bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice
Authors: Gao Yan-Yan , Gao Zeng-Yan
Published: July 2021

Asthma is an inflammatory disease associated with variable airflow obstruction and airway inflammation. This study aimed to explore the role and mechanism of extracellular adenosine diphosphate (ADP) in the occurrence of airway inflammation in asthma. The expression of ADP in broncho-alveolar lavage fluid (BALF) of asthmatic patients was determined by enzyme linked immunosorbent assay (ELISA) and the expression of P2Y1 receptor in lung tissues was determined by reverse transcription-quantitative polymerase chain reaction. Asthmatic mouse model was induced using ovalbumin and the mice were treated with ADP to assess its effects on the airway inflammation and infiltration of mast cells (MCs). Additionally, alveolar epithelial cells were stimulated with ADP, and the levels of interleukin-13 (IL-13) and C-X-C motif chemokine ligand 10 (CXCL10) were measured by ELISA. We finally analyzed involvement of NF-κB signaling pathway in the release of CXCL10 in ADP-stimulated alveolar epithelial cells. The extracellular ADP was enriched in BALF of asthmatic patients, and P2Y1 receptor is highly expressed in lung tissues of asthmatic patients. In the OVA-induced asthma model, extracellular ADP aggravated airway inflammation and induced MC infiltration. Furthermore, ADP stimulated alveolar epithelial cells to secrete chemokine CXCL10 by activating P2Y1 receptor, whereby promoting asthma airway inflammation. Additionally, ADP activated the NF-κB signaling pathway to promote CXCL10 release. As a “danger signal” extracellular ADP could trigger and maintain airway inflammation in asthma by activating P2Y1 receptor. This study highlights the extracellular ADP as a promising anti-inflammatory target for the treatment of asthma.
GWAS-Top Polymorphisms Associated With Late-Onset Alzheimer Disease in Brazil: Pointing Out Possible New Culprits Among Non-Coding RNAs
Authors: Kretzschmar Gabriela Canalli , Alencar Nina Moura , da Silva Saritha Suellen Lopes , Sulzbach Carla Daniela , Meissner Caroline Grisbach , Petzl-Erler Maria Luiza , Souza Ricardo Lehtonen R. , Boldt Angelica Beate Winter
Published: July 2021

Several genome-wide association studies (GWAS) have been carried out with late-onset Alzheimer’s disease (LOAD), mainly in European and Asian populations. Different polymorphisms were associated, but several of them without a functional explanation. GWAS are fundamental for identifying loci associated with diseases, although they often do not point to causal polymorphisms. In this sense, functional investigations are a fundamental tool for discovering causality, although the failure of this validation does not necessarily indicate a non-causality. Furthermore, the allele frequency of associated genetic variants may vary widely between populations, requiring replication of these associations in other ethnicities. In this sense, our study sought to replicate in 150 AD patients and 114 elderly controls from the South Brazilian population 18 single-nucleotide polymorphisms (SNPs) associated with AD in European GWAS, with further functional investigation using bioinformatic tools for the associated SNPs. Of the 18 SNPs investigated, only four were associated in our population: rs769449 (APOE), rs10838725 (CELF1), rs6733839, and rs744373 (BIN1–CYP27C1). We identified 54 variants in linkage disequilibrium (LD) with the associated SNPs, most of which act as expression or splicing quantitative trait loci (eQTLs/sQTLs) in genes previously associated with AD or with a possible functional role in the disease, such as CELF1, MADD, MYBPC3, NR1H3, NUP160, SPI1, and TOMM40. Interestingly, eight of these variants are located within long non-coding RNA (lncRNA) genes that have not been previously investigated regarding AD. Some of these polymorphisms can result in changes in these lncRNAs’ secondary structures, leading to either loss or gain of microRNA (miRNA)-binding sites, deregulating downstream pathways. Our pioneering work not only replicated LOAD association with polymorphisms not yet associated in the Brazilian population but also identified six possible lncRNAs that may interfere in LOAD development. The results lead us to emphasize the importance of functional exploration of associations found in large-scale association studies in different populations to base personalized and inclusive medicine in the future.
Crowding Effects on the Structure and Dynamics of the Intrinsically Disordered Nuclear Chromatin Protein NUPR1
Authors: Bonucci Alessio , Palomino-Schätzlein Martina , Malo de Molina Paula , Arbe Arantxa , Pierattelli Roberta , Rizzuti Bruno , Iovanna Juan L. , Neira José L.
Published: July 2021

The intracellular environment is crowded with macromolecules, including sugars, proteins and nucleic acids. In the cytoplasm, crowding effects are capable of excluding up to 40% of the volume available to any macromolecule when compared to dilute conditions. NUPR1 is an intrinsically disordered protein (IDP) involved in cell-cycle regulation, stress-cell response, apoptosis processes, DNA binding and repair, chromatin remodeling and transcription. Simulations of molecular crowding predict that IDPs can adopt compact states, as well as more extended conformations under crowding conditions. In this work, we analyzed the conformation and dynamics of NUPR1 in the presence of two synthetic polymers, Ficoll-70 and Dextran-40, which mimic crowding effects in the cells, at two different concentrations (50 and 150 mg/ml). The study was carried out by using a multi-spectroscopic approach, including: site-directed spin labelling electron paramagnetic resonance spectroscopy (SDSL-EPR), nuclear magnetic resonance spectroscopy (NMR), circular dichroism (CD), small angle X-ray scattering (SAXS) and dynamic light scattering (DLS). SDSL-EPR spectra of two spin-labelled mutants indicate that there was binding with the crowders and that the local dynamics of the C and N termini of NUPR1 were partially affected by the crowders. However, the overall disordered nature of NUPR1 did not change substantially in the presence of the crowders, as shown by circular dichroism CD and NMR, and further confirmed by EPR. The changes in the dynamics of the paramagnetic probes appear to be related to preferred local conformations and thus crowding agents partially affect some specific regions, further pinpointing that NUPR1 flexibility has a key physiological role in its activity.
Expression Characteristics and Significant Prognostic Values of PGK1 in Breast Cancer
Authors: Li Yanping , Wang Shanshan , Zhang Xiaoyuan , Yang Rui , Wei Xiaonan , Yan Ruirong , Jiang Yaru , Shen Wenzhi
Published: July 2021

