Search Results (36)

Background: Deaf and hard-of-hearing (DHH) adolescents in mainstream schools may face communication barriers and social challenges that can affect their well-being and health. However, population-based knowledge based on adolescents’ own reports—particularly including those with additional disabilities—remains limited. The aim of this study was to assess self-reported well-being, mental health complaints, somatic complaints, and perceived teacher support among DHH adolescents in Swedish mainstream schools and to compare these outcomes with those of hearing adolescents and DHH adolescents with additional disabilities. Methods: This cross-sectional study was based on data from the Swedish school survey Liv och Hälsa Ung (Life and Health of Young People). The sample comprised 5923 adolescents aged 13–18 years attending grades 7 and 9 in compulsory school and year 2 in upper-secondary school. Outcomes included well-being (WHO-5 or a single-item measure for grade 7), mental health complaints, somatic complaints, and perceived teacher support. Group differences by hearing status, additional disability, gender, and school level were examined using analysis of variance (ANOVA). Results: Hearing adolescents reported higher well-being, fewer somatic complaints, fewer mental health complaints, and higher perceived teacher support compared with DHH adolescents. DHH adolescents with additional disabilities consistently reported the poorest outcomes across all domains. For example, perceived teacher support was significantly lower among DHH adolescents with additional disabilities (M = 3.66, 95% CI [3.54–3.78]) compared with hearing adolescents (M = 4.01, 95% CI [3.99–4.03]). Across all groups, girls, particularly those with disabilities, reported poorer well-being and higher levels of somatic and mental health complaints than boys. Conclusions: The findings highlight substantial health disparities among adolescents with hearing loss in mainstream schools, especially among those with additional disabilities. Perceived teacher support emerged as an important contextual factor and may represent a key target for school-based interventions aimed at promoting well-being and mental health among DHH adolescents. Full article

Tuberculosis (TB) remains a global health issue exacerbated by spreading drug resistance and lengthy treatment regimens. Targeting bacterial DNA-repair pathways, particularly those counteracting host-generated genotoxic stress, represents a promising strategy to sensitize Mycobacterium tuberculosis to existing antibiotics. Through structure-based virtual screening of a compound library, we identified novel small-molecule inhibitors of M. tuberculosis uracil–DNA glycosylase (MtbUng), an enzyme essential for the repair of DNA damage inflicted by macrophage-produced reactive nitrogen species. Experimental validation revealed that four derivatives of usnic acid, a lichen-derived metabolite, significantly inhibited MtbUng activity, with the most potent compound, OL10-88-1, exhibiting IC₅₀ 26 ± 7 µM. Molecular docking suggests that OL10-88-1 inhibits MtbUng by occupying both the active site and the DNA-binding groove, thereby disrupting multiple steps of uracil recognition. The compounds also showed variable inhibitory activity against uracil–DNA glycosylases from Escherichia coli, humans, and vaccinia virus. Our findings establish that the compound could potentially be used in combination therapies to enhance the efficacy of current anti-TB drugs by exploiting the vulnerability of DNA-repair-deficient mycobacteria. Full article

