bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo tau pathology is associated with synaptic loss and altered synaptic function
Authors: Coomans Emma M. , Schoonhoven Deborah N. , Tuncel Hayel , Verfaillie Sander C. J. , Wolters Emma E. , Boellaard Ronald , Ossenkoppele Rik , den Braber Anouk , Scheper Wiep , Schober Patrick , Sweeney Steven P. , Ryan J. Michael , Schuit Robert C. , Windhorst Albert D. , Barkhof Frederik , Scheltens Philip , Golla Sandeep S. V. , Hillebrand Arjan , Gouw Alida A. , van Berckel Bart N. M. 
Published: February 2021

Abstract
Background
The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease.

Methods
Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models.

Results
Across subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe.

Conclusions
These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.
Detecting Alzheimer’s disease biomarkers with a brief tablet-based cognitive battery: sensitivity to Aβ and tau PET
Authors: Tsoy Elena , Strom Amelia , Iaccarino Leonardo , Erlhoff Sabrina J. , Goode Collette A. , Rodriguez Anne-Marie , Rabinovici Gil D. , Miller Bruce L. , Kramer Joel H. , Rankin Katherine P. , La Joie Renaud , Possin Katherine L. 
Published: February 2021

Abstract
Background
β-amyloid (Aβ) and tau positron emission tomography (PET) detect the pathological changes that define Alzheimer’s disease (AD) in living people. Cognitive measures sensitive to Aβ and tau burden may help streamline identification of cases for confirmatory AD biomarker testing.

Methods
We examined the association of Brain Health Assessment (BHA) tablet-based cognitive measures with dichotomized Aβ -PET status using logistic regression models in individuals with mild cognitive impairment (MCI) or dementia (N = 140; 43 Aβ-, 97 Aβ+). We also investigated the relationship between the BHA tests and regional patterns of tau-PET signal using voxel-wise regression analyses in a subsample of 60 Aβ+ individuals with MCI or dementia.

Results
Favorites (associative memory), Match (executive functions and speed), and Everyday Cognition Scale scores were significantly associated with Aβ positivity (area under the curve [AUC] = 0.75 [95% CI 0.66–0.85]). We found significant associations with tau-PET signal in mesial temporal regions for Favorites, frontoparietal regions for Match, and occipitoparietal regions for Line Orientation (visuospatial skills) in a subsample of individuals with MCI and dementia.

Conclusion
The BHA measures are significantly associated with both Aβ and regional tau in vivo imaging markers and could be used for the identification of patients with suspected AD pathology in clinical practice.
Dysentery as the only presentation of COVID-19 in a child: a case report
Authors: Tariverdi Marjan , Farahbakhsh Nazanin , Gouklani Hamed , Khosravifar Fatemeh , Tamaddondar Mohammad 
Published: February 2021

Abstract
Introduction
The coronavirus disease 2019 (COVID-19) pandemic has caused irreparable damage to society, and the damage continues. Pediatricians are confronted with COVID-19 in a variety of presentations, which may lead to delayed diagnosis and treatment. Early diagnosis of the disease plays an important role in preventing transmission of the virus in the community.

Case presentation
Here we report a 27-month-old previously healthy Iranian female child who presented with fever and bloody diarrhea, diagnosed with COVID-19 based on contact history, exclusion of enteric bacterial pathogens and parasites, and positive stool and nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction (RT-PCR) tests. The patient had viral shedding for more than a month.

Conclusions
The pediatric population usually does not present with typical clinical features of COVID-19, which are respiratory involvement. Dysentery may be the only presentation of this disease, and long-term isolation should be considered, as the viral shedding may last for more than a month.
Melatonin activates ABCA1 via the BiP/NRF1 pathway to suppress high-cholesterol-induced apoptosis of mesenchymal stem cells
Authors: Kim Jun Sung , Jung Young Hyun , Lee Hyun Jik , Chae Chang Woo , Choi Gee Euhn , Lim Jae Ryong , Kim Seo Yihl , Lee Joo Eun , Han Ho Jae 
Published: February 2021

Abstract
Background
Retarded wound healing in patients with obesity contributes to a risk of complications associated with vascular insufficiency and oxidative stress. The high cholesterol levels of patients with obesity are associated with apoptosis of engrafted umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). Melatonin contributes to the prevention of cholesterol accumulation in patients with obesity via a mechanism that is poorly understood. We therefore investigated the regulatory mechanism of melatonin in cholesterol-induced apoptosis.

