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Anterior cross bite is an occlusal etiological factor for the occurrence of gingival recession and resorption of the alveolar bone. Aim: To examine the condition of the alveolar bone in relation to incisor inclination in subjects with anterior cross bite. Materials and methods: Sixty one eligible subjects, with a mean age of 25.66±10.51 years, presented with anterior cross bite of a single teeth or a group of teeth. The distribution of patients by sex is women-42.6% and men-57.4%. The inclination of the upper and lower incisors was evaluated and analysed with Steiner C method. The bone resorption in the two jaws (distance from the enamel-cement junction of the incisors up to the beginning of the alveolar bone) was measured up to 0.01 mm. Results: Protrusions constituted a higher percentage than retrusion in both jaws. The mean value of bone resorption in the maxilla of subjects with retrusion was 4.01mm, whereas in subjects with protrusion, it was 3.42mm (p = 0.062). The mean value of bone resorption in the mandible of subjects with retrusion was 4.56mm, whereas in subjects with protrusion, it was 4.36mm. The bone resorption mean of the patients with retrusion in the mandible was 0.55mm higher than the mean of the patients with retrusion in the maxilla with high statistical significance (p = 0.008). Conclusion: Higher levels of bone resorption were observed in the mandible as compared to the maxilla. A significant linear relationship was found between the inclination of the incisors and the degree of bone resorption.

Aim: In this study, the best corrected visual acuity (BCVA) and refraction in preterm-born infants in South-Eastern Bulgaria after 12 years of treatment for type 1 prethreshold retinopathy of prematurity were presented, and the outcomes of laser treatment and cryotherapy were compared. Materials and methods: Since 2010, we have treated 319 eyes of 164 prematurely born children for type 1 prethreshold retinopathy of prematurity and were prospectively followed up. The mean (range) gestational age was 28.6 weeks of gestation (23–33) and the mean (range) birth weight was 1143 g (570–1990). Cryotherapy was applied on 76 eyes (23.2%), laser was used in 215 eyes (65.5%), anti-VEGF – in 10 eyes (3%) and surgery – in 18 eyes (5.5%). Twelve children (24 eyes, 7.3%) were lost to the follow-up. BCVA was tested in 114 eyes and refraction in 190 eyes. Because of the small number of eyes treated surgically or with anti-VEGF (18 and 10, respectively), these children’s eyes were excluded from the statistical analysis. Results: Fifty eyes showed BCVA between 0.6 and 1.0; 25 eyes – between 0.2 and 0.5; 5 eyes – between 0.04 and 0.1; 5 eyes between light perception –0.03 and 4 eyes were totally blind. Laser-treated eyes showed statistically significantly higher BCVA compared to the cryotherapy treated eyes (Fisher’s exact test, p=0.012). Myopia (any myopic refraction) was found in 50 eyes; hyperopia (>+2 D) – in 20 eyes; astigmatism (difference between the two principal meridians >0.75 D) – in 70 eyes, and emmetropia – in 30 eyes. Although in the laser-treated group more eyes showed emmetropic and hyperopic refraction compared to cryo treated group (25 eyes vs. 7 eyes – emmetropia and 15 eyes vs. 5 eyes – hyperopia, respectively), the difference did not reach statistical significance (Fisher’s exact test, p=0.106). Conclusion: Timely treatment of type 1 prethreshold retinopathy of prematurity leads to very good anatomical and functional results. Laser treatment leads to significantly higher BCVA, compared to cryotherapy. Emmetropia and hyperopia are more commonly seen in laser-treated eyes.

