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At least 235 records · Page 13Linked to original sources
PubMed2026

Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.

One of the ongoing challenges in childhood remains the unexplained sudden death. Autopsies identify a subset of cases that harbor rare variants in genes associated with cardiomyopathy in structurally normal hearts, suggesting a concealed cardiomyopathy. Our goal is to interpret all available data in each case to provide answers to unexplained deaths, while also implementing preventative measures for at-risk family members. Our retrospective study included 68 childhood cases of sudden death, classified as inconclusive at autopsy. Molecular autopsy analyzed all genes currently associated with inherited arrhythmogenic syndromes. Variants were reinterpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Seventeen autopsy-inconclusive childhood cases (70.59% males) carried at least one rare variant in any of the cardiomyopathy-susceptibility genes. A definite deleterious variant was identified in seven cases (10.3%), whereas ten (14.7%) carried only variants of uncertain significance. Slight non-diagnostic myocardial alterations were identified in five cases (7.35%), and three of them carried a deleterious variant. Clinical and genetic analyses of all families identified a carrier of deleterious variants with a diagnosis of cardiomyopathy in six of them (8.82%). Our data support the inclusion of a comprehensive analysis of all genes associated with inherited cardiomyopathies in childhood cases of unexpected death. A personalized multidisciplinary interpretation of post-mortem and genetic data, including family assessment, helps to clarify the role of rare variants and determine the most plausible cause of the unexpected death in one-tenth of the childhood individuals.

Journal Article↗
PubMed2025

Complex de novo structural variants are an underestimated cause of rare disorders.

Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conduct a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, obtained as part of the UK 100,000 Genomes Project. We identify 1,870 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n = 158; 8.4%) emerge as the third most common type of SV, following simple deletions and duplications. We classify 65% of these complex dnSVs into 11 subtypes. Among probands with dnSVs (n = 1,696), 9% exhibit exon-disrupting pathogenic dnSVs associated with the probands' phenotype. Notably, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or whole-exome sequencing methods are found to be complex dnSVs. We also find distinct genomic properties of de novo deletions depending on the parent of origin. This study highlights the importance of complex dnSVs in the cause of rare disorders and demonstrates the necessity of specific genomic analysis to avoid overlooking these variants.

Humans↗
PubMed2026

Denisovans from southwestern China and their subsistence strategies.

Growing fossil and genomic evidence has substantially advanced our understanding of Denisovans' evolutionary history1-9, yet their technological behaviours and subsistence strategies remain poorly documented. Here we present a comprehensive analysis of hominin fossils and associated archaeological remains from Bianfu Cave, Yunnan Province, southwestern China. The hominin fossils are dated to about 167-134 thousand years ago (ka), whereas the cultural sequence spanned from about 190 ka to 70 ka, representing one of the longest cultural records most parsimoniously attributed to Denisovans-identified through enamel-dentine junction morphology and palaeoproteomic analyses10. The new fossils include four teeth that expand the known dental variation of this group, two cranial fragments and a radius. Faunal and pollen records indicate a conifer-dominated forest or forest-steppe environment across Marine Isotope Stages 6 to 4. The inhabitants of Bianfu Cave practised specialized hunting of medium- to large-bodied prey and used a technological strategy characterized by expedient core reduction and tool production, alongside pervasive use of unmodified bones. This pattern suggests an adaptive system prioritizing the exploitation of object affordance over intensive tool manufacture. Bianfu Cave provides unprecedented insights into Denisovan biology, behaviour and ecology in eastern Asia and points to a substantial genetic and cultural legacy in later populations in Southeast Asia and Oceania.

Journal Article↗
PubMed2026

Multi-omic analyses of the same sample using metabolomics, lipidomics, proteomics, phosphoproteomics, and glycoproteomics.

Mass spectrometry (MS)-based multi-omics offers powerful tools to comprehensively characterize proteins, post-translational modifications, metabolites, and lipids. However, these measurements are typically performed using separate sample preparation workflows and modality-specific liquid chromatography mass spectrometry (LC-MS) platforms, limiting integration and constraining applications to small amounts of sample materials, especially scarce clinical specimens. Here, we describe a unified nano-LC-MS framework that enables metabolomic, lipidomic, proteomic, phosphoproteomic, and glycoproteomic analyses from the same starting material using a single nano-LC-MS platform, with only the chromatographic conditions, acquisition methods, and enrichment procedures tailored to each omics. This integrated strategy reduces workflow complexity and sample consumption while improves analytical continuity across molecular layers. By enabling deep multi-omics characterization from the same sample, this platform provides a practical foundation for comprehensive analysis of precious clinical samples.

