A novel stoploss mutation CYB5R3 c.906A>G(p.*302Trpext*42) involved in the pathogenesis of hereditary methemoglobinemia.

Recessive congenital methemoglobinemia (RCM) is a hereditary autosomal disorder with an extremely low incidence rate. Here, we report a case of methemoglobinemia type I in a patient with congenital persistent cyanosis. The condition was attributed to a novel compound heterozygous mutation in CYB5R3, characterized by elevated methemoglobin levels (13.4 % of total hemoglobin) and undetectable NADH cytochrome b5 reductase (CYB5R3) activity. Whole-exome sequencing (WES) revealed two heterozygous mutations in CYB5R3: a previously reported pathogenic missense mutation c.611G>A(p.Cys204Tyr) inherited from the father, and a novel stop codon mutation c.906A>G(p.*302Trpext*42) from the mother, the latter mutation assessed as likely pathogenic according to ACMG guidelines. In cells overexpressing the CYB5R3 c.906A>G mutant construct, the CYB5R3 mRNA level was significantly lower than in cells overexpressing the wild-type (WT) CYB5R3 construct. However, there was no significant difference in protein expression levels between the mutant and WT constructs. Notably, an additional protein band of approximately 55 kDa was detected in the mutant cells. Immunofluorescence localization showed that, compared to wild-type CYB5R3, the subcellular localization of the CYB5R3 p.*302Trpext*42 mutant protein did not show significant changes and remained distributed in the endoplasmic reticulum and mitochondria. However, the c.906A>G(p.*302Trpext*42) mutation resulted in increased intracellular reactive oxygen species (ROS) levels and decreased NAD+/NADH ratio, suggesting impaired CYB5R3 function and implicating this novel mutation as likely pathogenic.

SCN1A intronic variants impact on Nav1.1 protein expression and sodium channel function, and associated with epilepsy phenotypic severity.

High-throughput sequencing has identified numerous intronic variants in the SCN1A gene in epilepsy patients. Abnormal mRNA splicing caused by these variants can lead to significant phenotypic differences, but the mechanisms of epileptogenicity and phenotypic differences remain unknown. Two variants, c.4853-1 G>C and c.4853-25 T>A, were identified in intron 25 of SCN1A, which were associated with severe Dravet syndrome (DS) and mild focal epilepsy with febrile seizures plus (FEFS+), respectively. The impact of these variants on protein expression, electrophysiological properties of sodium channels and their correlation with epilepsy severity was investigated through plasmid construction and transfection based on the aberrant spliced mRNA. We found that the expression of truncated mutant proteins was significantly reduced on the cell membrane, and retained in the cytoplasmic endoplasmic reticulum. The mutants caused a decrease in current density, voltage sensitivity, and an increased vulnerability of channel, leading to a partial impairment of sodium channel function. Notably, the expression of DS-related mutant protein on the cell membrane was higher compared to that of FEFS+-related mutant, whereas the sodium channel function impairment caused by DS-related mutant was comparatively milder than that caused by FEFS+-related mutant. Our study suggests that differences in protein expression levels and altered electrophysiological properties of sodium channels play important roles in the manifestation of diverse epileptic phenotypes. The presence of intronic splice site variants may result in severe phenotypes due to the dominant-negative effects, whereas non-canonical splice site variants leading to haploinsufficiency could potentially cause milder phenotypes.

Genomic Pipeline for Analysis of Mutational Events in Bacteria.

Unveiling the strategies of bacterial adaptation to stress constitute a challenging area of research. The understanding of mechanisms governing emergence of resistance to antimicrobials is of particular importance regarding the increasing threat of antibiotic resistance on public health worldwide. In the last decades, the fast democratization of sequencing technologies along with the development of dedicated bioinformatical tools to process data offered new opportunities to characterize genomic variations underlying bacterial adaptation. Thereby, research teams have now the possibility to dive deeper in the deciphering of bacterial adaptive mechanisms through the identification of specific genetic targets mediating survival to stress. In this chapter, we proposed a step-by-step bioinformatical pipeline enabling the identification of mutational events underlying biocidal stress adaptation associated with antimicrobial resistance development using Escherichia marmotae as an illustrative model.

CFTR complex alleles and phenotypic variability in cystic fibrosis disease.

