Search Results (1,149)

Objective: To characterize the profiles of resistance mutations to HIV reverse transcriptase inhibitors in Gabon. Design: Cross-sectional study conducted over 37 months, from October 2019 to October 2022, at the IST/HIV/AIDS Reference Laboratory, a reference center for the biological monitoring of people living with the human immunodeficiency virus (PWHIV) in Gabon. Methods: Plasma from 666 PWHIV receiving antiretroviral treatment was collected, followed by RNA extraction, amplification, and reverse transcriptase gene sequencing. Statistical analyses were performed using Stata^® 14.0 software (USA). Results: Six hundred and sixty-six (666) PWHIV plasma collected from 252 male and 414 female patients were analyzed and 1654 mutations were detected in 388 patients, including 849 (51.3%) associated with nucleoside reverse transcriptase inhibitors (NRTIs) and 805 (48.7%) with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Three of the most prescribed treatment regimens were associated to the appearance of both NRTIs and NNRTIs resistance mutations: TDF + 3TC + EFV (24.02%; 160/666); TDF + FTC + EFV) (17.2%; 114/666) and AZT + 3TC + EFV (14.6%; 97/666). Additionally, stage 3 of CD4 T-lymphocyte deficiency, the higher viral load, and treatment duration are risk factors influencing the appearance of virus mutations. Also, treatment containing TDF-3TC + DTG is more protective against mutations. Conclusions: Drug resistance mutations are common in Gabon and compromise the efficacy of ART. Further study must search for other causes of therapeutic failure in Gabon in PWHIV. Full article

Metarhizium (M.) granulomatis and M. viride have previously been described as pathogens causing hyalohyphomycosis in various species of captive chameleons and bearded dragons (Pogona vitticeps). Previous studies yielded different genotypes of M. granulomatis and M. viride based on sequencing of the internal transcribed spacer 1-5.8S rDNA (ITS-1-5.8S) and a fragment of the large subunit of the 28S rDNA (LSU). The aim of this study was to clarify the relationships between these genotypes and obtain a more accurate phylogenetic classification by sequencing two different loci of the RNA polymerase II second largest subunit (NRPB2), referred to as RPB1 and RPB2, and the translation elongation factor 1 alpha (EF1α). A total of 23 frozen isolates from 21 lizards, including the first isolates of M. granulomatis and M. viride from Parson’s chameleons (Calumma parsonii), were available for phylogenetic analysis. A total of 13 isolates belonged to the M. granulomatis complex and 10 isolates belonged to the M. viride complex. Following the amplification and sequencing of the protein-coding genes, the resulting nucleotide sequences were analyzed, trimmed and assembled. These were further analyzed with regard to differences in single-nucleotide polymorphisms (SNPs) and amino acid structure. In consideration of the results of the present analyses, a phylogenetic reclassification is recommended. Three different genotypes of M. granulomatis can be distinguished, which can be phylogenetically addressed as subspecies. Six subspecies can be distinguished regarding M. viride. Full article

Background/Objectives: Autism spectrum disorders (ASDs) are neurodevelopmental conditions with early onset of clinical manifestations. ASD etiology is highly heterogeneous, with genetic factors being strong determinants of the behavioral problems and neurodevelopmental deficits. Fragile X syndrome (FXS) (OMIM #300624), caused by the transcriptional silencing of the FMR1 gene, represents the most common monogenic cause of autism. Our study included 226 boys with a diagnosis of ASD, for a systematic screening of genetic and epigenetic defects in the FMR1 gene promoter in a Romanian pediatric cohort. Methods: The methods, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and triplet-primed PCR (TP-PCR)/melt curve analysis (MCA), were chosen for their ability to detect the methylation anomalies (the former) as well as repeat expansions in the FMR1 promoter (the latter). Results: Both methods used in our screening generated concordant results, detecting FMR1 full mutation in 4 out of 226 patients (~1.8%). This yield is similar to data obtained in larger studies. Three out of four boys presented the typical clinical features, in correlation with genetic findings. Conclusions: The combined use of MS-MLPA and TP-PCR/MCA-based assay was, in our experience, useful to fully describe the genetic defects responsible for FXS. A significant variability of clinical presentations was observed in our small group of children with FXS, from mild to severe intellectual disability and from atypical to characteristic dysmorphic features, as well as various behavioral problems. Full article

