bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal CAR T-cell Immunotherapy Strategies for a Leukemia Treatment Model
Authors: Khailov Evgenii , Grigorieva Ellina , Klimenkova Anna
Published: November 2020

CAR T-cell immunotherapy is a new development in the treatment of leukemia, promising a new era in oncology. Although so far, this procedure only helps 50–90% of patients and, like other cancer treatments, has serious side effects. In this work, we have proposed a controlled model for leukemia treatment to explore possible ways to improve immunotherapy methodology. Our model is described by four nonlinear differential equations with two bounded controls, which are responsible for the rate of injection of chimeric cells, as well as for the dosage of the drug that suppresses the so-called “cytokine storm”. The optimal control problem of minimizing the cancer cells and the activity of the cytokine is stated and solved using the Pontryagin maximum principle. The five possible optimal control scenarios are predicted analytically using investigation of the behavior of the switching functions. The optimal solutions, obtained numerically using BOCOP-2.2.0, confirmed our analytical findings. Interesting results, explaining, why therapies with rest intervals (for example, stopping injections in the middle of the treatment interval) are more effective (within the model), rather than with continuous injections, are presented. Possible improvements to the mathematical model and method of immunotherapy are discussed.
The 2017 Rigopiano Avalanche—Dynamics Inferred from Field Observations
Authors: Issler Dieter
Published: November 2020

Data on the disastrous snow avalanche that occurred on 18 January 2017 at the spa hotel Rigopiano, municipality of Farindola in the Abruzzo region of central Italy, are analyzed in different ways. The main results are the following. (i) The 2017 Rigopiano avalanche went beyond the run-out point predicted by the topographic-statistical α-β model with standard Norwegian calibration, while avalanches in neighboring paths appear to have run no farther than the β-point of their respective paths during the same period. (ii) The curvature and super-elevation of the trimline between 1500 and 1300 m a.s.l. indicate that the velocity of the front was around 40 m s−1. In contrast, the tail velocity of the avalanche can hardly have exceeded 25 m s−1 in the same segment. (iii) The deposits observed along all of the lower track and in the run-out zone suggest that the avalanche eroded essentially the entire snow cover, but fully entrained only a moderate amount of snow (and debris). The entrainment appears to have had a considerable decelerating effect on the flow front. (iv) Estimates of the degree to which different parts of the building were damaged is combined with information about the location of the persons in the building and their fates. This allows to refine a preliminary vulnerability curve for persons in buildings obtained from the 2015 Longyearbyen avalanche, Svalbard.
Interdisciplinary Relationships, Influence, and Aspirations for Smart Heritage in Local Government
Authors: Batchelor David , Schnabel Marc Aurel
Published: November 2020

Local governments are responding to rising complexities in service delivery, governance, and civic stewardship with novel interdisciplinary discourses that converge previously separate disciplines. Smart Heritage, the novel convergence of smart city and heritage disciplines, is one interdisciplinary discourse that local governments utilise to address these demands. To successfully deliver Smart Heritage, local governments must understand how the interdisciplinary relationships, influence, and aspirations function within their organisation. However, due to the novelty of Smart Heritage, no academic research exists on these matters, particularly within local government contexts. Therefore, this article reports how relationships, influence, and strategic aspirations between the smart city and heritage discipline intersect as Smart Heritage. It draws on interviews with smart city and heritage advisors from three local governments in Australia. It finds a case-by-case working relationship between the disciplines, which indicates an emergent-yet-tenuous Smart Heritage discourse. Moreover, the interdisciplinary relationships influence broader considerations from the advisors than their single discipline. These considerations produce innovative aspirations for local governments on heritage and smart city matters. This finding establishes the first foundational understanding of Smart Heritage within local government.
Exposure Assessment of Environmental Tobacco Aerosol from Heated Tobacco Products: Nicotine and PM Exposures under Two Limited Conditions
Authors: Hirano Tomoyasu , Shobayashi Tokuaki , Takei Teiji , Wakao Fumihiko
Published: November 2020

It is too early to provide a clear answer on the impact of exposure to the second-hand aerosol of heated tobacco products (HTPs) in the planning of policy for smoke-free indoors legislation. Here, we conducted a preliminary study to evaluate indoor air quality with the use of HTPs. We first measured the concentration of nicotine and particulate matter (PM2.5) in the air following 50 puffs in the use of HTPs or cigarettes in a small shower cubicle. We then measured these concentrations in comparison with the use equivalent of smoking 5.4 cigarettes per hour in a 25 m3 room, as a typical indoor environment test condition. In the shower cubicle test, nicotine concentrations in indoor air using three types of HTP, namely IQOS, glo, and ploomTECH, were 25.9–257 μg/m3. These values all exceed the upper bound of the range of tolerable concentration without health concerns, namely 3 µg/m3. In particular, the indoor PM2.5 concentration of about 300 to 500 μg/m3 using IQOS or glo in the shower cubicle is hazardous. In the 25 m3 room test, in contrast, nicotine concentrations in indoor air with the three types of HTP did not exceed 3 μg/m3. PM2.5 concentrations were below the standard value of 15 μg/m3 per year for IQOS and ploomTECH, but were slightly high for glo, with some measurements exceeding 100 μg/m3. These results do not negate the inclusion of HTPs within a regulatory framework for indoor tolerable use from exposure to HTP aerosol, unlike cigarette smoke.
Did an Ultra-Low Emissions Policy on Coal-Fueled Thermal Power Reduce the Harmful Emissions? Evidence from Three Typical Air Pollutants Abatement in China
Authors: Ye Penghao , Xia Senmao , Xiong Yu , Liu Chaoyang , Li Fei , Liang Jiamin , Zhang Huarong
Published: November 2020

