Search Results (19)

Mandibular prognathism (Class III malocclusion) is a craniofacial anomaly characterized by an anteriorly positioned mandible, a concave facial profile and impaired mastication, and appears unusually frequently in Dolang sheep (Ovis aries). We combined clinical phenotyping and three-dimensional (3D) genome profiling to investigate this trait in a Dolang sheep flock. We examined 959 animals using standardized criteria, estimated a local prevalence of 10.3%, and assembled a 200 affected/200 unaffected case–control cohort for genomic analyses. As an exploratory pilot study of 3D genome architecture, we generated in situ Hi-C datasets from mandibular bone of two affected and two control sheep. At 40 kb resolution, global topologically associating domain (TAD) organization and boundary strength were broadly conserved between groups, but sliding-window analyses identified a small number of 1 Mb hotspots where affected animals showed increased TAD-boundary density and strengthened insulation. These UNDER-enriched windows lay near genes with plausible roles in craniofacial development, including ROBO2, COL27A1, VRK2 and a cytokine cluster (IL22/IL26/IFNG with MDM1). Together, our data indicate that mandibular prognathism in Dolang sheep is associated with localized remodeling of chromatin insulation at a restricted set of gene-proximal loci and highlight candidate regions and mechanisms for integration with whole-genome sequencing, association and transcriptomic data. Full article

Freshwater cladocerans such as Daphnia magna (D. magna) are keystone grazers whose hormone-regulated life history traits make them sensitive sentinels of endocrine-disrupting chemicals (EDCs). The organophosphate flame-retardant tris(2-butoxyethyl) phosphate (TBOEP) and perfluoroethylcyclohexane sulfonate (PFECHS) now co-occur at ng L⁻¹–µg L⁻¹ in surface waters, yet their chronic sub-lethal impacts on invertebrate endocrine networks remain unclear. We analysed two publicly available 21-day microarray datasets (TBOEP: GSE55132; PFECHS: GSE75607) using gene ontology enrichment, STRING protein interaction networks, Drosophila phenotype mapping, and KEGG (Kyoto Encyclopaedia of Genes and Genomes)-anchored frameworks to build putative adverse outcome pathways (AOPs) for D. magna. Differentially expressed genes were clustered into functional modules and hub nodes were ranked by degree and betweenness. TBOEP suppressed moulting and growth, altering 1157 genes enriched for metabolism and membrane processes; hubs VRK1, MIB2, and adenylosuccinate synthetase formed a muscle anatomical development sub-network. PFECHS down-regulated vitellogenin and shifted 879 genes dominated by oxidative-stress and glutathione-metabolism signatures; central nodes UBC9, eIF4A-III, Tra-2α, and HDAC1 linked meiotic-cycle, oogenesis, and cyclic-compound binding. Despite chemical dissimilarity, both compounds converged on Wnt-signalling nodes—TBOEP via presenilin-1, and PFECHS via CK1ε/CK2—thereby reducing TCF/LEF-dependent transcription. Predicted outcomes include impaired oocyte maturation, reduced fecundity, and stunted body size, consistent with observed decreases in length and vitellogenin protein. Our network analysis, based on high-dose, sub-lethal exposures used in the underlying microarray studies, indicates that TBOEP- and PFECHS-induced perturbations can destabilise endocrine, developmental, and metabolic pathways in D. magna without overt lethality, and highlights Wnt-centred key events and hub genes as candidate biomarkers to be evaluated in future low-dose studies that use environmentally realistic exposure scenarios. Hub genes and Wnt-mediated key events emerge as sensitive biomarkers for monitoring mixed EDC exposure. Full article

