bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroprotective Effect for Cerebral Ischemia by Natural Products: A Review
Authors: Xie Qian , Li Hongyan , Lu Danni , Yuan Jianmei , Ma Rong , Li Jinxiu , Ren Mihong , Li Yong , Chen Hai , Wang Jian , Gong Daoyin
Published: April 2021

Natural products have a significant role in the prevention of disease and boosting of health in humans and animals. Stroke is a disease with high prevalence and incidence, the pathogenesis is a complex cascade reaction. In recent years, it’s reported that a vast number of natural products have demonstrated beneficial effects on stroke worldwide. Natural products have been discovered to modulate activities with multiple targets and signaling pathways to exert neuroprotection via direct or indirect effects on enzymes, such as kinases, regulatory receptors, and proteins. This review provides a comprehensive summary of the established pharmacological effects and multiple target mechanisms of natural products for cerebral ischemic injury in vitro and in vivo preclinical models, and their potential neuro-therapeutic applications. In addition, the biological activity of natural products is closely related to their structure, and the structure-activity relationship of most natural products in neuroprotection is lacking, which should be further explored in future. Overall, we stress on natural products for their role in neuroprotection, and this wide band of pharmacological or biological activities has made them suitable candidates for the treatment of stroke.
No Efficacy of the Combination of Lopinavir/Ritonavir Plus Hydroxychloroquine Versus Standard of Care in Patients Hospitalized With COVID-19: A Non-Randomized Comparison
Authors: Gagliardini Roberta , Cozzi-Lepri Alessandro , Mariano Andrea , Taglietti Fabrizio , Vergori Alessandra , Abdeddaim Amina , Di Gennaro Francesco , Mazzotta Valentina , Amendola Alessandra , D’Offizi Giampiero , Palmieri Fabrizio , Marchioni Luisa , Piselli Pierluca , Agrati Chiara , Nicastri Emanuele , Capobianchi Maria Rosaria , Petrosillo Nicola , Ippolito Giuseppe , Vaia Francesco , Girardi Enrico , Antinori Andrea
Published: April 2021

Objectives: No specific treatment has been approved for COVID-19. Lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ) have been used with poor results, and a trial showed advantages of combined antiviral therapy vs. single antivirals. The aim of the study was to assess the effectiveness of the combination of antivirals (LPV/r and HCQ) or their single use in COVID-19 hospitalized patients vs. standard of care (SoC).

Methods: Patients ≥18 years with SARS-CoV-2 infection, defined as positive RT-PCR from nasal/oropharyngeal (NP/OP) swab or positive serology, admitted at L. Spallanzani Institute (Italy) were included.

Primary endpoint: time to invasive ventilation/death. Secondary endpoint: time to two consecutive negative SARS-CoV-2 PCRs in NP/OP swabs. In order to control for measured confounders, a marginal Cox regression model with inverse probability weights was used.

Results: A total of 590 patients were included in the analysis: 36.3% female, 64 years (IQR 51–76), and 91% with pneumonia. Cumulative probability of invasive ventilation/death at 14 days was 21.2% (95% CI 17.6, 24.7), without difference between SOC, LPV/r, hydroxychloroquine, HCQ + LPV/r, and SoC. The risk of invasive ventilation/death in the groups appeared to vary by baseline ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2). Overall cumulative probability of confirmed negative nasopharyngeal swabs at 14 days was 44.4% (95% CI 38.9, 49.9), without difference between groups.

Conclusion: In this retrospective analysis, we found no difference in the rate of invasive ventilation/death or viral shedding by different strategies, as in randomized trials performed to date. Moreover, even the combination HCQ + LPV/r did not show advantages vs. SoC.
Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation
Authors: Jiang Yuhong , Zhuo Xin , Fu Xiujuan , Wu Yue , Mao Canquan
Published: April 2021

Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the in vivo study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC.
Emulated Clinical Trials from Longitudinal Real-World Data Efficiently Identify Candidates for Neurological Disease Modification: Examples from Parkinson’s Disease
Authors: Laifenfeld Daphna , Yanover Chen , Ozery-Flato Michal , Shaham Oded , Rosen-Zvi Michal , Lev Nirit , Goldschmidt Yaara , Grossman Iris
Published: April 2021

Real-world healthcare data hold the potential to identify therapeutic solutions for progressive diseases by efficiently pinpointing safe and efficacious repurposing drug candidates. This approach circumvents key early clinical development challenges, particularly relevant for neurological diseases, concordant with the vision of the 21st Century Cures Act. However, to-date, these data have been utilized mainly for confirmatory purposes rather than as drug discovery engines. Here, we demonstrate the usefulness of real-world data in identifying drug repurposing candidates for disease-modifying effects, specifically candidate marketed drugs that exhibit beneficial effects on Parkinson’s disease (PD) progression. We performed an observational study in cohorts of ascertained PD patients extracted from two large medical databases, Explorys SuperMart (N = 88,867) and IBM MarketScan Research Databases (N = 106,395); and applied two conceptually different, well-established causal inference methods to estimate the effect of hundreds of drugs on delaying dementia onset as a proxy for slowing PD progression. Using this approach, we identified two drugs that manifested significant beneficial effects on PD progression in both datasets: rasagiline, narrowly indicated for PD motor symptoms; and zolpidem, a psycholeptic. Each confers its effects through distinct mechanisms, which we explored via a comparison of estimated effects within the drug classification ontology. We conclude that analysis of observational healthcare data, emulating otherwise costly, large, and lengthy clinical trials, can highlight promising repurposing candidates, to be validated in prospective registration trials, beneficial against common, late-onset progressive diseases for which disease-modifying therapeutic solutions are scarce.
Resveratrol in Rodent Models of Parkinson’s Disease: A Systematic Review of Experimental Studies
Authors: Su Cheng-Fu , Jiang Li , Zhang Xiao-Wen , Iyaswamy Ashok , Li Min
Published: April 2021