The article presents the current state of knowledge on genetic modifiers of ovarian cancer risk in women carrying pathogenic variants (PVs) in the BRCA1 and BRCA2 genes, which are major contributors to hereditary susceptibility to this malignancy. Although PV carriers have high disease penetrance (BRCA1: ~40% and BRCA2: 11–27%), substantial variability in individual risk is observed, suggesting the influence of additional genetic variants. Background: Ovarian cancer is characterized by late detection and high mortality, and a significant portion of risk among BRCA1/2 carriers is shaped by reproductive and environmental factors as well as genetic modifiers. The article emphasizes that carriers of the same BRCA PV can exhibit markedly different risk levels depending on additional variants that modulate key biological processes, such as DNA repair, cell cycle regulation, and apoptosis. Methods: A systematic literature search covering the years 1996–2025 was conducted in the PubMed database. Initially, 734 publications were identified; after removing duplicates, thematically irrelevant articles, non-full-text papers, and studies not meeting the inclusion criteria, 47 articles were included in the review. These studies covered candidate gene analyses, GWAS, and data from the CIMBA consortium, which enables the examination of large cohorts of PV carriers. Results: The review identified numerous variants associated with increased or decreased ovarian cancer risk in BRCA1 carriers, including the following: OGG1, DR4, MDM2, CYP2A7, CASP8, ITGB3, HRAS1, TRIM61, and MTHFR. The reviewed studies also identified both protective and risk-increasing variants among BRCA2 PV carriers: UNG, TDG, and PARP2, and haplotypes in ATM, BRIP1, BARD1, MRE11, RAD51, and 9p22.2. The analysis identified 11 variants affecting both BRCA1 and BRCA2 carriers, most of which increase risk, including the following: IRS1, RSPO1, SYNPO2, BABAM1, MRPL34, PLEKHM1, and TIPARP. Protective variants include BNC2 and LINC00824. The only SNP reaching genome-wide significance (p < 5 × 10⁻⁸) was in BNC2. Conclusions: The article summarizes the growing number of genetic modifiers of ovarian cancer risk among BRCA1/2 carriers and highlights their potential to improve individualized risk assessment, enhance patient stratification, support personalized prevention and surveillance strategies, deepen the understanding of disease biology, and identify potential therapeutic targets. Full article

DNA repair is a multifaceted biological process that involves multiple pathways to counter the types of damage the genome encounters throughout life. In the past decade zebrafish became a popular model organism to study various aspects of vertebrate DNA repair, and the characterization of several mutant lines deficient in key players of the repair pathways has significantly contributed to our understanding of the roles the corresponding proteins play in the maintenance of genomic integrity. Interestingly, the base-excision repair (BER) pathway remained one of the less characterized DNA repair processes in fish. Here we provide a detailed characterization of zebrafish deficient in one of the key components of BER, the uracil-DNA glycosylase Unga. We show that while these fish are viable, they display an altered response to genotoxic stress and unga mutant males show an interesting form of subfertility. Full article

Uracil−DNA glycosylases (UNGs) are DNA repair enzymes responsible for the removal of uracil, a canonical RNA nucleobase, from DNA, where it appears through cytosine deamination or incorporation from the cellular dUTP pool. While human and Escherichia coli UNGs have been extensively investigated, much less is known about their plant counterparts, of which UNGs from Arabidopsis thaliana are the only studied examples. Here, we show that in sugar beet (Beta vulgaris L.), an important crop species, cold and salt stress induce the expression of the UNG gene (BvUNG) and modulate the level of the uracil-excising activity in the roots. Purified recombinant BvUNG efficiently removes uracil from DNA both in vitro and in an E. coli reporter strain but does not excise 5-hydroxyuracil, 5,6-dihydrouracil, or 5-hydroxymethyluracil. The activity is abolished by Ugi, a protein UNG inhibitor from PBS1 bacteriophage, and by a mutation of a conserved active site His residue. Structural modeling shows the presence of a disordered N-tail prone to undergo phase separation, followed by a long α helix oriented differently from its counterpart in human UNG. Overall, BvUNG is a functional uracil–DNA glycosylase that might participate in the response to abiotic stress. Full article

Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1^{rtTAadv-TRE-UNG1Y147A}). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts (CTGF, FN1, PAI1, and SFRP1) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1^{rtTAadv-TRE-UNG1Y147A} cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction. Both models resulted in upregulation of CTGF, FN1, and PAI1; additionally, EtBr treatment but not Dox induction resulted in SFRP1 upregulation. In conclusion, two models of mitochondrial depletion were demonstrated in immortalized TM cells; damage was associated with increases in OAG-associated transcripts, supporting a link between mitochondrial damage and glaucoma phenotypes. Full article