Methods
The protective effects of melatonin on cholesterol-induced apoptosis were investigated in UCB-MSCs. We used a mouse model of induced obesity to show that melatonin treatment restored the survival rate of transplanted UCB-MSCs and their wound-healing capacity. The mean values of the treatment groups were compared with those of the control group using Student’s t test, and differences among three or more groups were analyzed using one-way analysis of variance with Dunnett’s multiple comparison test.

Results
Melatonin treatment increased the expression of ATP-binding cassette subfamily A member 1 (ABCA1), which reduced cholesterol accumulation and cholesterol-induced apoptosis. The mouse skin wound healing model showed that melatonin treatment restored the survival rate of transplanted UCB-MSCs and the wound-healing capacity of obese mice. Melatonin inhibited the expression of binding immunoglobulin protein (BiP) through the regulation of MT2/Sp1-dependent microRNA-597-5p. Melatonin decreased the co-localization of BiP with nuclear factor erythroid 2-related factor 1 (NRF1), which resulted in increased ABCA1 expression.

Conclusion
Melatonin induced the efflux of intracellular cholesterol through ABCA1 to decrease apoptosis of UCB-MSCs via an MT2-dependent BiP/NRF1 pathway.
The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure
Authors: Na Jingtao , Jin Haifeng , Wang Xin , Huang Kan , Sun Shuang , Li Qiang , Zhang Wenting 
Published: February 2021

Abstract
Background
Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3.

Methods
Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry.

Results
HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and −dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined.

Conclusion
Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.
DDB2 regulates DNA replication through PCNA-independent degradation of CDT2
Authors: Wu Xiaojun , Yu Min , Zhang Zhuxia , Leng Feng , Ma Yue , Xie Ni , Lu Fei 
Published: February 2021

Abstract
Background
Targeting ubiquitin-dependent proteolysis is one of the strategies in cancer therapy. CRLCDT2 and CRLDDB2 are two key E3 ubiquitin ligases involved in DNA replication and DNA damage repair. But CDT2 and DDB2 are opposite prognostic factors in kinds of cancers, and the underlining mechanism needs to be elucidated.

Methods
Small interfering RNAs were used to determine the function of target genes. Co-immunoprecipitation (Co-IP) was performed to detect the interaction between DDB2 and CDT2. Immunofluorescence assays and fluorescence activating cell sorting (FACS) were used to measure the change of DNA content. In vivo ubiquitination assay was carried out to clarify the ubiquitination of CDT2 mediated by DDB2. Cell synchronization was performed to arrest cells at G1/S and S phase. The mechanism involved in DDB2-mediated CDT2 degradation was investigated by constructing plasmids with mutant variants and measured by Western blot. Immunohistochemistry was performed to determine the relationship between DDB2 and CDT2. Paired two-side Student’s t-test was used to measure the significance of the difference between control group and experimental group.

Results
Knockdown of DDB2 stabilized CDT2, while over-expression of DDB2 enhanced ubiquitination of CDT2, and subsequentially degradation of CDT2. Although both DDB2 and CDT2 contain PIP (PCNA-interacting protein) box, PIP box is dispensable for DDB2-mediated CDT2 degradation. Knockdown of PCNA had negligible effects on the stability of CDT2, but promoted accumulation of CDT1, p21 and SET8. Silencing of DDB2 arrested cell cycle in G1 phase, destabilized CDT1 and reduced the chromatin loading of MCMs, thereby blocked the formation of polyploidy induced by ablation of CDT2. In breast cancer and ovarian teratoma tissues, high level of DDB2 was along with lower level of CDT2.

Conclusions
We found that CRL4DDB2 is the novel E3 ubiquitin ligases of CDT2, and DDB2 regulates DNA replication through indirectly regulates CDT1 protein stability by degrading CDT2 and promotes the assembly of pre-replication complex. Our results broaden the horizon for understanding the opposite function of CDT2 and DDB2 in tumorigenesis, and may provide clues for drug discovery in cancer therapy.
Transcriptomic and metabolomic profiling reveal the p53-dependent benzeneacetic acid attenuation of silica‐induced epithelial–mesenchymal transition in human bronchial epithelial cells
Authors: Ju Zhao , Shao Jianlin , Zhou Meiling , Jin Jing , Pan Huiji , Ding Ping , Huang Ruixue 
Published: February 2021

Abstract
Background
Silica exposure underlies the development of silicosis, one of the most serious occupational hazards worldwide. We aimed to explore the interaction of the silica-induced epithelial–mesenchymal transition (EMT)-related transcripts with the cellular metabolism regulated by p53.

