bluuebunny/crossref_metadata_2025 huggingface dataset:
Inter-Metastatic Heterogeneity of Tumor Marker Expression and Microenvironment Architecture in a Preclinical Cancer Model
Authors: Kalra Jessica , Baker Jennifer , Song Justin , Kyle Alastair , Minchinton Andrew , Bally Marcel
Published: June 2021

Background: Preclinical drug development studies rarely consider the impact of a candidate drug on established metastatic disease. This may explain why agents that are successful in subcutaneous and even orthotopic preclinical models often fail to demonstrate efficacy in clinical trials. It is reasonable to anticipate that sites of metastasis will be phenotypically unique, as each tumor will have evolved heterogeneously with respect to gene expression as well as the associated phenotypic outcome of that expression. The objective for the studies described here was to gain an understanding of the tumor heterogeneity that exists in established metastatic disease and use this information to define a preclinical model that is more predictive of treatment outcome when testing novel drug candidates clinically. Methods: Female NCr nude mice were inoculated with fluorescent (mKate), Her2/neu-positive human breast cancer cells (JIMT-mKate), either in the mammary fat pad (orthotopic; OT) to replicate a primary tumor, or directly into the left ventricle (intracardiac; IC), where cells eventually localize in multiple sites to create a model of established metastasis. Tumor development was monitored by in vivo fluorescence imaging (IVFI). Subsequently, animals were sacrificed, and tumor tissues were isolated and imaged ex vivo. Tumors within organ tissues were further analyzed via multiplex immunohistochemistry (mIHC) for Her2/neu expression, blood vessels (CD31), as well as a nuclear marker (Hoechst) and fluorescence (mKate) expressed by the tumor cells. Results: Following IC injection, JIMT-1mKate cells consistently formed tumors in the lung, liver, brain, kidney, ovaries, and adrenal glands. Disseminated tumors were highly variable when assessing vessel density (CD31) and tumor marker expression (mkate, Her2/neu). Interestingly, tumors which developed within an organ did not adopt a vessel microarchitecture that mimicked the organ where growth occurred, nor did the vessel microarchitecture appear comparable to the primary tumor. Rather, metastatic lesions showed considerable variability, suggesting that each secondary tumor is a distinct disease entity from a microenvironmental perspective. Conclusions: The data indicate that more phenotypic heterogeneity in the tumor microenvironment exists in models of metastatic disease than has been previously appreciated, and this heterogeneity may better reflect the metastatic cancer in patients typically enrolled in early-stage Phase I/II clinical trials. Similar to the suggestion of others in the past, the use of models of established metastasis preclinically should be required as part of the anticancer drug candidate development process, and this may be particularly important for targeted therapeutics and/or nanotherapeutics.
MicroRNAs: The Link between the Metabolic Syndrome and Oncogenesis
Authors: Fodor Adriana , Lazar Andrada Luciana , Buchman Cristina , Tiperciuc Brandusa , Orasan Olga Hilda , Cozma Angela
Published: June 2021

Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.
n-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway
Authors: Lee Jui-Hao , Lin Si-Yin , Liu Jen-Wei , Lin Shinn-Zong , Harn Horng-Jyh , Chiou Tzyy-Wen
Published: June 2021

Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3.
All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal
Authors: Margiotta Azzurra
Published: June 2021

Receptor tyrosine kinases (RTKs) are membrane receptors that regulate many fundamental cellular processes. A tight regulation of RTK signaling is fundamental for development and survival, and an altered signaling by RTKs can cause cancer. RTKs are localized at the plasma membrane (PM) and the major regulatory mechanism of signaling of RTKs is their endocytosis and degradation. In fact, RTKs at the cell surface bind ligands with their extracellular domain, become active, and are rapidly internalized where the temporal extent of signaling, attenuation, and downregulation are modulated. However, other mechanisms of signal attenuation and termination are known. Indeed, inhibition of RTKs’ activity may occur through the modulation of the phosphorylation state of RTKs and the interaction with specific proteins, whereas antagonist ligands can inhibit the biological responses mediated by the receptor. Another mechanism concerns the expression of endogenous inactive receptor variants that are deficient in RTK activity and take part to inactive heterodimers or hetero-oligomers. The downregulation of RTK signals is fundamental for several cellular functions and the homeostasis of the cell. Here, we will review the mechanisms of signal attenuation and termination of RTKs, focusing on FGFRs.
LncRSPH9-4 Facilitates Meningitic Escherichia coli-Caused Blood–Brain Barrier Disruption via miR-17-5p/MMP3 Axis
Authors: Xu Bojie , Yang Ruicheng , Fu Jiyang , Yang Bo , Chen Jiaqi , Tan Chen , Chen Huanchun , Wang Xiangru
Published: June 2021

