Deoxyribonucleic Research Articles

Interactive effect of air pollution and genetic risk of depression on processing speed by resting-state functional connectivity of occipitoparietal network

BackgroundAir pollution, a reversible environmental factor, was significantly associated with the cognitive domains that are impaired in major depressive disorder (MDD), notably processing speed. Limited evidence explores the interactive effect of air pollution and the genetic risk of depression on cognition. This cross-sectional study aims to extend the research by specifically examining how this interaction influences depression-related cognitive impairment and resting-state brain function.MethodsEligible participants were 497 healthy adult volunteers (48.7% males, mean age 24.5) living in Beijing for at least 1 year and exposed to relatively high air pollution from the local community controlling for socioeconomic and genomic. Six months’ ambient air pollution exposures were assessed based on residential addresses using monthly averages of fine particulate matter with a diameter of less than or equal to 2.5 μm (PM2.5). A cross-sectional analysis was conducted using functional magnetic resonance imaging (fMRI) and cognitive performance assessments. The polygenic risk score (PRS) of MDD was used to estimate genetic susceptibility.ResultsUsing a general linear model and partial least square regression, we observed a negative association between resting-state local connectivity in precuneus and PRS-by-PM2.5 interactive effect (PFWE = 0.028), indicating that PM2.5 exposure reduced the spontaneous activity in precuneus in individuals at high genetic risk for MDD. DNA methylation and gene expression of the SLC30A3 gene, responsible for maintaining zinc-glutamate homeostasis, was suggestively associated with this local connectivity. For the global functional connectivity, the polygenic risk for MDD augmented the neural impact of PM2.5 exposure, especially in the frontal-parietal and frontal-limbic regions of the default mode network (PFDR < 0.05). In those genetically predisposed to MDD, increased PM2.5 exposure positively correlated with resting-state functional connectivity between the left angular gyrus and left cuneus gyrus. This connectivity was negatively associated with processing speed.ConclusionsOur cross-sectional study suggests that air pollution may be associated with an increased likelihood of cognitive impairment in individuals genetically predisposed to depression, potentially through alterations in the resting-state function of the occipitoparietal and default mode network.

Nucleolus and centromere Tyramide Signal Amplification-Seq reveals variable localization of heterochromatin in different cell types

Genome differential positioning within interphase nuclei remains poorly explored. We extended and validated Tyramide Signal Amplification (TSA)-seq to map genomic regions near nucleoli and pericentric heterochromatin in four human cell lines. Our study confirmed that smaller chromosomes localize closer to nucleoli but further deconvolved this by revealing a preference for chromosome arms below 36-46 Mbp in length. We identified two lamina associated domain subsets through their differential nuclear lamina versus nucleolar positioning in different cell lines which showed distinctive patterns of DNA replication timing and gene expression across all cell lines. Unexpectedly, active, nuclear speckle-associated genomic regions were found near typically repressive nuclear compartments, which is attributable to the close proximity of nuclear speckles and nucleoli in some cell types, and association of centromeres with nuclear speckles in human embryonic stem cells (hESCs). Our study points to a more complex and variable nuclear genome organization than suggested by current models, as revealed by our TSA-seq methodology.

Decoding the Root Lignification Mechanism of Angelica sinensis through Genome-wide Methylation Analysis.

Angelica sinensis is a traditional Chinese herbal medicine with significant economic and medicinal value. However, early bolting and flowering can occur during the second year of the vegetative growth period, rendering the roots unviable for medicinal use and resulting in substantial economic losses. Consequently, the growing interest in studying the molecular mechanisms underlying early bolting or increased root lignification in A. sinensis. Here, we conducted whole-genome bisulfite sequencing and observed an increase in whole-genome DNA methylation levels on chromosomes after bolting in A. sinensis. Comparative analysis revealed methylation patterns in the upstream, gene body, and downstream regions in the context of CG, CHG, and CHH, suggesting a possible association between CHH-type methylation of promoters and phenylpropanoid biosynthesis. Furthermore, joint analysis of transcriptomic and methylomics data revealed a positive correlation between DNA methylation and gene expression. We identified the hyperDMR gene in the CHH background within the promoter region; this gene is also a key gene (AsCOMT1), exhibiting dual catalytic activity and facilitating the synthesis of both ferulic acid and lignin. Enzyme kinetic analysis demonstrated that AsCOMT1 preferentially catalyzes the synthesis of lignin monomer precursors. These findings highlight the important regulatory role of DNA methylation in bolting and the synthesis of secondary metabolites in A. sinensis, providing valuable insights into the underlying molecular mechanisms. Therefore, as DNA methylation plays an important regulatory role in A. sinensis bolting and secondary metabolite synthesis, it has potential significance in the analysis of the underlying molecular mechanism.