It was proven that PGK1 plays a vital role in the proliferation, migration, and invasion of human breast cancer. However, the correlation of PGK1 mRNA and protein expression with clinicopathologic characteristics and prognostic values according to various kinds of breast cancer patient classifications remains unsufficient. Here, we analyzed data from the Oncomine database, Breast cancer Gene-Expression Miner v4.5, TNMplot, MuTarget, PrognoScan database, and clinical bioinformatics to investigate PGK1 expression distribution and prognostic value in breast cancer patients. Our study revealed that the mRNA and protein expression levels of PGK1 were up-regulated in various clinicopathologic types of breast cancer. Moreover, the expression of PGK1 was correlated with mutations of common tumor suppressor genes TP53 and CDH1. In addition, we found that high mRNA level of PGK1 was significantly associated with poor OS, RFS, and DMFS. Notably, Cox regressionanalysis showed that PGK1 could be used as an independent prognostic marker. In summary, the aforementioned findings suggested that PGK1 might be not only explored as a potential biomarker, but also combined with TP53/CDH1 for chemotherapy in breast cancer.
Proximity to the Promoter and Terminator Regions Regulates the Transcription Enhancement Potential of an Intron
Authors: Dwyer Katherine , Agarwal Neha , Gega Alisa , Ansari Athar
Published: July 2021

An evolutionarily conserved feature of introns is their ability to enhance expression of genes that harbor them. Introns have been shown to regulate gene expression at the transcription and post-transcription level. The general perception is that a promoter-proximal intron is most efficient in enhancing gene expression and the effect diminishes with the increase in distance from the promoter. Here we show that the intron regains its positive influence on gene expression when in proximity to the terminator. We inserted ACT1 intron into different positions within IMD4 and INO1 genes. Transcription Run-On (TRO) analysis revealed that the transcription of both IMD4 and INO1 was maximal in constructs with a promoter-proximal intron and decreased with the increase in distance of the intron from the promoter. However, activation was partially restored when the intron was placed close to the terminator. We previously demonstrated that the promoter-proximal intron stimulates transcription by affecting promoter directionality through gene looping-mediated recruitment of termination factors in the vicinity of the promoter region. Here we show that the terminator-proximal intron also enhances promoter directionality and results in compact gene architecture with the promoter and terminator regions in close physical proximity. Furthermore, we show that both the promoter and terminator-proximal introns facilitate assembly or stabilization of the preinitiation complex (PIC) on the promoter. On the basis of these findings, we propose that proximity to both the promoter and the terminator regions affects the transcription regulatory potential of an intron, and the terminator-proximal intron enhances transcription by affecting both the assembly of preinitiation complex and promoter directionality.
White Matter Hyperintensity Volume and Location: Associations With WM Microstructure, Brain Iron, and Cerebral Perfusion
Authors: Bauer Christopher E. , Zachariou Valentinos , Seago Elayna , Gold Brian T.
Published: July 2021

Cerebral white matter hyperintensities (WMHs) represent macrostructural brain damage associated with various etiologies. However, the relative contributions of various etiologies to WMH volume, as assessed via different neuroimaging measures, is not well-understood. Here, we explored associations between three potential early markers of white matter hyperintensity volume. Specifically, the unique variance in total and regional WMH volumes accounted for by white matter microstructure, brain iron concentration and cerebral blood flow (CBF) was assessed. Regional volumes explored were periventricular and deep regions. Eighty healthy older adults (ages 60–86) were scanned at 3 Tesla MRI using fluid-attenuated inversion recovery, diffusion tensor imaging (DTI), multi-echo gradient-recalled echo and pseudo-continuous arterial spin labeling sequences. In a stepwise regression model, DTI-based radial diffusivity accounted for significant variance in total WMH volume (adjusted R2 change = 0.136). In contrast, iron concentration (adjusted R2 change = 0.043) and CBF (adjusted R2 change = 0.027) made more modest improvements to the variance accounted for in total WMH volume. However, there was an interaction between iron concentration and location on WMH volume such that iron concentration predicted deep (p = 0.034) but not periventricular (p = 0.414) WMH volume. Our results suggest that WM microstructure may be a better predictor of WMH volume than either brain iron or CBF but also draws attention to the possibility that some early WMH markers may be location-specific.
Cognitive Tele-Enhancement in Healthy Older Adults and Subjects With Subjective Memory Complaints: A Review
Authors: Alaimo Cristina , Campana Elena , Stoppelli Maria Rachele , Gobbi Elena , Baglio Francesca , Rossetto Federica , Binetti Giuliano , Zanetti Orazio , Manenti Rosa , Cotelli Maria
Published: July 2021

Background: In recent years, emphasis has been placed on cognitive enhancement to stimulate cognitive abilities and prevent functional decline. Considering that traditional face-to-face interventions can be very expensive and are not accessible to all individuals, the need to transfer care from the clinic to the patient's home is evident. In this regard, cognitive tele-enhancement interventions have received increased attention.

