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ConspectusBase excision repair (BER) enzymes are genomic superheroes that stealthily and accurately identify and remove chemically modified DNA bases. DNA base modifications erode the informational content of DNA and underlie many disease phenotypes, most conspicuously, cancer. The OG of oxidative base damage, 8-oxo-7,8-dihydroguanine (OG), is particularly insidious due to its miscoding ability that leads to the formation of rare, pro-mutagenic OG:A mismatches. Thwarting mutagenesis relies on the capture of OG:A mismatches prior to DNA replication and removal of the mis-inserted adenine by MutY glycosylases to initiate BER. The threat of OG and the importance of its repair are underscored by the association between inherited dysfunctional variants of the MutY human homologue (MUTYH) and colorectal cancer, known as MUTYH-associated polyposis (MAP). Our functional studies of the two founder MUTYH variants revealed that both have compromised activity and a reduced affinity for OG:A mismatches. Indeed, these studies underscored the challenge of the recognition of OG:A mismatches that are only subtly structurally different than T:A base pairs. Since the original discovery of MAP, many MUTYH variants have been reported, with most considered to be variants of uncertain significance. To reveal features associated with damage recognition and adenine excision by MutY and MUTYH, we have developed a multipronged chemical biology approach combining enzyme kinetics, X-ray crystallography, single-molecule visualization, and cellular repair assays. In this review, we highlight recent work in our laboratory where we defined MutY structure-activity relationship (SAR) studies using synthetic analogs of OG and A in cellular and in vitro assays. Our studies revealed the 2-amino group of OG as the key distinguishing feature of OG:A mismatches. Indeed, the unique position of the 2-amino group in the major groove of OGsyn:Aanti mismatches provides a means for its rapid detection among a large excess of highly abundant and structurally similar canonical base pairs. Furthermore, site-directed mutagenesis and structural analysis showed that a conserved C-terminal domain β-hairpin FSH loop is critical for OG recognition with the His serving as the lesion detector. Notably, MUTYH variants located within and near the FSH loop have been associated with different forms of cancer. Uncovering the role(s) of this loop in lesion recognition provided a detailed understanding of the search and repair process of MutY. Such insights are also useful to identify mutational hotspots and pathogenic variants, which may improve the ability of physicians to diagnose the likelihood of disease onset and prognosis. The critical importance of the FSH loop in lesion detection suggests that it may serve as a unique locus for targeting probes or inhibitors of MutY/MUTYH to provide new chemical biology tools and avenues for therapeutic development.

Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimers disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.

BackgroundMalignant glioma carries a poor prognosis despite current therapeutic modalities. Standard of care therapy consists of surgical resection, fractionated radiotherapy concurrently administered with temozolomide (TMZ), a DNA-alkylating chemotherapeutic agent, followed by adjuvant TMZ. O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylated lesions from tumor DNA, thereby promoting chemoresistance. MGMT promoter methylation status predicts responsiveness to TMZ; patients harboring unmethylated MGMT (~60% of glioblastoma) have a poorer prognosis with limited treatment benefits from TMZ.MethodsVia lentiviral-mediated delivery into LN18 glioma cells, we employed deactivated Cas9-CRISPR technology to target the MGMT promoter and enhancer regions for methylation, as mediated by the catalytic domain of the methylation enzyme DNMT3A. Methylation patterns were examined at a clonal level in regions containing Differentially Methylation Regions (DMR1, DMR2) and the Methylation Specific PCR (MSP) region used for clinical assessment of MGMT methylation status. Correlative studies of genomic and transcriptomic effects of dCas9/CRISPR-based methylation were performed via Illumina 850K methylation array platform and bulk RNA-Seq analysis.ResultsWe used the dCas9/DNMT3A catalytic domain to achieve targeted MGMT methylation at specific CpG clusters in the vicinity of promoter, enhancer, DMRs and MSP regions. Consequently, we observed MGMT downregulation and enhanced glioma chemosensitivity in survival assays in vitro, with minimal off-target effects.ConclusiondCas9/CRISPR is a viable method of epigenetic editing, using the DNMT3A catalytic domain. This study provides initial proof-of-principle for CRISPR technology applications in malignant glioma, laying groundwork for subsequent translational studies, with implications for future epigenetic editing-based clinical applications.

This study has provided new insights into the interaction between graphene and DNA nucleobases (adenine, cytosine, and guanine). It compares how each nucleobase interacts with graphene, examining their selectivity and binding energy. The research also explores how these interactions impact the electronic properties of graphene, showing potential applications in graphene‐based biosensors and DNA sequencing technologies. Additionally, the findings suggest potential uses in DNA sensing and the functionalization of graphene for various biomedical applications. This study employs density functional theory (DFT) methods, utilizing the B3LYP functional with the 6‐311G basis set, to explore the electronic interactions between DNA nucleobases (adenine, cytosine, and guanine) with pure graphene (Gr). We investigate various properties, including adsorption energy, HOMO‐LUMO energy levels, charge transfer mechanisms, dipole moments, energy gaps, and density of states (DOS). Our findings indicate that cytosine interacts most favorably with graphene through its oxygen site (Gr‐Cyt‐O), exhibiting the strongest adsorption. Additionally, adenine's interaction significantly enhances its electronegativity and chemical potential, particularly at the nitrogen position, while decreasing its electrophilicity. Guanine, characterized by the smallest energy gap, demonstrates the highest conductivity among the nucleobases. These results suggest that graphene possesses advantageous properties as an adsorbent for guanine, highlighting its potential applications in biosensor technology. [ABSTRACT FROM AUTHOR]

N-Arylsulfonamide-based adenosine analogues were previously shown to be potent inhibitors of SARS-CoV-2 RNA cap guanine N7-methyltransferase nsp14. Here, we synthesized three series of N-arylsulfonamide acyclic analogues of adenosine as bisubstrates of nsp14. Most of these acyclic compounds were barely active at 50 μM against this cap N7-methyltransferase. [ABSTRACT FROM AUTHOR]

Tubular self‐assembled architectures are highly appealing supramolecular objects that participate in diverse essential biological processes. Controlling with precision their dimensions, and in particular their pore diameter, is a key objective to develop the full applied potential of these structures. Here, using a strategy that relies on the controlled supramolecular polymerization of Watson–Crick H‐bonded macrocycles, we target the assembly of 3 sets of nanotubes in which pore diameter is finely controlled from 1.8, to 3.2 and to 4.3 nm. This is simply done by elongating the oligo(phenylene‐ethynylene) block placed in between guanine and cytosine nucleobases in the monomer. Moreover, this structural change leads to a gradual reduction in the chelate cooperativity of the cyclization process and, at the same time, to an enhancement in the tendency of the macrocycles to stack, which critically influences the coupling between these consecutive supramolecular processes. [ABSTRACT FROM AUTHOR]

