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PubMed1990

Aminoglycoside-induced ototoxicity.

One of the major side effects of aminoglycoside antibiotics (AG) is ototoxicity. The authors review the literature revealing many controversies on every aspect of this side-effect. Although epidemiological studies have to face the problem of reliable evaluation techniques, the incidence of cochleo- and vestibulotoxic side-effects has been estimated at 7.5% for each. Netilmicin appears to be less ototoxic. No definite risk factors can be proposed, although age, length of therapy, bacteremia, fever, liver and renal dysfunction are probably very important parameters. Most pathological changes at the cochlear level follow a clear spatial sequence, showing unspecific, degenerative lesions, involving every structure of the cochlea. This makes it impossible to draw etiopathological conclusions. Recent pharmacokinetic studies have rejected the 'accumulation theory' of AGs in perilymph, while also in endolymph no accumulation can be found. Only a few data are available on inner ear tissue levels. Among the different pharmacodynamic hypotheses on the action of AGs, binding of the drug to acidic glycosaminoglycans in the stria vascularis, and interference by the drug with phosphoinositide metabolism in the hair cells seem to be of major importance.

Aminoglycosides↗

PubMed2026

Omics in optic neuropathies: From molecular landscapes to personalized therapeutics.

Optic neuropathies comprise a heterogeneous group of disorders involving transient or permanent injury to retinal ganglion cells (RGCs) and their axons. Clinically, these neurodegenerative conditions manifest as dyschromatopsia, decreased visual acuity, and visual field defects, and in severe cases may ultimately lead to blindness and disability. The marked heterogeneity across disease subtypes, incompletely understood etiologies, and complex pathogenic mechanisms pose substantial challenges to precise diagnosis and effective treatment. Recent advances in omics technologies - including genomics, transcriptomics, proteomics, metabolomics, lipidomics, single-cell and spatial sequencing, and integrative multi-omics approaches - have ushered optic nerve degenerative disease research into an era of high-resolution comprehensive investigation. In this review, we summarize representative applications of omics approaches to elucidate genetic alterations, signaling dysregulation, metabolic reprogramming, and immune responses in optic neuropathies. We further discuss the emerging potential of multi-omics in identifying early diagnostic biomarkers and informing individualized therapeutic strategies. Finally, we provide a forward-looking perspective on the future trajectory of omics technologies and their prospects in both fundamental research and clinical translation, with the overarching aim of accelerating the bench-to-bedside transition in this critical eye disease field.

biomarkers↗

PubMed1992

Laser photoablation of ventricular tachycardia: correlation of diastolic activation times and photoablation effects on cycle length and termination--observations supporting a macroreentrant mechanism.

Neodymium:yttrium-aluminum-garnet (YAG) photocoagulation during ventricular tachycardia allows the electrophysiologic effects of the temporal and spatial sequence of energy delivery to be correlated with local activation times. A retrospective analysis was performed of the termination of 19 episodes of ventricular tachycardia for which the local diastolic activation time was known for all successful ablation sites and for 95% of all ablation sites. The mode of termination was compared with that of 26 episodes of spontaneously terminating ventricular tachycardias. Spontaneous terminations occurred without a change in cycle length (54%) or with a 7 +/- 15% change in cycle length over one to three terminal beats (46%). In contrast, laser ablation-induced terminations resulted in a 39 +/- 55% increase in cycle length over nine or more cycles. The effect of attempted laser ablation was compared with the local presystolic activation time and the local activation time expressed as a percent of the diastolic interval (end of QRS complex = 0%, onset of next QRS complex = 100%). With one exception, no tachycardia terminated at ablation sites activating less than -50 ms before the QRS complex. All 8 successful first ablation attempts and 13 of all 19 successful ablations occurred in the 35% to 50% interval of diastolic activation. All successful ablations at sites activating at greater than 50% of the diastolic interval required multiple ablation attempts. Successful ablation was performed from the epicardium in 6 and from the endocardium in 13 episodes of ventricular tachycardia. These results are most consistent with a macroreentrant mechanism with a region of high vulnerability represented by the 35% to 50% interval of diastolic activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Diastole↗

PubMed1990

Visualization and characterization of gastric contractions using a radionuclide technique.