Background: Due to their antibacterial activities, essential oils can be potential alternatives to antibiotics in certain cases. West Indian lemongrass (Cymbopogon citratus) essential oil (LEO) is effective against a broad range of bacteria by inhibiting spore formation, and is considered safe. In this study, we demonstrated its therapeutical potential in the treatment of pitted keratolysis (PK), a superficial skin infection affecting the pressure-bearing areas of plantar surfaces. Methods: For in vitro antibacterial efficacy testing, LEO was mixed into different ointment bases, including Hydrogelum methylcellulose FoNo VIII., Ungentum oleosum FoNo VIII. (Ung. oleoso), Unguentum stearini FoNo VIII. (Ung. stearin), and Vaselinum cholesterinatum FoNo VIII. (Vasel. cholest.), at different concentrations of 1, 3, and 5%. These formulations were tested on representatives of three bacterial species associated with PK: Kytococcus sedentarius, Dermatophilus congolensis, and Bacillus thuringiensis. Results: In the in vitro tests, Hydrogelum methylcellulose (HM) gel best supported the antibacterial effects of LEO, reducing the number of living bacteria on agar plates by 4–5 orders of magnitude in a concentration-dependent manner during the 30 min exposure times. This was also confirmed by the Franz diffusion cell drug release test; after 30 min, several active compounds could be detected in the HM samples, in contrast to the other bases. Shelf-life experiments showed that the HM base supported the antibacterial features of 3% LEO for at least 2 years without significant loss of efficacy. Conclusions: Our study highlights that ointments containing essential oils potentially have a place in the treatment of PK. Therefore, antibiotics may potentially be replaced for the treatment of PK, thereby reducing environmental antibiotic pressure, which is one of the driving forces behind the spread of antibiotic resistance. Full article

Unique genes refer to genes specific to a particular organism and play crucial roles in the biological functions, evolutionary processes, and adaptations to external environments. However, the roles of unique genes in plant pathogenic fungi remain largely unexplored. In this study, we identified a novel unique gene in the rice blast fungus Magnaporthe oryzae, named MoUNG (M. oryzae unique gene), through T-DNA insertion mutagenesis. The disruption of the MoUNG promoter region in the T-DNA insertion mutant (T30-104) led to an almost loss of MoUNG expression. MoUNG has no functional domains and lacks homologues in other organism. It is highly expressed during the early-infection stage between 16 and 32 h post-inoculation (HPI), in contrast to its expression in mycelia and at the later infection stage of 48 HPI. Notably, attempts to knock out MoUNG were unsuccessful, so we examined the T30-104 mutant and found it showed significantly reduced growth, conidiation, and pathogenicity. Introducing the full-length MoUNG with its promoter into T30-104 restored these phenotypic defects. Additionally, subcellular localization assays revealed that MoUNG exhibits a dot-like distribution within the cytoplasm of mycelium, conidium, appressorium, and invasive hypha. Furthermore, knock-down of MoUNG produced results similar to those observed with the insertion mutation. In conclusion, we identified a novel unique gene MoUNG in M. oryzae and demonstrated its involvement in growth, conidiation, and pathogenicity. Full article

The Human Immunodeficiency Virus (HIV) encodes several proteins that contort the host cell environment to promote viral replication and spread. This is often accomplished through the hijacking of cellular ubiquitin ligases. These reprogrammed complexes initiate or enhance the ubiquitination of cellular proteins that may otherwise act to restrain viral replication. Ubiquitination of target proteins may alter protein function or initiate proteasome-dependent destruction. HIV Viral Protein R (Vpr) and the related HIV-2 Viral Protein X (Vpx), engage the CRL4-DCAF1 ubiquitin ligase complex to target numerous cellular proteins. In this review we describe the CRL4-DCAF1 ubiquitin ligase complex and its interactions with HIV Vpr and Vpx. We additionally summarize the cellular proteins targeted by this association as well as the observed or hypothesized impact on HIV. Full article

Vesicles are characteristic structures within the outer layer of many stony meteorites’ fusion crusts. Although these features are well-developed in hydrated carbonaceous chondrites and some micrometeorites, their formation mechanism remains poorly understood. This study provides new insights into the understanding of physical vesiculation processes by presenting the results of vesicle size distribution (VSD)—i.e., a quantitative method for vesicle analysis—applied to the study of the Tagish Lake (C2-ung) meteorite fusion crust. Tagish Lake was chosen because it shows a scoriaceous texture and a significant number of vesicles (about 24,000 vesicles/mm²), thus allowing statistical analysis. Vesicles range from being spherical to irregular-shaped and from a few μm to ~70 μm (equivalent diameter) in size. Vesicle size distribution and cumulative number density analyses show a high nucleation event and a fractal distribution of the vesicle population, respectively. We suggest these features are due to disequilibrium degassing processes, which simultaneously produce continuous/accelerating vesicle nucleation and growth. Finally, possible analogies between the scoriaceous Tagish Lake fusion crust and the space-weathered “frothy layer” on the surface of Ryugu’s grains could be found in terms of vesicularity. Full article

