bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of Bcl-xL in Neuronal Function and Development
Authors: Bas Julie , Nguyen Trang , Gillet Germain
Published: March 2021

The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the cell death machinery, including Bcl-2 homologs, was reported to be essential for the central nervous system (CNS), notably with respect to synaptic transmission and axon pruning. Here we focused on Bcl-xL, a close Bcl-2 homolog, which plays a major role in neuronal development, as bclx knock out mice prematurely die at embryonic day 13.5, showing massive apoptosis in the CNS. In addition, we present evidence that Bcl-xL fosters ATP generation by the mitochondria to fuel high energy needs by neurons, and its contribution to synaptic transmission. We discuss how Bcl-xL might control local and transient activation of caspases in neurons without causing cell death. Consistently, Bcl-xL may contribute to morphological changes, such as sprouting and retractation of axon branches, in the context of CNS plasticity. Regarding degenerative diseases and aging, a better understanding of the numerous roles of the cell death machinery in neurons may have future clinical implications.
Hyaluronidases in Human Diseases
Authors: Kaul Aditya , Short Walker D. , Wang Xinyi , Keswani Sundeep G.
Published: March 2021

With the burgeoning interest in hyaluronic acid (HA) in recent years, hyaluronidases (HYALs) have come to light for their role in regulating catabolism of HA and its molecular weight (MW) distribution in various tissues. Of the six hyaluronidase-like gene sequences in the human genome, HYALs 1 and 2 are of particular significance because they are the primary hyaluronidases active in human somatic tissue. Perhaps more importantly, for the sake of this review, they cleave anti-inflammatory and anti-fibrotic high-molecular-weight HA into pro-inflammatory and pro-fibrotic oligosaccharides. With this, HYALs regulate HA degradation and thus the development and progression of various diseases. Given the dearth of literature focusing specifically on HYALs in the past decade, this review seeks to expound their role in human diseases of the skin, heart, kidneys, and more. The review will delve into the molecular mechanisms and pathways of HYALs and discuss current and potential future therapeutic benefits of HYALs as a clinical treatment.
Linear B-Cell Epitope Prediction for In Silico Vaccine Design: A Performance Review of Methods Available via Command-Line Interface
Authors: Galanis Kosmas A. , Nastou Katerina C. , Papandreou Nikos C. , Petichakis Georgios N. , Pigis Diomidis G. , Iconomidou Vassiliki A.
Published: March 2021

Linear B-cell epitope prediction research has received a steadily growing interest ever since the first method was developed in 1981. B-cell epitope identification with the help of an accurate prediction method can lead to an overall faster and cheaper vaccine design process, a crucial necessity in the COVID-19 era. Consequently, several B-cell epitope prediction methods have been developed over the past few decades, but without significant success. In this study, we review the current performance and methodology of some of the most widely used linear B-cell epitope predictors which are available via a command-line interface, namely, BcePred, BepiPred, ABCpred, COBEpro, SVMTriP, LBtope, and LBEEP. Additionally, we attempted to remedy performance issues of the individual methods by developing a consensus classifier, which combines the separate predictions of these methods into a single output, accelerating the epitope-based vaccine design. While the method comparison was performed with some necessary caveats and individual methods might perform much better for specialized datasets, we hope that this update in performance can aid researchers towards the choice of a predictor, for the development of biomedical applications such as designed vaccines, diagnostic kits, immunotherapeutics, immunodiagnostic tests, antibody production, and disease diagnosis and therapy.
An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates
Authors: Park Sungmin , Kim Daeun , Song Jaeseung , Joo Jong Wha J.
Published: March 2021

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease. Although genome-wide association studies (GWAS) have successfully identified many variants significantly associated with ALS, it is still difficult to characterize the underlying biological mechanisms inducing ALS. In this study, we performed a transcriptome-wide association study (TWAS) to identify disease-specific genes in ALS. Using the largest ALS GWAS summary statistic (n = 80,610), we identified seven novel genes using 19 tissue reference panels. We conducted a conditional analysis to verify the genes’ independence and to confirm that they are driven by genetically regulated expressions. Furthermore, we performed a TWAS-based enrichment analysis to highlight the association of important biological pathways, one in each of the four tissue reference panels. Finally, utilizing a connectivity map, a database of human cell expression profiles cultured with bioactive small molecules, we discovered functional associations between genes and drugs to identify 15 bioactive small molecules as potential drug candidates for ALS. We believe that, by integrating the largest ALS GWAS summary statistic with gene expression to identify new risk loci and causal genes, our study provides strong candidates for molecular basis experiments in ALS.
Crystal Structure of a Phospholipase D from the Plant-Associated Bacteria Serratia plymuthica Strain AS9 Reveals a Unique Arrangement of Catalytic Pocket
Authors: Wang Fanghua , Liu Siyu , Mao Xuejing , Cui Ruiguo , Yang Bo , Wang Yonghua
Published: March 2021

