bluuebunny/crossref_metadata_2025 huggingface dataset:
How Well Does a Sequential Minimal Optimization Model Perform in Predicting Medicine Prices for Procurement System?
Authors: Pentrakan Amarawan , Yang Cheng-Chia , Wong Wing-Keung
Published: May 2021

The lack of an efficient approach in managing pharmaceutical prices in the procurement system led to a substantial burden on government budgets. In Thailand, although the reference price policy was implemented to contain the drug expenditure, there have been some challenges with the price dispersion of medicines and pricing information transparency. This phenomenon calls for the development of a potential algorithm to estimate appropriate prices for medical products. To serve this purpose, in this paper, we first developed the model by the sequential minimal optimization (SMO) algorithm for predicting the range of the prices for each medicine, using the Waikato environment for knowledge analysis software, and applying feature selection techniques also to examine improving predictive accuracy. We used the dataset comprised of 2424 records listed on the procurement system in Thailand from January to March 2019 in the application and used a 10-fold cross-validation test to validate the model. The results demonstrated that the model derived by the SMO algorithm with the gain ratio selection method provided good performance at an accuracy of approximately 92.62%, with high sensitivity and precision. Additionally, we found that the model can distinguish the differences in the prices of medicines in the pharmaceutical market by using eight major features—the segmented buyers, the generic product groups, trade product names, procurement methods, dosage forms, pack sizes, manufacturers, and total purchase budgets—that provided the highest predictive accuracy. Our findings are useful to health policymakers who could employ our proposed model in monitoring the situation of medicine prices and providing feedback directly to suggest the best possible price for hospital purchasing managers based on the feature inputs in their procurement system.
Impacts of Thermal Environments on Health Risk: A Case Study of Harris County, Texas
Authors: Chun Bumseok , Hur Misun , Won Jaewoong
Published: May 2021

The loss of green spaces in urbanized areas has triggered a potential thermal risk in the urban environment. While the existing literature has investigated the direct relationship between urban temperatures and health risks, little is known about causal relationships among key components of urban sustainability and health risks, through a pathway involving urban temperature. This study examined the multiple connections between urbanized land use, urban greenery, urban temperatures and health risks in Harris County, Texas. The census tract-level health data from the 500 Cities Project (Centers for Disease Control and Prevention) is used for analysis. Structural equation model analyses showed that the urban temperature played a mediating role in associations between urbanized land use, urban greenery and health risk. Urban vegetation is associated with a decrease in health risks, while urban land use has associations with an increase in health risks. Findings suggest that proactive policies tailored to provide rich urban greenery in a neighborhood can alleviate urban land use effects on health risks.
Monetary Health Co-Benefits and GHG Emissions Reduction Benefits: Contribution from Private On-the-Road Transport
Authors: Liou Je-Liang , Wu Pei-Ing
Published: May 2021

This is the first study to provide a systematic monetary benefit matrix, including greenhouse gas (GHG) emissions reduction benefits and air pollution reduction health co-benefits, for a change in on-the-road transport to low-carbon types. The benefit transfer method is employed to estimate the social cost of carbon and the health co-benefits via impact pathway analysis in Taiwan. Specifically, the total emissions reduction benefits from changing all internal combustion vehicles to either hybrid electric vehicles, plug-in hybrid electric vehicles, or electric vehicles would generate an average of USD 760 million from GHG emissions reduction and USD 2091 million from health co-benefits based on air pollution reduction, for a total benefit of USD 2851 million annually. For a change from combustion scooters to light- or heavy-duty electric scooters, the average GHG emissions reduction benefits would be USD 96.02 million, and the health co-benefits from air pollution reduction would be USD 1008.83 million, for total benefits of USD 1104.85 million annually.
Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression
Authors: Park Hyun-Sun , Kim Jongmin , Ahn Seong Hoon , Ryu Hong-Yeoul
Published: May 2021

Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.
Viruses and Skin Cancer
Authors: Becerril Sara , Corchado-Cobos Roberto , García-Sancha Natalia , Revelles Leonor , Revilla David , Ugalde Tatiana , Román-Curto Concepción , Pérez-Losada Jesús , Cañueto Javier
Published: May 2021

Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the biology of skin cancer. In this paper, we review the viral agents responsible for different types of skin cancer, especially for solid skin tumors. We focus on human papillomavirus and squamous cell cancers, Merkel cell polyomavirus and Merkel cell carcinoma, and human herpesvirus 8 and Kaposi’s sarcoma.
KEAP1 Cancer Mutants: A Large-Scale Molecular Dynamics Study of Protein Stability
Authors: Wilson Carter J. , Chang Megan , Karttunen Mikko , Choy Wing-Yiu
Published: May 2021