Parkinson’s disease (PD) is a common neurodegenerative disease featured by progressive degeneration of nigrostriatal dopaminergic neurons (DA) accompanied with motor function impairment. Accumulating evidence has demonstrated that natural compounds from herbs have potent anti-PD efficacy in PD models. Among those compounds, resveratrol, a polyphenol found in many common plants and fruits, is more effective against PD. Resveratrol has displayed a potent neuroprotective efficacy in several PD animal models. However, there is still no systematic analysis of the quality of methodological design of these studies, nor of their results. In this review, we retrieved and analyzed 18 studies describing the therapeutic effect of resveratrol on PD animal models. There are 5 main kinds of PD rodent models involved in the 18 articles, including chemical-induced (MPTP, rotenone, 6-OHDA, paraquat, and maneb) and transgenic PD models. The neuroprotective mechanisms of resveratrol were mainly concentrated on the antioxidation, anti-inflammation, ameliorating mitochondrial dysfunction, and motor function. We discussed the disadvantages of different PD animal models, and we used meta-analysis approach to evaluate the results of the selected studies and used SYRCLE’s risk of bias tool to evaluate the methodological quality. Our analytical approach minimized the bias of different studies. We have also summarized the pharmacological mechanisms of resveratrol on PD models as reported by the researchers. The results of this study support the notion that resveratrol has significant neuroprotective effects on different PD models quantified using qualitative and quantitative methods. The collective information in our review can guide researchers to further plan their future experiments without any hassle regarding preclinical and clinical studies. In addition, this collective assessment of animal studies can provide a qualitative analysis of different PD animal models, either to guide further testing of these models or to avoid unnecessary duplication in their future research.
Targeting Ubiquitin-Specific Protease 7 (USP7) in Cancer: A New Insight to Overcome Drug Resistance
Authors: Lu Jiabin , Zhao He , Yu Caini , Kang Yuanyuan , Yang Xiaochun
Published: April 2021

Chemoresistance is one of the leading causes for the failure of tumor treatment. Hence, it is necessary to study further and understand the potential mechanisms of tumor resistance to design and develop novel anti-tumor drugs. Post-translational modifications are critical for proteins’ function under physiological and pathological conditions, among which ubiquitination is the most common one. The protein degradation process mediated by the ubiquitin-proteasome system is the most well-known function of ubiquitination modification. However, ubiquitination also participates in the regulation of many other biological processes, such as protein trafficking and protein-protein interaction. A group of proteins named deubiquitinases can hydrolyze the isopeptide bond and disassemble the ubiquitin-protein conjugates, thus preventing substrate proteins form degradation or other outcomes. Ubiquitin-specific protease 7 (USP7) is one of the most extensively studied deubiquitinases. USP7 exhibits a high expression signature in various malignant tumors, and increased USP7 expression often indicates the poor tumor prognosis, suggesting that USP7 is a marker of tumor prognosis and a potential drug target for anti-tumor therapy. In this review, we first discussed the structure and function of USP7. Further, we summarized the underlying mechanisms by which tumor cells develop resistance to anti-tumor therapies, provided theoretical support for targeting USP7 to overcome drug resistance, and some inspiration for the design and development of USP7 inhibitors.
Efficacy and Safety of Panax Notoginseng Saponins (Xueshuantong) in Patients With Acute Ischemic Stroke (EXPECT) Trial: Rationale and Design
Authors: Feng Luda , Han Fang , Zhou Li , Wu Shengxian , Du Yawei , Zhang Dandan , Zhang Chi , Gao Ying
Published: April 2021

Background: Although revascularization treatment is recommended as the first-line therapy for patients with non-minor acute ischemic stroke (AIS), it only benefits a minority of patients. Previous studies have reported the positive effects of Panax notoginseng saponins (PNS) (Xueshuantong lyophilized powder) on AIS, however, there have been no rigorous trials. This study aims to assess the efficacy and safety of PNS therapy for patients with AIS.

