bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxic Conditions Promote Rhythmic Contractile Oscillations Mediated by Voltage-Gated Sodium Channels Activation in Human Arteries
Authors: Virsolvy Anne , Fort Aurélie , Erceau Lucie , Charrabi Azzouz , Hayot Maurice , Aimond Franck , Richard Sylvain
Published: March 2021

Arterial smooth muscle exhibits rhythmic oscillatory contractions called vasomotion and believed to be a protective mechanism against tissue hypoperfusion or hypoxia. Oscillations of vascular tone depend on voltage and follow oscillations of the membrane potential. Voltage-gated sodium channels (Nav), responsible for the initiation and propagation of action potentials in excitable cells, have also been evidenced both in animal and human vascular smooth muscle cells (SMCs). For example, they contribute to arterial contraction in rats, but their physiopathological relevance has not been established in human vessels. In the present study, we investigated the functional role of Nav in the human artery. Experiments were performed on human uterine arteries obtained after hysterectomy and on SMCs dissociated from these arteries. In SMCs, we recorded a tetrodotoxin (TTX)-sensitive and fast inactivating voltage-dependent INa current. Various Nav genes, encoding α-subunit isoforms sensitive (Nav 1.2; 1.3; 1.7) and resistant (Nav 1.5) to TTX, were detected both in arterial tissue and in SMCs. Nav channels immunostaining showed uniform distribution in SMCs and endothelial cells. On arterial tissue, we recorded variations of isometric tension, ex vivo, in response to various agonists and antagonists. In arterial rings placed under hypoxic conditions, the depolarizing agent KCl and veratridine, a specific Nav channels agonist, both induced a sustained contraction overlaid with rhythmic oscillations of tension. After suppression of sympathetic control either by blocking the release of catecholamine or by antagonizing the target adrenergic response, rhythmic activity persisted while the sustained contraction was abolished. This rhythmic activity of the arteries was suppressed by TTX but, in contrast, only attenuated by antagonists of calcium channels, Na+/Ca2+ exchanger, Na+/K+-ATPase and the cardiac Nav channel. These results highlight the role of Nav as a novel key element in the vasomotion of human arteries. Hypoxia promotes activation of Nav channels involved in the initiation of rhythmic oscillatory contractile activity.
25-Hydroxycholesterol Effect on Membrane Structure and Mechanical Properties
Authors: Domingues Marco M. , Gomes Bárbara , Hollmann Axel , Santos Nuno C.
Published: March 2021

Cholesterol is responsible for the plasticity of plasma membranes and is involved in physiological and pathophysiological responses. Cholesterol homeostasis is regulated by oxysterols, such as 25-hydroxycholesterol. The presence of 25-hydroxycholesterol at the membrane level has been shown to interfere with several viruses’ entry into their target cells. We used atomic force microscopy to assess the effect of 25-hydroxycholesterol on different properties of supported lipid bilayers with controlled lipid compositions. In particular, we showed that 25-hydroxycholesterol inhibits the lipid-condensing effects of cholesterol, rendering the bilayers less rigid. This study indicates that the inclusion of 25-hydroxycholesterol in plasma membranes or the conversion of part of their cholesterol content into 25-hydroxycholesterol leads to morphological alterations of the sphingomyelin (SM)-enriched domains and promotes lipid packing inhomogeneities. These changes culminate in membrane stiffness variations.
Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles
Authors: Thomas Mervyn G. , Maconachie Gail D. E. , Kuht Helen J. , Chan Wai-Man , Sheth Viral , Hisaund Michael , McLean Rebecca J. , Barry Brenda , Al-Diri Bashir , Proudlock Frank A. , Tu Zhanhan , Engle Elizabeth C. , Gottlob Irene
Published: March 2021

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.
The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory
Authors: Lajqi Trim , Marx Christian , Hudalla Hannes , Haas Fabienne , Große Silke , Wang Zhao-Qi , Heller Regine , Bauer Michael , Wetzker Reinhard , Bauer Reinhard
Published: March 2021

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.
Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021
Authors: Lange Magdalena , Hartmann Karin , Carter Melody C. , Siebenhaar Frank , Alvarez-Twose Ivan , Torrado Inés , Brockow Knut , Renke Joanna , Irga-Jaworska Ninela , Plata-Nazar Katarzyna , Ługowska-Umer Hanna , Czarny Justyna , Belloni Fortina Anna , Caroppo Francesca , Nowicki Roman J. , Nedoszytko Bogusław , Niedoszytko Marek , Valent Peter
Published: March 2021

