douwes Jeroen , O’Brien Wendy J. , Corbin Marine , Miles-Chan Jennifer L. , Breier Bernhard H.
Published: May 2021

Objective: To assess associations between physical activity (PA), body composition, and biomarkers of metabolic health in Pacific and New Zealand European (NZE) women who are known to have different metabolic disease risks.

Methods: Pacific (n = 142) or NZE (n = 162) women aged 18–45 years with a self-reported body mass index (BMI) of either 18.5–25.0 kg⋅m–2 or ≥30.0 kg⋅m–2 were recruited and subsequently stratified as either low (<35%) or high (≥35%) BF%, with approximately half of each group in either category. Seven-day accelerometery was used to assess PA levels. Fasting blood was analysed for biomarkers of metabolic health, and whole body dual-energy X-ray absorptiometry (DXA) was used to estimate body composition.

Results: Mean moderate-to-vigorous physical activity (MVPA; min⋅day–1) levels differed between BF% (p < 0.05) and ethnic (p < 0.05) groups: Pacific high- 19.1 (SD 15.2) and low-BF% 26.3 (SD 15.6) and NZE high- 30.5 (SD 19.1) and low-BF% 39.1 (SD 18.4). On average Pacific women in the low-BF% group engaged in significantly less total PA when compared to NZE women in the low-BF% group (133 cpm); no ethnic difference in mean total PA (cpm) between high-BF% groups were observed: Pacific high- 607 (SD 185) and low-BF% 598 (SD 168) and NZE high- 674 (SD 210) and low-BF% 731 (SD 179). Multiple linear regression analysis controlling for age and deprivation showed a significant inverse association between increasing total PA and fasting plasma insulin among Pacific women; every 100 cpm increase in total PA was associated with a 6% lower fasting plasma insulin; no significant association was observed in NZE women. For both Pacific and NZE women, there was an 8% reduction in fasting plasma insulin for every 10-min increase in MVPA (p ≤ 0.05).

Conclusion: Increases in total PA and MVPA are associated with lower fasting plasma insulin, thus indicating a reduction in metabolic disease risk. Importantly, compared to NZE, the impact of increased total PA on fasting insulin may be greater in Pacific women. Considering Pacific women are a high metabolic disease risk population, these pre-clinical responses to PA may be important in this population; indicating promotion of PA in Pacific women should remain a priority.
Iron Biofortification in Rice: An Update on Quantitative Trait Loci and Candidate Genes
Authors: Swamy B. P. Mallikarjuna , Marathi Balram , Ribeiro-Barros Ana I. F. , Calayugan Mark Ian C. , Ricachenevsky Felipe Klein
Published: May 2021

Rice is the most versatile model for cereals and also an economically relevant food crop; as a result, it is the most suitable species for molecular characterization of Fe homeostasis and biofortification. Recently there have been significant efforts to dissect genes and quantitative trait loci (QTL) associated with Fe translocation into rice grains; such information is highly useful for Fe biofortification of cereals but very limited in other species, such as maize (Zea mays) and wheat (Triticum aestivum). Given rice’s centrality as a model for Poaceae species, we review the current knowledge on genes playing important roles in Fe transport, accumulation, and distribution in rice grains and QTLs that might explain the variability in Fe concentrations observed in different genotypes. More than 90 Fe QTLs have been identified over the 12 rice chromosomes. From these, 17 were recorded as stable, and 25 harbored Fe-related genes nearby or within the QTL. Among the candidate genes associated with Fe uptake, translocation, and loading into rice grains, we highlight the function of transporters from the YSL and ZIP families; transporters from metal-binding molecules, such as nicotianamine and deoxymugineic acid; vacuolar iron transporters; citrate efflux transporters; and others that were shown to play a role in steps leading to Fe delivery to seeds. Finally, we discuss the application of these QTLs and genes in genomics assisted breeding for fast-tracking Fe biofortification in rice and other cereals in the near future.
Upward Ingratiation Outside the Workplace and Supervisor’s Human Resource Decisions: Moderating Effect of Zhongyong Thinking
Authors: Sun Hui , Guo Haibing , Wang Kai , Sun Ling , Wang Lu
Published: May 2021

