bluuebunny/crossref_metadata_2025 huggingface dataset:
The Progression of COVID-19 and the Government Response in China
Authors: Hu Xinyi , Flahault Antoine , Temerev Alexander , Rozanova Liudmila
Published: March 2021

The ongoing pandemic of COVID-19 (Coronavirus Infectious Disease-2019) was first reported at the end of 2019 in Wuhan, China. On 30 January 2020, the WHO declared a Public Health Emergency for the novel coronavirus. On 11 March 2020, the WHO officially declared the COVID-19 outbreak as a pandemic. Due to the differences in population distribution, economic structure, degree of damage and other factors, the affected countries have introduced policies tailored to local conditions as a response to the pandemic, leading to different economic and social impacts. Considering the highly heterogeneous spreading of COVID-19 across regions, this paper takes a specific country (China) as a case study of the spread of the disease and national intervention models for the COVID-19 pandemic. The research period of this article is from 17 December to 26 April 2020, because this time period basically covered the important time nodes of the epidemic in China from animal-to-human transmission, limited human-to-human transmission, epidemic to gradual control. This study is useful for comparing the effectiveness of different interventions at various stages of epidemic development within the same country and can also promote the comparison of the epidemic response interventions of different countries. Based on the conclusions of the model simulation, this article evaluates the dual impact of the epidemic on people’s wellbeing and the economy.
A Comparison of the Effect of Two Types of Whole Body Vibration Platforms on Fibromyalgia. A Randomized Controlled Trial
Authors: Mingorance José Antonio , Montoya Pedro , Vivas Miranda José García , Riquelme Inmaculada
Published: March 2021

Whole body vibration has been proven to improve the health status of patients with fibromyalgia, providing an activation of the neuromuscular spindles, which are responsible for muscle contraction. The present study aimed to compare the effectiveness of two types of whole body vibrating platforms (vertical and rotational) during a 12-week training program. Sixty fibromyalgia patients (90% were women) were randomly assigned to one of the following groups: group A (n = 20), who performed the vibration training with a vertical platform; group B (n = 20), who did rotational platform training; or a control group C (n = 20), who did not do any training. Sensitivity measures (pressure pain and vibration thresholds), quality of life (Quality of Life Index), motor function tasks (Berg Scale, six-minute walking test, isometric back muscle strength), and static and dynamic balance (Romberg test and gait analysis) were assessed before, immediately after, and three months after the therapy program. Although both types of vibration appeared to have beneficial effects with respect to the control group, the training was more effective with the rotational than with vertical platform in some parameters, such as vibration thresholds (p < 0.001), motor function tasks (p < 0.001), mediolateral sway (p < 0.001), and gait speed (p < 0.05). Nevertheless, improvements disappeared in the follow-up in both types of vibration. Our study points out greater benefits with the use of rotational rather than vertical whole body vibration. The use of the rotational modality is recommended in the standard therapy program for patients with fibromyalgia. Due to the fact that the positive effects of both types of vibration disappeared during the follow-up, continuous or intermittent use is recommended.
Comparison of Major Clinical Outcomes between Accredited and Nonaccredited Hospitals for Inpatient Care of Acute Myocardial Infarction
Authors: Lee Bo Yeon , Chun You Jin , Lee Yo Han
Published: March 2021