Enriching geospatial data, particularly through address geocoding, is fundamental to many geospatial analytical solutions, facilitating resource allocation, accessibility assessment, and urban development planning. This paper explores the address geocoding approaches from traditional GIS-based methods to advanced data-driven solutions, emphasising their accuracy, efficiency, and complementarity. Geospatial data enrichment challenges are explored using the SemTUI framework and QGIS platform. SemTUI employs a data-driven approach that facilitates interactive semantic enrichment and address reconciliation. QGIS is utilised for address geocoding, using the MMQGIS plugin with two geocoding web services provided by OSM and Google. The comparison between SemTUI and QGIS workflows highlights their complementary strengths. SemTUI offers intuitive interfaces and an automated solution, while QGIS provides advanced geospatial visualisation and analysis capabilities. Practical applications in supply-demand analysis of social amenities and walkability index calculation demonstrate the significance of geocoding in urban planning. Further research efforts are focused on enhancing the integration between SemTUI and QGIS to improve the precision and performance of address geocoding and further spatial data analysis.

Abstract Bacterial cellulosic polymers constitute a prevalent class of biofilm matrix exopolysaccharides that are synthesized by several types of bacterial cellulose secretion (Bcs) systems, which include conserved cyclic diguanylate (c-di-GMP)-dependent cellulose synthase modules together with diverse accessory subunits. In E. coli, the biogenesis of phosphoethanolamine (pEtN)-modified cellulose relies on the BcsRQABEFG macrocomplex, encompassing inner-membrane and cytosolic subunits, and an outer membrane porin, BcsC. Here, we use cryogenic electron microscopy to shed light on the molecular mechanisms of BcsA-dependent recruitment and stabilization of a trimeric BcsG pEtN-transferase for polymer modification, and a dimeric BcsF-dependent recruitment of an otherwise cytosolic BcsE2R2Q2 regulatory complex. We further demonstrate that BcsE, a secondary c-di-GMP sensor, can remain dinucleotide-bound and retain the essential-for-secretion BcsRQ partners onto the synthase even in the absence of direct c-di-GMP-synthase complexation, likely lowering the threshold for c-di-GMP-dependent synthase activation. Such activation-by-proxy mechanism could allow Bcs secretion system activity even in the absence of substantial intracellular c-di-GMP increase, and is reminiscent of other widespread synthase-dependent polysaccharide secretion systems where dinucleotide sensing and/or synthase stabilization are carried out by key co-polymerase subunits.

Pseudomonas aeruginosa is a ubiquitous environmental Gram-negative bacterium and also an opportunistic pathogen for both humans and animals, causing acute or chronic infections. It has been frequently detected in healthy and diseased reptiles, more commonly in captive ones. Since most studies are primarily on clinical isolates, the pathogenic potential of strains originating from wild animals is poorly explored. We isolated the strain P. aeruginosa PM1012 from the cloacal microbiota of a common wall lizard (Podarcis muralis Laurenti, 1768) from a free-living population. The effect of temperature, pH and salinity on its growth was evaluated. Antibiotic resistance, the expression of several virulence factors as some extracellular enzymes, pyocyanin production and biofilm formation were also assessed. Apart from intrinsic resistance, the newly isolated strain P. aeruginosa PM1012 presented an antibiotic susceptibility profile with a low resistance rate limited to meropenem and intermediate to ceftazidime and aztreonam. Protease, lipase and gelatinase secretion was detected. Strong pyocyanin production was observed in the optimal range of growth conditions. An excellent biofilm-forming capacity was manifested.

The use of infrared (IR) light in dentistry has developed rapidly over the past few decades. Devices do not require an external energy source but can be activated by body heat. IR can be used to improve diagnosis or treatment. Currently, the use of infrared thermography (ITR) in modern medicine is experiencing continuous growth due to the technological advantages of the method in the prevention and monitoring of some diseases, the selection and evaluation of treatments, as well as its high diagnostic sensitivity and specificity reported by specialized studies. Technological advances in the new generations of infrared detectors have led to an increase in the level of precision offered by thermal imaging as an alternative method of medical diagnosis or treatment. The improved thermal sensitivity has contributed to the expansion of the use of IR in all medical fields, including dentistry, in specialities such as endodontics, odontology, periodontics, prosthetics, oral and maxillofacial surgery, TMJ pathology, implantology, allergology, oral pathology, photostimulation. Thermograms can be stored, processed and sent digitally, which makes them compatible with other modern technologies. Colour coded thermograms are easier to interpret. Infrared thermography has numerous advantages, such as speed of realization, comfort for the patient, absence of contraindications and side effects, qualitative evaluation of the examined affection.