Epicardial mesothelial cells (EMCs), which form the epicardium, play a crucial role in cardiac homeostasis and repair. Upon damage, EMCs reactivate embryonic development programs, contributing to wound healing, progenitor cell amplification, and regulation of lymphangiogenesis, angiogenesis, and fibrosis. However, the mechanisms governing EMC activation and subsequent regulation remain poorly understood. We hypothesized that hepatocyte growth factor (HGF), a pleiotropic regulator of various cellular functions, could modulate EMC activity. To verify this hypothesis, we developed HGF-overexpressing mesenchymal stromal cell sheets (HGF-MSC CSs) and evaluated their effects on EMCs in vitro and in vivo. This study has revealed, for the first time, that EMCs express the c-Met (HGF receptor) on their surface and that both recombinant HGF and HGF-MSC CSs secretome cause c-Met phosphorylation, triggering downstream intracellular signaling. Our findings demonstrate that the HGF-MSC CSs secretome promotes cell survival under hypoxic conditions by modulating the level of autophagy. At the same time, HGF-MSC CSs stimulate EMC proliferation, promoting their amplification in the damage zone. These data demonstrate that HGF-MSC CSs can be considered a promising regulator of epicardial cell activity involved in heart repair after ischemic damage. Full article

Background. Medulloblastoma (MB) prognosis and response to therapy depend largely on genetic changes in tumor cells. Many genes and chromosomal abnormalities have been identified as prognostic factors, including amplification of MYC oncogenes, gains in 1q and 17q, deletions in 10q and 21p, or isochromosomes 17 (i(17)(q10)). The frequency of these abnormalities varies greatly between ethnic populations, but the frequency of specific abnormalities, such as MYCC and MYCN amplification, 17q gain, and deletions, in the Russian population is unknown. Objective: The aim is to study the frequency of MYCC and MYCN amplifications, 17q gain, and 17p deletion and determine their prognostic value in Russian patients with MB. Methods. This study was performed on MB cells obtained from 18 patients (12 boys and 6 girls, aged between 3 months and 17 years, with a median age of 6.5 years). Determination of cytogenetic aberrations was carried out using FISH assays with MYCC-SO, MYCN-SO, and MYCN-SG/cen2 probes, as well as cen7/p53 dual color probes and PML/RARα dual color probes (Abbott Molecular, USA). One-way ANOVA and Fisher’s F-test were used to compare the two groups. The differences were considered significant when p < 0.05. Results. In 77.7% of patients (14/18), the classical type of MB was present; in 16.7% (3/18), desmoplastic type; and in 5.6% (1/18), nodular desmoplasic types of neoplasms. Amplification of MYC genes was detected in 22.2% of Russian patients (n = 4 out of 18). Patients with MYC amplification had the worst overall survival (OS: 0% vs. 68%, p = 0.0004). Changes on the 17th chromosome were found in 58.3% of patients. Deletion of 17p occurred in 23.1%, and gain of 17q occurred in 46.2%. There were no significant differences in OS, clinical signs, or the presence of additional 17q material or 17p deletion among patients with MB. Conclusions: Amplification of the MYC gene is a predictor of poor overall survival to therapy and a high risk of metastatic relapse. This allows us to more accurately stratify patients into risk groups in order to determine the intensity and duration of therapy. Full article

This paper develops a novel modeling framework that integrates time-varying quantile-based spillover effects into a regime-switching realized volatility model. A dynamic spillover factor is constructed by identifying the most influential contributors to Bitcoin’s realized volatility across different quantile levels. This quantile-layered structure enables the model to capture heterogeneous spillover paths under varying market conditions at a macro level while also enhancing the sensitivity of volatility regime identification via its incorporation into a time-varying transition probability (TVTP) Markov-switching mechanism at a micro level. Empirical results based on the cryptocurrency market demonstrate the superior forecasting performance of the proposed TVTP-MS-HAR model relative to standard benchmark models. The model exhibits strong capability in identifying state-dependent spillovers and capturing nonlinear market dynamics. The findings further reveal an asymmetric dual-tail amplification and time-varying interconnectedness in the spillover effects, along with a pronounced asymmetry between market capitalization and systemic importance. Compared to decomposition-based approaches, the X-RV type of models—especially when combined with the proposed quantile-driven factor—offers improved robustness and predictive accuracy in the presence of extreme market behavior. This paper offers a coherent approach that bridges phenomenon identification, source localization, and predictive mechanism construction, contributing to both the academic understanding and practical risk assessment of cryptocurrency markets. Full article