Methods: The Evaluation of Xueshuantong in Patients with acutE ischemiC sTroke (EXPECT) trial is a multicenter, randomized, placebo-controlled, double-blind study aiming to enroll 480 patients in China. Eligible patients with AIS within 72 h of symptom onset will randomly receive either PNS or PNS placebo for 10 days and subsequently be followed up to 90 days. The primary outcome will be a change in the National Institute of Health Stroke Scale (NIHSS) score from baseline to 10 post-randomization days. The secondary outcomes include early neurological improvement (proportion of patients with NIHSS score 0–1), and Patient-Reported Outcomes Scale for Stroke score at 10 post-randomization days, the proportion of patients with life independence (modified Rankin Scale score of 0–1), the proportion of patients with a favorable outcome (Barthel Index ≥90), and Stroke-Specific Quality of Life score at 90 days. Adverse events or clinically significant changes in vital signs and laboratory parameters, regardless of the severity, will be recorded during the trial to assess the safety of PNS.

Conclusions: To our knowledge, this study is the first double-blind trial to assess the efficacy and safety of PNS in patients with AIS. Findings of the EXPECT trial will be valuable in improving evidence regarding the clinical application of PNS therapy in patients with AIS ineligible for revascularization treatment in the reperfusion era.
Inhibition of Small-Conductance, Ca2+-Activated K+ Current by Ondansetron
Authors: Guo Shuai , Chen Zhenhui , Chen Peng-Sheng , Rubart Michael
Published: April 2021

Background:Small-conductance Ca2+-activated K+channels (SK channels) have been proposed as antiarrhythmic targets for the treatment of atrial fibrillation. We previously demonstrated that the 5-HT3receptor antagonist ondansetron inhibits heterologously expressed, human SK2 (hSK2) currents as well as native cardiac SK currents in a physiological extra-/intracellular [K+] gradient at therapeutic (i.e., sub-micromolar) concentrations. A recent study, using symmetrical [K+] conditions, challenged this result. The goal of the present study was to revisit the inhibitory effect of ondansetron on hSK2-mediated currents in symmetrical [K+] conditions.

Experimental Approach:The whole-cell patch clamp technique was used to investigate the effects of ondansetron and apamin on hSK2-mediated currents expressed in HEK 293 cells. Currents were measured in symmetrical [K+] conditions in the presence of 100 nM [Ca2+]o.

Results:Expression of hSK2 produced inwardly rectifying whole-cell currents in the presence of 400 nM free cytosolic Ca2+. Ondansetron inhibited whole-cell hSK2 currents withIC50values of 154 and 113 nM at −80 and 40 mV, respectively. Macroscopic current inhibited by ondansetron and current inhibited by apamin exhibited inwardly rectifying current-voltage relationships with similar reversal potentials (apamin, ∼5 mV and ondansetron, ∼2 mV). Ondansetron (1 μM) in the continuing presence of apamin (100 nM) had no effect on hSK2-mediated whole-cell currents. Wild-type HEK 293 cells did not express ondansetron- or apamin-sensitive currents.

Conclusion:Ondansetron in sub-micromolar concentrations inhibits hSK2 currents even under altered ionic conditions.
Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models
Authors: Haberkorn Bastian , Fromm Martin F. , König Jörg
Published: April 2021

Organic Cation Transporter 1 (OCT1, gene symbol: SLC22A1) is predominately expressed in human liver, localized in the basolateral membrane of hepatocytes and facilitates the uptake of endogenous compounds (e.g. serotonin, acetylcholine, thiamine), and widely prescribed drugs (e.g. metformin, fenoterol, morphine). Furthermore, exogenous compounds such as MPP+, ASP+ and Tetraethylammonium can be used as prototypic substrates to study the OCT1-mediated transport in vitro. Single-transfected cell lines recombinantly overexpressing OCT1 (e.g., HEK-OCT1) were established to study OCT1-mediated uptake and to evaluate transporter-mediated drug-drug interactions in vitro. Furthermore, double-transfected cell models simultaneously overexpressing basolaterally localized OCT1 together with an apically localized export protein have been established. Most of these cell models are based on polarized grown MDCK cells and can be used to analyze transcellular transport, mimicking the transport processes e.g. during the hepatobiliary elimination of drugs. Multidrug and toxin extrusion protein 1 (MATE1, gene symbol: SLC47A1) and the ATP-driven efflux pump P-glycoprotein (P-gp, gene symbol: ABCB1) are both expressed in the canalicular membrane of human hepatocytes and are described as transporters of organic cations. OCT1 and MATE1 have an overlapping substrate spectrum, indicating an important interplay of both transport proteins during the hepatobiliary elimination of drugs. Due to the important role of OCT1 for the transport of endogenous compounds and drugs, in vitro cell systems are important for the determination of the substrate spectrum of OCT1, the understanding of the molecular mechanisms of polarized transport, and the investigation of potential drug-drug interactions. Therefore, the aim of this review article is to summarize the current knowledge on cell systems recombinantly overexpressing human OCT1.
Impaired HSP70 Expression in the Aorta of Female Rats: A Novel Insight Into Sex-Specific Differences in Vascular Function
Authors: de Oliveira Amanda Almeida , Priviero Fernanda , Webb R. Clinton , Nunes Kenia Pedrosa
Published: April 2021

