High Mutation Rate Research Articles

Landscape of enhancer disruption and functional screen in melanoma cells

BackgroundThe high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma.ResultsHere, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions.ConclusionsOur study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.

Evolutionary stability of antigenically escaping viruses.

Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also induce large mutational loads and reduced fitness. It remains unclear how this cost-benefit trade-off selects the mutation rate of viruses. Using a traveling wave model for the coevolution of viruses and host immune systems in a finite population, we investigate how immunity affects the evolution of the mutation rate and other nonantigenic traits, such as virulence. We first show that the nature of the wave depends on how cross-reactive immune systems are, reconciling previous approaches. The immune-virus system behaves like a Fisher wave at low cross-reactivities, and like a fitness wave at high cross-reactivities. These regimes predict different outcomes for the evolution of nonantigenic traits. At low cross-reactivities, the evolutionarily stable strategy is to maximize the speed of the wave, implying a higher mutation rate and increased virulence. At large cross-reactivities, where our estimates place H3N2 influenza, the stable strategy is to increase the basic reproductive number, keeping the mutation rate to a minimum and virulence low.

A Comprehensive Genetic Study of Microtubule-Associated Gene Clusters for Male Infertility in a Taiwanese Cohort.

Advanced reproductive technologies are utilized to identify the genetic mutations that lead to spermatogenic impairment, and allow informed genetic counseling to patients to prevent the transmission of genetic defects to offspring. The purpose of this study was to identify potential single nucleotide polymorphisms (SNPs) associated with male infertility. Genetic variants that may cause infertility are identified by combining the targeted next-generation sequencing (NGS) panel and whole exome sequencing (WES). The validation step of Sanger sequencing adds confidence to the identified variants. Our analysis revealed five distinct affected genes covering seven SNPs based on the targeted NGS panel and WES data: SPATA16 (rs16846616, 1515442, 1515441), CFTR (rs213950), KIF6 (rs2273063), STPG2 (r2903150), and DRC7 (rs3809611). Infertile men have a higher mutation rate than fertile men, especially those with azoospermia. These findings strongly support the hypothesis that the dysfunction of microtubule-related and spermatogenesis-specific genes contributes to idiopathic male infertility. The SPATA16, CFTR, KIF6, STPG2, and DRC7 mutations are associated with male infertility, specifically azoospermia, and a further examination of this genetic function is required.

XCNN-SC: Explainable CNN for SARS-CoV-2 variants classification and mutation detection

The COVID-19 pandemic spread rapidly all over the world in 2019, causing the deaths of millions of people. One of the main challenges in controlling the pandemic was the high rate of virus mutation, which evaded the immune system and reduced the vaccine's effectiveness. Due to the differences in symptoms, transmission and mortality rate, and effective prevention strategies of each variant, identifying and classifying different variants is a great necessity. In the present study, 82802 whole genomes of Alpha, Beta, Delta, Eta, Epsilon, Lota, and Omicron variants of SARS-CoV-2 were obtained from the NCBI database. The label encoding method was applied to convert the genomic sequences to numeric sequences. Then, a single-layer 1D-CNN model was used to classify seven variants of SARS-CoV-2 and achieved 99.78% accuracy, 97.98% precision, 97.66% sensitivity, 99.95% specificity, and 98.68% F1-score. The max pool layer feature maps of this network were investigated to discover the sequence discriminative regions in SARS-CoV-2 variants and their effect on biological functional differences. The feature map examination led to the detection of three mutations; one of them was a missense mutation, which has been reported previously. The rest of the detected mutations were silent mutations. In conclusion, the achieved results indicated that CNN models can extract effective features to discriminate several SARS-CoV-2 variants. Also, investigation of CNN feature maps led to an explainable CNN revealing the learned knowledge of the network from the training database. This knowledge helped us to detect mutations and their functional effects in different variants.

Integrase inhibitors: current protagonists in antiretroviral therapy.