Schizophrenia is a complex disorder influenced by genetic, neurobiological, and environmental factors, with increasing evidence implicating immune dysregulation. This study examined potential molecular mimicry between autoantigens associated with schizophrenia and proteins from Toxoplasma gondii, a parasite previously linked to the disorder. Amino acid sequences of schizophrenia-related autoantigens were retrieved from databases (AAgAtlas, PubMed), and homologous sequences were searched within the T. gondii proteome. Sequence identity was evaluated, and conserved B-cell epitopes were predicted using three-dimensional structures from the Protein Data Bank or models generated in Swiss-Model, followed by epitope mapping with ElliPro. Five autoantigens—gamma-enolase (ENO2), thyroid peroxidase (TPO), glutamic acid decarboxylase 65 kDa isoform (GAD65), serine/threonine-protein kinase 2 (VRK2), and dihydropyrimidine dehydrogenase [NADP(+)] (DPYD)—showed similarities with T. gondii proteins. Among them, enolase exhibited the highest homology, with identities up to 65%. These findings provide preliminary evidence of shared antigenic features between the parasite and schizophrenia-related autoantigens. Such mimicry could contribute to disease mechanisms by triggering autoimmune responses in genetically susceptible individuals, supporting the hypothesis that T. gondii infection may influence schizophrenia pathogenesis. Nonetheless, the results are based exclusively on in silico analyses, and experimental validation will be required to confirm potential cross-reactivity. Full article

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders. Full article

DNA replication is a crucial biological process that ensures the accurate transmission of genetic information, underpinning the growth, development, and reproduction of organisms. Abnormalities in DNA replication are a primary source of genomic instability and tumorigenesis. During DNA replication, the assembly of the pre-RC at the G1-G1/S transition is a crucial licensing step that ensures the successful initiation of replication. Although many pre-replication complex (pre-RC) proteins have been identified, technical limitations hinder the detection of transiently interacting proteins. The APEX system employs peroxidase-mediated rapid labeling with high catalytic efficiency, enabling protein labeling within one minute and detection of transient protein interactions. MCM2 is a key component of the eukaryotic replication initiation complex, which is essential for DNA replication. In this study, we fused MCM2 with enhanced APEX2 to perform in situ biotinylation. By combining this approach with mass spectrometry, we identified proteins proximal to the replication initiation complex in synchronized mouse ESCs and NIH/3T3. Through a comparison of the results from both cell types, we identified some candidate proteins. Interactions between MCM2 and the candidate proteins CD2BP2, VRK1, and GTSE1 were confirmed by bimolecular fluorescence complementation. This research establishes a basis for further study of the component proteins of the conserved DNA replication initiation complex and the transient regulatory network involving its proximal proteins. Full article

The chromatin organization and its dynamic remodeling determine its accessibility and sensitivity to DNA damage oxidative stress, the main source of endogenous DNA damage. We studied the role of the VRK1 chromatin kinase in the response to oxidative stress. which alters the nuclear pattern of histone epigenetic modifications and phosphoproteome pathways. The early effect of oxidative stress on chromatin was studied by determining the levels of 8-oxoG lesions and the alteration of the epigenetic modification of histones. Oxidative stress caused an accumulation of 8-oxoG DNA lesions that were increased by VRK1 depletion, causing a significant accumulation of DNA strand breaks detected by labeling free 3′-DNA ends. In addition, oxidative stress altered the pattern of chromatin epigenetic marks and the nuclear phosphoproteome pathways that were impaired by VRK1 depletion. Oxidative stress induced the acetylation of H4K16ac and H3K9 and the loss of H3K4me3. The depletion of VRK1 altered all these modifications induced by oxidative stress and resulted in losses of H4K16ac and H3K9ac and increases in the H3K9me3 and H3K4me3 levels. All these changes were induced by the oxidative stress in the epigenetic pattern of histones and impaired by VRK1 depletion, indicating that VRK1 plays a major role in the functional reorganization of chromatin in the response to oxidative stress. The analysis of the nuclear phosphoproteome in response to oxidative stress detected an enrichment of the phosphorylated proteins associated with the chromosome organization and chromatin remodeling pathways, which were significantly decreased by VRK1 depletion. VRK1 depletion alters the histone epigenetic pattern and nuclear phosphoproteome pathways in response to oxidative stress. The enzymes performing post-translational epigenetic modifications are potential targets in synthetic lethality strategies for cancer therapies. Full article

Large datasets play a crucial role in the progression of surgical robotics, facilitating advancements in the fields of surgical task recognition and automation. Moreover, public datasets enable the comparative analysis of various algorithms and methodologies, thereby assessing their effectiveness and performance. The ROSMA (Robotics Surgical Maneuvers) dataset provides 206 trials of common surgical training tasks performed with the da Vinci Research Kit (dVRK). In this work, we extend the ROSMA dataset with two annotated subsets: ROSMAT24, which contains bounding box annotations for instrument detection, and ROSMAG40, which contains high and low-level gesture annotations. We propose an annotation method that provides independent labels for the right-handed tools and the left-handed tools. For instrument identification, we validate our proposal with a YOLOv4 model in two experimental scenarios. We demonstrate the generalization capabilities of the network to detect instruments in unseen scenarios. On the other hand, for gesture segmentation, we propose two label categories: high-level annotations that describe gestures at a maneuvers level, and low-level annotations that describe gestures at a fine-grain level. To validate this proposal, we have designed a recurrent neural network based on a bidirectional long-short term memory layer. We present results for four cross-validation experimental setups, reaching up to a 77.35% mAP. Full article

Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly, VRK1 and MAN1A2 were increased by several drugs in both cell lines. However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells. Full article

The accessibility of DNA to different cellular functions requires a dynamic regulation of chromatin organization that is mediated by different epigenetic modifications, which regulate chromatin accessibility and degree of compaction. These epigenetic modifications, particularly the acetylation of histone H4 in lysine 14 (H4K16ac), determine the degree of chromatin accessibility to different nuclear functions, as well as to DNA damage drugs. H4K16ac is regulated by the balance between two alternative histone modifications, acetylation and deacetylation, which are mediated by acetylases and deacetylases. Tip60/KAT5 acetylates, and SIRT2 deacetylates histone H4K16. However, the balance between these two epigenetic enzymes is unknown. VRK1 regulates the level of H4K16 acetylation by activating Tip60. We have shown that the VRK1 and SIRT2 are able to form a stable protein complex. For this work, we used in vitro interaction, pull-down and in vitro kinase assays. In cells, their interaction and colocalization were detected by immunoprecipitation and immunofluorescence. The kinase activity of VRK1 is inhibited by a direct interaction of its N-terminal kinase domain with SIRT2 in vitro. This interaction causes a loss of H4K16ac similarly to the effect of a novel VRK1 inhibitor (VRK-IN-1) or VRK1 depletion. The use of specific SIRT2 inhibitors in lung adenocarcinoma cells induces H4K16ac, contrary to the novel VRK-IN-1 inhibitor, which prevents H4K16ac and a correct DNA damage response. Therefore, the inhibition of SIRT2 can cooperate with VRK1 in the accessibility of drugs to chromatin in response to DNA damage caused by doxorubicin. Full article

Deaf students apparently experience hardship in conventional learning; however, despite their inability to hear, nothing can stop them from reading. Although they perform impressively in memorizing the information, their literacy and reading capability still appear to be weak since they lack the chance to revise by listening and practicing repetitively. Currently, the teaching media for deaf students are quite rare and inadequate, forcing them to face difficulties in integrating new knowledge, even though most of the contents are in a form of written, printed, downloaded, or even accessible via an e-learning platform. However, it is crucial to bear in mind that each learner is different. There is evidence showing that some learners prefer particular methods of learning, also known as learning preferences or learning styles. Thus, the present study reports the sequence of learning styles obtained by using a modified VRK + TSL model that categorized students based on their learning styles. We also propose four different ways of teaching using content-adaptive learning styles, namely visual, reading/writing, kinesthetic, and Thai sign language. Based on personal preferences and the principle of universal design under synthesized learning, an e-learning model was developed to identify deaf learners’ learning styles. The objective is to provide e-learning to identify the learning styles of hearing-impaired students and to respond with up-to-date e-learning materials that can be used anywhere and at any time. These materials must support the education of deaf students. As a result, learners have increased efficiency and increased learning outcomes. Full article