Brain microvascular endothelial cells (BMECs) constitute the structural and functional basis for the blood–brain barrier (BBB) and play essential roles in bacterial meningitis. Although the BBB integrity regulation has been under extensive investigation, there is little knowledge regarding the roles of long non-coding RNAs (lncRNAs) in this event. The present study aimed to investigate the roles of one potential lncRNA, lncRSPH9-4, in meningitic E. coli infection of BMECs. LncRSPH9-4 was cytoplasm located and significantly up-regulated in meningitic E. coli-infected hBMECs. Electrical cell-substrate impedance sensing (ECIS) measurement and Western blot assay demonstrated lncRSPH9-4 overexpression in hBMECs mediated the BBB integrity disruption. By RNA-sequencing analysis, 639 mRNAs and 299 miRNAs were significantly differentiated in response to lncRSPH9-4 overexpression. We further found lncRSPH9-4 regulated the permeability in hBMECs by competitively sponging miR-17-5p, thereby increasing MMP3 expression, which targeted the intercellular tight junctions. Here we reported the infection-induced lncRSPH9-4 aggravated disruption of the tight junctions in hBMECs, probably through the miR-17-5p/MMP3 axis. This finding provides new insights into the function of lncRNAs in BBB integrity during meningitic E. coli infection and provides the novel nucleic acid targets for future treatment of bacterial meningitis.
Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer
Authors: Liu Yaxuan , Axell Olga , van Leeuwen Tom , Konrat Robert , Kharaziha Pedram , Larsson Catharina , Wright Anthony P. H. , Bajalica-Lagercrantz Svetlana
Published: June 2021

Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual TP53 variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (n = 24) or exclusively reported in HBC (n = 24) were included. LFS-variants were over-represented in residues tending to be buried in the core of the tertiary structure of TP53 (p = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78−0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline TP53 missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling.
Molecular and Functional Evolution of the Spermatophyte Sesquiterpene Synthases
Authors: Liang Dongmei , Li Weiguo , Yan Xiaoguang , Caiyin Qinggele , Zhao Guangrong , Qiao Jianjun
Published: June 2021

Sesquiterpenes are important defense and signal molecules for plants to adapt to the environment, cope with stress, and communicate with the outside world, and their evolutionary history is closely related to physiological functions. In this study, the information of plant sesquiterpene synthases (STSs) with identified functions were collected and sorted to form a dataset containing about 500 members. The phylogeny of spermatophyte functional STSs was constructed based on the structural comparative analysis to reveal the sequence–structure–function relationships. We propose the evolutionary history of plant sesquiterpene skeletons, from chain structure to small rings, followed by large rings for the first time and put forward a more detailed function-driven hypothesis. Then, the evolutionary origins and history of spermatophyte STSs are also discussed. In addition, three newly identified STSs CaSTS2, CaSTS3, and CaSTS4 were analyzed in this functional evolutionary system, and their germacrene D products were consistent with the functional prediction. This demonstrates an application of the structure-based phylogeny in predicting STS function. This work will help us to understand evolutionary patterns and dynamics of plant sesquiterpenes and STSs and screen or design STSs with specific product profiles as functional elements for synthetic biology application.
HIF-1α Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn2+ Accumulation in Inflammatory Synoviocytes
Authors: Hatano Noriyuki , Matsubara Masaki , Suzuki Hiroka , Muraki Yukiko , Muraki Katsuhiko
Published: June 2021

Intracellular free zinc ([Zn2+]i) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn2+]i is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn2+ have been identified, proteins that are involved in Zn2+ supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn2+ transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn2+]i accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn2+]i. In human fibroblast-like synoviocytes (FLSs), treatment with inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α), evoked TRPA1-dependent intrinsic Ca2+ oscillations. Assays with fluorescent Zn2+ indicators revealed that the basal [Zn2+]i concentration was significantly higher in TRPA1-expressing HEK cells and inflammatory FLSs. Moreover, TRPA1 activation induced an elevation of [Zn2+]i level in the presence of 1 μM Zn2+ in inflammatory FLSs. Among the 17 out of 24 known Zn2+ transporters, FLSs that were treated with TNF-α and IL-1α exhibited a higher expression of ZIP8 and ZIP14. Their expression levels were augmented by transfection with an active component of nuclear factor-κB P65 and HIF-1α expression vectors, and they could be abolished by pretreatment with the HIF-1α inhibitor echinomycin (Echi). The functional expression of ZIP8 and ZIP14 in HEK cells significantly increased the basal [Zn2+]i level. Taken together, Zn2+ carrier proteins, TRPA1, ZIP8, and ZIP14, induced under HIF-1α mediated inflammation can synergistically change [Zn2+]i in inflammatory FLSs.
The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS
Authors: Obrador Elena , Salvador-Palmer Rosario , López-Blanch Rafael , Jihad-Jebbar Ali , Vallés Soraya L. , Estrela José M.
Published: June 2021