Cystic fibrosis (CF) is inherited by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. A variety of mutations have been identified in the CFTR gene that may be associated with cystic fibrosis, and these mutations demonstrate extensive molecular genetic heterogeneity in this disease. Little is known about the molecular mechanism by which mutations affect CFTR function, and only a minority of mutations have been characterized by functional studies. There has been an increase in the number of complex alleles. This may partly explain the difficulty in establishing genotype-phenotype correlations and complicate genetic counseling and diagnosis in some cases. Therefore, the identification of complex alleles has several important implications for recessive disorders. This will facilitate diagnosis; improve judgements concerning prognosis, and enable appropriate genetic counselling for affected families. This review describes the complex cystic fibrosis allele to better understand the contribution of this allele in the wide phenotypic variability of cystic fibrosis disease. It occurs in the complex allele that the second cis mutation can modulate the effects of the first mutation or vice versa. The phenotypic variability between CF or CFTR-RD (CFTR related disease) patients may be due to several factors, including different genetic and environmental backgrounds. It is important to determine the allele complex so that optimal treatment can be established.

Liquid biopsy in prostate cancer: A novel dual biomarker analysis approach integrating circulating tumor cells and circulating tumor DNA data.

This study aimed to explore the potential of liquid biopsy as a diagnostic tool by integrating two key biomarkers, Circulating Tumor Cells (CTCs) and Circulating Tumor DNA (ctDNA), and to enhance the detection fidelity of prostate cancer. A dual biomarker analysis approach was employed to synergize the sensitivities of CTCs and ctDNA. Various genetic mutations of ctDNA and tissues were scrutinized, investigating their prevalence, co-existence, and mutual exclusivity. The findings uncovered a more intricate mutation landscape than previously anticipated, indicating a complex interplay between cellular and genetic aberrations in prostate cancer. Through harnessing the combined power of CTCs and ctDNA, our dual biomarker approach provides a more comprehensive understanding of prostate cancer genetics. This has the potential to revolutionize early detection and guide personalized therapeutic interventions.

Two new mouse alleles of Ocm and Slc26a5.

The genes Ocm (encoding oncomodulin) and Slc26a5 (encoding prestin) are expressed strongly in outer hair cells and both are involved in deafness in mice. However, it is not clear if they influence the expression of each other. In this study, we characterise the auditory phenotype resulting from two new mouse alleles, Ocmtm1e and Slc26a5tm1Cre. Each mutation leads to absence of detectable mRNA transcribed from the mutant allele, but there was no evidence that oncomodulin regulates expression of prestin or vice versa. The two mutants show distinctive patterns of auditory dysfunction. Ocmtm1e homozygotes have normal auditory brainstem response thresholds at 4 weeks old followed by progressive hearing loss starting at high frequencies, while heterozygotes show largely normal thresholds until 6 months of age, when signs of worse thresholds are detected. In contrast, Slc26a5tm1Cre homozygotes have stable but raised thresholds across all frequencies tested, 3 to 42 kHz, at least from 4 to 8 weeks old, while heterozygotes have raised thresholds at high frequencies. Distortion product otoacoustic emissions and cochlear microphonics show deficits similar to auditory brainstem responses in both mutants, suggesting that the origin of hearing impairment is in the outer hair cells. Endocochlear potentials are normal in the two mutants. Scanning electron microscopy revealed normal development of hair cells in Ocmtm1e homozygotes but scattered outer hair cell loss even at 4 weeks old when thresholds appeared normal, indicating that there is not a direct relationship between numbers of outer hair cells present and auditory thresholds.

Recurrent SARS-CoV-2 spike mutations confer growth advantages to select JN.1 sublineages.

The recently dominant SARS-CoV-2 Omicron JN.1 has evolved into multiple sublineages, with recurrent spike mutations R346T, F456L, and T572I, some of which exhibit growth advantages, such as KP.2 and KP.3. We investigated these mutations in JN.1, examining their individual and combined effects on immune evasion, ACE2 receptor affinity, and in vitro infectivity. F456L increased resistance to neutralization by human sera, including those after JN.1 breakthrough infections, and by RBD class-1 monoclonal antibodies, significantly altering JN.1 antigenicity. R346T enhanced ACE2-binding affinity and modestly boosted the infectivity of JN.1 pseudovirus, without a discernible effect on serum neutralization, while T572I slightly bolstered evasion of SD1-directed mAbs against JN.1's ancestor, BA.2, possibly by altering SD1 conformation. Importantly, expanding sublineages such as KP.2 containing R346T, F456L, and V1104L, showed similar neutralization resistance as JN.1 with R346T and F456L, suggesting V1104L does not appreciably affect antibody evasion. Furthermore, the hallmark mutation Q493E in KP.3 significantly reduced ACE2-binding affinity and viral infectivity, without noticeably impacting serum neutralization. Our findings illustrate how certain JN.1 mutations confer growth advantages in the population and could inform the design of the next COVID-19 vaccine booster.

