bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MAP2K2 Gene as Potential Diagnostic Marker in Monitoring
Adalimumab Therapy of Psoriatic Arthritis
Authors: Strzałka-Mrozik Barbara , Krawczyk Agata , Juszczyk Karol , Kimsa-Dudek Magdalena , Wcisło-Dziadecka Dominika , Gola Joanna 
Published: June 2022

Background:
MAP kinases are some of the cascades that are specialized in the cell’s
response to external stimuli. Their impaired functioning can be observed during the course of psoriatic
arthritis. Currently, the best-known class of biological drugs is the inhibitors of the proinflammatory
cytokine TNF-α, including adalimumab.

Objective:
The aim of this study was to assess changes in the expression of MAP kinase genes in
patients with psoriatic arthritis treated with adalimumab, as well as to determine which of the analyzed
transcripts could be used as a diagnostic or therapeutic target.

Methods:
An analysis was performed on the total RNA extracted from PBMCs of patients with
psoriatic arthritis before and after three months of adalimumab therapy as well as from a control
group. Changes in the expression of the mitogen-activated protein kinase genes were assessed
using the HG-U133A 2.0 oligonucleotide microarray method, while the obtained results were validated
using the real-time RT-qPCR method.

Results:
Using the oligonucleotide microarray method, 14 genes coded for proteins from the
MAPK group were identified with at least a two-fold change of expression in the control group
and during adalimumab therapy. Validation of the results confirmed a statistically significant decrease
in the transcriptional activity of the MAP2K2 gene in the group of patients three months
after the administration of adalimumab relative to the control group.

Conclusion:
Adalimumab therapy alters the expression of MAPK-coding genes. The assessment
of the number of MAP2K2 mRNA molecules can potentially be used in diagnostic analyses or in
monitoring adalimumab therapy.
Integrated Bioinformatics Analysis for the Screening of Hub Genes and
Therapeutic Drugs in Hepatocellular Carcinoma
Authors: Su Qiuming , Li Wang , Zhang Xibing , Wu Ruichao , Zheng Kepu , Zhou Tao , Dong Yun , He Yutao , Wang Duo , Ran Jianghua 
Published: June 2022

Background:
Liver cancer is a major medical problem because of its high morbidity
and mortality. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Currently,
the mechanism of HCC is unclear, and the prognosis is poor with limited treatment.

Objective:
The purpose of this study is to identify hub genes and potential therapeutic drugs for
HCC.

Methods:
We used the GEO2R algorithm to analyze the differential expression of each gene in 4
gene expression profiles (GSE101685, GSE62232, GSE46408, and GSE45627) between HCC
and normal hepatic tissues. Next, we screened out the differentially expressed genes (DEGs) by
corresponding calculation data according to adjusted P-value < 0.05 and | log fold change (FC) | >
1.0. Subsequently, we used the DAVID software to analyze the DEGs by GO and KEGG enrichment
analysis. Then, we carried out the protein-protein interaction (PPI) network analysis of
DEGs using the STRING tool, and the PPI network was constructed by Cytoscape software.
MCODE plugin was used for module analysis, and the hub genes were screened out by the Cyto-
Hubba plugin. Meanwhile, we used The Kaplan-Meier plotter, GEPIA2 and HPA databases to
exert survival analysis and verify the expression alternation of hub genes. Furthermore, we used
ENCORI, TargetScan, miRDB and miRWalk database to predict the upstream regulated miRNA
of hub genes and construct a miRNA-hub genes network by Cytoscape software. Finally, we selected
potential therapeutic drugs for HCC through DGIdb databases.

Results:
A total of 415 DEGs were screened in HCC, including 196 up-regulated DEGs and 219
down-regulated DEGs. The results of KEGG pathway analysis suggested that the up-regulated
DEGs can regulate the cell cycle, and DNA replication signal pathway, while the down-regulated
DEGs were associated with metabolic pathways. In this study, we identified 11 hub genes
(AURKA, BUB1B, TOP2A, MAD2L1, CCNA2, CCNB1, BUB1, KIF11, CDK1, CCNB2 and
TPX2), which were independent risk factors of HCCand all up-regulated DEGs. We verified the
expression difference of hub genes through the GEPIA2 and HPA database, which was consistent
with the results of GEO data. We found that those hub genes were mutations in HCC according to
the cBioPortal database. Finally, we used the DGIdb database to select 32 potential therapeutic
targeting drugs for hub genes.