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3–5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.
Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression
Authors: Tolar Martin , Hey John , Power Aidan , Abushakra Susan
Published: June 2021

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.
Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives
Authors: Abatematteo Francesca Serena , Niso Mauro , Contino Marialessandra , Leopoldo Marcello , Abate Carmen
Published: June 2021

The sigma-1 (σ1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.
Influence of Paclitaxel and Doxorubicin Therapy of ßIII-Tubulin, Carbonic Anhydrase IX, and Survivin in Chemically Induced Breast Cancer in Female Rat
Authors: Pastornická Alena , Rybárová Silvia , Drahošová Slávka , Mihalik Jozef , Kreheľová Andrea , Pavliuk-Karachevtseva Andriana , Hodorová Ingrid
Published: June 2021

Breast cancer is the most common cancer in females. The aim of this study was to determine the effect of paclitaxel (PTX) and doxorubicin (DOX) therapy on the βIII-tubulin, carbonic anhydrase IX (CA IX), and survivin expression in chemically-induced rat mammary tumors. Animals with induced mammary carcinogenesis were randomly divided into treatment groups and an untreated group. The total proportion of tumors, the proportion of carcinoma in situ (CIS), and invasive carcinoma (IC) were evaluated. Protein expression in tumor tissue was determined using IHC. Statistical analysis of the data, evaluated by Fisher-exact test and unpaired t-test. Significantly increased levels of proteins in the tumor cells were confirmed using the IHC method for all studied proteins. The expression of βIII-tubulin, CA IX, and survivin increased significantly after treatment with both cytostatics (PTX and DOX). Depending on the type of tumor, a significant increase in all proteins was observed in IC samples after PTX treatment, and CA IX expression after DOX treatment. In CIS samples, a significant increase of βIII-tubulin and survivin expression was observed after a DOX treatment. The results suggest that βIII-tubulin, survivin, and CA IX may be significant drug resistance markers and the clinical regulation of their activity may be an effective means of reversing this resistance.
Factors Involved in Morphogenesis in the Muscle–Tendon–Bone Complex
Authors: Abe Shinichi , Yamamoto Masahito
Published: June 2021

A decline in the body’s motor functions has been linked to decreased muscle mass and function in the oral cavity and throat; however, aging of the junctions of the muscles and bones has also been identified as an associated factor. Basic and clinical studies on the muscles, tendons and bones, each considered independently, have been published. In recent years, however, research has focused on muscle attachment as the muscle–tendon–bone complex from various perspectives, and there is a growing body of knowledge on SRY-box9 (Sox9) and Mohawk(Mkx), which has been identified as a common controlling factor and a key element. Myostatin, a factor that inhibits muscle growth, has been identified as a potential key element in the mechanisms of lifetime structural maintenance of the muscle–tendon–bone complex. Findings in recent studies have also uncovered aspects of the mechanisms of motor organ complex morphostasis in the superaged society of today and will lay the groundwork for treatments to prevent motor function decline in older adults.
High Myopia and the Complement System: Factor H in Myopic Maculopathy
Authors: García-Gen Enrique , Penadés Mariola , Mérida Salvador , Desco Carmen , Araujo-Miranda Rafael , Navea Amparo , Bosch-Morell F.
Published: June 2021