Methods
We knocked out p53 using CRISPR/Cas9 in the human bronchial epithelial (HBE) cell line. The transcriptomic and metabolomic analyses and integrative omics were conducted using microarrays, GC–MS, and MetaboAnalyst, respectively.

Results
Fifty-two mRNAs showed significantly altered expression in the HBE p53-KO cells post-silica exposure. A total of 42 metabolites were putatively involved in p53-dependent silica-mediated HBE cell dysfunction. Through integrated data analysis, we obtained five significant p53-dependent metabolic pathways including phenylalanine, glyoxylate, dicarboxylate, and linoleic acid metabolism, and the citrate cycle. Through metabolite screening, we further identified that benzeneacetic acid, a key regulation metabolite in the phenylalanine metabolic pathway, attenuated the silica-induced EMT in HBE cells in a p53-dependent manner. Interestingly, despite the extensive p53-related published literature, the clinical translation of these studies remains unsubstantial.

Conclusions
Our study offers new insights into the molecular mechanisms by which epithelial cells respond to silica exposure and provide fresh perspective and direction for future clinical biomarker research and potential clinically sustainable and translatable role of p53.
Levosimendan use in patients with acute heart failure and reduced ejection fraction with or without severe renal dysfunction in critical cardiac care units: a multi-institution database study
Authors: Chan Cze-Ci , Lee Kuang-Tso , Ho Wan-Jing , Chan Yi-Hsin , Chu Pao-Hsien 
Published: February 2021

AbstractBackgroundAcute heart failure is a life-threatening clinical condition. Levosimendan is an effective inotropic agent used to maintain cardiac output, but its usage is limited by the lack of evidence in patients with severely abnormal renal function. Therefore, we analyzed data of patients with acute heart failure with and without abnormal renal function to examine the effects of levosimendan.MethodsWe performed this retrospective cohort study using data from the Chang Gung Research Database (CGRD) of Chang Gung Memorial Hospital (CGMH). Patients admitted for heart failure with LVEF ≤ 40% between January 2013 and December 2018 who received levosimendan or dobutamine in the critical cardiac care units (CCU) were identified. Patients with extracorporeal membrane oxygenation (ECMO) were excluded. Outcomes of interest were mortality at 30, 90, and 180 days after the cohort entry date.ResultsThere were no significant differences in mortality rate at 30, 90, and 180 days after the cohort entry date between the levosimendan and dobutamine groups, or between subgroups of patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2and eGFR < 30 mL/min/1.73 m2or on dialysis. The results were consistent before and after propensity score matching.ConclusionsLevosimendan did not increase short- or long-term mortality rates in critical patients with acute heart failure and reduced ejection fraction compared to dobutamine, regardless of their renal function. An eGFR less than 30 mL/min/1.73 m2was not necessarily considered a contraindication for levosimendan in these patients.
Barriers and facilitators to the implementation of social robots for older adults and people with dementia: a scoping review protocol
Authors: Koh Wei Qi , Felding Simone Anna , Toomey Elaine , Casey Dympna 
Published: February 2021

Abstract
Background
Psychosocial health issues such as depression and social isolation are an important cause of morbidity and premature mortality for older adults and people with dementia. Social robots are promising technological innovations to deliver effective psychosocial interventions to promote psychosocial wellbeing. Studies have reported positive findings regarding this technology on the psychosocial health of older adults and people with dementia. However, despite positive findings of the effects of social robots for older adults and people with dementia, little is known about factors affecting their implementation in practice.

Methods
This study follows Arksey and O’Malley’s approach and methodological enhancement by Levac et al. Relevant articles will be identified by searching electronic databases: MEDLINE, Embase, PsycINFO, Scopus, Web of Science, Compendex and PubMed. A two-phase screening process will be undertaken by two independent reviewers to determine articles’ inclusion. Findings will be summarised and reported thematically based on domains in the Consolidated Framework of Implementation Research (CFIR) and presented narratively. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) will guide the reporting of findings.