This study delves into the nature of individual hydrogen bonds and the relationship between metal cations and hydrogen bonding in the Watson–Crick guanine–cytosine (GC) base pair and its alkali and alkaline earth cation‐containing complexes (Mn+–GC). The findings reveal how metal cations affect the nature and strength of individual hydrogen bonds. The study employs interacting quantum atoms (IQA) analysis to comprehensively understand three individual hydrogen bonds within the GC base pair and its cationic derivatives. These analyses unveil the nature and strength of hydrogen bonds and serve as a valuable reference for exploring the impact of cations (and other factors) on each hydrogen bond. All the H⋯D interactions (H is hydrogen and D is oxygen or nitrogen) in the GC base pair are primarily electrostatic in nature, with the charge transfer component playing a substantial role. Introducing a metal cation perturbs all H⋯D interatomic interactions in the system, weakening the nearest hydrogen bond to the cation (indicated by a) and reinforcing the other (b and c) interactions. Notably, the interaction a, the strongest H⋯D interaction in the GC base pair, becomes the weakest in the Mn+–GC complexes. A broader perspective on the stability of GC and Mn+–GC complexes is provided through interacting quantum fragments (IQF) analysis. This approach considers all pairwise interactions between fragments and intra‐fragment components, offering a complete view of the factors that stabilize and destabilize GC and Mn+–GC complexes. The IQF analysis underscores the importance of electron sharing, with the dominant contribution arising from the inter‐fragment exchange‐correlation term, in shaping and sustaining GC and Mn+–GC complexes. From this point of view, alkaline and alkaline earth cations have distinct effects, with alkaline cations generally weakening inter‐fragment interactions and alkaline earth cations strengthening them. In addition, IQA and IQF calculations demonstrate that the hydration of cations led to small changes in the hydrogen bonding network. Finally, the IQA interatomic energies associated with the hydrogen bonds and also inter‐fragment interaction energies provide robust indicators for characterizing hydrogen bonds and complex stability, showing a strong correlation with total interaction energies. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway. Unconventional protein secretion emerges as an important mechanism in aggregate-prone protein removal. Here, the authors demonstrate that Plekhg5 mediates the unconventional secretion of Sod1 by presynaptic secretory autophagy. [ABSTRACT FROM AUTHOR]

Due to different solvent conditions, double helix DNA exists in various conformations, such as B-DNA, A-DNA, C-DNA, and Z-DNA. Studies have found that A-DNA is present in complexes with proteins and has an important biological role in the context of cellular defense mechanisms under harsh conditions. In this study, the well-tempered meta-dynamics (WTM-eABF) were used to explore the free energy barriers for base flipping of the four natural bases, adenine, guanine, cytosine, and thymine, in both A-form and B-form DNA duplex. The results show that the free energy barriers for base flipping were lower in A-DNA than that in B-DNA for all of the four natural bases. We analyzed the factors that may affect base flipping, such as π-π stacking, SASA, H-bonding, and conformational changes, and concluded that conformational changes and π-π stacking are the most important factors affecting base flipping. [ABSTRACT FROM AUTHOR]

The emergence of a crystal nucleus from disordered states is a critical and challenging aspect of the crystallization process, primarily due to the extremely short length and timescales involved. Methods such as liquid-cell or low-dose focal-series transmission electron microscopy (TEM) are often employed to probe these events. In this study, we demonstrate that ion mobility spectrometry-mass spectrometry (IMS-MS) offers a complementary and insightful perspective on the nucleation process by examining the sizes and shapes of small clusters, specifically those ranging from n = 2 to 40. Our findings reveal the significant role of sulfate ions in the growth of adeninediium sulfate clusters, which are the precursors to the formation of single crystals. Specifically, sulfate ions stabilize adenine clusters at the 1:1 ratio. In contrast, guanine sulfate forms smaller clusters with varied ratios, which become stable as they approach the 1:2 ratio. The nucleation size is predicted to be between n = 8 and 14, correlating well with the unit cell dimensions of adenine crystals. This correlation suggests that IMS-MS can identify critical nucleation sizes and provide valuable structural information consistent with established crystallographic data. We also discuss the strengths and limitations of IMS-MS in this context. IMS-MS offers rapid and robust experimental protocols, making it a valuable tool for studying the effects of various additives on the assembly of small molecules. Additionally, it aids in elucidating nucleation processes and the growth of different crystal polymorphs. [ABSTRACT FROM AUTHOR]

In this study, a novel quantum mechanics-based protocol for the evaluation of carcinogen-scavenging activity (QM-CSA) is developed. The QM-CSA protocol represents a universal and quantitative approach to evaluate and compare the activation-free energies for alkylation reactions between individual polyphenolic compounds and chemical carcinogens of the epoxy type at physiological conditions by applying two scales: the absolute scale allowing for the comparison with guanine and the relative scale allowing the comparison with glutathione as a reference compound. The devised quantum mechanical methodology was validated by comparing the activation-free energies calculated with 14 DFT functionals in conjunction with two implicit solvation models (SMD and CPCM) and the experimental activation-free energies for reactions between nine investigated chemical carcinogens and guanine. According to the obtained results, the best agreement with experimental data was achieved by applying DFT functionals M11-L and MN12-L in conjunction with the flexible 6-311++G(d,p) basis set and implicit solvation model SMD, and the obtained uncertainties were proven to be similar to the experimental ones. To demonstrate the applicability of the QM-CSA protocol, functionals M11-L, and MN12-L in conjunction with the SMD implicit solvation model were applied to calculate activation-free energies for the reactions of nine investigated chemical carcinogens of the epoxy type with three catechins, namely EGCG, EGC, and (+)-catechin. The order of CSA in this series of catechins in comparison to guanine and glutathione was determined as (+)-catechin > EGC > EGCG. The obtained results, for the first time, demonstrated the evaluation and comparison of CSA in a series of selected catechins with respect to glutathione and guanine. Moreover, the presented results provide valuable insights into the reaction mechanisms and configurations of the corresponding transition states. The novel QM-CSA protocol is also expected to expand the kinetic data for alkylation reactions between various polyphenolic compounds and chemical carcinogens of the epoxy type, which is currently lacking in the scientific literature. [ABSTRACT FROM AUTHOR]

Nitric oxide (●NO) participates in many biological activities, including enhancing DNA radiosensitivity in ionizing radiation-based radiotherapy. To help understand the radiosensitization of ●NO, we report reaction dynamics between ●NO and the radical cations of guanine (a 9HG●+ conformer) and 9-methylguanine (9MG●+). On the basis of the formation of 9HG●+ and 9MG●+ in the gas phase and the collisions of the radical cations with ●NO in a guided-ion beam mass spectrometer, the charge transfer reactions of 9HG●+ and 9MG●+ with ●NO were examined. For both reactions, the kinetic energy-dependent product ion cross sections revealed a threshold energy that is 0.24 (or 0.37) eV above the 0 K product 9HG (or 9MG) + NO+ asymptote. To interrogate this abnormal threshold behavior, the reaction potential energy surface for [9MG + NO]+ was mapped out at closed-shell singlet, open-shell singlet, and triplet states using density functional and coupled cluster theories. The results showed that the charge transfer reaction requires the interaction of a triplet-state surface originating from a reactant-like precursor complex 3[9MG●+(↑)⋅(↑)●NO] with a closed-shell singlet-state surface evolving from a charge-transferred complex 1[9MG⋅NO+]. During the reaction, an electron is transferred from π∗(NO) to perpendicular π∗(9MG), which introduces a change in orbital angular momentum. The latter offsets the change in electron spin angular momentum and facilitates intersystem crossing. The reaction threshold in excess of the 0 K thermochemistry and the low charge-transfer efficiency are rationalized by the vibrational excitation in the product ion NO+ and the kinetic shift arising from a long-lived triplet intermediate. [ABSTRACT FROM AUTHOR]

