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ACS Omega Jun 2024Glycosylation represents a major chemical challenge; while it is one of the most common reactions in Nature, conventional chemistry struggles with stereochemistry,...
GASP: A Pan-Specific Predictor of Family 1 Glycosyltransferase Acceptor Specificity Enabled by a Pipeline for Substrate Feature Generation and Large-Scale Experimental Screening.
Glycosylation represents a major chemical challenge; while it is one of the most common reactions in Nature, conventional chemistry struggles with stereochemistry, regioselectivity, and solubility issues. In contrast, family 1 glycosyltransferase (GT1) enzymes can glycosylate virtually any given nucleophilic group with perfect control over stereochemistry and regioselectivity. However, the appropriate catalyst for a given reaction needs to be identified among the tens of thousands of available sequences. Here, we present the glycosyltransferase acceptor specificity predictor (GASP) model, a data-driven approach to the identification of reactive GT1:acceptor pairs. We trained a random forest-based acceptor predictor on literature data and validated it on independent in-house generated data on 1001 GT1:acceptor pairs, obtaining an AUROC of 0.79 and a balanced accuracy of 72%. The performance was stable even in the case of completely new GT1s and acceptors not present in the training data set, highlighting the pan-specificity of GASP. Moreover, the model is capable of parsing all known GT1 sequences, as well as all chemicals, the latter through a pipeline for the generation of 153 chemical features for a given molecule taking the CID or SMILES as input (freely available at https://github.com/degnbol/GASP). To investigate the power of GASP, the model prediction probability scores were compared to GT1 substrate conversion yields from a newly published data set, with the top 50% of GASP predictions corresponding to reactions with >50% synthetic yields. The model was also tested in two comparative case studies: glycosylation of the antihelminth drug niclosamide and the plant defensive compound DIBOA. In the first study, the model achieved an 83% hit rate, outperforming a hit rate of 53% from a random selection assay. In the second case study, the hit rate of GASP was 50%, and while being lower than the hit rate of 83% using expert-selected enzymes, it provides a reasonable performance for the cases when an expert opinion is unavailable. The hierarchal importance of the generated chemical features was investigated by negative feature selection, revealing properties related to cyclization and atom hybridization status to be the most important characteristics for accurate prediction. Our study provides a GT1:acceptor predictor which can be trained on other data sets enabled by the automated feature generation pipelines. We also release the new in-house generated data set used for testing of GASP to facilitate the future development of GT1 activity predictors and their robust benchmarking.
PubMed: 38947828
DOI: 10.1021/acsomega.4c01583 -
ACS Omega Jun 2024Green surfactant (GS) flooding, an environmentally friendly chemical Enhanced Oil Recovery (cEOR) method, is explored in this molecular dynamics (MD) simulation study....
Green surfactant (GS) flooding, an environmentally friendly chemical Enhanced Oil Recovery (cEOR) method, is explored in this molecular dynamics (MD) simulation study. This study evaluates the ability of ()-2-dodecanamido-aminobutanedioic as a GS for cEOR, assessing its performance with hexane (C6), dodecane (C12), and eicosane (C20) as representative oils. In the case of the bulk system, a comprehensive molecular-level investigation provides structural details such as the radial distribution function, solvent-accessible surface area, GS adsorption dynamics, diffusivity, and emulsion stability of the GS, oil, and water systems. Also the impact of the three distinct oils on interfacial tension was examined in the existence of GS molecules. The findings reveal rapid GS molecule aggregation and adsorption on oil droplets, with various impacts on emulsion stability depending on the oil type. Additionally, GS enhances the aggregation of heavy C20 oil molecules in a water medium. The study demonstrates GS's role as an effective emulsifier, facilitating oil droplet recovery, with electrostatic interactions governing micelle formation and van der Waals interactions influencing oil droplet emulsification. These results align with prior experimental data, affirming GS's promising application potential in cEOR while prioritizing environmental sustainability.
PubMed: 38947786
DOI: 10.1021/acsomega.4c01332 -
ACS Omega Jun 2024Improving the sensitivity of the fluorescence method for the detection of bioactive molecules is crucial in biochemical analysis. In this work, an ultrasensitive sensing...
Improving the sensitivity of the fluorescence method for the detection of bioactive molecules is crucial in biochemical analysis. In this work, an ultrasensitive sensing strategy was constructed for the detection of ascorbic acid (AA) using high-quality 3-mercaptopropionic acid-capped CdSe/CdS/ZnS quantum dots (MPA-CdSe/CdS/ZnS QDs) as the fluorescent probe. The prepared water-soluble QDs exhibited a high photoluminescence quantum yield (PL QY) of up to 96%. Further, the fluorescence intensity of the QDs was intensively quenched through the dynamic quenching of Ag ions due to an efficient photoinduced electron transfer progress. While the existence of AA before adding Ag ions, Ag ions were reduced. Thus, the interaction of the QDs and Ag ions was destroyed, which led to the fluorescence distinct recovery. The detection limit of AA could be as low as 0.2 nM using this sensing system. Additionally, most relevant small molecules and physiological ions had no influence on the analysis of AA. Satisfactory results were obtained in orange beverages, showing its great potential as a meaningful platform for highly sensitive and selective AA sensing for clinical analysis.
PubMed: 38947783
DOI: 10.1021/acsomega.4c01045 -
ACS Omega Jun 2024Vesicle hydrogels are supramolecular structures formed by the self-assembly of surfactant molecules in solution, which have great application prospects. The phase...