With the use of the radionuclide gastric-emptying test and a new data processing method, the contraction characteristics of the stomach were analyzed. After ingestion of a radiolabeled test meal, dynamic images of the stomach were acquired and analyzed to determine the frequency, amplitude, and rate of gastric contractions in healthy subjects. The frequency of antral contractions was found to be inversely related with food retention in the stomach; in contrast, the amplitude of the contractions decreased progressively during the course of gastric emptying. The peaks of both antral contraction and filling rate and the time of their occurrence remained constant throughout gastric emptying. The observed patterns of phase distribution and sequential phase changes of the food in the stomach confirmed noninvasively what was already known from invasive technique, i.e., that the proximal stomach does not undergo phasic contractions and that, in the distal stomach, smooth muscle contraction originates in midcorpus and propagates aborally to the pylorus. The scintigraphic test can be used to noninvasively and quantitatively characterize gastric motor function and to delineate the spatial sequence of gastric contractions. This technique can be applied to study the pathophysiology of gastric emptying in various motor disorders.

Adult↗

PubMedDate not supplied

[Evoked potentials of the human brain during prolonged fasting].

Dynamics of the visual evoked potentials of human brain during a long-term alimentary starvation is studied. During a 14-day fasting in healthy male volunteers abrupt changes are found in an amplitude and shape of the evoked potentials in the site of occipital leads: increase of time and maximum amplitude of the response; level of residual murmur; duration and square of slow negative wave; integrated spectral densities (ISDs), ranged 0.1-1; 1-4 and 4-8 Hz; decrease of ISDs ranged 8-13 Hz. On a 14th day of food consumption, the measurements of all the evoke potential parameters are somewhat declined but significantly exceed the baseline levels. Also, fasting results in changing a pattern of spatial sequence of the evoked potentials: an increase of the mean values of response time in all the lead sites; a rise of maximum amplitude of response in occipital lead sites, and a slight statistically insignificant trend to a diminished amplitude of response in temporal lead sites.

Adult↗

PubMed1991

The extracellular matrix in hepatic regeneration. Localization of collagen types I, III, IV, laminin, and fibronectin.

After partial hepatectomy, the liver is capable of complete regeneration, restoring normal hepatic size, architecture, and function. To study the role of the extracellular matrix in regeneration, the temporal and spatial sequence of deposition of several of its components, including collagen types I, III, and IV, laminin, and fibronectin, in rat liver, after an 80% hepatectomy, was characterized by light microscopy immunohistochemistry. A minimum of five animals were studied for each date. In agreement with previous reports, subsequent to 80% hepatectomy, there was a brisk mitosis of hepatocytes. The mitotic activity was maximal at 48 hours, primarily in the periportal and centrilobular zones, and resulted in the formation of hepatocyte clusters and widening of the hepatic plates. Of the extracellular matrix components studied, laminin was the one demonstrating the most dramatic changes. By 24 hours, laminin appeared in the hepatic sinusoids reaching a maximum staining intensity at 48 hours. Intracellular laminin was prominent in numerous non-parenchymal cells, with many having the morphology, location, and desmin content characteristic of Ito cells. Laminin staining decreased in the sinusoids at 4 days; however, some intracellular staining of Ito cells was present even at 8 days after hepatectomy. At the completion of regeneration, there was no evidence of any substantial change in the ratio: extracellular matrix/cell mass. The results indicate that: (a) hepatocytes can divide without prior removal of the subsinusoidal extracellular matrix; (b) during regeneration, hepatocyte division precedes sinusoidal formation; (c) during hepatic regeneration, and in spite of the presence of laminin in Ito cells, no basement membranes are formed; (d) the prominent expression of laminin and its proposed functions in morphogenesis suggest a critical role for this matrix component in the formation and reorganization of the regenerating liver.

Animals↗

PubMed1979

Cell number in relation to primary pattern formation in the embryo of Xenopus laevis. II. Sequential cell recruitment, and control of the cell cycle, during mesoderm formation.