Ingratiation is a common strategy for subordinates to deal with their supervisors in eastern and western societies. Based on the theory of impression management, this study focuses on the impact of upward ingratiation outside the workplace on supervisor’s human resource (HR) decisions in the Chinese context and the mechanism behind this impact. The data were collected from 252 supervisor-subordinate dyads in four manufacturing firms. The results demonstrate the following: first, supervisors hold a more favorable view of upward ingratiation outside the workplace; second, upward ingratiation outside the workplace has a positive effect on the supervisor’s chance of promotion and bonus allocation decisions, and leader-member exchange (LMX) plays a mediation role in this influence; third, Zhongyong thinking (ZYT) moderates the relationship between LMX and supervisor’s chance of promotion and bonus allocation decisions; and finally, ZYT moderates the indirect effect of ingratiation behavior outside the workplace on supervisor’s chance of promotion and bonus allocation decisions through LMX, and the mediated relationship is weakened when a supervisor has a higher level of ZYT. This is one of the first empirical studies, which examines the validity of subordinate’s upward ingratiation outside the workplace from the perspective of supervisor’s ZYT. This study plays an important role in highlighting the effect of ZYT on the ingratiation behavior.
The Role of UID for the Usage of Verb Phrase Ellipsis: Psycholinguistic Evidence From Length and Context Effects
Authors: Schäfer Lisa , Lemke Robin , Drenhaus Heiner , Reich Ingo
Published: May 2021

We investigate the underexplored question of when speakers make use of the omission phenomenon verb phrase ellipsis (VPE) in English given that the full form is also available to them. We base the interpretation of our results on the well-established information-theoretic Uniform Information Density (UID) hypothesis: Speakers tend to distribute processing effort uniformly across utterances and avoid regions of low information by omitting redundant material through, e.g., VPE. We investigate the length of the omittable VP and its predictability in context as sources of redundancy which lead to larger or deeper regions of low information and an increased pressure to use ellipsis. We use both naturalness rating and self-paced reading studies in order to link naturalness patterns to potential processing difficulties. For the length effects our rating and reading results support a UID account. Surprisingly, we do not find an effect of the context on the naturalness and the processing of VPE. We suggest that our manipulation might have been too weak or not effective to evidence such an effect.
Exploring the Experiences and Well-Being of Australian Rio Olympians During the Post-Olympic Phase: A Qualitative Study
Authors: Bennie Andrew , Walton Courtney C. , O’Connor Donna , Fitzsimons Lauren , Hammond Thomas
Published: May 2021

Research about the Olympic Games has primarily focused on preparing athletes for competition. Less attention has been paid to the post-Olympic-phase (POP) and athlete well-being during this time. This study explored Australian Olympic athletes’ experiences following the conclusion of the 2016 Rio Olympic Games, including the factors that may have contributed to or challenged their well-being during this time. Eighteen athletes participated in semi-structured interviews and thematic analysis revealed that when Olympic performance appraisal met prior expectations, when athletes planned for a return to work or study, and when support from a variety of sources was readily available, this positively influenced athletes’ well-being during the POP. When these factors were not in place, more challenging post-Games experiences were present, and well-being was compromised. The findings contribute to the broader literature on elite athlete well-being and at an applied level, may be used to inform targeted programs that focus on supporting athletes after an Olympic campaign.
Associations of Caregiving Knowledge and Skills With Caregiver Burden, Psychological Well-Being, and Coping Styles Among Primary Family Caregivers of People Living With Schizophrenia in China
Authors: Zhou Zonglei , Wang Yao , Feng Ping , Li Tongxin , Tebes Jacob Kraemer , Luan Rongsheng , Yu Yu
Published: May 2021

Background: There is a lack of clarity regarding the correlation of caregiving knowledge and skills with caregiving experiences of people living with schizophrenia (PLSs). To address this gap, this comprehensive study examines the relationships of caregiving knowledge and skills to the primary family caregiver's experiences of burden, psychological well-being (stress, anxiety, depression, caregiving rewarding feelings), and coping styles in China.

Methods: A total of 395 primary family caregivers of PLSs were enrolled in a cross-sectional study between May 2019 and September 2019. Each family caregiver was independently assessed on caregiving knowledge and skills, caregiver burden, and psychological well-being, as well as coping styles.

Results: A higher level of caregiving knowledge and skills was positively correlated with less stress (b = −0.48, P < 0.001), anxiety (b = −0.23, P = 0.029), depression (b = −0.29, P = 0.013), and more caregiving rewarding feelings (b = 0.54, P < 0.001). Also, caregivers with more knowledge and skills were more inclined to adopt positive coping strategies (b = 0.44, P < 0.001). Despite these differences, caregivers with different levels of caregiving knowledge and skills reported comparable caregiver burden (b = 0.11, P = 0.705) and the use of a passive coping style (b = 0.10, P = 0.169).