We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise analysis of the Kelch domain points to stability as a possible target of cancer in KEAP1. Interestingly, structural analysis of the R470C ANCHOR mutant, the most prevalent missense mutation in KEAP1, revealed no significant change in structural stability or NRF2 binding site dynamics, possibly indicating an covalent modification as this mutant’s mode of action.
Omega-3 PUFAs Suppress IL-1β-Induced Hyperactivity of Immunoproteasomes in Astrocytes
Authors: Zgorzynska Emilia , Dziedzic Barbara , Markiewicz Monika , Walczewska Anna
Published: May 2021

The role of immunoproteasome (iP) in astroglia, the cellular component of innate immunity, has not been clarified. The results so far indicate that neuroinflammation, a prominent hallmark of Alzheimer’s disease, strongly activates the iP subunits expression. Since omega-3 PUFAs possess anti-inflammatory and pro-resolving activity in the brain, we investigated the effect of DHA and EPA on the gene expression of constitutive (β1 and β5) and inducible (iβ1/LMP2 and iβ5/LMP7) proteasome subunits and proteasomal activity in IL-1β-stimulated astrocytes. We found that both PUFAs downregulated the expression of IL-1β-induced the iP subunits, but not the constitutive proteasome subunits. The chymotrypsin-like activity was inhibited in a dose-dependent manner by DHA, and much strongly in the lower concentration by EPA. Furthermore, we established that C/EBPα and C/EBPβ transcription factors, being the cis-regulatory element of the transcription complex, frequently activated by inflammatory mediators, participate in a reduction in the iP subunits’ expression. Moreover, the expression of connexin 43 the major gap junction protein in astrocytes, negatively regulated by IL-1β was markedly increased in PUFA-treated cells. These findings indicate that omega-3 PUFAs attenuate inflammation-induced hyperactivity of iPs in astrocytes and have a beneficial effect on preservation of interastrocytic communication by gap junctions.
Double-Edged Sword of Vitamin D3 Effects on Primary Neuronal Cultures in Hypoxic States
Authors: Loginova Maria , Mishchenko Tatiana , Savyuk Maria , Guseva Svetlana , Gavrish Maria , Krivonosov Mikhail , Ivanchenko Mikhail , Fedotova Julia , Vedunova Maria
Published: May 2021

The use of vitamin D3 along with traditional therapy opens up new prospects for increasing the adaptive capacity of nerve cells to the effects of a wide range of stress factors, including hypoxia-ischemic processes. However, questions about prophylactic and therapeutic doses of vitamin D3 remain controversial. The purpose of our study was to analyze the effects of vitamin D3 at different concentrations on morpho-functional characteristics of neuron–glial networks in hypoxia modeling in vitro. We showed that a single administration of vitamin D3 at a high concentration (1 µM) in a normal state has no significant effect on the cell viability of primary neuronal cultures; however, it has a pronounced modulatory effect on the functional calcium activity of neuron–glial networks and causes destruction of the network response. Under hypoxia, the use of vitamin D3 (1 µM) leads to total cell death of primary neuronal cultures and complete negation of functional neural network activity. In contrast, application of lower concentrations of vitamin D3 (0.01 µM and 0.1 µM) caused a pronounced dose-dependent neuroprotective effect during the studied post-hypoxic period. While the use of vitamin D3 at a concentration of 0.1 µM maintained cell viability, preventive administration of 0.01 µM not only partially preserved the morphological integrity of primary neuronal cells but also maintained the functional structure and activity of neuron–glial networks in cultures. Possible molecular mechanisms of neuroprotective action of vitamin D3 can be associated with the increased expression level of transcription factor HIF-1α and maintaining the relationship between the levels of BDNF and TrkB expression in cells of primary neuronal cultures.
How to Target Spinal Metastasis in Experimental Research: An Overview of Currently Used Experimental Mouse Models and Future Prospects
Authors: Jelgersma Claudius , Vajkoczy Peter
Published: May 2021