Since HIV was identified as the etiological agent of AIDS, there have been significant advances in antiretroviral therapy (ART)that hasreduced morbidity/mortality. Still, the viral genome's high mutation rate, suboptimal ARTregimens, incomplete adherence to therapyand poor control of the viral loadgenerate variants resistant to multiple drugs. Licensing over 30anti-HIV drugs worldwide, including integrase inhibitors, has marked a milestone since they are potent and well-tolerated drugs. In addition, they favor a faster recovery of CD4+ T cells. They also increase the diversity profile of the gut microbiota and reduce inflammatory markers. All of these highlight the importance of including them in different ART regimens.

Pan-cancer genetic analysis of disulfidptosis-related gene set

BackgroundA recent study has identified a novel programmed cell death pathway, termed disulfidptosis, which is based on disulfide proteins. This discovery provides new insight into the mechanisms of cell death and may have implications for therapeutic strategies targeting cell death pathways. This study aimed to evaluate the pan-cancer genomics and clinical association of disulfidptosis and disulfidptosis-related cell death genes, including SLC7A11, INF2, CD2AP, PDLIM1, ACTN4, MYH9, MYH10, IQGAP1, FLNA, FLNB, TLN1, MYL6, ACTB, DSTN, and CAPZB. MethodsUsing multi-omics profiling data, this study provides a comprehensive and systematic characterization of disulfidptosis genes across more than 9000 samples of over 30 types of cancer. ResultsFLNA and FLNB were the two most frequently mutated disulfidptosis cell death genes in cancer. UCEC and SKCM were the two cancer types that have the highest mutation rates while the mutation of ACTN4 was associated with worse survival of CESC and ESCA. Breast cancer was potentially affected by disulfidptosis because its subtypes are different in disulfidptosis gene expression. Similarly, KIRC might also be associated with disulfidptosis. Additionally, the association of disulfidptosis-related cell death genes with survival was analyzed, with MESO and LGG as the top cancer types with survival associated with disulfidptosis cell death genes. The correlation between CNV and survival across multiple cancer types found that UCEC, KIRP, LGG, and KIRC were the top cancer types where the CNV level was associated with survival. There was a negative correlation between expression and methylation for most of the genes and there was only a slight correlation between methylation levels and survival of cancer in LGG. About half of the disulfidptosis-related cell death proteins were associated with the activation of EMT. Disulfidptosis genes were correlated to immune cell infiltration levels in cancers. Multiple compounds were identified as potential drugs that might be affected by disulfidptosis-related cell death for future study. ConclusionDisulfidptosis cell death genes are potentially involved in many cancer types and can be developed as candidates for cancer diagnosis, prognosis, and therapeutic biomarkers.

Survival analysis of patients with advanced non-small cell lung cancer receiving EGFR-TKI treatment of Yunnan in southwestern China: a real-world study.

