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Briefings in Bioinformatics May 2024This study proposes a novel approach to studying severe acute respiratory syndrome coronavirus 2 virus mutations through sequencing data comparison. Traditional... (Comparative Study)
Comparative Study
This study proposes a novel approach to studying severe acute respiratory syndrome coronavirus 2 virus mutations through sequencing data comparison. Traditional consensus-based methods, which focus on the most common nucleotide at each position, might overlook or obscure the presence of low-frequency variants. Our method, in contrast, retains all sequenced nucleotides at each position, forming a genomic matrix. Utilizing simulated short reads from genomes with specified mutations, we contrasted our genomic matrix approach with the consensus sequence method. Our matrix methodology, across multiple simulated datasets, accurately reflected the known mutations with an average accuracy improvement of 20% over the consensus method. In real-world tests using data from GISAID and NCBI-SRA, our approach demonstrated an increase in reliability by reducing the error margin by approximately 15%. The genomic matrix approach offers a more accurate representation of the viral genomic diversity, thereby providing superior insights into virus evolution and epidemiology.
Topics: SARS-CoV-2; Phylogeny; Genome, Viral; Humans; COVID-19; Mutation; Consensus Sequence; Genetic Variation
PubMed: 38920083
DOI: 10.1093/bib/bbae296 -
Nucleosides, Nucleotides & Nucleic Acids Jun 2024Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer...
BACKGROUND
Identifying subtypes of lung adenocarcinoma (LUAD) patients based on mitochondrial energy metabolism and immunotherapy sensitivity is essential for precision cancer treatment.
METHODS
LUAD subtypes were identified using unsupervised consensus clustering, and results were subjected to immune and tumor mutation analyses. DEGs between subtypes were identified by differential analysis. Functional enrichment and PPI network analyses were conducted. Patients were classified into high and low expression groups based on the expression of the top 10 hub genes, and survival analysis was performed. Drugs sensitive to feature genes were screened based on the correlation between hub gene expression and drug IC value. qRT-PCR and western blot were used for gene expression detection, and CCK-8 and flow cytometry were for cell viability and apoptosis analysis.
RESULTS
Cluster-1 had significantly higher overall survival and a higher degree of immunoinfiltration and immunophenotypic score, but a lower TIDE score, DEPTH score, and TMB. Enrichment analysis showed that pathways and functions of DEGs between two clusters were mainly related to the interaction of receptor ligands with intracellular proteases. High expression of hub genes corresponded to lower patient survival rates. The predicted drugs with high sensitivity to feature genes were CDK1: Ribavirin (0.476), CCNB2: Hydroxyurea (0.474), Chelerythrine (0.470), and KIF11: Ribavirin (0.471). KIF11 and CCNB2 were highly expressed in LUAD cells and promoted cell viability and inhibited cell apoptosis.
CONCLUSION
This study identified two subtypes of LUAD, with cluster-1 being more suitable for immunotherapy. These results provided a reference for the development of precision immunotherapy for LUAD patients.
PubMed: 38920027
DOI: 10.1080/15257770.2024.2369093 -
JCEM Case Reports Jun 2024Chiari 1 malformation (CM1) is a rare finding that has been described with growth hormone (GH)-secreting pituitary adenomas and with an endothelial PAS domain protein 1...
Chiari 1 malformation (CM1) is a rare finding that has been described with growth hormone (GH)-secreting pituitary adenomas and with an endothelial PAS domain protein 1 gain-of-function mutation syndrome. We describe the first reported case of a patient diagnosed with CM1 and nonfunctioning pituitary and adrenal incidentalomas. Our case describes a 45-year-old female who was found to have cerebellar tonsillar ectopia consistent with CM1, a pituitary tumor, and bilateral adrenal incidentalomas. She was diagnosed after presenting with 2 weeks of upper extremity weakness and paresthesia. A comprehensive endocrine workup including insulin like growth factor (IGF-1) was normal. She underwent posterior fossa decompression without complication. Pituitary adenectomy was not pursued as there was no evidence of compression of the chiasm or the surrounding structures. In previous case reports it has been proposed that GH-secreting adenomas contribute to CM1 by causing hypertrophy of soft tissue structures in the skull base, overcrowding the posterior fossa. Given that our patient had normal IGF-1 levels, there could be a different underlying mechanism that contributed to the concomitant occurrence of CM1 with the pituitary and adrenal tumors.
