bluuebunny/crossref_metadata_2025 huggingface dataset:
Myofascial Trigger Points and Central Sensitization Signs, but No Anxiety, Are Shown in Women with Dysmenorrhea: A Case-Control Study
Authors: Hoyos-Calderon Yennyt-Tatiana , Martínez-Merinero Patricia , Nunez-Nagy Susana , Pecos-Martín Daniel , Calvo-Lobo César , Romero-Morales Carlos , Abuín-Porras Vanesa , Serrano-Imedio Ana
Published: October 2022

Background primary dysmenorrhea (PD) is considered to be a cyclic chronic pelvic pain, with its onset in menstrual periods, often accompanied by the presence of myofascial trigger points (MTP). Most MTPs in subjects with chronic pelvic pain are in the inferior part of the abdomen, in the rectus abdominis (RA) area. Central sensitization is closely related to chronic pain processes. Previous studies in women with chronic pelvic pain reported central sensitization signs in their subjects, such as lower pain pressure threshold (PPT). Several authors agree that PPT in the tibialis anterior (TA) muscle, seems to be a reliable reference for signs of central sensitization. Amongst the factors that seem to accompany central sensitization, the presence of anxiety needs to be considered. The aim of the present study was to analyze the existence of hyperalgesic MTPs in RA, central sensitization signs and anxiety in women with PD, in comparison with a control group (CG). Methods: This study was designed following an observational, cross-sectional, case-control model. A total sample of 80 subjects was recruited trough social webs and advertising (PD n = 39) (CG n = 41). PPT in RA and AT was assessed bilaterally through algometry, and anxiety was evaluated through the State–Trait Anxiety Inventory. Results: Statistically significant differences (p < 0.001) were shown for NRS average and maximum increase, as well as lower bilaterally RA and TA PPT in favor of PD group compared to CG. State or trait STAI did not show any statistically significant differences (p > 0.05) between groups. Conclusions: In this study, women with PD reported symptoms of myofascial pain syndrome and central sensitization, when compared with healthy controls, without any sign of anxiety acting as a confounder for pain sensitivity.
Temporary Survival Increasing the Diversity of Culturable Heterotrophic Bacteria in the Newly Exposed Moraine at a Glacier Snout
Authors: Liu Yang , Xu Yeteng , Cui Xiaowen , Zhang Binglin , Wang Xinyue , Qin Xiang , Wang Jinxiu , Li Yanzhao , Zhang Wei , Liu Guangxiu , Chen Tuo , Zhang Gaosen
Published: October 2022

Laohugou Glacier No. 12 is located on the northern slope of the western Qilian Mountains with a temperate continental wet climate and an extremely cold winter. Bacteria in a newly exposed moraine have to cope with various pressures owing to deglaciation at the glacier snout. However, limited information is available regarding the high diversity and temporary survival of culturable heterotrophic bacteria under various environmental stresses. To examine the tolerance of extremophiles against varying environmental conditions in a newly exposed moraine, we simulated environmental stress in bacterial cultures. The results showed that the isolated strains belonged to actinobacteria, Proteobacteria, Bacteroidetes, Deinococcus-Thermus, and Firmicutes. Actinobacteria was the most abundant phylum, followed by Proteobacteria, at both high and low temperatures. Pseudarthrobacter was the most abundant genus, accounting for 14.2% of the total isolates. Although several microorganisms grew at 10 °C, the proportion of microorganisms that grew at 25 °C was substantially higher. In particular, 50% of all bacterial isolates grew only at a high temperature (HT), whereas 21.4% of the isolates grew at a low temperature (LT), and 38.6% of the isolates grew at both HT and LT. In addition, many radiation-resistant extremophiles were identified, which adapted to both cold and oxidative conditions. The nearest neighbors of approximately >90% of bacteria belonged to a nonglacial environment, such as oil-contaminated soil, rocks, and black sand, instead of glacial niches. This study provides insights into the ecological traits, stress responses, and temporary survival of culturable heterotrophic bacteria in a newly exposed moraine with variable environmental conditions and the relationship of these communities with the non-glacial environment. This study may help to understand the evolution, competition, and selective growth of bacteria in the transition regions between glaciers and retreats in the context of glacier melting and retreat owing to global warming.
Diet-Related Changes of Short-Chain Fatty Acids in Blood and Feces in Obesity and Metabolic Syndrome
Authors: Ilyés Tamás , Silaghi Ciprian N. , Crăciun Alexandra M.
Published: October 2022

Obesity-related illnesses are one of the leading causes of death worldwide. Metabolic syndrome has been associated with numerous health issues. Short-chain fatty acids (SCFAs) have been shown to have multiple effects throughout the body, both directly as well as through specific G protein-coupled receptors. The main SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are absorbed in varying degrees from the large intestine, with some acting mainly locally and others systemically. Diet has the potential to influence the gut microbial composition, as well as the type and amount of SCFAs produced. High fiber-containing foods and supplements increase the production of SCFAs and SCFA-producing bacteria in the gut and have been shown to have bodyweight-lowering effects. Dietary supplements, which increase SCFA production, could open the way for novel approaches to weight loss interventions. The aim of this review is to analyze the variations of fecal and blood SCFAs in obesity and metabolic syndrome through a systematic search and analysis of existing literature.
Maturation Selection Biases and Relative Age Effect in Italian Soccer Players of Different Levels
Authors: Toselli Stefania , Mauro Mario , Grigoletto Alessia , Cataldi Stefania , Benedetti Luca , Nanni Gianni , Di Miceli Riccardo , Aiello Paolo , Gallamini Davide , Fischetti Francesco , Greco Gianpiero
Published: October 2022