Background/Objectives: Miscarriage is an increasingly common event worldwide arising from various factors, and identifying its etiology is important for planning and managing any future pregnancies. It is estimated that about half of early pregnancy loss cases are caused by genetic abnormalities, while a significantly lower rate is found in late pregnancy loss. Multiplex ligation-dependent probe amplification (MLPA) can detect small changes within a gene with precise breakpoints at the level of a single exon. The aim of our study was to identify the rate of copy number variations (CNVs) in spontaneous pregnancy loss samples after having previously tested them via quantitative fluorescence PCR (QF-PCR), with no abnormal findings. Methods: DNA was extracted from product-of-conception tissue samples, followed by the use of an MLPA kit for the detection of 31 microdeletion/microduplication syndromes (SALSA^® MLPA^® Probemix P245 Microdeletion Syndromes-1A, MRC-Holland, Amsterdam, The Netherlands). Results: A total of 11 (13.1%) out of the 84 successfully tested samples showed CNVs. Duplications accounted for 9.5% of the analyzed samples (eight cases), while heterozygous or hemizygous deletions were present in three cases (3.6%). Among all the detected CNVs, only three were certainly pathogenic (3.6%), with two deletions associated with DiGeorge-2 syndrome and Rett syndrome, respectively, and a 2q23.1 microduplication syndrome, all detected in early pregnancy loss samples. For the remaining cases, additional genetic tests (e.g., aCGH/SNP microarray) are required to establish CNV size and gene content and therefore their pathogenicity. Conclusions: MLPA assays seem to have limited value in detecting supplementary chromosomal abnormalities in miscarriages. Full article

This research presents the development and management principles of mobile resonant electrical systems designed for high-voltage generation, intended for non-destructive diagnostics of insulation in high-power electrical equipment. The core of the system is a series inductive–capacitive (LC) circuit characterized by a high quality (Q) factor and operating at high frequencies, typically in the range of 40–50 kHz or higher. Practical implementations of the LC circuit with Q-factors exceeding 200 have been achieved using advanced materials and configurations. Specifically, ceramic capacitors with a capacitance of approximately 3.5 nF and Q-factors over 1000, in conjunction with custom-made coils possessing Q-factors above 280, have been employed. These coils are constructed using multi-core, insulated, and twisted copper wires of the Litzendraht type to minimize losses at high frequencies. Voltage amplification within the system is effectively controlled by adjusting the current frequency, thereby maximizing voltage across the load without increasing the system’s size or complexity. This frequency-tuning mechanism enables significant reductions in the weight and dimensional characteristics of the electrical system, facilitating the development of compact, mobile installations. These systems are particularly suitable for on-site testing and diagnostics of high-voltage insulation in power cables, large rotating machines such as turbogenerators, and other critical infrastructure components. Beyond insulation diagnostics, the proposed system architecture offers potential for broader applications, including the charging of capacitive energy storage units used in high-voltage pulse systems. Such applications extend to the synthesis of micro- and nanopowders with tailored properties and the electrohydropulse processing of materials and fluids. Overall, this research demonstrates a versatile, efficient, and portable solution for advanced electrical diagnostics and energy applications in the high-voltage domain. Full article

The in situ emulsification synergistic self-profile control system has wide application prospects for efficient development on offshore oil reservoirs. During water flooding in Bohai heavy oil reservoirs, random emulsification occurs with superimposed Jamin effects. Effectively utilizing this phenomenon can enhance the efficient development of offshore oilfields. This study addresses the challenges hindering water flooding development in offshore oilfields by investigating the emulsification mechanism and key influencing factors based on oil–water emulsion characteristics, thereby proposing a novel in situ emulsification flooding method. Based on a fundamental analysis of oil–water properties, key factors affecting emulsion stability were examined. Core flooding experiments clarified the impact of spontaneous oil–water emulsification on water flooding recovery. Two-dimensional T1–T2 NMR spectroscopy was employed to detect pure fluid components, innovating the method for distinguishing oil–water distribution during flooding and revealing the characteristics of in situ emulsification interactions. The results indicate that emulsions formed between crude oil and formation water under varying rheometer rotational speeds (500–2500 r/min), water cuts (30–80%), and emulsification temperatures (40–85 °C) are all water-in-oil (W/O) type. Emulsion viscosity exhibits a positive correlation with shear rate, with droplet sizes primarily ranging between 2 and 7 μm and a viscosity amplification factor up to 25.8. Emulsion stability deteriorates with increasing water cut and temperature. Prolonged shearing initially increases viscosity until stabilization. In low-permeability cores, spontaneous oil–water emulsification occurs, yielding a recovery factor of only 30%. For medium- and high-permeability cores (water cuts of 80% and 50%, respectively), recovery factors increased by 9.7% and 12%. The in situ generation of micron-scale emulsions in porous media achieved a recovery factor of approximately 50%, demonstrating significantly enhanced oil recovery (EOR) potential. During emulsification flooding, the system emulsifies oil at pore walls, intensifying water–wall interactions and stripping wall-adhered oil, leading to increased T2 signal intensity and reduced relaxation time. Oil–wall interactions and collision frequencies are lower than those of water, which appears in high-relaxation regions (T1/T2 > 5). The two-dimensional NMR spectrum clearly distinguishes oil and water distributions. Full article