Thermal power generation based on coal-fired power plants has the advantages of stability and controllability and has been the largest source of electricity supply in China. Coal-fired power plants, however, are also accompanied by high carbon emissions and the release of harmful substances (mainly including sulfur dioxide, nitrogen oxides, and smoke dust), and are even regarded as the “chief criminal” in terms of air pollution. However, thermal power is also a pioneering industry involved in several environmental regulations and cleaner production techniques before other industries. Evidence of this is China’s ultra-low emissions (ULE) policy on coal-fired power plants, implemented in 2015. To verify this policy’s effect, this study treats ULE as an exogenous impact variable, examining its emissions reduction effect on SO2, NOx, and smoke dust in Eastern and Central China using the difference-in-difference method (DID). The results show that the total emissions of the three pollutants were abated by 0.133%, 0.057% and 0.036% in Eastern, and by 0.120%, 0.035% and 0.043% in Central China at every 1% rise of thermal power generated after ULE. In addition, several other factors can also argue for the promotion of thermal power. Other industries, such as steel or chemical, have proven that they can contribute significant SO2 and NOx emissions. Based on these results, we provide suggestions on synergistic emissions reduction among multiple industries, as well as a discussion on the necessity of implementing ULE in Western China.
Injury Prevention, Safety Education and Violence in Relation to the Risk of Tooth Fracture among Korean Adolescents
Authors: Kim Han-Na , Kwon Yong-Bong , Byon Min-Ji , Kim Jin-Bom
Published: November 2020

This study aimed to determine the injury prevention-, safety education-, and violence-related factors pertaining to tooth fracture experience (TFE) in Korean adolescents. We used data from the 14th Korea Youth Risk Behavior Survey (KYRBS) in 2018. The 60,040 participants were selected using a complex sampling design from middle and high schools. The participants completed a self-administered questionnaire. The explanatory variables, including school safety education and violence, were assessed in relation to prevention of traumatic injuries. Complex-samples multivariable logistic regression models were applied to explain the factors related to TFE over the past 12 months. The overall prevalence of TFE was 11.4%. Risk factors related to tooth fractures were not wearing a seatbelt on an express bus, not wearing helmets while riding motorcycles and bicycles, clinical treatment due to injuries at school, injuries associated with earphone/smartphones use, and lack of school safety education such as danger evacuation training. The top risk factor was injuries associated with earphone/smartphone usage, followed by lack of familiarity with school safety education. Thus, to prevent tooth fractures among adolescents, schools should strengthen their safety education, including education regarding mobile device usage, and wearing a seatbelt and wearing a helmet. Care should be taken to manage facilities around the school and to prevent injury related to tooth fracture. Further studies on various risk factors related to tooth fractures are warranted.
Clinical Characteristics and Risk Factors for Fatality and Severity in Patients with Coronavirus Disease in Korea: A Nationwide Population-Based Retrospective Study Using the Korean Health Insurance Review and Assessment Service (HIRA) Database
Authors: Lee Seung-Geun , Park Geun U. , Moon Yeo Rae , Sung Kihoon
Published: November 2020

Background: We aimed to investigate the clinical characteristics and risk factors for fatality and severity in these patients. Methods: In this nationwide population-based retrospective study, we investigated the data of 7339 laboratory-confirmed COVID-19 patients, aged ≥ 18 years, using the Korean Health Insurance Review and Assessment Service (HIRA) database. Comorbidities and medications used were identified using HIRA codes, and severe COVID-19 was defined as that requiring oxygen therapy, mechanical ventilator, cardiopulmonary resuscitation, or extracorporeal membrane oxygenation. The outcomes were death due to COVID-19 and COVID-19 severity. Results: Mean patient age was 47.1 years; 2970 (40.1%) patients were male. Lopinavir/ritonavir, hydroxychloroquine, antibiotics, ribavirin, oseltamivir, and interferon were administered to 35.8%, 28.4%, 38.1%, 0.1%, 0.3%, and 0.9% of patients, respectively. After adjusting for confounding factors, diabetes mellitus, chronic kidney disease, previous history of pneumonia, aging, and male were significantly associated with increased risk of death and severe disease. No medication was associated with a reduced risk of fatality and disease severity. Conclusions: We found several risk factors for fatality and severity in COVID-19 patients. As the drugs currently used for COVID-19 treatment have not shown significant efficacy, all efforts should be made to develop effective therapeutic modalities for COVID-19.
The Role of Extracellular Vesicles (EVs) in the Epigenetic Regulation of Bone Metabolism and Osteoporosis
Authors: Muraca Maurizio , Cappariello Alfredo
Published: November 2020