Soccer is a sport practiced all over the world, in which players are expected to show specific physical and technical skills. Soccer academies look for young talented individuals to develop promising players. Although several parameters could affect the players’ performance, the relative age effect (RAE) and the maturity status appeared debated. Therefore, this study compared the differences in RAE and biological maturity among the players of two Italian soccer teams of different levels and to understand their interaction effects with the competition level on youth players’ physical characteristics and abilities. One hundred and sixty-two young soccer players from the U12 to U15 age categories of the elite (n = 98) and non-elite (n = 64) teams were recruited. The prevalence of maturity status and RAE was observed. Many anthropometric parameters, BIA vectors, and motor tests (CMJ, Sprint, RSA) were carried out. The maturity status had a greater effect on several anthropometric characteristics and on 15 m sprint, while it affected the CMJ only in U12 (F = 6.187, p ≤ 0.01). Differently, the RAE seemed to priorly affect the U13 and U15 categories in body composition, whereas its effect appeared on the 15-m sprint (F(3, 45) = 4.147, p ≤ 0.01) and the RSA (F(3, 45) = 3.179, p ≤ 0.05) in the U14 category. In addition, early matured players or those who were born in the first six months presented cellular characteristics similar to adult elite players. Soccer professionals should be encouraged to monitor the maturity status to better interpret changes in the physical performance of young soccer players to guide adequate training plans.
EP-Pred: A Machine Learning Tool for Bioprospecting Promiscuous Ester Hydrolases
Authors: Xiang Ruite , Fernandez-Lopez Laura , Robles-Martín Ana , Ferrer Manuel , Guallar Victor
Published: October 2022

When bioprospecting for novel industrial enzymes, substrate promiscuity is a desirable property that increases the reusability of the enzyme. Among industrial enzymes, ester hydrolases have great relevance for which the demand has not ceased to increase. However, the search for new substrate promiscuous ester hydrolases is not trivial since the mechanism behind this property is greatly influenced by the active site’s structural and physicochemical characteristics. These characteristics must be computed from the 3D structure, which is rarely available and expensive to measure, hence the need for a method that can predict promiscuity from sequence alone. Here we report such a method called EP-pred, an ensemble binary classifier, that combines three machine learning algorithms: SVM, KNN, and a Linear model. EP-pred has been evaluated against the Lipase Engineering Database together with a hidden Markov approach leading to a final set of ten sequences predicted to encode promiscuous esterases. Experimental results confirmed the validity of our method since all ten proteins were found to exhibit a broad substrate ambiguity.
Mitochondrial Dysfunction in a High Intraocular Pressure-Induced Retinal Ischemia Minipig Model
Authors: Pasák Michael , Vanišová Marie , Tichotová Lucie , Křížová Jana , Ardan Taras , Nemesh Yaroslav , Čížková Jana , Kolesnikova Anastasiia , Nyshchuk Ruslan , Josifovska Natasha , Lytvynchuk Lyubomyr , Kolko Miriam , Motlík Jan , Petrovski Goran , Hansíková Hana
Published: October 2022

Purpose: Retinal ischemia (RI) and progressive neuronal death are sight-threatening conditions. Mitochondrial (mt) dysfunction and fusion/fission processes have been suggested to play a role in the pathophysiology of RI. This study focuses on changes in the mt parameters of the neuroretina, retinal pigment epithelium (RPE) and choroid in a porcine high intraocular pressure (IOP)-induced RI minipig model. Methods: In one eye, an acute IOP elevation was induced in minipigs and compared to the other control eye. Activity and amount of respiratory chain complexes (RCC) were analyzed by spectrophotometry and Western blot, respectively. The coenzyme Q10 (CoQ10) content was measured using HPLC, and the ultrastructure of the mt was studied via transmission electron microscopy. The expression of selected mt-pathway genes was determined by RT-PCR. Results: At a functional level, increased RCC I activity and decreased total CoQ10 content were found in RPE cells. At a protein level, CORE2, a subunit of RCC III, and DRP1, was significantly decreased in the neuroretina. Drp1 and Opa1, protein-encoding genes responsible for mt quality control, were decreased in most of the samples from the RPE and neuroretina. Conclusions: The eyes of the minipig can be considered a potential RI model to study mt dysfunction in this disease. Strategies targeting mt protection may provide a promising way to delay the acute damage and onset of RI.
New Betulin Derivatives with Nitrogen Heterocyclic Moiety—Synthesis and Anticancer Activity In Vitro
Authors: Bębenek Ewa , Chrobak Elwira , Rzepka Zuzanna , Wrześniok Dorota
Published: October 2022