Hospital accreditation programs are used worldwide to improve the quality of care and improve patient safety. It is of great help in improving the structure of hospitals, but there are mixed research results on improving the clinical outcome of patients. The purpose of this study was to compare the levels of core clinical outcome indicators after receiving inpatient services from accredited and nonaccredited hospitals in patients with acute myocardial infarction (AMI). For all patients with AMI admitted to general hospitals in Korea from 2010 to 2017, their 30-day mortality and readmissions and length of stay were compared according to accreditation status. In addition, through a multivariate model that controls various patients’ and hospitals’ factors, the differences in those indicators were analyzed more accurately. The 30-day mortality of patients admitted to accredited hospitals was statistically significantly lower than that of patients admitted to nonaccredited hospitals. However, for 30-day readmission and length of stay, accreditation did not appear to yield more desirable results. This study shows that when evaluating the clinical impact of hospital accreditation programs, not only the mortality but also various clinical indicators need to be included, and a more comprehensive review is needed.
Coastal Tourism Spatial Planning at the Regional Unit: Identifying Coastal Tourism Hotspots Based on Social Media Data
Authors: Kim Gang Sun , Chun Joungyoon , Kim Yoonjung , Kim Choong-Ki
Published: March 2021

There is an increasing need for spatial planning to manage coastal tourism, and applying social media data has emerged as an effective strategy to support coastal tourism spatial planning. Researchers and decision-makers require spatially explicit information that effectively reveals the current visitation state of the region. The purpose of this study is to identify coastal tourism hotspots considering appropriate spatial units in the regional scale using social media data to examine the advantages and limitations of applying spatial hotspots to spatial planning. Data from Flickr and Twitter with 30″ spatial resolution were obtained from four South Korean regions. Coastal tourism hotspots were then derived using Getis-Ord Gi. Comparing the derived hotspot maps with the visitation rate distribution maps, the derived hotspot maps sufficiently identified the spatial influences of visitors and tourist attractions applicable for spatial planning. As the spatial autocorrelation of social media data differs based on the spatial unit, coastal tourism hotspots according to spatial unit are inevitably different. Spatial hotspots derived from the appropriate spatial unit using social media data are useful for coastal tourism spatial planning.
A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells
Authors: Cipolletti Manuela , Bartoloni Stefania , Busonero Claudia , Parente Martina , Leone Stefano , Acconcia Filippo
Published: March 2021

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.
Electromagnetic Field (EMF) Radiation Alters Estrogen Release from the Pig Myometrium during the Peri-Implantation Period
Authors: Drzewiecka Ewa Monika , Kozlowska Wiktoria , Zmijewska Agata , Wydorski Pawel Jozef , Franczak Anita
Published: March 2021

An electromagnetic field (EMF) may affect the functions of uterine tissues. This study hypothesized that EMF changes the estrogenic activity of pig myometrium during the peri-implantation period. Tissue was collected on days 15–16 of the gestation and incubated in the presence of EMF (50 and 120 Hz, 2 and 4 h). The cytochrome P450 aromatase type 3 (CYP19A3) and hydroxysteroid 17β dehydrogenase type 4 (HSD17B4) mRNA transcript abundance, cytochrome P450arom (aromatase), and 17β hydroxysteroid dehydrogenase 17βHSD) protein abundance and estrone (E1) and estradiol-17β (E2) release were examined using Real-Time PCR, Western blot and radioimmunoassay. Selected myometrial slices were treated with progesterone (P4) to determine whether it functions as a protector against EMF. CYP19A3 mRNA transcript abundance in slices treated with EMF was less at 50 Hz (2 h) and greater at 120 Hz (2 and 4 h). HSD17B4 mRNA transcript was greater in slices treated with EMF at 120 Hz (2 h). Progesterone diminished EMF-related effects on CYP19A3 and HSD17B4. When P4 was added, EMF had suppressive (50 and 120 Hz, 2 h) or enhancing (50 Hz, 4 h) effects on aromatase abundance. The E1 release was lower after 4 h of EMF treatment at 50 Hz and P4 did not protect myometrial E1 release. In conclusion, EMF alters the synthesis and release of E1 and did not affect E2 release in the myometrium during the peri-implantation period.
The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile
Authors: Abeyawardhane Dinendra L. , Godoy-Ruiz Raquel , Adipietro Kaylin A. , Varney Kristen M. , Rustandi Richard R. , Pozharski Edwin , Weber David J.
Published: March 2021