Analysis of oil accumulation mechanisms in plasma induced mutant Scenedesmus strains compared to original Scenedesmus strains.

Scenedesmus sp. is a species of the Scenedesmus genus within the phylum Chlorophyta, commonly found as a planktonic algal species in freshwater and known for its rapid growth rate. This study employs room-temperature, atmospheric-pressure plasma mutagenesis for the breeding of Scenedesmus sp., utilizing transcriptomic analysis to investigate the biosynthesis mechanism of triglycerides. Further analysis of differentially expressed genes in transcriptome by measuring the macroscopic biological indicators of mutant and original algal strains. The findings of the study suggest that the mutant strain's photosynthesis has been enhanced, leading to improved light energy utilization and CO2 fixation, thereby providing more carbon storage and energy for biomass and lipid production. The intensification of glycolysis and the TCA (tricarboxylic acid) cycle results in a greater shift in carbon flux towards lipid accumulation. An elevated expression level of related enzymes in starch and protein degradation pathways may enhance acetyl CoA accumulation, facilitating a larger substrate supply for fatty acid production and thereby increasing lipid yield.

Estimating carrier rates and prevalence of porphyria-associated gene variants in the Chinese population based on genetic databases.

Porphyria is a group of rare metabolic disorders caused by mutations in the genes encoding crucial enzymes in the heme biosynthetic pathway. However, the lack of comprehensive genetic analysis of porphyria patients in the Chinese population makes identifying and diagnosing carriers of the condition challenging. Using the ChinaMAP database, we determined the frequencies of P/LP porphyria-associated gene variants according to the ACMG guidelines. We also calculated the carrier rates and prevalence of each type of porphyria in the Chinese population under Hardy-Weinberg equilibrium. Compared with the variants in the gnomAD database, the genetic spectrum of porphyria-related P/LP variants in the Chinese population is distinct. In the ChinaMAP database, we identified 23 variants. We estimated the carrier rates for autosomal dominant porphyrias (AIP, HCP, VP, PCT) in the Chinese population to be 1/1059, 1/1513, 1/10588, and 1/1765, respectively. For autosomal recessive porphyrias (ADP, EPP, HEP, CEP), the estimated carrier rates were 1/5294, 1/2117, 1/1765, and 1/2647, respectively, with predicted prevalence rates of 8.92 × 10-9, 7.51 × 10-5, 8.02 × 10-8, and 3.57 × 10-8, respectively. Notably, 12 of the variants we identified were unique to the Chinese population. The predicted prevalence rate of EPP was the highest among the various types of porphyria in the Chinese population, while the others were moderate to low. This is the first comprehensive genetic study on porphyria in the Chinese population. Clarifying the genetic characteristics of various porphyria types among the Chinese population provides scientifically sound reference data for both research and genetic screening to identify porphyria carriers.

[Leigh syndrome caused by the mitochondrial m.8993T>G mutation with hypocitrullinemia: a report of four cases and literature review]. / m.8993T>Gç›¸å ³Leighç»¼åˆå¾åˆå¹¶ä½Žç“œæ°¨é ¸è¡€ç—‡æ‚£å„¿4ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To explore early diagnostic biological markers for Leigh syndrome caused by the m.8993T>G mutation. METHODS: A retrospective analysis was performed on the clinical data of four children diagnosed with m.8993T>G mutation-related mitochondrial disease at the Children's Hospital of Chongqing Medical University from January 2014 to January 2024. Additionally, a literature review was conducted. RESULTS: All four children had plasma amino acid and acylcarnitine analyses that revealed decreased citrulline levels, and one child was initially identified through neonatal genetic metabolic disease screening. According to the literature review, there were 26 children with mitochondrial disease and hypocitrullinemia caused by the m.8993T>G mutation (including the four children in this study). Among these, 12 children exhibited clinical phenotypes of Leigh syndrome or Leigh-like syndrome, while 18 children were identified with hypocitrullinemia and/or elevated levels of 3-hydroxyisovalerylcarnitine (C5-OH) during neonatal genetic metabolic disease screening. CONCLUSIONS: Hypocitrullinemia may serve as a potential biomarker for the early diagnosis of m.8993T>G mutation-associated Leigh syndrome, detectable as early as during neonatal genetic metabolic disease screening.