Phospholipases D (PLDs) play important roles in different organisms and in vitro phospholipid modifications, which attract strong interests for investigation. However, the lack of PLD structural information has seriously hampered both the understanding of their structure–function relationships and the structure-based bioengineering of this enzyme. Herein, we presented the crystal structure of a PLD from the plant-associated bacteria Serratia plymuthica strain AS9 (SpPLD) at a resolution of 1.79 Å. Two classical HxKxxxxD (HKD) motifs were found in SpPLD and have shown high structural consistence with several PLDs in the same family. While comparing the structure of SpPLD with the previous resolved PLDs from the same family, several unique conformations on the C-terminus of the HKD motif were demonstrated to participate in the arrangement of the catalytic pocket of SpPLD. In SpPLD, an extented loop conformation between β9 and α9 (aa228–246) was found. Moreover, electrostatic surface potential showed that this loop region in SpPLD was positively charged while the corresponding loops in the two Streptomyces originated PLDs (PDB ID: 1F0I, 2ZE4/2ZE9) were neutral. The shortened loop between α10 and α11 (aa272–275) made the SpPLD unable to form the gate-like structure which existed specically in the two Streptomyces originated PLDs (PDB ID: 1F0I, 2ZE4/2ZE9) and functioned to stabilize the substrates. In contrast, the shortened loop conformation at this corresponding segment was more alike to several nucleases (Nuc, Zuc, mZuc, NucT) within the same family. Moreover, the loop composition between β11 and β12 was also different from the two Streptomyces originated PLDs (PDB ID: 1F0I, 2ZE4/2ZE9), which formed the entrance of the catalytic pocket and were closely related to substrate recognition. So far, SpPLD was the only structurally characterized PLD enzyme from Serratia. The structural information derived here not only helps for the understanding of the biological function of this enzyme in plant protection, but also helps for the understanding of the rational design of the mutant, with potential application in phospholipid modification.
Phosphoproteomic Analysis of Subcutaneous and Omental Adipose Tissue Reveals Increased Lipid Turnover in Dairy Cows Supplemented with Conjugated Linoleic Acid
Authors: Daddam Jayasimha Rayalu , Hammon Harald M. , Tröscher Arnulf , Vogel Laura , Gnott Martina , Kra Gitit , Levin Yishai , Sauerwein Helga , Zachut Maya
Published: March 2021

Phosphoproteomics is a cutting-edge technique that can be utilized to explore adipose tissue (AT) metabolism by quantifying the repertoire of phospho-peptides (PP) in AT. Dairy cows were supplemented with conjugated linoleic acid (CLA, n = 5) or a control diet (CON, n = 5) from 63 d prepartum to 63 d postpartum; cows were slaughtered at 63 d postpartum and AT was collected. We performed a quantitative phosphoproteomics analysis of subcutaneous (SC) and omental (OM) AT using nanoUPLC-MS/MS and examined the effects of CLA supplementation on the change in the phosphoproteome. A total of 5919 PP were detected in AT, and the abundance of 854 (14.4%) were differential between CON and CLA AT (p ≤ 0.05 and fold change ± 1.5). The abundance of 470 PP (7.9%) differed between OM and SC AT, and the interaction treatment vs. AT depot was significant for 205 PP (3.5% of total PP). The integrated phosphoproteome demonstrated the up- and downregulation of PP from proteins related to lipolysis and lipogenesis, and phosphorylation events in multiple pathways, including the regulation of lipolysis in adipocytes, mTOR signaling, insulin signaling, AMPK signaling, and glycolysis. The differential regulation of phosphosite on a serine residue (S777) of fatty acid synthase (FASN) in AT of CLA-supplemented cows was related to lipogenesis and with more phosphorylation sites compared to acetyl-coenzyme A synthetase (ACSS2). Increased protein phosphorylation was seen in acetyl-CoA carboxylase 1 (ACACA;8 PP), FASN (9 PP), hormone sensitive lipase (LIPE;6 PP), perilipin (PLIN;3 PP), and diacylglycerol lipase alpha (DAGLA;1 PP) in CLA vs. CON AT. The relative gene expression in the SC and OM AT revealed an increase in LIPE and FASN in CLA compared to CON AT. In addition, the expression of DAGLA, which is a lipid metabolism enzyme related to the endocannabinoid system, was 1.6-fold higher in CLA vs. CON AT, and the expression of the cannabinoid receptor CNR1 was reduced in CLA vs. CON AT. Immunoblots of SC and OM AT showed an increased abundance of FASN and a lower abundance of CB1 in CLA vs. CON. This study presents a complete map of the SC and the OM AT phosphoproteome in dairy cows following CLA supplementation and discloses many unknown phosphorylation sites, suggestive of increased lipid turnover in AT, for further functional investigation.
The Histidine Phosphocarrier Kinase/Phosphorylase from Bacillus Subtilis Is an Oligomer in Solution with a High Thermal Stability
Authors: Neira José L. , Cámara-Artigas Ana , Hernández-Cifre José Ginés , Ortore María Grazia
Published: March 2021

The histidine phosphocarrier protein (HPr) kinase/phosphorylase (HPrK/P) modulates the phosphorylation state of the HPr protein, and it is involved in the use of carbon sources by Gram-positive bacteria. Its X-ray structure, as concluded from crystals of proteins from several species, is a hexamer; however, there are no studies about its conformational stability, and how its structure is modified by the pH. We have embarked on the conformational characterization of HPrK/P of Bacillus subtilis (bsHPrK/P) in solution by using several spectroscopic (namely, fluorescence and circular dichroism (CD)) and biophysical techniques (namely, small-angle X-ray-scattering (SAXS) and dynamic light-scattering (DLS)). bsHPrK/P was mainly a hexamer in solution at pH 7.0, in the presence of phosphate. The protein had a high conformational stability, with an apparent thermal denaturation midpoint of ~70 °C, at pH 7.0, as monitored by fluorescence and CD. The protein was very pH-sensitive, precipitated between pH 3.5 and 6.5; below pH 3.5, it had a molten-globule-like conformation; and it acquired a native-like structure in a narrow pH range (between pH 7.0 and 8.0). Guanidinium hydrochloride (GdmCl) denaturation occurred through an oligomeric intermediate. On the other hand, urea denaturation occurred as a single transition, in the range of concentrations between 1.8 and 18 µM, as detected by far-UV CD and fluorescence.
Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice
Authors: Andres-Mach Marta , Szewczyk Aleksandra , Zagaja Mirosław , Szala-Rycaj Joanna , Lemieszek Marta Kinga , Maj Maciej , Abram Michał , Kaminski Krzysztof
Published: March 2021