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell’s cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.
RBM20-Mediated Pre-mRNA Splicing Has Muscle-Specificity and Differential Hormonal Responses between Muscles and in Muscle Cell Cultures
Authors: Maimaiti Rexiati , Zhu Chaoqun , Zhang Yanghai , Ding Qiyue , Guo Wei
Published: March 2021

Pre-mRNA splicing plays an important role in muscle function and diseases. The RNA binding motif 20 (RBM20) is a splicing factor that is predominantly expressed in muscle tissues and primarily regulates pre-mRNA splicing of Ttn, encoding a giant muscle protein titin that is responsible for muscle function and diseases. RBM20-mediated Ttn splicing has been mostly studied in heart muscle, but not in skeletal muscle. In this study, we investigated splicing specificity in different muscle types in Rbm20 knockout rats and hormonal effects on RBM20-mediated splicing both in cellulo and in vivo studies. The results revealed that RBM20 is differentially expressed across muscles and RBM20-mediated splicing is muscle-type specific. In the presence of RBM20, Ttn splicing responds to hormones in a muscle-type dependent manner, while in the absence of RBM20, Ttn splicing is not affected by hormones. In differentiated and undifferentiated C2C12 cells, RBM20-mediated splicing in response to hormonal effects is mainly through genomic signaling pathway. The knowledge gained from this study may help further understand muscle-specific gene splicing in response to hormone stimuli in different muscle types.
Pre-Clinical Neuroprotective Evidences and Plausible Mechanisms of Sulforaphane in Alzheimer’s Disease
Authors: Kim Jiyoung
Published: March 2021

Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-β, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.
Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development–Review
Authors: Łukasik Paweł , Załuski Michał , Gutowska Izabela
Published: March 2021

Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer’s or Parkinson’s disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.
Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice
Authors: Esposito Giuseppe , Pesce Marcella , Seguella Luisa , Lu Jie , Corpetti Chiara , Del Re Alessandro , De Palma Fatima Domenica Elisa , Esposito Giovanni , Sanseverino Walter , Sarnelli Giovanni
Published: March 2021

Palmitoylethanolamide (PEA) is an N-acylethanolamide produced on-demand by the enzyme N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD). Being a key member of the larger family of bioactive autacoid local injury antagonist amides (ALIAmides), PEA significantly improves the clinical and histopathological stigmata in models of ulcerative colitis (UC). Despite its safety profile, high PEA doses are required in vivo to exert its therapeutic activity; therefore, PEA has been tested only in animals or human biopsy samples, to date. To overcome these limitations, we developed an NAPE-PLD-expressing Lactobacillus paracasei F19 (pNAPE-LP), able to produce PEA under the boost of ultra-low palmitate supply, and investigated its therapeutic potential in a murine model of UC. The coadministration of pNAPE-LP and palmitate led to a time-dependent release of PEA, resulting in a significant amelioration of the clinical and histological damage score, with a significantly reduced neutrophil infiltration, lower expression and release of pro-inflammatory cytokines and oxidative stress markers, and a markedly improved epithelial barrier integrity. We concluded that pNAPE-LP with ultra-low palmitate supply stands as a new method to increase the in situ intestinal delivery of PEA and as a new therapeutic able of controlling intestinal inflammation in inflammatory bowel disease.
Hydrolysis of Extracellular ATP by Vascular Smooth Muscle Cells Transdifferentiated into Chondrocytes Generates Pi but Not PPi
Authors: Buchet Rene , Tribes Camille , Rouaix Valentine , Doumèche Bastien , Fiore Michele , Wu Yuqing , Magne David , Mebarek Saida
Published: March 2021