The spine is one of the organs that is most affected by metastasis in cancer patients. Since the control of primary tumor is continuously improving, treatment of metastases is becoming one of the major challenges to prevent cancer-related death. Due to the anatomical proximity to the spinal cord, local spread of metastasis can directly cause neurological deficits, severely limiting the patient’s quality of life. To investigate the underlying mechanisms and to develop new therapies, preclinical models are required which represent the complexity of the multistep cascade of metastasis. Current research of metastasis focuses on the formation of the premetastatic niche, tumor cell dormancy and the influence and regulating function of the immune system. To unveil whether these influence the organotropism to the spine, spinal models are irreplaceable. Mouse models are one of the most suitable models in oncologic research. Therefore, this review provides an overview of currently used mouse models of spinal metastasis. Furthermore, it discusses technical aspects clarifying to what extend these models can picture key steps of the metastatic process. Finally, it addresses proposals to develop better mouse models in the future and could serve as both basis and stimulus for researchers and clinicians working in this field.
Prolonged Transcriptional Consequences in Survivors of Sepsis
Authors: Laudanski Krzysztof , Soh James , DiMeglio Matthew , Sullivan Kathleen E.
Published: May 2021

Survivors of sepsis often suffer from prolonged post-critical illness syndrome secondary to the immune system’s reprogramming. It is unclear if this process is static and pervasive due to methodological difficulties studying long-term outcomes of sepsis. The purpose of this study is to evaluate transcriptional profiles longitudinally in Drosophila melanogaster in the aftermath of sepsis to provide preliminary data for targets playing a role in post-sepsis immunostasis. Adult Drosophila melanogaster were infected with E. coli, and survivors were euthanized at 7, 14, and 21 days. Control flies were subjected to sham stress. Gene profiling was done with RNA-seq, and potential miRNA factors were computed. Profiling identified 55 unique genes at seven days, 61 unique genes at 14 days, and 78 genes at 21 days in sepsis survivors vs. sham control. Each post-sepsis timepoint had a distinctive transcriptional pattern with a signature related to oxidative stress at seven days, neuronal signal transduction at 14 days, and metabolism at 21 days. Several potential miRNA patterns were computed as potentially affecting several of the genes expressed in sepsis survivors. Our study demonstrated that post-sepsis changes in the transcriptome profile are dynamic and extend well into the Drosophila melanogaster natural life span.
Kidney Biopsy in Type 2 Diabetic Patients: Critical Reflections on Present Indications and Diagnostic Alternatives
Authors: Santoro Domenico , Torreggiani Massimo , Pellicanò Vincenzo , Cernaro Valeria , Messina Roberta Maria , Longhitano Elisa , Siligato Rossella , Gembillo Guido , Esposito Ciro , Piccoli Giorgina Barbara
Published: May 2021

Roughly 3% of patients worldwide with a new diagnosis of type 2 diabetes mellitus (T2DM) already have an overt nephropathy at diagnosis and about 20–30% of the remaining ones develop a complication of this kind later in life. The early identification of kidney disease in diabetic patients is important as it slows its progression, which is important not only because this reduces the need for renal replacement therapy, but also because it decreases the high rate of mortality and morbidity associated with a reduction in kidney function. The increasing prevalence of type 2 diabetes and the consequent greater probability of finding different types of kidney diseases in diabetic patients frequently gives rise to overlapping diagnoses, a definition encompassing the differential diagnosis between diabetic and non-diabetic kidney disease. The issue is made more complex by the acknowledgement of the increasing frequency of presentations of what is termed “diabetic kidney disease” without relevant proteinuria, in particular in T2DM patients. Distinguishing between diabetes related and non-diabetes related forms of kidney disease in diabetic patients is not only a semantic question, as different diseases require different clinical management. However, while the urologic and macrovascular complications of diabetes, as well as overlapping parenchymal damage, can be diagnosed by means of imaging studies, often only a kidney biopsy will make a differential diagnosis possible. In fact, the coexistence of typical diabetic lesions, such as nodular glomerulopathy or glomerulosclerosis, with different glomerular, vascular and tubulo-interstitial alterations has been extensively described, and an analysis of the dominant histological pattern can contribute to determining what therapeutic approach should be adopted. However, due to the high frequency of kidney diseases, and to the fact that T2DM patients are often affected by multiple comorbidities, a kidney biopsy is not generally performed in T2DM patients. What follows is a review aiming to discuss the diagnostic work-up, on the base of clinical, laboratory and imaging criteria, and evaluate the present indications and alternatives to renal biopsy.
A Review on Ionic Liquids-Based Membranes for Middle and High Temperature Polymer Electrolyte Membrane Fuel Cells (PEM FCs)
Authors: Ebrahimi Mohammad , Kujawski Wojciech , Fatyeyeva Kateryna , Kujawa Joanna
Published: May 2021