PubMed: 38919912
DOI: 10.1210/jcemcr/luae113 -
Archive of Clinical Cases 2024Mediastinal tumors are exceedingly rare during fetal development, presenting significant diagnostic challenges and potentially leading to severe outcomes such as...
Mediastinal tumors are exceedingly rare during fetal development, presenting significant diagnostic challenges and potentially leading to severe outcomes such as stillbirth or metastatic disease if not promptly identified and managed. Pleuropulmonary blastomas are primitive mesenchymal tumors often linked to mutations in the DICER1 gene, indicating a hereditary pattern associated with other common adult neoplasms with dominant inheritance. This report describes a case involving a 20-year-old Caucasian woman whose pregnancy was complicated by a stillbirth in the second trimester. Initial suspicions of a mediastinal tumor arose from blood tests and ultrasound examinations during pregnancy surveillance. However, the definitive diagnosis of a type II pleuropulmonary blastoma was established through a pathological examination at autopsy. This case underscores the complexities of diagnosing fetal mediastinal tumors and contributes to the sparse literature on neonatal pleuropulmonary blastomas. Our comprehensive review of the differential diagnoses and literature emphasizes the unique characteristics of pleuropulmonary blastoma and its similarities to other soft tissue sarcomas, enhancing understanding of their clinical and genetic profiles.
PubMed: 38919847
DOI: 10.22551/2024.43.1102.10286 -
Respirology Case Reports Jun 2024Granulocyte colony-stimulating factor (G-CSF)-producing lung tumours are rare, with their imaging features and effective treatments remaining elusive. Similarly,...
Mesenchymal-epithelial transition factor exon 14 skipping mutation-positive granulocyte colony-stimulating factor-producing lung adenocarcinoma mimicking lung abscess: A case report.
Granulocyte colony-stimulating factor (G-CSF)-producing lung tumours are rare, with their imaging features and effective treatments remaining elusive. Similarly, mesenchymal-epithelial transition (MET) exon 14 skipping mutations are also uncommon. Herein, we report a case of G-CSF-producing lung adenocarcinoma positive for a MET exon 14 skipping mutation, mimicking lung abscess. A 61-year-old man presented with cough and high fever. Contrast-enhanced chest computed tomography revealed a mass with a cavity and internal fluid accumulation. The patient initially underwent diagnostic treatment for a lung abscess but was ultimately diagnosed with lung adenocarcinoma positive for a MET exon 14 skipping mutation. Following tepotinib therapy, the primary lesion shrank, and serum G-CSF levels decreased, leading to a diagnosis of G-CSF-producing lung cancer. G-CSF-producing lung tumours can present imaging findings that mimic lung abscesses. Tepotinib therapy may be effective for patients with MET exon 14 skipping mutation, including those with G-CSF-producing lung cancer.
PubMed: 38919814
DOI: 10.1002/rcr2.1419 -
South Asian Journal of Cancer Apr 2024Atreye MajumdarSambit K. Mohanty This article identifies and evaluates the frequency of mutations in the BCR-ABL1 kinase domain (KD) of chronic myeloid leukemia (CML)...
A Retrospective Analysis of Kinase Domain Mutations in the Frontline Drug Intolerant or Resistant Chronic Myeloid Leukemia Patients: An Indian Experience from a High-End Referral Laboratory.