Aim: The aim of this review was to provide an overview of protocols that apply remotely controlled cognitive training with individualized feedback on performance by the therapist in healthy older adults or participants with subjective memory complaints.

Methods: Out of 35 articles assessed for eligibility, eight studies were identified. Of the selected studies, five included cognitively healthy older adults, while three included participants with subjective memory complaints.

Results: Most of the reviewed studies showed beneficial effects of cognitive tele-enhancement interventions, reporting improvements in memory, sustained attention, working memory, executive functions, and language abilities. Moreover, reductions in anxiety and depression symptomatology levels, as well as in subjective memory difficulties, were described in some of the studies.

Conclusions: Cognitive tele-enhancement treatment could be a good alternative to face-to-face intervention. This literature review highlights the importance of applying preventive cognitive interventions to subjects with initial subjective memory complaints. Remote modalities seem to facilitate the application of such interventions.
The Clinicopathological Distinction Between Seropositive and Seronegative Immune-Mediated Necrotizing Myopathy in China
Authors: Ma Xue , Xu Li , Ji Suqiong , Li Yue , Bu Bitao
Published: July 2021

Objectives: The present study aimed to compare the clinicopathological features of patients with seronegative immune-mediated necrotizing myopathy (IMNM) and those positive for anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme-a reductase (HMGCR) antibodies.

Methods: We retrospectively analyzed the data of patients with IMNM treated in the Neurology Department of Tongji Hospital from January 1, 2013, to December 31, 2019.

Results: Among the 117 patients with IMNM, 30.8% (36/117) were positive for anti-SRP antibodies, 6.0% (7/117) were positive for anti-HMGCR antibodies, and 13.7% (16/117) were seronegative. Myalgia at presentation (62.5 vs. 23.3%, p = 0.0114) was more commonly observed in patients with seronegative IMNM than in those with seropositive IMNM. Subclinical cardiac involvement was more frequently detected in seronegative IMNM than in seropositive IMNM (6/13 vs. 5/33, p = 0.0509, echocardiogram; 7/7 vs. 12/24, p = 0.0261, cardiac MRI). Deposition of membrane attack complex (MAC) on the sarcolemma of myofibers in biopsied muscle was less commonly observed in patients with seronegative IMNM than in patients with seropositive IMNM (16.7 vs. 68.2%, p = 0.0104). The rate of marked improvement following immunotherapy tended to be higher in patients with seronegative IMNM than in those with seropositive IMNM (87.5 vs. 61%, p = 0.0641).

Conclusions: Patients with seronegative IMNM more frequently present with myalgia at onset, exhibit more subclinical cardiac involvement and uncommon MAC deposition on myofibers, and experience better outcomes than those with seropositive IMNM.
Moderate Alcohol Intake Changes Visual Perception by Enhancing V1 Inhibitory Surround Interactions
Authors: Wang Huan , Wang Zhengchun , Zhou Yifeng , Tzvetanov Tzvetomir
Published: July 2021

Moderate alcohol consumption is considered to enhance the cortical GABA-ergic inhibitory system and it also variously affects visual perception. However, little behavioral evidence indicates changes of visual perception due to V1 modulated by alcohol intoxication. In this study, we investigated this issue by using center-surround tilt illusion (TI) as a probe of V1 inhibitory interactions, by taking into account possible higher-order effects. Participants conducted TI measures under sober, moderate alcohol intoxication, and placebo states. We found alcohol significantly increased repulsive TI effect and weakened orientation discrimination performance, which is consistent with the increase of lateral inhibition between orientation sensitive V1 neurons caused by alcohol intoxication. We also observed no visible changes in the data for global orientation processing but a presence of global attentional modulation. Thus, our results provide psychophysics evidence that alcohol changed V1 processing, which affects visual perception of contextual stimuli.
Direct Targeting of the Anterior Nucleus of the Thalamus via 3 T Quantitative Susceptibility Mapping
Authors: Yu Kaijia , Ren Zhiwei , Yu Tao , Wang Xueyuan , Hu Yongsheng , Guo Song , Li Jianyu , Li Yongjie
Published: July 2021

Objective: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a potentially effective, minimally invasive, and reversible method for treating epilepsy. The goal of this study was to explore whether 3 T quantitative susceptibility mapping (QSM) could delineate the ANT from surrounding structures, which is important for the direct targeting of DBS surgery.

Methods: We obtained 3 T QSM, T1-weighted (T1w), and T2-weighted (T2w) images from 11 patients with Parkinson’s disease or dystonia who received subthalamic nucleus (STN) or globus pallidus interna (GPi) DBS surgery in our center. The ANT and its surrounding white matter structures on QSM were compared with available atlases. The contrast-to-noise ratios (CNRs) of ANT relative to the external medullary lamina (eml) were compared across the three imaging modalities. Additionally, the morphology and location of the ANT were depicted in the anterior commissure (AC)-posterior commissure (PC)-based system.

