Search Results (57)

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional processes, playing essential roles in nutrient metabolism and metabolic homeostasis. This literature review explores how RBPs influence the metabolism of glucose, lipid, and amino acid metabolism by controlling processes like mRNA stability and translation regulation. The dysregulation of RBPs, including HuR, PTB, and YTHDF1, is linked to metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease. Advances in techniques like TREX technology and transcriptome analysis have deepened our understanding of RBP functions. Additionally, RBPs show promise as potential biomarkers and targets for new therapies. Future research directions in RBPs could focus on tissue-specific regulation and nutrient–RBP interactions. This could pave the way for more personalized treatments and improved metabolic health. Full article

Direct stochastic optical reconstruction microscopy (dSTORM) circumvents the diffraction limit of light, emerging as a powerful superresolution technique for visualizing subcellular structures with a nanoscale resolution of 10–20 nm. Yet achieving ultrastructural resolution using dSTORM alone remains challenging, despite its advantage of requiring only minimal modifications to the imaging setup and sample preparation compared to conventional fluorescence microscopy. A recent advancement that integrates expansion microscopy (ExM), which embeds specimens in a swellable polymer gel, with dSTORM holds promise for attaining imaging resolutions below 10 nm. The combined resolution, however, is governed by the expansion factor of samples, and prior studies have primarily focused on integrations involving approximately 4-fold gel expansion, as dSTORM imaging of high-fold-expanded specimens is still technically demanding. Here, we propose a pragmatic expansion strategy—post-labeling ten-fold robust expansion microscopy (plTREx)—and outline a workflow to facilitate its compatibility with dSTORM, collectively termed plTREx-dSTORM. Specifically, this workflow enhances the mechanical stability of the expansion hydrogel and improves fluorescence signal density across both widefield and dSTORM imaging platforms. Furthermore, we optimize the re-embedding protocol to integrate hydrogel expansion with dSTORM while preventing gel shrinkage. Together, plTREx-dSTORM enables highly refined imaging capable of ultrastructural interpretation of cellular proteins, effectively bridging the resolution gap between electron microscopy and optical microscopy. Full article

Precise and modular reconstruction of 3D tooth structures is crucial for creating interpretable, adaptable models for digital dental applications. To address the limitations of conventional segmentation approaches under conditions such as missing teeth, misalignment, or incomplete anatomical structures, we propose a process-oriented reconstruction pipeline composed of discrete yet integrated modules. The pipeline begins by decomposing 3D dental meshes into a series of 2D projections, allowing multi-view capture of morphological features. A fine-tuned Segment Anything Model (SAM), enhanced with task-specific bounding box prompts, performs segmentation on each view. T-Rex2, a general object detection module, enables automated prompt generation for high-throughput processing. Segmented 2D components are subsequently reassembled and mapped back onto the original 3D mesh to produce complete and anatomically faithful tooth models. This modular approach enables clear separation of tasks—view projection, segmentation, and reconstruction—enhancing flexibility and robustness. Evaluations on the MICCAI 3DTeethSeg’22 dataset show comparable or superior performance to existing methods, particularly in challenging clinical scenarios. Our method establishes a scalable, interpretable framework for 3D dental modeling, supporting downstream applications in simulation, treatment planning, and morphological analysis. Full article