(1) Background: Tissue non-specific alkaline phosphatase (TNAP) is suspected to induce atherosclerosis plaque calcification. TNAP, during physiological mineralization, hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PPi). Since atherosclerosis plaques are characterized by the presence of necrotic cells that probably release supraphysiological concentrations of ATP, we explored whether this extracellular adenosine triphosphate (ATP) is hydrolyzed into the mineralization inhibitor PPi or the mineralization stimulator inorganic phosphate (Pi), and whether TNAP is involved. (2) Methods: Murine aortic smooth muscle cell line (MOVAS cells) were transdifferentiated into chondrocyte-like cells in calcifying medium, containing ascorbic acid and β-glycerophosphate. ATP hydrolysis rates were determined in extracellular medium extracted from MOVAS cultures during their transdifferentiation, using 31P-NMR and IR spectroscopy. (3) Results: ATP and PPi hydrolysis by MOVAS cells increased during transdifferentiation. ATP hydrolysis was sequential, yielding adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine without any detectable PPi. The addition of levamisole partially inhibited ATP hydrolysis, indicating that TNAP and other types of ectonucleoside triphoshatediphosphohydrolases contributed to ATP hydrolysis. (4) Conclusions: Our findings suggest that high ATP levels released by cells in proximity to vascular smooth muscle cells (VSMCs) in atherosclerosis plaques generate Pi and not PPi, which may exacerbate plaque calcification.
Proteomics Profiling of Neuron-Derived Small Extracellular Vesicles from Human Plasma: Enabling Single-Subject Analysis
Authors: Anastasi Federica , Masciandaro Silvia Maria , Carratore Renata Del , Dell’Anno Maria Teresa , Signore Giovanni , Falleni Alessandra , McDonnell Liam A. , Bongioanni Paolo
Published: March 2021

Small extracellular vesicles have been intensively studied as a source of biomarkers in neurodegenerative disorders. The possibility to isolate neuron-derived small extracellular vesicles (NDsEV) from blood represents a potential window into brain pathological processes. To date, the absence of sensitive NDsEV isolation and full proteome characterization methods has meant their protein content has been underexplored, particularly for individual patients. Here, we report a rapid method based on an immunoplate covalently coated with mouse monoclonal anti-L1CAM antibody for the isolation and the proteome characterization of plasma-NDsEV from individual Parkinson’s disease (PD) patients. We isolated round-shaped vesicles with morphological characteristics consistent with exosomes. On average, 349 ± 38 protein groups were identified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, 20 of which are annotated in the Human Protein Atlas as being highly expressed in the brain, and 213 were shared with a reference NDsEV dataset obtained from cultured human neurons. Moreover, this approach enabled the identification of 23 proteins belonging to the Parkinson disease KEGG pathway, as well as proteins previously reported as PD circulating biomarkers.
Editorial to the Special Issue “Electrophysiology”
Authors: Wu Sheng-Nan , Huang Chin-Wei
Published: March 2021

Ion channels are well recognized to select ions to pass through the cell membrane in a wide variety of cells [...]
Role of Rho in Salt-Sensitive Hypertension
Authors: Kawarazaki Wakako , Fujita Toshiro
Published: March 2021

A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies.
Grainyhead-Like 3 Influences Migration and Invasion of Urothelial Carcinoma Cells
Authors: Wezel Felix , Lustig Johannes , Azoitei Anca , Liu Junnan , Meessen Sabine , Najjar Gregoire , Zehe Viktor , Faustmann Philipp , Zengerling Friedemann , John Axel , Martini Thomas , Bolenz Christian , Günes Cagatay
Published: March 2021

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells.
Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma
Authors: Orcheston-Findlay Louise , Bax Samuel , Utama Robert , Engel Martin , Govender Dinisha , O’Neill Geraldine
Published: March 2021

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models—namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon.
Antenna Protein Clustering In Vitro Unveiled by Fluorescence Correlation Spectroscopy
Authors: Crepin Aurélie , Cunill-Semanat Edel , Kuthanová Trsková Eliška , Belgio Erica , Kaňa Radek
Published: March 2021