Status epilepticus (SE) is a frequent medical emergency that can lead to a variety of neurological disorders, including cognitive impairment and abnormal neurogenesis. The aim of the presented study was the in vitro evaluation of potential neuroprotective properties of a new pyrrolidine-2,5-dione derivatives compound C11, as well as the in vivo assessment of the impact on the neurogenesis and cognitive functions of C11 and levetiracetam (LEV) after pilocarpine (PILO)-induced SE in mice. The in vitro results indicated a protective effect of C11 (500, 1000, and 2500 ng/mL) on astrocytes under trophic stress conditions in the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) test. The results obtained from the in vivo studies, where mice 72 h after PILO SE were treated with C11 (20 mg/kg) and LEV (10 mg/kg), indicated markedly beneficial effects of C11 on the improvement of the neurogenesis compared to the PILO control and PILO LEV mice. Moreover, this beneficial effect was reflected in the Morris Water Maze test evaluating the cognitive functions in mice. The in vitro confirmed protective effect of C11 on astrocytes, as well as the in vivo demonstrated beneficial impact on neurogenesis and cognitive functions, strongly indicate the need for further advanced molecular research on this compound to determine the exact neuroprotective mechanism of action of C11.
The First Treatment for PKU: The Pioneers—Birmingham 1951
Authors: Green Anne
Published: March 2021

Prior to the introduction of newborn screening, Phenylketonuria (PKU) was a devastating disorder with affected individuals usually committed to a life in care in large institutions (asylums). Newborn screening only began after it was shown that those with PKU could be treated with a modified diet and could subsequently lead normal lives. The first production of a diet and the demonstration of its effectiveness was thus a key milestone in the history of both PKU and newborn screening, and took place in Birmingham, UK, in 1951. The pioneers were a two-year-old girl called Sheila Jones, her mother Mary, and three dedicated professionals at Birmingham Children’s Hospital: Evelyn Hickmans, John Gerrard and Horst Bickel. Together, they changed the course of PKU for those across the world. This review summarises the history and achievements of this team who opened the door to PKU treatment and the introduction of newborn screening.
The Preterm Heart-Brain Axis in Young Adulthood: The Impact of Birth History and Modifiable Risk Factors
Authors: Lapidaire Winok , Clark Chris , Fewtrell Mary S. , Lucas Alan , Leeson Paul , Lewandowski Adam J.
Published: March 2021

People born preterm are at risk of developing both cardiac and brain abnormalities. We aimed to investigate whether cardiovascular physiology may directly affect brain structure in young adulthood and whether cardiac changes are associated with modifiable biomarkers. Forty-eight people born preterm, followed since birth, underwent cardiac MRI at age 25.1 ± 1.4 years and brain MRI at age 33.4 ± 1.0 years. Term born controls were recruited at both time points for comparison. Cardiac left and right ventricular stroke volume, left and right ventricular end diastolic volume and right ventricular ejection fraction were significantly different between preterm and term born controls and associated with subcortical brain volumes and fractional anisotropy in the corpus callosum in the preterm group. This suggests that cardiovascular abnormalities in young adults born preterm are associated with potentially adverse future brain health. Associations between left ventricular stroke volume indexed to body surface area and right putamen volumes, as well as left ventricular end diastolic length and left thalamus volumes, remained significant when adjusting for early life factors related to prematurity. Although no significant associations were found between modifiable biomarkers and cardiac physiology, this highlights that cardiovascular health interventions may also be important for brain health in preterm born adults.
Prediction of Long-Term Stroke Recurrence Using Machine Learning Models
Authors: Abedi Vida , Avula Venkatesh , Chaudhary Durgesh , Shahjouei Shima , Khan Ayesha , Griessenauer Christoph J , Li Jiang , Zand Ramin
Published: March 2021

