Synthesis and functional characterization of a recombinant HIV-1 reverse transcriptase variant carrying twelve drug-resistance mutations as a platform for antiretroviral screening.

The aim : to perform surveillance over HIV-1 drug resistance mutations among people living with HIV without history of antiretroviral therapy as well as among those receiving antiretroviral treatment and residing in different territories of the Far Eastern Federal district. Materials and methods . A total number of 420 patients diagnosed with HIV-infection and residing in 8 constituent entities of the Far Eastern Federal district were examined. «AmpliSense® HIV-Resist-Seq» kit was used to perform sequencing of the amplified fragments of HIV-1 pol-gene coding protease and a part of reverse transcriptase to detect drug resistance mutations. Stanford University HIVdb Program was employed to retrieve information on drug-resistance mutations. Results and discussion : sub-subtype A6, which is prevalent in Russia, was also dominant in the surveyed group of patients and was isolated in 282 cases (67.1%). A total number of 49 samples were typed as subtype B (11.7%), 12 samples as subtype C (2.9%), 4 samples as subtype G (1.0%). Subtype A7 (0.2%) was detected in one patient from the Republic of Sakha (Yakutia). Different recombinant forms of the virus were identified in 72 patients (17.1%). Percentage of recombinant forms derived from subtypes A and G totaled 80.6% (n=58). Surveillance drug resistance mutations were revealed in 108 out of 248 patients undergoing antiretroviral treatment (43.5%) and in 6 out of 172 treatment-naïve patients (3.5%). Drug resistance to non-nucleoside inhibitors of reverse transcriptase drugs was most common in both treatment naïve patients and those with a prior experience of antiretroviral therapy. Conclusion : regular surveillance of acquired drug resistance provides insight into the effectiveness of HIV prevention and treatment programs in the constituent entities of the Russian Federation and will allow the development of recommendations for treatment strategies.

Computational prediction and SLN formulation of Narcissin for reverse transcriptase inhibition and controlled drug delivery applications.

Doravirine is a non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) designed to address the limitations of other NNRTIs, particularly resistance due to common RT substitutions including K103N, Y181C, and G190A. This report summarizes the development of genotypic and phenotypic resistance to doravirine through week 192 of the DRIVE-FORWARD (NCT02275780) and DRIVE-AHEAD (NCT02403674) phase 3 studies in adults with previously untreated HIV-1. Participants were randomized (1:1) to the doravirine or comparator regimen (darunavir/ritonavir or efavirenz) for 96 weeks (double-blind phase), followed by 96 weeks of the doravirine regimen (open-label extension). Resistance was evaluated in participants with protocol-defined virologic failure (PDVF; nonresponse or rebound) or treatment discontinuation (d/c) for other reasons and HIV-1 RNA >400 copies/mL. Of 747 participants randomized to doravirine, 51 (34 PDVF, 17 d/c) met resistance-testing criteria. Doravirine resistance-associated mutations (RAMs) were detected in 12/51 participants, by week 48 in 9/12, with phenotypic resistance to doravirine in 10. Of 502 participants who switched from comparator to doravirine, 9 (6 PDVF, 3 d/c) met resistance-testing criteria: Doravirine RAMs were detected in 4/9, conferring phenotypic resistance to doravirine in 3. The most common doravirine RAMs were V106A/I/M and F227C. Common RAMs observed with other NNRTIs (K103N, Y181C, K101E, E138K, and G190A) were not detected in any participant who met resistance-testing criteria. In DRIVE-FORWARD and DRIVE-AHEAD, the development of resistance to doravirine was uncommon (genotypic 1.3%; phenotypic 1.0%) and occurred mainly during the first 48 weeks of treatment. Overall, the RAMs observed with doravirine were distinct from those of other NNRTIs.

Discovery of novel diarylpyrimidine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors: Design, synthesis and biological activity evaluation.

Association between facial lipoatrophy and self-esteem in people living with HIV/AIDS on antiretroviral therapy in Brazil: A cross-sectional study.

Molecular characterization of non-polio enterovirus in children with acute flaccid paralysis in Iraq.

Investigating the mechanism by which telomere dysfunction affects mitochondrial homeostasis in anthracosilicosis using a Terc knockout model.