Chirality-induced spin selectivity has been attracting extensive interest in recent years and is demonstrated in a variety of chiral molecules, all of which arise from inherent molecular chirality. Here, we first propose a theoretical model to study the spin-dependent electron transport along guanine-quadruplex (G4) DNA molecules, connected to two nonmagnetic electrodes, by considering the molecule–electrode contact and weak spin–orbit coupling. Our results indicate that the G4-DNA molecular junctions exhibit pronounced spin-selectivity effect, and the asymmetric contact-induced external chirality, instead of the inherent molecular chirality, dominates their spin filtration efficiency. Furthermore, the spin-selectivity effect is robust against the disorder and hold in a wide range of model parameters. These results could be checked by charge transport measurements and provide an alternative way to improve the spin-selectivity effect of chiral nanodevices. [ABSTRACT FROM AUTHOR]

Huntington’s Disease (HD) is a rare neurodegenerative condition inherited in an autosomal dominant pattern, where Gamma Amino Butyric Acid-ergic (GABAergic) neurons in the basal ganglia progressively deteriorate. Symptoms include subcortical dementia, behavioural changes, midlife psychosis, and involuntary choreoathetosis movements. Imaging techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) show shrinkage of the caudate nucleus and putamen, alongside enlarged lateral ventricles. Diagnosis is confirmed through molecular analysis identifying the hallmark amplified Cytosine Adenine Guanine (CAG) triplet. The case report describes a 57-year-old female diagnosed with HD, presenting symptoms of accidental falls caused by involuntary jerky movements, along with behavioural changes and cognitive decline over three years. Initial Non Contrast Computed Tomography (NCCT) of the brain revealed bilateral basal ganglia and diffuse cerebral atrophy. Quantitative analysis indicated a decreased frontal horn width to intercaudate distance (FH/CC) ratio of 1.24 and an increased Intercaudate distance to inner table width (CC/IT) ratio of 0.30. Multivoxel Magnetic Resonance Spectroscopy (MRS) showed reduced N-Acetyl Alanine (NAA) and creatine (Cr) levels with an NAA/Cr ratio of 0.84. Magnetic Resonance Tractography and Diffusion Tensor Imaging (DTI) revealed elevated Fractional Anisotropy (FA) and diffusivity in the basal ganglia, and reduced FA with increased diffusivity in white matter tracts. Genetic analysis by Polymerase Chain Reaction (PCR) confirmed HD. Newer MRI like DTI allows early identification of disease and better assessment of disease progression and response to therapy. A multidisciplinary approach involving neurologists, psychiatrists, and other healthcare professionals is essential. Genetic counseling and psychosocial support are crucial for patients and their families. Early and accurate identification of HD is vital for timely interventions and improved symptom control.

A regioselective novel one-pot synthesis of heterocyclic purine derivative antiviral agent Ganciclovir in which initially guanine is treated with acetic anhydride in the presence of iodine (5%) to get diacetyl guanine intermediate, which undergoes in situ N-alkylation with AMDP in presence of catalytic acidic Amberlite IR-120 to get N-alkylated intermediate and finally deacetylation to get pure regioselective Ganciclovir, which is commercially viable and eco-friendly. We developed one-pot synthesis of antiviral drug Ganciclovir. Initially, Guanine is treated with acetic anhydride and iodine to yield diacetyl guanine 3. This intermediate then reacted with AMDP in the presence of acidic Amberlite IR-120 to obtain compound 5. Finally, deacetylation yields Ganciclovir 1, a commercially viable and eco-friendly process. [ABSTRACT FROM AUTHOR]

This work evaluates the electrochemical performance of copper and nitrogen codoped Ti3C2Tx MXene (or Cu@N − Ti3C2Tx) for purine sensing. Aniline/cupric ion solid complex was synthesized by reaction of aniline with CuCl2 (Cu(aniline)2Cl2). Subsequently, the obtained CuCl2-aniline coordination complex was mixed with Ti3C2Tx MXene and carbonized in an autoclave. Subsequently, a new electrochemical sensor was designed based on a hybrid of Cu/N-codoped Ti3C2Tx MXene on a glassy carbon electrode modified to be a Cu@N − Ti3C2Txelectrode. The nanomaterials were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy techniques. The analytes were determined using differential pulse voltammetry. The detection limits were 0.01 for adenine and 0.02 μM for guanine, while the linear response ranges of both analytes were from 0.1 to 10 μM. This sensing device has been further employed in the individual and simultaneous detection of adenine and guanine in artificial sweat with 98–102% recoveries. [ABSTRACT FROM AUTHOR]

The microperoxidase-11 hemopeptide exhibits configuration-dependent selectivity for guanine-quadruplexes by specifically uncaging c-MYC guanine-quadruplexes from a duplex DNA. [ABSTRACT FROM AUTHOR]

Archaeosine (G+) is an archaea-specific tRNA modification synthesized via multiple steps. In the first step, archaeosine tRNA guanine transglucosylase (ArcTGT) exchanges the G15 base in tRNA with 7-cyano-7-deazaguanine (preQ0). In Euryarchaea, preQ015 in tRNA is further modified by archaeosine synthase (ArcS). Thermococcus kodakarensis ArcS catalyzes a lysine-transfer reaction to produce preQ0-lysine (preQ0-Lys) as an intermediate. The resulting preQ0-Lys15 in tRNA is converted to G+15 by a radical S-adenosyl-L-methionine enzyme for archaeosine formation (RaSEA), which forms a complex with ArcS. Here, we focus on the substrate tRNA recognition mechanism of ArcS. Kinetic parameters of ArcS for lysine and tRNA-preQ0 were determined using a purified enzyme. RNA fragments containing preQ0 were prepared from Saccharomyces cerevisiae tRNAphe-preQ015. ArcS transferred 14C-labeled lysine to RNA fragments. Furthermore, ArcS transferred lysine to preQ0 nucleoside and preQ0 nucleoside 50 -monophosphate. Thus, the L-shaped structure and the sequence of tRNA are not essential for the lysine-transfer reaction by ArcS. However, the presence of D-arm structure accelerates the lysine-transfer reaction. Because ArcTGT from thermophilic archaea recognizes the common D-arm structure, we expected the combination of T. kodakarensis ArcTGT and ArcS and RaSEA complex would result in the formation of preQ0-Lys15 in all tRNAs. This hypothesis was confirmed using 46 T. kodakarensis tRNA transcripts and three Haloferax volcanii tRNA transcripts. In addition, ArcTGT did not exchange the preQ0-Lys15 in tRNA with guanine or preQ0 base, showing that formation of tRNA-preQ0-Lys by ArcS plays a role in preventing the reverse reaction in G+biosynthesis. [ABSTRACT FROM AUTHOR]