Results: ANT can be clearly distinguished from the surrounding white matter laminas and appeared hyperintense on QSM. The CNRs of the ANT-eml on QSM, T1w, and T2w images were 10.20 ± 4.23, 1.71 ± 1.03, and 1.35 ± 0.70, respectively. One-way analysis of variance (ANOVA) indicated significant differences in CNRs among QSM, T1w, and T2w imaging modalities [F(2) = 85.28, p < 0.0001]. In addition, both the morphology and location of the ANT were highly variable between patients in the AC–PC-based system.

Conclusion: The potential utility of QSM for the visualization of ANTs in clinical imaging is promising and may be suitable for targeting the ANT for DBS to treat epilepsy.
Knockdown of Dehydrodolichyl Diphosphate Synthase in the Drosophila Retina Leads to a Unique Pattern of Retinal Degeneration
Authors: Brandwine Tal , Ifrah Reut , Bialistoky Tzofia , Zaguri Rachel , Rhodes-Mordov Elisheva , Mizrahi-Meissonnier Liliana , Sharon Dror , Katanaev Vladimir L. , Gerlitz Offer , Minke Baruch
Published: July 2021

Dehydrodolichyl diphosphate synthase (DHDDS) is a ubiquitously expressed enzyme that catalyzes cis-prenyl chain elongation to produce the poly-prenyl backbone of dolichol. It appears in all tissues including the nervous system and it is a highly conserved enzyme that can be found in all animal species. Individuals who have biallelic missense mutations in the DHDDS gene are presented with non-syndromic retinitis pigmentosa with unknown underlying mechanism. We have used the Drosophila model to compromise DHDDS ortholog gene (CG10778) in order to look for cellular and molecular mechanisms that, when defective, might be responsible for this retinal disease. The Gal4/UAS system was used to suppress the expression of CG10778 via RNAi-mediated-knockdown in various tissues. The resulting phenotypes were assessed using q-RT-PCR, transmission-electron-microscopy (TEM), electroretinogram, antibody staining and Western blot analysis. Targeted knockdown of CG10778-mRNA in the early embryo using the actin promoter or in the developing wings using the nub promoter resulted in lethality, or wings loss, respectively. Targeted expression of CG10778-RNAi using the glass multiple reporter (GMR)-Gal4 driver (GMR-DHDDS-RNAi) in the larva eye disc and pupal retina resulted in a complex phenotype: (a) TEM retinal sections revealed a unique pattern of retinal-degeneration, where photoreceptors R2 and R5 exhibited a nearly normal structure of their signaling-compartment (rhabdomere), but only at the region of the nucleus, while all other photoreceptors showed retinal degeneration at all regions. (b) Western blot analysis revealed a drastic reduction in rhodopsin levels in GMR-DHDDS-RNAi-flies and TEM sections showed an abnormal accumulation of endoplasmic reticulum (ER). To conclude, compromising DHDDS in the developing retina, while allowing formation of the retina, resulted in a unique pattern of retinal degeneration, characterized by a dramatic reduction in rhodopsin protein level and an abnormal accumulation of ER membranes in the photoreceptors cells, thus indicating that DHDDS is essential for normal retinal formation.
Prediction of Srebp-1 as a Key Target of Qing Gan San Against MAFLD in Rats via RNA-Sequencing Profile Analysis
Authors: Yang Bendong , Sun Jingyue , Liang Shufei , Wu Peixuan , Lv Rui , He Yanping , Li Deqi , Sun Wenlong , Song Xinhua
Published: July 2021

Metabolism-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, and the use of traditional Chinese medicines (TCMs) to treat this disease has attracted increasing attention. The Qing Gan San (QGS) formula comprises Polygonatum sibiricum, the peel of Citrus reticulata Blanco, the leaves of Morus alba L, Cichorium intybus, Glycyrrhiza uralensis Fisch, and Cirsium setosum. The present study aimed to uncover the anti-hyperlipidaemic effects, hepatic fat accumulation-lowering effects and mechanisms of QGS in high-fat diet-induced MAFLD rats. QGS significantly reduced the levels of total cholesterol and triglycerides in both serum and liver tissue and partially protected hepatic function. Additionally, QGS significantly ameliorated hepatic lipid accumulation with histopathology observation, as demonstrated by H&E and oil red O staining. RNA sequencing was used to further investigate the key genes involved in the development and treatment of MAFLD. Hierarchical clustering analysis showed that the gene expression profiles in rats with MAFLD were reversed to normal after QGS treatment. QGS had 222 potential therapeutic targets associated with MAFLD. Enrichment analysis among these targets revealed that QGS affected biological functions/pathways such as the regulation of lipid metabolic processes (GO: 0019216) and the non-alcoholic fatty liver disease pathway (hsa04932), and identified Srebp-1 as a key regulator in the synthesis of cholesterol and triglycerides. Subsequently, both immunofluorescence and Western blot analyses demonstrated that QGS suppressed the transfer of Srebp-1 to the nucleus from the cytoplasm, suggesting that the activation of Srebp-1 was inhibited. Our study reveals the effects and mechanisms of QGS in the treatment of MAFLD and provides insights and prospects to further explore the pathogenesis of MAFLD and TCM therapies.
Targeting SARS-CoV-2-Platelet Interactions in COVID-19 and Vaccine-Related Thrombosis
Authors: Cox Dermot
Published: July 2021

