Search Results (369)

Since the initial use of biological ion channels to detect single-stranded genomic base pair differences, label-free and highly sensitive resistive pulse sensing (RPS) with nanopores has made remarkable progress in single-molecule analysis. By monitoring transient ionic current disruptions caused by molecules translocating through a nanopore, this technology offers detailed insights into the structure, charge, and dynamics of the analytes. In this work, the RPS platforms based on biological, solid-state, and other sensing pores, detailing their latest research progress and applications, are reviewed. Their core capability is the high-precision characterization of tiny particles, ions, and nucleotides, which are widely used in biomedicine, clinical diagnosis, and environmental monitoring. However, current RPS methods involve bottlenecks, including limited sensitivity (weak signals from sub-nanometer targets with low SNR), complex sample interference (high false positives from ionic strength, etc.), and field consistency (solid-state channel drift, short-lived bio-pores failing POCT needs). To overcome this, bio-solid-state fusion channels, in-well reactors, deep learning models, and transfer learning provide various options. Evolving into an intelligent sensing ecosystem, RPS is expected to become a universal platform linking basic research, precision medicine, and on-site rapid detection. Full article

Pregnancy introduces significant physiological changes that alter the pharmacokinetics (PK) of antiretroviral therapy (ART), impacting its safety and efficacy in HIV-positive women. Optimizing ART during pregnancy is critical to maintaining maternal virological suppression and preventing mother-to-child transmission (MTCT) of HIV. This review evaluates the impact of pregnancy-induced PK changes on ART and proposes strategies for tailored regimens to improve outcomes. A comprehensive review of published literature was conducted, focusing on PK adaptations during pregnancy and their implications for different ART classes, including protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). Key studies were analyzed to assess drug exposure, efficacy, and safety. Pregnancy significantly alters the PK of antiretrovirals, with increased hepatic metabolism, renal clearance, and changes in plasma protein binding leading to reduced drug exposure. For example, drugs like lopinavir and atazanavir require dose adjustments, while dolutegravir maintains efficacy despite reduced plasma levels. Integrase inhibitors demonstrate favorable virological suppression, although cobicistat-boosted regimens show subtherapeutic levels. Tailored approaches, such as therapeutic drug monitoring (TDM), optimize ART efficacy while minimizing toxicity. Pregnancy-specific PK changes necessitate evidence-based ART adjustments to ensure virological suppression and reduce MTCT risk. Incorporating TDM, leveraging pharmacogenomic insights, and prioritizing maternal and neonatal safety are critical for personalized ART management. Further research into long-acting formulations and global guideline harmonization is needed to address disparities in care and improve outcomes for HIV-positive pregnant women. Full article

The advent of effective antiretroviral therapy in the mid-1990s, which successfully prevented the progression to AIDS in people living with HIV (PLWH), was associated with the appearance of the so-called HIV-associated lipodystrophy. This condition involved subcutaneous fat atrophy; abdominal fat hypertrophy; and, in some cases, lipomatosis. It was also associated with systemic metabolic disturbances, primarily insulin resistance and dyslipidemia. Following the replacement of certain antiretroviral drugs, particularly the thymidine-analog reverse transcriptase inhibitors stavudine and zidovudine, with less toxic alternatives, the incidences of lipoatrophy and lipomatosis significantly declined. However, lipodystrophy resulting from first-generation antiretroviral therapy does not always resolve after switching to newer agents. Although the widespread use of modern antiretroviral drugs—especially integrase strand transfer inhibitors and non-lipoatrophic reverse transcriptase inhibitors such as tenofovir alafenamide—has reduced the incidences of severe forms of lipodystrophy, these regimens are not entirely free of adipose tissue-related effects. Notably, they are associated with weight gain that resembles common obesity and can have adverse cardiometabolic consequences. Recent evidence also suggests the hypertrophy of specific fat depots, such as epicardial and perivascular adipose tissue, in PLWH on last-generation treatments, potentially contributing to increased cardiovascular risk. This evolving landscape underscores the persistent vulnerability of PLWH to adipose tissue alterations. While these morphological changes may not be as pronounced as those seen in classic HIV-associated lipodystrophy, they can still pose significant health risks. The continued optimization of treatment regimens and the vigilant monitoring of adipose tissue alterations and metabolic status remain essential strategies to improve the health of PLWH. Full article