Conclusions:
In summary, our study provided a new perspective for researching the molecular
mechanism of HCC. Hub genes, miRNAs, and candidate drugs provide a new direction for the
early diagnosis and treatment of HCC.
Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?
Authors: Alexiou Athanasios , Batiha Gaber El-Saber , Al-kuraishy Hayder M. , Al-Gareeb Ali I. 
Published: June 2022

Abstract:Natriuretic peptide system [NPS] is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and natriuretic peptide precursor C [NPC], that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is also produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase [NEP], also known as neprilysin. Coronavirus disease 2019 [Covid-19] pandemic may lead to acute lung injury [ALI] and/or respiratory distress syndrome [ARDS]. The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of a pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in the management of Covid-19.
A Comprehensive Comparative Review of Protein Sequence-Based Computational
Prediction Models of Lysine Succinylation Sites
Authors: Mollah Md. Nurul Haque , Tasmia Samme Amena , Kibria Md. Kaderi , Islam Md. Ariful , Khatun Mst Shamima 
Published: June 2022

Abstract:
Lysine succinylation is a post-translational modification (PTM) of protein in which a succinyl
group (-CO-CH2-CH2-CO2H) is added to a lysine residue of protein that reverses lysine's positive
charge to a negative charge and leads to the significant changes in protein structure and function. It occurs
on a wide range of proteins and plays an important role in various cellular and biological processes
in both eukaryotes and prokaryotes. Beyond experimentally identified succinylation sites, there have
been a lot of studies for developing sequence-based prediction using machine learning approaches, because
it has the promise of being extremely time-saving, accurate, robust, and cost-effective. Despite
these benefits for computational prediction of lysine succinylation sites for different species, there are a
number of issues that need to be addressed in the design and development of succinylation site predictors.
In spite of the fact that many studies used different statistical and machine learning computational
tools, only a few studies have focused on these bioinformatics issues in depth. Therefore, in this comprehensive
comparative review, an attempt is made to present the latest advances in the prediction models,
datasets, and online resources, as well as the obstacles and limits, to provide an advantageous guideline
for developing more suitable and effective succinylation site prediction tools.
Phytochemical based Modulation of Endoplasmic Reticulum Stress in
Alzheimer's Disease
Authors: Dsouza Venzil Lavie , Shivakumar Apoorva Bettagere , Kulal Nikshitha , Gangadharan Gireesh , Kumar Dileep , Kabekkodu Shama Prasada 
Published: June 2022

Abstract:
Alzheimer's disease (AD) is a severe progressive neurodegenerative condition that shows misfolding and aggregation of proteins contributing to a decline in cognitive function involving multiple behavioral, neuropsychological, and cognitive domains. Multiple epi (genetic) changes and environmental agents have been shown to play an active role in ER stress induction. Neurodegener-ation due to endoplasmic reticulum (ER) stress is considered one of the major underlying causes of AD. ER stress may affect essential cellular functions related to biosynthesis, assembly, folding, and post-translational modification of proteins leading to neuronal inflammation to promote AD pathol-ogy. Treatment with phytochemicals has been shown to delay the onset and disease progression and improve the well-being of patients by targeting multiple signaling pathways in AD. Phytochemical's protective effect against neuronal damage in AD pathology may be associated with the reversal of ER stress and unfolding protein response by enhancing the antioxidant and anti-inflammatory prop-erties of the neuronal cells. Hence, pharmacological interventions using phytochemicals can be a potential strategy to reverse ER stress and improve AD management. Towards this, the present re-view discusses the role of phytochemicals in preventing ER stress in the pathology of AD.
Protective Effect of Artemisia absinthium Extract Against Glutamate-
Induced Toxicity in PC12 Cells
Authors: Rashidi Roghayeh , Akaberi Maryam , Mobasheri Leila , Sadeghi Mahmood , Mousavi Seyed Hadi , Forouzanfar Fatemeh 
Published: June 2022

Objectives:
Glutamatergic dysfunction has been implicated in the pathogenesis of numerous
central nervous system disorders. Artemisia absinthium (A. absinthium), has been reported to have neuro protective and antioxidant activities. The current study examined the effect of A. absinthium extract on
glutamate-induced cytotoxicity using PC12 cells.