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.
The Archaeal Small Heat Shock Protein Hsp17.6 Protects Proteins from Oxidative Inactivation
Authors: Ma Pengfei , Li Jie , Qi Lei , Dong Xiuzhu
Published: March 2021

Small heat shock proteins (sHsps) are widely distributed among various types of organisms and function in preventing the irreversible aggregation of thermal denaturing proteins. Here, we report that Hsp17.6 from Methanolobus psychrophilus exhibited protection of proteins from oxidation inactivation. The overexpression of Hsp17.6 in Escherichia coli markedly increased the stationary phase cell density and survivability in HClO and H2O2. Treatments with 0.2 mM HClO or 10 mM H2O2 reduced malate dehydrogenase (MDH) activity to 57% and 77%, whereas the addition of Hsp17.6 recovered the activity to 70–90% and 86–100%, respectively. A similar effect for superoxide dismutase oxidation was determined for Hsp17.6. Non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis assays determined that the Hsp17.6 addition decreased H2O2-caused disulfide-linking protein contents and HClO-induced degradation of MDH; meanwhile, Hsp17.6 protein appeared to be oxidized with increased molecular weights. Mass spectrometry identified oxygen atoms introduced into the larger Hsp17.6 molecules, mainly at the aspartate and methionine residues. Substitution of some aspartate residues reduced Hsp17.6 in alleviating H2O2- and HClO-caused MDH inactivation and in enhancing the E. coli survivability in H2O2 and HClO, suggesting that the archaeal Hsp17.6 oxidation protection might depend on an “oxidant sink” effect, i.e., to consume the oxidants in environments via aspartate oxidation.
Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History
Authors: Kaneto Hideaki , Kimura Tomohiko , Obata Atsushi , Shimoda Masashi , Kaku Kohei
Published: March 2021

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.
Surface Activation of Titanium Dental Implants by Using UVC-LED Irradiation
Authors: Arroyo-Lamas Nagore , Arteagoitia Iciar , Ugalde Unai
Published: March 2021

Organic contaminants significantly limit the bioactivity of titanium implants, resulting in the degradation known as the ageing of titanium. To reactivate the surfaces, they can be photofunctionalized, i.e., irradiated with C-range ultraviolet (UVC) light. This descriptive in vitro study compares the effectiveness of novel light-emitting diode (LED) technology to remove contaminant hydrocarbons from three different commercially available titanium dental implants: THD, TiUnite, and SLA. The surface topography and morphology were characterized by scanning electron microscopy (SEM). The chemical compositions were analyzed by X-ray photoelectron spectroscopy (XPS), before and after the lighting treatment, by a pair of closely placed UVC (λ = 278 nm) and LED devices for 24 h. SEM analysis showed morphological differences at the macro- and micro-scopic level. XPS analysis showed a remarkable reduction in the carbon contents after the UVC treatment: from 25.6 to 19.5 C at. % (carbon atomic concentration) in the THD; from 30.2 to 20.2 C at. % in the TiUnite; from 26.1 to 19.2 C at. % in the SLA surface. Simultaneously, the concentration of oxygen and titanium increased. Therefore, LED-based UVC irradiation decontaminated titanium surfaces and improved the chemical features of them, regardless of the kind of surface.
RNA-Binding Proteins and the Complex Pathophysiology of ALS
Authors: Kim Wanil , Kim Do-Yeon , Lee Kyung-Ha
Published: March 2021

Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.
Nanomaterials and the Serosal Immune System in the Thoracic and Peritoneal Cavities
Authors: Kuper C. Frieke , Pieters Raymond H. H. , van Bilsen Jolanda H. M.
Published: March 2021

The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune system. Innate lymphoid cells (ILCs) are found abundantly in the thoracic and peritoneal cavities, and they are crucial in first defense against pathogenic viruses and bacteria. Nanomaterials (NMs) can enter the cavities intentionally for medical purposes, or unintentionally following environmental exposure; subsequent serosal inflammation and cancer (mesothelioma) has gained significant interest. However, reports on adverse effects of NM on ILCs and other components of the serosal immune system are scarce or even lacking. As ILCs are crucial in the first defense against pathogenic viruses and bacteria, it is possible that serosal exposure to NM may lead to a reduced resistance against pathogens. Additionally, affected serosal lymphoid tissues and cells may disturb adipose tissue homeostasis. This review aims to provide insight into key effects of NM on the serosal immune system.
Shorter P1m Response in Children with Autism Spectrum Disorder without Intellectual Disabilities
Authors: Yoshimura Yuko , Ikeda Takashi , Hasegawa Chiaki , An Kyung-Min , Tanaka Sanae , Yaoi Ken , Iwasaki Sumie , Saito Daisuke N. , Kumazaki Hirokazu , Hiraishi Hirotoshi , Kikuchi Mitsuru
Published: March 2021