Morphological evidence is presented that definitive mesoderm formation in Xenopus is best understood as extending to the end of the neurula phase of development. A process of recruitment of cells from the deep neurectoderm layers into mesodermal position and behaviour, strictly comparable with that already agreed to occur around the internal blastoporal 'lip' during gastrula stage 20 (earliest tail bud). Spatial patterns of incidence of mitosis are described for the fifteen hours of development between the late gastrula and stage 20--22. These are related to the onset of new cell behaviours and overt cyto-differentiations characterizing the dorsal axial pattern, which occur in cranio-caudal and then medio-lateral spatial sequence as development proceeds. A relatively abrupt cessation of mitosis, among hitherto asynchronously cycling cells, precedes the other changes at each level in the presumptive axial pattern. The widespread incidence of cells still in DNA synthesis, anterior to the last mitoses in the posterior-to-anterior developmental sequence of axial tissue, strongly suggests that cells of notochord and somites in their prolonged, non-cycling phase are G2-arrested, and thus tetraploid. This is discussed in relation to what is known of cell-cycle control in other situations. Best estimates for cell-cycle time in the still-dividing, posterior mesoderm of the neurula lie between 10 and 15 h. The supposition of continuing recruitment from neurectoderm can resolve an apparent discrepancy whereby total mesodermal cell number nevertheless contrives to double over a period of approximately 12 h during neurulation when most of the cells are leaving the cycle. Because of pre-existing evidence that cells maintain their relative positions (despite distortion) during the movements that form the mesodermal mantle, the patterns presented in this paper can be understood in two ways: as a temporal sequence of developmental events undergone by individual, posteriorly recruited cells as they achieve their final positions in the body pattern, or alternatively as a succession of wavefronts with respect to changes of cell state, passing obliquely across the presumptive body pattern in antero-posterior direction. These concepts are discussed briefly in relation to recent ideas about pattern formation in growing systems.

Animals↗

PubMed1975

The macromolecular structure of the first component of complement.

The binding of C1 to IgG and the interactions between C1 subcomponents have been studied by affinity chromatography of serum C1 and purified C1 proteins on Sepharose-IgG. Affinity chromatography of serum on Sepharose-IgG resulted in the binding of C1; subsequent washing with EDTA removed only C1s and C1t. Affinity chromatography of serum-EDTA on Sepharose-IgG resulted in binding of only C1q and C1r. Affinity chromatography of serum on Sepharose-tryptophan-modified-IgG resulted in the binding of only C1r and C1s. By the use of purified C1 proteins and Sepharose-IgG in binding studies it was confirmed that both C1q and C1r bind independently to sites on IgG and hold C1s and C1t by Ca++-dependent bonds. Measurements of the hemolytic activity of various combinations of C1 subcomponents confirmed the data obtained by the affinity binding studies. Both C1t and C1r independently enhanced the C1 activity of C1q-C1s mixtures; maximal activity required all four subcomponents. Sucrose gradient ultracentrifugation of mixtures of C1 proteins showed formation of the following complexes: C1qs (12S), C1qrs (15S), C1qst (18-23S), and C1qrst (19S). The evidence suggests that the spatial sequence of the components of the Sepharose-IgG-Serum C1 complex is: Sepharose-IgG: C1q: C1t: C1s: C1r: IgG-Sepharose. The probable physiologic significance of this model is discussed.

Blood Proteins↗

PubMed2025

Balancing LncRNA H19 and miR-675 Bioconversion as a Key Regulator of Embryonic Myogenesis Under Maternal Obesity.