Background: The long-term risk of recurrent ischemic stroke, estimated to be between 17% and 30%, cannot be reliably assessed at an individual level. Our goal was to study whether machine-learning can be trained to predict stroke recurrence and identify key clinical variables and assess whether performance metrics can be optimized. Methods: We used patient-level data from electronic health records, six interpretable algorithms (Logistic Regression, Extreme Gradient Boosting, Gradient Boosting Machine, Random Forest, Support Vector Machine, Decision Tree), four feature selection strategies, five prediction windows, and two sampling strategies to develop 288 models for up to 5-year stroke recurrence prediction. We further identified important clinical features and different optimization strategies. Results: We included 2091 ischemic stroke patients. Model area under the receiver operating characteristic (AUROC) curve was stable for prediction windows of 1, 2, 3, 4, and 5 years, with the highest score for the 1-year (0.79) and the lowest score for the 5-year prediction window (0.69). A total of 21 (7%) models reached an AUROC above 0.73 while 110 (38%) models reached an AUROC greater than 0.7. Among the 53 features analyzed, age, body mass index, and laboratory-based features (such as high-density lipoprotein, hemoglobin A1c, and creatinine) had the highest overall importance scores. The balance between specificity and sensitivity improved through sampling strategies. Conclusion: All of the selected six algorithms could be trained to predict the long-term stroke recurrence and laboratory-based variables were highly associated with stroke recurrence. The latter could be targeted for personalized interventions. Model performance metrics could be optimized, and models can be implemented in the same healthcare system as intelligent decision support for targeted intervention.
Lung Ultrasound Patterns and Clinical-Laboratory Correlates during COVID-19 Pneumonia: A Retrospective Study from North East Italy
Authors: Senter Riccardo , Capone Federico , Pasqualin Stefano , Cerruti Lorenzo , Molinari Leonardo , Fonte Basso Elisa , Zanforlin Nicolò , Previato Lorenzo , Toffolon Alessandro , Sensi Caterina , Arcidiacono Gaetano , Gorgi Davide , Ippolito Renato , Nessi Enrico , Pettenella Pietro , Cellini Andrea , Fossa Claudio , Vania Eleonora , Gardin Samuele , Sukthi Andi , Luise Dora , Giordani Maria Teresa , Zanatta Mirko , Savino Sandro , Cianci Vito , Sattin Andrea , Maria Anna , Vianello Andrea , Pesavento Raffaele , Giannini Sandro , Avogaro Angelo , Vettor Roberto , Fadini Gian Paolo , Saller Alois
Published: March 2021

Background and Aim. Lung ultrasound (LUS) is a convenient imaging modality in the setting of coronavirus disease-19 (COVID-19) because it is easily available, can be performed bedside and repeated over time. We herein examined LUS patterns in relation to disease severity and disease stage among patients with COVID-19 pneumonia. Methods. We performed a retrospective case series analysis of patients with confirmed SARS-CoV-2 infection who were admitted to the hospital because of pneumonia. We recorded history, clinical parameters and medications. LUS was performed and scored in a standardized fashion by experienced operators, with evaluation of up to 12 lung fields, reporting especially on B-lines and consolidations. Results. We included 96 patients, 58.3% men, with a mean age of 65.9 years. Patients with a high-risk quick COVID-19 severity index (qCSI) were older and had worse outcomes, especially for the need for high-flow oxygen. B-lines and consolidations were located mainly in the lower posterior lung fields. LUS patterns for B-lines and consolidations were significantly worse in all lung fields among patients with high versus low qCSI. B-lines and consolidations were worse in the intermediate disease stage, from day 7 to 13 after onset of symptoms. While consolidations correlated more with inflammatory biomarkers, B-lines correlated more with end-organ damage, including extrapulmonary involvement. Conclusions. LUS patterns provide a comprehensive evaluation of patients with COVID-19 pneumonia that correlated with severity and dynamically reflect disease stage. LUS patterns may reflect different pathophysiological processes related to inflammation or tissue damage; consolidations may represent a more specific sign of localized disease, whereas B-lines seem to be also dependent upon generalized illness due to SARS-CoV-2 infection.
Categorization of Marketed Artificial Tear Formulations Based on Their Ingredients: A Rational Approach for Their Use
Authors: Kathuria Avani , Shamloo Kiumars , Jhanji Vishal , Sharma Ajay
Published: March 2021

Dry eye disease is a common ocular condition affecting millions of people worldwide. Artificial tears are the first line therapy for the management of dry eye disease. Artificial tear formulations contain a variety of active ingredients, biologically active excipients, and preservatives. Many of these formulations are also available as preservative-free. This study was conducted to inspect artificial tear formulations currently marketed in the United States for their active ingredients, biologically relevant excipients, and preservatives. The marketed artificial tears were examined at various US retail pharmacy chains and using the manufacturers’ website to compile information about active ingredients, inactive ingredients, and preservatives. The currently marketed artificial tears can be grouped into four categories based on their active ingredients. The artificial tears also contain biologically active chemicals listed as inactive ingredients, which have osmoprotectant, humectant, and tear film lipid layer or mucous layer mimicking properties. Most artificial tears contain vanishing type preservatives such as purite or sodium perborate and safer quaternary compound polyquaternium-1. The majority of these artificial tear formulations are also available as preservative-free single dose unit. The study provides a formulary of artificial tears based on active ingredients, biologically active excipients, and the preservative-free option. The formulary should assist healthcare providers in making a stepwise and rational selection of appropriate artificial tears for patients suffering from dry eye disease.
Periodontal Disease Is Associated with Increased Vulnerability of Coronary Atheromatous Plaques in Patients Undergoing Coronary Computed Tomography Angiography—Results from the Atherodent Study
Authors: Rodean Ioana-Patricia , Lazăr Luminița , Halațiu Vasile-Bogdan , Biriș Carmen , Benedek Imre , Benedek Theodora
Published: March 2021