Listeria monocytogenes is a significant concern in the food industry due to its association with outbreaks of listeriosis, particularly affecting vulnerable populations. High-throughput technologies such as RNA sequencing (RNA-seq) and proteomics offer valuable insights into the molecular responses of L. monocytogenes to stress environments. In this study, a combined transcriptomic and immunoproteomic approach was applied to explore the stress response mechanisms of the L. monocytogenes strain ST7, which was responsible for an outbreak in central Italy. The bacterium was exposed to both optimal conditions and a stress environment representative of pork product matrices (pH 5.5; 7 % NaCl) and thermal abuse prior to consumption (12 °C).Transcriptomic analysis revealed variations in gene expression related to pathogenesis, stress responses, and virulence factors under different environmental conditions. Transcriptomic analysis of Listeria involves studying the complete set of RNA transcripts produced by the bacterium under various conditions or during different stages of its lifecycle. It can provide insights into its pathogenicity and virulence mechanisms. Immunoproteomic analysis identified proteins involved in stress response pathways, including oxidoreductases and DNA repair enzymes, uniquely expressed under stress conditions. Furthermore, the study highlighted proteins linked to antibiotic resistance and cell wall biosynthesis. By delineating specific proteins crucial in the stress response pathways, these findings not only deepen our comprehension of L. monocytogenes biology but also pave the way for designing more targeted mitigation strategies to safeguard food safety and public health effectively.

The subject of analysis in the current theoretical and practical research is an act with a high degree of social danger that exists in objective reality and manifests within the tourism sector – sexual exploitation in the field of travel and tourism. This exploitation is characterised by prerequisites for being carried out in a hidden and unnoticed manner. It is a multidimensional activity with objective and subjective features that affect the diverse rights of victims, primarily children. The primary goal of this study is to illustrate the necessity for adequate criminal law protection for every child worldwide from this form of abuse and to present several specific proposals. This article applies comparative legal research and socio-legal research of legal provisions of different legislation regulating sexual exploitation in travel and tourism. MAXQDA software was used for data analysis.

Background: Despite scientific advances, the management of procedural pain in neonates remains suboptimal. Applying adequate therapy to control pain during the neonatal period is a moral and ethical act. In recent decades, ample evidence has accumulated regarding the risks, associated with both untreated pain and the use of more aggressive analgesic therapy. Thus, the emphasis in neonatal clinical practice is on non-aggressive pain management techniques, including non-pharmacological methods, such as glucose and homeopathic agents. The efficacy and safety of homeopathic agents for reducing procedural pain in neonates is the subject of the present study. Materials and methods: Healthy full-term newborn babies with an average age of 72–84 hours were included. They were divided into three study groups: group (A) – without analgesia, (n = 67), group (B) – analgesic with Arnica D30 (n = 57) and group (C) – analgesic with Sol.Glucose 25% (n = 40). The severity of the pain was assessed using the multimodal - Neonatal Infant Pain Scale (NIPS) and the unimodal - Neonatal Facial Coding System (NFCS) scale. Assessments were done 30s before, 30 seconds after, and 5 minutes after the painful stimulus caused by the heel prick. Heart rate, transcutaneous oxygen saturation, respiratory rate and blood pressure were examined at the same intervals. The results obtained were processed statistically by descriptive analysis and ANOVA at a significance level of p < 0.05. Results: Five minutes after heel prick both scales showed a score near 3, i.e. no significant pain, and statistically significant lower score in those given Arnica D30, compared to those who received Sol.Glucose 25% (p < 0.05). When monitoring the physiological indicators, we found a significant increase in the heart rate 30 seconds after the procedure between group B and C. Five minutes after the heel prick we recorded significantly values of respiratory rate and systolic blood pressure in all three groups compared to accounted for pre-procedural values. Conclusion: Arnica D30 has better analgesic effects compared to Sol.Glucose 25% for newborn babies after heel prick tests.