(1) Background: Atypical auditory perception has been reported in individuals with autism spectrum disorder (ASD). Altered auditory evoked brain responses are also associated with childhood ASD. They are likely to be associated with atypical brain maturation. (2) Methods: This study examined children aged 5–8 years old: 29 with ASD but no intellectual disability and 46 age-matched typically developed (TD) control participants. Using magnetoencephalography (MEG) data obtained while participants listened passively to sinusoidal pure tones, bilateral auditory cortical response (P1m) was examined. (3) Results: Significantly shorter P1m latency in the left hemisphere was found for children with ASD without intellectual disabilities than for children with TD. Significant correlation between P1m latency and language conceptual ability was found in children with ASD, but not in children with TD. (4) Conclusions: These findings demonstrated atypical brain maturation in the auditory processing area in children with ASD without intellectual disability. Findings also suggest that ASD has a common neural basis for pure-tone sound processing and language development. Development of brain networks involved in language concepts in early childhood ASD might differ from that in children with TD.
CNBP Binds and Unfolds In Vitro G-Quadruplexes Formed in the SARS-CoV-2 Positive and Negative Genome Strands
Authors: Bezzi Georgina , Piga Ernesto J. , Binolfi Andrés , Armas Pablo
Published: March 2021

The Coronavirus Disease 2019 (COVID-19) pandemic has become a global health emergency with no effective medical treatment and with incipient vaccines. It is caused by a new positive-sense RNA virus called severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). G-quadruplexes (G4s) are nucleic acid secondary structures involved in the control of a variety of biological processes including viral replication. Using several G4 prediction tools, we identified highly putative G4 sequences (PQSs) within the positive-sense (+gRNA) and negative-sense (−gRNA) RNA strands of SARS-CoV-2 conserved in related betacoronaviruses. By using multiple biophysical techniques, we confirmed the formation of two G4s in the +gRNA and provide the first evidence of G4 formation by two PQSs in the −gRNA of SARS-CoV-2. Finally, biophysical and molecular approaches were used to demonstrate for the first time that CNBP, the main human cellular protein bound to SARS-CoV-2 RNA genome, binds and promotes the unfolding of G4s formed by both strands of SARS-CoV-2 RNA genome. Our results suggest that G4s found in SARS-CoV-2 RNA genome and its negative-sense replicative intermediates, as well as the cellular proteins that interact with them, are relevant factors for viral genes expression and replication cycle, and may constitute interesting targets for antiviral drugs development.
Two Siblings Homozygous for F508del-CFTR Have Varied Disease Phenotypes and Protein Biomarkers
Authors: Zhang Zhihong , Wang Jin , Zhang Yanhui H. , Gardner Tonia E. , Fitzpatrick Elizabeth A. , Zhang Weiqiang
Published: March 2021

Two siblings with CF are homozygous for F508del (referred to as Subject A and Subject B). Despite having the same CFTR genotype and similar environment, these two subjects exhibited different disease phenotypes. We analyzed their medical records and CF Foundation Registry data and measured inflammatory protein mediators in their sputum samples. Then, we examined the longitudinal relationships between inflammatory markers and disease severity for each subject and compared between them. Subject A presented a more severe disease than Subject B. During the study period, Subject A had two pulmonary exacerbations (PEs) whereas Subject B had one mild PE. The forced expiratory volume in 1 s (FEV1, % predicted) values for Subject A were between 34–45% whereas for Subject B varied between 48–90%. Inflammatory protein mediators associated with neutrophils, Th1, Th2, and Th17 responses were elevated in sputum of Subject A compared with Subject B, and also in samples collected prior to and during PEs for both subjects. Neutrophilic elastase (NE) seemed to be the most informative biomarkers. The infectious burden between these two subjects was different.
Effects of a Catechol-Functionalized Hyaluronic Acid Patch Combined with Human Adipose-Derived Stem Cells in Diabetic Wound Healing
Authors: Pak Chang Sik , Heo Chan Yeong , Shin Jisoo , Moon Soo Young , Cho Seung-Woo , Kang Hyo Jin
Published: March 2021