As part of the search for new medicinal substances with potential application in oncology, the synthesis of new compounds combining the betulin molecule and the indole system was carried out. The structure of the ester derivatives obtained in the Steglich reaction was confirmed by spectroscopic methods (1H and 13C NMR, HR-MS). The obtained new 3-indolyl betulin derivatives were evaluated for anticancer activity against several human cancer cell lines (melanomas, breast cancers, colorectal adenocarcinomas, lung cancer) as well as normal human fibroblasts. The significant reduction in MCF-7 cells viability for 28-hydroxy-(lup-20(29)-ene)-3-yl 2-(1H-indol-3-yl)acetate was observed at a concentration of 10 µg/mL (17 µM). In addition, cytometric analysis showed that this compound strongly reduces the proliferation rate of breast cancer cells. For this, the derivative showing the promising cytotoxic effect on MCF-7 breast cancer cells, the pharmacokinetic profile prediction was performed using in silico methods. Based on the results obtained in the study, it can be concluded that indole-functionalized triterpene EB367 is a promising starting point for further research in the field of breast cancer therapy or the synthesis of new derivatives.
Cholesterol Content of Very-Low-Density Lipoproteins Is Associated with 1-Year Mortality in Acute Heart Failure Patients
Authors: Degoricija Vesna , Klobučar Iva , Potočnjak Ines , Dokoza Terešak Sanda , Vidović Luka , Pregartner Gudrun , Berghold Andrea , Habisch Hansjörg , Madl Tobias , Frank Saša
Published: October 2022

Considering the relationship between the extent of metabolic derangement and the disease severity in heart failure, we hypothesized that the lipid content of very-low-density lipoprotein (VLDL) may have prognostic value for 1 year mortality in acute heart failure (AHF). Baseline serum levels of VLDL cholesterol (VLDL-C), VLDL triglycerides (VLDL-TG), VLDL phospholipids (VLDL-PL), and VLDL apolipoprotein B (VLDL-apoB) were measured using NMR spectroscopy. We calculated the ratios of the respective VLDL lipids and VLDL apoB (VLDL-C/VLDL-apoB, VLDL-TG/VLDL-apoB, and VLDL-PL/VLDL-apoB), as estimators of the cholesterol, triglyceride, and phospholipid content of VLDL particles and tested their association with mortality. Out of 315 AHF patients, 118 (37.5%) patients died within 1 year after hospitalization for AHF. Univariable Cox regression analyses revealed a significant inverse association of VLDL-C/VLDL-apoB (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.29–0.64, p < 0.001), VLDL-TG/VLDL-apoB (HR 0.79, 95% CI 0.71–0.88, p < 0.001), and VLDL-PL/VLDL-apoB (HR 0.37, 95% CI 0.25–0.56, p < 0.001) with 1 year mortality. Of the tested parameters, only VLDL-C/VLDL-apoB remained significant after adjustment for age and sex, as well as other clinical and laboratory parameters that showed a significant association with 1 year mortality in the univariable analyses. We conclude that cholesterol content of circulating VLDL (VLDL-C/VLDL-apoB) might be of prognostic value in AHF.
MARGINAL: An Automatic Classification of Variants in BRCA1 and BRCA2 Genes Using a Machine Learning Model
Authors: Karalidou Vasiliki , Kalfakakou Despoina , Papathanasiou Athanasios , Fostira Florentia , Matsopoulos George K.
Published: October 2022

Implementation of next-generation sequencing (NGS) for the genetic analysis of hereditary diseases has resulted in a vast number of genetic variants identified daily, leading to inadequate variant interpretation and, consequently, a lack of useful clinical information for treatment decisions. Herein, we present MARGINAL 1.0.0, a machine learning (ML)-based software for the interpretation of rare BRCA1 and BRCA2 germline variants. MARGINAL software classifies variants into three categories, namely, (likely) pathogenic, of uncertain significance and (likely) benign, implementing the criteria established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP). We first annotated BRCA1 and BRCA2 variants using various sources. Then, we automatically implemented the ACMG-AMP criteria, and we finally constructed the ML model for variant classification. To maximize accuracy, we compared the performance of eight different ML algorithms in a classification scheme based on a serial combination of two classifiers. The model showed high predictive abilities with maximum accuracy of 92% and 98%, recall of 92% and 98% and specificity of 90% and 98% for the first and second classifiers, respectively. Our results indicate that using a gene and disease-specific ML automated software for clinical variant evaluation can minimize conflicting interpretations.
Prognostic Impact of LAG-3 mRNA Expression in Early Breast Cancer
Authors: Heimes Anne-Sophie , Almstedt Katrin , Krajnak Slavomir , Runkel Anne , Droste Annika , Schwab Roxana , Stewen Kathrin , Lebrecht Antje , Battista Marco J. , Brenner Walburgis , Hasenburg Annette , Gehrmann Mathias , Hengstler Jan G. , Schmidt Marcus
Published: October 2022

Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject of current research. In the present retrospective gene-expression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICP and CD8 expressions. Methods: Using microarray-based gene-expression analysis, we examined the prognostic significance of LAG-3 mRNA expression for metastasis-free survival (MFS) in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed using Spearman’s rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, log-rank). In the subgroup analyses, there was a trend that a higher LAG-3 expression was associated with a favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in a multivariate Cox regression analysis, adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369–0.894; p = 0.014). High LAG-3 significantly correlated with CD8 (ρ = 0.571; p < 0.001). Conclusions: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer.
Inflammation Related to Obesity in the Etiopathogenesis of Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Budek Marlena , Nuszkiewicz Jarosław , Piórkowska Anna , Czuczejko Jolanta , Szewczyk-Golec Karolina
Published: October 2022

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare neoplasms, which, due to their heterogeneous nature, non-specific symptoms, and lack of specific tumor markers pose many diagnostic and clinical challenges. In recent years, the effectiveness of GEP-NEN diagnosis has increased, which is probably associated with the greater availability of diagnostic tests and the cooperation of many experienced specialists in various scientific disciplines. In addition to the possible genetic etiology, the cause of GEP-NET development is not fully understood. Inflammation and obesity are known risks that contribute to the development of many diseases. Chronic inflammation accompanying obesity affects the hormonal balance and cell proliferation and causes the impairment of the immune system function, leading to neoplastic transformation. This review explores the role of inflammation and obesity in GEP-NETs. The exact mechanisms inducing tumor growth are unknown; however, the profile of inflammatory factors released in the GEP-NET tumor microenvironment is responsible for the progression or inhibition of tumor growth. Both the excess of adipose tissue and the impaired function of the immune system affect not only the initiation of cancer but also reduce the comfort and lifetime of patients.
Temporal Evolution of Multiday, Epileptic Functional Networks Prior to Seizure Occurrence
Authors: Laiou Petroula , Biondi Andrea , Bruno Elisa , Viana Pedro , Winston Joel , Rashid Zulqarnain , Ranjan Yatharth , Conde Pauline , Stewart Callum , Sun Shaoxiong , Zhang Yuezhou , Folarin Amos , Dobson Richard , Schulze-Bonhage Andreas , Dümpelmann Matthias , Richardson Mark ,   RADAR-CNS Consortium
Published: October 2022

Epilepsy is one of the most common neurological disorders, characterized by the occurrence of repeated seizures. Given that epilepsy is considered a network disorder, tools derived from network neuroscience may confer the valuable ability to quantify the properties of epileptic brain networks. In this study, we use well-established brain network metrics (i.e., mean strength, variance of strength, eigenvector centrality, betweenness centrality) to characterize the temporal evolution of epileptic functional networks over several days prior to seizure occurrence. We infer the networks using long-term electroencephalographic recordings from 12 people with epilepsy. We found that brain network metrics are variable across days and show a circadian periodicity. In addition, we found that in 9 out of 12 patients the distribution of the variance of strength in the day (or even two last days) prior to seizure occurrence is significantly different compared to the corresponding distributions on all previous days. Our results suggest that brain network metrics computed fromelectroencephalographic recordings could potentially be used to characterize brain network changes that occur prior to seizures, and ultimately contribute to seizure warning systems.
Multiple Sclerosis: Enzymatic Cross Site-Specific Recognition and Hydrolysis of H3 Histone by IgGs against H3, H1, H2A, H2B, H4 Histones, Myelin Basic Protein, and DNA
Authors: Nevinsky Georgy A. , Buneva Valentina N. , Dmitrenok Pavel S.
Published: October 2022

Histones have a specific key role in the remodeling of chromatin and gene transcription. In the blood, free histones are damage-connected proteins. Myelin basic protein (MBP) is the major component of the myelin-proteolipid sheath of axons. Antibodies possessing enzymatic activities (abzymes, ABZs) are the specific features of several autoimmune pathologies. IgGs against five histones, MBP, and DNA were obtained from the sera of multiple sclerosis (MS) patients using several affinity chromatographies. The sites of H3 histone splitting by Abs against five individual histones, MBP, and DNA were revealed by MALDI mass spectrometry. It was shown that the number of H3 splitting sites by IgGs against five various histones is different (number of sites): H3 (11), H1 (14), H2A (11), H4 (17), MBP (22), and DNA (29). IgGs against five different histones hydrolyze H3 at different sites, and only a few them coincide. The main reason for the enzymatic cross-reactivity of Abs against H3 and four other histones, as well as MBP, might be the high level of these proteins’ homology. The effective hydrolysis of the H3 histone at 29 sites with IgGs against DNA can be explained by the formation of chimeric abzymes against hybrid antigenic determinants formed by different histones and MBP at the junction of these protein sequences with DNA. The active centers of such abzymes contain structural elements of canonical DNases and proteases. Since free histones are pernicious proteins, antibodies–ABZs against five histones, MBP, and DNA could have a negative role in the pathogenesis of MS and probably other various autoimmune diseases.
Genetic Markers for Thrombophilia and Cardiovascular Disease Associated with Multiple Sclerosis
Authors: Hadjiagapiou Maria S. , Krashias George , Deeba Elie , Kallis George , Papaloizou Andri , Costeas Paul , Christodoulou Christina , Pantzaris Marios , Lambrianides Anastasia
Published: October 2022