Methods:
PC12 cells were pretreated with A. absinthium extract (70% ethanol) at concentration ranges of
6.25-25 µg/ml for 2 h, followed by exposure to glutamate (8 mM) for 24 hr. The cells viability, reactive
oxygen species (ROS) accumulation, and lipid peroxidation were measured. Moreover, a propidium iodide flow cytometry assay was performed for the assessment of apoptosis.

Results:
Pretreatment with A. absinthium extract markedly attenuated the loss of cell viability, ROS gen-eration, lipid peroxidation, and cell apoptosis in glutamate-injured PC-12 cells.

Conclusion:
Our results indicate that A. absinthium extract protects PC12 cells against glutamate-induced
injury, possibly by reducing oxidative stress and apoptosis.
Heavy Metal Pollution and Male Fertility: An Overview on Adverse Biological Effects and Socio-Economic Implications
Authors: Ballini Andrea , Arrigoni Roberto , Crocetto Felice , Risolo Rossella , Colapietro Rita , Bellavita Rosa , Barone Biagio , Francesco Caputo Vincenzo , Luca Giovanni , Grieco Paolo , Santini Giunio , Brancorsini Stefano 
Published: June 2022

Abstract:Trace metals can be divided into two subgroups considering their pathophysiological effects: the first consists of microelements essential for life (arsenic, cobalt, chromium, copper, fluorine, iron, iodine, manganese, molybdenum, nickel, selenium, silicon, tin, vanadium and zinc), implicated in important metabolic processes; the second includes toxic microelements, such as cadmium (Cd), mercury (Hg), chromium (Cr), and lead (Pb) for living organisms, even at low concentrations. These metals contribute to serious consequences for human health, including male infertility. Studies performed in several in vitro and in vivo models revealed that environmental exposure to toxic pollutants, as heavy metals, negatively affects human male fertility. Stem cells, due to their ability to self-renew and differentiate in several cell types, have been proposed as a useful tool in assisted reproductive technology, permitting the spermatogenesis recovery in patients with irreversible infertility. Considering the effects of heavy metals on male fertility and, from a demographic point of view, the decreased fertility ratio, further strategies are required to maintain a sustainable turn-over of 2 children for woman. We discuss here the findings on the biological effects of heavy metal pollution in the male fertility and underline the related socioeconomic impact on population demography.
Synthesis, Characterization, and Antitubercular Evaluation of Tetrahydrotetrazolo
Quinazoline Derivatives
Authors: Babu N. Raghavendra , Raju R. Subhakar , Alavala Rajasekhar Reddy , Rao G.S.N. Koteswara , Desu Prasanna Kumar , Namratha J. Risy , Muralidharan V. 
Published: June 2022

Background:
Tuberculosis is a highly contagious disease that is one of the major
causes of mortality worldwide and the leading infectious organism-related cause of death.
Various tetrazole and quinazoline compounds have been successfully developed in the past
for tuberculosis treatment. In this case, we planned to design the hybrid moieties by combining
both tetrazole and quinazoline nuclei to create novel compounds with increased activity.

Methods:
6, 6-dimethyl-5, 6, 7, 9–tetrahydrotetrazolo [5, 1-b] Quinazolin-8(4H) -one derivatives
were synthesized, characterized by using spectral data. The antitubercular activity
of the synthesized compounds was tested against the H37RV strain of Mycobacterium tuberculosis.
In order to identify the interactions with the target protein Mtb Pks13 Thioesterase
domain in complex with an inhibitor, docking analysis of the final compounds was performed
(Protein data bank ID: 5V41). To verify their drug-like potential, the synthesized
compounds were subjected to Pharmacokinetic prediction experiments. Zebrafish larvae
had been used to test the teratogenicity of the synthesized compounds.