Introduction: Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. To overcome the limitations of current diabetic wound (DBW) management interventions, we investigated the effects of a catechol-functionalized hyaluronic acid (HA-CA) patch combined with adipose-derived mesenchymal stem cells (ADSCs) in DBW mouse models. Methods: Diabetes in mice (C57BL/6, male) was induced by streptozotocin (50 mg/kg, >250 mg/dL). Mice were divided into four groups: control (DBW) group, ADSCs group, HA-CA group, and HA-CA + ADSCs group (n = 10 per group). Fluorescently labeled ADSCs (5 × 105 cells/100 µL) were transplanted into healthy tissues at the wound boundary or deposited at the HA-CA patch at the wound site. The wound area was visually examined. Collagen content, granulation tissue thickness and vascularity, cell apoptosis, and re-epithelialization were assessed. Angiogenesis was evaluated by immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot. Results: DBW size was significantly smaller in the HA-CA + ADSCs group (8% ± 2%) compared with the control (16% ± 5%, p < 0.01) and ADSCs (24% ± 17%, p < 0.05) groups. In mice treated with HA-CA + ADSCs, the epidermis was regenerated, and skin thickness was restored. CD31 and von Willebrand factor-positive vessels were detected in mice treated with HA-CA + ADSCs. The mRNA and protein levels of VEGF, IGF-1, FGF-2, ANG-1, PIK, and AKT in the HA-CA + ADSCs group were the highest among all groups, although the Spred1 and ERK expression levels remained unchanged. Conclusions: The combination of HA-CA and ADSCs provided synergistic wound healing effects by maximizing paracrine signaling and angiogenesis via the PI3K/AKT pathway. Therefore, ADSC-loaded HA-CA might represent a novel strategy for the treatment of DBW.
The Role of Immunogenetics in COVID-19
Authors: Pojero Fanny , Candore Giuseppina , Caruso Calogero , Di Bona Danilo , Groneberg David A. , Ligotti Mattia E. , Accardi Giulia , Aiello Anna
Published: March 2021

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies. In the frenetic look for universally shared treatment plans, those genetic variants that are common to other diseases/models may also help in addressing future research in terms of drug repurposing. In this paper, we discuss the most recent updates about the role of immunogenetics in determining the susceptibility to and the history of SARS-CoV-2 infection. We propose a narrative review of available data, speculating about lessons that we have learnt from other viral infections and immunosenescence, and discussing what kind of aspects of research should be deepened in order to improve our knowledge of how host genetic variability impacts the outcome for COVID-19 patients.
Estimating Freeway Level-of-Service Using Crowdsourced Data
Authors: Hoseinzadeh Nima , Gu Yangsong , Han Lee D. , Brakewood Candace , Freeze Phillip B.
Published: March 2021

In traffic operations, the aim of transportation agencies and researchers is typically to reduce congestion and improve safety. To attain these goals, agencies need continuous and accurate information about the traffic situation. Level-of-Service (LOS) is a beneficial index of traffic operations used to monitor freeways. The Highway Capacity Manual (HCM) provides analytical methods to assess LOS based on traffic density and highway characteristics. Generally, obtaining reliable density data on every road in large networks using traditional fixed location sensors and cameras is expensive and otherwise unrealistic. Traditional intelligent transportation system facilities are typically limited to major urban areas in different states. Crowdsourced data are an emerging, low-cost solution that can potentially improve safety and operations. This study incorporates crowdsourced data provided by Waze to propose an algorithm for LOS assessment on an hourly basis. The proposed algorithm exploits various features from big data (crowdsourced Waze user alerts and speed/travel time variation) to perform LOS classification using machine learning models. Three categories of model inputs are introduced: Basic statistical measures of speed; travel time reliability measures; and the number of hourly Waze alerts. Data collected from fixed location sensors were used to calculate ground truth LOS. The results reveal that using Waze crowdsourced alerts can improve the LOS estimation accuracy by about 10% (accuracy = 0.93, Kappa = 0.83). The proposed method was also tested and confirmed by using data from after coronavirus disease 2019 (COVID-19) with severe traffic breakdown due to a stay-at-home policy. The proposed method is extendible for freeways in other locations. The results of this research provide transportation agencies with a LOS method based on crowdsourced data on different freeway segments, regardless of the availability of traditional fixed location sensors.
Detection of Urothelial Bladder Cancer Based on Urine and Tissue Telomerase Activity Measured by Novel RT-TRAP-2PCR Method
Authors: Glukhov Alexander , Potoldykova Natalya , Taratkin Mark , Gordeev Sergey , Polyakovsky Konstantin , Laukhtina Ekaterina , Moschini Marco , Abufaraj Mohammad , Shariat Shahrokh F. , Sekacheva Marina , Enikeev Dmitry , Glybochko Petr
Published: March 2021