[Autosomal recessive polycystic kidney disease in a girl]. / å¸¸æŸ“è‰²ä½“éšæ€§é—ä¼ æ€§å¤šå›Šè‚¾1例.

A 5-year-old girl was admitted due to one episode of melena and one episode of hematemesis. Upon admission, gastroscopy revealed esophageal and gastric varices. Abdominal CT scan, MRI, and color Doppler ultrasound suggested cirrhosis, intrahepatic bile duct dilation, and bilateral kidney enlargement. Genetic testing identified compound heterozygous mutations in the PKHD1 gene: c.2264C>T (p.Pro755Leu) and c.1886T>C (p.Val629Ala). The c.2264C>T (p.Pro755Leu) mutation is a known pathogenic variant with previous reports, while c.1886T>C (p.Val629Ala) is a novel mutation predicted to have pathogenic potential according to Mutation Taster and PolyPhen2. The child was diagnosed with autosomal recessive polycystic kidney disease. In children presenting with gastrointestinal bleeding without obvious causes, particularly those with liver or kidney disease, consideration should be given to the possibility of autosomal recessive polycystic kidney disease, and genetic testing should be conducted for definitive diagnosis when necessary.

[A case of progressive ossifying myositis caused by ACVR1 gene mutation]. / ACVR1åŸºå› çªå˜è‡´è¿›è¡Œæ€§éª¨åŒ–æ€§è‚Œç‚Ž1例.

A 2-year-and-10-month-old boy presented with multiple masses in the neck and chest for over 3 months. The child had a history of unstable walking, with hard lumps visible at the injury sites after falls, which would resolve on their own. Following a recent injury, a mass was discovered in the posterior neck, protruding above the skin surface and accompanied by limited joint movement. Gradually, new masses were found on the left side of the neck, back near the scapular lower angle, in the scapular fossa, and along the left axillary midline. Magnetic resonance imaging examination showed diffuse low signal on T1-weighted images and high signal on T2-weighted images in the bilateral posterior neck and back muscles two months ago. A CT scan revealed muscle swelling, with areas of patchy low density and multiple nodular high-density ossifications within some muscles. Genetic testing results indicated a mutation in the ACVR1 gene, leading to the final diagnosis of progressive ossifying myositis in this patient. This article summarizes the etiology, diagnosis, and treatment of one case of progressive ossifying myositis, providing a reference for clinicians.

[Clinical and genetic characterization of three families with Nance-Horan syndrome caused by NHS gene mutations].

Objective: To explore the clinical phenotypes and pathogenic gene variation characteristics of three Chinese Han ethnic families affected by Nance-Horan syndrome, a rare X-linked genetic disorder. Methods: A pedigree investigation study was conducted at the First Affiliated Hospital of Zhengzhou University, collecting clinical data from three Chinese Han families with Nance-Horan syndrome between February 2009 and September 2018. Detailed family histories, comprehensive ophthalmological and systemic examinations were documented. Pedigree charts were created, and genetic inheritance patterns were analyzed to preliminarily diagnose the probands and other affected individuals. Genomic DNA was extracted from peripheral blood samples of family members, and next-generation sequencing was used to screen for target gene variations, which were confirmed by Sanger sequencing. Pathogenicity of the genetic variants and their impact on three-dimensional protein structure were analyzed using MutationTaster and computer-aided protein modeling. Results: In Family 1, there are 5 patients, including 4 females (aged 42, 37, 9 and 7) and 1 males (aged 12). In Family 2, there are 5 patients, including 3 females (aged 54, 32 and 16) and 2 males (aged 26 and 9). In Family 3, there are 8 patients, including 5 females (aged 69, 42, 37, 35 and 14) and 3 males (aged 10, 7 and 4). All probands in the three families exhibited nuclear cataracts with typical congenital hereditary cataract features, but no noticeable abnormalities in facial appearance or teeth. Next-generation sequencing identified new variation sites in the NHS gene, specifically c.2519_2520del, exon3del, and c.3847C>T. These variations included nonsense mutation p.(Ser840*), exon deletion p.(?), and nonsense mutation p.(Gln1283*). Combined clinical and genetic sequencing results confirmed X-linked Nance-Horan syndrome in all three families. Bioinformatics analysis indicated these variation sites were pathogenic and resulted in abnormal three-dimensional protein structures, likely being the main cause of Nance-Horan syndrome. Conclusion: The majority of patients from the three Nance-Horan syndrome families studied were affected by congenital hereditary cataracts characterized by nuclear opacities.The NHS gene variations c.2519_2520del, exon3del, and c.3847C>T are newly identified pathogenic sites in Nance-Horan syndrome, reported for the first time across three different families.

Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.

MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild-type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a ß5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.

PHYTOCHROME-INTERACTING FACTOR 7 and RELATIVE OF EARLY FLOWERING 6 act in shade avoidance memory in Arabidopsis.

Shade avoidance helps plants maximize their access to light for growth under crowding. It is unknown, however, whether a priming shade avoidance mechanism exists that allows plants to respond more effectively to successive shade conditions. Here, we show that the shade-intolerant plant Arabidopsis can remember a first experienced shade event and respond more efficiently to the next event on hypocotyl elongation. The transcriptional regulator PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) and the histone H3K27-demethylase RELATIVE OF EARLY FLOWERING 6 (REF6) are identified as being required for this shade avoidance memory. RNA-sequencing analysis reveals that shade induction of shade-memory-related genes is impaired in the pif7 and ref6 mutants. Based on the analyses of enrichments of H3K27me3, REF6 and PIF7, we find that priming shade treatment induces PIF7 accumulation, which further recruits REF6 to demethylate H3K27me3 on the chromatin of certain shade-memory-related genes, leading to a state poised for their transcription. Upon a second shade treatment, enhanced shade-mediated inductions of these genes result in stronger hypocotyl growth responses. We conclude that the transcriptional memory mediated by epigenetic modification plays a key role in the ability of primed plants to remember previously experienced shade and acquire enhanced responses to recurring shade conditions.

HIV-1 adapts to lost IP6 coordination through second-site mutations that restore conical capsid assembly.

The HIV-1 capsid is composed of capsid (CA) protein hexamers and pentamers (capsomers) that contain a central pore hypothesised to regulate capsid assembly and facilitate nucleotide import early during post-infection. These pore functions are mediated by two positively charged rings created by CA Arg-18 (R18) and Lys-25 (K25). Here we describe the forced evolution of viruses containing mutations in R18 and K25. Whilst R18 mutants fail to replicate, K25A viruses acquire compensating mutations that restore nearly wild-type replication fitness. These compensating mutations, which rescue reverse transcription and infection without reintroducing lost pore charges, map to three adaptation hot-spots located within and between capsomers. The second-site suppressor mutations act by restoring the formation of pentamers lost upon K25 mutation, enabling closed conical capsid assembly both in vitro and inside virions. These results indicate that there is no intrinsic requirement for K25 in either nucleotide import or capsid assembly. We propose that whilst HIV-1 must maintain a precise hexamer:pentamer equilibrium for proper capsid assembly, compensatory mutations can tune this equilibrium to restore fitness lost by mutation of the central pore.

Replication licensing regulated by a short linear motif within an intrinsically disordered region of origin recognition complex.

In eukaryotes, the origin recognition complex (ORC) faciliates the assembly of pre-replicative complex (pre-RC) at origin DNA for replication licensing. Here we show that the N-terminal intrinsically disordered region (IDR) of the yeast Orc2 subunit is crucial for this process. Removing a segment (residues 176-200) from Orc2-IDR or mutating a key isoleucine (194) significantly inhibits replication initiation across the genome. These Orc2-IDR mutants are capable of assembling the ORC-Cdc6-Cdt1-Mcm2-7 intermediate, which exhibits impaired ATP hydrolysis and fails to be convered into the subsequent Mcm2-7-ORC complex and pre-RC. These defects can be partially rescued by the Orc2-IDR peptide. Moreover, the phosphorylation of this Orc2-IDR region by S cyclin-dependent kinase blocks its binding to Mcm2-7 complex, causing a defective pre-RC assembly. Our findings provide important insights into the multifaceted roles of ORC in supporting origin licensing during the G1 phase and its regulation to restrict origin firing within the S phase.

Differential genotoxicity of Polygoni Multiflori in rat and human: insights from Ames test and S9 metabolic activation system.