Results:
At 6.25 μg/mL, compounds F4 and F7 exhibited good efficacy against Mycobacterium
tuberculosis strains. Docking studies aided in determining the most likely binding mode
within the binding cavity of the concerned target protein.

Conclusion:
Compounds containing p-fluorophenyl and p-nitrophenyl groups as substituents
were found to have excellent anti-tubercular activity.
Identifying Potential Gamification Elements for A New Chatbot for Families With Neurodevelopmental Disorders: User-Centered Design Approach
Authors: Bui Truong An , Pohl Megan , Rosenfelt Cory , Ogourtsova Tatiana , Yousef Mahdieh , Whitlock Kerri , Majnemer Annette , Nicholas David , Demmans Epp Carrie , Zaiane Osmar , Bolduc François V 
Published: June 2022

Background
Chatbots have been increasingly considered for applications in the health care field. However, it remains unclear how a chatbot can assist users with complex health needs, such as parents of children with neurodevelopmental disorders (NDDs) who need ongoing support. Often, this population must deal with complex and overwhelming health information, which can make parents less likely to use a software that may be very helpful. An approach to enhance user engagement is incorporating game elements in nongame contexts, known as gamification. Gamification needs to be tailored to users; however, there has been no previous assessment of gamification use in chatbots for NDDs.

Objective
We sought to examine how gamification elements are perceived and whether their implementation in chatbots will be well received among parents of children with NDDs. We have discussed some elements in detail as the initial step of the project.

Methods
We performed a narrative literature review of gamification elements, specifically those used in health and education. Among the elements identified in the literature, our health and social science experts in NDDs prioritized five elements for in-depth discussion: goal setting, customization, rewards, social networking, and unlockable content. We used a qualitative approach, which included focus groups and interviews with parents of children with NDDs (N=21), to assess the acceptability of the potential implementation of these elements in an NDD-focused chatbot. Parents were asked about their opinions on the 5 elements and to rate them. Video and audio recordings were transcribed and summarized for emerging themes, using deductive and inductive thematic approaches.

Results
From the responses obtained from 21 participants, we identified three main themes: parents of children with NDDs were familiar with and had positive experiences with gamification; a specific element (goal setting) was important to all parents, whereas others (customization, rewards, and unlockable content) received mixed opinions; and the social networking element received positive feedback, but concerns about information accuracy were raised.

Conclusions
We showed for the first time that parents of children with NDDs support gamification use in a chatbot for NDDs. Our study illustrates the need for a user-centered design in the medical domain and provides a foundation for researchers interested in developing chatbots for populations that are medically vulnerable. Future studies exploring wide range of gamification elements with large number of potential users are needed to understand the impact of gamification elements in enhancing knowledge mobilization.
Urine Output Monitoring for the Diagnosis of Early-Onset Acute Kidney Injury in Very Preterm Infants
Authors: De Mul Aurélie , Parvex Paloma , Héneau Alice , Biran Valérie , Poncet Antoine , Baud Olivier , Saint-Faust Marie , Wilhelm-Bals Alexandra 
Published: June 2022

Background and objectives
The current threshold used for oliguria in the definition of neonatal AKI has been empirically defined as 1 ml/kg per hour. Urine output criteria are generally poorly documented, resulting in uncertainty in the most accurate threshold to identify AKI in very preterm infants with known tubular immaturity.

Design, setting, participants, & measurements
We conducted a bicentric study including 473 very preterm infants (240/7–296/7 weeks of gestation) born between January 2014 and December 2018 with urine output measurements every 3 hours during the first 7 days of life and two serum creatinine measurements during the first 10 days of life. AKI was defined using the neonatal Kidney Disease Improving Global Outcomes (KDIGO) definition. We tested whether higher urine output thresholds (1.5 or 2 ml/kg per hour) in modified AKI definitions may better discriminate neonatal mortality compared with the current definition.