Extracellular vesicles (EVs) are complex phospholipidic structures actively released by cells. EVs are recognized as powerful means of intercellular communication since they contain many signaling molecules (including lipids, proteins, and nucleic acids). In parallel, changes in epigenetic processes can lead to changes in gene function and finally lead to disease onset and progression. Recent breakthroughs have revealed the complex roles of non-coding RNAs (microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)) in epigenetic regulation. Moreover, a substantial body of evidence demonstrates that non-coding RNAs can be shuttled among the cells and tissues via EVs, allowing non-coding RNAs to reach distant cells and exert systemic effects. Resident bone cells, including osteoclasts, osteoblasts, osteocytes, and endothelial cells, are tightly regulated by non-coding RNAs, and many of them can be exported from the cells to neighboring ones through EVs, triggering pathological conditions. For these reasons, researchers have also started to exploit EVs as a theranostic tool to address osteoporosis. In this review, we summarize some recent findings regarding the EVs’ involvement in the fine regulation of non-coding RNAs in the context of bone metabolism and osteoporosis.
Substrate Specificity and Structural Modeling of Human Carboxypeptidase Z: A Unique Protease with a Frizzled-Like Domain
Authors: Garcia-Pardo Javier , Tanco Sebastian , Garcia-Guerrero Maria C. , Dasgupta Sayani , Avilés Francesc Xavier , Lorenzo Julia , Fricker Lloyd D.
Published: November 2020

Metallocarboxypeptidase Z (CPZ) is a secreted enzyme that is distinguished from all other members of the M14 metallocarboxypeptidase family by the presence of an N-terminal cysteine-rich Frizzled-like (Fz) domain that binds Wnt proteins. Here, we present a comprehensive analysis of the enzymatic properties and substrate specificity of human CPZ. To investigate the enzymatic properties, we employed dansylated peptide substrates. For substrate specificity profiling, we generated two different large peptide libraries and employed isotopic labeling and quantitative mass spectrometry to study the substrate preference of this enzyme. Our findings revealed that CPZ has a strict requirement for substrates with C-terminal Arg or Lys at the P1′ position. For the P1 position, CPZ was found to display specificity towards substrates with basic, small hydrophobic, or polar uncharged side chains. Deletion of the Fz domain did not affect CPZ activity as a carboxypeptidase. Finally, we modeled the structure of the Fz and catalytic domains of CPZ. Taken together, these studies provide the molecular elucidation of substrate recognition and specificity of the CPZ catalytic domain, as well as important insights into how the Fz domain binds Wnt proteins to modulate their functions.
tert-Butyl Hydroperoxide (tBHP)-Induced Lipid Peroxidation and Embryonic Defects Resemble Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in C. elegans
Authors: Yang Hung-Chi , Yu Hsiang , Ma Tian-Hsiang , Tjong Wen-Ye , Stern Arnold , Chiu Daniel
Published: November 2020

G6PD is required for embryonic development in animals, as severe G6PD deficiency is lethal to mice, zebrafish and nematode. Lipid peroxidation is linked to membrane-associated embryonic defects in Caenorhabditis elegans (C. elegans). However, the direct link between lipid peroxidation and embryonic lethality has not been established. The aim of this study was to delineate the role of lipid peroxidation in gspd-1-knockdown (ortholog of g6pd) C. elegans during reproduction. tert-butyl hydroperoxide (tBHP) was used as an exogenous inducer. Short-term tBHP administration reduced brood size and enhanced germ cell death in C. elegans. The altered phenotypes caused by tBHP resembled GSPD-1 deficiency in C. elegans. Mechanistically, tBHP-induced malondialdehyde (MDA) production and stimulated calcium-independent phospholipase A2 (iPLA) activity, leading to disturbed oogenesis and embryogenesis. The current study provides strong evidence to support the notion that enhanced lipid peroxidation in G6PD deficiency promotes death of germ cells and impairs embryogenesis in C. elegans.
The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer
Authors: Leong Alessandra , Kim Minah
Published: November 2020

Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy. Further, emerging evidence suggests a fundamental link between vascular abnormalities and tumor immune evasion, supporting the rationale for combination strategies of immunotherapy with antiangiogenic drugs. In this review, we discuss the recent mechanistic and clinical advances in targeting angiopoietin signaling, focusing on ANG2 inhibition, to enhance therapeutic efficacy of antiangiogenic and ICI therapies. In short, we propose that a better mechanistic understanding of ANG2-mediated vascular changes will provide insight into the significance of ANG2 in treatment response and resistance to current antiangiogenic and ICI therapies. These advances will ultimately improve therapeutic modalities for cancer treatment.
Genomic Amplification and Functional Dependency of the Gamma Actin Gene ACTG1 in Uterine Cancer
Authors: Richter Camden , Mayhew David , Rennhack Jonathan P. , So Jonathan , Stover Elizabeth H. , Hwang Justin H. , Szczesna-Cordary Danuta
Published: November 2020