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with an unknown etiology, although genetic, epigenetic, and environmental factors are thought to play a role. Recently, coagulation components have been shown to provide immunomodulatory and pro-inflammatory effects in the CNS, leading to neuroinflammation and neurodegeneration. The current study aimed to determine whether patients with MS exhibited an overrepresentation of polymorphisms implicated in the coagulation and whether such polymorphisms are associated with advanced disability and disease progression. The cardiovascular disease (CVD) strip assay was applied to 48 MS patients and 25 controls to analyze 11 genetic polymorphisms associated with thrombosis and CVD. According to our results, FXIIIVal34Leu heterozygosity was less frequent (OR: 0.35 (95% CI: 0.12–0.99); p = 0.04), whereas PAI-1 5G/5G homozygosity was more frequent in MS (OR: 6.33 (95% CI: 1.32–30.24); p = 0.016). In addition, carriers of the HPA-1a/1b were likely to have advanced disability (OR: 1.47 (95% CI: 1.03–2.18); p = 0.03) and disease worsening (OR: 1.42 (95% CI: 1.05–2.01); p = 0.02). The results of a sex-based analysis revealed that male HPA-1a/1b carriers were associated with advanced disability (OR: 3.04 (95% CI: 1.22–19.54); p = 0.01), whereas female carriers had an increased likelihood of disease worsening (OR: 1.56 (95% CI: 1.04–2.61); p = 0.03). Our findings suggest that MS may be linked to thrombophilia-related polymorphisms, which warrants further investigation.
Nrf2 Modulation in Breast Cancer
Authors: Ghareghomi Somayyeh , Habibi-Rezaei Mehran , Arese Marzia , Saso Luciano , Moosavi-Movahedi Ali Akbar
Published: October 2022

Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.
Clinical Characteristics and In-Hospital Mortality in Patients with STEMI during the COVID-19 Outbreak in Thailand
Authors: Lertsanguansinchai Piyoros , Chokesuwattanaskul Ronpichai , Limjaroen Thitima , Wanlapakorn Chaisiri , Lertsuwunseri Vorarit , Athisakul Siriporn , Chaipromprasit Jarkarpun , Udayachalerm Wasan , Buddhari Wacin , Srimahachota Suphot
Published: October 2022

Background: Nowadays, current evidence on the effects of the COVID-19 outbreak on ST-elevation myocardial infarction (STEMI) patients is discrepant. The aim of this study was to compare and identify any changes in STEMI patients between the pre-COVID-19 period and during the COVID-19 outbreak. Methods: We conducted a retrospective cohort study to evaluate consecutive STEMI patients admitted from 1 September 2018 to 30 September 2021. We designated 14 March 2020 as the commencement of the COVID-19 outbreak in Thailand. Results: A total of 513 consecutive STEMI patients were included in this study: 330 (64%) admitted during the pre-COVID-19 outbreak period and 183 (36%) admitted during the COVID-19 outbreak. There was a significant 45% decline in the number of STEMI cases admitted during the COVID-19 outbreak period. During the outbreak, STEMI patients had significantly increased intra-aortic balloon pump (IABP) insertion (23% vs. 15%, p-value = 0.004), higher high-sensitivity troponin T level (11,150 vs. 5213, p-value < 0.001), and lower pre- and post-PCI TIMI flow. The time-to-diagnosis (59 vs. 7 min, p-value < 0.001), pain-to-first medical contact (FMC) time (250 vs. 214 min, p-value = 0.020), FMC-to-wire-crossing time (39 vs. 23 min, p-value < 0.001), and pain-to-wire-crossing time (292 vs. 242 min, p-value = 0.005) were increased in STEMI patients during the outbreak compared with pre-outbreak. There was no statistical difference in in-hospital mortality between both periods (p-value = 0.639). Conclusions: During the COVID-19 outbreak, there was a significant decline in the total number of admitted STEMI cases. Unfortunately, the time-to-diagnosis, pain-to-FMC time, FMC-to-wire-crossing time, and pain-to-wire-crossing time were significantly delayed during the COVID-19 outbreak. However, in-hospital mortality showed no significant differences between these two time periods. Highlights: 45% decline in the number of STEMI cases admitted and a significant delay in the treatment timeline during the COVID-19 outbreak. In-hospital mortality showed no significant difference between these two periods. Our study will motivate healthcare professionals to optimize treatments, screenings, and infectious control protocols to reduce the time from the onset of chest pain to wire crossing in STEMI patients during the outbreak.
The Myth of The Annular Lipids
Authors: Gómez-Fernández Juan C. , Goñi Félix M.
Published: October 2022