Atreye MajumdarSambit K. Mohanty This article identifies and evaluates the frequency of mutations in the BCR-ABL1 kinase domain (KD) of chronic myeloid leukemia (CML) patients who showed suboptimal response to their current tyrosine kinase inhibitor (TKI) regime and assesses their clinical value in further treatment decisions. Peripheral and/or bone marrow were collected from 791 CML patients. Ribonucleic acid was extracted, reverse transcribed, and Sanger sequencing method was utilized to detect single-nucleotide variants (SNVs) in BCR-ABL1 KD. Thirty-eight different SNVs were identified in 29.8% ( = 236/791) patients. T315I, E255K, and M244V were among the most frequent mutations detected. In addition, one patient harbored a novel L298P mutation. A subset of patients from the abovementioned harbored compound mutations (13.3%, = 33/236). Follow-up data was available in 28 patients that demonstrated the efficacy of TKIs in correlation with mutation analysis and quantitation. Molecular response was attained in 50% patients following an appropriate TKI shift. A dismal survival rate of 40% was observed in T315I-harboring patients on follow-up. This study shows the incidence and pattern of mutations in one of the largest sets of Indian CML patients. In addition, our findings strengthen the prognostic value of KD mutation analysis among strategies to overcome TKI resistance.
PubMed: 38919665
DOI: 10.1055/s-0042-1757911 -
Frontiers in Immunology 2024Complement factor H (FH) is a major regulator of the complement alternative pathway, its mutations predispose to an uncontrolled activation in the kidney and on blood...
INTRODUCTION
Complement factor H (FH) is a major regulator of the complement alternative pathway, its mutations predispose to an uncontrolled activation in the kidney and on blood cells and to secondary C3 deficiency. Plasma exchange has been used to correct for FH deficiency and although the therapeutic potential of purified FH has been suggested by experiments in animal models, a clinical approved FH concentrate is not yet available. We aimed to develop a purification process of FH from a waste fraction rather than whole plasma allowing a more efficient and ethical use of blood and plasma donations.
METHODS
Waste fractions from industrial plasma fractionation (pooled human plasma) were analyzed for FH content by ELISA. FH was purified from unused fraction III and its decay acceleration, cofactor, and C3 binding capacity were characterized Biodistribution was assessed by high-resolution dynamic PET imaging. Finally, the efficacy of the purified FH preparation was tested in the mouse model of C3 glomerulopathy (Cfh-/- mice).
RESULTS
Our purification method resulted in a high yield of highly purified (92,07%), pathogen-safe FH. FH concentrate is intact and fully functional as demonstrated by functional assays. The biodistribution revealed lower renal and liver clearance of human FH in Cfh-/- mice than in wt mice. Treatment of Cfh-/- mice documented its efficacy in limiting C3 activation and promoting the clearance of C3 glomerular deposits.
CONCLUSION
We developed an efficient and economical system for purifying intact and functional FH, starting from waste material of industrial plasma fractionation. The FH concentrate could therefore constitute possible treatments options of patients with C3 glomerulopathy, particularly for those with FH deficiency, but also for patients with other diseases associated with alternative pathway activation.
Topics: Complement Factor H; Animals; Humans; Mice; Complement C3; Mice, Knockout; Disease Models, Animal; Proof of Concept Study; Mice, Inbred C57BL
PubMed: 38919628
DOI: 10.3389/fimmu.2024.1334151 -
Horticulture Research Jun 2024Establishing an efficient plant regeneration system is a crucial prerequisite for genetic engineering technology in plants. However, the regeneration rate exhibits...