Today, the use of polymer electrolyte membranes (PEMs) possessing ionic liquids (ILs) in middle and high temperature polymer electrolyte membrane fuel cells (MT-PEMFCs and HT-PEMFCs) have been increased. ILs are the organic salts, and they are typically liquid at the temperature lower than 100 °C with high conductivity and thermal stability. The membranes containing ILs can conduct protons through the PEMs at elevated temperatures (more than 80 °C), unlike the Nafion-based membranes. A wide range of ILs have been identified, including chiral ILs, bio-ILs, basic ILs, energetic ILs, metallic ILs, and neutral ILs, that, from among them, functionalized ionic liquids (FILs) include a lot of ion exchange groups in their structure that improve and accelerate proton conduction through the polymeric membrane. In spite of positive features of using ILs, the leaching of ILs from the membranes during the operation of fuel cell is the main downside of these organic salts, which leads to reducing the performance of the membranes; however, there are some ways to diminish leaching from the membranes. The aim of this review is to provide an overview of these issues by evaluating key studies that have been undertaken in the last years in order to present objective and comprehensive updated information that presents the progress that has been made in this field. Significant information regarding the utilization of ILs in MT-PEMFCs and HT-PEMFCs, ILs structure, properties, and synthesis is given. Moreover, leaching of ILs as a challenging demerit and the possible methods to tackle this problem are approached in this paper. The present review will be of interest to chemists, electrochemists, environmentalists, and any other researchers working on sustainable energy production field.
Heparin-Tagged PLA-PEG Copolymer-Encapsulated Biochanin A-Loaded (Mg/Al) LDH Nanoparticles Recommended for Non-Thrombogenic and Anti-Proliferative Stent Coating
Authors: Adepu Shivakalyani , Luo Hongrong , Ramakrishna Seeram
Published: May 2021

Drug-eluting stents have been widely implanted to prevent neointimal hyperplasia associated with bare metal stents. Conventional polymers and anti-proliferative drugs suffer from stent thrombosis due to the non-selective nature of the drugs and hypersensitivity to polymer degradation products. Alternatively, various herbal anti-proliferative agents are sought, of which biochanin A (an isoflavone phytoestrogen) was known to have anti-proliferative and vasculoprotective action. PLA-PEG diblock copolymer was tagged with heparin, whose degradation releases heparin locally and prevents thrombosis. To get a controlled drug release, biochanin A was loaded in layered double hydroxide nanoparticles (LDH), which are further encapsulated in a heparin-tagged PLA-PEG copolymer. LDH nanoparticles are synthesized by a co-precipitation process; in situ as well as ex situ loading of biochanin A were done. PLA-PEG-heparin copolymer was synthesized by esterification reaction, and the drug-loaded nanoparticles are coated. The formulation was characterized by FTIR, XRD, DSC, DLS, and TEM. In vitro drug release studies, protein adhesion, wettability, hemocompatibility, and degradation studies were performed. The drug release was modeled by mathematical models to further emphasize the mechanism of drug release. The developed drug-eluting stent coating is non-thrombogenic, and it offers close to zero-order release for 40 days, with complete polymer degradation in 14 weeks.
Existing Drugs Considered as Promising in COVID-19 Therapy
Authors: Janik Edyta , Niemcewicz Marcin , Podogrocki Marcin , Saluk-Bijak Joanna , Bijak Michal
Published: May 2021

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.
Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a
Authors: Goerg Jana , Sommerfeld Manuela , Greiner Bettina , Lauer Dilyara , Seckin Yasemin , Kulikov Alexander , Ivkin Dmitry , Kintscher Ulrich , Okovityi Sergey , Kaschina Elena
Published: May 2021