Heat-shock protein 70 (HSP70) contributes to cellular calcium (Ca2+) handling mechanisms during receptor-mediated vascular contraction. Interestingly, previous studies have independently reported sex-related differences in HSP70 expression and Ca2+ dynamics. Still, it is unknown if sex, as a variable, plays a role in the impact that HSP70 has upon vascular contraction. To narrow this gap, we investigated if differences exist in the expression levels of HSP70 in the aorta, and if targeting this protein contributes to sex disparity in vascular responses. We report that, compared with male animals, female rats present a reduction in the basal levels of HSP70. More compelling, we found that the blockade of HSP70 has a greater impact on phenylephrine-induced phasic and tonic vascular contraction in female animals. In fact, it seems that the inhibition of HSP70 significantly affects vascular Ca2+ handling mechanisms in females, which could be associated with the fact that these animals have impaired HSP70 expression. Corroborating this idea, we uncovered that the higher sensitivity of female rats to HSP70 inhibition does not involve an increase in NO-dependent vasodilation nor a decrease in vascular oxidative stress. In summary, our findings reveal a novel mechanism associated with sex-specific differences in vascular responses to α-1 adrenergic stimulation, which might contribute to unraveling the network of intertwined pathways conferring female protection to (cardio)vascular diseases.
Secreted in Xylem Genes: Drivers of Host Adaptation in Fusarium oxysporum
Authors: Jangir Pooja , Mehra Namita , Sharma Karuna , Singh Neeraja , Rani Mamta , Kapoor Rupam
Published: April 2021

Fusarium oxysporum(Fo) is a notorious pathogen that significantly contributes to yield losses in crops of high economic status. It is responsible for vascular wilt characterized by the browning of conductive tissue, wilting, and plant death. Individual strains ofFoare host specific (formae speciales), and approximately, 150 forms have been documented so far. The pathogen secretes small effector proteins in the xylem, termed as Secreted in Xylem (Six), that contribute to its virulence. Most of these proteins contain cysteine residues in even numbers. These proteins are encoded bySIXgenes that reside on mobile pathogenicity chromosomes. So far, 14 proteins have been reported. However,formae specialesvary inSIXprotein profile and their respective gene sequence. Thus,SIXgenes have been employed as ideal markers for pathogen identification. Acquisition ofSIX-encoding mobile pathogenicity chromosomes by non-pathogenic lines, through horizontal transfer, results in the evolution of new virulent lines. Recently, someSIXgenes present on these pathogenicity chromosomes have been shown to be involved in defining variation in host specificity amongformae speciales. Along these lines, the review entails the variability (formae speciales, races, and vegetative compatibility groups) and evolutionary relationships among members ofF. oxysporumspecies complex (FOSC). It provides updated information on the diversity, structure, regulation, and (a)virulence functions ofSIXgenes. The improved understanding of roles ofSIXin variability and virulence ofFohas significant implication in establishment of molecular framework and techniques for disease management. Finally, the review identifies the gaps in current knowledge and provides insights into potential research landscapes that can be explored to strengthen the understanding of functions ofSIXgenes.
CRISPR/Cas9-Induced fad2 and rod1 Mutations Stacked With fae1 Confer High Oleic Acid Seed Oil in Pennycress (Thlaspi arvense L.)
Authors: Jarvis Brice A. , Romsdahl Trevor B. , McGinn Michaela G. , Nazarenus Tara J. , Cahoon Edgar B. , Chapman Kent D. , Sedbrook John C.
Published: April 2021

Pennycress (Thlaspi arvense L.) is being domesticated as an oilseed cash cover crop to be grown in the off-season throughout temperate regions of the world. With its diploid genome and ease of directed mutagenesis using molecular approaches, pennycress seed oil composition can be rapidly tailored for a plethora of food, feed, oleochemical and fuel uses. Here, we utilized Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology to produce knockout mutations in the FATTY ACID DESATURASE2 (FAD2) and REDUCED OLEATE DESATURATION1 (ROD1) genes to increase oleic acid content. High oleic acid (18:1) oil is valued for its oxidative stability that is superior to the polyunsaturated fatty acids (PUFAs) linoleic (18:2) and linolenic (18:3), and better cold flow properties than the very long chain fatty acid (VLCFA) erucic (22:1). When combined with a FATTY ACID ELONGATION1 (fae1) knockout mutation, fad2 fae1 and rod1 fae1 double mutants produced ∼90% and ∼60% oleic acid in seed oil, respectively, with PUFAs in fad2 fae1 as well as fad2 single mutants reduced to less than 5%. MALDI-MS spatial imaging analyses of phosphatidylcholine (PC) and triacylglycerol (TAG) molecular species in wild-type pennycress embryo sections from mature seeds revealed that erucic acid is highly enriched in cotyledons which serve as storage organs, suggestive of a role in providing energy for the germinating seedling. In contrast, PUFA-containing TAGs are enriched in the embryonic axis, which may be utilized for cellular membrane expansion during seed germination and seedling emergence. Under standard growth chamber conditions, rod1 fae1 plants grew like wild type whereas fad2 single and fad2 fae1 double mutant plants exhibited delayed growth and overall reduced heights and seed yields, suggesting that reducing PUFAs below a threshold in pennycress had negative physiological effects. Taken together, our results suggest that combinatorial knockout of ROD1 and FAE1 may be a viable route to commercially increase oleic acid content in pennycress seed oil whereas mutations in FAD2 will likely require at least partial function to avoid fitness trade-offs.
Intensified Job Demands and Cognitive Stress Symptoms: The Moderator Role of Individual Characteristics
Authors: Rantanen Johanna , Lyyra Pessi , Feldt Taru , Villi Mikko , Parviainen Tiina
Published: April 2021