In the early 1970s, the existence of a “lipid annulus” stably surrounding the individual intrinsic protein molecules was proposed by several authors. They referred to a number of lipid molecules in slow exchange with the bulk lipid in the bilayer, i.e., more or less protein-bound, and more ordered than the bulk lipid. The annular lipids would control enzyme activity. This idea was uncritically accepted by most scientists working with intrinsic membrane proteins at the time, so that the idea operated like a myth in the field. However, in the following decade, hard spectroscopic and biochemical evidence showed that the proposed annular lipids were not immobilized for a sufficiently long time to influence enzyme or transporter activity, nor were they ordered by the protein. Surprisingly, forty years later, the myth survives, and the term ‘annular lipid’ is still in use, in a different, but even more illogical sense.
Impact of COVID-19 Infection, Vaccination, and Serological Response in Immune Thrombocytopenic Purpura Patients: A Single-Center Global Analysis
Authors: Dainese Cristina , Valeri Federica , Bardetta Marco , Sella Carola , Porreca Annamaria , Valpreda Alessandra , Pittaluga Fabrizia , Mengozzi Giulio , Bruno Benedetto , Borchiellini Alessandra
Published: October 2022

Both SARS-CoV-2 infection and vaccination have raised concern in immune-mediated diseases, including immune thrombocytopenic purpura (ITP) considering risk of de novo ITP development and ITP recurrence. Here, we report on data from a single-center retrospective–prospective collection aiming to evaluate platelet (plt) dynamics in patients (pts) with chronic ITP after COVID-19 infection (before and after vaccination) and after the first, second and third vaccine doses. Furthermore, we analyzed the serological response after the first two doses of COVID-19 vaccination. A total of 64 pts currently followed for chronic ITP who experienced COVD-19 infection and/or vaccination with an available plt count before and after such events were included in the analysis. A low incidence of ITP exacerbation following vaccine sessions (6–16%) was observed in comparison with a high frequency of exacerbation and rescue treatment necessity after COVID-19 infection in unvaccinated pts (83%). Moreover, the lower ITP exacerbation rate observed in infected pts previously vaccinated (18%) suggests further protective effects in this population. Finally, a high seroconversion rate was observed, confirming data reported in previously published studies on immune cytopenia and rheumatological diseases, but more evidence is awaited to establish the clinical impact of serological response.
Differential Affinity Chromatography Coupled to Mass Spectrometry: A Suitable Tool to Identify Common Binding Proteins of a Broad-Range Antimicrobial Peptide Derived from Leucinostatin
Authors: Müller Joachim , Boubaker Ghalia , Imhof Dennis , Hänggeli Kai , Haudenschild Noé , Uldry Anne-Christine , Braga-Lagache Sophie , Heller Manfred , Ortega-Mora Luis-Miguel , Hemphill Andrew
Published: October 2022

Leucinostatins are antimicrobial peptides with a broad range of activities against infectious agents as well as mammalian cells. The leucinostatin-derivative peptide ZHAWOC_6027 (peptide 6027) was tested in vitro and in vivo for activity against the intracellular apicomplexan parasite Toxoplasma gondii. While highly efficacious in vitro (EC50 = 2 nM), subcutaneous application of peptide 6027 (3 mg/kg/day for 5 days) in mice experimentally infected with T. gondii oocysts exacerbated the infection, caused mild clinical signs and elevated cerebral parasite load. Peptide 6027 also impaired the proliferation and viability of mouse splenocytes, most notably LPS-stimulated B cells, in vitro. To identify common potential targets in Toxoplasma and murine splenocytes, we performed differential affinity chromatography (DAC) with cell-free extracts from T. gondii tachyzoites and mouse spleens using peptide 6027 or an ineffective analogue (peptide 21,358) coupled to N-hydroxy-succinimide sepharose, followed by mass spectrometry. Proteins specifically binding to peptide 6027 were identified in eluates from the peptide 6027 column but not in peptide 21,358 nor the mock column eluates. In T. gondii eluates, 269 proteins binding specifically to peptide 6027 were identified, while in eluates from mouse spleen extracts 645 proteins specifically binding to this peptide were detected. Both datasets contained proteins involved in mitochondrial energy metabolism and in protein processing and secretion. These results suggest that peptide 6027 interacts with common targets in eukaryotes involved in essential pathways. Since this methodology can be applied to various compounds as well as target cell lines or organs, DAC combined with mass spectrometry and proteomic analysis should be considered a smart and 3R-relevant way to identify drug targets in pathogens and hosts, thereby eliminating compounds with potential side effects before performing tedious and costly safety and efficacy assessments in animals or humans.
Exploring the Association between Gut and Urine Microbiota and Prostatic Disease including Benign Prostatic Hyperplasia and Prostate Cancer Using 16S rRNA Sequencing
Authors: Tsai Kai-Yen , Wu Deng-Chyang , Wu Wen-Jeng , Wang Jiunn-Wei , Juan Yung-Shun , Li Ching-Chia , Liu Chung-Jung , Lee Hsiang-Ying
Published: October 2022