This study assesses the environmental status and water quality of the Saraswati River, an ancient and endangered waterway in Bengal, using an integrated approach. By combining traditional knowledge, advanced geospatial tools, and field analysis, it examines natural and human-induced factors driving the river’s degradation and proposes sustainable restoration strategies. Tools such as the Garmin Global Positioning System (GPS) eTrex10, Google Earth Pro, Landsat imagery, ArcGIS 10.8, and Google Earth Engine (GEE) were used to map the river’s trajectory and estimate its water quality. Remote sensing-derived indices, including the Normalized Difference Water Index (NDWI), Modified Normalized Difference Water Index (MNDWI), Normalized Difference Salinity Index (NDSI), Normalized Difference Turbidity Index (NDTI), Floating Algae Index (FAI), and Normalized Difference Chlorophyll Index (NDCI), Total Dissolved Solids (TDS), were computed to evaluate parameters such as the salinity, turbidity, chlorophyll content, and water extent. Additionally, field data from 27 sampling locations were analyzed for 11 critical water quality parameters, such as the pH, Total Dissolved Solids (TDS), Electrical Conductivity (EC), Dissolved Oxygen (DO), Biochemical Oxygen Demand (BOD), and microbial content, using an arithmetic weighted water quality index (WQI). The results highlight significant spatial variation in water quality, with WQI values ranging from 86.427 at Jatrasudhi (indicating relatively better conditions) to 358.918 at Gobra Station Road (signaling severe contamination). The pollution is primarily driven by urban solid waste, industrial effluents, agricultural runoff, and untreated sewage. A microbial analysis revealed the presence of harmful species, including Escherichia coli (E. coli), Bacillus, and Entamoeba, with elevated concentrations in regions like Bajra, Chinsurah, and Chandannagar. The study detected heavy metals, fertilizers, and pesticides, highlighting significant anthropogenic impacts. The recommended mitigation measures include debris removal, silt extraction, riverbank stabilization, modern hydraulic structures, improved waste management, systematic removal of water hyacinth and decomposed materials, and spoil bank design in spilling zones to restore the river’s natural flow. Full article

High-grade B-cell lymphoma (HGBL), not otherwise specified (NOS), is a rare entity within the spectrum of B-cell lymphomas. HGBL, NOS remains a diagnosis of exclusion with limited data available on the optimal clinical approach. We report a case of a 67-year-old man with HGBL, NOS with a germinal center B-cell (GCB) immunophenotype. The disease was characterized by an aggressive clinical course, refractory to multiple lines of cytotoxic chemotherapy, immunotargeted treatment, therapy with a PD-1 inhibitor, and haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Ultimately, the disease progression led to the patient’s death nine months post-diagnosis. A FISH assay identified a sole genetic rearrangement: BCL2/IGH. Whole-exome sequencing revealed a number of significant somatic mutations, such as TP53 p.C238G, B2M p.L12R, STAT6 p.D419G, STAT3 p.S614R, TREX1 p.T49fs, and CREBBP p.C367Ter, as well as a high focal amplification of the MUC3A gene and the deletion of the short arm of chromosome 17 (del(17p)). An inactivating somatic mutation in the TREX1 gene (p.T49fs) has not been previously described in patients with non-Hodgkin lymphomas. Additionally, our analysis uncovered a key cancer hallmark: tumor genomic instability, manifested as a high tumor mutational burden, which likely contributed to the aggressive disease course. Full article

Oases are part of the natural wealth and heritage of Morocco and contribute to the social, economic, and touristic environment. Morocco has lost more than 2/3 of its oases during the past century due to water scarcity, succession of drought periods, climate change and over-exploitation of groundwater resources. Palm trees are strongly dependent on irrigation and availability of surface water as soon as the water table depth falls below the root zone of 9 m. Improving management and monitoring of oasis ecosystems is strongly encouraged by UNESCO Biosphere Reserve and RAMSAR guidelines. The Boudenib and Tafilalet oases are among the biggest palm groves located in the south-eastern part of Morocco. These oases belong to catchments of the rivers Guir and Ziz, respectively. This paper uses remotely sensed data from PROBA-V for monitoring vegetation in oases, and linking vegetation characteristics to water availability, water management and quality and quantity of date crops. The Normalized Differential Vegetation Index (NDVI) derived from optical images provides a good estimation of changes in vegetation cover over time. Images of various spatial resolutions (100 m, 300 m and 1 km) obtained with the frequently revisiting Belgian satellite PROBA-V and available since 2014, can be successfully used for deriving time series of vegetation dynamics. TREX—Tool for Raster data Exploration—is a Python-GDAL processing tool of PROBA-V NDVI images for analyzing vegetation dynamics, developed at the Vrije Universiteit Brussel and available online. TREX has various applications, but the main functionality is to provide an automatic processing of PROBA-V satellite images into time series of NDVI and LAI, used in vegetation monitoring of user-defined points of interest. This study presents the results of application of TREX in the arid ecosystems of the Boudenib oasis for the period 2014–2018. The resulting NDVI and LAI time series are also compared to time series of groundwater depth and date crops quantity and quality. Low LAI is observed when water depth is low, and the palm trees lose their greenery. Low LAI is also correlated to low quantity and quality of dates in October 2015 and October 2017. PROBA-V images can therefore be used for monitoring the health of palm trees in oasis environments. However, considering the fact that the PROBA-V satellite mission has ended, this approach could instead be applied to Sentinel-3 data using the same analysis. These results have important implications for water management in the area and can help decision-makers to make better decisions about prevention of water scarcity in the region. Full article