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated colorectal cancer.

BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E CRC in vivo. We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E CRC models. A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor suppressor genes. Combined inhibition of PRC activity through EZH2 inhibitor with 5-azacitidine treatment additively improved efficacies in BRAFV600E CRC cells. In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.

Striving for clarity in language about gene expression.

What do we mean when we say 'gene expression'? In the decades following Crick's 1958 central dogma of molecular biology, whereby genetic information flows from DNA (genes) to RNA (transcripts) to protein (products), we have learned a great deal about DNA, RNA, proteins, and the ensuing phenotypic changes. With the advent of high-throughput technologies (1990s), molecular biologists and computer scientists forged critical collaborations to understand the vast amount of data being generated, rapidly escalating gene expression research to the 'omics' level: entire sets of genes (genomes), transcribed RNAs (transcriptomes), and synthesized proteins (proteomes). However, some concessions came to be made for molecular biologists and computer scientists to understand each other-one of the most prevalent being the increasingly widespread use of 'gene' to mean 'RNAs originating from a DNA segment'. This loosening of terminology, we will argue, creates ambiguity and confusion. We propose guidelines to increase precision and clarity when communicating about gene expression, most notably to reserve 'gene' for the DNA template and 'transcript' for the RNA transcribed from that gene. Striving to use perspicuous terminology will promote rigorous gene expression science and accelerate discovery in this highly promising area of biology.

Enhanced skin benefits of EGCG loaded in nonapeptide-1-conjugated mesoporous silica nanoparticles to reverse skin photoaging

Epigallocatechin-3-gallate (EGCG), a catechin present in green tea, has been studied extensively for its potential as a cosmetic ingredient due to its various biological properties. However, the low stability and bioavailability of EGCG have hindered its effective utilization in cosmetic applications. This study, to improve the stability and bioavailability of EGCG for reversing skin photo-aging, nonapeptide-1-conjugated mesoporous silica nanoparticles (EGCG@NP-MSN) were fabricated to load EGCG. MSNs can regulate the EGCG release and provide ultraviolet light (UV) protection to possess excellent photostability. Nonapeptide-1 exhibits melanin transfer interference properties and reduces the melanin content in treated skin areas. In vitro and in vivo results confirmed that the EGCG-loaded MSNs retained antioxidant properties, effectively scavenged the melanin and significantly reduced the deoxyribonucleic acid (DNA) damage in skin cells exposed to UV irradiation. The melanin inhibition rate is 5.22 times and the tyrosinase inhibition rate is 1.57 times that of free EGCG. The utilization of this innovative platform offers the potential for enhanced stability, controlled release, and targeted action of EGCG, thereby providing significant advantages for skin application.This delivery system combines the advantages of antioxidant, anti-aging, and anti-UV radiation properties, paving the way for the cosmetics development with improved efficacy and better performance in promoting skin health and appearance.