Discussion
Reporting the protocol in advance of conducting the review will ensure that rigorous and transparent methodological approach is undertaken. The outcomes of the review include identifying variants in terminologies used to describe implementation, identifying the scope of the literature regarding the barriers and facilitators affecting the implementation of social robots and identifying research gaps to guide further empirical research in this field. This evidence synthesis constitutes part of a bigger project aimed to develop implementation guidelines for social robotics for older adults with dementia. Since the methodological process consists of reviewing and collecting data from publicly available data, this study does not require approval from a research ethics board.

Scoping review registration
Our protocol is registered with the Open Science Framework (https://osf.io/2x3y9/) as an open access article, under the Creative Commons Attribution Non Commercial (CC BY-NC-4.0) license, which allows others to distribute, remix, adapt and build on this work on a non-commercial basis, and license their derivative work using different terms, on the basis that the original basis is properly cited and the use is non-commercial (http://creativecommons.org/licenses/by-nc/4.0/).
Electronic cigarettes’ withdrawal severity symptoms among users during intermittent fasting: a cross-sectional study
Authors: Barakat Muna M. , Al-Qudah Raja’a A. , Alfayoumi Ibrahim , Al-Obaidi Hala Jehad , Jirjees Feras Jassim , Basheti Iman 
Published: February 2021

Abstract
Background
Recently, electronic cigarette (e-cig) usage has increased significantly, making it a potentially effective smoking cessation tool. In Muslim countries, most people who use e-cigarettes fast the month of Ramadan, which results in intermittent fasting. This study aims to reveal the severity of e-cig withdrawal symptoms among users during this intermittent fasting period.

Methods
A self-administered survey was developed and validated to solicit anonymous responses from e-cig users living in Jordan, through a cross-sectional study design. Participants were recruited through social media resources. Severity scores of physical (out of 11) and psychological (out of 8) withdrawal symptoms for each participant were assessed and calculated for each participant, depending on the symptoms reported.

Results
A convenience sample (n = 523) of e-cig adult users were recruited. The majority of the participants were males (96.4%) aged between 18 and 40 years (86.4%). Many participants replaced tobacco smoking with e-cig (53.5%) in order to help them stop smoking. More than half of the participants experienced relatively weak physical (0.82 ± 1.78) and psychological (1.24 ± 1.89) withdrawal symptoms during the month of fasting. Most of the participants (63.2%) preferred to engage themselves with a busy schedule to tolerate the related withdrawal symptoms they experienced.

Conclusion
E-cigs could play a vital role in smoking cessation among tobacco smokers during intermittent fasting. Ramadan offers a good opportunity for smokers to quit, as the reported physical and psychological e-cig withdrawal symptoms were found to be relatively weak. Awareness and behavioral interventions would help clarify the effect of e-cigs and help determine alternative ways to cease smoking.
Design, synthesis, and evaluation of 4-chromenone derivatives combined with N-acylhydrazone for aurora kinase A inhibitor
Authors: Shin Soon Young , Lee Junho , Ahn Seunghyun , Yoo Miri , Lee Young Han , Koh Dongsoo , Lim Yoongho 
Published: February 2021

AbstractThere is accumulating evidence that compounds containingN-acylhydrazone or 4-chromenone moieties can be active against multiple cancer cell types, yet the combined effect of these chemical groups is unclear. This study aimed to develop more effective anti-cancer compounds by combining 4-chromenone andN-acylhydrazone. Thirteen derivatives were designed, synthesized, and characterized, and their structures were identified using nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Most of the derivatives exhibited moderate to high efficacy in inhibiting the clonogenicity of HCT116 colon cancer cells. In particular, derivative12, (E)-N'-((6-methoxy-4-oxo-4H-chromen-3-yl)methylene)isonicotinohydrazide, strongly inhibited clonogenicity (GI50 = 34.8 μM) of HCT116 cells and aurora kinase A (aurA) activity in vitro (IC50 = 1.4 μM). In silico docking experiment predicted that derivative12interacts with aurA based on computational docking and calculations of binding free energy. When derivative12was exposed to HCT116 cells, the phosphorylation of aurA at Thr288 was dose-dependently decreased within 60 min. Further analysis showed that derivative12destroyed the mitotic spindle in HCT116 cells. These results suggest that derivatives of 4-chromenone combined withN-acylhydrazone are feasible in the development of selective aurA inhibitor and could be considered potential chemotherapeutic agents.