It is clear that COVID-19 is more than a pneumonia and is associated with a coagulopathy and multi-organ failure. While the use of anti-coagulants does reduce the incidence of pulmonary emboli, it does not help with survival. This suggests that the coagulopathy is more likely to be platelet-driven rather than thrombin-driven. There is significant evidence to suggest that SARS-CoV-2 virions directly interact with platelets to trigger activation leading to thrombocytopenia and thrombosis. I propose a model of multiple interactions between SARS-CoV-2 and platelets that has many similarities to that withStaphylococcus aureusand Dengue virus. As platelet activation and thrombosis are major factors in poor prognosis, therapeutics that target the platelet-SARS-CoV-2 interaction have potential in treating COVID-19 and other virus infections.
Endocannabinoids in Bladder Sensory Mechanisms in Health and Diseases
Authors: Christie Stewart , Brookes Simon , Zagorodnyuk Vladimir
Published: July 2021

The recent surge in research on cannabinoids may have been fueled by changes in legislation in several jurisdictions, and by approval for the use of cannabinoids for treatment of some chronic diseases. Endocannabinoids act largely, but not exclusively on cannabinoid receptors 1 and 2 (CBR1 and CBR2) which are expressed in the bladder mainly by the urothelium and the axons and endings of motor and sensory neurons. A growing body of evidence suggests that endocannabinoid system constitutively downregulates sensory bladder function during urine storage and micturition, under normal physiological conditions. Similarly, exogenous cannabinoid agonists have potent modulatory effects, as do inhibitors of endocannabinoid inactivation. Results suggest a high potential of cannabinoids to therapeutically ameliorate lower urinary tract symptoms in overactive bladder and painful bladder syndromes. At least part of this may be mediated via effects on sensory nerves, although actions on efferent nerves complicate interpretation. The sensory innervation of bladder is complex with at least eight classes identified. There is a large gap in our knowledge of the effects of endocannabinoids and synthetic agonists on different classes of bladder sensory neurons. Future studies are needed to reveal the action of selective cannabinoid receptor 2 agonists and/or peripherally restricted synthetic cannabinoid receptor 1 agonists on bladder sensory neurons in animal models of bladder diseases. There is significant potential for these novel therapeutics which are devoid of central nervous system psychotropic actions, and which may avoid many of the side effects of current treatments for overactive bladder and painful bladder syndromes.
Numerical Simulation of Long-Wave Infrared Generation Using an External Cavity Diamond Raman Laser
Authors: Chen Hui , Bai Zhenxu , Zhao Chen , Yang Xuezong , Ding Jie , Qi Yaoyao , Wang Yulei , Lu Zhiwei
Published: July 2021

Diamond has a broad spectral transmission range (>0.2 μm) and the largest Raman frequency shift (1,332 cm−1) among known Raman crystals. Hence, the diamond Raman laser has the potential to achieve lasing in the long-wave infrared (LWIR) range, which is difficult to reach via other crystalline lasers. Here, we report a new approach to achieve LWIR output using diamond Raman conversion and provide the corresponding analysis model and simulation results. The conversion efficiency is analyzed as function of the pump waist size, output-coupler transmission, and crystal length, at constant pump power. The maximum output power at which a diamond of relatively large size can be operated without damage is predicted. This study paves a way for high-power LWIR lasing in diamond.
Hypoxia-Inducible Factor Regulates Endothelial Metabolism in Cardiovascular Disease
Authors: Ullah Karim , Wu Rongxue
Published: July 2021

Endothelial cells (ECs) form a physical barrier between the lumens and vascular walls of arteries, veins, capillaries, and lymph vessels; thus, they regulate the extravasation of nutrients and oxygen from the circulation into the perivascular space and participate in mechanisms that maintain cardiovascular homeostasis and promote tissue growth and repair. Notably, their role in tissue repair is facilitated, at least in part, by their dependence on glycolysis for energy production, which enables them to resist hypoxic damage and promote angiogenesis in ischemic regions. ECs are also equipped with a network of oxygen-sensitive molecules that collectively activate the response to hypoxic injury, and the master regulators of the hypoxia response pathway are hypoxia-inducible factors (HIFs). HIFs reinforce the glycolytic dependence of ECs under hypoxic conditions, but whether HIF activity attenuates or exacerbates the progression and severity of cardiovascular dysfunction varies depending on the disease setting. This review summarizes how HIF regulates the metabolic and angiogenic activity of ECs under both normal and hypoxic conditions and in a variety of diseases that are associated with cardiovascular complications.
Cardiovascular Issues in Tyrosine Kinase Inhibitors Treatments for Chronic Myeloid Leukemia: A Review
Authors: Santoro Marco , Mancuso Salvatrice , Accurso Vincenzo , Di Lisi Daniela , Novo Giuseppina , Siragusa Sergio
Published: July 2021