The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular systolic pressure, mean pressure, and the max dP/dt (p < 0.05). Similarly, treatment with empagliflozin (1 mg/kg, p.o.) for one week increased the cardiac output, stroke volume, and fractional shortening (p < 0.05). Myocardial infarction (MI) was induced by ligation of the left coronary artery. On day 7 post MI, empagliflozin (1 mg/kg, p.o.) improved the systolic heart function as shown by the global longitudinal strain (−21.0 ± 1.1% vs. −16.6 ± 0.7% in vehicle; p < 0.05). In peri-infarct tissues, empagliflozin decreased the protein expression of matrix metalloproteinase 9 (MMP9) and favorably regulated the cardiac transporters sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and sodium hydrogen exchanger 1 (NHE1). In H9c2 cardiac cells, empagliflozin decreased the MMP2,9 activity and prevented apoptosis. Empagliflozin did not alter the arterial stiffness, blood pressure, markers of fibrosis, and necroptosis. Altogether, short-term treatment with low-dose empagliflozin increased the cardiac contractility in normoglycemic rats and improved the systolic heart function in the early phase after MI. These effects are attributed to a down-regulation of MMP9 and NHE1, and an up-regulation of SERCA2a. This study is of clinical importance because it suggests that a low-dose treatment option with empagliflozin may improve cardiovascular outcomes post-MI. Down-regulation of MMPs could be relevant to many remodeling processes including cancer disease.
The Molecular Basis of COVID-19 Pathogenesis, Conventional and Nanomedicine Therapy
Authors: Kouhpayeh Shirin , Shariati Laleh , Boshtam Maryam , Rahimmanesh Ilnaz , Mirian Mina , Esmaeili Yasaman , Najaflu Malihe , Khanahmad Negar , Zeinalian Mehrdad , Trovato Maria , Tay Franklin R , Khanahmad Hossein , Makvandi Pooyan
Published: May 2021

In late 2019, a new member of the Coronaviridae family, officially designated as “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.
Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH)
Authors: Weiland Judith , Beez Alexandra , Westermaier Thomas , Kunze Ekkehard , Sirén Anna-Leena , Lilla Nadine
Published: May 2021

Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.
C60 Fullerene Reduces 3-Nitropropionic Acid-Induced Oxidative Stress Disorders and Mitochondrial Dysfunction in Rats by Modulation of p53, Bcl-2 and Nrf2 Targeted Proteins
Authors: Gonchar Olga O. , Maznychenko Andriy V. , Klyuchko Olena M. , Mankovska Iryna M. , Butowska Kamila , Borowik Agnieszka , Piosik Jacek , Sokolowska Inna
Published: May 2021

C60 fullerene as a potent free radical scavenger and antioxidant could be a beneficial means for neurodegenerative disease prevention or cure. The aim of the study was to define the effects of C60 administration on mitochondrial dysfunction and oxidative stress disorders in a 3-nitropropionic acid (3-NPA)-induced rat model of Huntington’s disease. Animals received 3-NPA (30 mg/kg i.p.) once a day for 3 consecutive days. C60 was applied at a dose of 0.5 mg/kg of body weight, i.p. daily over 5 days before (C60 pre-treatment) and after 3-NPA exposure (C60 post-treatment). Oxidative stress biomarkers, the activity of respiratory chain enzymes, the level of antioxidant defense, and pro- and antiapoptotic markers were analyzed in the brain and skeletal muscle mitochondria. The nuclear and cytosol Nrf2 protein expression, protein level of MnSOD, γ-glutamate-cysteine ligase (γ-GCLC), and glutathione-S-transferase (GSTP) as Nrf2 targets were evaluated. Our results indicated that C60 can prevent 3-NPA-induced mitochondrial dysfunction through the restoring of mitochondrial complexes’ enzyme activity, ROS scavenging, modulating of pro/antioxidant balance and GSH/GSSG ratio, as well as inhibition of mitochondria-dependent apoptosis through the limitation of p53 mitochondrial translocation and increase in Bcl-2 protein expression. C60 improved mitochondrial protection by strengthening the endogenous glutathione system via glutathione biosynthesis by up-regulating Nrf2 nuclear accumulation as well as GCLC and GSTP protein level.
Regulation and Role of Transcription Factors in Osteogenesis
Authors: Chan Wilson Cheuk Wing , Tan Zhijia , To Michael Kai Tsun , Chan Danny
Published: May 2021

Bone is a dynamic tissue constantly responding to environmental changes such as nutritional and mechanical stress. Bone homeostasis in adult life is maintained through bone remodeling, a controlled and balanced process between bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoblasts secrete matrix, with some being buried within the newly formed bone, and differentiate to osteocytes. During embryogenesis, bones are formed through intramembraneous or endochondral ossification. The former involves a direct differentiation of mesenchymal progenitor to osteoblasts, and the latter is through a cartilage template that is subsequently converted to bone. Advances in lineage tracing, cell sorting, and single-cell transcriptome studies have enabled new discoveries of gene regulation, and new populations of skeletal stem cells in multiple niches, including the cartilage growth plate, chondro-osseous junction, bone, and bone marrow, in embryonic development and postnatal life. Osteoblast differentiation is regulated by a master transcription factor RUNX2 and other factors such as OSX/SP7 and ATF4. Developmental and environmental cues affect the transcriptional activities of osteoblasts from lineage commitment to differentiation at multiple levels, fine-tuned with the involvement of co-factors, microRNAs, epigenetics, systemic factors, circadian rhythm, and the microenvironments. In this review, we will discuss these topics in relation to transcriptional controls in osteogenesis.
Leptin in Atherosclerosis: Focus on Macrophages, Endothelial and Smooth Muscle Cells
Authors: Raman Priya , Khanal Saugat
Published: May 2021