RNA-mediated double-strand break repair by end-joining mechanisms

Double-strand breaks (DSBs) in DNA are challenging to repair. Cells employ at least three DSB-repair mechanisms, with a preference for non-homologous end joining (NHEJ) over homologous recombination (HR) and microhomology-mediated end joining (MMEJ). While most eukaryotic DNA is transcribed into RNA, providing complementary genetic information, much remains unknown about the direct impact of RNA on DSB-repair outcomes and its role in DSB-repair via end joining. Here, we show that both sense and antisense-transcript RNAs impact DSB repair in a sequence-specific manner in wild-type human and yeast cells. Depending on its sequence complementarity with the broken DNA ends, a transcript RNA can promote repair of a DSB or a double-strand gap in its DNA gene via NHEJ or MMEJ, independently from DNA synthesis. The results demonstrate a role of transcript RNA in directing the way DSBs are repaired in DNA, suggesting that RNA may directly modulate genome stability and evolution.

Association between real-time polymerase chain reaction cycle threshold value and clinical presentation in children with Bordetella pertussis

BackgroundThe cycle threshold (Ct) value is inversely proportional to the number of copies of the target region in a sample, suggesting that a low Ct value indicates a high pathogen load. The relationship between Ct value and clinical presentation in children with pertussis is not well-defined.MethodsWe investigated the relationships between the Ct value of nasopharyngeal samples positive for Bordetella pertussis deoxyribonucleic acid via real-time polymerase chain reaction (PCR), collected from children on admission and their adult family members between May 2022 and March 2024 at Hangzhou Children’s Hospital, China. The study focused on the correlation between Ct value and clinical presentation in children with pertussis.ResultsThe Ct value was positively correlated with age (r = 0.362, P = 0.001). The mean Ct value for children with pertussis was 28.0 (range: 22.0–32.0), which was lower than the 32.0 (range: 30.0–34.0) observed in adults. Ct value was inversely correlated with length of stay, an indicator of disease severity (r = -0.356, P = 0.001). Logistic regression analyses revealed that both Ct value (OR: 0.891, 95% CI: 0.799–0.993, P = 0.036) and white blood cell count (OR: 1.127, 95% CI: 1.005–1.263, P = 0.040) were independently associated with severity of pertussis.ConclusionsReal-time PCR Ct values at initial diagnosis for pertussis may potentially predict severe disease outcomes in children.

DNA palette code for time-series archival data storage

Abstract The long-term preservation of large volumes of infrequently accessed cold data poses challenges to the storage community. Deoxyribonucleic Acid (DNA) is considered a promising solution due to its inherent physical stability and significant storage density. The information density and decoding sequence coverage are two important metrics that influence the efficiency of DNA data storage. In this study, we propose a novel coding scheme called DNA Palette code, which is suitable for cold data, especially time-series archival datasets. These datasets are not frequently accessed but necessitate reliable long-term storage for retrospective research. The DNA Palette code employs unordered combinations of index-free oligonucleotides (oligos) to represent binary information. It can achieve high net information density encoding and lossless decoding with low sequencing coverage. When sequencing reads are corrupted, it can still effectively recover partial information, preventing the complete failure of file retrieval. The in vitro testing of clinical brain magnetic resonance imaging (MRI) data storage, as well as simulation validations using large-scale public MRI datasets (10 GB), planetary science datasets, and meteorological datasets, demonstrate the advantages of our coding scheme, including high information density, low decoding sequence coverage, and wide applicability.

Identification of activating somatic mutations in the &lt;i&gt;PIK3CA&lt;/i&gt; gene in breast tumors and determination of their minimal set for clinical diagnostic testing