BACKGROUND: Maternal obesity (MO) impairs fetal skeletal muscle development, but the underlying mechanisms remain poorly defined. The regulatory roles of lncRNA H19 and its first exon derived microRNA675 (miR675) in prenatal muscle development remain to be examined. H19/Igf2 are in the same imprinting cluster with H19 expressed from the maternal allele while Igf2 expresses paternally. H19 contains a G-rich loop, and KH-type splicing regulatory protein (KHSRP) mediates the biogenesis of pre-miRNAs containing G-rich loops, which depends on its phosphorylation by AKT, a key mediator of IGF2 signalling. This study aims to depict the elusive function of these regulators that are affected by MO during embryonic myogenesis. METHODS: Single-cell transcriptomic sequencing and GeoMx spatial RNA sequencing were performed to identify the differentially expressed genes between embryos from MO and control (CT) mice. Both E11.5 and E13.5 embryos were collected and analysed to validate the sequencing data. The roles of H19 and miR657 in myogenesis were further analysed in P19 embryonic cells via CRISPR/dCas9-mediated H19 activation and inhibition. The epigenetic changes of H19 were analysed by methylated DNA immunoprecipitation, and allele-targeted analysis of H19 was performed by crossing C57BL/6J and CAST/EiJ mice. RESULTS: Transcriptomic analysis showed that MO embryos contained less differentiated myocytes (1.34%) than CT embryos (2.86%). Myogenesis-related GO biological processes were down-regulated in the MO embryonic myotome region. MO embryos showed lower expression of myogenic transcription factors such as Myf5, Myod1, Myog, Mef2c and Myh3 (p < 0.05). MO altered epigenetic modifications of the H19 genomic cluster, showing a decreased methylation level in H19 imprinting control region (p < 0.05) and a diallelic expression pattern of H19, which elevated its expression in MO embryos. Overexpression of H19 inhibited myogenesis in P19 cells, but miR675 promoted myogenesis, suggesting the critical regulatory roles of bioconversion of H19 to miR675. A KHSRP mediates the biogenesis of miR675, a process that relies on its phosphorylation by IGF2/AKT signalling. Knocking-down of KHSRP and inhibition of AKT abolished miR675 biogenesis. MO suppressed IGF2/AKT signalling and blocked KHSRP-dependent miR675 biogenesis in embryos. CONCLUSIONS: We found differential effects of H19 and miR675 on embryonic myogenesis. MO up-regulates H19 but blocks its miR675 bioconversion via suppressing IGF2/AKT/KHSRP signalling axis. Myogenesis in MO embryos was impeded due to the highly accumulated H19 and blocked miR675 biogenesis.

RNA, Long Noncoding↗

PubMed2026

Mapping antibody sequences and effector functions across spatial niches.

Antibodies are fundamental to human health but can also drive pathology. Each antibody has a molecular specificity, encoded by their clonally heritable B cell receptor (BCR). Recent advances in spatial transcriptomics coupled with repertoire sequencing have enabled capturing antibody-secreting cells (ASCs) and their clonal BCR within their tissue microenvironment. However, our understanding of antibody production niches remains limited. Furthermore, where antibodies are produced can be distinct from where antibodies exert their effector function. Here, we propose a conceptual spatial framework to distinguish between 'antibody production niches', defined by the ASC, BCR, and niche composition, versus 'antibody functional niches', composed of the antibody, antigen, and effector landscape. We then examine the possibilities and challenges to map and link antibody-encoding sequences and antibody effector functions using current and emerging technologies. Combined, we argue that integrating spatial sequence data with the antibody functional context is essential to decode the architecture of antibody-mediated immunity.

Humans↗

PubMed1990

Identification and DNA sequence of the Shope fibroma virus DNA topoisomerase gene.

The Shope fibroma virus (SFV) DNA topoisomerase gene has been identified and mapped to the BamHI D fragment near the midpoint of the genome. The DNA sequence of the SFV BamHI S fragment together with the contiguous BamHI-ClaI subfragment of BamHI D which encompasses the topoisomerase gene and two flanking genes has been determined and analyzed. Both the SFV DNA topoisomerase and the two flanking genes are closely related in terms of sequence and spatial organization to the homologous sequences from the midpoint of the vaccinia virus genome, indicating that these proteins are conserved not only in their sequence but also by position within the poxvirus genome. To confirm the assignment of the SFV gene, the putative SFV DNA topoisomerase has been expressed as an active fusion protein in Escherichia coli and this system should be useful in the analysis of topoisomerase function following the introduction of targeted mutations into the topoisomerase gene. The results of this work shed further light on the evolutionary relationship of the different poxvirus genera and indicate that central unique regions of the poxvirus genomes contain many of the essential viral genes and are thus highly conserved.

Amino Acid Sequence↗

PubMed1991

Spatial organization of nucleic acid sequences within cells.