The present study aimed to investigate the link between the severity of periodontal disease (PD), coronary calcifications and unstable plaque features in patients who underwent coronary computed tomography for unstable angina (UA). Fifty-two patients with UA, included in the ATHERODENT trial (NCT03395041), underwent computed tomographic coronary angiography (CCTA) and dental examination. Based on the median value of the periodontal index (PI), patients were assigned to the low periodontal index (LPI) group (PI < 22) and a high periodontal index (HPI) group (PI > 22). Patients with HPI had higher plaque volume (p = 0.013) and noncalcified plaque volume (p = 0.0003) at CCTA. In addition, the presence of vulnerability features in the atheromatous plaques was significantly correlated with PI (p = 0.001). Among periodontal indices, loss of gingival attachment (p = 0.009) and papillary bleeding index (p = 0.002) were strongly associated with high-risk plaques. PI significantly correlated with coronary calcium score (r = 0.45, p = 0.0008), but not with traditional markers of subclinical atherosclerosis. Overall, this subgroup analysis of the ATHERODENT study indicates that patients with advanced PD and UA present a higher amount of calcium in the coronary tree and have a more vulnerable phenotype of their culprit plaques.
Longitudinal Femoral Cartilage T2 Relaxation Time and Thickness Changes with Fast Sequential Radiographic Progression of Medial Knee Osteoarthritis—Data from the Osteoarthritis Initiative (OAI)
Authors: Edd Shannon N. , Omoumi Patrick , Jolles Brigitte M. , Favre Julien
Published: March 2021

This study tested for longitudinal changes in femoral cartilage T2 relaxation time and thickness in fast-progressing medial femorotibial osteoarthritis (OA). From the Osteoarthritis Initiative (OAI) database, nineteen knees fulfilled the inclusion criteria, which included medial femorotibial OA and sequential progression from Kellgren–Lawrence grade (KL) 1 to KL2 to KL3 within five years. Median T2 value and mean thickness were calculated for six condylar volumes of interest (VOIs; medial/lateral anterior, central, posterior) and six sub-VOIs (medial/lateral anterior external, central, internal). T2 value and thickness changes between severity timepoints were tested using repeated statistics. T2 values increased between KL1 and KL2 and between KL1 and KL3 in the medial compartment (p ≤ 0.02), whereas both increases and decreases were observed between the same timepoints in the lateral compartment (p ≤ 0.02). Cartilage thickness decreased in VOI/subVOIs of the medial compartment from KL1 to KL2 and KL3 (p ≤ 0.014). Cartilage T2 value and thickness changes varied spatially over the femoral condyles. While all T2 changes occurred in the early radiographic stages of OA, thickness changes occurred primarily in the later stages. These data therefore support the use of T2 relaxation time analyses in methods of detecting disease-related change during early OA, a valuable period for therapeutic interventions.
Gut Microbiota Interaction with the Central Nervous System throughout Life
Authors: Ojeda Jorge , Ávila Ariel , Vidal Pía M.
Published: March 2021

During the last years, accumulating evidence has suggested that the gut microbiota plays a key role in the pathogenesis of neurodevelopmental and neurodegenerative diseases via the gut–brain axis. Moreover, current research has helped to elucidate different communication pathways between the gut microbiota and neural tissues (e.g., the vagus nerve, tryptophan production, extrinsic enteric-associated neurons, and short chain fatty acids). On the other hand, altering the composition of gut microbiota promotes a state known as dysbiosis, where the balance between helpful and pathogenic bacteria is disrupted, usually stimulating the last ones. Herein, we summarize selected findings of the recent literature concerning the gut microbiome on the onset and progression of neurodevelopmental and degenerative disorders, and the strategies to modulate its composition in the search for therapeutical approaches, focusing mainly on animal models studies. Readers are advised that this is a young field, based on early studies, that is rapidly growing and being updated as the field advances.
Changes in EEG Recordings in COVID-19 Patients as a Basis for More Accurate QEEG Diagnostics and EEG Neurofeedback Therapy: A Systematic Review
Authors: Kopańska Marta , Banaś-Ząbczyk Agnieszka , Łagowska Anna , Kuduk Barbara , Szczygielski Jacek
Published: March 2021

Introduction and purpose: The SARS-CoV-2 virus is able to cause abnormalities in the functioning of the nervous system and induce neurological symptoms with the features of encephalopathy, disturbances of consciousness and concentration and a reduced ability to sense taste and smell as well as headaches. One of the methods of detecting these types of changes in COVID-19 patients is an electroencephalogram (EEG) test, which allows information to be obtained about the functioning of the brain as well as diagnosing diseases and predicting their consequences. The aim of the study was to review the latest research on changes in EEG in patients with COVID-19 as a basis for further quantitative electroencephalogram (QEEG) diagnostics and EEG neurofeedback training. Description of the state of knowledge: Based on the available scientific literature using the PubMed database from 2020 and early 2021 regarding changes in the EEG records in patients with COVID-19, 17 publications were included in the analysis. In patients who underwent an EEG test, changes in the frontal area were observed. A few patients were not found to be responsive to external stimuli. Additionally, a previously non-emerging, uncommon pattern in the form of continuous, slightly asymmetric, monomorphic, biphasic and slow delta waves occurred. Conclusion: The results of this analysis clearly indicate that the SARS-CoV-2 virus causes changes in the nervous system that can be manifested and detected in the EEG record. The small number of available articles, the small number of research groups and the lack of control groups suggest the need for further research regarding the short and long term neurological effects of the SARS-CoV-2 virus and the need for unquestionable confirmation that observed changes were caused by the virus per se and did not occur before. The presented studies described non-specific patterns appearing in encephalograms in patients with COVID-19. These observations are the basis for more accurate QEEG diagnostics and EEG neurofeedback training.
Dynamic FDG PET Imaging to Probe for Cardiac Metabolic Remodeling in Adults Born Premature
Authors: Corrado Philip A. , Barton Gregory P. , Razalan-Krause Francheska C. , François Christopher J. , Chesler Naomi C. , Wieben Oliver , Eldridge Marlowe , McMillan Alan B. , Goss Kara N.
Published: March 2021