Purpose: To assess the diagnostic performance of urine telomerase activity (TA) in detecting bladder cancer (BCa) using the modified Telomeric Repeat Amplification Protocol (TRAP) and the Real Time Telomeric Repeat Amplification Protocol with double Polymerase Chain Reaction (RT-TRAP-2PCR). Methods: In this case-control study, matching urine (in the pre- and post-surgical period) and tissue samples from 68 patients with BCa were assessed for TA. As a control, 45 urine samples were examined from non-BCa patients. TA levels were measured using TRAP and RT-TRAP-2 PCR methods. Results: Preoperative urinary TA was elevated in 64 (94.1%) of the 68 BCa patients. Urine TA was undetectable in 44 control patients, while TA was detected in one patient with histologically verified cystitis. Sensitivity for BCa detection of 94.1% and specificity of 97.8% were observed for urinary TA, while tissue TA had 100% sensitivity and 97.8% specificity. Both urine and tissue TA levels were not significantly higher in patients with muscle-invasive disease compared to those with non-muscle invasive BCa (p > 0.05). Urine and tissue TA levels were not associated with higher tumor grade, stage, and number of tumors (p > 0.05). However, the association was found between higher urinary and tissue TA levels with tumor size ≥ 3 cm (p = 0.02 and p = 0.01, respectively). During the first postoperative year, 17 BCa patients experienced disease recurrence, and urinary TA was present in 14 (82.4%) of these patients. The sensitivity and specificity of urinary TA levels for BCa recurrence in patients with non-muscle invasive bladder cancer (NMIBC) during follow-up were 82% and 94.4%, respectively. Conclusions: This pilot study demonstrates a high diagnostic performance of urinary and tissue TA levels measured by a new RT-TRAP-2PCR method for detecting and monitoring BCa. Additionally, the association was found between higher urinary and tissue TA levels with tumor size ≥ 3 cm; however, higher TA levels failed for significant correlation with advanced tumor stage and grade. Our study could serve as a benchmark for the evaluation of novel biomarkers using the RT-TRAP-2PCR method.
Cardiac Rupture—The Most Serious Complication of Takotsubo Syndrome: A Series of Five Cases and a Systematic Review
Authors: Zalewska-Adamiec Małgorzata , Bachórzewska-Gajewska Hanna , Dobrzycki Sławomir
Published: March 2021

Background: The most serious complication of the acute Takotsubo phase is a myocardial perforation, which is rare, but it usually results in the death of the patient. Methods: In the years 2008–2020, 265 patients were added to the Podlasie Takotsubo Registry. Cardiac rupture was observed in five patients (1.89%), referred to as the Takotsubo syndrome with complications of cardiac rupture (TS+CR) group. The control group consisted of 50 consecutive patients with uncomplicated TS. The diagnosis of TS was based on the Mayo Clinic Criteria. Results: Cardiac rupture was observed in women with TS aged 74–88 years. Patients with TS and CR were older (82.20 vs. 64.84; p = 0.011), than the control group, and had higher troponin, creatine kinase, aspartate aminotransferase, and blood glucose levels (168.40 vs. 120.67; p = 0.010). The TS+CR group demonstrated a higher heart rate (95.75 vs. 68.38; p < 0.0001) and the Global Registry of Acute Coronary Events (GRACE) scores (186.20 vs. 121.24; p < 0.0001) than the control group. In patients with CR, ST segment elevation was recorded significantly more often in the III, V4, V5 and V6 leads. Left ventricular free wall rupture was noted in four patients, and in one case, rupture of the ventricular septum. In a multivariate logistic regression, the factors that increase the risk of CR in TS were high GRACE scores, and the presence of ST segment elevation in lead III. Conclusions: Cardiac rupture in TS is rare but is the most severe mechanical complication and is associated with a very high risk of death. The main risk factors for left ventricular perforation are female gender, older age, a higher concentration of cardiac enzymes, higher GRACE scores, and ST elevations shown using electrocardiogram (ECG).
Long-Term Survival and Complication Rates of Porcelain Laminate Veneers in Clinical Studies: A Systematic Review
Authors: Alenezi Ali , Alsweed Mohammad , Alsidrani Saleh , Chrcanovic Bruno R.
Published: March 2021