Increasing adipose tissue mass in obesity directly correlates with elevated circulating leptin levels. Leptin is an adipokine known to play a role in numerous biological processes including regulation of energy homeostasis, inflammation, vascular function and angiogenesis. While physiological concentrations of leptin may exhibit multiple beneficial effects, chronically elevated pathophysiological levels or hyperleptinemia, characteristic of obesity and diabetes, is a major risk factor for development of atherosclerosis. Hyperleptinemia results in a state of selective leptin resistance such that while beneficial metabolic effects of leptin are dampened, deleterious vascular effects of leptin are conserved attributing to vascular dysfunction. Leptin exerts potent proatherogenic effects on multiple vascular cell types including macrophages, endothelial cells and smooth muscle cells; these effects are mediated via an interaction of leptin with the long form of leptin receptor, abundantly expressed in atherosclerotic plaques. This review provides a summary of recent in vivo and in vitro studies that highlight a role of leptin in the pathogenesis of atherosclerotic complications associated with obesity and diabetes.
Role of Arachidonic Acid and Its Metabolites in the Biological and Clinical Manifestations of Idiopathic Nephrotic Syndrome
Authors: Turolo Stefano , Edefonti Alberto , Mazzocchi Alessandra , Syren Marie Louise , Morello William , Agostoni Carlo , Montini Giovanni
Published: May 2021

Studies concerning the role of arachidonic acid (AA) and its metabolites in kidney disease are scarce, and this applies in particular to idiopathic nephrotic syndrome (INS). INS is one of the most frequent glomerular diseases in childhood; it is characterized by T-lymphocyte dysfunction, alterations of pro- and anti-coagulant factor levels, and increased platelet count and aggregation, leading to thrombophilia. AA and its metabolites are involved in several biological processes. Herein, we describe the main fields where they may play a significant role, particularly as it pertains to their effects on the kidney and the mechanisms underlying INS. AA and its metabolites influence cell membrane fluidity and permeability, modulate platelet activity and coagulation, regulate lymphocyte activity and inflammation, preserve the permeability of the glomerular barrier, influence podocyte physiology, and play a role in renal fibrosis. We also provide suggestions regarding dietary measures that are able to prevent an imbalance between arachidonic acid and its parental compound linoleic acid, in order to counteract the inflammatory state which characterizes numerous kidney diseases. On this basis, studies of AA in kidney disease appear as an important field to explore, with possible relevant results at the biological, dietary, and pharmacological level, in the final perspective for AA to modulate INS clinical manifestations.
Can the COVID-19 Pandemic Disrupt the Current Drug Development Practices?
Authors: Won Jung-Hyun , Lee Howard
Published: May 2021

Therapeutics and vaccines against the COVID-19 pandemic need to be developed rapidly and efficiently, given its severity. To maximize the efficiency and productivity of drug development, the world has adopted disruptive technologies and approaches in various drug development areas. Telehealth, characterized by the heavy use of digital technologies; drug repositioning strategies, aided by computational breakthroughs; and data tracking tool hubs, enabling real-time information sharing, have received much attention. Moreover, drug developers have engaged in open innovation by establishing various types of collaborations, many of which have been carried out across nations and enterprises. Finally, regulatory agencies have attempted to operate on a more flexible review basis than before. Although such disruptive approaches have partly reshaped drug development practices, issues and challenges remain before the completion of this paradigm shift in conventional drug development practices for the post-pandemic era. In this review, we have highlighted the role of a collaborative community of experts in order to figure out how disruptive technologies can be fully integrated into the current drug development practices and improve drug development efficiency for the post-pandemic era.
An Approach for Realizing Hybrid Digital Twins Using Asset Administration Shells and Apache StreamPipes
Authors: Jacoby Michael , Jovicic Branislav , Stojanovic Ljiljana , Stojanović Nenad
Published: May 2021