The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense oligonucleotides and synthetic mimics of small interfering RNA (siRNA), microRNA (miRNA), transfer RNA-derived small RNA (tsRNA), and PIWI-interacting RNA (piRNA), elucidating their intricate interactions with crucial cellular machinery, specifically RNase H1, RNase P, AGO, and PIWI proteins, mediating their biological effects. The functional and structural characteristics of these endonucleases are examined in relation to their mechanisms of action and resultant therapeutic outcomes. This comprehensive analysis illuminates the interactions between single-stranded nucleic acids and their endonuclease partners, covering antisense inhibition pathways as well as RNA interference processes. This field of research has important implications for advancing targeted RNA modulation strategies across various disease contexts. Full article

(1) Background: Second-generation integrase strand transfer inhibitors (INSTIs) are now the preferred first-line therapies for human immunodeficiency virus (HIV). However, concerns regarding their side effects, such as weight gain and metabolic disturbances, have emerged. This scoping review aims to assess the effects of INSTIs on the gut microbiota, with a focus on differences between agents and their clinical implications. (2) Methods: A scoping review was conducted using PubMed, Web of Science, and Embase, with reports collected following PRISMA for Scoping Reviews (PRISMA-ScR). (3) Results: The majority of available evidence focused on dolutegravir, which demonstrated beneficial effects on microbiota diversity and composition. However, factors such as younger age, lower CD4+ counts, and extreme BMI were associated with proinflammatory changes. Limited data on bictegravir also suggested favorable alterations in the gut microbiota. Raltegravir, a first-generation INSTI, was associated with improvements in alpha diversity and microbial composition, although these changes were not consistently beneficial. Moreover, associated changes in inflammatory and microbial translocation markers suggested unfavorable alterations. (4) Conclusions: Based on the evidence mapped, second-generation INSTIs may generally induce favorable changes in the gut microbiota. However, further research is needed to explore the clinical implications of these microbiota alterations, particularly in specific patient groups. Full article

The need to prevent crossing planetary boundaries has accelerated sustainable product development and production research. This resulted in the introduction of tools and methods to support the development of sustainable products. However, practice is still challenged by changing requirements, regulations, guidelines, and a plethora of tools. This study aims to identify different tools and methods that support transferring sustainability aspects into technical requirements during product and production development through a systematic literature review in Scopus. The search was limited to articles in the engineering, manufacturing sector, and journal or conference publications in the period between 2014 and 2024. Multiple authors were involved in the selection process to avoid bias. 56 articles were selected and analyzed based on purpose, user, production support, and utilization of the requirements management process. Results indicated that good support for product development and design engineers exists, but not for production, product production co-development, and other stakeholders. A need for a requirements management-based method to support the integration of sustainability aspects during product production co-development is identified. A research framework and three research strands are proposed based on this identified need, which will be developed as future work. Exclusion criteria can introduce some limitations, but the review provides an extensive overview of existing methods and gaps. Full article

The genome is continuously exposed to different harmful factors whose activity causes different types of lesions. On the other hand, during the DNA replication process, a ribonucleoside (rN) can be inserted more frequently than the occurrence of DNA damage in the genome. Notably, it can be expected that their presence and chemical lability change the electronic properties of the double helix. In this study, a short ds-oligo with a single rN was taken into consideration. The ground-state molecular geometry was obtained at the M06-2x/D95* level of theory in the aqueous phase, while the energy and vertical and adiabatic electron affinity and ionisation potential were obtained at M06-2x/6-31++G**. The obtained results indicate that the 3′,5′-phosphodiester bond cleavage is favourable after the adiabatic cation and anion states are achieved by ds-DNA. Moreover, the lowest ionisation potential and highest electron affinity of 2.76 and 5.55 eV, respectively, which make it a suitable endpoint for electrons and holes, have been found for the final product that contains a single-strand break. Additionally, after the internucleotide 3′,5′→2′,5′ bond migration process, proton-coupled electron transfer was found to occur. In this article, the electronic properties of short ds-DNA fragments with ribonucleoside inserts are reported for the first time. The obtained results suggest that rNs can play a significant role in the communication of repair and replication proteins via electron transfer, especially after rearrangement. Moreover, the discussed internucleotide bond stability changes after one-electron oxidation or reduction and can support new radiotherapy strategies that are safer and more effective. Further theoretical and experimental studies are highly warranted. Full article