Patients with EGFR mutations who have advanced-stage non-small cell lung cancer (NSCLC) already receive tyrosine kinase inhibitors (TKIs) as the standard first-line therapy. Notably, Yunnan is a regional high incidence area of lung cancer in the highlands with a high rate of rare EGFR mutations. Overall, lung cancer patients in Xuanwei may present a distinct subgroup globally. Recent studies suggested that the NSCLC cohort in Xuanwei harbored a significantly higher uncommon mutation rate. However, little was known about the clinicopathological features and treatment efficacy of EGFR-TKI in Yunnan NSCLC patients. This study aimed to investigate the clinical impact of histologic type on the survival outcomes of patients with stage IIIB and IV NSCLC receiving EGFR-TKI treatment of Yunnan in southwestern China. In this retrospective study, we enrolled advanced NSCLC patients (IIIB-IV) with EGFR mutations who were first diagnosed and treated at Yunnan Cancer hospital from January 2016 to December 2019. Sociodemographics, lifestyle, survival, and clinicopathological characteristics of the patients were collected. The Kaplan-Meier method was used to assess the OS and PFS of patients. An analysis of prognostic factors was conducted using Cox regression. A total of 468 eligible patients were included. The median progression-free survival (PFS) and overall survival(OS) were 11.30(95% CI, 10.12-12.48) months and 30.30(95% CI, 26.24-34.36) months. Based on survival analysis among all the patients,females(HR=0.815;95% CI:0.671-0.989; P=0.017), Xuanwei origin (HR=0.776; 95% CI: 0.609-0.989; P=0.040), sample types(HR=0.780; 95% CI: 0.642-0.947; P=0.012) had a longer PFS. Multivariable analysis showed that only the sample type was an independent factor on median PFS with EGFR-TKI therapy. Patients less than 60 years old (HR=1.433; 95% CI:1.134-1.812, P=0.003)had better OS, but objectives with BMI≥24kg/m2(HR=0.653; 95% CI: 0.500-0.864; P=0.002), females(HR=0.776; 95% CI:0.613-0.982; P=0.035)and patients with tissue sample type (HR=0.760; 95% CI:0.600-.0961; P=0.022) had better OS. Notably, subgroup analysis of our study also found that PFS was significantly better in patients with G719X, L861Q, S768I, G719X+L861Q, and G719X+S768I in Xuanwei than classical mutation ones, including 19-Del and L858R (median 22.7 vs. 12.0 months, HR=0.523, P=0.010), while PFS was inferior in patients with rare mutations of EGFR in non-Xuanwei than the classical mutation ones (median 5.10 vs. 11.10 months, HR=1.760, P=0.015). NSCLC patients in Yunnan displayed a unique EGFR mutation profile, especially a higher prevalence of EGFR uncommon and compound mutations subtype. This study indicates prognostic factors of NSCLC treated with EGFR-TKI in Yunan and Xuanwei. This study will provide new clinical evidence for EGFR-TKI-targeted therapy in patients with rare EGFR mutations in China and worldwide. More researchs were needed for NSCLC EGFR-TKI therapy and medical insurance policy-making in Yunnan, Xuanwei area and uncommon especially.

Implication of cytoplasmic p53 expression in pulmonary neuroendocrine carcinoma using next-generation sequencinganalysis.

Cytoplasmic p53 expression indicates a high frequency of TP53 abnormalities in gynaecological carcinoma. However, the implication of this expression in pulmonary neuroendocrine carcinoma (NEC) remains unclear. Thus, our study aimed to fill this research gap. Immunohistochemistry (IHC) of p53 was performed on 146 cases of resected small-cell lung carcinoma and large-cell NEC, and next-generation sequencing was conducted on cases showing cytoplasmic and wild-type p53 expression. IHC revealed overexpression in 57% of the cases (n = 83), complete absence in 31% (n = 45), cytoplasmic expression in 8% (n = 12) and wild-type expression in 4% (n = 6) of the cases. TP53 mutations were identified in nine of the 13 cases with available genetic analysis. The TP53 mutation rates in cases with cytoplasmic and wild-type p53 expression were 88% (seven of eight) and 40% (two of five), respectively. All seven cases showing cytoplasmic expression with TP53 mutations harboured loss-of-function type mutations: four had mutations in the DNA-binding domain, two in the nuclear localisation domain and one in the tetramerisation domain. Clinically, cases with cytoplasmic p53 expression had a poor prognosis similar to that in cases with p53 overexpression or complete absence. Cytoplasmic p53 expression in patients with pulmonary NEC suggests a high TP53 mutation rate, which is associated with a poor prognosis similar to that in patients with p53 overexpression or complete absence. This cytoplasmic expression should not be misidentified as a wild-type expression. This is the first report, to our knowledge, that demonstrates the implication of cytoplasmic p53 expression in pulmonary NEC.