In billion years of evolution, eukaryotes preserved the chromosome ends with arrays of guanine repeats surrounded by thymines and adenines, which can form stacks of four‐stranded planar structure known as G‐quadruplex (G4). The rationale behind the evolutionary conservation of the G4 structure at the telomere remained elusive. Our recent study has shed light on this matter by revealing that telomere G4 undergoes oscillation between at least two distinct folded conformations. Additionally, tumor suppressor BRCA2 exhibits a unique mode of interaction with telomere G4. To elaborate, BRCA2 directly interacts with G‐triplex (G3)‐derived intermediates that form during the interconversion of the two different G4 states. In doing so, BRCA2 remodels the G4, facilitating the restart of stalled replication forks. In this review, we succinctly summarize the findings regarding the dynamicity of telomeric G4, emphasize its importance in maintaining telomere replication homeostasis, and the physiological consequences of losing G4 dynamicity at the telomere. [ABSTRACT FROM AUTHOR]

In this study, a new electrochemical sensor using a glassy carbon electrode modified with graphene oxide (GO) and Zn-doped magnetite Fe3O4 nanosheets is proposed for simultaneous trace determinations of guanine (GA) and adenine (AD). First, graphene oxide nanoparticles were synthesized by the Hammer method, and then UV–Vis, FTIR, and XRD techniques were used to characterize them. The second step involved hydrothermal preparation of Zn-doped magnetite Fe3O4 nanosheets. Different methods, such as scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy (FTIR), vibrating sample magnetometer, and energy dispersive X-ray spectroscopy, were utilized to investigate Zn-doped magnetite Fe3O4 nanosheets. The electrochemical behavior of guanine (GA) and adenine (AD) was investigated using different voltammetric techniques, including cyclic voltammetry, electrochemical impedance spectroscopy, differential pulse voltammetry, and chronoamperometry (CA). It was found that by combining GO with Zn-doped magnetite Fe3O4 nanosheets, the electrochemical sensitivity of the sensor can be improved, and low levels of guanine and adenine can be measured. In a differential pulse voltammetry experiment conducted with this electrode under optimal conditions, such as buffer type, accumulation time, and PH, the electrode showed great sensitivity to both guanine and adenine. The detection limit values were 0.08 and 0.14 µM for GA and AD, respectively. The suggested sensor's performance was tested using human serum as a real sample, and the proposed sensor showed high recovery. As a result of the investigation, it was found that the proposed electrode displayed high sensitivity, good repeatability, and high stability. [ABSTRACT FROM AUTHOR]

Clarias meladerma Bleeker, 1846, a native catfish species in Indonesia belonging to the family Clariidae. The present study the complete mitochondrial genome sequence of C. meladerma from the Rokan River was sequenced by using next-generation sequencing, and its phylogenetic relationship was analyzed. The mitochondrial genome comprises 13 protein-coding genes (PCGs), 22 tRNA genes, and two rRNA genes, with a total length of 16,808 bp. The mitogenome of C. meladerma exhibits a base composition of 32.49% adenine, 25.75% thymine, 14.51% guanine, and 27.25% cytosine. Phylogenetic analysis indicated that C. meladerma has the same clade with C. macrocephalus, C. batrachus, and C. fucus. In essence, the findings of this study lay down a genetic foundation for future investigations into C. meladerma. [ABSTRACT FROM AUTHOR]

In animals, pigments but also nanostructures determine skin coloration, and many shades are produced by combining both mechanisms. Recently, we discovered a new mechanism for blue coloration in the ribbontail stingray Taeniura lymma, a species with electric blue spots on its yellow-brown skin. Here, we characterize finescale differences in cell composition and architecture distinguishing blue from non-blue regions, the first description of elasmobranch chromatophores and the nanostructures responsible for the stingray's novel structural blue, contrasting with other known mechanisms for making nature's rarest color. In blue regions, the upper dermis comprised a layer of chromatophore units --iridophores and melanophores entwined in compact clusters framed by collagen bundles-- this structural stability perhaps the root of the skin color's robustness. Stingray iridophores were notably different from other vertebrate light-reflecting cells in having numerous fingerlike processes, which surrounded nearby melanophores like fists clenching a black stone. Iridophores contained spherical iridosomes enclosing guanine nanocrystals, suspended in a 3D quasi-order, linked by a cytoskeleton of intermediate filaments. We argue that intermediate filaments form a structural scaffold with a distinct optical role, providing the iridosome spacing critical to produce the blue color. In contrast, black-pigmented melanosomes within melanophores showed space-efficient packing, consistent with their hypothesized role as broadbandabsorbers for enhancing blue color saturation. The chromatophore layer's ultrastructure was similar in juvenile and adult animals, indicating that skin color and perhaps its ecological role are likely consistent through ontogeny. In non-blue areas, iridophores were replaced by pale cells, resembling iridophores in some morphological and nanoscale features, but lacking guanine crystals, suggesting that the cell types arise from a common progenitor cell. The particular cellular associations and structural interactions we demonstrate in stingray skin suggest that pigment cells induce differentiation in the progenitor cells of iridophores, and that some features driving color production may be shared with bony fishes, although the lineages diverged hundreds of millions of years ago and the iridophores themselves differ drastically. [ABSTRACT FROM AUTHOR]

In this study, a molecular beacon (MB) was designed for colorimetric loop-mediated isothermal amplification (cLAMP). The length of complementary bases on the MB, guanine and cytosine content (GC content), and hybridization sites of complementary bases were investigated as key factors affecting the design of the MB. We designed MBs consisting of 10, 15, and 20 complementary bases located at both ends of the HRPzyme. In the case of the long dumbbell DNA structure amplified from the hlyA gene of Listeria monocytogenes, possessing a flat region (F1c-B1) of 61 base pairs (bp), an MB was designed to intercalate into the flat region between the F1c and B1 regions of the LAMP amplicons. In the case of the short dumbbell DNA structure amplified from the bcfD gene of Salmonella species possessing a flat region (F1c-B1) length of 6 bp, another MB was designed to intercalate into the LoopF or LoopB regions of the LAMP amplicons. The results revealed that the hybridization site of the MB on the LAMP amplicons was not crucial in designing the MB, but the GC content was an important factor. The highest hybridization efficiencies for LAMP amplicons were obtained from hlyA gene-specific and bcfD gene-specific MBs containing 20- and 15-base complementary sequences, respectively, which exhibited the highest GC content. Therefore, designing MBs with a high GC content is an effective solution to overcome the low hybridization efficiency of cLAMP assays. The results obtained can be used as primary data for designing MBs to improve cLAMP accessibility. [ABSTRACT FROM AUTHOR]

RNA polymerases (RNAPs) carry out the first step in the central dogma of molecular biology by transcribing DNA into RNA. Despite their importance, much about how RNAPs work remains unclear, in part because the small (3.4 Angstrom) and fast (~40 ms/nt) steps during transcription were difficult to resolve. Here, we used high-resolution nanopore tweezers to observe the motion of single Escherichia coli RNAP molecules as it transcribes DNA ~1,000 times improved temporal resolution, resolving single-nucleotide and fractional-nucleotide steps of individual RNAPs at saturating nucleoside triphosphate concentrations. We analyzed RNAP during processive transcription elongation and sequence-dependent pausing at the yrbL elemental pause sequence. Each time RNAP encounters the yrbL elemental pause sequence, it rapidly interconverts between five translocational states, residing predominantly in a half-translocated state. The kinetics and force-dependence of this half-translocated state indicate it is a functional intermediate between pre-and post-translocated states. Using structural and kinetics data, we show that, in the half-translocated and post-translocated states, sequence-specific protein-DNA interaction occurs between RNAP and a guanine base at the downstream end of the transcription bubble (core recognition element). Kinetic data show that this interaction stabilizes the half-translocated and post-translocated states relative to the pre-translocated state. We develop a kinetic model for RNAP at the yrbL pause and discuss this in the context of key structural features. [ABSTRACT FROM AUTHOR]