Purpose: To study the treatment and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). Design: Multicenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naive patients. Cases with microscopic orbital extension detected postenucleation were excluded from the study. Participants: A total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE. Intervention: Chemotherapy, enucleation, exenteration, radiotherapy. Main Outcome Measures: Systemic metastasis and death. Results: Of the 3435 RB patients included in this study, 309 (9%) were from low-income countries (LIC), 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from LIC, 197 (6%) lower-middle income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (P = 0.0001). The outcomes were statistically significant for RB-EOE compared with RB-w/o-EOE: systemic metastasis (32% vs. 4% respectively; P = 0.0001) and metastasis-related death (63% vs. 6% respectively; P = 0.0001). Multimodal treatment was the most common form of treatment (n = 177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n = 97; 30%). Adjuvant external beam radiotherapy (EBRT) after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan–Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk of death from RB-EOE was greater in patients aged >4 years than

Objective: This study involving automated external defibrillators (AEDs) in early treatment of refibrillation aims to evaluate the performance of a new shock advisory system (SAS) during chest compressions (CC) in out-of-hospital cardiac arrest (OHCA) patients. Methods: This work focuses on AED SAS performance as a secondary outcome of DEFI 2022 clinical prospective study, which included first-analysis shockable OHCA patients. SAS employs the Analyze Whilst Compressing (AWC) algorithm to interact with both cardiopulmonary resuscitation (CPR) and shock advice by conditional operation of two-stage ECG analysis in presence or absence of chest compressions. AWC is triggered by the first-shock recommendation. Then, after 1 min of CPR, ECG analysis during CC decides between two treatment scenarios. For patients with refibrillation, CPR is paused for immediate confirmation analysis and shock advice. For patients with non-shockable rhythms, CPR is continued for 2 min until standard analysis. Results: Clinical data from 285 OHCA patients with shock recommendation at the first-analysis by AEDs (DEFIGARD TOUCH7, Schiller Médical) consisted of 576 standard analyses, 2011 analyses during CC, 577 confirmation analyses in absence of CC. Global AED SAS performance meets the standard recommendations for arrhythmia analysis sensitivity (94.9%) and specificity (>99.3%). AWC provided innovative treatment of shockable rhythms by stopping CPR earlier than 2 min in most ventricular fibrillations (92.9%), while most non-shockable patients (86.5–95.2%) benefitted from continuous CPR for at least 2 min. Conclusion: This study provides positive evidence for routine use of AEDs with AWC-integrated algorithm for ECG analysis during CPR by first-responders in early OHCA treatment.Clinical Trial Registration: Registration number: NCT04691089, trial register: ClinicalTrials.gov.

In the present work, we have investigated a novel recombinant cystatin dgECP1 and its mutant form, dgECP1m1, focused on their impact on the adhesive behaviour of two breast cell lines: the cancerous, MDA-MB-231, and the normal, MCF-10A. DgECP1 cystatin is intriguing with its RGD motif, responsible for cell adhesion and typical for mammalian extracellular matrix proteins but uncommon for plant cystatins. The presence of the RGD sequence suggests the potential of the dgECP1 to influence the adhesion of cancer cells and, respectively, cancer metastasis. A mutant form of the dgECP1cystatin, dgECP1m1, where RGD is replaced with HGD tripeptide, was also investigated. We found that both phytocystatins exerted differential effects on the adhesion behaviour of normal and cancer cells. In the case of dgECP1 cystatins, the effect on cancer cell adhesion also depends on the mode of administration of the cystatin to cells. When dgECP1 is pre-adsorbed on a substrate, it improves the attachment of breast cancer cells and induces cell aggregation, which is more typical for normal breast cells, and oppositely suppressed adhesion of cancer cells when added to the medium. The mutant form, dgECP1m1, inhibited cancer cell adhesion independently on the way of administration. On the other hand, both plant cystatins only slightly reduced the adhesion of normal mammary cells pointing to the higher sensitivity of cancer cells to both cystatins. These preliminary results open the possibility of considering the plant cystatin dgECP1 for anti-cancer strategies.;