High-resolution in situ hybridization has allowed the distribution of specific nucleic acids to be visualized within cells. This has revealed the extent to which nucleic acids exhibit intracellular spatial organization. Hybridization of nonisotopically labeled probes can be detected with high resolution using fluorescence or alkaline phosphatase for light microscopy or colloidal gold for electron microscopy. Results of this approach have shown that messenger RNAs for specific proteins, nuclear transcripts, or the gene for those transcripts all can exhibit non-random intracellular locations. Actin mRNA can be seen localized in the periphery of motile cells, just proximal to the lamellipodia. Highly localized distributions of EBV primary transcripts can be visualized in some cases creating an elongated track of specific RNA. These nuclear transcripts could be seen associated with the nuclear matrix. Further evidence indicates that the genes from which specific RNAs derive may themselves show defined spatial organization. This work sheds light on a level of cellular organization indicating that nucleic acid sequences contain spatial positioning information and therefore can influence the genesis of cellular structure and function.

Animals↗

PubMed2025

Colorectal Liver Metastasis Pathomics Model: Integrating Single-Cell and Spatial Transcriptome Analysis With Pathomics for Predicting Liver Metastasis in Colorectal Cancer.

The liver is the primary target organ for hematologic metastasis of colorectal cancer (CRC), and CRC liver metastasis (CRLM) often precludes radical resection, making it the leading cause of death in patients with CRC. To improve the identification and prediction of liver metastasis risk, we identified a cell type of liver metastasis--triggering malignant cells (LMTMCs) through integrating single-cell RNA sequencing and spatial transcriptome analysis. Multiomics cell communication analysis indicated that the interaction between fibroblasts and LMTMCs through the COL1A1-CD44/SDC4 and LAMA4-CD44 signaling axes could promote CRLM. By applying the one-class logistic regression algorithm, we developed a CRLM scoring system in the bulk RNA-sequencing data according to the abundance of LMTMCs in each individual. Using the grouping labels derived from the CRLM scoring system in the bulk data and the corresponding whole-slide images without any manual annotations at the region or pixel level, processed via slide-level weakly supervised learning, a deep-learning model based on the ResNet18 architecture, called Colorectal Liver Metastasis Pathomics Model, was developed to predict the risk of liver metastasis in patients with CRC. The Colorectal Liver Metastasis Pathomics Model achieved an area under the curve of 0.84 at the internal test set of The Cancer Genome Atlas-CRC histology images. In the external independent validation sets, namely the Affiliated Hospital of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University cohorts, the areas under the curve were 0.89 and 0.72, respectively, indicating effective classification performances. This study provided new insights and tools for the early identification of CRLM and demonstrated the potential of combining multiomics with deep learning-based pathomics in cancer research.

Humans↗

PubMed1992

Short-term retention of spatial information.

Four experiments investigated the recall of a subspan set of spatial locations over short intervals of 5 and 15 s. The intervals were filled by one of three activities: simple tapping, repeated tapping at spatial targets and backwards counting. Spatial tapping, which decreases spatial memory span, led to further small but significant errors in recall, as did backward counting. These errors were larger than those found with simple tapping over the same intervals. Backwards counting led to further decreases in recall performance if it was also present during encoding, but this was not the case for spatial tapping. Spatial tapping had little effect on recall of three digits, whereas backwards counting had a large effect, which was much larger than that found with spatial memory items in any condition. The results are interpreted in terms of the use of place-keeping functions in spatial memory sequences, which may not be specific to spatial material.

Female↗

PubMed2026

Multi-omics identification and functional validation of signal regulatory protein gamma as a prognostic biomarker and immune regulator in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) comprises biologically diverse tumors, and durable responses to immune-checkpoint blockade are achieved by only a subset of patients. There remains a need for markers that connect clinical outcome with malignant-cell phenotypes and tissue-level immune organization. METHODS: We integrated The Cancer Genome Atlas HNSCC cohort (TCGA-HNSC), five Gene Expression Omnibus (GEO) validation cohorts, single-cell RNA sequencing, Visium spatial transcriptomics, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)-informed protein-potential inference, pharmacogenomic screening, genetic-risk analysis and experimental validation. A reconstructed 296-pipeline survival modelling framework was used to prioritize prognostic hub genes across validation-cohort-specific analyses. RESULTS: SIRPG was repeatedly ranked among the top ten selected genes in all five validation cohorts. At single-cell resolution, SIRPG-high tumor cells showed stronger malignant-cell features, immune-inhibitory and metabolic programs, Scissor-positive risk association, CLCA2/P53-related perturbation signals and inferred SIRPG-CD47/signal regulatory protein (SIRP) communication. Spatial analyses placed this axis within an immune-checkpoint-coupled niche, supported by Maxspin/multiview intercellular spatial modelling (MISTy) spatial coupling, communication analysis by optimal transport (COMMOT)-inferred CD47-SIRPG communication and scProTrans-inferred CD47/SIRPG protein-potential overlap. Functionally, SIRPG knockdown reduced HNSCC cell viability and increased apoptosis, whereas re-expression of short hairpin RNA (shRNA)-resistant SIRPG restored the CLCA2-BAX/BCL2 protein response. CONCLUSION: Together, these findings identify SIRPG as an immune-related prognostic hub and context-dependent tumor-cell regulator associated with apoptosis, immune communication and spatial microenvironmental organization in HNSCC.

Humans↗

PubMed2025

BISON: bi-clustering of spatial omics data with feature selection.

MOTIVATION: The advent of next-generation sequencing-based spatially resolved transcriptomics (SRT) techniques has reshaped genomic studies by enabling high-throughput gene expression profiling while preserving spatial and morphological context. Understanding gene functions and interactions in different spatial domains is crucial, as it can enhance our comprehension of biological mechanisms, such as cancer-immune interactions and cell differentiation in various regions. It is necessary to cluster tissue regions into distinct spatial domains and identify discriminating genes (DGs) that elucidate the clustering result, referred to as spatial domain-specific DGs. Existing methods for identifying these genes typically rely on a two-stage approach, which can lead to the phenomenon known as double-dipping. RESULTS: To address the challenge, we propose a unified Bayesian latent block model that simultaneously detects a list of DGs contributing to spatial domain identification while clustering these DGs and spatial locations. The efficacy of our proposed method is validated through a series of simulation experiments, and its capability to identify DGs is demonstrated through applications to benchmark SRT datasets. AVAILABILITY AND IMPLEMENTATION: The R/C++ implementation of BISON is available at https://github.com/new-zbc/BISON.

Software↗

PubMed1977

Some factors affecting the perceived ordering of natural speech stimuli.

Primary auditory stream segregation--the perceptual segregation of acoustically related elements of a continuous auditory sequence into spatially distinct streams--disrupts recovery of the relative temporal order of repeated sequences of consonant and vowel syllables. Three experiments were performed to determine why the apparent temporal order of natural speech is not similarly disrupted. Exp. 1 (N =24) showed that the disruption is not dependent on repetition of the 32 experimental sequences of consonant and vowel syllables. Exps. 2 (N = 48) and 3 (N = 20) showed that when 4 English monosyllables are used as stimuli and syntactic and intonational structure is present then the temporal integrity of the acoustic signal is preserved perceptually. Despite accurate resolution of order for the 40 experimental sequences, errors of words were common. These errors often imposed a syntactic organization on the resulting sequence.

Auditory Perception↗

PubMed1990

Identification of the calmodulin binding domain of alpha-fodrin and implications for folding.

A cDNA clone producing a protein that binds calmodulin has been isolated from a mouse macrophage library. The cDNA was sequenced and identified as coding for fodrin. By deleting part of the sequence, the calmodulin binding domain was located. The site is situated on repeat 11 of fodrin probably on its extra arm. This part of the sequence exhibits great similarity to other calmodulin binding proteins. Analysis of the sequence and spatial structure of calmodulin revealed a domain which is quite complementary to the sequence identified on fodrin. These results provide a new insight into the structure of fodrin and consequently into the structure of proteins of the spectrin family. A model for the general folding of these molecules is proposed, involving a simple three-layer folding. The structure was further corroborated by analysis of charge distribution in the vicinity of the calmodulin binding site. The folding we propose is in good agreement with digestion experiments and explains observations in diseases resulting from mutations of human spectrin.

Amino Acid Sequence↗