Numerous microorganisms residing in the gastrointestinal and genitourinary tracts affect host health. We investigated stool and voided urine samples collected from patients with benign prostatic hyperplasia (BPH) or prostate cancer (PC) and a control group to explore the potential relationship between human microbiota and prostatic disease, and aimed to identify correlations and pathogenic taxonomic units. We studied microbial composition using 16S rRNA sequencing to identify operational taxonomic units (OTUs). Extracted genome was amplified and filtered sequences were used to classify OTUs based on their specific taxonomy. No statistically significant differences were observed in stool samples among the groups. However, urine samples indicated different microbiota compositions in different patient populations. The top five microbial genera that showed significant differences between the BPH and control groups were Alcaligenes, Pseudomonas, Lactobacillus, Akkermansia, and Cetobacterium. Faecalibacterium, Staphylococcus, Ruminococcaceae_UCG_002, Neisseria, and Agathobacter were the genera with the largest proportion differences when comparing the PC and control groups. We discovered that the urine microbiota composition of the BPH and PC groups was distinct from that of the control group. Due to the impact of microbiota on prostatic disease, it is necessary to identify specific microbes for further research.
Responsive Neurostimulation for Seizure Control: Current Status and Future Directions
Authors: Boddeti Ujwal , McAfee Darrian , Khan Anas , Bachani Muzna , Ksendzovsky Alexander
Published: October 2022

Electrocorticography (ECoG) data are commonly obtained during drug-resistant epilepsy (DRE) workup, in which subdural grids and stereotaxic depth electrodes are placed on the cortex for weeks at a time, with the goal of elucidating seizure origination. ECoG data can also be recorded from neuromodulatory devices, such as responsive neurostimulation (RNS), which involves the placement of electrodes deep in the brain. Of the neuromodulatory devices, RNS is the first to use recorded ECoG data to direct the delivery of electrical stimulation in order to control seizures. In this review, we first introduced the clinical management for epilepsy, and discussed the steps from seizure onset to surgical intervention. We then reviewed studies discussing the emergence and therapeutic mechanism behind RNS, and discussed why RNS may be underperforming despite an improved seizure detection mechanism. We discussed the potential utility of incorporating machine learning techniques to improve seizure detection in RNS, and the necessity to change RNS targets for stimulation, in order to account for the network theory of epilepsy. We concluded by commenting on the current and future status of neuromodulation in managing epilepsy, and the role of predictive algorithms to improve outcomes.
Nitro Capsaicin Suppressed Microglial Activation and TNF-α-Induced Brain Microvascular Endothelial Cell Damage
Authors: Jamornwan Sopana , Chokpanuwat Tanida , Uppakara Kwanchanok , Laorob Thanet , Wichai Uthai , Ketsawatsomkron Pimonrat , Saengsawang Witchuda
Published: October 2022

Chronically activated microglia and brain vascular damage are major causes of neuroinflammation. The aim of this study was to determine the anti-inflammatory effects of nitro capsaicin, a newly modified capsaicin with less irritating characteristics, against microglial activation and brain microvascular endothelial cell damage. Using the SIMA9 microglia cell line, we found that nitro capsaicin reduced nitric oxide (NO) production in LPS-activated microglia better than its parent compound, capsaicin. Nitro capsaicin also decreased the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhanced the levels of anti-inflammatory factors, IL-4 and IL-10, both at the mRNA and protein levels. In the TNF-α-induced vascular damage model, nitro capsaicin decreased expression and secretion of the proinflammatory cytokines IL-1β and IL-6. Phosphorylated NF-κB p65, a key transcription factor that stimulates the signaling of inflammatory pathways, was also reduced in the presence of nitro capsaicin, suggesting that the anti-inflammatory effects of nitro capsaicin were created through reducing NF-κB activation. Together, we concluded that nitro capsaicin has the potential to be further developed as an anti-neuroinflammatory agent.
Disease- and Medication-Specific Differences of the Microbial Spectrum in Perianal Fistulizing Crohn’s Disease—Relevant Aspects for Antibiotic Therapy
Authors: Kelm Matthias , Kusan Simon , Surat Güzin , Anger Friedrich , Reibetanz Joachim , Germer Christoph-Thomas , Schlegel Nicolas , Flemming Sven
Published: October 2022

Perianal fistulizing Crohn’s Disease (CD) with abscess formation represents an aggressive phenotype in Inflammatory Bowel Disease (IBD) with increased morbidity. Treatment is multidisciplinary and includes antibiotics, but knowledge about the microbial spectrum is rare often resulting in inadequate antimicrobial therapy. In this single center retrospective study, all patients who were operated due to perianal abscess formation were retrospectively analyzed and the microbial spectrum evaluated. Patients were divided into a CD and non-CD group with further subgroup analysis. 138 patients were finally included in the analysis with 62 patients suffering from CD. Relevant differences were detected for the microbial spectrum with anaerobic bacteria being significantly more often isolated from non-CD patients. In a subgroup-analysis of CD patients only, medical therapy had a relevant effect on the microbial spectrum since Streptococcus groups and Enterobacterales were significantly more often isolated in patients treated with steroids compared to those being treated by antibodies. In conclusion, the microbial spectrum of patients suffering from CD varies significantly from non-CD patients and immunosuppressive medication has a relevant effect on isolated pathogens. Based on that, adaption of antibiotic treatment might be discussed in the future.
Polymer Thin Film Promotes Tumor Spheroid Formation via JAK2-STAT3 Signaling Primed by Fibronectin-Integrin α5 and Sustained by LMO2-LDB1 Complex
Authors: Seo Sunyoung , Hong Nayoung , Song Junhyuk , Kim Dohyeon , Choi Yoonjung , Lee Daeyoup , Jon Sangyong , Kim Hyunggee
Published: October 2022