Individuals born very premature have an increased cardiometabolic and heart failure risk. While the structural differences of the preterm heart are now well-described, metabolic insights into the physiologic mechanisms underpinning this risk are needed. Here, we used dynamic fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET-MRI) in young adults born term and preterm during normoxic (N = 28 preterm; 18 term) and hypoxic exposure (12% O2; N = 26 preterm; 17 term) to measure the myocardial metabolic rate of glucose (MMRglc) in young adults born term (N = 18) and preterm (N = 32), hypothesizing that young adults born preterm would have higher rates of MMRglc under normoxic conditions and a reduced ability to augment glucose metabolism under hypoxic conditions. MMRglc was calculated from the myocardial and blood pool time-activity curves by fitting the measured activities to the 3-compartment model of FDG kinetics. MMRglc was similar at rest between term and preterm subjects, and decreased during hypoxia exposure in both groups (p = 0.02 for MMRglc hypoxia effect). There were no differences observed between groups in the metabolic response to hypoxia, either globally (serum glucose and lactate measures) or within the myocardium. Thus, we did not find evidence of altered myocardial metabolism in the otherwise healthy preterm-born adult. However, whether subtle changes in myocardial metabolism may preceed or predict heart failure in this population remains to be determined.
Effect of Sleep Bruxism Intensity on Blood Pressure in Normotensives
Authors: Michalek-Zrabkowska Monika , Wieckiewicz Mieszko , Gac Pawel , Smardz Joanna , Poreba Rafal , Wojakowska Anna , Goslawska Katarzyna , Mazur Grzegorz , Martynowicz Helena
Published: March 2021

The present research aimed to investigate the influence of sleep bruxism (SB) intensity on blood pressure parameters in normotensive subjects by using an ambulatory blood pressure device. The study group included 65 normotensive individuals suspected of having SB. All participants underwent one-night video-polysomnography, and ambulatory blood pressure monitoring was performed the next day; 86.15% of them were diagnosed with SB. Statistical analysis included correlation and regression analysis. The obtained results showed that systolic blood pressure variability during sleep significantly increased in individuals with BEI > 4 (bruxism episodes index; episodes/hour) compared to those with BEI ≤ 4 (8.81 ± 3.36 versus 10.57 ± 3.39, p = 0.05). Multivariable regression analysis showed that systolic blood pressure variability at nighttime was also associated with the following independent risk factors: higher apnea-to-bruxism index, male gender, BEI > 4 episodes/hour, body mass index (BMI) ≥ 25 kg/m2, higher arousal index, and shorter total sleep time. In summary, sleep bruxism intensity was associated with increased systolic blood pressure variability during sleep. Coincidental apnea, male gender, severe sleep bruxism (SB intensity with BEI > 4/hour), excess weight and obesity, higher arousal index, and shorter sleep time seem to be the main determinants that influence blood pressure in normotensive sleep bruxers.
Clinical Phase I/II Study: Local Disease Control and Survival in Locally Advanced Pancreatic Cancer Treated with Electrochemotherapy
Authors: Izzo Francesco , Granata Vincenza , Fusco Roberta , D'Alessio Valeria , Petrillo Antonella , Lastoria Secondo , Piccirillo Mauro , Albino Vittorio , Belli Andrea , Tafuto Salvatore , Avallone Antonio , Patrone Renato , Palaia Raffaele
Published: March 2021

Objective. To assess local disease control rates (LDCR) and overall survival (OS) in locally advanced pancreatic cancer (LAPC) treated with electrochemotherapy (ECT). Methods. Electrochemotherapy with bleomycin was performed in 25 LAPC patients who underwent baseline Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and Position Emission Tomography (PET) scans before ECT and 1 and 6 months post ECT. LDCR were assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Choi criteria. Needle electrodes with fixed linear (N-30-4B) or fixed hexagonal configurations (N-30-HG or I-40-HG or H-30-ST) or variable geometry (VGD1230 or VGD1240) (IGEA S.p.A., Carpi, Italy) were used to apply electric pulses. Pain evaluation was performed pre-ECT, after 1 month and after 6 months with ECT. Overall survival estimates were calculated by means of a Kaplan-Meier analysis. Results. At 1 month after ECT, 76% of patients were in partial response (PR) and 20% in stable disease (SD). Six months after ECT, 44.0% patients were still in PR and 12.0% in SD. A LDCR of 56.0% was reached six months after ECT: 13 patients treated with fixed geometry had a LDCR of 46.1%, while for the 12 patients treated with variable geometry, the LDCR was 66.7%. The overall survival median value was 11.5 months: for patients treated with fixed geometry the OS was 6 months, while for patients treated with variable geometry it was 12 months. Electrochemotherapy was well-tolerated and abdominal pain was rapidly resolved. Conclusions. Electrochemotherapy obtained good results in terms of LDCR and OS in LAPC. Multiple needle insertion in a variable geometry configuration optimized by pre-treatment planning determined an increase in LDCR and OS compared to a fixed geometry configuration.
Inhaled Anesthetics: Environmental Role, Occupational Risk, and Clinical Use
Authors: Gaya da Costa Mariana , Kalmar Alain F. , Struys Michel M. R. F.
Published: March 2021