Sarcomere and cytoskeleton genes, or actomyosin genes, regulate cell biology including mechanical stress, cell motility, and cell division. While actomyosin genes are recurrently dysregulated in cancers, their oncogenic roles have not been examined in a lineage-specific fashion. In this report, we investigated dysregulation of nine sarcomeric and cytoskeletal genes across 20 cancer lineages. We found that uterine cancers harbored the highest frequencies of amplification and overexpression of the gamma actin gene, ACTG1. Each of the four subtypes of uterine cancers, mixed endometrial carcinomas, serous carcinomas, endometroid carcinomas, and carcinosarcomas harbored between 5~20% of ACTG1 gene amplification or overexpression. Clinically, patients with ACTG1 gains had a poor prognosis. ACTG1 gains showed transcriptional patterns that reflect activation of oncogenic signals, repressed response to innate immunity, or immunotherapy. Functionally, the CRISPR-CAS9 gene deletion of ACTG1 had the most robust and consistent effects in uterine cancer cells relative to 20 other lineages. Overall, we propose that ACTG1 regulates the fitness of uterine cancer cells by modulating cell-intrinsic properties and the tumor microenvironment. In summary, the ACTG1 functions relative to other actomyosin genes support the notion that it is a potential biomarker and a target gene in uterine cancer precision therapies.
Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications
Authors: Saik Olga V. , Klimontov Vadim V.
Published: November 2020

Glucose variability (GV) has been recognized recently as a promoter of complications and therapeutic targets in diabetes. The aim of this study was to reconstruct and analyze gene networks related to GV in diabetes and its complications. For network analysis, we used the ANDSystem that provides automatic network reconstruction and analysis based on text mining. The network of GV consisted of 37 genes/proteins associated with both hyperglycemia and hypoglycemia. Cardiovascular system, pancreas, adipose and muscle tissues, gastrointestinal tract, and kidney were recognized as the loci with the highest expression of GV-related genes. According to Gene Ontology enrichment analysis, these genes are associated with insulin secretion, glucose metabolism, glycogen biosynthesis, gluconeogenesis, MAPK and JAK-STAT cascades, protein kinase B signaling, cell proliferation, nitric oxide biosynthesis, etc. GV-related genes were found to occupy central positions in the networks of diabetes complications (cardiovascular disease, diabetic nephropathy, retinopathy, and neuropathy) and were associated with response to hypoxia. Gene prioritization analysis identified new gene candidates (THBS1, FN1, HSP90AA1, EGFR, MAPK1, STAT3, TP53, EGF, GSK3B, and PTEN) potentially involved in GV. The results expand the understanding of the molecular mechanisms of the GV phenomenon in diabetes and provide molecular markers and therapeutic targets for future research.
Matrix Metalloproteinases MMP-2 and MMP-9, Their Inhibitors TIMP-1 and TIMP-2, Vascular Endothelial Growth Factor and sVEGFR-2 as Predictive Markers of Ischemic Retinopathy in Patients with Systemic Sclerosis—Case Series Report
Authors: Waszczykowska Arleta , Podgórski Michał , Waszczykowski Michał , Gerlicz- Kowalczuk Zofia , Jurowski Piotr
Published: November 2020

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder associated with multiple organ involvement. The aim of the study was to present two SSc patients who were diagnosed with ischemic retinopathy in both eyes. As a background to our case study, we decided to investigate the imbalance of angiogenesis factors in 25 SSc patients in relation to 25 healthy controls. Assays of matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1) and -2 (TIMP-2), vascular endothelial growth factor (VEGF), and soluble VEGF receptor-2 (sVEGFR-2) in blood serum and tears were performed. A significantly increased levels of MMP-9 in serum and tears, (p = 0.0375 and p < 0.001, respectively) as well as VEGF/sVEGFR-2 ratio in tears (p < 0.001) were found in the whole SSc patients group compared with controls, while reduced levels of these parameters in patients with ischemic sclerodermic retinopathy were noted. We also observed decreased level MMP-2 in tears and increased levels of TIMP-2 in blood serum and tears of SSc patients with retinal ischemic changes. MMP-9, MMP-2, TIMP-2, and VEGF/sVEGFR-2 may play a crucial role in ischemic retinal degeneration or retinal reorganization in SSc.
Developmental Programming and Reprogramming of Hypertension and Kidney Disease: Impact of Tryptophan Metabolism
Authors: Hsu Chien-Ning , Tain You-Lin
Published: November 2020

The concept that hypertension and chronic kidney disease (CKD) originate in early life has emerged recently. During pregnancy, tryptophan is crucial for maternal protein synthesis and fetal development. On one hand, impaired tryptophan metabolic pathway in pregnancy impacts fetal programming, resulting in the developmental programming of hypertension and kidney disease in adult offspring. On the other hand, tryptophan-related interventions might serve as reprogramming strategies to prevent a disease from occurring. In the present review, we aim to summarize (1) the three major tryptophan metabolic pathways, (2) the impact of tryptophan metabolism in pregnancy, (3) the interplay occurring between tryptophan metabolites and gut microbiota on the production of uremic toxins, (4) the role of tryptophan-derived metabolites-induced hypertension and CKD of developmental origin, (5) the therapeutic options in pregnancy that could aid in reprogramming adverse effects to protect offspring against hypertension and CKD, and (6) possible mechanisms linking tryptophan metabolism to developmental programming of hypertension and kidney disease.
A Novel Promising Frontier for Human Health: The Beneficial Effects of Nutraceuticals in Cardiovascular Diseases
Authors: Carrizzo Albino , Izzo Carmine , Forte Maurizio , Sommella Eduardo , Di Pietro Paola , Venturini Eleonora , Ciccarelli Michele , Galasso Gennaro , Rubattu Speranza , Campiglia Petro , Sciarretta Sebastiano , Frati Giacomo , Vecchione Carmine
Published: November 2020