The image of the Apsara, a celestial dancer in Cambodian myth, is closely associated with Cambodian cultural preservation practices like Cambodian classical dance. The Apsara, its aesthetic features and its association with Cambodian cultural preservation have taken on new meaning in Cambodia’s diasporic communities. In the diaspora, Apsara aesthetics have come to symbolize Cambodian heritage, history and identity, becoming a major feature of performances by Cambodian diasporic artists. However, orientalist expectations of Asian performers in the diaspora, paired with both the forgotten history of colonial intervention in Cambodian arts and state-sanctioned initiatives towards Cambodian nationalism, contributes to orientalist (and thus racialized) expectations of Cambodian diasporic performance. Mixed-race artists fail to fit neatly into the dominant narratives of Cambodian performance and have been marginalized by the Cambodian diasporic community’s dominant conceptions of performance that are rooted in cultural preservation. As people that sit outside of the aestheticized markers of Cambodian-ness, mixed-race artists often struggle to have their work and their subjectivities recognized by their communities. To circumvent questions of their racial legibility, mixed-race Cambodian American artists construct performances that are strategically padded with markers of Khmer identity by engaging with Apsara aesthetics. This article will explore how three different SoCal-based artists have negotiated their Cambodian American identity and cultural politics through performance and/or performance related materials (ads, images, etc.). I will be using examples from the work of music artist and violinist Chrysanthe Tan, theater practitioner Kalean Ung, and autoethnographic engagement with my own creative projects to show how examining the work of multi-racial Cambodian American performing artists can bring forth the complex dynamics of Cambodian diasporic cultural politics and belonging. Full article

Vacuolar sugar transporters transport sugar across the tonoplast, are major players in maintaining sugar homeostasis, and therefore play vital roles in plant growth, development, and biomass yield. In this study, we analyzed the physiological roles of the tonoplast monosaccharide transporter 2 (TMT2) in Arabidopsis. In contrast to the wild type (WT) that produced uniform seedlings, the tmt2 mutant produced three types of offspring: un-germinated seeds (UnG), seedlings that cannot form true leaves (tmt2-S), and seedlings that develop normally (tmt2-L). Sucrose, glucose, and fructose can substantially, but not completely, rescue the abnormal phenotypes of the tmt2 mutant. Abnormal cotyledon development, arrested true leaf development, and abnormal development of shoot apical meristem (SAM) were observed in tmt2-S seedlings. Cotyledons from the WT and tmt2-L seedlings restored the growth of tmt2-S seedlings through micrografting. Moreover, exogenous sugar sustained normal growth of tmt2-S seedlings with cotyledon removed. Finally, we found that the TMT2 deficiency resulted in growth defects, most likely via changing auxin signaling, target of rapamycin (TOR) pathways, and cellular nutrients. This study unveiled the essential functions of TMT2 for seed germination and initial seedling development, ensuring cotyledon function and mobilizing sugars from cotyledons to seedlings. It also expanded the current knowledge on sugar metabolism and signaling. These findings have fundamental implications for enhancing plant biomass production or seed yield in future agriculture. Full article

DNA-mimicking proteins encoded by viruses can modulate processes such as innate cellular immunity. An example is Ung-family uracil-DNA glycosylase inhibition, which prevents Ung-mediated degradation via the stoichiometric protein blockade of the Ung DNA-binding cleft. This is significant where uracil-DNA is a key determinant in the replication and distribution of virus genomes. Unrelated protein folds support a common physicochemical spatial strategy for Ung inhibition, characterised by pronounced sequence plasticity within the diverse fold families. That, and the fact that relatively few template sequences are biochemically verified to encode Ung inhibitor proteins, presents a barrier to the straightforward identification of Ung inhibitors in genomic sequences. In this study, distant homologs of known Ung inhibitors were characterised via structural biology and structure prediction methods. A recombinant cellular survival assay and in vitro biochemical assay were used to screen distant variants and mutants to further explore tolerated sequence plasticity in motifs supporting Ung inhibition. The resulting validated sequence repertoire defines an expanded set of heuristic sequence and biophysical signatures shared by known Ung inhibitor proteins. A computational search of genome database sequences and the results of recombinant tests of selected output sequences obtained are presented here. Full article

