Broadening the scope of high structural dimensionality nanomaterials using pyridine-based curcuminoids.
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ABSTRACT:
SUBMITTER: Rodriguez-Cid L
PROVIDER: S-EPMC8145613 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC3484944 | biostudies-literature
Project description:Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application in prioritizing the synthesis of novel drug candidates. Relative binding free energy (RBFE) calculations have emerged as an industry-standard approach to achieve highly accurate rank-order predictions of the potency of related compounds; however, this approach requires that the ligands share a common scaffold and a common binding mode, restricting the methods' domain of applicability. This is a critical limitation since complex modifications to the ligands, especially core hopping, are very common in drug design. Absolute binding free energy (ABFE) calculations are an alternate method that can be used for ligands that are not congeneric. However, ABFE suffers from a known problem of long convergence times due to the need to sample additional degrees of freedom within each system, such as sampling rearrangements necessary to open and close the binding site. Here, we report on an alternative method for RBFE, called Separated Topologies (SepTop), which overcomes the issues in both of the aforementioned methods by enabling large scaffold changes between ligands with a convergence time comparable to traditional RBFE. Instead of only mutating atoms that vary between two ligands, this approach performs two absolute free energy calculations at the same time in opposite directions, one for each ligand. Defining the two ligands independently allows the comparison of the binding of diverse ligands without the artificial constraints of identical poses or a suitable atom-atom mapping. This approach also avoids the need to sample the unbound state of the protein, making it more efficient than absolute binding free energy calculations. Here, we introduce an implementation of SepTop. We developed a general and efficient protocol for running SepTop, and we demonstrated the method on four diverse, pharmaceutically relevant systems. We report the performance of the method, as well as our practical insights into the strengths, weaknesses, and challenges of applying this method in an industrial drug design setting. We find that the accuracy of the approach is sufficiently high to rank order ligands with an accuracy comparable to traditional RBFE calculations while maintaining the additional flexibility of SepTop.
| S-EPMC10413862 | biostudies-literature
Project description:Deep ultraviolet (DUV)-treatment is an efficient method for the removal of high-energy-barrier polymeric or aliphatic organic ligands from nanomaterials. Regardless of morphology and material, the treatment can be used for nanoparticles, nanowires, and even nanosheets. The high-energy photon irradiation from low-pressure mercury lamps or radio frequency (RF) discharge excimer lamps could enhance the electrical conductivity of various nanomaterial matrixes, such as Ag nanoparticles, Bi2Se3 nanosheets, and Ag nanowires, with the aliphatic alkyl chained ligand (oleylamine; OAm) and polymeric ligand (polyvinyl pyrrolidone; PVP) as surfactants. In particular, Ag nanoparticles (AgNPs) that are DUV-treated with polyvinyl pyrrolidone (PVP) for 90 min (50-60 °C) exhibited a sheet resistance of 0.54 Ω □-1, while thermal-treated AgNP with PVP had a sheet resistance of 7.5 kΩ □-1 at 60 °C. The simple photochemical treatment on various dimensionality nanomaterials will be an efficient sintering method for flexible devices and wearable devices with solution-processed nanomaterials.
| S-EPMC9059487 | biostudies-literature
Project description:The ideal airway stent is still not available. Indications for 3D stents currently are limited to rare cases. Therefore, further research is required to investigate whether personalised airway stents will perform better than conventional stents. https://bit.ly/3GLjPa4.
| S-EPMC9986767 | biostudies-literature
Project description:We described the integration of the general reversibility of glycosyltransferase-catalyzed reactions, artificial glycosyl donors, and a high throughput colorimetric screen to enable the engineering of glycosyltransferases for combinatorial sugar nucleotide synthesis. The best engineered catalyst from this study, the OleD Loki variant, contained the mutations P67T/I112P/T113M/S132F/A242I compared with the OleD wild-type sequence. Evaluated against the parental sequence OleD TDP16 variant used for screening, the OleD Loki variant displayed maximum improvements in k(cat)/K(m) of >400-fold and >15-fold for formation of NDP-glucoses and UDP-sugars, respectively. This OleD Loki variant also demonstrated efficient turnover with five variant NDP acceptors and six variant 2-chloro-4-nitrophenyl glycoside donors to produce 30 distinct NDP-sugars. This study highlights a convenient strategy to rapidly optimize glycosyltransferase catalysts for the synthesis of complex sugar nucleotides and the practical synthesis of a unique set of sugar nucleotides.
| S-EPMC3651490 | biostudies-literature
Project description:ObjectiveEpilepsy is a suitable target for gene panel sequencing because a considerable portion of epilepsy is now explained by genetic components, especially in syndromic cases. However, previous gene panel studies on epilepsy have mostly focused on pediatric patients.MethodsWe enrolled adult epilepsy patients meeting any of the following criteria: family history of epilepsy, seizure onset age ≤ 19 years, neuronal migration disorder, and seizure freedom not achieved by dual anti-seizure medications. We sequenced the exonic regions of 211 epilepsy genes in these patients. To confirm the pathogenicity of a novel MTOR truncating variant, we electroporated vectors with different MTOR variants into developing mouse brains.ResultsA total of 92 probands and 4 affected relatives were tested, and the proportion of intellectual disability (ID) and/or developmental disability (DD) was 21.7%. As a result, twelve probands (13.0%) had pathogenic or likely pathogenic variants in the following genes or regions: DEPDC5, 15q12-q13 duplication (n = 2), SLC6A1, SYNGAP1, EEF1A2, LGI1, MTOR, KCNQ2, MEF2C, and TSC1 (n = 1). We confirmed the functional impact of a novel truncating mutation in the MTOR gene (c.7570C > T, p.Gln2524Ter) that disrupted neuronal migration in a mouse model. The diagnostic yield was higher in patients with ID/DD or childhood-onset seizures. We also identified additional candidate variants in 20 patients that could be reassessed by further studies.SignificanceOur findings underscore the clinical utility of gene panel sequencing in adult epilepsy patients suspected of having genetic etiology, especially those with ID/DD or early-onset seizures. Gene panel sequencing could not only lead to genetic diagnosis in a substantial portion of adult epilepsy patients but also inform more precise therapeutic decisions based on their genetic background.Plain language summaryThis study demonstrated the effectiveness of gene panel sequencing in adults with epilepsy, revealing pathogenic or likely pathogenic variants in 13.0% of patients. Higher diagnostic yields were observed in those with neurodevelopmental disorders or childhood-onset seizures. Additionally, we have shown that expanding genetic studies into adult patients would uncover new types of pathogenic variants for epilepsy, contributing to the advancement of precision medicine for individuals with epilepsy. In conclusion, our results highlight the practical value of employing gene panel sequencing in adult epilepsy patients, particularly when genetic etiology is clinically suspected.