High myopia (HM) is both a medical problem and refractive error of the eye owing to excessive eyeball length, which progressively makes eye tissue atrophic, and is one of the main causes for diminishing visual acuity in developed countries. Despite its high prevalence and many genetic and proteomic studies, no molecular pattern exists that explain the degenerative process underlying HM, which predisposes patients to other diseases like glaucoma, cataracts, retinal detachment and chorioretinal atrophy that affect the macular area. To determine the relation between complement Factors H (CFH) and D (CFD) and the maculopathy of patients with degenerative myopia, we studied aqueous humor samples that were collected by aspiration from 122 patients during cataract surgery. Eyes were classified according to eyeball axial length as high myopia (axial length > 26 mm), low myopia (axial length 23.5–25.9 mm) and control (axial length ˂ 23.4 mm). The degree of maculopathy was classified according to fundus oculi findings following IMI’s classification. Subfoveal choroid thickness was measured by optical coherence tomography. CFH and CFD measurements were taken by ELISA. CFH levels were significantly high in the high myopia group vs. the low myopia and control groups (p ˂ 0.05). Significantly high CFH values were found in those eyes with choroid atrophy and neovascularization (p ˂ 0.05). In parallel, the CFH concentration correlated inversely with choroid thickness (R = −0.624). CFD levels did not correlate with maculopathy. All the obtained data seem to suggest that CFH plays a key role in myopic pathology.
Systemic Antibiotics and Obesity: Analyses from a Population-Based Cohort
Authors: Park So Young , Ustulin Morena , Park SangHyun , Han Kyung-Do , Kim Joo Young , Shin Dong Wook , Rhee Sang Youl
Published: June 2021

Background: In this study, we analyzed the association between antibiotic use and obesity and metabolic syndrome (MS) in a Korean adult population. Methods: Subjects using the Korean National Health Insurance Service sample cohort were retrospectively analyzed in 2015. The differences in obesity and metabolic syndrome (MS) status were compared and analyzed according to duration of systemic antibiotic treatment in the previous 10 years (non-users, 1st, 2nd, and 3rd tertile). Results: Subjects who used systemic antibiotics for longer periods were older, satisfied more criteria for MS, and had more comorbidities than non-users (non-users vs. 3rd tertile, p < 0.0001 for all). After adjusting for confounding factors, the risk of obesity was higher in subjects who used systemic antibiotics for longer periods than in non-users (non-users vs. 3rd tertile, OR (odds ratio) (95% CI (confidence interval)); 1.20 (1.12–1.38)). The criteria for MS were more satisfied in the 3rd tertile than in non-users. A higher obesity risk was also found in subjects treated with antibiotics targeting Gram-negative organisms than in those targeting Gram-positive organisms. Conclusion: The risk of obesity was higher in subjects who took systemic antibiotics more frequently. The risk was more prominent when they took antibiotics targeting Gram-negative bacteria.
Incidence and Risk Factors for Acute Kidney Injury during the Treatment of Methicillin-Sensitive Staphylococcus aureus Infections with Cloxacillin Based Antibiotic Regimens: A French Retrospective Study
Authors: Crochette Romain , Ravaiau Camille , Perez Lucia , Coindre Jean-Philippe , Piccoli Giorgina Barbara , Blanchi Sophie
Published: June 2021

Background: Cloxacillin has been associated with the occurrence of acute kidney injury (AKI). The incidence of this complication in the literature is low (2.5–3.5%) and probably underestimated, since most studies were done by selecting the presence of AKI in discharge codes. Objectives: The primary goal was to define the incidence of AKI in patients with a methicillin-sensitive Staphylococcus aureus infection treated with cloxacillin based antibiotic regimens. The secondary goals were to identify the risk factors associated with this complication and to describe the characteristics of AKI. Patients and methods: We carried out a retrospective study. The inclusion criteria were adult patients hospitalized in a medical department at the Le Mans Hospital between 1 July 2012 and 1 July 2019 with a diagnosis of methicillin-sensitive Staphylococcus aureus infection treated with cloxacillin. Results: One hundred twenty-three patients were included in the study. Forty-two patients (34.2%) developed AKI. In the multivariate analysis, age, the use of diuretics and the presence of endocarditis were independently associated with AKI. Age was associated with an OR of 4.38 (p = 0.002) for patients older than 75, being treated with diuretics was associated with an OR of 2.94 (p = 0.036) for loop diuretics and an OR of 3.05 (p = 0.027) for non-loop diuretics; type of infection was associated with an OR of 3.42 (p = 0.012) for endocarditis. Conclusions: The occurrence of AKI is frequent during cloxacillin based antibiotic regimens for methicillin-sensitive Staphylococcus aureus infections. Being older than 75, being treated with diuretics and the presence of endocarditis were the main risk factors for AKI in our population.
Psoriatic Dactylitis: Current Perspectives and New Insights in Ultrasonography and Magnetic Resonance Imaging
Authors: Girolimetto Nicolò , Giovannini Ivan , Crepaldi Gloria , De Marco Gabriele , Tinazzi Ilaria , Possemato Niccolò , Macchioni Pierluigi , McConnell Rebecca , McGonagle Dennis , Iagnocco Annamaria , Zabotti Alen
Published: June 2021