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by a fusion gene, encoding for the chimeric protein BCR-ABL, with constitutive tyrosine kinase activity. The use of tyrosine kinase inhibitors (TKIs) has drastically improved survival, but there are significant concerns about cardiovascular toxicity. Cardiovascular risk can be lowered with appropriate baseline evaluation, accurate choice of TKI therapy, improvement of modifiable cardiovascular risk factors through lifestyle modifications, and prescription of drugs for primary or secondary prevention. Which examinations are necessary, and when do they have to be scheduled? How often should a TKI-treated patient undergo which cardiology test or exam? Is there an accurate way to estimate the risk that each TKI may determine a cardiovascular adverse event in a CML patient? In a few words, how can we optimize the cardiovascular risk management in CML patients before and during TKI treatment? The aim of this review is to describe cardiac and vascular toxicity of TKIs used for CML treatment according to the most recent literature and to identify unmet clinical needs in cardiovascular risk management and complications in these patients. Regarding the TKI-induced cardiovascular toxicity, the full mechanism is still unclear, but it is accepted that different factors may play different roles: endothelial damage and atherosclerosis, metabolic impairment, hypertensive effect, glomerular impairment, and mast-cell disruption. Preventive strategies are aimed at minimizing cardiovascular risk when CML is diagnosed. Cardio-oncology units in specialized hematology centers may afford a personalized and multidisciplinary approach to the patient, optimizing the balance between treatment of the neoplasm and management of cardiovascular risk.
HADLN: Hybrid Attention-Based Deep Learning Network for Automated Arrhythmia Classification
Authors: Jiang Mingfeng , Gu Jiayan , Li Yang , Wei Bo , Zhang Jucheng , Wang Zhikang , Xia Ling
Published: July 2021

In recent years, with the development of artificial intelligence, deep learning model has achieved initial success in ECG data analysis, especially the detection of atrial fibrillation. In order to solve the problems of ignoring the correlation between contexts and gradient dispersion in traditional deep convolution neural network model, the hybrid attention-based deep learning network (HADLN) method is proposed to implement arrhythmia classification. The HADLN can make full use of the advantages of residual network (ResNet) and bidirectional long–short-term memory (Bi-LSTM) architecture to obtain fusion features containing local and global information and improve the interpretability of the model through the attention mechanism. The method is trained and verified by using the PhysioNet 2017 challenge dataset. Without loss of generality, the ECG signal is classified into four categories, including atrial fibrillation, noise, other, and normal signals. By combining the fusion features and the attention mechanism, the learned model has a great improvement in classification performance and certain interpretability. The experimental results show that the proposed HADLN method can achieve precision of 0.866, recall of 0.859, accuracy of 0.867, and F1-score of 0.880 on 10-fold cross-validation.
Growth and Antioxidant-Related Effects of the Reestablished Ascorbic Acid Pathway in Zebrafish (Danio rerio) by Genomic Integration of L-Gulonolactone Oxidase From Cloudy Catshark (Scyliorhinus torazame)
Authors: Shanaka K. A. S. N. , Jung Sumi , Janson N. D. , Jayasingha J. R. P. , Madushani K. P. , Kim Myoung-Jin , Lee Jehee
Published: July 2021

Loss of L-gulonolactone oxidase (GULO), which catalyzes the last step of the ascorbic acid (AA) biosynthesis pathway, results in a complete lack of AA in several Osteichthyes fish species, including zebrafish. In this study, sGULO, the active GULO gene from cloudy catshark (Scyliorhinus torazame) was cloned into zebrafish using the Gateway cloning method. The resulting Tg(b-actin:sGULO:mCherry) fish were analyzed for the effects of a reestablished AA pathway. Fluorescent microscopy and PCR were used to analyze the integration of the construct into the zebrafish genome. Catalytic activity of sGULO, AA production, growth-related characteristics, and gene expression were investigated to evaluate the effects of AA production in Tg fish. The mCherry fluorescent protein indicated the proper integration and expression of the sGULO construct in zebrafish. The sGULO gene was ubiquitously expressed in all the studied tissues and the enzyme activity indicated an increased AA production in Tg fish. The growth of Tg fish was also increased, and antioxidant system analysis suggests that reactive oxygen species production was reduced in Tg fish compared with wild type. Expression of the AA transporter slc23a1 was significantly downregulated in Tg homozygous fish. These results collectively indicate the effects of reestablished AA synthesis in zebrafish.
Death Zone Weather Extremes Mountaineers Have Experienced in Successful Ascents
Authors: Szymczak Robert K. , Marosz Michał , Grzywacz Tomasz , Sawicka Magdalena , Naczyk Marta
Published: July 2021

Background

Few data are available on mountaineers’ survival prospects in extreme weather above 8000 m (the Death Zone). We aimed to assess Death Zone weather extremes experienced in climbing-season ascents of Everest and K2, all winter ascents of 8000 m peaks (8K) in the Himalayas and Karakoram, environmental records of human survival, and weather extremes experienced with and without oxygen support.

Materials and Methods

We analyzed 528 ascents of 8K peaks: 423 non-winter ascents without supplemental oxygen (Everest–210, K2–213), 76 ascents in winter without oxygen, and 29 in winter with oxygen. We assessed environmental conditions using the ERA5 dataset (1978–2021): barometric pressure (BP), temperature (Temp), wind speed (Wind), wind chill equivalent temperature (WCT), and facial frostbite time (FFT).

Results

The most extreme conditions that climbers have experienced with and without supplemental oxygen were: BP 320 hPa (winter Everest) vs. 329 hPa (non-winter Everest); Temp –41°C (winter Everest) vs. –45°C (winter Nanga Parbat); Wind 46 m⋅s–1 (winter Everest) vs. 48 m⋅s–1 (winter Kangchenjunga). The most extreme combined conditions of BP ≤ 333 hPa, Temp ≤ −30°C, Wind ≥ 25 m⋅s–1, WCT ≤ −54°C and FFT ≤ 3 min were encountered in 14 ascents of Everest, two without oxygen (late autumn and winter) and 12 oxygen-supported in winter. The average extreme conditions experienced in ascents with and without oxygen were: BP 326 ± 3 hPa (winter Everest) vs. 335 ± 2 hPa (non-winter Everest); Temp −40 ± 0°C (winter K2) vs. −38 ± 5°C (winter low Karakoram 8K peaks); Wind 36 ± 7 m⋅s–1 (winter Everest) vs. 41 ± 9 m⋅s–1 (winter high Himalayan 8K peaks).