Results
Early-onset AKI was developed by 101 of 473 (21%) very preterm infants. AKI was diagnosed on the basis of urine output criteria alone (no rise in creatinine) for 27 of 101 (27%) participants. Early-onset AKI was associated with higher risk of death before discharge (adjusted odds ratio, 3.9; 95% confidence interval, 1.9 to 7.8), and the AKI neonatal KDIGO score showed good discriminative performance for neonatal mortality, with an area under the receiver operating characteristic (ROC) curve of 0.68 (95% confidence interval, 0.61 to 0.75). Modified AKI definitions that included higher urine output thresholds showed significantly improved discriminative performance, with areas under the ROC curve of 0.73 (95% confidence interval, 0.66 to 0.80) for the 1.5-ml/kg per hour threshold and 0.75 (95% confidence interval, 0.68 to 0.81) for the 2-ml/kg per hour threshold.

Conclusions
Early-onset AKI was diagnosed on the basis of urine output exclusively for a quarter of the cases. Furthermore, modified AKI definitions that included higher urine output improved the discriminative performance for predicting mortality.
EVALUATION OF TRACE METAL CONTENTS IN MUSHROOM SAMPLES FROM AZDAVAY DISTRICT, KASTAMONU, TURKEY
Authors: ATASOY Muhammet , YILDIZ Dilek 
Published: June 2022

Mushrooms are a popular food because they are an important source of essential amino acids, proteins and dietary fibers, but they have a great capacity to accumulate metals from substrate. Due to this reason, the content of 5 trace metals (Fe, Cr, Zn, Pb, Se) of fruit bodies of 21 fungi species originally found in Azdavay, Kastamonu Region, Turkey were analyzed by atomic absorption spectroscopy. The contents of investigated trace metals in mushroom samples were found to be in the range of 4.6–3478.7 mg kg-1 for Fe, 5.1–19.9 mg kg-1 for Cr, 10.4–138.6 mg kg-1 for Zn, 5.8–28.0 mg kg-1 for Pb and 0.65–1.47 mg kg-1 for Se. The relative standard deviations (R.S.D.) were found below 10%. The accuracy of procedure was confirmed by CRMs (BCR 191 Brown bread, ERM-BD 151 Skimmed milk powder).
The Effect of Technological and Task Considerations on Auditors' Acceptance of Blockchain Technology
Authors: Li Yuan , Juma'h Ahmad H. 
Published: June 2022

ABSTRACT
The increasing automation of accounting information makes it imperative for auditors to help organizations design and implement blockchain-based solutions to facilitate transactions. A precursor of this initiative is their acceptance of blockchain. From the task-technology fit and fit-as-mediation perspective, this paper proposes that the technological features of blockchain must fit the task needs of auditors to boost acceptance. A survey of 112 auditors confirms that auditors' task needs fully mediate the effect of blockchain features on acceptance. Not all blockchain features are equally important: While timestamping is most important for a shared database, the prevention of double-spending is most important for other task needs. It also finds that perceptions of blockchain features and task needs are influenced by auditors' accounting knowledge and accounting software knowledge, as well as their technology awareness. This shows the importance of strengthening auditors' knowledge and awareness to boost the acceptance of blockchain.
The Disclosure and Consequences of U.S. Critical Audit Matters
Authors: Burke Jenna J. , Hoitash Rani , Hoitash Udi , Xiao Summer 
Published: June 2022

ABSTRACT
This study uses difference-in-differences (DiD) analyses to examine the consequences of adopting the U.S. critical audit matter (CAM) disclosure requirement for preparers and users of financial reports. The CAM requirement is one of the largest expansions of the U.S. audit report since the 1940s. We document significant changes to financial statement footnotes referenced by CAMs, which suggests an indirect consequence where management disclosure changes in areas that are expected to be scrutinized following auditor-provided disclosure. Results also suggest that, on average, CAM disclosures do not provide incremental information to the market. To further examine market reaction, we develop well-specified prediction models for the expected number and subject areas of CAMs. We find limited initial evidence that the market reacts negatively when unexpected CAMs are disclosed. Overall, our findings provide insights on the new CAM standard and particularly demonstrate its relevance to management disclosure decisions and to the market.