Cardiovascular diseases (CVDs) such as hypertension, atherosclerosis, myocardial infarction, and diabetes are a significant public health problem worldwide. Although several novel pharmacological treatments to reduce the progression of CVDs have been discovered during the last 20 years, the better way to contain the onset of CVDs remains prevention. In this regard, nutraceuticals seem to own a great potential in maintaining human health, exerting important protective cardiovascular effects. In the last years, there has been increased focus on identifying natural compounds with cardiovascular health-promoting effects and also to characterize the molecular mechanisms involved. Although many review articles have focused on the individual natural compound impact on cardiovascular diseases, the aim of this manuscript was to examine the role of the most studied nutraceuticals, such as resveratrol, cocoa, quercetin, curcumin, brassica, berberine and Spirulina platensis, on different CVDs.
PlGF Immunological Impact during Pregnancy
Authors: Albonici Loredana , Benvenuto Monica , Focaccetti Chiara , Cifaldi Loredana , Miele Martino Tony , Limana Federica , Manzari Vittorio , Bei Roberto
Published: November 2020

During pregnancy, the mother’s immune system has to tolerate the persistence of paternal alloantigens without affecting the anti-infectious immune response. Consequently, several mechanisms aimed at preventing allograft rejection, occur during a pregnancy. In fact, the early stages of pregnancy are characterized by the correct balance between inflammation and immune tolerance, in which proinflammatory cytokines contribute to both the remodeling of tissues and to neo-angiogenesis, thus, favoring the correct embryo implantation. In addition to the creation of a microenvironment able to support both immunological privilege and angiogenesis, the trophoblast invades normal tissues by sharing the same behavior of invasive tumors. Next, the activation of an immunosuppressive phase, characterized by an increase in the number of regulatory T (Treg) cells prevents excessive inflammation and avoids fetal immuno-mediated rejection. When these changes do not occur or occur incompletely, early pregnancy failure follows. All these events are characterized by an increase in different growth factors and cytokines, among which one of the most important is the angiogenic growth factor, namely placental growth factor (PlGF). PlGF is initially isolated from the human placenta. It is upregulated during both pregnancy and inflammation. In this review, we summarize current knowledge on the immunomodulatory effects of PlGF during pregnancy, warranting that both innate and adaptive immune cells properly support the early events of implantation and placental development. Furthermore, we highlight how an alteration of the immune response, associated with PlGF imbalance, can induce a hypertensive state and lead to the pre-eclampsia (PE).
New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications
Authors: Usiello Alessandro , Di Fiore Maria Maddalena , De Rosa Arianna , Falvo Sara , Errico Francesco , Santillo Alessandra , Nuzzo Tommaso , Chieffi Baccari Gabriella
Published: November 2020

The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.
Airway Epithelial Dysfunction in Asthma: Relevant to Epidermal Growth Factor Receptors and Airway Epithelial Cells
Authors: Inoue Hideki , Akimoto Kaho , Homma Tetsuya , Tanaka Akihiko , Sagara Hironori
Published: November 2020

Airway epithelium plays an important role as the first barrier from external pathogens, including bacteria, viruses, chemical substances, and allergic components. Airway epithelial cells also have pivotal roles as immunological coordinators of defense mechanisms to transfer signals to immunologic cells to eliminate external pathogens from airways. Impaired airway epithelium allows the pathogens to remain in the airway epithelium, which induces aberrant immunological reactions. Dysregulated functions of asthmatic airway epithelium have been reported in terms of impaired wound repair, fragile tight junctions, and excessive proliferation, leading to airway remodeling, which contributes to aberrant airway responses caused by external pathogens. To maintain airway epithelium integrity, a family of epidermal growth factor receptors (EGFR) have pivotal roles in mechanisms of cell growth, proliferation, and differentiation. There are extensive studies focusing on the relation between EGFR and asthma pathophysiology, which describe airway remodeling, airway hypermucus secretion, as well as immunological responses of airway inflammation. Furthermore, the second EGFR family member, erythroblastosis oncogene B2 (ErbB2), has been recognized to be involved with impaired wound recovery and epithelial differentiation in asthmatic airway epithelium. In this review, the roles of the EGFR family in asthmatic airway epithelium are focused on to elucidate the pathogenesis of airway epithelial dysfunction in asthma.
Organoids and Liquid Biopsy in Oral Cancer Research
Authors: Eguchi Takanori
Published: November 2020