Graphene and its derivatives have become promising materials for biomedical applications in the last decade. Before their widespread application, however, evaluating their toxicity and mechanisms underlying interactions with cellular components is imperative. Aims: Assessment of the effect of two graphene derivatives, pristine graphene oxide (GO) and ammonia-modified GO (GO-NH2) particles, on the ATPase activity of rat liver mitochondria and ROS production. Methods: Liver mitochondria were isolated from male albino rats and treated with different concentrations of GO and GO-NH2 particles (4, 10, 25, and 50 μg/ml). ATPase activity of both, intact and uncoupled by freezing/thawing mitochondria was determined by the measurement of inorganic phosphate (Pi) released from ATP. The generation of hydrogen peroxide (H2O2) after exposure of mitochondria to GO and GO-NH2 particles was determined by a DCFH-D assay. Results: GO and GO-NH2 particles applied at concentrations of 4 and 50 μg/ml did not affect the ATPase activity of intact mitochondria. In contrast, in uncoupled mitochondria, they demonstrated a stimulating effect on ATPase activity. The impact of GO-NH2 was more substantial and concentration-dependent. ROS production was also higher in GO-NH2-treated mitochondria. Conclusion: The present study demonstrated that GO and GO-NH2 particles can exert a cytotoxic effect on mitochondria even after a short-time of exposure to both types of particles.;

For centuries, plants have been a leading point in the identification of potential therapeutic agents. Monoamine oxidase inhibition is a key mechanism in the treatment of various neurological and psychiatric diseases. Some triterpenoid saponins are reported to inhibit this enzyme. An extract from the aerial parts of Astragalus glycyphyllos was purified and separated by chromatographic techniques, which led to the isolation of one triterpene saponin. Its structure was analysed by ultra-high-performance liquid chromatography coupled with high-resolution electrospray ionisation mass spectrometry. The compound was subjected to a pharmacological study where human recombinant monoamine oxidase enzymes type A and B (hMAOA and hMAOB) were used. On the activity of hMAOA, the saponin had no effect, but on hMAOB, it exhibited statistically significant inhibition in comparison to the control, Selegiline. The compound could have potential in other models, so further investigations are required.

We report on a novel behavior of the electromagnetically induced absorption (EIA) resonance observed on the D2 line of Cs for atoms confined in cells with micrometric thickness. With the enhancement of light intensity, the EIA resonance amplitude suffers from fast reduction, and even at very low intensity (W

AimThe aim of this study was to investigate baseline characteristics and outcome of patients after endovascular therapy (EVT) for acute large vessel occlusion (LVO) in relation to their history of symptomatic vascular disease and sex.MethodsConsecutive EVT-eligible patients with LVO in the anterior circulation admitted to our stroke center between 04/2015 and 04/2020 were included in this observational cohort study. All patients were treated according to a standardized acute ischaemic stroke (AIS) protocol. Baseline characteristics and successful reperfusion, recurrent/progressive in-hospital ischaemic stroke, symptomatic in-hospital intracranial hemorrhage, death at discharge and at 3 months, and functional outcome at 3 months were analyzed according to previous symptomatic vascular disease and sex.Results995 patients with LVO in the anterior circulation (49.4% women, median age 76 years, median admission NIHSS score 14) were included. Patients with multiple vs. no previous vascular events showed higher mortality at discharge (20% vs. 9.3%, age/sex − adjustedOR = 1.43, p = 0.030) and less independency at 3 months (28.8% vs. 48.8%, age/sex − adjustedOR = 0.72, p = 0.020). All patients and men alone with one or multiple vs. patients and men with no previous vascular events showed more recurrent/progressive in-hospital ischaemic strokes (19.9% vs. 6.4% in all patients, age/sex − adjustedOR = 1.76, p = 0.028) (16.7% vs. 5.8% in men, age-adjustedOR = 2.20, p = 0.035). Men vs. women showed more in-hospital symptomatic intracranial hemorrhage among patients with one or multiple vs. no previous vascular events (23.7% vs. 6.6% in men and 15.4% vs. 5.5% in women, OR = 2.32, p = 0.035/age − adjustedOR = 2.36, p = 0.035).ConclusionsPrevious vascular events increased the risk of in-hospital complications and poorer outcome in the analyzed patients with EVT-eligible LVO-AIS. Our findings may support risk assessment in these stroke patients and could contribute to the design of future studies.