Antenna protein aggregation is one of the principal mechanisms considered effective in protecting phototrophs against high light damage. Commonly, it is induced, in vitro, by decreasing detergent concentration and pH of a solution of purified antennas; the resulting reduction in fluorescence emission is considered to be representative of non-photochemical quenching in vivo. However, little is known about the actual size and organization of antenna particles formed by this means, and hence the physiological relevance of this experimental approach is questionable. Here, a quasi-single molecule method, fluorescence correlation spectroscopy (FCS), was applied during in vitro quenching of LHCII trimers from higher plants for a parallel estimation of particle size, fluorescence, and antenna cluster homogeneity in a single measurement. FCS revealed that, below detergent critical micelle concentration, low pH promoted the formation of large protein oligomers of sizes up to micrometers, and therefore is apparently incompatible with thylakoid membranes. In contrast, LHCII clusters formed at high pH were smaller and homogenous, and yet still capable of efficient quenching. The results altogether set the physiological validity limits of in vitro quenching experiments. Our data also support the idea that the small, moderately quenching LHCII oligomers found at high pH could be relevant with respect to non-photochemical quenching in vivo.
Exendin-4 Promotes Schwann Cell Survival/Migration and Myelination In Vitro
Authors: Takaku Shizuka , Tsukamoto Masami , Niimi Naoko , Yako Hideji , Sango Kazunori
Published: March 2021

Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron–IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3′-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.
The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability
Authors: Fitieh Amira , Locke Andrew J. , Motamedi Mobina , Ismail Ismail Hassan
Published: March 2021

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.
Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study
Authors: Abdelaal Ahmed Mahmoud M. Alkhatip Ahmed , Georgakis Michail , Montero Valenzuela Lucio R. , Hamza Mohamed , Farag Ehab , Hodgkinson Jaqui , Hosny Hisham , Kamal Ahmed M. , Wagih Mohamed , Naguib Amr , Yassin Hany , Algameel Haytham , Elayashy Mohamed , Abdelhaq Mohamed , Younis Mohamed I. , Mohamed Hassan , Abdulshafi Mohammed , Elramely Mohamed A.
Published: March 2021

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.
The Effects of Tgfb1 and Csf3 on Chondrogenic Differentiation of iPS Cells in 2D and 3D Culture Environment
Authors: Wang Chie-Hong , Tsai Chun-Hao , Lin Tsung-Li , Liu Shih-Ping
Published: March 2021

Mesenchymal stem (MS) cells, embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells are known for their ability to differentiate into different lineages, including chondrocytes in culture. However, the existing protocol for chondrocyte differentiation is time consuming and labor intensive. To improve and simplify the differentiation strategy, we have explored the effects of interactions between growth factors (transforming growth factor β1 (Tgfb1) and colony stimulating factor 3 (Csf3), and culture environments (2D monolayer and 3D nanofiber scaffold) on chondrogenic differentiation. For this, we have examined cell morphologies, proliferation rates, viability, and gene expression profiles, and characterized the cartilaginous matrix formed in the chondrogenic cultures under different treatment regimens. Our data show that 3D cultures support higher proliferation rate than the 2D cultures. Tgfb1 promotes cell proliferation and viability in both types of culture, whereas Csf3 shows positive effects only in 3D cultures. Interestingly, our results indicate that the combined treatments of Tgfb1 and Csf3 do not affect cell proliferation and viability. The expression of cartilaginous matrix in different treatment groups indicates the presence of chondrocytes. We found that, at the end of differentiation stage 1, pluripotent markers were downregulated, while the mesodermal marker was upregulated. However, the expression of chondrogenic markers (col2a1 and aggrecan) was upregulated only in the 3D cultures. Here, we report an efficient, scalable, and convenient protocol for chondrogenic differentiation of iPS cells, and our data suggest that a 3D culture environment, combined with tgfb1 and csf3 treatment, promotes the chondrogenic differentiation.
Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function
Authors: Kim Kyeongmin , Lee Sungmin , Kang Hyunkoo , Shin Eunguk , Kim Hae Yu , Youn HyeSook , Youn BuHyun
Published: March 2021