Cancer stem-like cells (CSCs) are considered promising targets for anti-cancer therapy owing to their role in tumor progression. Extensive research is, therefore, being carried out on CSCs to identify potential targets for anti-cancer therapy. However, this requires the availability of patient-derived CSCs ex vivo, which remains restricted due to the low availability and diversity of CSCs. To address this limitation, a functional polymer thin-film (PTF) platform was invented to induce the transformation of cancer cells into tumorigenic spheroids. In this study, we demonstrated the functionality of a new PTF, polymer X, using a streamlined production process. Polymer X induced the formation of tumor spheroids with properties of CSCs, as revealed through the upregulated expression of CSC-related genes. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in the cancer cells cultured on polymer X was upregulated by the fibronectin-integrin α5-Janus kinase 2 (JAK2) axis and maintained by the cytosolic LMO2/LBD1 complex. In addition, STAT3 signaling was critical in spheroid formation on polymer X. Our PTF platform allows the efficient generation of tumor spheroids from cancer cells, thereby overcoming the existing limitations of cancer research.
Coefficient of Friction and Height Loss: Two Criteria Used to Determine the Mechanical Property and Stability of Regenerated Versus Natural Articular Cartilage
Authors: Schwarz Markus L. , Reisig Gregor , Schneider-Wald Barbara , Weiß Christel , Hauk Luisa , Schütte Andy
Published: October 2022

Background: The coefficient of friction (CoF) serves as an indicator for the mechanical properties of natural and regenerated articular cartilage (AC). After tribological exposure, a height loss (HL) of the cartilage pair specimens can be measured. Our aim was to determine the CoF and HL of regenerated AC tissue and compare them with those of natural AC from non-operated joints and AC from joints where the regenerated tissues had been created after different treatments. Methods: In partial-thickness defects of the trochleae of the stifle joints of 60 Göttingen Minipigs, regenerated AC was created. In total, 40 animals received a Col I matrix, 20 laden with autologous chondrocytes, and 20 without. The defects of 20 animals were left empty. The healing periods were 24 and 48 weeks. A total of 10 not-operated animals, delivered the “external” control specimens. Osteochondral pins were harvested from defect and non-defect areas, the latter serving as “internal” controls. Using a pin-on-plate tribometer, we measured the CoF and the HL. Results: The CoF of the regenerated AC ranged from 0.039 to 0.069, and the HL, from 0.22 mm to 0.33 mm. The differences between the regenerated AC of the six groups and the “external” controls were significant. The comparison with the “internal” controls revealed four significant differences for the CoF and one for the HL in the operated groups. No differences were seen within the operated groups. Conclusions: The mechanical quality of the regenerated AC tissue showed inferior behavior with regard to the CoF and HL in comparison with natural AC. The comparison of regenerated AC tissue with AC from untreated joints was more promising than with AC from the treated joints.
The Role of CYP3A in Health and Disease
Authors: Klyushova Lyubov S. , Perepechaeva Maria L. , Grishanova Alevtina Y.
Published: October 2022

CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics (including drugs); almost the only common characteristic of these compounds is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in human organs and tissues, and consequences of these enzymes’ activities play a major role both in normal regulation of physiological levels of endogenous compounds and in various pathological conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological conditions and their involvement in the initiation and progression of diseases.
Systemic Optimization of Gene Electrotransfer Protocol Using Hard-to-Transfect UT-7 Cell Line as a Model
Authors: Vadeikienė Roberta , Jakštys Baltramiejus , Ugenskienė Rasa , Šatkauskas Saulius , Juozaitytė Elona
Published: October 2022

Non-adherent cells are difficult to transfect with chemical-mediated delivery methods. Electroporation is an attractive strategy to transfer the molecules of interest into suspension cells. Care must be taken with the viability of the transfected cells since parameters, which increase cell membrane permeability, subsequently increase transfection efficiency, leading to higher cell death indices. We intended to evaluate the distribution of hard-to-transfect UT-7 cells among different subpopulations: transfected/viable, untransfected/viable, transfected/dead, and untransfected/dead populations, for a better understanding of the relation between gene electrotransfer efficacy and cell death. The following electroporation parameters were tested: pulse strength, duration, plasmid DNA concentration, and ZnSO4 as DNase inhibitor. BTX T820 square-wave generator was used, and 48 h after electroporation, cells were observed for viability and fluorescence analysis. Increasing pulse strength correlated directly with an increased ratio of pEGFP-positive cells and inversely with cell viability. The best results, representing 21% pEGFP positive/viable cells, were obtained after EP with 1 HV 1400 V/cm pulse of 250 µs duration using 200 µg/mL plasmid concentration. Results demonstrated that plasmid concentration played the most significant role in pEGFP electrotransfer into UT-7 cells. These results can represent a relevant improvement of gene electrotransfer to obtain genetically modified suspension cells for further downstream experiments.