DNA is frequently damaged by genotoxic stresses such as ionizing radiation, reactive oxygen species, and nitrogen species. DNA damage is a key contributor to cancer initiation and progression, and thus the precise and timely repair of these harmful lesions is required. Recent studies revealed transcription as a source of genome instability, and transcription-coupled DNA damage has been a focus in cancer research. Impaired mRNA export is closely related to DNA damage through R-loop formation. The molecular machineries of transcription-coupled DNA damage have been extensively analyzed in Saccharomyces cerevisiae. However, the molecular basis of these phenomena in higher eukaryotes remains elusive. In this review, we focus on the relationship between deregulated mRNA export through the transcription-export-2 (TREX-2) complex and cancer development. Particularly, the expression of germinal center-associated nuclear protein (GANP), a molecular scaffold in the TREX-2 complex, is highly associated with tumorigenesis in mice and humans. Although the deregulated expression of other components in the TREX-2 complex might affect cancer development, we have directly demonstrated the significance of GANP in tumorigenesis using genetically modified mice. Additionally, we describe recent evidence for medical applications demonstrating that the downregulation of the other components may be a good candidate for a chemotherapeutic target in terms of reducing the side effects. Full article

Chromosomal instability and DNA damage are hallmarks of cancers that can result in the accumulation of micronuclei, cytosolic chromatin fragments (CCFs), or cytosolic DNA species (cytoDNA). The cyclic GMP-AMP synthase (cGAS) is a DNA sensor that recognizes cytosolic DNA and chromatin fragments and subsequently triggers a systemic type I interferon response via the cGAS-STING pathway. Although cancer cells usually contain a high level of chromosomal instability, these cells can avoid the induction of the interferon (IFN) response either by silencing cGAS-STING or the upregulation of the three prime exonuclease 1 (TREX1). TREX1 restricts the spontaneous activation of the cGAS-STING pathway through the degradation of cytoDNA; this in turn limits tumor immunogenicity allowing cancer cells to evade immune detection. Deletion of TREX1 in different cancer types has been shown to decrease tumor growth and increase tumor immune infiltration in pre-clinical mice models. These recent studies also showed the efficacy of TREX1-targeting in combination with anti-PD-1 immune checkpoint blockade. Therefore, targeting TREX1 represents a unique therapeutic strategy to induce an amplified induction of a type I IFN response, promoting the host’s immune response against chromosomally unstable cancer cells. We here discuss these recent advances obtained in preclinical cancer models that pave the way to develop TREX1 inhibitors and to find new avenues to target the broad cGAS-STING pathway signaling in cancer therapy. Full article

Background: Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Methods: Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23–40 years) with no known pathogenic variants in BRCA genes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28–80 years). Analysis of novel exonic variants was based on protein structure modeling. Results: Five novel, deleterious variants in the genes WRN, RNF8, TOP3A, ERCC2, and TREX2 were found in addition to a splice acceptor variant in RNF4 and two frameshift variants in EXO1 and POLE genes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Conclusions: Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes. Full article