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.
Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin
Authors: Gammella Elena , Correnti Margherita , Cairo Gaetano , Recalcati Stefania
Published: March 2021

Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.
Antiosteoarthritic Effect of Morroniside in Chondrocyte Inflammation and Destabilization of Medial Meniscus-Induced Mouse Model
Authors: Park Eunkuk , Lee Chang Gun , Han Seong Jae , Yun Seung Hee , Hwang Seokjin , Jeon Hyoju , Kim Jeonghyun , Choi Chun Whan , Yang Siyoung , Jeong Seon-Yong
Published: March 2021

Osteoarthritis (OA) is a common degenerative disease that results in joint inflammation as well as pain and stiffness. A previous study has reported that Cornus officinalis (CO) extract inhibits oxidant activities and oxidative stress in RAW 264.7 cells. In the present study, we isolated bioactive compound(s) by fractionating the CO extract to elucidate its antiosteoarthritic effects. A single bioactive component, morroniside, was identified as a potential candidate. The CO extract and morroniside exhibited antiosteoarthritic effects by downregulating factors associated with cartilage degradation, including cyclooxygenase-2 (Cox-2), matrix metalloproteinase 3 (Mmp-3), and matrix metalloproteinase 13 (Mmp-13), in interleukin-1 beta (IL-1β)-induced chondrocytes. Furthermore, morroniside prevented prostaglandin E2 (PGE2) and collagenase secretion in IL-1β-induced chondrocytes. In the destabilization of the medial meniscus (DMM)-induced mouse osteoarthritic model, morroniside administration attenuated cartilage destruction by decreasing expression of inflammatory mediators, such as Cox-2, Mmp3, and Mmp13, in the articular cartilage. Transverse microcomputed tomography analysis revealed that morroniside reduced DMM-induced sclerosis in the subchondral bone plate. These findings suggest that morroniside may be a potential protective bioactive compound against OA pathogenesis.
Numerical Markov Logic Network: A Scalable Probabilistic Framework for Hybrid Knowledge Inference
Authors: Zhong Ping , Li Zhanhuai , Chen Qun , Hou Boyi , Ahmed Murtadha
Published: March 2021

In recent years, the Markov Logic Network (MLN) has emerged as a powerful tool for knowledge-based inference due to its ability to combine first-order logic inference and probabilistic reasoning. Unfortunately, current MLN solutions cannot efficiently support knowledge inference involving arithmetic expressions, which is required to model the interaction between logic relations and numerical values in many real applications. In this paper, we propose a probabilistic inference framework, called the Numerical Markov Logic Network (NMLN), to enable efficient inference of hybrid knowledge involving both logic and arithmetic expressions. We first introduce the hybrid knowledge rules, then define an inference model, and finally, present a technique based on convex optimization for efficient inference. Built on decomposable exp-loss function, the proposed inference model can process hybrid knowledge rules more effectively and efficiently than the existing MLN approaches. Finally, we empirically evaluate the performance of the proposed approach on real data. Our experiments show that compared to the state-of-the-art MLN solution, it can achieve better prediction accuracy while significantly reducing inference time.
An Experimental Analysis of Data Annotation Methodologies for Emotion Detection in Short Text Posted on Social Media
Authors: Krommyda Maria , Rigos Anastasios , Bouklas Kostas , Amditis Angelos
Published: March 2021