Dactylitis, one of the most typical features of psoriatic arthritis (PsA), is the diffuse swelling of the digits and is determined by the involvement of different anatomic structures, including: the subcutaneous fibrous tissue “accessory pulley” system; flexor tendons, with their related structures; the articular synovium; the small enthesis of the hands. Dactylitis is currently considered both a marker of disease activity and severe prognosis and its importance in PsA is emphasized by the inclusion in the classification criteria of PsA. This review focuses on the role of imaging in the management of PsA patients with dactylitis in clinical practice and in a research setting. Furthermore, imaging could be a valuable tool to assist in unravelling some of the underlying mechanisms of the onset and chronicization of dactylitis in PsA patients.
The Awareness of Pulmonologists and Patients with Respiratory Diseases about the Impact of Air Pollution on Health in Poland
Authors: Zielonka Tadeusz M.
Published: June 2021

Within the European Union, air pollution is highest in Poland. The aim of this study was to compare the awareness of Polish pulmonologists and that of patients with respiratory diseases about the impact of air pollution on health. It was a crossover study with voluntary and anonymous participation. The study included 309 pulmonologists and 262 patients with respiratory diseases. The majority of the patients declared good knowledge about the impact of air pollution on health, and only 16% of the pulmonologists declared sufficient knowledge on this topic. The main sources of information on air pollution were radio and television for patients and the medical press for doctors. Doctors rarely informed patients about the impact of air pollution on their disease. Patients followed information on the quality of air in their areas more often than doctors. Polish patients’ knowledge about the main sources of air pollution in their areas was higher than the knowledge of pulmonologists. Patients declared knowledge of air pollution standards twice as often as doctors. Patients with respiratory diseases are interested in the effects of air pollution on their health. Polish patients’ knowledge about air pollution and its health effects is higher than that of the specialists treating them. Professional education of Polish pulmonologists in this field is needed.
Classification of dental x-ray images
Authors:   ,   West Virginia University, Qureshi Usman
Published: June 2021

Forensic dentistry is concerned with identifying people based on their dental records. Forensic specialists have a large number of cases to investigate and hence, it has become important to automate forensic identification systems. The radiographs acquired after a person is deceased are called the Post-mortem (PM) radiographs, and the radiographs acquired while the person is alive are called the Ante-mortem (AM) radiographs. Dental biometrics automatically analyzes dental radiographs to identify the deceased individuals. While, ante mortem (AM) identification is usually possible through comparison of many biometric identifiers, postmortem (PM) identification is impossible using behavioral biometrics (e.g. speech, gait). Moreover, under severe circumstances, such as those encountered in mass disasters (e.g. airplane crashes and natural disasters such as Tsunami) most physiological biometrics may not be employed for identification, because of the decay of soft tissues of the body to unidentifiable states. Under such circumstances, the best candidates for postmortem biometric identification are the dental features because of their survivability and diversity.;In my work, I present two different techniques to classify periapical images as maxilla (upper jaw) or mandible (lower jaw) images and we show a third technique to classify dental bitewing images as horizontally flipped/rotated or horizontally un-flipped/un-rotated. In our first technique I present an algorithm to classify whether a given dental periapical image is of a maxilla (upper jaw) or a mandible (lower jaw) using texture analysis of the jaw bone. While the bone analysis method is manual, in our second technique, I propose an automated approach for the identification of dental periapical images using the crown curve detection Algorithm. The third proposed algorithm works in an automated manner for a large number of database comprised of dental bitewing images. Each dental bitewing image in the data base can be classified as a horizontally flipped or un-flipped image in a time efficient manner.
Heuristics for the dynamic facility layout problem with unequal area departments
Authors:   ,   West Virginia University, Hakobyan Artak
Published: June 2021