Intensified job demands (IJDs) originate in the general accelerated pace of society and ever-changing working conditions, which subject workers to increasing workloads and deadlines, constant planning and decision-making about one’s job and career, and the continual learning of new professional knowledge and skills. This study investigated how individual characteristics, namely negative and positive affectivity related to competence demands, and multitasking preference moderate the association between IJDs and cognitive stress symptoms among media workers (n = 833; 69% female, mean age 48 years). The results show that although IJDs were associated with higher cognitive stress symptoms at work, that is, difficulties in concentration, thinking clearly, decision-making, and memory, competence demands-related negative affectivity explained the most variance in cognitive stress symptoms. In addition, IJDs were more strongly associated with cognitive stress symptoms at work in individuals with high competence demand-related negative affectivity, and low multitasking preference (moderation effects). Altogether, the present findings suggest that HR practices or workplace interventions to ease employees’ negative affectivity from increasing competence demands at work could usefully support employees’ effective cognitive functioning when confronted with IJDs.
Usability and User Experience of Cognitive Intervention Technologies for Elderly People With MCI or Dementia: A Systematic Review
Authors: Contreras-Somoza Leslie María , Irazoki Eider , Toribio-Guzmán José Miguel , de la Torre-Díez Isabel , Diaz-Baquero Angie Alejandra , Parra-Vidales Esther , Perea-Bartolomé María Victoria , Franco-Martín Manuel Ángel
Published: April 2021

Introduction

Incorporating technology in cognitive interventions represents an innovation, making them more accessible, flexible, and cost-effective. This will not be feasible without adequate user-technology fit. Bearing in mind the importance of developing cognitive interventions whose technology is appropriate for elderly people with cognitive impairment, the objective of this systematic review was to find evidence about usability and user experience (UX) measurements and features of stimulation, training, and cognitive rehabilitation technologies for older adults with mild cognitive impairment (MCI) or dementia.

Method

The Medline, PubMed, Scopus, ScienceDirect, and PsycINFO databases were searched for literature published in the last 10 years (2009–2019), and three researchers independently reviewed potentially eligible studies, following specific inclusion criteria. A systematic review of the studies was conducted, presenting a qualitative synthesis of usability and UX measures with their outcomes, study characteristics and features of the cognitive intervention technologies.

Results

Ten studies were selected: five were cognitive stimulation and five were cognitive training. Most of them (60%) were computer-based programs with a serious game format. Efficiency and effectiveness were the most frequent measurements used for collecting objective usability data, showing that elderly people with cognitive impairment require more time (45%) and help (40%) but can complete tasks (60%). Regarding UX or subjective usability data, questionnaires and scales were the most used methods, reporting positive experience despite certain difficulties with the interface in five studies.

Conclusion

Measuring usability and UX in cognitive intervention technologies for older adults with MCI or dementia provides an integrated view that can contribute to their development according to the needs and characteristics of the target population. More research is required to include this population group in usability and UX studies, as well as standardized tools and consensus on the relationship of these terms to guarantee the future effectiveness of cognitive intervention technologies.

Review registration

This review was registered in the PROSPERO (CRD42020158147) International Register of Systematic Review Protocols.
Modeling Input Factors in Second Language Acquisition of the English Article Construction
Authors: Zhao Helen , Fan Jason
Published: April 2021

Based on the Competition Model, the current study investigated how cue availability and cue reliability as two important input factors influenced second language (L2) learners' cue learning of the English article construction. Written corpus data of university-level Chinese-L1 learners of English were sampled for a comparison of English majors and non-English majors who demonstrated two levels of L2 competence in English article usage. The path model analysis in structural equation modeling was utilized to investigate the relationship between the input factors and L2 usage (frequency and accuracy of article cue production). The findings contribute novel and scarce empirical evidence that confirms a central claim of the Competition Model, i.e., the changing importance of cue availability and cue reliability in the frequency and accuracy of production. Cue availability was found to determine L2 production frequency regardless of level of L2 competence. Cue reliability was the input factor that differentiated competence levels. When learners stayed at a relatively lower L2 proficiency, cue reliability played an important role in influencing L2 frequency of usage rather than accuracy of usage. When learners developed increased exposure to and stronger competence in the target language, cue reliability played a significant role in determining learners' success of cue learning. The study is methodologically innovative and expands the empirical applicability of the Competition Model to the domain of second language production and construction learning.
Family Business Internationalization in Paradox: Effects of Socioemotional Wealth and Entrepreneurial Spirit
Authors: Jin Chenfei , Wu Bao , Hu Yingjie
Published: April 2021