Establishing an efficient plant regeneration system is a crucial prerequisite for genetic engineering technology in plants. However, the regeneration rate exhibits considerable variability among genotypes, and the key factors underlying shoot regeneration capacity remain largely elusive. Blueberry leaf explants cultured on a medium rich in cytokinins exhibit direct shoot organogenesis without prominent callus formation, which holds promise for expediting genetic transformation while minimizing somatic mutations during culture. The objective of this study is to unravel the molecular and genetic determinants that govern cultivar-specific shoot regeneration potential in highbush blueberry ( L.). We conducted comparative transcriptome analysis using two highbush blueberry genotypes: 'Blue Muffin' ('BM') displaying a high regeneration rate (>80%) and 'O'Neal' ('ON') exhibiting a low regeneration rate (<10%). The findings revealed differential expression of numerous auxin-related genes; notably, 'BM' exhibited higher expression of auxin signaling genes compared to 'ON'. Among blueberry orthologs of transcription factors involved in meristem formation in , expression of (), (), and were significantly higher in 'BM' relative to 'ON'. Exogenous application of auxin promoted regeneration, as well as and expression, whereas inhibition of auxin biosynthesis yielded the opposite effects. Overexpression of in 'BM' promoted shoot regeneration under phytohormone-free conditions by activating the expression of cytokinin- and auxin-related genes. These findings provide new insights into the molecular mechanisms underlying blueberry regeneration and have practical implications for enhancing plant regeneration and transformation techniques.
PubMed: 38919558
DOI: 10.1093/hr/uhae114 -
Horticulture Research Jun 2024Stem cell homeostasis is pivotal for continuous and programmed formation of organs in plants. The precise control of meristem proliferation is mediated by the...
Stem cell homeostasis is pivotal for continuous and programmed formation of organs in plants. The precise control of meristem proliferation is mediated by the evolutionarily conserved signaling that encompasses complex interactions among multiple peptide ligands and their receptor-like kinases. Here, we identified compensation mechanisms involving the CLAVATA1 (CLV1) receptor and its paralogs, BARELY ANY MERISTEMs (BAMs), for stem cell proliferation in two Solanaceae species, tomato and groundcherry. Genetic analyses of higher-order mutants deficient in multiple receptor genes, generated via CRISPR-Cas9 genome editing, reveal that tomato and compensate for mutations. Unlike the compensatory responses between orthologous receptors observed in , tomato mutations do not trigger transcriptional upregulation of four genes. The compensation mechanisms within receptors are also conserved in groundcherry, and critical amino acid residues of the receptors associated with the physical interaction with peptide ligands are highly conserved in Solanaceae plants. Our findings demonstrate that the evolutionary conservation of both compensation mechanisms and critical coding sequences between receptor-like kinases provides a strong buffering capacity during stem cell homeostasis in tomato and groundcherry.
PubMed: 38919555
DOI: 10.1093/hr/uhae126 -
Horticulture Research Jun 2024In monoecious species, female flowering constitutes the developmental process that determines the onset and production of fruit and is therefore closely related to crop...
In monoecious species, female flowering constitutes the developmental process that determines the onset and production of fruit and is therefore closely related to crop yield. This article presents the identification and phenotypic and molecular characterization of , an ethylmethane sulfonate loss-of-function mutation that completely blocks the female floral transition, converting all female flowers into male flowers. BSA-seq analysis coupled with WGS showed that corresponds to a C>T transition in the coding region of the gene , generating a premature stop codon and a truncated transcription factor without its N-terminal effector domain. The phenotype was partially rescued by exogenous ethylene application, indicating that the function of is mediated by ethylene. Different evidence supports this conclusion: first, the reduced ethylene production of the mutant, and second, the male flower productive phenotype of the double mutant between and the ethylene-insensitive mutant , which demonstrated that is epistatic over . Furthermore, transcriptomic analysis of WT and apical shoots confirmed that regulates master sex-determining genes, upregulating those encoding the ethylene biosynthesis enzymes and and those encoding for transcription factors that promote the development of carpels(), but downregulating those involved in the arrest of carpels (), In the gene network controlling sex determination in cucurbits, CpMYB62 occupies the most upstream position, activating ethylene and other sex determining genes involved in female flower determination in .
PubMed: 38919554
DOI: 10.1093/hr/uhae115