Conclusion: Caregiving knowledge and skills are a reliable predictor of psychological well-being and active coping among the primary family caregivers of PLSs. These findings inform the development of psychoeducational interventions to support family caregivers of PLSs.
Diffusion Tensor Imaging Before and 3 Months After Concentrated Exposure Response Prevention in Obsessive-Compulsive Disorder
Authors: Brecke Vilde , Thorsen Anders Lillevik , Ousdal Olga Therese , Vriend Chris , Alnæs Dag , Hagen Kristen , Hansen Bjarne , Kvale Gerd , van den Heuvel Odile A.
Published: May 2021

Background: Subtle differences in white matter microstructure have been found in obsessive-compulsive disorder (OCD) compared to controls using diffusion tensor imaging (DTI), but it is unclear if and how this change after treatment. The primary aim of this pre-registered study was to investigate white matter integrity between OCD patients and controls and changes after concentrated exposure and response prevention (ERP).

Methods: Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) and mean diffusivity (MD) were estimated using FMRIB Software Library (FSL). The images were registered to a study-specific template using a longitudinal pipeline based on full tensor information in DTI-TK. Voxel-based analysis was performed using tract-based spatial statistics (TBSS). Using SPSS, we compared the integrity in three bilateral regions of interest (ROI), the sagittal stratum, posterior thalamic radiation and cingulum, in 32 OCD patients and 30 matched healthy controls at baseline. Patients received a four-day concentrated ERP format. We investigated longitudinal changes in 26 OCD patients and 22 healthy controls at 3months follow-up using repeated-measures ANOVA. Exploratory t-tests were conducted for AD and MD. Secondary hypothesis used linear regression to investigate if baseline FA predict treatment outcome 3 months later, and if patients with illness onset before 18 years of age would show lower FA in sagittal stratum. Finally, we performed sensitivity analysis on medication and comorbidity influences on FA.

Results: Three months after treatment, 77% of the patients were in remission. Contrary to our hypotheses, we did not find any significant differences in FA, RD, AD or MD between the groups before treatment, nor significant group by time effects in any of the ROI. None of the baseline FA measures significantly predicted treatment outcome. Illness onset before 18 years of age did not significantly predict FA in the sagittal stratum. Adjusting for medication or comorbid anxiety or mood disorder did not influence the results.

Conclusions: Although concentrated ERP in OCD lead to high remission, we did not find significant long-term changes by DTI. Future studies will benefit from using larger sample sizes and multi-shell diffusion-weighted imaging when investigating white matter microstructure in OCD and underlying neurobiological mechanisms of treatment.
Mental Health Status of Late-Middle-Aged Adults in China During the Coronavirus Disease 2019 Pandemic
Authors: Zheng Yong-Bo , Shi Le , Lu Zheng-An , Que Jian-Yu , Yuan Kai , Huang Xiao-Lin , Liu Lin , Wang Yun-He , Lu Qing-Dong , Wang Zhong , Yan Wei , Han Ying , Sun Xin-Yu , Bao Yan-Ping , Shi Jie , Lu Lin
Published: May 2021

Background: The novel coronavirus 2019 (COVID-19) pandemic and related compulsory measures have triggered a wide range of psychological issues. However, the effect of COVID-19 on mental health in late-middle-aged adults remains unclear.

Methods: This cross-sectional, web-based survey recruited 3,730 participants (≥ 50 years old) between February 28 and March 11 of 2020. The Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Insomnia Severity Index, and Acute Stress Disorder Scale were used to evaluate depression, anxiety, insomnia, and acute stress symptoms. Multivariate logistic regression analysis was fitted to explore risk factors that were associated with the selected outcomes.

Results: The mean age of the participants was 54.44 ± 5.99 years, and 2,026 (54.3%) of the participants were female. The prevalence of depression, anxiety, insomnia, and acute stress symptoms among late-middle-aged adults in China during the COVID-19 pandemic was 20.4, 27.1, 27.5, and 21.2%, respectively. Multivariable logistic regression analyses showed that participants who were quarantined had increased odds ratios for the four mental health symptoms, and those with a good understanding of the COVID-19 pandemic displayed a decreased risk for all mental health symptoms among late-middle-aged adults. In addition, participants with a low income and with a risk of COVID-19 exposure at work had a remarkably high risk of depression, anxiety, and acute stress symptoms.

Conclusions: Mental health symptoms in late-middle-aged adults in China during the COVID-19 pandemic are prevalent. Population-specific mental health interventions should be developed to improve mental health outcomes in late-middle-aged adults during this public health emergency.