Background: For effective screening of breast cancer patients for candidates for target therapy with alpelisib, it is necessary to identify activating somatic mutations in the PIK3CA gene by allele specific polymerase chain reaction (PCR); this requires that an optimal list of mutations should be compiled. Aim: To determine the spectrum of somatic mutations in the PIK3CA gene in breast cancer tumors by means of high performance sequencing (next generation sequencing, NGS) and to identify their minimal set for clinical diagnostic testing by allele specific PCR. Methods: Targeted NGS was used to identify mutations in the PIK3CA gene in DNA obtained from paraffin blocks with tumor material from 431 patients with HR+HER2- breast cancer. A set of the most common somatic mutations was also detected by allele specific PCR. Results: We have developed a set of reagents and a protocol for targeted NGS of frequently mutating regions of the PIK3CA and ESR1 genes, which was used to analyze samples from 451 HR+/HER2- breast cancer patients. Clinically significant activating mutations in the PIK3CA gene were found in 32.7% of the samples (141/431). The frequency of the mutant allele ranged from 0.15 to 0.65. Six mutations were most common: c.3140AG p.His1047Arg (69), c.1633GA p.Glu545Lys (32), c.1035TA p.Asn345Lys (12), c.1624GA p.Glu542Lys (9), c.3140AT p.His1047Leu (8), Cys420Arg c.1258TC (3). In total, these mutations amounted to 94.3% (133/141). In 3.5% of the samples (15/431), there were clinically significant somatic mutations in the ESR1 gene: c.1613AG p, Asp538Gly (7), c.1610AC p.Tyr537Ser (6), c.1609TA p.Tyr537Asn (1), c.1610AG p.Tyr537Cys (1), causing resistance to hormone therapy in patients with breast cancer. While rare mutations comprised only 5.7% of our sample, we validated a set of reagents to identify the six mutations described above by allele specific PCR. NGS and PCR were completely concordant. Conclusion: PCR testing of activating somatic mutations of the PIK3CA gene meets the requirements for sensitivity ( 90%) and specificity (100%) for a clinical test and can be used in the selection of patients for targeted therapy with PIK3CA inhibitors.

Liquid water radiolysis induced by secondary electrons generated from MeV-energy carbon ions.

Fast ion beams induce damage to deoxyribonucleic acid (DNA) by chemical products, including secondary electrons, produced from interaction with liquid water in living cells. However, the production process of these chemical products in the Bragg peak region used in particle therapy is not fully understood. To investigate this process, we conducted experiments to evaluate the radiolytic yields produced when a liquid water jet in vacuum is irradiated with MeV-energy carbon beams. We used secondary ion mass spectrometry to measure the products, such as hydronium cations (H3O+) and hydroxyl anions (OH-), produced along with ·OH radicals, which are significant inducers of DNA damage formation. In addition, we simulated the ionization process in liquid water by incident ions and secondary electrons using a Monte Carlo code for radiation transport. Our results showed that secondary electrons, rather than incident ions, are the primary cause of ionization in water. We found that the production yield of H3O+ or OH- was linked to the frequency of ionization by secondary electrons in water, with these electrons having energies between 10.9 and 550eV. These electrons are responsible for ionizing the outer-shell electrons of water molecules. Finally, we present that the elementary processes contribute to advancing radiation biophysics and biochemistry, which study the formation mechanism of DNA damage.

Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells.

The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblocks and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast Saccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z is needed for proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.

Chaos-driven seven-core optical transmission scheme based on DNA full information chained analog-transcription

This paper proposes a chaos-driven seven-core optical transmission scheme based on DNA full information chained analog-transcription. Unlike traditional deoxyribonucleic acid (DNA) coded encryption schemes in the bit dimension, this scheme uses chaotic sequences to generate perturbed bit streams corresponding to the initial bit stream. These two sets of bit streams are encoded from a set of DNA double-stranded sequences, which are then intertwined into a single-stranded DNA containing all the information through the full-information class transcription algorithm proposed in this paper. Finally, the DNA decoding process is driven by a set of sequences derived from another chaotic model to transform the DNA sequence containing all information back into a bit sequence for subsequent transmission. Additional chaotic sequences interfere with the subcarriers, symbols, and constellation angles. Moreover, to maintain spectral efficiency, hiding the key in the frame header allows for the dynamic simultaneous transmission of signal and key. The transmission of encrypted 16 quadrature amplitude modulation-orthogonal chirp division multiplexing (16QAM-OCDM) signals is experimentally demonstrated at a net bit rate of 51.72 Gb/s over 2 km weakly coupled seven-core fiber. At the receiving end, the correct key decoder is able to accurately recover the data, while the bit error ratio (BER) at the illegal receiving end is 0.5. Finally, quantitative experiments validate the receiver-side decryption algorithm, showing that the proposed encryption scheme achieves a large key space of 10397. The key can be fully decoded when the optical power is above -20dBm. This scheme significantly enhances the security and flexibility of the communication system, making it a promising candidate for future optical communication physical layer encryption.