The facility layout problem (FLP) is a well researched problem of finding positions of departments on a plant floor such that departments do not overlap and some objective(s) is (are) optimized. In this dissertation, the FLP with unequal area rectangular shaped departments is considered, when material flows between departments change during the planning horizon. This problem is known as the dynamic FLP. The change in material flows between pairs of departments in consecutive periods may require rearrangements of departments during the planning horizon in order to keep material handling costs low. The objective of our problem is to minimize the sum of the material handling and rearrangement costs. Because of the combinatorial structure of the problem, only small sized problems can be solved in reasonable time using exact techniques. As a result, construction and improvement heuristics are developed for the proposed problem. The construction algorithms are boundary search heuristics as well as a dual simplex method, and the improvement heuristics are tabu search and memetic heuristics with boundary search and dual simplex (linear programming model) techniques. The heuristics were tested on a generated data set as well as some instances from the literature. In summary, the memetic heuristic with the boundary search technique out-performed the other techniques with respect to solution quality.
Identifying Common Patterns and Unusual Dependencies in Faults, Failures and Fixes for Large-scale Safety-critical Software
Authors:   ,   West Virginia University, Hamill Margaret
Published: June 2021

As software evolves, becoming a more integral part of complex systems, modern society becomes more reliant on the proper functioning of such systems. However, the field of software quality assurance lacks detailed empirical studies from which best practices can be determined. The fundamental factors that contribute to software quality are faults, failures and fixes, and although some studies have considered specific aspects of each, comprehensive studies have been quite rare. Thus, the fact that we establish the cause-effect relationship between the fault(s) that caused individual failures, as well as the link to the fixes made to prevent the failures from (re)occurring appears to be a unique characteristic of our work. In particular, we analyze fault types, verification activities, severity levels, investigation effort, artifacts fixed, components fixed, and the effort required to implement fixes for a large industrial case study. The analysis includes descriptive statistics, statistical inference through formal hypothesis testing, and data mining. Some of the most interesting empirical results include (1) Contrary to popular belief, later life-cycle faults dominate as causes of failures. Furthermore, over 50% of high priority failures (e.g., post-release failures and safety-critical failures) were caused by coding faults. (2) 15% of failures led to fixes spread across multiple components and the spread was largely affected by the software architecture. (3) The amount of effort spent fixing faults associated with each failure was not uniformly distributed across failures; fixes with a greater spread across components and artifacts, required more effort. Overall, the work indicates that fault prevention and elimination efforts focused on later life cycle faults is essential as coding faults were the dominating cause of safety-critical failures and post-release failures. Further, statistical correlation and/or traditional data mining techniques show potential for assessment and prediction of the locations of fixes and the associated effort. By providing quantitative results and including statistical hypothesis testing, which is not yet a standard practice in software engineering, our work enriches the empirical knowledge needed to improve the state-of-the-art and practice in software quality assurance.
Pain Index
Authors:   ,   West Virginia University, Beans Lisa
Published: June 2021

This is a collection of lyrical poems that nearly always have a small narrative. The poems are grounded in a specific landscape usually that of the prairie of Nebraska or the mountains of West Virginia. The speaker's awe of the world is shown through the ugly and the beautiful and how those two can often be blurred. Emotional clarity is important.
Impacts of Boundary Conditions on Premixed Combustion in Obstructed Conduits: A Computational Analysis
Authors:   ,   West Virginia University, Alkandari Rawan
Published: June 2021

Premixed flame acceleration in channels or pipes has various practical applications, starting with fire safety problems and ending with advanced technologies such as pulse-detonation engines. In particular, a flame accelerates extremely fast when propagating through a comb-shaped array of narrow, tightly-spaced obstacles in a so-called "Bychkov tube". In the present thesis, the role of boundary conditions in such geometry is studied by means of the comprehensive computational simulations of combustion equations, with a fully-compressible hydrodynamics and an Arrhenius chemical kinetics. Specifically, the mechanistic (slip/nonslip) and thermal (adiabatic/isothermal) conditions at the walls/obstacles' surfaces, as well as the boundaries at the conduits' extremes (open/closed) are considered. The parametric study includes: the thermal expansion ratio in the range 5≤theta≤10; the wall temperature Tw being 298K≤Tw≤1000K; the pipe radius R exceeding the thermal flame thickness Lƒ by a factor of 12~48; the obstacles blockage ratio in the range 1/3≤alpha≤2/3; and the spacing between the obstacles Deltaz being 0.25R≤Deltaz≤2R.;It is shown that the impacts of both mechanistic and thermal surface conditions on flame propagation are minor and can be omitted. This is because the flame dynamics if mainly driven by flame spreading in an unobstructed portion of an obstructed pipe, i.e. far from the walls. With a fact that real walls are neither slip nor nonslip; neither adiabatic nor isothermal, but in between these categories, the minor role of surface conditions, identified here, validates the Bychkov model, which employs a number of simplifying assumptions, including slip and adiabatic surfaces.;In contrast, the role of the conditions at a pipe extreme is shown to be substantial. While in a semi-open pipe (one end is closed; a flame is ignited at this end and propagates towards the open end), the entire flame-generated jet-flow is pushed towards a single exit, in a pipe with two ends open, this flow is distributed between the upstream and downstream flows, thereby moderating flame propagation. As a result, in this geometry, a flame either accelerates much weaker (in a relatively wide pipe), with a possibility of blowout, or oscillates (in a narrow pipe). The oscillations appear nonlinear in all the situations when they are observed, and the present thesis quantifies the oscillation period and amplitude as well as the average flame velocity in the theta- Tw-alpha-Deltaz-R space.;Since these flame oscillations can be treated as fluctuations around a quasi-steady solution, the present thesis qualitatively supports the recent experiments, modeling and theory of flames in obstructed pipes with both ends open, which all yielded steady or quasi-steady flame propagation prior to an onset of spontaneous flame acceleration and deflagration-to-detonation transition.
Through Babel
Authors:   ,   West Virginia University, Foglio Hailey
Published: June 2021