Vesicle hydrogels are supramolecular structures formed by the self-assembly of surfactant molecules in solution, which have great application prospects. The phase behavior of perfluorononanoic acid (CFCOOH) and an amphoteric hydrocarbon surfactant, tetradecyl dimethylaminoxide (CDMAO), in an aqueous solution has been studied. By changing the mixing ratio and concentration of CFCOOH and CDMAO, the phase diagram of the system was drawn, and interestingly, a hydrogel composed of polyhedral and spherical vesicles was successfully constructed. The formation mechanism of the polyhedral and spherical vesicle hydrogel was studied by differential scanning calorimetry (DSC), small-angle X-ray diffraction (XRD), wide-angle X-ray scattering (WAXS), and H nuclear magnetic resonance (H NMR) measurements, and the rheological properties and influencing factors of the hydrogel were systematically investigated. The formation of the vesicle hydrogels in this system was considered to be caused by the "cocrystallization" of two surfactant molecular chains.
PubMed: 38947782
DOI: 10.1021/acsomega.4c02696 -
Cancer Innovation Jun 2024Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has...
BACKGROUND
Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.
METHODS
Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.
RESULTS
We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c-Jun n-terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.
CONCLUSION
Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.
PubMed: 38947754
DOI: 10.1002/cai2.117 -
Genes & Diseases Sep 2024The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the... (Review)
Review
The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance mutations. Therefore, finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system (UPS) has emerged as a focus. The UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological processes. In recent years, the study of UPS in hematological malignant tumors has resulted in effective treatments, such as bortezomib in the treatment of multiple myeloma and mantle cell lymphoma. In CML, the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL, interfering with CML-related signaling pathways, and negatively or positively affecting leukemia stem cells. Some of these molecules may help overcome TKI resistance and treat CML. In this review, the mechanism of TKI resistance is briefly described, the components of UPS are introduced, existing studies on UPS participating in TKI resistance are listed, and UPS as the therapeutic target and strategies are discussed.
PubMed: 38947742
DOI: 10.1016/j.gendis.2023.101150 -
Cureus May 2024Pemphigus vulgaris (PV) stands as a rare autoimmune disorder characterized by blistering and erosion of mucocutaneous membranes. The pathogenesis of PV implicates both B...
Pemphigus vulgaris (PV) stands as a rare autoimmune disorder characterized by blistering and erosion of mucocutaneous membranes. The pathogenesis of PV implicates both B and T cells, which target cell-to-cell adhesion molecules within the epithelia of the skin and oral mucosa, leading to acantholysis. Typically, the presentation involves blistering of the oral mucosa, often followed by cutaneous lesions. Given the considerable risk of morbidity and mortality associated with PV, early diagnosis is crucial, typically relying on a combination of clinical features, histopathology, and direct immunofluorescence. Bruton tyrosine kinase (BTK) plays a significant role in the pathophysiology of autoimmune diseases and inflammation. Herein, we present a case of PV that demonstrated resistance to first-line therapy with steroids. Subsequently, treatment with the BTK inhibitor ibrutinib was initiated, yielding favorable outcomes. This case underscores the potential of targeted therapies, such as BTK inhibitors, in managing PV refractory to conventional treatment modalities.
PubMed: 38947690
DOI: 10.7759/cureus.61317 -
Cureus May 2024Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is... (Review)
Review
Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.
PubMed: 38947632
DOI: 10.7759/cureus.61373 -
The alarmin IL-33 exacerbates pulmonary inflammation and immune dysfunction in SARS-CoV-2 infection.IScience Jun 2024Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In...
Dysregulated host immune responses contribute to disease severity and worsened prognosis in COVID-19 infection and the underlying mechanisms are not fully understood. In this study, we observed that IL-33, a damage-associated molecular pattern molecule, is significantly increased in COVID-19 patients and in SARS-CoV-2-infected mice. Using IL-33 mice, we demonstrated that IL-33 deficiency resulted in significant decreases in bodyweight loss, tissue viral burdens, and lung pathology. These improved outcomes in IL-33 mice also correlated with a reduction in innate immune cell infiltrates, i.e., neutrophils, macrophages, natural killer cells, and activated T cells in inflamed lungs. Lung RNA-seq results revealed that IL-33 signaling enhances activation of inflammatory pathways, including interferon signaling, pathogen phagocytosis, macrophage activation, and cytokine/chemokine signals. Overall, these findings demonstrate that the alarmin IL-33 plays a pathogenic role in SARS-CoV-2 infection and provides new insights that will inform the development of effective therapeutic strategies for COVID-19.
PubMed: 38947521
DOI: 10.1016/j.isci.2024.110117 -
IScience Jun 2024Retinal ganglion cell (RGC) differentiation is tightly controlled by extrinsic and intrinsic factors. Growth and differentiation factor 15 (GDF-15) promotes RGC...
Retinal ganglion cell (RGC) differentiation is tightly controlled by extrinsic and intrinsic factors. Growth and differentiation factor 15 (GDF-15) promotes RGC differentiation, opposite to GDF-11 which inhibits RGC differentiation, both in the mouse retina and in human stem cells. To deepen our understanding of how these two closely related molecules confer opposing effects on retinal development, here we assess the transcriptional profiles of mouse retinal progenitors exposed to exogenous GDF-11 or -15. We find a dichotomous effect of GDF-15 on RGC differentiation, decreasing RGCs expressing residual pro-proliferative genes and increasing RGCs expressing non-proliferative genes, suggestive of greater RGC maturation. Furthermore, GDF-11 promoted the differentiation of photoreceptors and amacrine cells. These data enhance our understanding of the mechanisms underlying the differentiation of RGCs and photoreceptors from retinal progenitors and suggest new approaches to the optimization of protocols for the differentiation of these cell types.
PubMed: 38947520
DOI: 10.1016/j.isci.2024.110100