The presented study aimed to assess the survival rate of porcelain laminate veneers (PLV) based on a systematic review of the literature. An electronic search was last updated in February 2021. Eligibility criteria included clinical series of patients rehabilitated with PLVs published in the last 25 years, with a minimum follow-up of 3 years. Survival analysis methods were applied. Twenty-five studies were included, with 6500 PLVs. The 10-year estimated cumulative survival rate (CSR) of PLVs was 95.5%. The 10-year CSR of PLVs when fracture, debonding, occurrence of secondary caries, and need of endodontic treatment were considered as isolated reasons for failure were 96.3%, 99.2%, 99.3%, and 99.0%, respectively. PLVs without incisal coverage had a higher failure rate than PLVs with incisal coverage. Non-feldspathic PLVs performed better than feldspathic PLVs. As a conclusion, the 10-year CSR of PLVs was 95.5%, when fracture, debonding, occurrence of secondary caries, and need of endodontic treatment were considered as reasons for restoration failure. Fracture seems to be most common complication of PLVs, followed by debonding, with both more commonly happening within the first years after PLV cementation. PLVs with incisal coverage and non-feldspathic PLVs presented lower failure rates than PLVs without incisal coverage and feldspathic PLVs.
Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review
Authors: Donnez Jacques , Dolmans Marie-Madeleine
Published: March 2021

Background: The first objective of this review was to present, based on recent literature, the most frequently applied medical options (oral contraceptive pills (OCPs) and progestogens) for the management of symptomatic endometriosis, and evaluate their effectiveness in treating premenopausal women with endometriosis-associated pelvic pain, dysmenorrhea, non-menstrual pelvic pain and dyspareunia. The second objective was to review the concept of progesterone resistance and newly available treatment options. Methods: We reviewed the most relevant papers (n = 73) on the efficacy of OCPs and progestogens as medical therapy for endometriosis, as well as those on progesterone resistance and new medical alternatives (oral gonadotropin-releasing hormone (GnRH) antagonist). Eleven papers, essentially reviews, were selected and scrutinized from among 94 papers discussing the concept of progesterone resistance. Results: Having reviewed the most significant papers, we can confirm that OCPs and progestogens are effective in two-thirds of women suffering from endometriosis, but that other options are required in case of failure (in one-third of women due to progesterone resistance) or intolerance to these compounds. It is clear that there is a need for effective long-term oral treatment capable of managing endometriosis symptoms, while mitigating the impact of side effects. Biochemical, histological and clinical evidence show that estrogens play a critical role in the pathogenesis of endometriosis, so lowering levels of circulating estrogens should be considered an effective medical approach. The efficacy of three oral GnRH antagonists is discussed on the basis of published studies. Conclusion: There is a place for GnRH antagonists in the management of symptomatic endometriosis and clinical trials should be conducted, taking into account the different phenotypes in order to propose novel algorithms.
Neuroimaging of Acute Intracerebral Hemorrhage
Authors: Sporns Peter B. , Psychogios Marios-Nikos , Boulouis Grégoire , Charidimou Andreas , Li Qi , Fainardi Enrico , Dowlatshahi Dar , Goldstein Joshua N. , Morotti Andrea
Published: March 2021

Intracerebral hemorrhage (ICH) accounts for 10% to 20% of all strokes worldwide and is associated with high morbidity and mortality. Neuroimaging is clinically important for the rapid diagnosis of ICH and underlying etiologies, but also for identification of ICH expansion, often as-sociated with an increased risk for poor outcome. In this context, rapid assessment of early hema-toma expansion risk is both an opportunity for therapeutic intervention and a potential hazard for hematoma evacuation surgery. In this review, we provide an overview of the current literature surrounding the use of multimodal neuroimaging of ICH for etiological diagnosis, prediction of early hematoma expansion, and prognostication of neurological outcome. Specifically, we discuss standard imaging using computed tomography, the value of different vascular imaging modalities to identify underlying causes and present recent advances in magnetic resonance imaging and computed tomography perfusion.
Symptomatic and Asymptomatic Patients in the Polish Atrial Fibrillation (POL-AF) Registry
Authors: Kiliszek Marek , Uziębło-Życzkowska Beata , Gorczyca Iwona , Maciorowska Małgorzata , Jelonek Olga , Wożakowska-Kapłon Beata , Wójcik Maciej , Błaszczyk Robert , Gawałko Monika , Kapłon-Cieślicka Agnieszka , Tokarek Tomasz , Rajtar-Salwa Renata , Bil Jacek , Wojewódzki Michał , Szpotowicz Anna , Krzciuk Małgorzata , Bednarski Janusz , Bakuła-Ostalska Elwira , Tomaszuk-Kazberuk Anna , Szyszkowska Anna , Wełnicki Marcin , Mamcarz Artur , Krzesiński Paweł
Published: March 2021