This study investigates the internationalization (i. e., foreign investment) of small family businesses by classifying the effects of external socioemotional wealth (family reputation) vs. internal socioemotional wealth (family involvement). The study involved 2,704 small family businesses in China, and the results support the hypothesis that family reputation has a positive effect on internationalization, while family involvement has a negative effect on internationalization. Moreover, entrepreneurial spirit reinforces the positive effect of family reputation on internationalization and enhances the negative relationship between family involvement and internationalization. This study contributes by examining the effect of entrepreneurial spirit as a potential balancing factor for the paradoxical influence of internal vs. external socioemotional wealth.
Brain Functional and Structural Alterations in Women With Bipolar Disorder and Suicidality
Authors: Guo Huiling , Zhang Ran , Wang Pengshuo , Zhang Luheng , Yin Zhiyang , Zhang Yifan , Wei Shengnan , Chang Miao , Jiang Xiaowei , Tang Yanqing , Wang Fei
Published: April 2021

Objective: Suicide is the leading cause of death from bipolar disorder (BD). At least 25–50% of the patients with BD will attempt suicide, with suicide rates much higher in women patients than in men. It is crucial to explore the potential neural mechanism underlying suicidality in women with BD, which will lead to understanding and detection of suicidality and prevent death and injury from suicide.

Methods: Brain function and structure were measured by amplitude of low-frequency fluctuation (ALFF) and gray matter volume (GMV) in 155 women [30 women with BD and a history of suicidality, 50 women with BD without suicidality, and 75 healthy controls (HC)]. The differences in ALFF and GMV across the BD with suicidality, BD without suicidality, and HC groups were investigated.

Results: BD with suicidality showed significantly increased ALFF in the left and right cuneus compared with BD without suicidality and HC groups. Moreover, the GMV in the left lateral prefrontal cortex and left cuneus in BD with suicidality were significantly lower than those in BD without suicidality and HC groups, while the GMV of the right ventral prefrontal cortex was significantly decreased in both BD with and without suicidality groups.

Conclusions: This study, combining functional and structural neuroimaging techniques, may help to identify specific pathophysiological changes in women with BD and suicidality. Increased ALFF and less GMV in cuneus might represent the neuroimaging features of suicidality in women with BD. Investigating this potential neuromarker for suicidality in women with BD may lead to the ability to prevent suicidality.
A Mini-Review of Relationships Between Cannabis Use and Neural Foundations of Reward Processing, Inhibitory Control and Working Memory
Authors: Morie Kristen P. , Potenza Marc N.
Published: April 2021

Cannabis is commonly used, and use may be increasing in the setting of increasing legalization and social acceptance. The scope of the effects of cannabis products, including varieties with higher or lower levels of Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD), on domains related to addictive behavior deserves attention, particularly as legalization continues. Cannabis use may impact neural underpinnings of cognitive functions linked to propensities to engage in addictive behaviors. Here we consider these neurocognitive processes within the framework of the dual-process model of addictions. In this mini-review, we describe data on the relationships between two main constituents of cannabis (THC and CBD) and neural correlates of reward processing, inhibitory control and working memory.
The Psychological Status of General Population in Hubei Province During the COVID-19 Outbreak: A Cross-Sectional Survey Study
Authors: Chen Guanmao , Gong Jiaying , Qi Zhangzhang , Zhong Shuming , Su Ting , Wang Jurong , Fu Siying , Huang Li , Wang Ying
Published: April 2021

Introduction: The current outbreak of the novel coronavirus disease 2019 (COVID-19), originating from Wuhan (Hubei, China), has rapidly spread across China and several other countries. During the outbreak of COVID-19, mental health of the general population in Hubei province may be affected. This study aimed to assess the psychological status and associated risk factors of the general population in Hubei province during the COVID-19 outbreak.

Methods: A cross-sectional online survey was used to evaluate the symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety, which were assessed by the Chinese version of the Impact of Event Scale—Revised, the Patient Health Questionnaire 9, and the seven-item Generalized Anxiety Disorder Scale, respectively. Coping style was assessed by the Simplified Coping Style Questionnaire. Multivariate logistic regression analysis was carried out to detect factors associated with mental health outcomes.

Results: Among 9,225 participants, 44.5% rated symptoms of PTSD, and 17.9 and 12.7% suffered from moderate and severe symptoms of depression and anxiety, respectively. Individuals who were geographically located in Wuhan and familiar with someone who has COVID-19 had more severe symptoms of PTSD, depression, and anxiety, as well as a higher score in passive coping style (P < 0.05). Multivariate logistic regression analysis showed that people who were geographically located in Wuhan [odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.14–1.36, P < 0.001] were associated with severe symptoms of PTSD. Besides, individuals who were familiar with someone who had COVID-19 (OR = 2.33, 95% CI = 2.07–2.63, P < 0.001; OR = 1.90, 95% CI = 1.66–2.17, P < 0.001; OR = 2.06, 95% CI = 1.78–2.39, P < 0.001) and had a higher score in passive coping style (OR = 1.16, 95% CI = 1.14–1.17, P < 0.001; OR = 1.17, 95% CI = 1.15–1.19, P < 0.001; OR = 1.17, 95% CI = 1.15–1.19, P < 0.001) were associated with severe symptoms of PTSD, depression, and anxiety. Moreover, a higher score in active coping style (OR = 0.96, 95% CI = 0.95–0.97, P < 0.001; OR = 0.94, 95% CI = 0.93–0.94, P < 0.001; OR = 0.95, 95% CI = 0.94–0.96, P < 0.001) was associated with a lower risk of symptoms of PTSD, depression, and anxiety.