Caridina boehmei is an ornamental shrimp native to Sulawesi that has been successfully cultured and marketed in Indonesia. However, molecular information about this shrimp is not yet available. This study aimed to characterize cytochrome c oxidase subunit I (CO1) and small subunit ribosomal RNA (18S rDNA) genes. Shrimp samples were extracted, and DNA was amplified using CO1 and 18S rDNA primers. The sequencing results were then analyzed by the neighbor-joining method. The 654 bp partial coding sequence (cds) of the CO1 and 380 bp partial cds of 18S rDNA have been successfully amplified from genomic DNA. The CO1 sequencing produced fragments consisting of 25.84% adenine, 20.95% cytosine, 19.11% guanine, and 34.10% thymine. The 18S rDNA sequencing produced fragments consisting of 24.47% adenine, 26.05% cytosine, 28.16% guanine, and 21.32% thymine. Phylogenetic analysis based on the CO1 gene revealed that C. boehmei was grouped with C. variabilis (MK190014), C. brachydactyla (MK190011), and Caridina sp. (MK190012). Phylogenetic analysis based on the 18S rDNA gene revealed that C. boehmei was identical to Caridina sp. Suphan Buri-1 MF622000, C. serratirostris KP725708, C. multidentata JF346236, C. formosae GQ131924, and Caridina sp. Suphan Buri-2 MF622001. The lowest-highest pairwise distance based on CO1 and 18S rDNA was consecutively 0.0017-0.2247 (0.17-22.47%) and 0.0000-0.1218 (0-12.18%). [ABSTRACT FROM AUTHOR]

The electroanalytical characteristics of double-stranded DNA (dsDNA) and the complex of dsDNA with the anticancer drug metabolite, abiraterone D4A, in the concentration range of 25–200 μM were investigated using differential pulse voltammetry. The effect of D4A on dsDNA was detected by changes in the intensity of the electrochemical oxidation of the heterocyclic bases guanine, adenine, and thymine. This investigation used screen-printed electrodes modified with carbon nanotubes. Binding constants (Kb) for guanine, adenine, and thymine in the dsDNA/D4A complexes were calculated to be 1.1 × 104, 5.5 × 103, and 2.5 × 103 M–1, respectively. The DNA-mediated electrochemical coefficients of the toxic effect were calculated as the ratio of the signal intensities of guanine and adenine in the presence of D4A compared to those without the drug (T, %). Based on an analysis of electrochemical parameters and binding constant values, an assumption was made regarding the mechanism of the interaction between D4A and DNA, predominantly through electrostatic interactions and the formation of hydrogen bonds with the minor groove. Conclusions about the mechanism of the interaction of the abiraterone D4A metabolite with the dsDNA minor groove, obtained by electrochemical methods, were supported by the molecular simulation of the DNA/D4A complex. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation has been identified as biomarkers for breast cancer detection. Coiled-coil domain containing 12 gene (CCDC12) implicated in tumorigenesis. This study aims to investigate the potential of blood-based CCDC12 methylation for breast cancer detection. DNA methylation level of CpG sites (Cytosine-phosphate Guanine dinucleotides) in CCDC12 gene was measured by mass spectrometry in 255 breast cancer patients, 155 patients with benign breast nodules and 302 healthy controls. The association between CCDC12 methylation and breast cancer risk was evaluated by logistic regression and receiver operating characteristic curve analysis. A total of eleven CpG sites were analyzed. The CCDC12 methylation levels were higher in breast cancer patients. Compared to the lowest tertile of methylation level in CpG_6,7, CpG_10 and CpG_11, the highest quartile was associated with 82, 91 and 95% increased breast cancer risk, respectively. The CCDC12 methylation levels were associated with estrogen receptor (ER) and human epidermal growth factor 2 (HER2) status. In ER-negative and HER2-positive (ER-/HER2+) breast cancer subtype, the combination of four sites CpG_2, CpG_5, CpG_6,7 and CpG_11 methylation levels could distinguish ER−/HER2+ breast cancer from the controls (AUC = 0.727). The hypermethylation levels of CCDC12 in peripheral blood could be used for breast cancer detection. Breast cancer detection could be facilitated by novel blood-based DNA methylation biomarkers. The methylation levels of CpG sites in CCDC12 were higher in breast cancer than those in controls. The combination of four sites CpG_2, CpG_5, CpG_6,7 and CpG_11 methylation levels could distinguish ER-/HER2+ breast cancer subtype from the controls. [ABSTRACT FROM AUTHOR]

Understanding the diversity of DNA structure and functions in biology requires tools to study this biomolecule selectively and thoroughly. Fluorescence methods are powerful technique for non-invasive research. Due to the low quantum yield, the intrinsic fluorescence of nucleotides has not been considered for use in the detection and differentiation of nucleic acid bases. Here, we have studied the influence of protonation of nucleotides on their fluorescence properties. We show that protonation of ATP and GTP leads to enhanced intrinsic fluorescence. Fluorescence enhancement at acidic pH has been observed for double-stranded DNA and single-stranded oligonucleotides. The formation of G4 secondary structures apparently protected certain nucleotides from protonation, resulting in less pronounced fluorescence enhancement. Furthermore, acid-induced depurination under protonation was less noticeable in G4 structures than in double-stranded and single-stranded DNA. We show that changes in the intrinsic fluorescence of guanine can be used as a sensitive sensor for changes in the structure of the DNA and for the protonation of specific nucleotides. • Protonation of purine nucleoside triphosphates leads to enhanced intrinsic fluorescence. • The intrinsic fluorescence of protonated purines depends on the DNA structure. • Formation of G4 structures protects certain guanines from protonation. [ABSTRACT FROM AUTHOR]

The heterotrimeric eIF2 complex consists of a core eIF2γ subunit to which binds eIF2α and eIF2β subunits and plays an important role in delivering the Met-tRNAi Met to the 40S ribosome and start codon selection. The intricacies of eIF2β-γ interaction in promoting Met-tRNAi Met binding are not clearly understood. Previously, the zinc-binding domain (ZBD) eIF2βS264Y mutation was reported to cause Met-tRNAi Met binding defect due to the intrinsic GTPase activity. We showed that the eIF2βS264Y mutation has eIF2β-γ interaction defect. Consistently, the eIF2βT238A intragenic suppressor mutation restored the eIF2β-γ and Met-tRNAi Met binding. The eIF2β-ZBD residues Asn252Asp and Arg253Ala mutation caused Met-tRNAi Met binding defect that was partially rescued by the eIF2βT238A mutation, suggesting the eIF2β-ZBD modulates Met-tRNAi Met binding. The suppressor mutation rescued the translation initiation fidelity defect of the eIF2γN135D SW-I mutation and eIF2βF217A/Q221A double mutation in the HTH domain. The eIF2βT238A suppressor mutation could not rescue the eIF2β binding defect of the eIF2γV281K mutation; however, combining the eIF2βS264Y mutation with the eIF2γV281K mutation was lethal. In addition to the previously known interaction of eIF2β with the eIF2γ subunit via its α1-helix, the eIF2β-ZBD also interacts with the eIF2γ subunit via guanine nucleotide-binding interface; thus, the eIF2β-γ interacts via two distinct binding sites. [ABSTRACT FROM AUTHOR]