In quantum computing, noisy intermediate-scale quantum (NISQ) devices offer unprecedented computational capabilities but are vulnerable to errors, notably measurement inaccuracies that impact computation accuracy. This study explores the efficacy of error mitigation techniques in improving quantum circuit performance on NISQ devices. Techniques such as dynamic decoupling (DD), twirled readout error extraction (T-REx) and zero-noise extrapolation (ZNE) are examined through extensive experimentation on an ideal simulator, IBM Kyoto, and IBM Osaka quantum computers. Results reveal significant performance discrepancies across scenarios, with error mitigation techniques notably enhancing both estimator result and variance values, aligning more closely with ideal simulator outcomes. The comparison results with ideal simulator (having expected result value 0.8284) shows that T-Rex has improved results on IBM Kyoto and enhanced average expected result value from 0.09 to 0.35. Similarly, DD has improved average expected result values from 0.2492 to 0.3788 on IBM Osaka. These findings underscore the critical role of error mitigation in bolstering quantum computation reliability. The results suggest that selection of mitigation technique depends upon quantum circuit and its depth, type of hardware and operations to be performed. Full article

LPA₃ receptors were expressed in TREx HEK 293 cells, and their signaling and phosphorylation were studied. The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes. Phorbol myristate acetate, but not LPA, desensitizes LPA₃-mediated calcium signaling, the agonists, and the phorbol ester-induced LPA₃ internalization. Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid β-arrestin–LPA₃ receptor association. The agonist and the phorbol ester-induced marked LPA₃ receptor phosphorylation, and phosphorylation sites were detected using mass spectrometry. Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343). Interestingly, phosphorylation sites are within sequences predicted to constitute β-arrestin binding sites. These data provide insight into LPA₃ receptor signaling and regulation. Full article

Introduction: Interferon I (IFN I) signaling hyperactivation is considered one of the most important pathogenetic mechanisms in systemic lupus erythematosus (SLE). Early manifestation and more severe SLE courses in children suggest a stronger genetic influence in childhood-onset SLE (cSLE). Aim: To evaluate IFN-I score and SLE-associated genetic variants in cSLE. Material and Methods: 80 patients with cSLE were included in the study. IFN I-score was assessed by real-time PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1) in 60 patients. Clinical exome sequencing (CES) was performed in 51 patients. Whole-exome sequencing was performed in 32 patients with negative results of CES. Results: 46/60 patients (77%) had elevated IFN-I scores. Leucopenia and skin involvement were associated with over-expression of IFI44 and IFI44L, while hypocomplementemia—with hyperactivation of IFIT3, LY6E, and MX1. No correlation of IFN-I score with disease activity was found. At least one rare genetic variant, potentially associated with SLE, was found in 29 (56.9%) patients. The frequency of any SLE-genetic variants in patients with increased IFN scores was 84%, in patients with normal IFN scores—33%, and in the group whose IFN score was not assessed was 65% (p = 0.040). The majority of genetic variants (74%) are functionally related to nucleic acid sensing and IFN-signaling. The highest frequency of genetic variants was observed in Sakha patients (9/14; 64.3%); three and two unrelated patients had identical variants in PTPN22 and TREX1 genes, respectively. Conclusions: More than half of patients with childhood-onset SLE have rare variants in SLE-associated genes. The IFN-I score could be considered a tool for the selection of patients for further genetic assessment in whom monogenic lupus is suspected. Full article