The Ames test is used worldwide to initially screen the mutagenic potential of new chemicals. In the standard Ames test, S. typhimurium strains (TA100, TA98, TA1535, and TA1537) and Escherichia coli (WP2uvrA) are treated with substances with/without cytochrome P450s (CYPs)-induced rat S9 fractions for identifying mutagens and pro-mutagens. However, many substances show completely different toxicity patterns depending on whether the liver S9 fraction belongs to rats or humans. The natural product Polygoni Multiflori Radix (PMR) can also show bacterial reverse mutation, followed by the rat or human liver S9 fraction. While PMR elicits reverse mutations in the TA1537 strain in rat liver S9 but not in human liver S9, this mechanism has not been verified yet. To explain this, the differences in metabolic enzymes compositions commonly observed between rats and humans have been implicated. This study aimed to explore the key factors that cause differences in the genotoxicity of PMR between rat and human liver S9 metabolic enzymes. The results of next-generation sequencing (NGS) analysis showed that both rat and human metabolic enzymes caused similar mutations in TA1537. However, when the metabolic enzymes in each S9 fraction were analyzed using ion mobility tandem mass spectrometry (IM-MS), rat- and human-specific enzymes were identified among the cytochrome (CYP) family, especially aryl hydrocarbon receptor (AHR)-related CYPs. These findings suggest that CYP1A1 isoforms contribute to the mechanism of PMR in the Ames test. Therefore, an in vitro Ames test might be more reliable in predicting genotoxicity for both rodents and humans. This will also help overcome the limitations of laboratory animal-based toxicity evaluations, which provide unreliable results due to interspecies differences between humans and rodents.

Energy metabolism-related GLUD1 contributes to favorable clinical outcomes of IDH-mutant glioma.

BACKGROUND: Glioma is the most common brain tumor. IDH mutations occur frequently in glioma, indicating a more favorable prognosis. We aimed to explore energy metabolism-related genes in glioma to promote the research and treatment. METHODS: Datasets were obtained from TCGA and GEO databases. Candidate genes were screened by differential gene expression analysis, then functional enrichment analysis was conducted on the candidate genes. PPI was also carried out to help determine the target gene. GSEA and DO analysis were conducted in the different expression level groups of the target gene. Survival analysis and immune cell infiltrating analysis were performed as well. RESULTS: We screened 34 candidate genes and selected GLUD1 as the target gene. All candidate genes were significantly enriched in 10 KEGG pathways and 330 GO terms. GLUD1 expression was higher in IDH-mutant samples than IDH-wildtype samples, and higher in normal samples than tumor samples. Low GLUD1 expression was related to poor prognosis according to survival analysis. Most types of immune cells were negatively related to GLUD1 expression, but monocytes and activated mast cells exhibited significantly positive correlation with GLUD1 expression. GLUD1 expression was significantly related to 119 drugs and 6 immune checkpoint genes. GLUD1 was able to serve as an independent prognostic indicator of IDH-mutant glioma. CONCLUSION: In this study, we identified an energy metabolism-related gene GLUD1 potentially contributing to favorable clinical outcomes of IDH-mutant glioma. In glioma, GLUD1 related clinical outcomes and immune landscape were clearer, and more valuable information was provided for immunotherapy.

HIV drug resistance: analysis of viral genotypes and mutation loci in people living with HIV in Chongqing, China (2016-2023).

BACKGROUND: Large-scale HIV genotype drug resistance study has not been conducted in Chongqing. METHODS: A retrospective study was conducted on people living with HIV(PLWH) who received HIV-1 genotype resistance testing at Chongqing Public Health Medical Center from May 2016 to June 2023. The HIV-1pol gene was amplified through RT-PCR and analyzed in terms of genotypic drug resistance. RESULTS: Of the 3015 PLWH tested for HIV-1 drug resistance, 1405 (46.6%) were resistant to at least one antiviral drug. Among non-nucleoside reverse transcriptase inhibitors (NNRTIs), 43.8% were resistant, compared to 29.5% for nucleoside reverse transcriptase inhibitors (NRTIs) and 3.4% for protease inhibitors (PIs). V179D/E and K103N/S were identified as the common mutation sites in the NNRTIs class of drugs, M184V/I and K65R/N were reported as the most common mutation sites in NRTIs, while thymidine analogue mutation (TAM) group was identified in 373 samples. L10FIV was the most common mutation in PIs. The dominant HIV-1 subtype was CRF07_BC. CONCLUSIONS: The high prevalence of HIV-1 drug resistance in Chongqing underscores the imperative for rigorous surveillance of the local HIV epidemic. Furthermore, TAMs are associated with HIV-1 multidrug resistance, and timely detection of drug resistance is helpful to reduce the emergence and spread of such drug-resistant strains.