Centriole duplication is a vital process for cellular organisation and function, underpinning essential activities such as cell division, microtubule organisation and ciliogenesis. This review summarises the latest research on the mechanisms and regulatory pathways that control this process, focusing on important proteins such as polo-like kinase 4 (PLK4), SCL/TAL1 interrupting locus (STIL) and spindle assembly abnormal protein 6 (SAS-6). This study examines the complex steps involved in semi-conservative duplication, from initiation in the G1–S phase to the maturation of centrioles during the cell cycle. Additionally, we will explore the consequences of dysregulated centriole duplication. Dysregulation of this process can lead to centrosome amplification and subsequent chromosomal instability. These factors are implicated in several cancers and developmental disorders. By integrating recent study findings, this review emphasises the importance of centriole duplication in maintaining cellular homeostasis and its potential as a therapeutic target in disease contexts. The presented findings aim to provide a fundamental understanding that may inform future research directions and clinical interventions related to centriole biology. Full article

Background: Sex differences play a significant role in the epidemiology, biology, and outcomes of many cancers, including glioblastoma (GB), the most common and aggressive primary brain tumor. GB is more frequent in males, while females tend to have longer survival, though the underlying reasons for these differences remain poorly understood. Potential contributors include hormonal influences, sex-specific risk factors, and treatment disparities. Understanding these differences is critical for optimizing personalized treatment strategies. Methods: We conducted a retrospective analysis of patients with gliomas from a neuro-oncological database, with a primary focus on GB cases. Variables collected included sex, age, tumor type, molecular biomarker, and treatment modalities. The primary objective was to assess sex-based differences in tumor characteristics and outcomes, while the secondary objective was to identify predictors of time to progression and mortality. Results: The cohort comprised 125 GB, 48 astrocytomas, and 16 oligodendrogliomas, with no significant sex-based differences in age or tumor type distribution. Among GB patients, multifocality was more prevalent in females (14% vs. 8%; p = 0.01); also, EGFR amplification was more frequent in females (25.5% vs. 52.5%; p = 0.007). Males received chemotherapy (80% vs. 63%; p = 0.04) and radiotherapy (84% vs. 67%; p = 0.03) more frequently than females. Survival was positively associated with MGMT methylation (p = 0.002) and negatively associated with TERT mutation (p = 0.01). Multivariable analysis identified TERT mutation as a predictor of increased mortality (HR = 4.1; 95% CI: 1.2–14; p = 0.025), while multifocality predicted both mortality (HR = 2.3; 95% CI: 1.3–3.9; p = 0.003) and reduced time to progression (HR = 3.3; 95% CI: 1.02–10.6; p = 0.04). Conclusions: This study underscores the importance of sex and molecular profiling in GB management, revealing distinct patterns in tumor characteristics and treatment administration between males and females. Our findings advocate for the integration of sex-specific considerations and molecular profiling into clinical decision-making to improve outcomes for GB patients. Full article

This study investigates the impact of nonlinear constitutive models on one-dimensional seismic site response analysis (SRA) for soft, reclaimed soil deposits in Saemangeum, South Korea. Two widely used models, MKZ and GQ/H, were applied to three representative soil profiles using the DEEPSOIL program. Ground motions were scaled to bedrock peak ground accelerations (PGAs) corresponding to annual return periods (ARPs) of 1000, 2400, and 4800 years. Seismic response metrics include the ratio of GQ/H to MKZ shear strain, effective PGA (EPGA), and short- and long-term amplification factors (F_a and F_v). The results highlight the critical role of the site-to-motion period ratio (T_g/T_m) in controlling seismic behavior. Compared to the MKZ, the GQ/H model, which features strength correction and improved stiffness retention, predicts lower shear strains and higher surface spectral accelerations, particularly under strong shaking and shallow conditions. Model differences are most pronounced at low T_g/T_m values, where MKZ tends to underestimate amplification and overestimate strain due to its limited ability to reflect site-specific shear strength. Relative to code-based amplification factors, the GQ/H model yields lower short-term estimates, reflecting the disparity between stiff inland reference sites and the soft reclaimed conditions at Saemangeum. These findings emphasize the need for strength-calibrated constitutive models to improve the accuracy of site-specific seismic hazard assessments. Full article