Lysophosphatidic acid (LPA) type 3 (LPA₃) receptor mutants were generated in which the sites detected phosphorylated were substituted by non-phosphorylatable amino acids. Substitutions were made in the intracellular loop 3 (IL3 mutant), the carboxyl terminus (Ctail), and both domains (IL3/Ctail). The wild-type (WT) receptor and the mutants were expressed in T-REx HEK293 cells, and the consequences of the substitutions were analyzed employing different functional parameters. Agonist- and LPA-mediated receptor phosphorylation was diminished in the IL3 and Ctail mutants and essentially abolished in the IL3/Ctail mutant, confirming that the main phosphorylation sites are present in both domains and their role in receptor phosphorylation eliminated by substitution and distributed in both domains. The WT and mutant receptors increased intracellular calcium and ERK 1/2 phosphorylation in response to LPA and PMA. The agonist, Ki16425, diminished baseline intracellular calcium, which suggests some receptor endogenous activity. Similarly, baseline ERK1/2 phosphorylation was diminished by Ki16425. An increase in baseline ERK phosphorylation was detected in the IL3/Ctail mutant. LPA and PMA-induced receptor interaction with β-arrestin 2 and LPA₃ internalization were severely diminished in cells expressing the mutants. Mutant-expressing cells also exhibit increased baseline proliferation and response to different stimuli, which were inhibited by the antagonist Ki16425, suggesting a role of LPA receptors in this process. Migration in response to different attractants was markedly increased in the Ctail mutant, which the Ki16425 antagonist also attenuated. Our data experimentally show that receptor phosphorylation in the distinct domains is relevant for LPA₃ receptor function Full article

The myostatin (MSTN) gene also regulates the developmental balance of skeletal muscle after birth, and has long been linked to age-related muscle wasting. Many rodent studies have shown a correlation between MSTN and age-related diseases. It is unclear how MSTN and age-associated muscle loss in other animals are related. In this study, we utilized MSTN gene-edited bovine skeletal muscle cells to investigate the mechanisms relating to MSTN and muscle cell senescence. The expression of MSTN was higher in older individuals than in younger individuals. We obtained consecutively passaged senescent cells and performed senescence index assays and transcriptome sequencing. We found that senescence hallmarks and the senescence-associated secretory phenotype (SASP) were decreased in long-term-cultured myostatin inactivated (MT-KO) bovine skeletal muscle cells (bSMCs). Using cell signaling profiling, MSTN was shown to regulate the SASP, predominantly through the cycle GMP-AMP synthase-stimulator of antiviral genes (cGAS-STING) pathway. An in-depth investigation by chromatin immunoprecipitation (ChIP) analysis revealed that MSTN influenced three prime repair exonuclease 1 (TREX1) expression through the SMAD2/3 complex. The downregulation of MSTN contributed to the activation of the MSTN-SMAD2/3-TREX1 signaling axis, influencing the secretion of SASP, and consequently delaying the senescence of bSMCs. This study provided valuable new insight into the role of MSTN in cell senescence in large animals. Full article

TREX1 acts in the initial prevention of an autoimmune response, but it may contribute to the permissiveness of retrovirus infections. This study investigated the association between the levels of TREX1 gene expression with the polymorphisms TREX1 rs3135941 (T/C) and TREX1 rs3135945 (G/A), and the presence of antinuclear antibodies (ANA) in antiretroviral therapy (ART)-naïve individuals and after 1 year of treatment. Blood samples from 119 individuals with HIV-1 were subjected to genotyping of polymorphisms and quantification of TREX1 gene expression and HIV-1 viral load by qPCR. The concentration of IFN-α and the number of CD4⁺/CD8⁺ T lymphocytes were determined by ELISA and flow cytometry, respectively; ANA was investigated by immunofluorescence. A control group of 167 seronegative individuals was used for the comparison of genotypic frequencies. The frequency of the polymorphisms were not associated with HIV infection or with variations in the expression of TREX1 and IFN-α (p > 0.05). ART-naïve individuals exhibited higher TREX1 expression and lower IFN-α expression. After 1 year of ART, TREX1 levels were reduced, while IFN-α and CD4⁺ T lymphocytes were elevated (p < 0.05). Some individuals on ART presented ANA. These results suggest that ART-mediated restoration of immune competence is associated with a reduction in TREX1 expression, which may induce the development of ANA, regardless of the polymorphism investigated. Full article