Several phytochemicals exhibited high level of antiviral activity. Medicinal plant possessed antiviral activity via many mechanisms included inhibition of viral replication, inhibition of the assembly of intracellular infectious virus particles, inhibition of viral infectivity, inhibition of RNA polymerase, DNA polymerase, viral neuraminidase, protease, reverse transcriptase and viral protein expression and many other mechanisms. Many natural products showed potent anti- herpes activity. The current research reviewed the medicinal with anti-herpes effect to encourage further research for development of future anti-herpes remedies.

Background/Objectives: Telomeres and telomerase play crucial roles in cellular aging and genome stability. Emerging evidence indicates that alterations in telomerase activity and telomerase reverse transcriptase (hTERT) gene expression may be involved in cardiovascular pathophysiology. However, data on telomerase regulation in patients with stable coronary artery disease (CAD) are limited. This study aimed to compare serum telomerase concentration and hTERT gene expression levels between patients with stable CAD and healthy controls. Methods: A total of 52 patients diagnosed with stable CAD and 50 age-matched healthy controls were enrolled prospectively. Telomerase concentrations were measured in serum samples using the ELISA method, and hTERT mRNA expression was measured in blood samples using RT-PCR. Results: Serum telomerase levels were significantly higher in patients with stable CAD compared with controls (p < 0.05). Similarly, hTERT gene expression was upregulated in the patient group (p < 0.05). Multivariable analysis showed that increased log-transformed telomerase levels (AOR: 2.12, 95% CI: 1.14–5.13, p = 0.024) and hTERT expression (AOR: 1.79, 95% CI: 1.09–3.27, p = 0.037) were independently associated with coronary vessel involvement in stable CAD. These findings indicate an increase in both telomerase level and hTERT transcriptional activity in stable CAD. Conclusions: Increased telomerase level and hTERT expression may reflect a compensatory response to chronic vascular stress and are associated with disease severity in stable CAD.

The Arabidopsis thaliana La1 (AtLa1) protein is a member of the genuine La family of RNA biogenesis proteins, which are structurally similar to the La-related protein 7 (LARP7) family. LARP7 proteins participate in the biogenesis of the telomerase ribonucleoprotein complex in model systems, but are absent in plants. We show that AtLa1 binds to telomerase RNA in a manner reminiscent of the Tetrahymena LARP7 protein p65. Classical in vitro methods and microscale thermophoresis (MST) were used to specify the molecular structures involved in this multi-surface interaction. AtLa1 also enhances the binding of TR to the telomerase reverse transcriptase RNA binding domain. We therefore propose that biogenesis of telomerase RNA in plants and ciliates is achieved by a similar pathway, differing in the employment of genuine La or LARP7-like proteins, respectively. We also report that the domain of unknown function (DUF3223, DeCL) found in the AtLa1 protein binding partner, Domino, is an RNA binding domain with modest TR-binding capacity. This domain is also found in plant and ciliate proteins, including plant polymerases IV/V and the Tetrahymena La protein Mlp1. Together, these suggest that RNA biogenesis pathways in plants and ciliates have a conserved evolutionary relationship, with parallels between their La proteins.

Azvudine is a nucleoside reverse transcriptase inhibitor (NRTI) and belongs to the family of 2', 3'-dideoxynucleoside (ddNs) that can mimic natural nucleosides and block viral DNA or RNA chain synthesis and prevent viral replication. Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, Azvudine has been used to treat patients with COVID-19. Therefore, the objective of this meta-analysis study was to compare Azvudine and Nirmatrelvir-Ritonavir in hospitalised patients. The global online databases were used to identify relevant studies published between January 2019 and October 2024. The quality of all articles was determined using the Newcastle-Ottawa Scale (NOS) checklist. In this study, heterogeneity assay was assessed using the Cochran's Q-test and the I2 index, and STATA software version.14 (StataCorp) was used for statistical analysis. Egger's test, Begg's test, and funnel plot were performed to estimate of the publication bias, and the impact of each study on the overall estimate was assessed using sensitivity analysis. In this study, 19 studies were included in this meta-analysis. The results of the meta-analysis showed that the relative risk of death in the Azvudine treatment group compared with the Nirmatrelvir-Ritonavir treatment group was 0.64 (95% CI: 0. 44, 0. 93). These results suggest that treatment with Azvudine may provide significant clinical benefit in patients hospitalised with COVID-19.