To investigate the impermeability characteristics of composite geomembranes in rigid landfills, a three-dimensional finite element seepage analysis model, which incorporates a composite geomembrane, was established based on a case study of a rigid landfill project in Tongling. Utilizing the seepage mechanism of the composite geomembrane, the seepage distribution patterns of the hazardous waste leachate within the unit cell were computed under representative operating conditions. Different thickness amplification factor schemes for the equivalent treatment of the composite geomembrane were comparatively analyzed, considering both isotropic and anisotropic seepage conditions. The relationships between the seepage flow rate, velocity, and thickness amplification factor were determined. The results showed that the leachate experiences a rapid drop in the water head as it passes through the composite geomembrane, with a low seepage flow rate and velocity, highlighting the membrane’s significant impermeability effect. The finite element analysis indicated that thickness amplification of the composite geomembrane based on the flow equivalence is feasible to some degree, but treating the geomembrane as an anisotropic material during the equivalent process better approximates the actual conditions. Full article

Anticoagulants, including warfarin, are often administered to patients who are exhibiting early symptoms of thromboembolic episodes or who have already experienced such episodes. However, warfarin has a limited therapeutic index and might cause bleeding and other clinical problems. Warfarin inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme essential for activating vitamin K, in the coagulation cascade. Genetic factors, such as polymorphisms, can change the natural function of VKORC1, causing variations in the medication reaction among individuals. Hence, before prescribing warfarin, the patient’s genetic profile should also be considered. In this study, an electrochemical genosensor capable of detecting the VKORC1 1639 G>A polymorphism was designed and optimized. This analytical approach detects the electric current obtained during the hybridization reaction between two 52 base pair complementary oligonucleotide sequences. Investigating public bioinformatic platforms, two DNA sequences with the A and G single-nucleotide variants were selected and designed. The experimental protocol of the genosensor implied the formation of a bilayer composed of a thiolate DNA and an alkanethiol immobilized onto gold electrodes, as well as the formation of a DNA duplex using a sandwich-format hybridization reaction through a fluorescein labelled DNA signalling probe and the enzymatic amplification of the electrochemical signal, detected by chronoamperometry. A detection limit of 20 pM and a linear range of 0.05–1.00 nM was obtained. A clear differentiation between A/A, G/A and G/G genotypes in biological samples was successfully identified by his novel device. Full article

Immune checkpoints such as PD-1/PD-L1, CTLA-4, LAG-3, TIM-3, and TIGIT play critical roles in regulating anti-tumor immunity and are exploited by hematological malignancies to evade immune surveillance. While classic Hodgkin lymphoma (HL) demonstrates notable responsiveness to immune checkpoint inhibitors (ICIs), which is attributed to genetic alterations like chromosome 9p24.1 amplification, the responsiveness of non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM) remain inconsistent and generally modest. In NHL, the heterogeneous immune microenvironment, particularly variations in tumor-infiltrating lymphocytes and PD-L1 expression, drives differential ICI outcomes. AML shows limited responsiveness to monotherapy, but the combination of monotherapy with hypomethylating agents yield encouraging results, particularly in selected patient subsets. Conversely, MM trials have largely failed, potentially due to genetic polymorphisms influencing checkpoint signaling pathways and the inherently immunosuppressive bone marrow microenvironment. Both intrinsic tumor factors (low tumor mutational burden, impaired antigen presentation, IFN-γ pathway alterations) and extrinsic factors (immunosuppressive cells and alternative checkpoint upregulation) contribute significantly to primary and acquired resistance mechanisms. Future strategies to overcome resistance emphasize combination therapies, such as dual checkpoint blockade, epigenetic modulation, and reprogramming the tumor microenvironment, as well as biomarker-driven patient selection, aiming for precision-based, tailored immunotherapy across hematological malignancies. Full article