The small GTPase Ras plays an important role in intracellular signal transduction and functions as a molecular switch. In this study, we used a photoresponsive protein as the molecular regulatory device to photoregulate Ras GTPase activity. Photo zipper (PZ), a variant of the photoresponsive protein Aureochrome1 developed by Hisatomi et al. was incorporated into the C-terminus of Ras as a fusion protein. The three constructs of the Ras–PZ fusion protein had spacers of different lengths between Ras and PZ. They were designed using an Escherichia coli expression system. The Ras–PZ fusion proteins exhibited photoisomerization upon blue light irradiation and in the dark. Ras–PZ dimerized upon light irradiation. Moreover, Ras GTPase activity, which is accelerated by the Ras regulators guanine nucleotide exchange factors and GTPase-activating proteins, is controlled by photoisomerization. It has been suggested that light-responsive proteins are applicable to the photoswitching of the enzymatic activity of small GTPases as photoregulatory molecular devices. [ABSTRACT FROM AUTHOR]

The increasing incidence of tick-borne diseases and the growing resistance to conventional acaricides underscore the urgent need for innovative and sustainable tick management strategies. This study investigates the potential of assembly and sex pheromones for the control of larval stages of Rhipicephalus sanguineus, the brown dog tick, which poses significant health risks to dogs. The ticks were collected from various canine hosts in Thrissur, Kerala and subjected to Petri-dish bioassays using vapour patches impregnated with synthetic assembly pheromone (AP) and sex pheromone (SP), both individually and in combination. The efficacy of these semiochemicals was assessed based on the attraction and clustering behaviour of unfed larvae and partially fed adult ticks over a 24-hour period. Results demonstrated a significantly higher attraction to AP-impregnated patches, with notable efficacy observed in causing tick aggregation, particularly beyond 30 min of exposure. While SP also showed potential in attracting ticks, the combination of SP and AP did not result in a synergistic effect. The study highlights the potential of using semiochemicals as an environmentally sustainable alternative to traditional acaricides, highlighting their role in integrated pest management strategies. [ABSTRACT FROM AUTHOR]

Anhydrous guanine (AG) crystals are widely applied in organisms due to their excellent optical properties. However, the influence of biomolecules on the biomineralization process of guanine crystals in organisms remains unexplored. In this study, mixed proteins from the silver film of carp fish scales were extracted and were used as a model system to elucidate the effect of biomolecules on guanine crystallization for the first time. The mixed proteins were enriched with amino acids such as Asp, Glu, Leu and Lys. Elongated hexagonal microplates of α-form AG (α-AG) mixed with a small amount of β-form AG (β-AG) mainly exposing the (100) plane were obtained in the presence of the mixed proteins under mild conditions while irregular particles were formed in the absence of proteins, indicating that the extracted mixed proteins have a strong influence on the formation of AG microplates exposing the (100) plane. It is found that the proteins not only adsorb on the surface but also occluded into the AG crystals. We also find that guanine analogues have profound synergetic effects on the morphology and polymorphs of guanine in the in vitro synthetic system. The obtained α-AG exhibit superior optical properties such as high reflectivity, strong depolarization and pearlescent luster. This in vitro synthesis work shows clearly the strong influence of biomolecules for the biomineralization process of guanine crystals in organisms. [ABSTRACT FROM AUTHOR]

AbstractThe chemical synthesis of guanosine nucleosides generates both the N9 and N7 regioisomers, which require careful separation to obtain the desired N9 isomer. To preferentially obtain the N9 isomer, a bulky diphenylcarbamoyl (DPC) group can be installed at the O6 position of guanine. However, installation of the DPC group presents a challenging task due to low solubility of the N-acetyl protected guanine. Here we report the usage of commercially available 2-amino-6-chloro purine as a new strategy that offers a more efficient route to the synthesis of the guanine phosphoramidite of threose nucleic acid (TNA). [ABSTRACT FROM AUTHOR]

Alkaline earth metal (Mg2+, Ca2+, Sr2+, Ba2+) complexes of guanine (Gu), a purine-based nucleobase were synthesized. The characterization of these complexes involved elemental analysis (CHN), determination of metal and chloride contents, FTIR, UV–Visible, 1H-NMR spectroscopy, thermal analysis (TGA, DSC), molar conductance, and PXRD measurements. Based on the elemental analysis, the molecular formulae of the complexes were proposed as [Mg(Gu)2Cl2]·4H2O, [Ca(Gu)2Cl2]·3H2O, [Sr(Gu)3Cl2]·5H2O and [Ba(Gu)3Cl2](Gu)·5H2O. The molar conductance measurement showed that the complexes were non-electrolytic. The mode of chelation of guanine through N(7) and O(6) sites was explained using FTIR and 1H-NMR spectral analysis. Thermal analysis in a nitrogen atmosphere showed that the complexes were fairly stable up to 100 °C, with decomposition starting above this temperature and indicating the presence of hydrated water. The crystallite size, microstrain, and dislocation density of the complexes were determined using XRD data. The antibacterial and antifungal activities of guanine and its complexes were screened against five gram-positive, eight gram-negative bacteria, and three fungi. Guanine did not exhibit any antibacterial activity, while the metal complexes showed significant antibacterial and antifungal activities. In vitro cytotoxicity testing revealed that the alkaline earth metal complexes exhibited potential cytotoxic activity, with LC50 values ranging from 18.55 to 40.61 µg mL−1. HeLa cervical cancer cell lines were used to investigate the anticancer activity of metal complexes, and each complex demonstrated cytotoxicity toward HeLa cell lines. [ABSTRACT FROM AUTHOR]

Nucleotide base composition plays an influential role in the molecular mechanisms involved in gene function, phenotype, and amino acid composition. GC content (proportion of guanine and cytosine in DNA sequences) shows a high level of variation within and among species. Many studies measure GC content in a small number of genes, which may not be representative of genome-wide GC variation. One challenge when assembling extensive genomic data sets for these studies is the significant amount of resources (monetary and computational) associated with data processing, and many bioinformatic tools have not been optimized for resource efficiency. Using a high-performance computing (HPC) cluster, we manipulated resources provided to the targeted gene assembly program, automated target restricted assembly method (aTRAM), to determine an optimum way to run the program to maximize resource use. Using our optimum assembly approach, we assembled and measured GC content of all of the protein-coding genes of a diverse group of parasitic feather lice. Of the 499 426 genes assembled across 57 species, feather lice were GC-poor (mean GC = 42.96%) with a significant amount of variation within and between species (GC range = 19.57%-73.33%). We found a significant correlation between GC content and standard deviation per taxon for overall GC and GC3, which could indicate selection for G and C nucleotides in some species. Phylogenetic signal of GC content was detected in both GC and GC3. This research provides a large-scale investigation of GC content in parasitic lice laying the foundation for understanding the basis of variation in base composition across species. [ABSTRACT FROM AUTHOR]