Digital twins (DTs) are digital representations of assets, capturing their attributes and behavior. They are one of the cornerstones of Industry 4.0. Current DT standards are still under development, and so far, they typically allow for representing DTs only by attributes. Yet, knowledge about the behavior of assets is essential to properly control and interact with them, especially in the context of industrial production. This behavior is typically represented by multiple different models, making integration and orchestration within a DT difficult to manage. In this paper, we propose a new approach for hybrid DTs by intertwining different DT models. We also show how to realize this approach by combining the Fraunhofer Asset Administration Shell (AAS) Tools for Digital Twins (FAST) to create Industry 4.0-compliant DTs with Apache StreamPipes to implement and manage multiple DT models. Our prototype implementation is limited to a subset of the AAS metamodel and pull-based communication between FAST and an external Apache StreamPipes instance. Future work should provide full support for the AAS metamodel, publish/subscribe-based communication, and other execution environments as well as deployment strategies. We also present how this approach has been applied to a real-world use case in the steel production industry.
Use of Machine Learning Algorithms to Predict Subgrade Resilient Modulus
Authors: Pahno Steve , Yang Jidong J. , Kim S. Sonny
Published: May 2021

Modern machine learning methods, such as tree ensembles, have recently become extremely popular due to their versatility and scalability in handling heterogeneous data and have been successfully applied across a wide range of domains. In this study, two widely applied tree ensemble methods, i.e., random forest (parallel ensemble) and gradient boosting (sequential ensemble), were investigated to predict resilient modulus, using routinely collected soil properties. Laboratory test data on sandy soils from nine borrow pits in Georgia were used for model training and testing. For comparison purposes, the two tree ensemble methods were evaluated against a regression tree model and a multiple linear regression model, demonstrating their superior performance. The results revealed that a single tree model generally suffers from high variance, while providing a similar performance to the traditional multiple linear regression model. By leveraging a collection of trees, both tree ensemble methods, Random Forest and eXtreme Gradient Boosting, significantly reduced variance and improved prediction accuracy, with the eXtreme Gradient Boosting being the best model, with an R2 of 0.95 on the test dataset.
Solvothermal Synthesis Routes to Substituted Cerium Dioxide Materials
Authors: Annis James W. , Fisher Janet M. , Thompsett David , Walton Richard I.
Published: May 2021

We review the solution-based synthesis routes to cerium oxide materials where one or more elements are included in place of a proportion of the cerium, i.e., substitution of cerium is performed. The focus is on the solvothermal method, where reagents are heated above the boiling point of the solvent to induce crystallisation directly from the solution. This yields unusual compositions with crystal morphology often on the nanoscale. Chemical elements from all parts of the periodic table are considered, from transition metals to main group elements and the rare earths, including isovalent and aliovalent cations, and surveyed using the literature published in the past ten years. We illustrate the versatility of this synthesis method to allow the formation of functional materials with applications in contemporary applications such as heterogeneous catalysis, electrodes for solid oxide fuel cells, photocatalysis, luminescence and biomedicine. We pick out emerging trends towards control of crystal habit by use of non-aqueous solvents and solution additives and identify challenges still remaining, including in detailed structural characterisation, the understanding of crystallisation mechanisms and the scale-up of synthesis.
Effects of Landscape Patterns and Their Changes to Species Richness, Species Composition, and the Conservation Value of Odonates (Insecta)
Authors: Dolný Aleš , Ožana Stanislav , Burda Michal , Harabiš Filip
Published: May 2021

Understanding the impact of the changing proportion of land-use patterns on species diversity is a critical issue in conservation biology, and odonates are good bioindicators of these environmental changes. Some freshwater ecosystems that have been modified due to human activities can serve as important secondary habitats for odonate assemblages; however, the majority of studies addressing the value of secondary habitats in industrial and urban areas for adult dragonfly diversity have been limited to the local scale, and the value of such habitats for gamma diversity is still unclear. The aim of this study was to determine the relationship between human transformations of land use/land cover and dragonfly diversity. We interpolated the information based on dragonfly occurrence per grid cell and land cover data, indicating naturalness and degradation in 677 grid cells in the Czech Republic. Species richness did not correspond to habitat naturalness, but the occurrence of endangered species was significantly positively correlated with increasing naturalness; thus, habitat degradation and/or the level of naturalness significantly affected species composition, while species richness remained unchanged. Threatened species that occur predominantly in natural areas and threatened species with a dominant occurrence in degraded squares were also separated, which indicated that the conservation of the latter should be prioritised.
Towards a Knowledge-Based Decision Support System for Integrated Control of Woolly Apple Aphid, Eriosoma lanigerum, with Maximal Biological Suppression by the Parasitoid Aphelinus mali
Authors: Bangels Eva , Alhmedi Ammar , Akkermans Wannes , Bylemans Dany , Belien Tim
Published: May 2021