Opinion mining techniques, investigating if text is expressing a positive or negative opinion, continuously gain in popularity, attracting the attention of many scientists from different disciplines. Specific use cases, however, where the expressed opinion is indisputably positive or negative, render such solutions obsolete and emphasize the need for a more in-depth analysis of the available text. Emotion analysis is a solution to this problem, but the multi-dimensional elements of the expressed emotions in text along with the complexity of the features that allow their identification pose a significant challenge. Machine learning solutions fail to achieve a high accuracy, mainly due to the limited availability of annotated training datasets, and the bias introduced to the annotations by the personal interpretations of emotions from individuals. A hybrid rule-based algorithm that allows the acquisition of a dataset that is annotated with regard to the Plutchik’s eight basic emotions is proposed in this paper. Emoji, keywords and semantic relationships are used in order to identify in an objective and unbiased way the emotion expressed in a short phrase or text. The acquired datasets are used to train machine learning classification models. The accuracy of the models and the parameters that affect it are presented in length through an experimental analysis. The most accurate model is selected and offered through an API to tackle the emotion detection in social media posts.
Potential Role of L-Carnitine in Autism Spectrum Disorder
Authors: Kępka Alina , Ochocińska Agnieszka , Chojnowska Sylwia , Borzym-Kluczyk Małgorzata , Skorupa Ewa , Knaś Małgorzata , Waszkiewicz Napoleon
Published: March 2021

L-carnitine plays an important role in the functioning of the central nervous system, and especially in the mitochondrial metabolism of fatty acids. Altered carnitine metabolism, abnormal fatty acid metabolism in patients with autism spectrum disorder (ASD) has been documented. ASD is a complex heterogeneous neurodevelopmental condition that is usually diagnosed in early childhood. Patients with ASD require careful classification as this heterogeneous clinical category may include patients with an intellectual disability or high functioning, epilepsy, language impairments, or associated Mendelian genetic conditions. L-carnitine participates in the long-chain oxidation of fatty acids in the brain, stimulates acetylcholine synthesis (donor of the acyl groups), stimulates expression of growth-associated protein-43, prevents cell apoptosis and neuron damage and stimulates neurotransmission. Determination of L-carnitine in serum/plasma and analysis of acylcarnitines in a dried blood spot may be useful in ASD diagnosis and treatment. Changes in the acylcarnitine profiles may indicate potential mitochondrial dysfunctions and abnormal fatty acid metabolism in ASD children. L-carnitine deficiency or deregulation of L-carnitine metabolism in ASD is accompanied by disturbances of other metabolic pathways, e.g., Krebs cycle, the activity of respiratory chain complexes, indicative of mitochondrial dysfunction. Supplementation of L-carnitine may be beneficial to alleviate behavioral and cognitive symptoms in ASD patients.
Renal Manifestations of Covid-19: Physiology and Pathophysiology
Authors: Armaly Zaher , Kinaneh Safa , Skorecki Karl
Published: March 2021