Conclusions: During the midphase of COVID-19 outbreak, quite a few people have mental health problems; nearly half of the respondents rated symptoms of PTSD, and approximately one-fifth reported moderate to severe symptoms of anxiety and depression. Our findings may lead to better comprehend the psychological status of the general public and alleviate the public mental health crisis during the COVID-19 outbreak.
Comparative Utility of Genetic Determinants of Drug Resistance and Phenotypic Drug Susceptibility Profiling in Predicting Clinical Outcomes in Patients With Multidrug-Resistant Mycobacterium tuberculosis
Authors: Che Yang , Yang Tianchi , Lin Lv , Xiao Yue , Jiang Feng , Chen Yanfei , Chen Tong , Zhou Jifang
Published: April 2021

Setting: Programmatic management of drug-resistant tuberculosis in Ningbo, China.

Objective: To assess whether data-driven genetic determinants of drug resistance patterns could outperform phenotypic drug susceptibility testing in predicting clinical meaningful outcomes among patients with multidrug-resistant tuberculosis (MDR-TB).

Design: We conducted a prospective cohort study of 104 MDR-TB patients. All MDR-TB isolates underwent drug susceptibility testing and genotyping for mutations that could cause drug resistance. Study outcomes were time to sputum smear conversion and probability of treatment success, as well as time to culture conversion within 6 months. Data were analyzed using latent class analysis, Kaplan–Meier curves, and Cox regression models.

Results: We report that latent class analysis of data identified two latent classes that predicted sputum smear conversion with P = 0.001 and area under receiver-operating characteristic curve of 0.73. The predicted latent class memberships were associated with superior capability in predicting sputum culture conversion at 6 months and overall treatment success compared to phenotypic drug susceptibility profiling using boosted logistic regression models.

Conclusion: These results suggest that genetic determinants of drug resistance in combination with phenotypic drug-resistant tests could serve as useful biomarkers in predicting treatment prognosis in MDR-TB.
Irradiation-Induced Changes in the Immunogenicity of Lung Cancer Cell Lines: Based on Comparison of X-rays and Carbon Ions
Authors: Ran Juntao , Wang Jiangtao , Dai Ziying , Miao Yandong , Gan Jian , Zhao Chengpeng , Guan Quanlin
Published: April 2021

Increasing the immunogenicity of tumors is considered to be an effective means to improve the synergistic immune effect of radiotherapy. Carbon ions have become ideal radiation for combined immunotherapy due to their particular radiobiological advantages. However, the difference in time and dose of immunogenic changes induced by Carbon ions and X-rays has not yet been fully clarified. To further explore the immunogenicity differences between carbon ions and X-rays induced by radiation in different “time windows” and “dose windows.” In this study, we used principal component analysis (PCA) to screen out the marker genes from the single-cell RNA-sequencing (scRNA-seq) of CD8+ T cells and constructed a protein-protein interaction (PPI) network. Also, ELISA was used to test the exposure levels of HMGB1, IL-10, and TGF-β under different “time windows” and “dose windows” of irradiation with X-rays and carbon ions for A549, H520, and Lewis Lung Carcinoma (LLC) cell lines. The results demonstrated that different marker genes were involved in different processes of immune effect. HMGB1 was significantly enriched in the activated state, while the immunosuppressive factors TGF-β and IL-10 were mainly enriched in the non-functional state. Both X-rays and Carbon ions promoted the exposure of HMGB1, IL-10, and TGF-β in a time-dependent manner. X-rays but not Carbon ions increased the HMGB1 exposure level in a dose-dependent manner. Besides, compared with X-rays, carbon ions increased the exposure of HMGB1 while relatively reduced the exposure levels of immunosuppressive factors IL-10 and TGF-β. Therefore, we speculate that Carbon ions may be more advantageous than conventional X-rays in inducing immune effects.
How Do Economic Fluctuations Affect the Mortality of Infectious Diseases?
Authors: Sun Ting-Ting , Tao Ran , Su Chi-Wei , Umar Muhammad
Published: April 2021

This paper uses the mixed frequency vector autoregression model to explore the impact of economic fluctuations on infectious diseases mortality (IDM) from China perspective. We find that quarterly gross domestic product (GDP) fluctuations have a negative impact on the annual IDM, indicating that the mortality of infectious diseases varies counter-cyclically with the business cycle in China. Specifically, IDM usually increases with deterioration in economic conditions, and vice versa. The empirical results are consistent with the hypothesis I derived from the theoretical analysis, which highlights that economic fluctuations can negatively affect the mortality of infectious diseases. The findings can offer revelations for the government to consider the role of economic conditions in controlling the epidemic of infectious diseases. Policymakers should adopt appropriate and effective strategies to mitigate the potential negative effects of macroeconomic downturns on the mortality of infectious diseases. In the context of the COVID-19 pandemic, these analyses further emphasize the importance of promoting economic growth, increasing public health expenditure, and preventing and controlling foreign infectious diseases.
Highly Cited Papers at the Spanish Domestic Level
Authors: García-Zorita Carlos , Marugán Sergio , De Filippo Daniela , Sanz-Casado Elías
Published: April 2021