Conclusions

1.

The most extreme combined environmental BP, Temp and Wind were experienced in winter and off-season ascents of Everest.

2.

Mountaineers using supplemental oxygen endured more extreme conditions than climbers without oxygen.

3.

Climbing-season weather extremes in the Death Zone were more severe on Everest than on K2.

4.

Extreme wind speed characterized winter ascents of Himalayan peaks, but severely low temperatures marked winter climbs in Karakoram.
Maternal Psychological Control and Rural Left-Behind Children's Anxiety: The Moderating Role of Externalizing Problem Behavior and Teacher Support
Authors: Deng Na , Bi Hongyan , Zhao Jinxia
Published: July 2021

Based on the risk and protective factor framework and context-dependent theory, the present study investigated the association between maternal psychological control and anxiety among left-behind children in rural China as well as the moderating roles of externalizing problem behavior and teacher support in this association. A total of 149 children with two migrant parents, 306 children with only a migrant father, and 287 accompanied children aged 11–16 years (M = 13.85 years, SD = 0.50) in the rural areas of Shandong Province, Eastern China, participated in the study. Children reported their perceived levels of maternal psychological control, teacher support, externalizing problem behavior, and anxiety. The results provided evidence that a higher level of psychological control was associated with more anxiety symptoms in all three groups of children, and this association was stronger in children with two migrant parents than in accompanied children. Hierarchical regression analysis supported our hypotheses that the moderating effects of externalizing problem behavior and teacher support varied as a function of parents' migrant status, with externalizing problem behavior exacerbating the impact of psychological control on anxiety in accompanied children, and teacher support buffering the impact of psychological control on anxiety in children with a migrant father. These findings broaden our understanding of the factors and processes that contribute to anxiety problems in left-behind children in rural China.
Function Follows Form: Using the Aesthetic Association Principle to Enhance Haptic Interface Design
Authors: Breitschaft Stefan Josef , Carbon Claus-Christian
Published: July 2021

Novel tangible user interface technologies facilitate current trends toward seamless user interfaces. They enable the design of yet unseen interfaces and thus the creation of a new kind of haptic language. In order to use the benefits of a touch-and-feel design for a positive user experience, carefully designed haptic feedback plays an important role by providing aesthetically pleasing and sustainable product features. Haptic feedback may exceed mere acquiring of buttons and input-confirmation but enable orientation and even identification of functionality governed by the haptic impression. We employed the aesthetic association principle as a deeply grounded psychological mechanism that assists effective linkage between haptic form factors and associated functional attributes. In order to illustrate this powerful principle, we analyzed the specific associations between certain main haptic surface qualities and associated functional aspects. In a series of three subsequent studies (Pre-Study 1:perception, Pre-Study 2:similarity, and Main Study:association), we explored paradigmatic associations of that kind to develop guidelines which forms are distinct to be used in interfaces. We show how forms are implicitly categorized into functional qualities (on/off, more-less, selection), using a multidimensional scaling procedure and explore explicit form-functionality associations, using a think-aloud method in the context of an automotive interface. For a series of forms, we revealed clear associative relations to specific functions. We will discuss the general value and opportunities of an association-based approach to user experience in order to create intuitive user interfaces. We will also develop ideas for specific areas of applications.
Promoting Foundation Reading Skills With At-Risk Students
Authors: Sucena Ana , Silva Ana Filipa , Marques Cátia
Published: July 2021

This paper presents an early reading intervention program, the PPCL (Programa de Promoção das Competências Leitoras—Promoting Reading Skills Program). PPCL focuses on the promotion of reading foundation abilities—letter-sound, phonemic awareness, decoding, and spelling—with at-risk first graders. This study assessed the impact of PPCL on the reading foundation abilities with 311 first graders (173 boys and 138 girls), divided between intervention and comparative group (respectively, 206 and 105 first graders). Results were analyzed with an inter- (intervention and comparative group) and intra- (pre-and post-test) group design. A mixed two-way Manova indicated the presence of statistically significant differences between the two assessment moments, with the intervention group presenting higher values than the comparative group in all abilities at the post-test and also above the cutoff score in all variables, which indicates that at-risk students eventually concluded the school year with satisfactory levels of reading skills. On the other hand, the comparative group scored below the cutoff score in all variables. The magnitude of the effect on the intervention group was higher than the one observed in the comparative group. Reading promotion with PPCL significantly improved at-risk students reading skills. In future studies, the authors intend to follow up on reading and writing participants’ skills.
Hair-Pulling Does Not Necessarily Serve an Emotion Regulation Function in Adults With Trichotillomania
Authors: Lochner Christine , Demetriou Salome , Kidd Martin , Coetzee Bronwynè , Stein Dan J.
Published: July 2021

Background: Trichotillomania (TTM) has been associated with childhood trauma and perceived stress. While it has been hypothesized that hair-pulling regulate negative emotions, the relationship between childhood trauma, perceived stress, emotion regulation, and hair-pulling has not been well-studied.