This critical and selective review synthesizes the accumulating body of biological evidence supporting a process we term epigenetic-genetic coupling as a mechanistic basis for Lamarckian inheritance of somatically acquired adaptations. We propose that evolutionary processes in mammals and higher vertebrates can involve deaminase-driven, reverse transcriptase-mediated, RNA-templated targeted homologous recombination. We contrast well-established examples of "Soft", reversible epigenetic inheritance with historical and contemporary evidence suggestive of stable, DNA-integrated "Hard" Lamarckian transgenerational inheritance. Our analysis indicates that the establishment of "Hard" Lamarckian inheritance may require specific population dynamics, including inbreeding or interbreeding among phenotypically affected offspring, together with sustained and defined environmental stimuli over one or more generations to consolidate the acquired traits at the genomic level. We also present molecular and cellular evidence supporting RNA-to-DNA genetic feedback mechanisms involving targeted genomic integration, primarily mediated by the DNA repair-associated reverse transcriptase activity of DNA polymerase η. Finally, we review diversification mechanisms in molecular and cellular immunology that now routinely employ single-molecule, real-time, long-read genomic sequencing (6-8 kb). We recommend the broader application of these technologies in future breeding and experimental programs across other somatic systems. Their deployment offers a robust strategy for securing definitive "Hard" molecular evidence of Lamarckian acquired inheritance in diverse biological contexts; including somatically acquired immunity, as well as adaptive behavioral and central nervous system phenotypes. This is compatible with our over-arching goal-to provide an experimental road map of conceptual options to drive future experimentation in acquired inheritance breeding programs.

Short interspersed elements (SINEs) are non-autonomous retroelements that are transcribed by RNA polymerase III from an internal promoter. Most SINE families originate from tRNAs, but a few, exclusively within supraprimates (primates, rodents, tree shrews) and, exceptionally, hagfish, derive from the 7SL RNA. These 7SL-derived SINEs all arose after an ~ 183-nt central deletion in the 7SL RNA sequence and are mobilized by LINE1-encoded reverse transcriptase. No 7SL-derived SINE has previously been reported outside these taxa. Mining of mole (Talpidae) genomes revealed no mole-specific tRNA-derived SINE in the gracile shrew mole Uropsilus gracilis. Instead, ~ 280 000 copies of a dimeric 7SL RNA-derived SINE, named Urop, populate its genome but not five other talpid species. Three subfamilies (a-c) share two 7SL-derived monomers joined by an A-rich linker. The left monomer and Urop_a right monomer carry the canonical central deletion; Urop_b/c right monomers additionally harbor a 24-nt tandem duplication, paralleling the 29-nt quasi-dimer of murid B1. Monomeric fossils suggest they preceded dimeric Urop formation. Sequence divergence and subfamily analysis date the origin of Urop soon after the Uropsilinae split from other moles. Urop_c, the youngest subfamily, displays a striking excess of extra-long pure poly(A) tails, far exceeding those in young human AluY elements. Urop represents a remarkable case of convergent evolution, independently generating an Alu-like dimeric SINE in a distantly related mammal. Its independent origin from 7SL RNA, parallel structural trajectory (monomer → dimer via identical deletion boundaries), and suppression of tRNA-derived SINEs mirror the evolutionary history of primate Alu. The abundance of long intact poly(A) tails in Urop_c suggests unique biochemical controls on tail dynamics and hint at continued retropositional activity. These findings underscore the exceptional evolutionary potential of rare, large-scale deletions within 7SL RNA as a SINE progenitor and raises new questions about poly(A) tail regulation and SINE family dynamics.

Telomere recapping via gene therapy as a beneficial strategy for cardio-renal syndrome type 4.

ABSTRACTHuman telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers and is an important target for cancer therapy. In this study, HS1002 was synthesized based on the amino acid sequences of gonadotropin‐releasing hormone (GnRH) and hTERT. This study aimed to evaluate HS1002's anticancer activity and its effects on the gonadotropin‐releasing hormone receptor (GnRHR) and hTERT in prostate cancer cells. HS1002 increased cytosolic calcium influx in GnRHR‐overexpressing HEK293 cells and showed specific molecular docking interactions with GnRHR. Compared with prostate cancer cell lines, HS1002 exhibited the highest cytotoxicity against LNCaP cells. The hTERT expression correlated with telomerase activity was suppressed by HS1002, resulting in reduced metastasis and increased apoptosis and autophagy. Additionally, HS1002 suppressed c‐Myc and ERK protein expressions in LNCaP cells. Furthermore, HS1002 inhibited tumor growth and downregulated hTERT expression in the xenograft model tumor tissues. HS1002/IL‐2‐pretreated PBMCs also exhibited potent cytotoxicity toward LNCaP cells. In addition, HS1002 increased the production of granzyme B and IFN‐γ in CD8+ T cells in MC38 syngeneic mice. These findings demonstrate that HS1002 suppresses prostate cancer cell growth and induces anticancer immunity, suggesting its potential as a novel therapeutic agent against prostate cancer.