Corona virus disease 2019 (COVID-19) imposes a serious public health pandemic affecting the whole world, as it is spreading exponentially. Besides its high infectivity, SARS-CoV-2 causes multiple serious derangements, where the most prominent is severe acute respiratory syndrome as well as multiple organ dysfunction including heart and kidney injury. While the deleterious impact of SARS-CoV-2 on pulmonary and cardiac systems have attracted remarkable attention, the adverse effects of this virus on the renal system is still underestimated. Kidney susceptibility to SARS-CoV-2 infection is determined by the presence of angiotensin-converting enzyme 2 (ACE2) receptor which is used as port of the viral entry into targeted cells, tissue tropism, pathogenicity and subsequent viral replication. The SARS-CoV-2 cellular entry receptor, ACE2, is widely expressed in proximal epithelial cells, vascular endothelial and smooth muscle cells and podocytes, where it supports kidney integrity and function via the enzymatic production of Angiotensin 1-7 (Ang 1-7), which exerts vasodilatory, anti-inflammatory, antifibrotic and diuretic/natriuretic actions via activation of the Mas receptor axis. Loss of this activity constitutes the potential basis for the renal damage that occurs in COVID-19 patients. Indeed, several studies in a small sample of COVID-19 patients revealed relatively high incidence of acute kidney injury (AKI) among them. Although SARS-CoV-1 -induced AKI was attributed to multiorgan failure and cytokine release syndrome, as the virus was not detectable in the renal tissue of infected patients, SARS-CoV-2 antigens were detected in kidney tubules, suggesting that SARS-CoV-2 infects the human kidney directly, and eventually induces AKI characterized with high morbidity and mortality. The mechanisms underlying this phenomenon are largely unknown. However, the fact that ACE2 plays a crucial role against renal injury, the deprivation of the kidney of this advantageous enzyme, along with local viral replication, probably plays a central role. The current review focuses on the critical role of ACE2 in renal physiology, its involvement in the development of kidney injury during SARS-CoV-2 infection, renal manifestations and therapeutic options. The latter includes exogenous administration of Ang (1-7) as an appealing option, given the high incidence of AKI in this ACE2-depleted disorder, and the benefits of ACE2/Ang1-7 including vasodilation, diuresis, natriuresis, attenuation of inflammation, oxidative stress, cell proliferation, apoptosis and coagulation.
Severe Acute Kidney Injury in Critically Ill Patients with COVID-19 Admitted to ICU: Incidence, Risk Factors, and Outcomes
Authors: Ghosn Muriel , Attallah Nizar , Badr Mohamed , Abdallah Khaled , De Oliveira Bruno , Nadeem Ashraf , Varghese Yeldho , Munde Dnyaseshwar , Salam Shameen , Abduljawad Baraa , Saleh Khaled , Elkambergy Hussam , Wahla Ali , Taha Ahmed , Dibu Jamil , Bayrlee Ahmed , Hamed Fadi , Rahman Nadeem , Mallat Jihad
Published: March 2021

Background: Critically ill patients with COVID-19 are prone to develop severe acute kidney injury (AKI), defined as KDIGO (Kidney Disease Improving Global Outcomes) stages 2 or 3. However, data are limited in these patients. We aimed to report the incidence, risk factors, and prognostic impact of severe AKI in critically ill patients with COVID-19 admitted to the intensive care unit (ICU) for acute respiratory failure. Methods: A retrospective monocenter study including adult patients with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection admitted to the ICU for acute respiratory failure. The primary outcome was to identify the incidence and risk factors associated with severe AKI (KDIGO stages 2 or 3). Results: Overall, 110 COVID-19 patients were admitted. Among them, 77 (70%) required invasive mechanical ventilation (IMV), 66 (60%) received vasopressor support, and 9 (8.2%) needed extracorporeal membrane oxygenation (ECMO). Severe AKI occurred in 50 patients (45.4%). In multivariable logistic regression analysis, severe AKI was independently associated with age (odds ratio (OR) = 1.08 (95% CI (confidence interval): 1.03–1.14), p = 0.003), IMV (OR = 33.44 (95% CI: 2.20–507.77), p = 0.011), creatinine level on admission (OR = 1.04 (95% CI: 1.008–1.065), p = 0.012), and ECMO (OR = 11.42 (95% CI: 1.95–66.70), p = 0.007). Inflammatory (interleukin-6, C-reactive protein, and ferritin) or thrombotic (D-dimer and fibrinogen) markers were not associated with severe AKI after adjustment for potential confounders. Severe AKI was independently associated with hospital mortality (OR = 29.73 (95% CI: 4.10–215.77), p = 0.001) and longer hospital length of stay (subhazard ratio = 0.26 (95% CI: 0.14–0.51), p < 0.001). At the time of hospital discharge, 74.1% of patients with severe AKI who were discharged alive from the hospital recovered normal or baseline renal function. Conclusion: Severe AKI was common in critically ill patients with COVID-19 and was not associated with inflammatory or thrombotic markers. Severe AKI was an independent risk factor of hospital mortality and hospital length of stay, and it should be rapidly recognized during SARS-CoV-2 infection.