| S-EPMC11296137 | biostudies-literature
Project description:Purpose of reviewDiamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid failure, congenital anomalies and predisposition to cancer. Recently, the notion of DBA as a disorder of ribosome biogenesis has been clarified. Correlations between molecular underpinnings and disease pathophysiology, while elusive, are beginning to emerge. Advances in these areas will be explored in this review.Recent findingsAll known genes mutated in DBA encode ribosomal proteins associated with either the small (RPS) or large (RPL) subunit and in these cases ribosomal protein haploinsufficiency gives rise to the disease. The number of genes affected, their potential interactions with the environment and modifier genes, and the myriad of potential signaling pathways linking abortive ribosome synthesis to cell-cycle regulators may all contribute to disease heterogeneity. Genotype/phenotype relationships emerging over the past year promise to shed light on these complex interrelationships and their role in DBA pathophysiology.SummaryThe nosology of DBA has recently expanded to include two distinct disease categories: a classical inherited bone marrow failure syndrome and a 'ribosomopathy'. The description of DBA as a ribosomopathy has provided a context for scientific inquiry analogous to the description of Fanconi anemia as a disorder of DNA repair.
| S-EPMC2886588 | biostudies-literature
Project description:RNA-guided nucleases (RGNs) based on CRISPR systems permit installing short and large edits within eukaryotic genomes. However, precise genome editing is often hindered due to nuclease off- target activities and the multiple-copy character of the vast majority of chromosomal sequences. Dual nicking RGNs and high-specificity RGNs both exhibit low off-target activities. Here, we report that high-specificity Cas9 nucleases are convertible into nicking Cas9D10A variants whose precision is superior to that of the commonly used Cas9D10A nickase. Dual nicking RGNs based on a selected group of these Cas9D10A variants can yield gene knockouts and gene knock-ins at frequencies similar to or higher than those achieved by their conventional counterparts. Moreover, high-specificity dual nicking RGNs are capable of distinguishing highly similar sequences by “tiptoeing” over pre-existing single base-pair polymorphisms. Finally, high-specificity RNA-guided nicking complexes generally preserve genomic integrity, as demonstrated by unbiased genome-wide high-throughput sequencing assays. Thus, in addition to substantially enlarging the Cas9 nickase toolkit, we demonstrate the feasibility in expanding the range and precision of genome editing procedures. The herein introduced tools and multi-tier high-specificity genome editing strategies might be particularly beneficial whenever predictability and/or safety of genetic manipulations are paramount.
2020-12-08 | GSE153471 | GEO
Project description:BackgroundCommon complex traits may involve multiple genetic and environmental factors and their interactions. Many methods have been proposed to identify these interaction effects, among them several machine learning and data mining methods. These are attractive for identifying interactions because they do not rely on specific genetic model assumptions. To handle the computational burden arising from an exhaustive search, including all possible combinations of factors, filter methods try to select promising factors in advance.MethodsModel-based multifactor dimensionality reduction (MB-MDR), a semiparametric machine learning method allowing adjustment for confounding variables and lower level effects, is applied to Genetic Analysis Workshop 19 (GAW19) data to identify interaction effects on different traits. Several filtering methods based on the nearest neighbor algorithm are assessed in terms of compatibility with MB-MDR.ResultsSingle nucleotide polymorphism (SNP) rs859400 shows a significant interaction effect (corrected p value <0.05) with age on systolic blood pressure (SBP). We identified 23 SNP-SNP interaction effects on hypertension status (HS), 42 interaction effects on SBP, and 26 interaction effects on diastolic blood pressure (DBP). Several of these SNPs are in strong linkage disequilibrium (LD). Three of the interaction effects on HS are identified in filtered subsets.ConclusionsThe considered filtering methods seem not to be appropriate to use with MB-MDR. LD pruning is further quality control to be incorporated, which can reduce the combinatorial burden by removing redundant SNPs.
| S-EPMC5133504 | biostudies-literature
Project description:Methods for facile site-selective modifications of proteins are in high demand. We have recently shown that a flavin transferase can be used for site-specific covalent attachment of a chromo- and fluorogenic flavin (FMN) to any targeted protein. Although this Flavin-tag method resulted in efficient labeling of proteins in vitro, labelling in E. coli cells resulted in partial flavin incorporation. It was also restricted in the type of installed label with only one type of flavin, FMN, being incorporated. Here, we report on an extension of the Flavin-tag method that addresses previous limitations. We demonstrate that co-expression of FAD synthetase improves the flavin incorporation efficiency, allowing complete flavin-labeling of a target protein in E. coli cells. Furthermore, we have found that various flavin derivatives and even a nicotinamide can be covalently attached to a target protein, rendering this method even more versatile and valuable.
| S-EPMC9400968 | biostudies-literature