To promote the newest discoveries in oral cancer research, a special issue “Frontiers in Oral Cancer—Basic and Clinical Sciences” in the Journal of Clinical Medicine (JCM) was opened from September 2019 to April 2020 [...]
Contemporary National Outcomes of Acute Myocardial Infarction-Cardiogenic Shock in Patients with Prior Chronic Kidney Disease and End-Stage Renal Disease
Authors: Vallabhajosyula Saraschandra , Ya’Qoub Lina , Kumar Vinayak , Verghese Dhiran , Subramaniam Anna V. , Patlolla Sri Harsha , Desai Viral K. , Sundaragiri Pranathi R. , Cheungpasitporn Wisit , Deshmukh Abhishek J. , Kashani Kianoush , Barsness Gregory W.
Published: November 2020

Background: There are limited data on acute myocardial infarction with cardiogenic shock (AMI-CS) stratified by chronic kidney disease (CKD) stages. Objective: To assess clinical outcomes in AMI-CS stratified by CKD stages. Methods: A retrospective cohort of AMI-CS during 2005–2016 from the National Inpatient Sample was categorized as no CKD, CKD stage-III (CKD-III), CKD stage-IV (CKD-IV) and end-stage renal disease (ESRD). CKD-I/II were excluded. Outcomes included in-hospital mortality, use of coronary angiography, percutaneous coronary intervention (PCI) and mechanical circulatory support (MCS). We also evaluated acute kidney injury (AKI) and acute hemodialysis in non-ESRD admissions. Results: Of 372,412 AMI-CS admissions, CKD-III, CKD-IV and ESRD comprised 20,380 (5.5%), 7367 (2.0%) and 18,109 (4.9%), respectively. Admissions with CKD were, on average, older, of the White race, bearing Medicare insurance, of a lower socioeconomic stratum, with higher comorbidities, and higher rates of acute organ failure. Compared to the cohort without CKD, CKD-III, CKD-IV and ESRD had lower use of coronary angiography (72.7%, 67.1%, 56.9%, 61.1%), PCI (53.7%, 43.8%, 38.4%, 37.6%) and MCS (47.9%, 38.3%, 33.3%, 34.2%), respectively (all p < 0.001). AKI and acute hemodialysis use increased with increase in CKD stage (no CKD–38.5%, 2.6%; CKD-III–79.1%, 6.5%; CKD-IV–84.3%, 12.3%; p < 0.001). ESRD (adjusted odds ratio [OR] 1.25 [95% confidence interval {CI} 1.21–1.31]; p < 0.001), but not CKD-III (OR 0.72 [95% CI 0.69–0.75); p < 0.001) or CKD-IV (OR 0.82 [95 CI 0.77–0.87] was predictive of in-hospital mortality. Conclusions: CKD/ESRD is associated with lower use of evidence-based therapies. ESRD was an independent predictor of higher in-hospital mortality in AMI-CS.
Focus Prosody Varies by Phrase-Initial Tones in Seoul Korean: Production, Perception, and Automatic Classification
Authors: Lee Yong-cheol , Cho Sunghye
Published: November 2020

Production and perception experiments were conducted to examine whether focus prosody varies by phrase-initial tones in Seoul Korean. We also trained an automatic classifier to locate prosodic focus within a sentence. Overall, focus prosody in Seoul Korean was weak and confusing in production, and poorly identified in perception. However, Seoul Korean’s focus prosody differed between phrase-initial low and high tones. The low tone group induced a smaller pitch increase by focus than the high tone group. The low tone group was also subject to a greater degree of confusion, although both tone groups showed some degree of confusion spanning the entire phrase as a focus effect. The identification rate was, therefore, approximately half in the low tone group (23.5%) compared to the high tone group (40%). In machine classification, the high tone group was also more accurately identified (high: 86% vs. low: 68%) when trained separately, and the machine’s general performance when the two tone groups were trained together was much superior to the human’s (machine: 65% vs. human: 32%). Although the focus prosody in Seoul Korean was weak and confusing, the identification rate of focus was higher under certain circumstances, which avers that focus prosody can vary within a single language.
Potential Anti-Aging Substances Derived from Seaweeds
Authors: Cao Lei , Lee Sang Gil , Lim Kwon Taek , Kim Hyeung-Rak
Published: November 2020

Aging is a major risk factor for many chronic diseases, such as cancer, cardiovascular disease, and diabetes. The exact mechanisms underlying the aging process are not fully elucidated. However, a growing body of evidence suggests that several pathways, such as sirtuin, AMP-activated protein kinase, insulin-like growth factor, autophagy, and nuclear factor erythroid 2-related factor 2 play critical roles in regulating aging. Furthermore, genetic or dietary interventions of these pathways can extend lifespan by delaying the aging process. Seaweeds are a food source rich in many nutrients, including fibers, polyunsaturated fatty acids, vitamins, minerals, and other bioactive compounds. The health benefits of seaweeds include, but are not limited to, antioxidant, anti-inflammatory, and anti-obese activities. Interestingly, a body of studies shows that some seaweed-derived extracts or isolated compounds, can modulate these aging-regulating pathways or even extend lifespans of various animal models. However, few such studies have been conducted on higher animals or even humans. In this review, we focused on potential anti-aging bioactive substances in seaweeds that have been studied in cells and animals mainly based on their anti-aging cellular and molecular mechanisms.
Impact of Permeable Membrane on the Hydrocyclone Separation Performance for Oily Water Treatment
Authors: Nunes Sirlene A. , Magalhães Hortência L. F. , de Farias Neto Severino R. , Lima Antonio G. B. , Nascimento Lucas P. C. , Farias Fabiana P. M. , Lima Elisiane S.
Published: November 2020