Abstract Background Airway tuft cells, formerly called brush cells have long been described only morphologically in human airways. More recent RNAseq studies described a chemosensory cell population, which includes tuft cells, by a distinct gene transcription signature. Yet, until which level in the tracheobronchial tree in native human airway epithelium tuft cells occur and if they function as regulators of innate immunity, e.g., by regulating mucociliary clearance, remained largely elusive. Methods We performed immunohistochemistry, RT-PCR and immunoblotting analyses for various tuft cell markers to confirm the presence of this cell type in human tracheal samples. Immunohistochemistry was conducted to study the distribution of tuft cells along the intrapulmonary airways in humans. We assessed the influence of bitter substances and the taste transduction pathway on mucociliary clearance in mouse and human tracheal samples by measuring particle transport speed. Results Tuft cells identified by the expression of their well-established marker POU class 2 homeobox 3 (POU2F3) were present from the trachea to the bronchioles. We identified choline acetyltransferase in POU2F3 expressing cells as well as the transient receptor potential melastatin 5 (TRPM5) channel in a small population of tracheal epithelial cells with morphological appearance of tuft cells. Application of bitter substances, such as denatonium, led to an increase in mucociliary clearance in human tracheal preparations. This was dependent on activation of the TRPM5 channel and involved cholinergic and nitric oxide signalling, indicating a functional role for human tuft cells in the regulation of mucociliary clearance. Conclusions We were able to detect tuft cells in the tracheobronchial tree down to the level of the bronchioles. Moreover, taste transduction and cholinergic signalling occur in the same cells and regulate mucociliary clearance. Thus, tuft cells are potentially involved in the regulation of innate immunity in human airways.

Abstract Background Caveolins are the principal structural components of plasma membrane caveolae. Dominant pathogenic mutations in the muscle‐specific caveolin‐3 (Cav3) gene isoform, such as the limb girdle muscular dystrophy type 1C (LGMD‐1C) P104L mutation, result in dramatic loss of the Cav3 protein and pathophysiological muscle weakness/wasting. We hypothesize that such muscle degeneration may be linked to disturbances in signalling events that impact protein turnover. Herein, we report studies assessing the effects of Cav3 deficiency on mammalian or mechanistic target of rapamycin complex 1 (mTORC1) signalling in skeletal muscle cells. Methods L6 myoblasts were stably transfected with Cav3P104L or expression of native Cav3 was abolished by CRISPR/Cas9 genome editing (Cav3 knockout [Cav3KO]) prior to performing subcellular fractionation and immunoblotting, analysis of real‐time mitochondrial respiration or fixed cell immunocytochemistry. Skeletal muscle from wild‐type and Cav3−/− mice was processed for immunoblot analysis of downstream mTORC1 substrate phosphorylation. Results Cav3 was detected in lysosomal‐enriched membranes isolated from L6 myoblasts and observed by confocal microscopy to co‐localize with lysosomal‐specific markers. Cav3P104L expression, which results in significant (~95%) loss of native Cav3, or CRISPR/Cas9‐mediated Cav3KO, reduced amino acid‐dependent mTORC1 activation. The decline in mTORC1‐directed signalling was detected by immunoblot analysis of L6 muscle cells and gastrocnemius Cav3−/− mouse muscle as judged by reduced phosphorylation of mTORC1 substrates that play key roles in the initiation of protein synthesis (4EBP1S65 and S6K1T389). S6K1T389 and 4EBP1S65 phosphorylation reduced by over 75% and 80% in Cav3KO muscle cells and by over 90% and 30% in Cav3−/− mouse skeletal muscle, respectively. The reduction in protein synthetic capacity in L6 muscle cells was confirmed by analysis of puromycylated peptides using the SUnSET assay. Cav3 loss was also associated with a 26% increase in lysosomal cholesterol, and pharmacological manipulation of lysosomal cholesterol was effective in replicating the reduction in mTORC1 activity observed in Cav3KO cells. Notably, re‐expression of Cav3 in Cav3KO myoblasts normalized lysosomal cholesterol content, which coincided with a recovery in protein translation and an associated increase in mTORC1‐directed phosphorylation of downstream targets. Conclusions Our findings indicate that Cav3 can localize on lysosomal membranes and is a novel regulator of mTORC1 signalling in muscle. Cav3 deficiency associated with the Cav3P104L mutation impairs mTORC1 activation and protein synthetic capacity in skeletal muscle cells, which may be linked to disturbances in lysosomal cholesterol trafficking and contribute to the pathology of LGMD‐1C.