DNA base editors enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here we develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants. By several rounds of structure-informed rational mutagenesis on UNG in cultured human cells, we obtain gTBE and gCBE with high activity of T-to-S (i.e., T-to-C or T-to-G) and C-to-G conversions, respectively. Furthermore, we conduct parallel comparison of gTBE/gCBE with those recently developed using other protein engineering strategies, and find gTBE/gCBE show the outperformance. Thus, we provide several base editors, gTBEs and gCBEs, with corresponding engineered UNG variants, broadening the targeting scope of base editors. Efficient base editors for direct thymine (T) editing are highly desirable. Here, authors develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by rounds of structure-informed mutagenesis on human DNA glycosylase UNG and further engineering. [ABSTRACT FROM AUTHOR]

The reactions of purine nucleic base perchlorates with the simplest 1,3-diketone – acetylacetone – were studied for the first time. It was demonstrated that adenine reacts with acetylacetone in a 1:2 molar ratio via opening of the pyrimidine fragment of the bicyclic struc- ture, elimination of a one-carbon fragment in the form of a formic acid molecule, and recyclization into 8-(4,6-dimethylpyrimidin-2-yl)- 2,4-dimethylimidazo[1,5-a]pyrimidine. Guanine, in turn, reacted with acetylacetone in a 1:1 ratio and formed 7,9-dimethyl-3H-pyrimido- [2,1-b]purin-10-ium-4-olate. In this case, the direction of heterocyclization differed from that observed in the reaction of guanine with malondialdehyde during the in vitro and in vivo formation of the minor nucleotide base M1G. The synthesized compounds were capable of causing single-strand breaks in DNA macromolecules. [ABSTRACT FROM AUTHOR]

Pierisin-1 was serendipitously discovered as a strong cytotoxic and apoptosis-inducing protein from pupae of the cabbage butterfly Pieris rapae against cancer cell lines. This 98-kDa protein consists of the N-terminal region (27 kDa) and C-terminal region (71 kDa), and analysis of their biological function revealed that pierisin-1 binds to cell surface glycosphingolipids on the C-terminal side, is taken up into the cell, and is cleaved to N- and C-terminal portions, where the N-terminal portion mono-ADP-ribosylates the guanine base of DNA in the presence of NAD to induce cellular genetic mutation and apoptosis. Unlike other ADP-ribosyltransferases, pieisin-1 was first found to exhibit DNA mono-ADP-ribosylating activity and show anti-cancer activity in vitro and in vivo against various cancer cell lines. Pierisin-1 was most abundantly produced during the transition from the final larval stage to the pupal stage of the cabbage butterfly, and this production was regulated by ecdysteroid hormones. This suggests that pierisn-1 might play a pivotal role in the process of metamorphosis. Moreover, pierisin-1 could contribute as a defense factor against parasitization and microbial infections in the cabbage butterfly. Pierisin-like proteins in butterflies were shown to be present not only among the subtribe Pierina but also among the subtribes Aporiina and Appiadina, and pierisin-2, -3, and -4 were identified in these butterflies. Furthermore, DNA ADP-ribosylating activities were found in six different edible clams. Understanding of the biological nature of pierisin-1 with DNA mono-ADP-ribosylating activity could open up exciting avenues for research and potential therapeutic applications, making it a subject of great interest in the field of molecular biology and biotechnology. [ABSTRACT FROM AUTHOR]

Context: A systematic study of hydrogen bonds in base pairs and the interaction of cisplatin with DNA fragments was carried out. Structure, binding energies, and electron density were analyzed. xTB has proven to be an accurate method for obtaining structures and binding energies in DNA structures. Our xTB values for DNA base binding energy were in the same order and in some cases better than CAM-B3LYP values compared to experimental values. Double-stranded DNA-cisplatin structures have been calculated and the hydrogen bonds of water molecules are a decisive factor contributing to the preference for the cisplatin-Guanine interaction. Higher values of the water hydrogen bonding energies were obtained in cisplatin-Guanine structures. Furthermore, the electrostatic potential was used to investigate and improve the analysis of DNA-cisplatin structures. Methods: We applied the xTB method and the CAM-B3LYP functional combined with def2-SVP basis set to perform and analyze of the bonding energies of the cisplatin interaction and the effects of the hydrogen bonds. Results were calculated employing the xTB and the ORCA software. [ABSTRACT FROM AUTHOR]

Schizophrenia is associated with increased risk of developing multiple aging-related diseases, including metabolic, respiratory, and cardiovascular diseases, and Alzheimer's and related dementias, leading to the hypothesis that schizophrenia is accompanied by accelerated biological aging. This has been difficult to test because there is no widely accepted measure of biological aging. Epigenetic clocks are promising algorithms that are used to calculate biological age on the basis of information from combined cytosine-phosphate-guanine sites (CpGs) across the genome, but they have yielded inconsistent and often negative results about the association between schizophrenia and accelerated aging. Here, we tested the schizophrenia-aging hypothesis using a DNA methylation measure that is uniquely designed to predict an individual's rate of aging. We brought together 5 case-control datasets to calculate DunedinPACE (Pace of Aging Calculated from the Epigenome), a new measure trained on longitudinal data to detect differences between people in their pace of aging over time. Data were available from 1812 psychosis cases (schizophrenia or first-episode psychosis) and 1753 controls. Mean chronological age was 38.9 (SD = 13.6) years. We observed consistent associations across datasets between schizophrenia and accelerated aging as measured by DunedinPACE. These associations were not attributable to tobacco smoking or clozapine medication. Schizophrenia is accompanied by accelerated biological aging by midlife. This may explain the wide-ranging risk among people with schizophrenia for developing multiple different age-related physical diseases, including metabolic, respiratory, and cardiovascular diseases, and dementia. Measures of biological aging could prove valuable for assessing patients' risk for physical and cognitive decline and for evaluating intervention effectiveness. [ABSTRACT FROM AUTHOR]

The development of highly selective, cost-effective, and energy-efficient electrocatalysts is critical for carbon dioxide reduction reaction (CO2RR) to produce high-value products. Herein, we propose a facile strategy to obtain F, N co-doped carbon-coated iron carbide (Fe3C) nanoparticles by using biomolecule guanine and hexadecafluorophthalocyanine iron as raw materials. Remarkably, this method involves only one-step pyrolysis and does not require any guiding agent or sacrificial template. Benefiting from the advantageous surface microenvironment adjustments achieved through graphitic N (GN) and F co-doping, Fe3C@NF-G-1000 demonstrates exceptional efficacy in the electroreduction of CO2 to carbon monoxide (CO) with an impressive Faradic efficiency (FEco) up to 98% at the potential of −0.55 V (vs. reversible hydrogen electrode (RHE)). Furthermore, it delivers a remarkable current density of up to −43 mA·cm−2 and exhibits virtually no current attenuation over a span of 20 h within the flow cell. Insights from density functional theory (DFT) calculations reveal that the composite structure of GN and F co-doped graphitic layer and Fe3C exhibits different electron density distributions from that of iron carbide nanoparticles. This is attributed to the synergistic effect of the composite structure leading to the enrichment of electrons in the graphite layer on the surface, which contributes to the stability of the key reaction intermediate *COOH, thus, resulting in an enhanced catalytic activity and efficiency. Overall, this work introduces a new and promising approach to the design of green and low-cost carbon-coated metal materials for CO2 reduction reactions. [ABSTRACT FROM AUTHOR]