Bridelia ferruginea phytocompounds interact with SARS-COV-2 drug targets: Experimental validation of corilagin contribution

The high mutation rate of SARS-CoV-2 genomic RNA has made COVID-19 more difficult to eradicate using currently available interventions. Hence, newer pharmaceutical strategies must be developed, especially those generally complementary and alternative medicines. In the current study, stem bark of Bridelia ferruginea Benth is presented as plausible source of ethno-pharmaceuticals actionable against key SARS-CoV-2 life cycle-dependent enzymes based on in vitro inhibition studies, LC-ESI-MS characterization and molecular docking studies. Bridelia ferruginea stem bark extracted with 1 % HCL-acidified water, water, butanol, chloroform, ethyl-acetate, and petroleum ether and assayed for in vitro inhibition of SARS-COV-2-gp/human ACE2 interaction. The lowest and the highest IC50 value were recorded for ethyl-acetate (3.550 mg/L) and chloroform (413.4 mg/L) extracts respectively. When the ethyl-acetate extract was tested for SARS-COV-2 protease inhibition in vitro, papain-like protease (PL-pro, IC50=1.981 mg/L) presented as the better target in comparison to the main protease (3CL-pro, IC50=10.13 mg/L). LC/MS analysis identified corilagin and Gallocatechin-[4-O-7]-epigallocatechin as the active principles whilst molecular docking revealed the plausible poses of the compounds within the binding pockets of SARS-COV-2-glycoprotien receptor binding pocket, 3CL-pro and PL-pro. Taken together, these findings identified Bridelia ferruginea stem bark as a plausible source of anti-SARS-COV-2 phytochemicals and propose that corilagin may play important role in this activity.

COVID-19 in 16 West African Countries: An Assessment of the Epidemiology and Genetic Diversity of SARS-CoV-2 after Four Epidemic Waves.

West Africa faced the COVID-19 pandemic in early March 2020 and, as of March 31, 2022, had more than 900,000 confirmed cases and more than 12,000 deaths. During this period, SARS-CoV-2 genomes evolved genetically, resulting in the emergence of distinct lineages. This review was conducted to provide the epidemiological profile of COVID-19, the mutational profile of SARS-CoV-2, and the dynamics of its lineages in the 16 west African countries by analyzing data from 33 studies and seven situation reports. For a more complete representation of the epidemiology and genetic diversity of SARS-CoV-2, we used reliable public data in addition to eligible studies. As of March 31, 2022, the 16 west African countries experienced four epidemic waves with variable intensities. Higher mortality was noted during the third wave with a case fatality rate (CFR) of 1.9%. After these four epidemic waves, Liberia recorded the highest CFR (4.0%), whereas Benin had the lowest CFR (0.6%). Through mutational analysis, a high genetic heterogeneity of the genomes was observed, with a predominance of mutations in the spike protein. From this high mutational rate, different lineages emerged. Our analysis of the evolutionary diversity allowed us to count 205 lineages circulating in west Africa. This study has provided a good representation of the mutational profile and the prevalence of SARS CoV-2 lineages beyond the knowledge of the global epidemiology of the 16 African countries.

M gene targeted qRT-PCR approach for SARS-CoV-2 virus detection

Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) is the gold standard method for SARS-CoV-2 detection, and several qRT-PCR kits have been established targeting different genes of the virus. Due to the high mutation rate of these genes, false negative results arise thus complicating the interpretation of the diagnosis and increasing the need of alternative targets. In this study, an alternative approach for the detection of SARS-CoV-2 viral RNA targeting the membrane (M) gene of the virus using qRT-PCR was described. Performance evaluation of this newly developed in-house assay against commercial qRT-PCR kits was done using clinical oropharyngeal specimens of COVID-19 positive patients. The limit of detection was determined using successive dilutions of known copies of SARS-CoV-2 pseudovirus. The M gene based assay was able to detect a minimum of 100 copies of virus/mL indicating its capacity to detect low viral load. The assay showed comparable accuracy, sensitivity and specificity with commercially available kits while detecting all the variants efficiently. The study concluded that the in-house M gene based assay might be an effective alternative for the currently available commercial qRT-PCR kits.

Viral inhibitory potential of hyoscyamine in Japanese encephalitis virus-infected embryonated chicken eggs involving multiple signaling pathways.

Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis worldwide. The emergence of new genotypes of the virus and a high rate of mutation make it necessary to develop alternative treatment strategies against this deadly pathogen. Although the antiviral properties of Atropa belladonna and some of its active components, such as atropine and scopolamine, have been studied, the effect of another important component, hyoscyamine, against JEV infection has not yet been investigated. In this study, we investigated the antiviral effect of hyoscyamine against JEV and its immunomodulatory activity in embryonated chicken eggs. Pretreatment with hyoscyamine sulphate resulted in a significant decrease in the viral load in both chorioallantoic membrane (CAM) and brain tissues at 48 and 96hours postinfection. In silico studies showed stable binding and interaction between hyoscyamine and non-structural protein 5 (NS5), suggesting that this could be the basis of its antiviral effect. Embryonated eggs pretreated with hyoscyamine sulphate showed upregulation of Toll-like receptor 3 (TLR3), TLR7, TLR8, interleukin 4 (IL-4), and IL-10 as well as interferons and regulatory factors. Hyoscyamine sulphate was also found to cause significant downregulation of TLR4. The potential use of hyoscyamine for controlling JEV replication and its dissemination to the brain suggest that it may be a promising therapy option against JEV in the future.

New strategies for developing vaccines against the H5N1 avian influenza virus. Proceeding of The First International Avian Influenza Summit, University of Arkansas- October 16-17, 2023”

The H5N1 avian influenza virus poses a significant threat to poultry populations and human health, with sporadic outbreaks and the potential for pandemic emergence. Traditional vaccine development approaches have faced challenges in achieving broad-spectrum protection due to the high mutation rate of the virus. This abstract outlines novel strategies that have emerged to address these hurdles. Firstly, advances in reverse genetics technology have enabled the creation of recombinant vaccines, allowing for the precise manipulation of viral genes to enhance immunogenicity. These platforms facilitate the development of multi-valent vaccines capable of targeting multiple H5N1 strains simultaneously. Additionally, viral replicant or no-replicant vector vaccines employing non-pathogenic viruses as delivery systems show promise in eliciting robust immune responses against H5N1. Secondly, integrating computational modeling and artificial intelligence techniques in antigen design has accelerated the identification of conserved epitopes within H5N1, including MHC I, enabling the development of more effective and broadly protective vaccine candidates. Furthermore, using adjuvants, immune potentiators, antigen labeling for immune system cells, and novel delivery systems has enhanced the efficacy of H5N1 vaccines, providing more durable and cross-protective immunity. Moreover, implementing advanced manufacturing technologies of protein expression, such as cell-based (animal/plants/yeasts/bacteria) and virus-like particle (VLP) platforms, has streamlined production processes and increased vaccine accessibility. These platforms offer scalable and adaptable solutions to meet global demands during outbreaks and potential pandemics. Lastly, incorporating one health approach, emphasizing collaborative efforts between human, animal, and environmental health sectors, is crucial for comprehensive pandemic preparedness. Surveillance systems, early warning mechanisms, and rapid response strategies are integral to a proactive defense against H5N1 outbreaks. In conclusion, this abstract highlights the promising strides in developing vaccines against the H5N1 avian influenza virus through innovative approaches. These strategies, ranging from advanced genetic engineering techniques to cutting-edge computational modeling, offer a comprehensive toolkit for achieving broader and more durable protection against this formidable pathogen. By synergizing these advancements with a holistic health framework, we can significantly enhance our ability to mitigate the impact of H5N1 outbreaks on animal and human populations.

A multitier virtual screening of antagonists targeting PD-1/PD-L1 interface for the management of triple-negativebreastcancer.