This paper presents a methodological proposal based on the identification of highly cited papers (HCPs) at domestic-level in the Spanish Public University System (SUPE), in order to find the most outstanding publications in the local context. The principal aim is to detect different activity and impact profiles among Spanish universities and differentiate those institutions that play a more significant role. To determine which and how many are the highly cited papers at the domestic level (HCP-DL) collected in the Web of Science, three citation thresholds (1, 5, and 10%) were established. Thematic classification in Incites/Essential Science Indicators areas is used. The results show a preponderance of HCPs in the field of Space Science, while the polytechnic universities have high visibility in the Computer Science area. It has been observed that the presence of HCPs in a given area is involved with universities specialized in teaching and research activities. In absolute terms, the big non-specialized universities are major producers of HCPs and hold the leading positions in our results. However, when efficiency is analyzed in relative terms, some small, specialized universities reveal themselves to be more efficient at producing HCPs (% of HCPs or citations per HCP). We think that this methodology, due to its simplicity, its ease of calculation, and the knowledge it provides, can be very useful to analyze the national systems of any country, in order to know the impact and visibility of the research carried out in its scientific institutions or research areas.
Dynamic Turning of a Soft Quadruped Robot by Changing Phase Difference
Authors: Tanaka Hiroaki , Chen Tsung-Yuan , Hosoda Koh
Published: April 2021

Dynamic locomotion of a quadruped robot emerges from interaction between the robot body and the terrain. When the robot has a soft body, dynamic locomotion can be realized using a simple controller. This study investigates dynamic turning of a soft quadruped robot by changing the phase difference among the legs of the robot. We develop a soft quadruped robot driven by McKibben pneumatic artificial muscles. The phase difference between the hind and fore legs is fixed whereas that between the left and right legs is changed to enable the robot to turn dynamically. Since the robot legs are soft, the contact pattern between the legs and the terrain can be varied adaptively by simply changing the phase difference. Experimental results demonstrate that changes in the phase difference lead to changes in the contact time of the hind legs, and as a result, the soft robot can turn dynamically.
Validation of a Modified Submaximal Balke Protocol to Assess Cardiorespiratory Fitness in Individuals at High Risk of or With Chronic Health Conditions—A Pilot Study
Authors: Eike Gert Sander Hamre , Aadland Eivind , Blom Ellen Eimhjellen , Riiser Amund
Published: April 2021

Objectives: This study aims to validate a submaximal treadmill walking test for estimation of maximal oxygen consumption (VO2max) in individuals at high risk of or with chronic health conditions.

Method: Eighteen participants (age 62 ± 16 years; VO2max 31.2 ± 5.9 ml kg−1 min−1) at high risk of getting or with established chronic diseases performed two valid modified Balke treadmill walking protocols, one submaximal protocol, and one maximal protocol. Test duration, heart rate (HR), and rate of perceived exertion (RPE) were measured during both tests. VO2max was measured during the maximal test. VO2max was estimated from the submaximal test by multiple regression using time to RPE ≥ 17, gender, age, and body mass as independent variables. Model fit was reported as explained variance (R2) and standard error of the estimate (SEE).

Results: The model fit for estimation of VO2max from time to RPE ≥ 17 at the submaximal test, body mass, age, and gender was R2 = 0.78 (SEE = 3.1 ml kg−1 min−1, p ≤ 0.001). Including heart rate measurement did not improve the model fit.

Conclusions: The submaximal walking test is feasible and valid for assessing cardiorespiratory fitness in individuals with high risk of or chronic health conditions.
Childhood Sports Participation Is Associated With Health-Related Quality of Life in Young Men: A Retrospective Cross-Sectional Study
Authors: Appelqvist-Schmidlechner Kaija , Kyröläinen Heikki , Häkkinen Arja , Vasankari Tommi , Mäntysaari Matti , Honkanen Tuomas , Vaara Jani P.
Published: April 2021

The aim of the study was to examine whether sports participation (SP), engagement in competitive sports (CS), and the type of sport undertaken at the age of 12 are associated with the physical and mental components of health-related quality of life (HRQoL) in young adulthood. The data were collected using questionnaires prior to a compulsory military refresher training course in Finland. The sample consisted of 784 men (mean age 26 years). HRQoL was measured with RAND 36 and childhood SP with a series of questions. Data were analyzed with logistic regression. Higher frequency of SP, participation in district-level CS; performing team, endurance, or extreme sports; and playing yard games in childhood were after adjustments all associated with better HRQoL in early adulthood. The association was mainly found with the mental component, and to a lesser extent with the physical component, of HRQoL. Team (OR 1.43, CI 1.00–2.06) and extreme sports (OR 1.77, CI 1.19–2.63) were associated with better mental HRQoL, while playing yard games (OR 0.62, CI 0.44–0.89) reduced the likelihood for having low physical HRQoL. SP in childhood—in the forms of team or individual sports, but also as informal physical activity, such as playing yard games—is associated with HRQoL in young adulthood.