Onset and progression of cardiovascular diseases are tightly linked to the aging process. Aging results in structural and functional changes including endothelial dysfunction and senescence, thereby impairing vascular functions. The molecules involved in these processes are far from understood. The cellular redox homeostasis and proteostasis as well as mitochondrial functionality play key roles in the maintenance of the endothelium and are impaired in senescence and aging. Over the last few years, several proteins, which were previously ascribed functions in other pathways and/or cellular compartments, have been shown to be involved in the regulation of these processes. These include G protein-coupled receptors, chaperones in the endoplasmic reticulum, and the proteins cyclin-dependent kinase inhibitor 1B/p27KIP1 and telomerase reverse transcriptase, which were assigned previously unknown functions in the mitochondria. Based on the specific functions of these proteins, modulation of their signaling pathways, activity or subcellular localization, might provide leads for new therapeutic approaches targeting aging-associated endothelial dysfunction and vascular diseases. The proteins described in this review undoubtedly have functions in endothelial cells and the vasculature. However, before they are considered as potential therapeutic targets, potential side effects in other cell types and tissues should be critically investigated. This might be most important for proteins, which have diverging functions in different compartments of a cell. Although several new pathways affecting endothelial functionality have been identified and might be of therapeutic relevance, further research is required to fully understand the exact molecular mechanisms. Antioxid. Redox Signal. 00, 000-000.

Retrons represent a novel class of bacterial defense systems that employ reverse transcriptase (RT), noncoding RNA, and effector proteins to counteract phage infections. In this study, we elucidate the molecular mechanism of a retron system, Retron–Eco8. Biochemical experiments reveal that the Retron–Eco8 holocomplex, rather than the effector alone, exhibits double-stranded DNA cleavage activity, triggering abortive infection and therefore effectively halting phage propagation. Cryo-electron microscopy (cryo-EM) analysis reveals a supramolecular assembly comprising four RT subunits, four multicopy single-stranded DNA molecules, and four overcoming lysogenization defect (OLD) nucleases—a configuration critical for antiphage defense. Notably, we examine the activation of Retron–Eco8 by diverse single-stranded DNA-binding (SSB) proteins, and phylogenetic analysis of these SSB proteins elucidates the phage resistance specificity. Collectively, our findings delineate the structural architecture of the Retron–Eco8 defense complex and provide mechanistic insights into retron-mediated bacterial immunity.

Molecular regulation of telomeric elongation and TERT splicing in planarians.

Human endogenous retroviruses (HERVs) occupy nearly 8% of the human genome, yet their protein-coding potential remains largely unexplored. Originating from ancestral retroviruses that infected germline cells, HERVs typically follow the canonical proviral structure LTR–gag–pol–env–LTR, where gag, pol, and env encode structural, enzymatic, and envelope proteins. We present a comprehensive resource annotating conserved retroviral domains across 120 000 + ORFs derived from internal HERV regions. Using a reproducible pipeline based on HMMER and InterProScan, we identified over 17 000 domain hits—primarily from pol genes such as reverse transcriptase, RNase H, and protease—and quantified their structural conservation. Hundreds of domains exceed 95% alignment coverage, revealing a surprising abundance of full-length retrovirus-like domains in both young and ancient families. The HERVK (HML-2) subfamily retains the most complete polyprotein architecture, including 13 loci with nearly intact Gag, Pol, and Env, but full-length Pol domains are also found in HERVH, HERVW, and HERVE. Our annotations recover conserved catalytic motifs in Pol and transmembrane features in Env, enabling fine-grained functional interpretation. All results—including BED, FASTA, domain sequences, InterProScan outputs, and transmembrane predictions—are provided as an open resource at Zenodo to support downstream analyses of HERV protein expression, immune modulation, and co-option in health and disease.