Immunotherapies are promising therapeutic options for the management of triple-negative breast cancer because of its high mutation rate and genomic instability. Of note, the blockade of the immune checkpoint protein PD-1 and its ligand PD-L1 has been proven to be an efficient and potent strategy to combat triple-negative breast cancer.To date, various anti-PD-1/anti-PD-L1 antibodies have been approved. However, the intrinsic constraints of these therapeutic antibodies significantly limit their application, making small molecules a potentially significant option for PD-1/PD-L1 inhibition. In light of this, the current study aims to use a high-throughput virtual screening technique to identify potential repurposed candidates as PD-L1 inhibitors. Thus, the present study explored binding efficiency of 2509 FDA-approved compounds retrieved from the drug bank database against PD-L1 protein. The binding affinity of the compounds was determined using the glide XP docking programme. Furthermore, prime-MM/GBSA, DFT calculations, and RF score were used to precisely re-score the binding free energy of the docked complexes. In addition, the ADME and toxicity profiles for the lead compounds were also examined to address PK/PD characteristics. Altogether, the screening process identified three molecules, namely DB01238, DB06016 and DB01167 as potential therapeutics for the PD-L1 protein. To conclude, a molecular dynamic simulation of 100ns was run to characterise the stability and inhibitory action of the three lead compounds. The results from the simulation study confirm the robust structural and thermodynamic stability of DB01238 than other investigated molecules.Thus, our findings hypothesize that DB01238 could serve as potential PD-L1 inhibitor in the near future for triple-negative breast cancer patients.

Characterization of Omicron XBB subvariants in Vietnam

SARS-CoV-2, an RNA virus that causes COVID-19, is known for its high mutation rate. Its latest variant, Omicron, has raised concerns due to several amino acid substitutions in the spike protein that could increase its transmissibility and virulence. Omicron has also produced subvariants with specific nucleotide mutations to evade antibodies and enhance infectivity. One of these subvariants, XBB, has become prevalent in Vietnam. Therefore, it is essential to accurately assess the genetic diversity of this emerging variant. This study analyzed the April 15th, 2023 updated data and identified nine XBB and subvariants in Vietnam, with XBB.1.5 being the most common. Phylogenetic analysis revealed that the original XBB variant was related to BA.2.75, and XBB.1.5 had a close relationship with XBB.1.2. A crucial mutation, G22317T (G252V), played an essential role in the emergence of the XBB subvariant, and XBB.1.5 split from XBB.1.2 with an A22405T (E281D) mutation, as shown by the mutation network.

Characterization of mutations conferring streptomycin resistance in \(\textit{Mycobacterium tuberculosis}\) in Vietnam

Recently, World Health Organization (WHO) has listed streptomycin (STR) in the list of second-line injectable drugs in the multidrug-resistant tuberculosis (MDR-TB) regimens and may replace amikacin under the same conditions. Nevertheless, molecular characterizations associated with STR resistance in the Mycobacterium tuberculosis population have not been fully investigated in Vietnam. The present study aimed to explore the variation and frequency of mutations in rpsL and rrs genes and their relationship with drug-resistant patterns and M. tuberculosis genotypes in 163 STR-resistant strains from Vietnam. The mutation frequency of the rpsL and rrs genes were 62% and 20.9%, respectively, and the mutation combination in both genes covered 81% of STR-resistant strains. The most prevalent mutations included rpsL Lys43Arg (38.7%), Lys88Arg (19.6%), rrs A514C (10.4%) and A517C (5.5%). Thus, sequence analysis of rpsL and rrs exhibited a sensitivity of 81% and specificity of 100% for the prediction of STR resistance in Vietnamese M. tuberculosis strains. The prevalence of STR-resistant mutations in double, triple and quadruple resistance strains was significantly different, compared with mono STR-resistant ones. Similarly, mutation frequency associated with STR resistance in MDR strains was significantly higher than that in non-MDR strains. In addition, the lineage 2 genotype was significantly correlated with a high rate of STR resistance-conferring mutation, as well as the mutation rpsL Lys43Arg (P < 0.01), while the lineage 1 genotype was associated with a low rate of STR resistance-conferring mutation and rrs mutations (P<0.05). In conclusion, sequence analysis may be useful for the rapid detection of STR resistance in MDR M. tuberculosis strains, which in turn could contribute to better control strategies of TB in Vietnam. Other molecular mechanisms associated with STR resistance in STR-resistant strains without mutations in the rpsL and rrs genes need to be further investigated.