Oligodeoxynucleotides (ODNs) containing unmethylated cytosine–phosphate–guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an immunomodulatory cascade, induce a Th1 -biased immune milieu, and have great potential as an adjuvant in cancer vaccines. In this study, a green one-step synthesis process was adopted to prepare an amino-rich metal–organic nanoplatform (FN). The synthesized FN nanoplatform can simultaneously and effectively load model tumor antigens (OVA)/autologous tumor antigens (dLLC) and immunostimulatory CpG ODNs with an unmodified PD backbone and a guanine quadruplex structure to obtain various cancer vaccines. The FN nanoplatform and immunostimulatory CpG ODNs generate synergistic effects to enhance the immunogenicity of different antigens and inhibit the growth of established and distant tumors in both the murine E.G7-OVA lymphoma model and the murine Lewis lung carcinoma model. In the E.G7-OVA lymphoma model, vaccination efficiently increases the CD4+, CD8+, and tetramer+CD8+ T cell populations in the spleens. In the Lewis lung carcinoma model, vaccination efficiently increases the CD3+CD4+ and CD3+CD8+ T cell populations in the spleens and CD3+CD8+, CD3−CD8+, and CD11b+CD80+ cell populations in the tumors, suggesting the alteration of tumor microenvironments from cold to hot tumors. [ABSTRACT FROM AUTHOR]

Huntington's Disease (HD) is a rare neurodegenerative condition inherited in an autosomal dominant pattern, where Gamma Amino Butyric Acid-ergic (GABAergic) neurons in the basal ganglia progressively deteriorate. Symptoms include subcortical dementia, behavioural changes, midlife psychosis, and involuntary choreoathetosis movements. Imaging techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) show shrinkage of the caudate nucleus and putamen, alongside enlarged lateral ventricles. Diagnosis is confirmed through molecular analysis identifying the hallmark amplified Cytosine Adenine Guanine (CAG) triplet. The case report describes a 57-year-old female diagnosed with HD, presenting symptoms of accidental falls caused by involuntary jerky movements, along with behavioural changes and cognitive decline over three years. Initial Non Contrast Computed Tomography (NCCT) of the brain revealed bilateral basal ganglia and diffuse cerebral atrophy. Quantitative analysis indicated a decreased frontal horn width to intercaudate distance (FH/CC) ratio of 1.24 and an increased Intercaudate distance to inner table width (CC/IT) ratio of 0.30. Multivoxel Magnetic Resonance Spectroscopy (MRS) showed reduced N-Acetyl Alanine (NAA) and creatine (Cr) levels with an NAA/Cr ratio of 0.84. Magnetic Resonance Tractography and Diffusion Tensor Imaging (DTI) revealed elevated Fractional Anisotropy (FA) and diffusivity in the basal ganglia, and reduced FA with increased diffusivity in white matter tracts. Genetic analysis by Polymerase Chain Reaction (PCR) confirmed HD. Newer MRI like DTI allows early identification of disease and better assessment of disease progression and response to therapy. A multidisciplinary approach involving neurologists, psychiatrists, and other healthcare professionals is essential. Genetic counseling and psychosocial support are crucial for patients and their families. Early and accurate identification of HD is vital for timely interventions and improved symptom control. [ABSTRACT FROM AUTHOR]

The selection of cytosine, guanine, thymine, and adenine as components of the information biopolymers was a complex process influenced by several factors. Among them, the intermolecular interactions may have played a determinant role. Thus, a deep understanding of the intermolecular interactions between nucleobases and other prebiotic molecules may help understand the first instants of chemical evolution. Following this hypothesis, we present here a combined spectroscopic and computational study of theobromine2-adenine and thebromine-adenine2 trimers. While adenine is a nucleobase, theobromine was probably part of the prebiotic chemistry. The trimers were formed in jets and probed by a combination of UV and IR spectroscopic techniques. The spectra were interpreted in light of the predictions obtained using density-functional methods. The results suggest the existence of a subtle balance between formation of hydrogen bonds and π-π interactions. Thus, while theobromine2-adenine tends to form complex in stacked structures, theobromine-adenine2 prefers formation of planar structures, maximizing the interaction by hydrogen bonds. The small energy difference between planar and stacked structures highlights the importance of accurately modeling the dispersion forces in the functionals to produce reliable predictions. [ABSTRACT FROM AUTHOR]

Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data1,2. Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions3,4. We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences5,6.

Bacterial tRNA guanine transglycosylases (TGTs) catalyze the exchange of guanine for the 7-deazaguanine queuine precursor, prequeuosine1 (preQ1). While the native nucleic acid substrate for bacterial TGTs is the anticodon loop of queuine-cognate tRNAs, the minimum recognition sequence for the enzyme is a structured hairpin containing the target G nucleobase in a "UGU" loop motif. Previous work has established an RNA modification system, RNA-TAG, in which Escherichia coli TGT exchanges the target G on an RNA of interest for chemically modified preQ1 substrates linked to a small-molecule reporter such as biotin or a fluorophore. While extending the substrate scope of RNA transglycosylases to include DNA would enable numerous applications, it has been previously reported that TGT is incapable of modifying native DNA. Here, we demonstrate that TGT can in fact recognize and label specific DNA substrates. Through iterative testing of rationally mutated DNA hairpin sequences, we determined the minimal sequence requirements for transglycosylation of unmodified DNA by E. coli TGT. Controlling steric constraint in the DNA hairpin dramatically affects labeling efficiency, and, when optimized, can lead to near-quantitative site-specific modification. We demonstrate the utility of our newly developed DNA-TAG system by rapidly synthesizing probes for fluorescent Northern blotting of spliceosomal U6 RNA and RNA FISH visualization of the long noncoding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The ease and convenience of the DNA-TAG system will provide researchers with a tool for accessing a wide variety of versatile and affordable modified DNA substrates.

Five derived forms of 2-oxo-2-H-chromene clubbed guanine, thiazole and imidazoline derivatives 10 (i–v), 11 (i–v), and 12 (i–v) were synthesized, characterized, and biologically tested for in vitro antimicrobial activity against two types of bacteria viz. Staphylococcus aureus (MTCC 87) and Escherichia coli (MTCC 40). The synthesized compounds demonstrated mild to moderate antibacterial activity against Escherichia coli and Staphylococcus aureus at all concentrations (100 μg/ml, 250 μg/ml, and 500 μg/ml) in comparison to standard drug ciprofloxacin. It was observed that the compounds 10i, 10v, 11i, 11v, 12i, 12ii, 12iv and 12v have noticeable activity at higher dose in comparison to standard drug. Zone of inhibition values indicated higher antimicrobial activity at 500 μg/ml against Escherichia coli and Staphylococcus aureus in case of imidazoline and thiazole clubbed coumarin derivatives in comparison to guanine derivatives. The guanine derivatives have been found to be potent at lower dose (100 μg/ml) in comparison to thiazole and imidazoline derivatives having negligible activity at 100 μg/ml. This suggests a differential efficacy profile among the synthesized compounds, with guanine derivatives showing promising activity at lower doses while thiazole and imidazole derivatives manifesting increased potency at higher concentrations. These findings underscore the potential of these novel compounds as antimicrobial agents, warranting further investigation into their mechanisms of action and therapeutic applications.