Inhaled anesthetics have been in clinical use for over 150 years and are still commonly used in daily practice. The initial view of inhaled anesthetics as indispensable for general anesthesia has evolved during the years and, currently, its general use has even been questioned. Beyond the traditional risks inherent to any drug in use, inhaled anesthetics are exceptionally strong greenhouse gases (GHG) and may pose considerable occupational risks. This emphasizes the importance of evaluating and considering its use in clinical practices. Despite the overwhelming scientific evidence of worsening climate changes, control measures are very slowly implemented. Therefore, it is the responsibility of all society sectors, including the health sector to maximally decrease GHG emissions where possible. Within the field of anesthesia, the potential to reduce GHG emissions can be briefly summarized as follows: Stop or avoid the use of nitrous oxide (N2O) and desflurane, consider the use of total intravenous or local-regional anesthesia, invest in the development of new technologies to minimize volatile anesthetics consumption, scavenging systems, and destruction of waste gas. The improved and sustained awareness of the medical community regarding the climate impact of inhaled anesthetics is mandatory to bring change in the current practice.
Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia in Children Treated Using Early Corticosteroids
Authors: Han Hye Young , Park Ki Cheol , Yang Eun-Ae , Lee Kyung-Yil
Published: March 2021

We have found that early corticosteroid therapy was effective for reducing morbidity during five Korea-wide epidemics. We evaluated the clinical and laboratory parameters of 56 children who received early corticosteroid treatment for pneumonia that was caused by macrolide-resistant Mycoplasma pneumoniae (M. pneumoniae) or macrolide-sensitive M. pneumoniae between July 2019 and February 2020. All subjects had dual positive results from a PCR assay and serological test, and received corticosteroids within 24–36 h after admission. Point mutation of residues 2063, 2064, and 2067 was identified in domain V of 23S rRNA. The mean age was 6.8 years and the male:female ratio was 1.2:1 (31:25 patients). Most of the subjects had macrolide-resistant M. pneumoniae (73%), and all mutated strains had the A2063G transition. No significant differences in clinical and laboratory parameters were observed between macrolide-resistant and macrolide-sensitive M. pneumoniae groups that were treated with early dose-adjusted corticosteroids. Higher-dose steroid treatment may be needed for patients who have fever that persists for >48 h or increased biomarkers such as lactate dehydrogenase concentration at follow-up despite a usual dose of steroid therapy.
Expanding the Junction: New Insights into Non-Occluding Roles for Septate Junction Proteins during Development
Authors: Rice Clinton , De Oindrila , Alhadyian Haifa , Hall Sonia , Ward Robert E.
Published: March 2021

The septate junction (SJ) provides an occluding function for epithelial tissues in invertebrate organisms. This ability to seal the paracellular route between cells allows internal tissues to create unique compartments for organ function and endows the epidermis with a barrier function to restrict the passage of pathogens. Over the past twenty-five years, numerous investigators have identified more than 30 proteins that are required for the formation or maintenance of the SJs in Drosophila melanogaster, and have determined many of the steps involved in the biogenesis of the junction. Along the way, it has become clear that SJ proteins are also required for a number of developmental events that occur throughout the life of the organism. Many of these developmental events occur prior to the formation of the occluding junction, suggesting that SJ proteins possess non-occluding functions. In this review, we will describe the composition of SJs, taking note of which proteins are core components of the junction versus resident or accessory proteins, and the steps involved in the biogenesis of the junction. We will then elaborate on the functions that core SJ proteins likely play outside of their role in forming the occluding junction and describe studies that provide some cell biological perspectives that are beginning to provide mechanistic understanding of how these proteins function in developmental contexts.
Response of Point-Absorbing Wave Energy Conversion System in 50-Years Return Period Extreme Focused Waves
Authors: Katsidoniotaki Eirini , Nilsson Erik , Rutgersson Anna , Engström Jens , Göteman Malin
Published: March 2021

This work evaluates the survivability of a point-absorbing wave energy converter at sea states along and inside the 50-year environmental contour for a selected-site in North Sea, by utilizing CFD simulations. Focused wave groups based on NewWave theory are used to model the extreme waves. The numerical breaking waves have been previously predicted by the analytical breaking criterion, showing that the latter provides an accurate estimate for the breaking state. The forces on key components of the device and the system’s dynamics are studied and compared. Slamming loads are identified in the interaction with extreme waves, particularly with breaking waves, and compared with the analytical formulas for slamming estimation as suggested by industrial standards. Considering the extreme wave characteristics, the accompanied phenomena and the resulting WEC’s response, this work contributes to the identification of the design-waves given the environmental contour of the selected site. The top-left side of the contour is identified as the more critical area as it consists of steep and high waves inducing significant nonlinear phenomena, resulting in high loads.
Validation of the MORET 5 Monte Carlo Transport Code on Reactor Physics Experiments
Authors: Leclaire Nicolas , Duhamel Isabelle
Published: March 2021