Methods: Fifty-six adults with TTM and 31 healthy controls completed the Childhood Trauma Questionnaire (CTQ), Perceived Stress Scale (PSS), and Difficulties in Emotion Regulation Scale (DERS). Hair-pulling severity was measured with the Massachusetts General Hospital-Hair Pulling Scale. CTQ, PSS, and DERS total scores were compared across groups using ANCOVA and the correlation between hair-pulling severity and emotion dysregulation was determined. Regression analyses were used to estimate the association of CTQ and PSS totals with DERS, and to determine whether associations between predictors and dependent variable (DERS) differed across groups.

Results: TTM patients reported higher rates of childhood trauma (p <= 0.01), perceived stress (p = 0.03), and emotion dysregulation (p <= 0.01). There was no association between emotion dysregulation and pulling severity (r = −0.02, p = 0.89). Perceived stress was associated with emotion dysregulation in both groups (p < 0.01), and no association between childhood trauma and emotion dysregulation in either group. Perceived stress was the only significant predictor of emotion dysregulation in both groups (F = 28.29, p < 0.01).

Conclusion: The association between perceived stress and emotion dysregulation is not specific to TTM, and there is no association between emotion dysregulation and hair-pulling severity, suggesting that key factors other than emotion dysregulation contribute to hair-pulling. Alternative explanatory models are needed.
Anxious Attachment Mediates the Associations Between Early Recollections of Mother's Own Parental Bonding and Mother–Infant Bonding: A 2-Month Path Analysis Model
Authors: Kalfon Hakhmigari Maor , Peled Yoav , Krissi Haim , Levy Sigal , Molmen-Lichter Maayan , Handelzalts Jonathan E.
Published: July 2021

Parental bonding (recollection of own parents' parenting), adult attachment, and mother–infant bonding are all closely related yet distinct concepts of the parent–child relationship, sometimes used interchangeably in the literature. This study aimed to examine the associations between these concepts in a longitudinal path analysis design. A total of 262 postpartum women who gave birth at the maternity ward of a large tertiary health center in Israel completed a demographic questionnaire, the Experiences in Close Relationships Scale (ECR), the Parental Bonding Instrument (PBI) at 1–4 days postpartum, and the Postpartum Bonding Questionnaire (PBQ) at 2 months postpartum. Parental care factor (PBI) was found to be associated with mother–infant bonding (PBQ), directly and indirectly through insecure anxious attachment (ECR). Denial of autonomy factor (PBI) was found to be associated with mother–infant bonding (PBQ) only through insecure anxious attachment (ECR). Encouragement of behavioral freedom factor (PBI) was found to be associated with mother–infant bonding (PBQ) in a simple correlation but not in the complete model. The results highlight the intergenerational aspects of parenting and suggest that early childhood interventions with parents may have a long-term impact on child-rearing though generations, and by that on children's development.
From the Clinic to the Laboratory, and Back Again: Investigations on Cannabinoids and Endocannabinoid System Modulators for Treating Schizophrenia
Authors: Hoffman Kurt Leroy
Published: July 2021

The present mini-review focuses on animal models of schizophrenia that have explored the effects of cannabidiol (CBD; a non-psychoactive component of cannabis) or the pharmacological manipulation of the endocannabinoid system on behavioral and cognitive outcome measures. First, results of some relevant clinical studies in this area are summarized, and then pre-clinical work on animal models of schizophrenia based on NMDA receptor antagonism or neurodevelopmental manipulations are discussed. A brief overview is given of the theoretical framework on which these models are based, along with a concise summary of results that have been obtained. Clinical results using CBD for schizophrenia seem promising and its effects in animal models of schizophrenia support its potential as a useful pharmacotherapy. Animal models have been paramount for elucidating the actions of CBD and the function of the endocannabinoid system and for identifying novel pharmacological targets, such as cannabinoid receptors and anandamide. However, more attention needs to be placed on defining and applying independent variables and outcome measures that are comparable between pre-clinical and clinical studies. The objective of this review is, on the one hand, to emphasize the potential of such models to predict clinical response to experimental drugs, and on the other hand, to highlight areas in which research on such models could be improved.
The Optimal Machine Learning-Based Missing Data Imputation for the Cox Proportional Hazard Model
Authors: Guo Chao-Yu , Yang Ying-Chen , Chen Yi-Hau
Published: July 2021

An adequate imputation of missing data would significantly preserve the statistical power and avoid erroneous conclusions. In the era of big data, machine learning is a great tool to infer the missing values. The root means square error (RMSE) and the proportion of falsely classified entries (PFC) are two standard statistics to evaluate imputation accuracy. However, the Cox proportional hazards model using various types requires deliberate study, and the validity under different missing mechanisms is unknown. In this research, we propose supervised and unsupervised imputations and examine four machine learning-based imputation strategies. We conducted a simulation study under various scenarios with several parameters, such as sample size, missing rate, and different missing mechanisms. The results revealed the type-I errors according to different imputation techniques in the survival data. The simulation results show that the non-parametric “missForest” based on the unsupervised imputation is the only robust method without inflated type-I errors under all missing mechanisms. In contrast, other methods are not valid to test when the missing pattern is informative. Statistical analysis, which is improperly conducted, with missing data may lead to erroneous conclusions. This research provides a clear guideline for a valid survival analysis using the Cox proportional hazard model with machine learning-based imputations.