Breast Cancer (BC) is one of the most common and challenging cancers among females worldwide. Conventional treatments for oral cancer rely on the use of radiology and surgery accompanied by chemotherapy. Chemotherapy presents many side effects, and the cells often develop resistance to this chemotherapy. It will be urgent to adopt alternative or complementary treatment strategies that are new and more effective without these negative effects to improve the well-being of patients. A substantial number of epidemiological and experimental studies reported that many compounds are derived from natural products such as curcumin and their analogs, which have a great deal of beneficial anti-BC activity by inducing apoptosis, inhibiting cell proliferation, migration, and metastasis, modulating cancer-related pathways, and sensitizing cells to radiotherapy and chemotherapy. In the present study, we investigated the effect of the curcumin-analog PAC on DNA repair pathways in MCF-7 and MDA-MB-231 human breast-cancer cell lines. These pathways are crucial for genome maintenance and cancer prevention. MCF-7 and MDA-MB-231 cells were exposed to PAC at 10 µM. MTT and LDH assays were conducted to evaluate the effects of PAC on cell proliferation and cytotoxicity. Apoptosis was assessed in breast cancer cell lines using flow cytometry with annexin/Pi assay. The expression of proapoptotic and antiapoptotic genes was determined by RT-PCR to see if PAC is active in programming cell death. Additionally, DNA repair signaling pathways were analyzed by PCR arrays focusing on genes being related and confirmed by quantitative PCR. PAC significantly inhibited breast-cancer cell proliferation in a time-dependent manner, more on MDA-MB-231 triple-negative breast cancer cells. The flow cytometry results showed an increase in apoptotic activity. These data have been established by the gene expression and indicate that PAC-induced apoptosis by an increased Bax and decreased Bcl-2 expression. Moreover, PAC affected multiple genes involved in the DNA repair pathways occurring in both cell lines (MCF-7 and MDA-MB231). In addition, our results suggest that PAC upregulated more than twice 16 genes (ERCC1, ERCC2, PNKP, POLL, MPG, NEIL2, NTHL1, SMUG1, RAD51D, RAD54L, RFC1, TOP3A, XRCC3, XRCC6BP1, FEN1, and TREX1) in MDA-MB-231, 6 genes (ERCC1, LIG1, PNKP, UNG, MPG, and RAD54L) in MCF-7, and 4 genes (ERCC1, PNKP, MPG, and RAD54L) in the two cell lines. In silico analysis of gene–gene interaction shows that there are common genes between MCF-7 and MDA-MB-321 having direct and indirect effects, among them via coexpression, genetic interactions, pathways, predicted and physical interactions, and shared protein domains with predicted associated genes indicating they are more likely to be functionally related. Our data show that PAC increases involvement of multiple genes in a DNA repair pathway, this certainly can open a new perspective in breast-cancer treatment. Full article

Base excision repair (BER) is one of the important systems for the maintenance of genome stability via repair of DNA lesions. BER is a multistep process involving a number of enzymes, including damage-specific DNA glycosylases, apurinic/apyrimidinic (AP) endonuclease 1, DNA polymerase β, and DNA ligase. Coordination of BER is implemented by multiple protein–protein interactions between BER participants. Nonetheless, mechanisms of these interactions and their roles in the BER coordination are poorly understood. Here, we report a study on Polβ’s nucleotidyl transferase activity toward different DNA substrates (that mimic DNA intermediates arising during BER) in the presence of various DNA glycosylases (AAG, OGG1, NTHL1, MBD4, UNG, or SMUG1) using rapid-quench-flow and stopped-flow fluorescence approaches. It was shown that Polβ efficiently adds a single nucleotide into different types of single-strand breaks either with or without a 5′-dRP–mimicking group. The obtained data indicate that DNA glycosylases AAG, OGG1, NTHL1, MBD4, UNG, and SMUG1, but not NEIL1, enhance Polβ’s activity toward the model DNA intermediates. Full article