A novel image encryption method based on improved two-dimensional logistic mapping and DNA computing

In the digital era, the significance of cryptographic algorithms has grown significantly within the realm of cybersecurity. This research presents an innovative approach to image encryption that eliminates the security limitations of the conventional one-dimensional logistic mapping. This approach relies on an enhanced two-dimensional logistic-fraction hybrid chaotic mapping (2D-LFHCM) and deoxyribonucleic acid (DNA) computing. Initially, the improved 2D-LFHCM is utilized to effectively scramble the image by incorporating chaotic sequences. Then, two novel algebraic DNA computing rules are introduced to enhance diffusion encryption. Experimental findings show that this approach offers superior security performance, even with renowned attacks.

The Genetic Diversity of Bali Sardinella (Sardinella lemuru) Caught at Bali Strait and Its Possible Relation to The Ocean Circulation

Graphical Abstract Highlight Research A low sequence divergence of lemuru between Bali Strait and the northern latitude. S. lemuru migration route through ITF will maintain its nucleotide variation. The high haplotype diversity of lemuru is a testament to its adaptability. S. lemuru's high haplotype diversity supports their stock recovery in the Bali Strait. Two sardine species are morphologically and genetically highly distinct, even though they prefer overlapping water mass conditions from each other. Abstract Sardinella lemuru is known as the native pelagic fish of the Bali Strait. However, its presence has become difficult to find recently. This study aimed to validate S. lemuru using molecular taxonomy and link it to water circulations for sustainable management. It is the first study of relatively complete sequence data on S. lemuru in the Bali Strait. A total of 47 sequences were amplified using the control region gene of mitochondrial DNA. Other S. lemuru (n = 4) and Amblygaster sirm (n = 12) sequences were retrieved from GenBank. Low sequence divergence is observed in clade-1 of S. lemuru across the Bali Strait, Manado-Sulawesi, and Kudat-Malaysia. This is probably due to its migration using the main Indonesian ThroughFlow (ITF). There is evolutionary divergence between two groups of S. lemurs, measuring 35.3%±4.1. The first signs of these cryptic groups were found at Canggu and Prigi, with 87 base-pair differences between the two groups. This study also presents strong evidence that A. sirm prefers overlapping water mass conditions with S. lemuru in the Bali Strait but is morphologically and genetically distinct. Notably, three samples of A. sirm in Kedonganan-Bali are clustered with other A. sirm locations passed by the primary and secondary South China Sea throughflow. The high genetic diversity of S. lemuru among Bali Strait sites demonstrates its adaptive ability, with scattered single-frequency haplotypes. The adaptive ability traits of S. lemuru support its stock recovery. The stock recovery recommendation is based on finding S. lemuru's adaptive traits within their populations in suitable habitats and climatic conditions.

Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth.

The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth.

Characterization of mesothelin gene expression in dogs and overexpression in canine mesotheliomas.