In this study, we investigated the proportion of transmitted drug resistance (TDR) mutations and human immunodeficiency virus (HIV)-1 subtypes among 487 antiretroviral therapy (ART)-naïve individuals in South Korea from 2021 to 2024 to inform more effective treatment strategies. Consistent with previous reports, subtype B was most prevalent among HIV-1 subtypes at 50.7%; however, its proportion decreased annually (p = 0.047). Various subtypes of circulating recombinant forms (CRFs) were analyzed in this study, resulting in high genetic diversity. The subtype distributions of Korean and non-Korean patients differed, with subtype B (53.7%) and CRF01_AE (34.4%) being dominant in the former and latter, respectively. TDR across antiretroviral drug classes was approximately 3.5% in South Korea. Non-nucleoside reverse transcriptase inhibitors elicited the greatest drug resistance, which increased from 2021 to 2023, with a slight decrease in 2024. The integrase strand transfer inhibitor drugs, elvitegravir and raltegravir, most frequently exhibited high resistance scores. We provide a comprehensive overview of the HIV-1 genetic distribution and TDR patterns in South Korea from 2021 to 2024. Within the broader context of HIV-1 epidemiology in Asia and the Pacific, the findings contribute to a comprehensive understanding of the global distribution of HIV-1 resistance and genotypes, enabling the development of effective interventions. Full article

Dolutegravir-based antiretroviral therapy (ART) simplification is increasingly common, although some patients cannot take this drug due to intolerance or drug resistance. Boosted-protease inhibitors (bPI) might be an option in this scenario. Nevertheless, long-term outcomes have not been studied yet. A controlled cohort study comparing 5-year outcomes of ART simplification bPI-based regimens (without integrase strand transfer inhibitor—INSTI) versus ART maintenance was conducted in a Brazilian referral center. Viral suppression rates and mortality after 5 years were the primary outcomes of the study. Eighty individuals were included in each group; 47.5% were women, and the mean age was 56 years. The five-year survival rate was 88.8% in the simplified group and 87.5% in the maintenance arm (log-rank = 0.41). Viral suppression rate was 78.8% and 70.0%, respectively (p = 0.28). Individuals presented less renal function decline (−5 vs. −10 mL/min/1.73 m²; p < 0.05) in the simplified arm. No difference was observed in metabolic parameters. Based on our findings, ART simplification without INSTI has shown efficacy and safety comparable to maintenance of triple therapy even in the long term, and could be an option in these situations, which might be even more important in settings with limited options. Full article

A treatment-experienced, highly adherent person living with HIV for over 25 years developed resistance mutations against all four major ART classes, including bictegravir (BIC). This led to viral failure on a quadruple regimen including BIC and doravirine (DOR). Resistance emergence was associated with M184V, thymidine analog mutations (TAMs), NNRTI mutations (108I, 234I, 318F), and INSTI mutations (T97A, G140S, Q148H, G149A), likely driven by suboptimal BIC levels due to divalent cation interactions. During a two-month ART interruption, the resistant virus was rapidly replaced by an ancient wild-type strain. Despite resistance to all four ART classes, a genotype-adapted salvage regimen, including fostemsavir, achieved viral suppression within seven months. Full article

The effects of magnesium and sodium on the interactions between aptamer, its specific ligand, and short complementary oligonucleotides (cDNAs) differing in affinity of their binding with the aptamer were studied. Aflatoxin B1 (AFB1) and AFB1-binding aptamer were used in the study. Dependencies for the aptamer binding with the fluorophore-labeled AFB1 under varied concentrations of the cations were obtained using fluorescence anisotropy measurements. The increase of the aptamer affinity to AFB1 in the presence of cations was demonstrated using fluorescence anisotropy and isothermal calorimetry. The collected data indicate that 300 mM Mg²⁺ (significantly more than the range commonly used in aptamer sensors) provides the best affinity (16.5 ± 2.2 nM) of the aptamer–AFB1 complexation. Sodium decreases the Mg²⁺-modulated affinity at some Na⁺/Mg²⁺ ratios. The aptamer affinity with cDNAs increases with concentration of cations, but not in the same way as for AFB1. Based on the characterized conditions for bimolecular interactions, the ligand-induced displacement of cDNAs was studied with the registration of the Forster fluorescence energy transfer (FRET). The most sensitive revealing of AFB1 (IC10% 3.2 ± 0.3 nM) in this three-compound FRET system was demonstrated for cDNA having an equilibrium constant of the aptamer binding close to the constant of the aptamer–AFB1 reaction. Full article

The spatial distribution of equiaxed crystal zones during extra-thick slab solidification exerts a critical influence on the mechanical performance of the final product. This investigation establishes a dual-pathway control framework for solidification structure modulation, differentiating between intrinsic regulation through columnar-to-equiaxed transition (CET) positioning and extrinsic intervention via strand electromagnetic stirring (S-EMS) parameter adjustment. The aim is to improve the internal quality of extra-thick slabs, enabling further investigations into the material properties. To achieve this, a solidification heat transfer model along with a cellular automata–finite element model were developed to characterize the thermal conditions at CET initiation, with experimental validation conducted on a 475 mm extra-thick slab. The systematic analysis identified a significant correlation between continuous casting parameters, alloy concentrations, and CET positioning, while S-EMS experiments further elucidated the distribution patterns of the solidification structure and the formation mechanism of the white band in the mushy zone. This methodology bridges computational metallurgy with process engineering, offering systematic guidance for solidification structure control in extra-thick slabs. Full article