Background: Atrial fibrillation (AF) can cause severe symptoms, but it is frequently asymptomatic. We aimed to compare the clinical features of patients with asymptomatic and symptomatic AF. Methods: A prospective, observational, multicenter study was performed (the Polish Atrial Fibrillation (POL-AF) registry). Consecutive hospitalized AF patients over 18 years of age were enrolled at ten centers. The data were collected for two weeks during each month of 2019. Results: A total of 2785 patients were analyzed, of whom 1360 were asymptomatic (48.8%). Asymptomatic patients were more frequently observed to have coronary artery disease (57.5% vs. 49.1%, p < 0.0001), heart failure with preserved ejection fraction (39.8% vs. 26.5%, p < 0.0001), a previous thromboembolic event (18.2% vs. 13.1%, p = 0.0002), and paroxysmal AF (52.3% vs. 45.2%, p = 0.0002). In multivariate analysis, history of electrical cardioversion, paroxysmal AF, heart failure, coronary artery disease, previous thromboembolic event, and higher left ventricular ejection fraction were predictors of a lack of AF symptoms. First-diagnosed AF was a predictor of AF symptoms. Conclusions: In comparison to symptomatic patients, more of those hospitalized with asymptomatic AF had been previously diagnosed with this arrhythmia and other cardiovascular diseases. However, they presented with better left ventricular function and were more frequently treated with cardiovascular medicines.
Clinical Significance of TNFRSF1A36T/C Polymorphism in Cachectic Patients with Chronic Heart Failure
Authors: Sobieszek Grzegorz , Powrózek Tomasz , Skwarek-Dziekanowska Aneta , Małecka-Massalska Teresa
Published: March 2021

Introduction: One of the main factors contributing to the development of nutritional deficits in chronic heart failure (CHF) patients is the systemic inflammatory process. Progressing inflammatory response leads to exacerbation of the disease and could develop into cardiac cachexia (CC), characterized by involuntary weight loss followed by muscle wasting. The aim of this study was to assess the relationship between rs767455 (36 T/C) of the TNFRSF1A and the occurrence of nutritional disorders in CHF patients with cachexia. Materials and Methods: We enrolled 142 CHF individuals who underwent cardiac and nutritional screening in order to assess cardiac performance and nutritional status. The relationship between TNFRSF1A rs767455 genotypes and patients’ features was investigated. Results: A greater distribution of the TT genotype among cachectic patients in contrast to non-cachectic individuals was found (TT frequencies of 62.9% and 37.1%, respectively; p = 0.013). We noted a significantly lower albumin concentration (p = 0.039) and higher C-reactive protein (CRP) levels (p = 0.019) in patients with the TT genotype. Regarding cardiac parameters, CHF individuals bearing the TT genotype demonstrated a significant reduction in ejection fraction (EF) (p = 0.033) in contrast to other genotype carriers; moreover, they had a significantly higher concentration of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in the blood (p = 0.018). We also noted a lower frequency of TT genotype carriers among individuals qualified as grades I or II of the New York Heart Association (NYHA) (p = 0.006). The multivariable analysis selected the TT genotype as an unfavorable factor related to a higher chance of cachexia in CHF patients (Odds ratio (OR) = 2.56; p = 0.036). Conclusions: The rs767455TT genotype of TNFRSF1A can be considered as an unfavorable factor related to a higher risk of cachexia in CHF patients.
Genome-Wide Marker Analysis for Traits of Economic Importance in Asian Seabass Lates calcarifer
Authors: Nguyen Nguyen Hong , Van Khang Pham
Published: March 2021