Canine mesotheliomas are uncommon malignant tumors typically detected late. Minimally invasive diagnostic biomarkers would facilitate diagnosis at earlier stages, thereby improving clinical outcomes. We hypothesized that mesothelin could be used as a reliable diagnostic biomarker for canine mesotheliomas since it has been used as a cancer biomarker for human mesothelioma. We aimed to explore and characterize mesothelin gene expression in dogs and assess its use as a diagnostic biomarker for canine mesotheliomas. We quantified expressed canine mesothelin transcripts via reverse transcription polymerase chain reaction (RT-PCR) and sequenced them using ribonucleic acid (RNA) extracted from a canine mesothelioma cell line. After confirming mesothelin expression, we assessed its levels in major organ tissues and compared them with those in the mesothelioma tissues using quantitative PCR (qPCR). Mesothelin overexpression in mesotheliomas was detected, and we further compared its levels using qPCR between mesotheliomas and non-mesotheliomas using tumor tissues and clinical sample effusions, confirming its significance as a diagnostic biomarker for canine mesothelioma. Mesothelin complementary deoxyribonucleic acid (cDNA) was amplified via RT-PCR, yielding a single band of expected upon DNA electrophoresis. Sequence analyses confirmed it as a predicted canine mesothelin transcript from the genome sequence database. Comparative sequence analysis of the deduced amino acid sequence of the expressed canine mesothelin demonstrated molecular signature similarities with the human mesothelin. However, the pre-sequence of canine mesothelin lacks the mature megakaryocyte potentiating factor (MPF) portion, which is typically cleaved post-translationally with furin. Mesothelin expression was quantified via qPCR revealing low levels in the mesothelial and lung tissues, with negligible expression in the other major organs. Canine mesothelin exhibited significantly higher expression in the canine mesotheliomas than in the noncancerous tissues. Moreover, analysis of clinical samples using qPCR demonstrated markedly elevated mesothelin expression in canine mesotheliomas compared to non-mesothelioma cases. Canine mesothelin exhibits molecular and biological characteristics akin to human mesothelin. It could serve as a vital biomarker for diagnosing canine mesotheliomas, applicable to both tissue- and effusion-based samples.

An Experimental Dynamic Investigation of the Influence of Melatonin, Serotonin and Tryptophan on the Stability of the DNA Structure

Background: Small molecules play a crucial role in the exploration of physiological pathways and in drug development by targeting deoxyribonucleic acid (DNA). DNA is a central focus for both endogenous and exogenous ligands, which interact directly or indirectly to regulate transcription and replication processes, thus controlling genetic expression in specific cells. Among these molecules, indole derivatives like tryptophan, serotonin, and melatonin are notable for their widespread presence in nature and significant biological effects. Tryptophan, an essential amino acid, serves as a vital structural element in proteins and a precursor for bioactive compounds like serotonin and melatonin, which impact various physiological functions. Methods: Experimental studies have been conducted to reveal the interaction mechanisms of these endogenous indole derivatives with calf thymus DNA (ct-DNA). These investigations involve viscosity measurements and analysis of double-stranded DNA behavior in the presence of indole molecules, using spectrophotometric UV absorption techniques to assess their impact on DNA stability. Additionally, the influence of calcium and magnesium ions on the resulting complexes of these indole derivatives with ct-DNA has been evaluated. Molecular docking validated our findings, offering additional insights into potential DNA–ligand interactions. Utilizing a crystallographic oligomer with an intercalation gap improved docking accuracy, distinguishing intercalation from groove recognition and enhancing assessment precision. Results: Our study offers detailed insights into the interaction patterns of the indole derivatives with DNA and is highly supported by molecular docking analyses: the indole derivatives were predominantly localized between C and G, interacting via π-π interactions and hydrogen bonds and aligning with known data on conventional intercalators. These findings underscore the importance of small compounds’ planar structure and appropriate size, facilitating tight insertion between adjacent base pairs and disrupting regular DNA stacking. Conclusions: Indoles’ physiological roles and potential as drug candidates targeting specific pathways are highlighted, emphasizing their significance as ubiquitous molecules with the ability to modulate biological effects on DNA structure.

Improving prediction performance of general protein language model by domain-adaptive pretraining on DNA-binding protein

DNA-protein interactions exert the fundamental structure of many pivotal biological processes, such as DNA replication, transcription, and gene regulation. However, accurate and efficient computational methods for identifying these interactions are still lacking. In this study, we propose a method ESM-DBP through refining the DNA-binding protein sequence repertory and domain-adaptive pretraining based the general protein language model. Our method considers the lacking exploration of general language model for DNA-binding protein domain-specific knowledge, so we screen out 170,264 DNA-binding protein sequences to construct the domain-adaptive language model. Experimental results on four downstream tasks show that ESM-DBP provides a better feature representation of DNA-binding protein compared to the original language model, resulting in improved prediction performance and outperforming the state-of-the-art methods. Moreover, ESM-DBP can still perform well even for those sequences with only a few homologous sequences. ChIP-seq on two predicted cases further support the validity of the proposed method.

Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors.

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies.