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Hui Zhao

Publications and source records attributed to Hui Zhao.

At least 19 recordsLinked to original sources
PubMed2026

Integration of single-cell transcriptomics and genomic mutation analysis identifies an immunotherapy-resistant tumor subcluster and validates ARNTL2 as a malignant driver in lung adenocarcinoma.

BACKGROUND: Immunotherapy resistance in lung adenocarcinoma (LUAD) remains a critical clinical challenge, and the mechanisms underlying resistance-associated intratumoral heterogeneity are poorly characterized. METHODS: We performed single-cell RNA sequencing of LUAD patients receiving neoadjuvant immunotherapy (responders vs. non-responders), integrating inferCNV, GSVA, and differential expression analyses. Cluster-specific genes were validated across seven independent cohorts (TCGA-LUAD, GSE13213, GSE26939, GSE29016, GSE30219, GSE31210, GSE42127). A multi-algorithm machine learning framework was used to construct a prognostic model, and the immune microenvironment was characterized using TCIA scoring, seven infiltration algorithms, and ESTIMATE. ARNTL2 function was assessed by CCK-8 and Transwell assays in A549 and H1299 cells. RESULTS: Non-responders showed significant enrichment of epithelial cells, depletion of cytotoxic T/NK cells, and elevated copy number variation burden versus responders (p < 0.0001). A resistance-enriched malignant subcluster (Cluster 2) exhibited hyperproliferative and metabolic reprogramming signatures with upregulated KRT17, S100A2, and CST6, which showed tumor-specific overexpression, adverse prognostic value, and genomic amplification across cohorts. CoxBoost combined with survivalSVM achieved optimal predictive performance (C-index = 0.686), yielding robust risk stratification (HR: 2.54-10.51, all p < 0.05). Low-risk patients showed greater immune infiltration and higher TCIA immunophenoscores. ARNTL2 was an independent prognostic factor (HR: 2.07-4.64) strongly correlated with risk score (r = 0.69), and its knockdown suppressed proliferation and invasion in both LUAD cell lines (all p < 0.05). CONCLUSION: This study identifies a resistance-associated malignant subcluster in LUAD, constructs a validated CoxBoost + survivalSVM prognostic model with robust immune stratification, and establishes ARNTL2 as a core oncogenic driver and therapeutic target.

ARNTL2↗
PubMed2026

A Biomimetic Dual-Targeting Nano-APA-Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy.

Targeting post-transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally-repressed, long-3'UTR isoforms. To therapeutically "re-engineer" this APA switch, we design a "Nano-APA-editor." This platform features an HMSN core with an sgRNA-NUDT21 payload and a hierarchical targeting strategy: a cancer-educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, "gated" by a TA-aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short-3'UTR isoforms. Consequently, the Nano-APA-editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21-down) and functional restoration (PTEN-, WEE1-, TGF-&#x3b2;-up). This work validates a "post-transcriptional re-engineering" strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.

Humans↗
PubMed2026

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22&#xb7;3 months (95% CI 21&#xb7;5-23&#xb7;0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6&#xb7;8 months (95% CI 5&#xb7;7-7&#xb7;1) in the ivonescimab plus chemotherapy group versus 4&#xb7;4 months (4&#xb7;1-5&#xb7;5) in the placebo plus chemotherapy group (hazard ratio [HR] 0&#xb7;52; 95% CI 0&#xb7;41-0&#xb7;66; p<0&#xb7;0001). At a median follow-up of 29&#xb7;7 months (95% CI 27&#xb7;7-31&#xb7;0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16&#xb7;8 months (14&#xb7;3-19&#xb7;0) in the ivonescimab plus chemotherapy group versus 14&#xb7;0 months (12&#xb7;8-15&#xb7;7) in the placebo plus chemotherapy group (HR 0&#xb7;79; 0&#xb7;62-1&#xb7;01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING: Summit Therapeutics.

Humans↗
PubMed2025

Long COVID in Elderly COPD Patients: Clinical Features, Pulmonary Function Decline, and Proteomic Insights.

BACKGROUND: Elderly patients with chronic obstructive pulmonary disease (COPD) face a heightened risk of developing long coronavirus disease (COVID); however the exact clinical characteristics and underlying mechanisms remain unclear. METHODS: We enrolled 85 elderly COPD patients, of whom 43 reported newly onset persistent fatigue (the most dominant complaint of long COVID) within 1 year after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and they were allocated to the Long-COVID group. The remaining 42 patients were assigned to the Control group. Patients completed questionnaires, pulmonary function tests, chest CT, routine laboratory tests, and blood proteomic analysis. RESULTS: Long-COVID patients had a longer course of COPD (> 5 years, 76.8% vs 52.4%) and duration of SARS-CoV-2 infection (10.0 days vs 7.0 days) (All P < 0.05), higher symptom burden, worse pulmonary ventilation function and a more rapid decrease in DLCO (All P < 0.05). Proteomic analysis indicated disruptions in inflammation and energy metabolism, potentially underlying long COVID in these patients. The machine learning model identified wheezing, the duration of SARS-CoV-2 infection, EIF2S3 (eukaryotic translation initiation factor 2 subunit gamma), current FEV1/FVC (%), and the course of COPD as key features distinguishing Long-COVID patients, and exhibited excellent performance. CONCLUSION: Elderly COPD patients with a longer COPD course and duration of COVID-19 are more prone to develop long COVID, with decreased pulmonary ventilation and diffusion ability. Disordered inflammation regulation and energy metabolism may be the potential mechanisms, highlighting the importance of monitoring inflammation and metabolic dysregulation in elderly COPD patients after recovery from COVID-19.

Humans↗
PubMed2024

metaExpertPro: A Computational Workflow for Metaproteomics Spectral Library Construction and Data-Independent Acquisition Mass Spectrometry Data Analysis.

Analysis of large-scale data-independent acquisition mass spectrometry metaproteomics data remains a computational challenge. Here, we present a computational pipeline called metaExpertPro for metaproteomics data analysis. This pipeline encompasses spectral library generation using data-dependent acquisition MS, protein identification and quantification using data-independent acquisition mass spectrometry, functional and taxonomic annotation, as well as quantitative matrix generation for both microbiota and hosts. By integrating FragPipe and DIA-NN, metaExpertPro offers compatibility with both Orbitrap and timsTOF MS instruments. To evaluate the depth and accuracy of identification and quantification, we conducted extensive assessments using human fecal samples and benchmark tests. Performance tests conducted on human fecal samples indicated that metaExpertPro quantified an average of 45,000 peptides in a 60-min diaPASEF injection. Notably, metaExpertPro outperformed three existing software tools by characterizing a higher number of peptides and proteins. Importantly, metaExpertPro maintained a low factual false discovery rate of approximately 5% for protein groups across four benchmark tests. Applying a filter of five peptides per genus, metaExpertPro achieved relatively high accuracy (F-score&#xa0;=&#xa0;0.67-0.90) in genus diversity and showed a high correlation (rSpearman&#xa0;=&#xa0;0.73-0.82) between the measured and true genus relative abundance in benchmark tests. Additionally, the quantitative results at the protein, taxonomy, and function levels exhibited high reproducibility and consistency across the commonly adopted public human gut microbial protein databases IGC and UHGP. In a metaproteomic analysis of dyslipidemia patients, metaExpertPro revealed characteristic alterations in microbial functions and potential interactions between the microbiota and the host.

Proteomics↗
PubMed2006

Poly[[di-mu3-acetato-di-mu2-aqua-diaqua-di-mu3-hydroxo-tricopper(II)] naphthalene-1,5-disulfonate].

The crystal structure of the title complex, {[Cu3(C2H3O2)2(OH)2(H2O)4](C10H6O6S2)}n, is built of infinite polymeric cationic {[Cu3(C2H3O2)2(H2O)4(OH)2]2+}n chains stretching along the a axis, with naphthalene-1,5-disulfonate (1,5-nds) anions in between. One independent Cu(II) cation and the 1,5-nds anion occupy special positions on crystallographic inversion centres. Each Cu(II) cation has an octahedral coordination environment formed by two carboxyl O atoms, two hydroxo O atoms and two water molecules. The carboxylate and hydroxo groups perform a bridging function, linking adjacent Cu atoms in the chain, with a shortest Cu...Cu distance of 2.990 (3) A. The chains are further linked into a three-dimensional supramolecular framework via hydrogen-bonding interactions involving the sulfonate groups of the 1,5-nds dianions.

Journal Article↗
PubMed2006

Silencing stathmin gene expression by survivin promoter-driven siRNA vector to reverse malignant phenotype of tumor cells.

Stathmin gene overexpression has been shown to play an important role in maintenance of malignant phenotype in tumor cells, and the blocking efficacy and tumor specificity of this target has been concerned in clinical trails. In this report, we designed survivin promoter-driven siRNA eukaryotic expression vector that expressed the small interfering RNA targeting stathmin gene to selectively knock down the stathmin gene expression in two different kinds of tumor cell lines while sparing normal cell lines. The therapeutic potential of this recombinant vector was tested in human cervical cancer Hela cells and osteosarcoma SSOP-9607 cells, and in human umbilical vein endothelial cell line ECV304 cells as control. The siRNA vector- transfected Hela cells and SSOP-9607 cells revealed marked inhibition of stathmin expression and a dramatic growth inhibition comparing with ECV304 cells, parental-vector transfected cells and untransfected cells. Cell cycle analysis of siRNA vector transfected tumor cells by Flow Cytometry showed G(2)/M phase block, while morphologic analysis by TURNEL staining method showed marked increase of apoptosis. Our study indicates that survivin gene promoter-driven stathmin siRNA expression vector may have potential use in tumor gene therapy with targeted tumor gene silencing effect.

Apoptosis↗
PubMed2006

Dihydropyridines inhibit acetylcholine-induced hyperpolarization in cochlear artery via blockade of intermediate-conductance calcium-activated potassium channels.

Acetylcholine (ACh) induces hyperpolarization and dilation in a variety of blood vessels, including the cochlear spiral modiolar artery (SMA) via the endothelium-derived hyperpolarization factor (EDHF). We demonstrated previously that the ACh-induced hyperpolarization in the SMA originated in the endothelial cells (ECs) by activating a Ca(2+)-activated K(+) channel (K(Ca)); the hyperpolarization in smooth muscle cells was mainly an electrotonic spread via gap junction coupling. In the present study, using intracellular recording, immunohistology, and vascular diameter tracking techniques on in vitro SMA preparations, we found that 1) ACh-induced hyperpolarization was suppressed by intermediate-conductance K(Ca) (IK) blockers clotrimazole (IC(50) = 116 nM) and nitrendipine and by the calmodulin antagonist trifluoperazine, but it was not suppressed by the big-conductance K(Ca) blocker iberiotoxin. The immunoreactivity to anti-SK4/IK1 antibody was localized mainly in ECs. 2) The three dihydropyridines--nifedipine, nitrendipine, and nimodipine--all concentration-dependently inhibited the ACh-induced hyperpolarization, with an IC(50) value of 455, 34, and 3.2 nM, respectively. 3) Among other L-type Ca(2+) channel (I(L)) blockers, 10 microM verapamil exerted a 20% inhibition on ACh-induced hyperpolarization, whereas diltiazem and the metal ion Ca(2+) channel blockers Cd(2+) and Ni(2+) had no effect. 4) Nitrendipine and charybdotoxin abolished ACh-induced dilation in the SMA. We conclude that ACh-induced hyperpolarization in the SMA is generated mainly by activation of the IK in the ECs, and dihydropyridines suppress the EDHF-mediated hyperpolarization by blocking the IK channel, not the I(L) channel. The clinical relevance of this dihydropyridine action is discussed.

Acetylcholine↗
PubMed2006

Expression and regulation of heme oxygenase isozymes in the developing mouse cortex.

Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, plays a role in neonatal jaundice. Understanding the regulation of the developmental expression patterns of the two HO isozymes, HO-1 and HO-2, is essential for targeting HO to control pathologic jaundice, and uncovering the fundamental role that they play in mammalian development. Here we characterized the ontogeny of HO-1 and HO-2 expression in the developing mouse cortex by in vivo bioluminescence imaging, quantitative RT-PCR, and Western blot. HO-2, the predominant isoform in the adult cortex, was relatively stable throughout all ages. HO-1 was observed to be progressively down-regulated in an age-related manner. HO-1 expression in the adult cortex was also the lowest among the eight adult tissues analyzed. Because there is a 283-bp CpG island region in the HO-1 promoter, we hypothesized that methylation of the island is responsible for the age-related HO-1 down-regulation in the cortex. Methylation status was assessed using regular and quantitative methylation-specific PCR and the CpG island was found to be hypomethylated at all ages. Therefore, we conclude that HO-1 gene expression in the cortex is developmentally-regulated and that methylation of the HO-1 CpG island is not associated with the down-regulation of the gene.

Animals↗
PubMed2006

[A comparison of T3 sympathectomy versus T4 sympathectomy in the treatment of primary palmer hyperhidrosis].

OBJECTIVE: To evaluate the effect and side effect of T(3) versus T(4) sympathectomy in the surgical management of primary palmar hyperhidrosis through prospective multi-center randomized controlled trial. METHODS: From Sep 2004 to Feb 2006, 106 consecutive patients (49 males and 54 females) with primary palmar hyperhidrosis were enrolled in the study and randomly assigned into T(3) or T(4) level sympathectomy groups. 66 patients received T(3) sympathetic chain transection and 37 patients received T(4) sympathetic chain transection. The two groups were comparable in all other parameters. RESULTS: All procedures were carried out successfully without severe morbidity or mortality. After a mean follow-up period of 8.6 months, both groups remained satisfactory in palmar sweating control. The T(4) group had more moisture hands compared with the T(3) branch (54.1% vs 15.2%, P < 0.01), but this didn't compromise the patients' satisfactory. The patients in T(4) group showed significantly less dry hand problems than the patients in the T(3) group (5.4% vs. 25.8%, P < 0.05), and so did compensatory sweating (21.6% vs. 45.6%, P < 0.05). CONCLUSION: The procedure of T(3) or T(4) sympathectomy, both transecting the sympathetic chain in one single position in relatively lower segment, are comparatively effective in the treatment of primary palmar hyperhidrosis, but T(4) sympathectomy shows less side effect.

Adolescent↗
PubMed2006

Enhancer blocking by chicken beta-globin 5'-HS4: role of enhancer strength and insulator nucleosome depletion.

The 5'-HS4 chicken beta-globin insulator functions as a positional enhancer blocker on chromatinized episomes in human cells, blocking the HS2 enhancer of the human beta-globin locus control region from activating a downstream epsilon-globin gene. 5'-HS4 interrupted formation of a domain of histone H3 and H4 acetylation encompassing the 6-kb minilocus and inhibited transfer of RNA polymerase from the enhancer to the gene promoter. We found that the enhancer blocking phenotype was amplified when the insulated locus contained a weakened HS2 enhancer in which clustered point mutations eliminated interaction of the transcription factor GATA-1. The GATA-1 mutation compromised recruitment of histone acetyltransferases and RNA polymerase II to HS2. Enhancer blocking correlated with a significant depletion of nucleosomes in the core region of the insulator as revealed by micrococcal nuclease and DNase I digestion studies. Nucleosome depletion at 5'-HS4 was dependent on interaction of the insulator protein CCCTC-binding factor (CTCF) and was required for enhancer blocking. These findings provide evidence that a domain of active chromatin is formed by spreading from an enhancer to a target gene and can be blocked by a nucleosome-free gap in an insulator.

Animals↗
PubMed2006

Numerical distance effect in the N240 component in a number-matching task.

The event-related potential technique was used to investigate the time course and scalp-potential topography for the numerical distance effect in a number-matching task. Twenty undergraduates judged whether a number matched or did not match another number presented 1.5 s earlier. Compared with number pairs with a 'small' numerical distance (distance=1), number pairs with a 'large' numerical distance (greater than 2) showed a longer latency and a greater positive amplitude in the N240 component. This numerical distance effect was limited to fronto-central electrodes. These results were discussed in terms of the neural bases of the numerical distance effect during the automatic processing of numbers.

Adult↗
PubMed2006

Event-related potentials of single-digit addition, subtraction, and multiplication.

This study compared the event-related potentials elicited by single-digit addition, subtraction, and multiplication problems. With a delayed verification paradigm, 18 Chinese undergraduates were first asked to solve the arithmetic problems that were presented visually for 200 ms and, after 1.5 s, to judge whether a presented solution was correct or not. Results showed that, compared to addition and subtraction, multiplication elicited a greater N300 at the left frontal electrodes peaking around 320 ms (in the interval between 275 and 334 ms after the onset of the arithmetic problem). To control for the confounding effects of task difficulty and solution size, comparisons were further made between "large" addition problems (with sums between 11 and 17) and "small" multiplication problems (with products between 6 and 24). Similar results were obtained (i.e., a significant difference between addition and multiplication in the N300 component between 296 and 444 ms). Source analyses demonstrated that a single dipole in the left anterior brain areas could have contributed to the topographies of the difference waveforms ("multiplication-addition", "multiplication-subtraction", and "'small' multiplication-'large' addition"). These results are interpreted in terms of the greater reliance on phonological processing for the retrieval of multiplication facts than for the retrieval of addition and subtraction facts.

Adolescent↗
PubMed2006

Expression of mRNA for multiple serotonin (5-HT) receptor types/subtypes by the peripheral blood mononuclear cells of rhesus macaques.

To find out whether rhesus macaque peripheral blood mononuclear cells (PBMCs) express mRNA for 5-HT receptors, blood samples from normal healthy rhesus monkeys were used to isolate PBMCs by Ficoll-paque density gradient centrifugation. Total RNA was extracted from MT-2 cells, Hut-78 cells, naive or phytohemagglutinin (PHA) stimulated human and monkey PBMCs. One tube RT-PCR was performed using primers specific for human 5-HT1A, 5-HT1B, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors. Amplicons of expected sizes were obtained from human cell lines as well as both human and monkey PBMCs. Both PHA stimulated human and monkey PBMCs express mRNAs for 5-HT1A, 5-HT1B, 5-HT1E, 5-HT2A, 5-HT3, 5-HT4, 5-HT6 receptor types/subtypes. However, mRNAs for 5-HT1B, 5-HT1E and 5-HT2A cannot be confidently detected in some of the PBMC samples without PHA stimulation. 5-HT2B and 5-HT7 receptor mRNA was not detected in most of the samples and 5-HT2C receptor mNRA was not detected at all. FACS analysis revealed that CD3+ lymphocyte increased more than 20% among lymphocytes in the PHA stimulated PBMCs. These data indicate that similar to human PBMC, rhesus macaque PBMC may express multiple types of 5-HT receptors and the expression profile could change after PHA stimulation due to either the changes in cell composition or changes in gene transcription level. This provided a basis for further studies on the neuroimmunomodulatory interactions of 5-HT in rhesus macaques.

Animals↗
PubMed2006

Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations.

The human mitochondrial 12S ribosomal RNA (rRNA) A1555G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the A1555G mutation is a primary factor underlying the development of deafness but is not sufficient to produce a deafness phenotype. However, it has been proposed that nuclear-modifier genes modulate the phenotypic manifestation of the A1555G mutation. Here, we identified the nuclear-modifier gene TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab-Israeli kindred, 210 European (Italian pedigrees and Spanish pedigrees) families, and 31 Chinese pedigrees carrying the A1555G or the C1494T mutation revealed a missense mutation (G28T) altering an invariant amino acid residue (A10S) in the evolutionarily conserved N-terminal region of the TRMU protein. Interestingly, all 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and 12S rRNA A1555G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation leads to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial-protein synthesis. Resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicate that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations.

Amino Acid Sequence↗
PubMed2006

Fetal cardiac repolarization abnormalities.

Abnormal cardiac repolarization renders the heart susceptible to lethal ventricular tachyarrhythmias, increasing the risk of sudden cardiac death in all ages; however, little is known about the incidence and etiology of T-wave abnormalities in utero. In this study, magnetocardiography was used to better define fetal T-wave characteristics, including the QT interval in the normal fetus, and to characterize T-wave abnormalities in the fetus with arrhythmia. The QT interval and T-wave alternans were assessed from magnetocardiographic recordings obtained at 14 to 39 weeks' gestation from 120 fetuses. Of these fetuses, 78 were from uncomplicated pregnancies and 42 had various forms of fetal arrhythmia (supraventricular tachycardia in 14, congenital atrioventricular block in 17, long QT syndrome with Torsades de pointes in 1, ventricular tachycardia in 2, sinus bradycardia in 4, and bradycardia due to blocked premature atrial contractions in 4). Although the corrected QT interval in normal sinus rhythm was accurately described by Bazett's formula, the corrected QT interval in fetal arrhythmia exhibited a systematic deviation at heart rate extremes. The dependence of the QT interval on the RR interval in arrhythmia was approximately described by QT alpha RR0.8. T-wave alternans was detected in 7 fetuses with arrhythmia, often in association with QT prolongation, suboptimal outcome, or fetal demise. The results of our study have demonstrated that QT-interval abnormalities exist and can be detected in fetal patients. The potential importance of T-wave assessment in the fetus with cardiac arrhythmia was evidenced by the high incidence of marked QT prolongation and T-wave alternans in the fetuses with suboptimal outcomes.

Arrhythmias, Cardiac↗