In the oil industry and academy, the treatment of water contaminated with oil using conventional hydrocyclones and membranes has been an alternative to meet the requirements established by environmental control agencies. However, such equipment is not fully efficient in the treatment of much diluted oily water, with both presenting restrictions in their performance. In this sense, the present work proposes to study the separation process of oily water using a new configuration of hydrocyclone, equipped with a porous ceramic membrane in the conical part’s wall (filtering hydrocyclone). For the theoretical study, a Eulerian–Eulerian approach was applied to solve the mass and momentum conservation equations, and the turbulence model, using the computational fluid dynamics technique. The results of the velocity, pressure and volumetric fraction of the involved phases, and the separation performance of the hydrocyclone, are presented, analyzed, and compared with those obtained with a conventional hydrocyclone. The results confirmed the high potential of the proposed equipment to be used in the separation of the water and oil mixture.
Effect of Alloying Mn by Selective Laser Melting on the Microstructure and Biodegradation Properties of Pure Mg
Authors: Xie Bin , Zhao Ming-Chun , Zhao Ying-Chao , Tian Yan , Yin Dengfeng , Gao Chengde , Shuai Cijun , Atrens Andrej
Published: November 2020

This work studied the effect of alloying Mn by selective laser melting on the microstructure and biodegradation properties of pure Mg. The grains in the microstructure were quasi-polygon in shape. The average grain size was similar (~10 μm) for the SLMed Mg-xMn with different Mn contents. The XPS spectra of the corrosion surface showed that alloying Mn into Mg by SLM produced a relatively protective manganese oxide film, which contributed to decreasing the biodegradation rate. All the results of the electrochemistry test, immersion test and the corrosion surface morphologies coincided well. The SLMed Mg-0.8Mn had the lowest biodegradation rate. When Mn content was more than 0.8 wt.%, the influence of the undissolved Mn phase on the decrease of the biodegradation resistance counteracted the influence of the relatively protective manganese oxide layer on the increase of the biodegradation resistance.
TiPd- and TiPt-Based High-Temperature Shape Memory Alloys: A Review on Recent Advances
Authors: Yamabe-Mitarai Yoko
Published: November 2020

In this paper high-temperature shape memory alloys based on TiPd and TiPt are reviewed. The effect of the alloying elements in ternary TiPd and TiPt alloys on phase transformation and strain recovery is also discussed. Generally, the addition of alloying elements decreases the martensitic transformation temperature and improves the strength of the martensite and austenite phases. Additionally, it also decreases irrecoverable strain, but without perfect recovery due to plastic deformation. With the aim to improve the strength of high-temperature shape memory alloys, multi-component alloys, including medium- and high-entropy alloys, have been investigated and proposed as new structural materials. Notably, it was discovered that the martensitic transformation temperature could be controlled through a combination of the constituent elements and alloys with high austenite finish temperatures above 500 °C. The irrecoverable strain decreased in the multi-component alloys compared with the ternary alloys. The repeated thermal cyclic test was effective toward obtaining perfect strain recoveries in multi-component alloys, which could be good candidates for high-temperature shape memory alloys.
Crystallization of FCC and BCC Liquid Metals Studied by Molecular Dynamics Simulation
Authors: Louzguine-Luzgin Dmitri V. , Bazlov Andrey I.
Published: November 2020

The atomic structure variations on cooling, vitrification and crystallization processes in liquid metals face centered cubic (FCC) Cu are simulated in the present work in comparison with body centered cubic (BCC) Fe. The process is done on continuous cooling and isothermal annealing using a classical molecular-dynamics computer simulation procedure with an embedded-atom method potential at constant pressure. The structural changes are monitored with direct structure observation in the simulation cells containing from about 100 k to 1 M atoms. The crystallization process is analyzed under isothermal conditions by monitoring density and energy variation as a function of time. A common-neighbor cluster analysis is performed. The results of thermodynamic calculations on estimating the energy barrier for crystal nucleation and a critical nucleus size are compared with those obtained from simulation. The differences in crystallization of an FCC and a BCC metal are discussed.
Molecular Dynamics Study on the Impact of Cu Clusters at the BCC-Fe Grain Boundary on the Tensile Properties of Crystal
Authors: Zhang Haichao , Wang Xufeng , Li Huirong , Li Changqing , Li Yungang
Published: November 2020