To date, it is not known whether animal breeding values in Asian seabass (Lates calcarifer) can be estimated using single nucleotide polymorphisms (SNPs) generated from new high-throughput genotyping by sequencing platforms. The principal aim of the present study was to assess the genomic prediction accuracy for growth traits, survival, cannibalism, and disease resistance against Streptococcus iniae in this species L. calcarifer. Additionally, this study attempted to identify markers associated with the five traits studied as well as to understand if the genotype data can be used to estimate genetic parameters for these complex traits. The genomic best linear unbiased prediction (gBLUP) method was used to analyze 11,084 SNPs and showed that the prediction accuracies for growth traits (weight and length) were high (0.67–0.75). By contrast, these estimates for survival were low (0.25). Multi-locus mixed model analyses identified four SNPs significantly associated with body weight (p < 5 × 10−8 or −log10 p ≥ 5). There were, however, no significant associations detected for other traits. Similarly, the SNP heritability was moderate, while the estimates for other traits were approximated to zero and not significant. Genetic correlations between body weight and standard length were close to unity. Collectively, the results obtained from this study suggest that genotyping by sequencing platforms can provide informative DNA markers to conduct genome-wide association analysis, estimation of genetic parameters, and evaluation of genomic prediction accuracy for complex traits in Asian seabass.
Comparison of Existing Equations for the Design of Crown Walls: Application to the Case Study of Ericeira Breakwater (Portugal)
Authors: Pereira Fábio , Neves Maria Graça , López-Gutiérrez José-Santos , Esteban María Dolores , Negro Vicente
Published: March 2021

The correct calculation of forces and moments caused by wave action over crown wall structures is critical for their design. There are several existing equations for this, some of which are sanctioned in practice as it is the case for Jensen (1984) and Bradbury et al. (1998), Günback and Gökce (1984), Martin et al. (1999), Berenguer and Baonza (2006), and Pedersen (1996) and Nørgaard et al. (2013). These equations are the main tool for the design of breakwater crown walls and their accuracy is crucial to ensure the stability of the crown wall, especially when considering the sea level rise due to climate change and the possible damage of the armor, since both aspects are not usually considered in most original design studies. In a scenario of climate change, it is very important to estimate the possible changes in security factors due to both these aspects, comparing the results with the original design ones. This paper has as main objective to analyze it for the case study of Ericeira rubble mound breakwater in Portugal. For this, a comparison of the results using those equations and different scenarios including the current, considering sea level rise and armor damage, were performed to extract some conclusions: the increase in the sea level in the case study was not significant and therefore its incidence is very small; and the damage to the main armor by losing pieces at the berm is much more important in this case study, so it is essential to carry out the proper maintenance of the design section. On the other hand, horizontal forces are more conservative using Pedersen and Nørgaard equations, obtaining the lowest value with Martin. Regarding uplift pressures, Martin gives the lowest value, while the most conservative values are given by Günbak and Gökce’s for two scenarios, and Pedersen and Nørgaard for the other two scenarios. Furthermore, the sliding safety coefficient is more conditioning than overturning the safety coefficient in all the scenarios.
Higher-Harmonic Response of a Slender Monopile to Fully Nonlinear Focused Wave Groups
Authors: Liu Jiawang , Teng Bin
Published: March 2021

The “ringing” response of a monopile foundation to focused wave groups was investigated in this study. Such responses are of practical interest in the context of offshore wind turbine foundations. Moderately steep transient focused wave groups were generated in a novel numerical wave tank, based on the high-order spectral method, which was verified and in good agreement with published laboratory data. The monopile was simplified into a slender linear elastic cantilever beam to measure the severity of the structural response. The resonant behavior was excited at the triple-wave frequency of the wave loads. The influence of the damping ratio on the ringing response was considered. Different incident wave models and hydrodynamic models were used to predict the wave loads and induced responses over different wave steepness. The wavelet transform was successfully applied to reveal the local characteristics of the wave loads and ringing response.
Financial Sustainability of Cultural Heritage: A Review of Crowdfunding in Europe
Authors: Jelinčić Daniela Angelina , Šveb Marta
Published: March 2021

Most cultural heritage projects strive in ensuring financial sustainability, mainly relying on public subsidies. At the same time, they lack fund management policies which directly affects their financial sustainability. European Union heritage policies focus on sustainability but after investments have been made, there are rare cases which can boast about it. A number of heritage funding mechanisms exist which are explained in this review paper, while the focus is on crowdfunding as an alternative mechanism. The study used literature review method based on PRISMA guidelines to analyze new trends and suitability of crowdfunding for cultural heritage projects, and to detect possible factors influencing its success. The purpose was to add to the existing knowledge while offering a systematic review which can be applied in practice. Findings indicate the trend of participatory approach to heritage, which is in line with the participatory nature of crowdfunding campaigns. Further, crowdfunding suitability for cultural heritage projects was confirmed while its success factors majorly depend on the policy framework, heritage project nature and management of the campaign itself.