The woolly apple aphid Eriosoma lanigerum (Homoptera: Aphidiae) is an important pest in apple orchards worldwide. Since the withdrawal or restricted use of certain broad-spectrum insecticides, E. lanigerum has become one of the most severe pests in apple growing areas across Western Europe. At present, effective limitation of woolly aphid populations relies on a good synergy between chemical control treatments and biological suppression by beneficial arthropods, especially by its main specific natural enemy, the parasitoid Aphelinus mali (Hymenoptera: Aphelinidae). To develop a knowledge-based decision support system, detailed monitoring data of both species were collected in the field (region of Sint-Truiden, Belgium) for a period of ten years (2010–2020). Aphelinus mali flights were monitored in the field, starting before flowering until the end of the second-generation flight at minimum. The seasonal occurrence of the most important management stages of E. lanigerum, e.g., start of wool production or activity on aerial parts in spring and migration of crawlers from colonies towards flower clusters or shoots, were thoroughly monitored. All obtained data were compared with historical and literature data and analysed in a population dynamics phenological model. Our outcomes showed that the emergence of first-generation A. mali adults (critical for the first parasitation activity and the basis for following A. mali generations in the continuation of the season) can be accurately predicted by the developed model. Hence, this information can be utilized to avoid insecticide sprayings with detrimental side effects at this particular moment as demonstrated by the outcomes of a field trial. In addition, the start of migration of E. lanigerum crawlers towards flower clusters or shoots is accurately predicted by the model. In conclusion, our results demonstrate that the model can be used as decision support system for the optimal timing of control treatments in order to achieve effective control of E. lanigerum with maximal biological suppression by its main natural enemy.
Patterns of Genetic Diversity and Mating Systems in a Mass-Reared Black Soldier Fly Colony
Authors: Hoffmann Lelanie , Hull Kelvin L. , Bierman Anandi , Badenhorst Rozane , Bester-van der Merwe Aletta E. , Rhode Clint
Published: May 2021

The black soldier fly (BSF), Hermetia illucens, is a promising candidate for the emerging insect farming industry with favourable characteristics for both bioremediation and production of animal delivered nutritive and industrial compounds. The genetic management of commercial colonies will become increasingly important for the sustainability of the industry. However, r-selected life history traits of insects pose challenges to conventional animal husbandry and breeding approaches. In this study, the long-term genetic effects of mass-rearing were evaluated as well as mating systems in the species to establish factors that might influence genetic diversity, and by implication fitness and productivity in commercial colonies. Population genetic parameters, based on microsatellite markers, were estimated and compared amongst two temporal wild sampling populations and four generations (F28, F48, F52, and F62) of a mass-reared colony. Furthermore, genetic relationships amongst mate pairs were evaluated and parentage analysis was performed to determine the oc-currence of preferential mate choice and multiple paternity. The mass-reared colony showed a reduction in genetic diversity and evidence for inbreeding with significant successive generational genetic differentiation from the wild progenitor population. Population-level analysis also gave the first tentative evidence of positive assortative mating and genetic polyandry in BSF. The homoge-neity of the mass-reared colony seems to result from a dual action caused by small effective popu-lation size and increased homozygosity due to positive assortative mating. However, the high ge-netic diversity in the wild and a polyandrous mating system might suggest the possible restoration of diversity in mass-reared colonies through augmentation with the wild population.
Effects of Delayed Mating on Mating Performance and Reproductive Fitness of the Willow Leaf Beetle (Coleoptera: Chrysomelidae) under Laboratory Conditions
Authors: Zhao Lvquan , Liu Zheng , Lin Yuqun , Liu Shouzhu
Published: May 2021

Age at mating is one of the most important factors that affect mating selection, sexual performance, and fecundity. We studied the effects of mating age on the mating performance and reproductive fitness of Plagiodera versicolora Laicharting, a serious pest of poplar and willow, by measuring the time from pairing to successful mating, mating duration, fecundity, hatching probability, and female lifespan. Delayed mating of females and males significantly prolonged the time from pairing to successful mating and the mating duration, but had no effect on the duration of the egg-laying period. Delayed mating of females did not significantly affect fecundity or egg hatching, but significantly prolonged the female lifespan. Although delayed mating of males had a significant negative impact on egg hatching, it had no effect on the lifespan or fecundity of females. These results indicate that delayed mating affects the mating performance of P. versicolora, although it has a limited effect on reproductive fitness. This suggests that delayed mating is unlikely to contribute to the success of mating disruption, when applied to control P. versicolora.