This thesis details the fictional story of three teenagers living in New Orleans, Louisiana. Each plagued by their own traumas, Sadie Mae, Mary, and Abram learn to depend on one another to find the path to a more hopeful future. Part coming-of-age story and part philosophical examination of faith and the faithful, this novel attempts to observe and comment on the human experience of suffering and grief, as told through the eyes of three young protagonists.
Factors affecting the emergence of antibiotic-resistant enterobacteria
Authors: Galiakbarova Alsu Anvarovna
Published: June 2021

The biological properties of the archival strains of Escherichia were studied using automatic analyzers Vitek 2 and Sensititre. In addition, the antibiotic sensitivity, genetic identification, and enzymatic properties were determined.
Recombinant thyroid antigens: preparation and application in the diagnosis and treatment of autoimmune diseases
Authors: Zubkov Alexander Vladimirovich
Published: June 2021

New opportunities are opening up in the study of the relationship between the antigenic structure of thyroid autoantigens and autoantibodies in the pathogenesis of such autoimmune diseases as Graves’ disease (GD) and autoimmune thyroiditis (AIT) using synthesized recombinant proteins of the thyroid-stimulating hormone receptor (TSHR) and human thyroid peroxidase (TPO). In the present work, the results of cloning of the fragments of the TPO extracellular domain and fragments of the RNA sequence of the α-subunit of TSHR, which do not contain nucleotide substitutions, are demonstrated. Recombinant vectors for the expression of proteins of the α-subunit of thyroid-stimulating hormone receptor and fragments of the TPO extracellular domain have been obtained.
Procedure for forming the fair value of non-financial assets in public sector organizations
Authors: Kovalenko Svetlana Nikolaevna , Kalutskaya Natalia Alekseevna , Kuligina Svetlana Viktorovna
Published: June 2021

This article presents the concept of “non-financial asset” in relation to public sector organizations, discusses the conditions for classifying objects as non-financial assets, refers to legislative and regulatory acts related to the problem under study, forms the concept of “fair value”, provides parameters for assessing fair value and options for determining it, including on the basis of using market criteria in compliance with certain parameters, describes the procedure for establishing fair value for lease and gratuitous use.
On the problem of implementing the national project “Health”
Authors: Sharipova Elmira Ravilievna
Published: June 2021

Providing high-quality and timely medical care is the duty of any state, regardless of the economic and political situation in the country. Thanks to the implementation of the decrees of the President of the Russian Federation and the national project “Healthcare”, the healthcare system is improving. However, the achievement of all target indicators is not always possible, in connection with these, it becomes necessary to carry out external state control annually to prevent and identify errors and violations.
Inovação em Educação Ambiental: um estudo de caso sobre a trilha dos sentidos do Parque Estadual Mata do Limoeiro
Authors: Oliveira Alex Luiz Amaral , Carvalho Frederico Mendes de , Oliveira Fernanda de Fátima , Oliveira Junior Arnaldo Freitas de , Moreira Simone Magela
Published: June 2021