The molecular dynamics (MD) method was used to simulate and calculate the segregation energy and cohesive energy of Cu atoms at the Σ3{111}(110) and Σ3{112}(110) grain boundaries, and the tensile properties of the BCC-Fe crystal, with the grain boundaries containing coherent Cu clusters of different sizes (a diameter of 10 Å, 15 Å and 20 Å). The results showed that Cu atoms will spontaneously segregate towards the grain boundaries and tend to exist in the form of large-sized, low-density Cu clusters at the grain boundaries. When Cu cluster exists at the Σ3{111}(110) grain boundary, the increase in the size of the Cu cluster leads to an increase in the probability of vacancy formation inside the Cu cluster during the tensile process, weakening the breaking strength of the crystal. When the Cu cluster exists at the Σ3{112}(110) grain boundary, the Cu cluster with a diameter of 10 Å will reduce the strain hardening strength of the crystal, but the plastic deformation ability of the crystal will not be affected, and the existence of Cu clusters with a diameter of 15 Å and 20 Å will suppress the structural phase transformation of the crystal, and significantly decrease the plastic deformation ability of the crystal, thereby resulting in embrittlement of the crystal.
Geometric Optimization of Drills Used to Repair Holes in Magnesium Aeronautical Components
Authors: Berzosa Fernando , Rubio Eva María , de Agustina Beatriz , Davim J. Paulo
Published: November 2020

Magnesium alloys are used in the aeronautical sector due to their excellent strength/weight ratios, motivated by the reduction of weight that their use entails. In this sector, drilling is one of the most common operations, if not the most, due to the large number of holes that are used in joining processes, mainly by riveting. The appearance of cracks is a risk to the structural safety of the components, such that it is necessary to regularly check them for maintenance and/or repair tasks. The present study tries to determine the optimization of the characteristics of the twist drills, which are re-sharpened successively to restore the cutting edge after use, as well as the operating parameters in machining. For this purpose, a full factorial experimental design was established, analyzing through the analysis of the variance (ANOVA) the response variables. Surface integrity was considered to carry out a global vision of the quality obtained, covering as response variables the surface roughness, the size of the burrs and the modification of the hardness produced, in addition to a topological characterization by optical means of machined surfaces. The main conclusion is that it is possible that the geometric optimization of the tools and the operating parameters considered in this study in drilling processes allow them to be performed, while maintaining quality and environmental requirements, and at the same time, maximize the productivity of operations.
Application of Lanthanide Shift Reagent to the 1H-NMR Assignments of Acridone Alkaloids
Authors: Lam Sio-Hong , Hung Hsin-Yi , Kuo Ping-Chung , Kuo Daih-Huang , Chen Fu-An , Wu Tian-Shung
Published: November 2020

This study investigates the application of the paramagnetic shift reagent tris(dipivaloylmethanato)-europium(III) in NMR spectral studies of permethoxyacridone alkaloids (1–3) and pyranoacridone alkaloids (4–6). The induced chemical shifts (∆δ) of all protons were observed for the same molecule, and were compared to deduce the positions resulting from the distance nearby the Eu(dpm)3. Assignment of the H-2, H-4 and H-8 of polysubstituted acridones could be distinguished based on the least-squares method of lanthanide-induced shifts plotted against the mole ratios of Eu(dpm)3 to the substrate. The developed method is not only potentially useful for determining the planar structures of polysubstituted compounds, such as acridones, anthraquinones, xanthones, flavonoids, and phenanthrenes, but also applicable for their stereochemistry.
Cyclooxygenase Inhibition Safety and Efficacy in Inflammation-Based Psychiatric Disorders
Authors: Perrone Maria Grazia , Centonze Antonella , Miciaccia Morena , Ferorelli Savina , Scilimati Antonio
Published: November 2020

According to the World Health Organization, the major psychiatric and neurodevelopmental disorders include major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. The potential role of inflammation in the onset and progression of these disorders is increasingly being studied. The use of non-steroidal anti-inflammatory drugs (NSAIDs), well-known cyclooxygenase (COX) inhibitors, combined with first-choice specific drugs have been long investigated. The adjunctive administration of COX inhibitors to classic clinical treatments seems to improve the prognosis of people who suffer from psychiatric disorders. In this review, a broad overview of the use of COX inhibitors in the treatment of inflammation-based psychiatric disorders is provided. For this purpose, a critical analysis of the use of COX inhibitors in the last ten years of clinical trials of the major psychiatric disorders was carried out.
Curcumin Formulations and Trials: What’s New in Neurological Diseases
Authors: Gagliardi Stella , Morasso Carlo , Stivaktakis Polychronis , Pandini Cecilia , Tinelli Veronica , Tsatsakis Aristides , Prosperi Davide , Hickey Miriam , Corsi Fabio , Cereda Cristina
Published: November 2020

Curcumin’s pharmacological properties and its possible benefits for neurological diseases and dementia have been much debated. In vitro experiments show that curcumin modulates several key physiological pathways of importance for neurology. However, in vivo studies have not always matched expectations. Thus, improved formulations of curcumin are emerging as powerful tools in overcoming the bioavailability and stability limitations of curcumin. New studies in animal models and recent double-blinded, placebo-controlled clinical trials using some of these new formulations are finally beginning to show that curcumin could be used for the treatment of cognitive decline. Ultimately, this work could ease the burden caused by a group of diseases that are becoming a global emergency because of the unprecedented growth in the number of people aged 65 and over worldwide. In this review, we discuss curcumin’s main mechanisms of action and also data from in vivo experiments on the effects of curcumin on cognitive decline.