Triterpenoid saponins from the Astragalus species possess valuable effects (cytotoxic, adjuvant, hepatoprotective, neuroprotective, antiviral, etc.). Some also have immunomodulatory activities. Astragalus glycyphyllos is distributed in Bulgaria and mainly accumulates cycloartane saponins. From the overground parts of the species, a triterpenoid cyloartane-type saponin (AGOS3) was isolated by different chromatographic techniques. A quantitative LC-MS method for the determination of the saponin was developed and validated. Further, the saponin was loaded in copolymeric micelles based on triblock copolymers of polyethylene oxide and polypropylene oxide (Pluronics). The LC-MS method was applied on the developed micelles to determine their loading degrees. Afterwards, the possible pharmacological effects of free and encapsulated in polymeric nanoparticles of triterpenoid saponin (1, 5, 10, 25, 50, and 100 µg/mL) were evaluated in isolated murine macrophages and lymphocytes in vitro. Free AGOS3 stimulated proliferation only at the highest tested concentrations (50–100 µg/mL), and the effect was more evident in isolated macrophages. Interestingly, AGOS3-loaded polymeric micelles caused concentration dependency and statistically significant increases in the proliferation of both isolated lymphocytes and macrophages, even at a lower concentration (10 µg/mL). These results could serve as the basis for further research on the immunomodulatory effect of this saponin.

The aim of this study is to address the challenge of 12-lead ECG delineation by different encoder–decoder architectures of deep neural networks (DNNs). This study compares four concepts for encoder–decoders based on a fully convolutional architecture (CED-Net) and its modifications with a recurrent layer (CED-LSTM-Net), residual connections between symmetrical encoder and decoder feature maps (CED-U-Net), and sequential residual blocks (CED-Res-Net). All DNNs transform 12-lead representative beats to three diagnostic ECG intervals (P-wave, QRS-complex, QT-interval) used for the global delineation of the representative beat (P-onset, P-offset, QRS-onset, QRS-offset, T-offset). All DNNs were trained and optimized using the large PhysioNet ECG database (PTB-XL) under identical conditions, applying an advanced approach for machine-based supervised learning with a reference algorithm for ECG delineation (ETM, Schiller AG, Baar, Switzerland). The test results indicate that all DNN architectures are equally capable of reproducing the reference delineation algorithm’s measurements in the diagnostic PTB database with an average P-wave detection accuracy (96.6%) and time and duration errors: mean values (−2.6 to 2.4 ms) and standard deviations (2.9 to 11.4 ms). The validation according to the standard-based evaluation practices of diagnostic electrocardiographs with the CSE database outlines a CED-Net model, which measures P-duration (2.6 ± 11.0 ms), PQ-interval (0.9 ± 5.8 ms), QRS-duration (−2.4 ± 5.4 ms), and QT-interval (−0.7 ± 10.3 ms), which meet all standard tolerances. Noise tests with high-frequency, low-frequency, and power-line frequency noise (50/60 Hz) confirm that CED-Net, CED-Res-Net, and CED-LSTM-Net are robust to all types of noise, mostly presenting a mean duration error < 2.5 ms when compared to measurements without noise. Reduced noise immunity is observed for the U-net architecture. Comparative analysis with other published studies scores this research within the lower range of time errors, highlighting its competitive performance.