The MORET 5 code, which has been developed over more than 50 years at IRSN, has recently evolved, in its continuous energy version, from a criticality oriented code to a code also focused on reactor physics applications. Some developments such as the implementation of kinetics parameters contribute to that evolution. The aim of the paper is to present the validation of the code for the keff multiplication factor used in criticality studies as well as for other parameters commonly used in reactor physics applications. Special attention will be paid on commission tests performed in the CABRI French Reactor (CABRI is a pool-type research reactor operated by CEA and located in the Cadarache site in southern France used to simulate a sudden and instantaneous increase in power, known as a power transient, typical of a reactivity-initiated accident (RIA).) and the IPEN/MB-01 LCT-077 benchmark.
P2Y12 Antiplatelet Choice for Patients with Chronic Kidney Disease and Acute Coronary Syndrome: A Systematic Review and Meta-Analysis
Authors: Park Sohyun , Choi Yeo Jin , Kang Ji Eun , Kim Myeong Gyu , Jung Geum Min , Kim So Dam , Rhie Sandy Jeong
Published: March 2021

This study aims to evaluate potentially appropriate antiplatelet therapy in patients with chronic kidney disease. A systematic analysis was conducted to identify the clinical outcomes of available antiplatelet therapy regimens with enhanced platelet inhibition activity (intervention of 5 regimens) over the standard dose of clopidogrel-based dual antiplatelet therapy in patients with renal insufficiency. An electronic keyword search was performed on Pubmed, Embase, and Cochrane Library per PRISMA guidelines. We performed a prespecified net clinical benefit analysis (a composite of the rates of all-cause or cardiac-related death, myocardial infarction, major adverse cardiac outcomes, and minor and major bleeding), and included 12 studies. The intervention substantially lowered the incidence of all-cause mortality (RR 0.67; p = 0.003), major adverse cardiac outcomes (RR 0.79; p < 0.00001), and myocardial infarction (RR 0.28; p = 0.00007) without major bleeding (RR 1.14; p = 0.33) in patients with renal insufficiency, but no significant differences were noticed with cardiac-related mortality and stent thrombosis. The subgroup analysis revealed substantially elevated bleeding risk in patients with severe renal insufficiency or on hemodialysis (RR 1.68; p = 0.002). Our study confirmed that the intervention considerably enhances clinical outcomes in patients with renal insufficiency, however, a standard dose of clopidogrel-based antiplatelet therapy is favorable in patients with severe renal insufficiency.
Histone Deacetylase Inhibitors in the Treatment of Hepatocellular Carcinoma: Current Evidence and Future Opportunities
Authors: Garmpis Nikolaos , Damaskos Christos , Garmpi Anna , Georgakopoulou Vasiliki E. , Sarantis Panagiotis , Antoniou Efstathios A. , Karamouzis Michalis V. , Nonni Afroditi , Schizas Dimitrios , Diamantis Evangelos , Koustas Evangelos , Farmaki Paraskevi , Syllaios Athanasios , Patsouras Alexandros , Kontzoglou Konstantinos , Trakas Nikolaos , Dimitroulis Dimitrios
Published: March 2021

Hepatocellular carcinoma (HCC) remains a major health problem worldwide with a continuous increasing prevalence. Despite the introduction of targeted therapies like the multi-kinase inhibitor sorafenib, treatment outcomes are not encouraging. The prognosis of advanced HCC is still dismal, underlying the need for novel effective treatments. Apart from the various risk factors that predispose to the development of HCC, epigenetic factors also play a functional role in tumor genesis. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone lysine residues of proteins, such as the core nucleosome histones, in this way not permitting DNA to loosen from the histone octamer and consequently preventing its transcription. Considering that HDAC activity is reported to be up-regulated in HCC, treatment strategies with HDAC inhibitors (HDACIs) showed some promising results. This review focuses on the use of HDACIs as novel anticancer agents and explains the mechanisms of their therapeutic effects in HCC.
The Link between Attachment and Gambling in Adolescence: A Multiple Mediation Analysis with Developmental Perspective, Theory of Mind (Friend) and Adaptive Response
Authors: Terrone Grazia , Gori Alessio , Topino Eleonora , Musetti Alessandro , Scarinci Alessia , Guccione Camilla , Caretti Vincenzo
Published: March 2021

Introduction: Several studies have supported the evidence that attachment styles are a central factor in adolescent gambling problems. On this theoretical basis, the aim of the present study is to analyze a hypothesized mediation model exploring both the direct and indirect effects of insecure attachment on gambling disorder by investigating the role of the developmental perspective, theory of mind (friend) and adaptive response in that relationship. Method: The sample consists of 178 adolescents who underwent the Measures: South Oaks Gambling Screen—Revised for Adolescents and Friends and Family Interview. Result: The mediation analysis was conducted following Hayes’ (2018) procedure, using Model 6. The results showed a significant association between insecure attachment and gambling disorder (β = 0.669; p < 0.001). The findings also highlighted a significant chained mediation model in which insecure attachment negatively influenced the developmental perspective (β = −0.742; p < 0.001), which affected the theory of mind toward one’s own best friend (β = 0.352; p < 0.001). Conclusions: The results highlighted a significant role of insecure attachment in predicting the symptomatic expression of gambling among adolescents, specifically impacting the development perspective, theory of mind toward one’s best friend and adaptive response to stress, which were linked to each other by a sequential influence. Therefore, our results showed that a poor developmental self-vision predicted a dysfunctional theory of mind toward the best friend. This could hinder the formation of positive peer relationships, which are crucial for the development of one’s identity.