A Educação Ambiental, voltada para conscientização dos indivíduos, contribui para a solução dos problemas ambientais atuais por meio da mudança de mentalidade e de posturas. A Trilha dos Sentidos, desenvolvida pelo Parque Estadual Mata do Limoeiro, foi criada como uma estratégia para as atividades de Educação Ambiental, como forma de despertar a importância da natureza e da conservação do meio ambiente. Com os olhos vendados e os pés descalços, o visitante entra na trilha, guiado por uma corda e descobre uma nova forma de perceber a floresta, estimulado pelos canais sensoriais, redescobrindo a natureza. Este texto descreve como o projeto reitera o uso das Unidades de Conservação como território de atividades práticas no contexto da educação, oferecendo recursos que propiciam atividades e o contato direto com o meio ambiente.
Ambiente natural e o imaginário: mar, deserto, mata e chuva em representações pictóricas na educação infantil
Authors: Rocha Ana Gabriela da Silva , Dal-Farra Rossano André
Published: June 2021

A educação infantil se constitui na base da formação do sujeito no que tange à interação com o ambiente. Com base nesta premissa, o presente estudo apresenta o trabalho realizado em uma escola localizada no Rio Grande do Sul voltado à percepção da natureza dos estudantes. Foram analisadas representações pictóricas de mar, deserto, mata e chuva e os relatos das crianças por meio da Estatística Descritiva e análise qualitativa das falas dos alunos sobre os desenhos. Os resultados proporcionaram caracterizar o olhar dos alunos a respeito dos ambientes e as dificuldades de percepção do papel do ser humano na natureza, assim como a relevância das falas das crianças a respeito de suas representações pictóricas, evidenciando a importância de práticas educativas desta natureza na Educação Ambiental.
Educação Ambiental: aplicação do princípio dos “3R’sul” no resíduo sólido a partir de um núcleo ambiental
Authors: Geller Ana Maria , Scheibler Jeferson , Carvalho Claudia Wollmann , Lima Ismael de , Sperb William Junior , Oliveira Wemerson de Castro
Published: June 2021

Na escola temos a possibilidade de envolver a Educação Ambiental interdisciplinarmente, procurando conscientizar, de forma crítica e transformadora, a comunidade, interferindo nos hábitos para além de seus muros. Este trabalho retrata as ações desenvolvidas, durante dois anos, numa escola técnica, com estudantes do ensino médio, a partir do Núcleo de Gestão Ambiental Integrada. As ações perpassaram palestras, campanhas de sensibilização, separação de resíduos, horta, confecção de sabão e o agir na comunidade, introduzindo, também, aspectos da metodologia científica. Somente através da conscientização poderemos desenvolver uma cultura ambiental e sustentável, em que a qualidade de vida pode prevalecer, garantindo o futuro para a atual e próximas gerações.
Ferramentas de Educomunicação Socioambiental: subsídios para a Gestão Integrada da Zona Costeira
Authors: Marques Vanessa Caetano , Nicolodi Joao Luiz
Published: June 2021

A Gestão Costeira Integrada (GCI) pressupõe a difusão de informações e capacitação de atores sociais visando à participação efetiva neste processo. No âmbito da Política Nacional de Educação Ambiental  (PNEA), o Programa Nacional de Educomunicação Socioambiental aporta subsídios para produção da informação, difusão e acesso democrático. Este trabalho apresenta o processo de criação de material audiovisual sobre temáticas da GCI e analisa suas potencialidades sob a ótica do percurso formativo da Educação Ambiental  (EA) e da compatibilidade com os princípios da Educomunicação Socioambiental. Os resultados demonstram que essa compatibilidade é positiva, bem como permitem inferir que o mesmo tem potencial para auxiliar no fortalecimento dos indicadores de maturidade e eficácia da GCI, uma vez estar embasado na integração de distintas políticas públicas, seguindo estruturas normativas etjá existentes e incorporando a participação do órgão competente pela gestão costeira do país.
Livros didáticos do ensino médio e o conhecimento escolar sobre mudanças climáticas
Authors: Liotti Luciane Cortiano , Campos Marília Andrade Torales
Published: June 2021

Este artigo analisa em que medida o conhecimento escolar sobre Mudanças Climáticas (MC), abordado nos Livros Didáticos (LD) do Ensino Médio, pode contribuir para que os estudantes construam concepções científico-sociais, econômicas e políticas sobre este fenômeno que afeta a sociedade global. Apresenta-se uma análise dos dados, considerando três critérios: os conteúdos textuais, as iconografias e as propostas de atividades. Por meio dos dados produzidos, verificou-se a falta de uma abordagem interdisciplinar e contextualizada sobre essa temática nos materiais de ensino, fato que dificulta a compreensão do fenômeno das mudanças climáticas em sua totalidade pelos estudantes.