The scale-up of antiretroviral therapy (ART) has markedly increased pretreatment drug resistance (PDR) among newly diagnosed HIV-infected individuals. This study aims to assess the prevalence and characteristics of PDR, infer the genetic transmission network, and evaluate the effect of PDR on ART in Nanning City, Guangxi. Methods: This study was conducted in the Fourth People’s Hospital of Nanning from 2019 to 2023. PDR was estimated using the Stanford algorithm. Genetic transmission networks were inferred by HIV-TRACE and visualized with Cytoscape. Logistic regression identified PDR-related factors. The Cox proportional hazards model assessed the impact of drug resistance on virological and immunological failure. Among 234 participants, the prevalence of PDR was 8.97%. CRF07_BC (35.9%), CRF-01AE (27.35%), and CRF08_BC (23.9%) were the top three HIV-1 strains. Resistance to non-nucleoside reverse-transcriptase inhibitors, protease inhibitors, nucleoside reverse-transcriptase inhibitors, and integrase strand-transfer inhibitors was 4.27%, 2.56%, 1.28%, and 0.43%, respectively. Overall, 21.37% of the participants exhibited drug resistance mutations (DRMs). Homosexuals were less likely to have PDR compared to heterosexuals ([aOR] 0.09, 95% CI 0.01–0.86). In the genetic network, V179D/E was also the most frequent DRM. Additionally, the incidence of virological failure (19.23%) and immune failure (20.09%) after one year of treatment did not show significant differences in different drug resistance groups. Conclusions: The prevalence of PDR in Nanning City is moderate, driven largely by the V179D and K103N mutations. The cross-transmission networks emphasize the imperative of PDR testing and targeted interventions. Full article

In this study, novel fluorescent DNA biosensors for mercury (Hg²⁺) and silver (Ag⁺) ions were developed based on thymine (T)- and cytosine (C)-rich recognition elements in combination with exonuclease III and a mismatch-catalyzed hairpin assembly (MCHA)-based cascade isothermal signal-amplification strategy. In the presence of the respective target analytes, the recognition element terminals form so-called T-Hg²⁺-T or C-Ag⁺-C structures, resulting in cleavage by Exo III and the release of the trigger strand for MCHA. This binds to the H1 hairpin, which is fluorescently labeled with carboxyfluorescein (FAM) and tetramethylrhodamine (TAMRA), disrupting fluorescence resonance energy transfer between them and, thus, restoring FAM fluorescence, generating a strong signal at 520 nm. The linear range of the Hg²⁺ sensor is 0.5 to 3 pM, with a detection limit of 0.07 pM. The recovery range in actual spiked water samples is between 98.5% and 105.2%, with a relative standard deviation (RSD) ranging from 2.0% to 4.2%. The linear range of the Ag⁺ sensor is 10 to 90 pM, with a detection limit of 7.6 pM. The recovery range in actual spiked water samples is between 96.2% and 104.1%, with an RSD ranging from 3.2% to 6.3%. The cascade isothermal signal amplification strategy effectively enhances sensor sensitivity, while MCHA decreases the false-positive rate. The aptamer sensor exhibits high specificity, is resistant to interference, and can be used for the detection of Hg²⁺ and Ag⁺ in environmental water samples. Full article

Here, we demonstrate through AFM imaging and CD spectroscopy that the binding of silver ions (Ag⁺) to poly(dGdC), a double-stranded (ds) DNA composed of two identical repeating strands, at a stoichiometry of one Ag⁺ per GC base pair induces a one-base shift of one strand relative to the other. This results in a ds nucleic acid-Ag⁺ conjugate consisting of alternating CC and GG base pairs coordinated by silver ions. The proposed organization of the conjugate is supported by the results of our Quantum Mechanical (QM) and Molecular Mechanics (MMs) calculations. The reduction of Ag⁺ ions followed by the partial oxidation of silver atoms yields a highly fluorescent conjugate emitting at 720 nm. This fluorescent behavior in conjugates of long, repetitive ds DNA (thousands of base pairs) with silver has never been demonstrated before. We propose that the poly(dGdC)–Ag conjugate functions as a dynamic system, comprising various small clusters embedded within the DNA and interacting with one another through energy transfer. This hypothesis is supported by the results of our QM and MMs calculations. Additionally, these DNA–silver conjugates, comprising silver nanoclusters, may possess conductive properties, making them potential candidates for use as nanowires in nanodevices and nanosensors. Full article