Background and Objectives: Circadian rhythms have an important implication in numerous physiological and metabolic processes, including the sleep/wake cycle. Inter-individual differences in factors associated with circadian system may be due to gene differences in gene expression. Although several studies have analyzed the association between DNA polymorphisms and circadian variables, the influence on gene expression has been poorly analyzed. Our goal was to analyze the association of genetic variations in the clock genes and the gene expression level. Materials and Methods: We carried out a cross-sectional study of 102 adults (50.9% women). RNA and DNA were isolated from blood and single-nucleotide polymorphisms (SNPs), and the main circadian clock genes were determined. Gene expression of CLOCK, PER1, and VRK2 genes was measured by Reverse-transcription polymerase chain reaction (RT-PCR). The association between the DNA-SNPs and gene expression was analyzed at the gene level. In addition, a polygenic risk score (PRS), including all the significant SNPs related to gene expression, was created for each gene. Multivariable model analysis was performed. Results: Sex-specific differences were detected in PER1 expression, with these being higher in women (p = 0.034). No significant differences were detected in clock genes expression and lifestyle variables. We observed a significant association between the ARNTL-rs7924734, ARNTL-rs10832027, VRK2- rs2678902 SNPs, and CLOCK gene expression; the PER3-rs228642 and PER3-rs10127838 were related to PER1 expression, and the ARNTL-rs10832027, ARNTL-rs11022778, and MNTR1B-rs10830963 were associated with VRK2 gene expression (p < 0.05). The specific PRS created was significantly associated with each of the gene expressions analyzed (p < 0.001). Finally, sleep duration was associated with PER3-rs238666 (p = 0.008) and CLOCK-rs4580704 (p = 0.023). Conclusion: We detected significant associations between DNA-SNPs in the clock genes and their gene expression level in leukocytes and observed some differences in gene expression per sex. Moreover, we reported for the first time an association between clock gene polymorphisms and CLOCK, PER1, and VRK2 gene expression. These findings need further investigation. Full article

Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life. Full article

Agricultural producers are already experiencing the adverse effects of climate change, highlighting the urgent need for adaptation. While incremental changes to cope with interannual variability are widely applied, there is limited understanding of the social contexts that inform, enable, or constrain more transformational adaptations in response to anticipated or actual climate change and other stressors. Systematic review methods are used to identify 31 empirical examples of land management change as an adaptation response by agricultural producers in developed countries. We then applied the values-rules-knowledge (vrk) framework to analyse interactions between societal values, institutional rules, and scientific and experiential knowledge. The vrk is a heuristic to help decision makers analyze how the social system shapes their decision context. Three propositions highlighting the relative influence of different values–rules, values–knowledge, and rules–knowledge relationships on agri-food and forestry land-management decisions are presented and discussed. We suggest that further testing of these propositions will provide evidence for decision makers about how decision contexts can be shifted to enable anticipatory transformative adaptation in the primary industries and support sustainable transitions towards more resilient futures. Full article

A comprehensive understanding of molecular and biochemical changes during sperm capacitation is critical to the success of assisted reproductive technologies. We reported involvement of the testis-specific isoform of Angiotensin Converting Enzyme (tACE) in bovine sperm capacitation. The objective of this study was to characterize the tACE interactome in fresh and heparin-capacitated bovine sperm through immunoprecipitation coupled with mass spectrometry. These interactions were validated by co-localization of tACE with beta-tubulin as an identified interactome constituent. Although interactions between tACE and several proteins remained unchanged in fresh and capacitated sperm, mitochondrial aldehyde dehydrogenase 2 (ALDH2), inactive serine/threonine protein-kinase 3 (VRK3), tubulin-beta-4B chain (TUBB4B), and tubulin-alpha-8 chain (TUBA8) were recruited during capacitation, with implications for cytoskeletal and membrane reorganization, vesicle-mediated transport, GTP-binding, and redox regulation. A proposed tACE interactional network with identified interactome constituents was generated. Despite tACE function being integral to capacitation, the relevance of interactions with its binding partners during capacitation and subsequent events leading to fertilization remains to be elucidated. Full article

THeterogeneous nuclear ribonucleoprotein (HNRNP) A1 is the most abundant and ubiquitously expressed member of the HNRNP protein family. In recent years, it has become more evident that HNRNP A1 contributes to the development of neurodegenerative diseases. However, little is known about the underlying role of HNRNP A1 in cancer development. Here, we report that HNRNP A1 expression is significantly increased in lung cancer tissues and is negatively correlated with the overall survival of patients with lung cancer. Additionally, HNRNP A1 positively regulates vaccinia-related kinase 1 (VRK1) translation via binding directly to the 3′ untranslated region (UTR) of VRK1 mRNA, thus increasing cyclin D1 (CCND1) expression by VRK1-mediated phosphorylation of the cAMP response element–binding protein (CREB). Furthermore, HNRNP A1 binding to the cis-acting region of the 3′UTR of VRK1 mRNA contributes to increased lung cancer cell proliferation. Thus, our study unveils a novel role of HNRNP A1 in lung carcinogenesis via post-transcriptional regulation of VRK1 expression and suggests its potential as a therapeutic target for patients with lung cancer. Full article