An organism-wide ATAC-seq peak catalog for the bovine and its use to identify regulatory variants.

We report the generation of an organism-wide catalog of 976,813 cis-acting regulatory elements for the bovine detected by the assay for transposase accessible chromatin using sequencing (ATAC-seq). We regroup these regulatory elements in 16 components by nonnegative matrix factorization. Correlation between the genome-wide density of peaks and transcription start sites, correlation between peak accessibility and expression of neighboring genes, and enrichment in transcription factor binding motifs support their regulatory potential. Using a previously established catalog of 12,736,643 variants, we show that the proportion of single-nucleotide polymorphisms mapping to ATAC-seq peaks is higher than expected and that this is owing to an approximately 1.3-fold higher mutation rate within peaks. Their site frequency spectrum indicates that variants in ATAC-seq peaks are subject to purifying selection. We generate eQTL data sets for liver and blood and show that variants that drive eQTL fall into liver- and blood-specific ATAC-seq peaks more often than expected by chance. We combine ATAC-seq and eQTL data to estimate that the proportion of regulatory variants mapping to ATAC-seq peaks is approximately one in three and that the proportion of variants mapping to ATAC-seq peaks that are regulatory is approximately one in 25. We discuss the implication of these findings on the utility of ATAC-seq information to improve the accuracy of genomic selection.

Radiofrequency ablation for stage

Pulmonary carcinoma represents the second common cancer for human race while its mortality rate ranked the first all over the world. Surgery remains the primary option for early-stage non-small cell lung cancer (NSCLC) in some surgical traditions. Nevertheless, only less than half of patients are operable subjected to the limited lung function and multiple primary/metastatic lesions. Recent improvements in minimally invasive surgical techniques have made the procedure accessible to more patients, but this percentage still does not exceed half. In recent years, radiofrequency ablation (RFA), one of the thermal ablation procedures, has gradually advanced in the treatment of lung cancer in addition to being utilized to treat breast and liver cancer. Several guidelines, including the American College of Chest Physicians (ACCP), include RFA as an option for some patients with NSCLC although the level of evidence is mostly limited to retrospective studies. In this review, we emphasize the use of the RFA technique in patients with early-stage NSCLC and provide an overview of the RFA indication population, prognosis status, and complications. Meanwhile, the advantages and disadvantages of RFA proposed in existing studies are compared with surgical treatment and radiotherapy. Due to the high rate of gene mutation and immunocompetence in NSCLC, there are considerable challenges to clinical translation of combining targeted drugs or immunotherapy with RFA that the field has only recently begun to fully appreciate.

The epidemiological and genetic characteristics of human parvovirus B19 in patients with febrile rash illnesses in China

To understand the epidemiological and genetic characteristics of B19V, a multiple-province surveillance of patients with febrile rash illnesses (FRIs) were conducted in China during 2009 ~ 2021. The clinical specimens of 3,820 FRI patients were collected and tested for B19V DNA. A total of 99 (2.59%) patients were positive for B19V, and 49 (49.49%) were children under 5 years old. B19V infections occurred throughout the year without obvious seasonal pattern. Ten NS1-VP1u sequences and seven genome sequences were obtained in this study, identified as subgenotype 1a. Combined with the globally representative genome sequences, no temporal and geographic clustering trends of B19V were observed, and there was no significant correlation between B19V sequences and clinical manifestations. The evolutionary rate of the B19V genome was 2.30 × 10–4 substitutions/site/year. The number of negative selection sites was higher than that of positive selection sites. It was the first to comprehensively describe the prevalence patterns and evolutionary characteristics of B19V in FRI patients in China. B19V played the role in FRI patients. Children under 5 years old were the main population of B19V infection. Subgenotype 1a was prevalent in FRI patients in China. B19V showed a high mutation rate, while negative selection acted on the genome.

Identification of SULF1 as a Shared Gene in Idiopathic Pulmonary Fibrosis and Lung Adenocarcinoma

Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer. Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases. A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts. This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.