Proteomics↗
PubMed1988

Immunoblotting and the immune response to leprosy.

Immunoblotting has provided a powerful and effective approach to dissection of the immune response to mycobacterial antigens in a situation in which the availability of isolated antigenic components is severely limited. The basic approach of blotting on to a solid-phase support has been used in combination with SDS/polyacrylamide-gel electrophoresis, t.l.c., recombinant DNA technology and T-cell cloning in order to carry out a comprehensive analysis of glycolipid and protein antigens involved in the immune response to mycobacterial infection.

Antigens, Bacterial↗
PubMed1987

[Stress on the Achilles tendon in Alpine skiing].

In an attempt to gain more systematic knowledge of the biomechanical mechanism involved in the genesis of injuries caused by a fall during skiing, we undertook a comprehensive analysis of more than 100 experimental ski falls simulated under controlled conditions. The well-known relation between speed, release time of the ski binding and injury risk of the lower extremity was confirmed by our experimental results. The EMG investigations revealed the central importance of the musculus triceps surae, and hence of the Achilles tendon, during a fall. The results of our biomechanical model indicate that the present method of setting the ski binding according to the tibial strength, is rather questionable, to say the least.

Achilles Tendon↗
PubMed1988

Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study.

We conducted a prospective study of 321 patients with cirrhosis of the liver and esophageal varices with no history of bleeding to see whether a comprehensive analysis of their clinical features and of the endoscopic appearances of their varices could help to identify those at highest risk for bleeding. Varices were classified endoscopically as suggested by the Japanese Research Society for Portal Hypertension. Patients were followed for 1 to 38 months (median, 23), during which 85 patients (26.5 percent) bled. Multiple regression analysis (Cox's model) revealed that the risk of bleeding was significantly related to the patient's modified Child class (an index of liver dysfunction based on serum albumin concentration, bilirubin level, prothrombin time, and the presence of ascites and encephalopathy), the size of the varices, and the presence of red wale markings (longitudinal dilated venules resembling whip marks) on the varices. A prognostic index based on these variables was devised that enabled us to identify a subset of patients with a one-year incidence of bleeding exceeding 65 percent. The index was prospectively validated on an independent sample of 75 patients with varices and no history of bleeding. We conclude that our prognostic index, which identifies groups of patients with one-year probabilities of bleeding ranging from 6 to 76 percent, can be used to identify candidates for prophylactic treatment.

Esophageal and Gastric Varices↗
PubMed1991

Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene.

Hemophilia A is an X chromosome-linked disorder resulting from deficiency of factor VIII, an important protein in blood coagulation. A large number of disease-producing mutations have been reported in the factor VIII gene. However, a comprehensive analysis of the mutations has been difficult because of the large gene size, its many scattered exons, and the high frequency of de novo mutations. Recently, we have shown that nearly all mutations resulting in mild-to-moderate hemophilia A can be detected by PCR and denaturing gradient gel electrophoresis (DGGE). In this study, we attempted to discover the mutations causing severe hemophilia A by analyzing 47 unselected patients, 30 of whom had severe hemophilia and 17 of whom had mild-to-moderate disease. Using DGGE as a screening method, we analyzed 99% of the coding region, 94% of the splice junctions, the promoter region, and the polyadenylylation site of the gene. We found the mutation in 16 of 17 (94%) patients with mild-to-moderate disease but in only 16 of 30 (53%) patients with severe hemophilia A. Since DGGE after computer analysis appears to detect all mutations in a given fragment, the lower-than-expected yield of mutations in patients with severe disease is likely not due to failure of the detection method; it is probably due to the presence of mutations in DNA sequences outside the regions studied. Such sequences may include locus-controlling regions, other sequences within introns or outside the gene that are important for its expression, or another gene involved in factor VIII expression that is very closely linked to the factor VIII gene.

Amino Acid Sequence↗
PubMed1989

The effect of dietary interventions to reduce blood pressure in normal humans.

Changes in electrolyte intake have been advocated to lower the prevalence of hypertension in the normal population. To elucidate the potential impact of such strategies, we conducted a comprehensive analysis of data from three interventions, namely, salt (NaCl) restriction, calcium (Ca) supplementation, and potassium (K) supplementation in normal volunteers. Eighty-two adults lowered their Na intake from 157 +/- 6 S.E. to 68 +/- 3 mEq/day for 12 weeks. Population mean systolic and diastolic blood pressure decreased less than or equal to 2 mm Hg. Ca supplementation, 1.5 g daily for 12 weeks in 37 men, decreased blood pressure compared to 38 men receiving placebo. Ca supplementation, 1 g daily for 8 weeks in an older group of 44 normal subjects, decreased supine diastolic and standing systolic blood pressure. K supplementation with a nonchloride salt in 64 normal adults for 4 weeks had no effect on systolic or diastolic blood pressure even though urinary excretion was increased by 20 mmol/day. The responses to all interventions were Gaussian in distribution. A potentially adverse effect on blood pressure in some normal individuals cannot be excluded on the basis of the currently available data. Although all three interventions may benefit some hypertensive and some normal individuals, the data from these relatively short-term cross-sectional studies are insufficient to warrant generalized dietary recommendations for the normal population.

Adult↗
PubMed1985

A pH-dependent structural transition in the homopurine-homopyrimidine tract in superhelical DNA.

We have inserted the 509-bp-long fragment of sea urchin P. miliaris histone gene spacer region into plasmid pUC19. The fragment contains the 60-bp-long homopurine-homopyrimidine tract that is known to be hypersensitive to the S1 endonuclease. Using two-dimensional gel electrophoresis we have observed a sharp structural transition in the insert with increasing DNA superhelicity. As in the cases of cruciform and Z form formation, the observed transition partly relaxes the superhelical stress. In contrast with the other two well documented transitions, the observed transition strongly depends on pH. At pH7 and above the transition occurs at negative superhelicities exceeding the physiological range (- sigma greater than 0.08). For pH6 the transition occurs at -sigma = 0.055, whereas for pH4.3 it takes place at -sigma = 0.001. A comprehensive analysis of the obtained data has made it possible to define the nature of the observed transition. We conclude that under superhelical stress or/and at low pH homopurinehomopyrimidine tracts adopt a novel spatial structure called the H form.

Animals↗
PubMed1979

Influence of sonic noise on human stereoscopic depth perception.

Scientific establishment of the no-effect response to finite levels of exposure to a physical or chemical agent is indeed a rigorous exercise and is frequently controversial. In earlier research by Slutsky under direction of the senior author, a statistically significant increase in stereoscopic depth perception error was noted among 24 test subjects exposed to high intensity noise. Additional extensive research reported in this paper indicates that error in stereoscopic depth perception is not significantly altered by exposure to continuous white noise of short duration at levels ranging from 70 to 115 dBA. Furthernore, exposure of humans for periods of a few minutes to white noise in octave bands centered on 250 Hz, 1000 Hz, 4 kHz and 16 kHz at 115 dB does not affect their depth perception measured by the Howard-Dolman test. A comprehensive analysis of depth perception errors measured under noise exposure conditions (n = 4040) in comparison with those obtained under control conditions (n = 1430) produced a mean change in error of -0.38 mm, a statistically insignificant difference (p = 0.17). Even if such an error were attributable to high level noise, it should be noted that minus sign designates an improvement of depth perception in noise and that it is difficult to imagine visual tasks in which change in error of +/-0.38 mm at a distance of 6.0 meters is meaningful.

Depth Perception↗
PubMed2025

CREMSA: compressed indexing of (ultra) large multiple sequence alignments.

MOTIVATION: Recent viral outbreaks motivate the systematic collection of pathogenic genomes in order to accelerate their study and monitor the apparition/spread of variants. Due to their limited length and temporal proximity of their sequencing, viral genomes are usually organized, and analyzed as oversized Multiple Sequence Alignments (MSAs). Such MSAs are largely ungapped, and mostly homogeneous on a column-wise level but not at a sequential level due to local variations, hindering the performances of sequential compression algorithms. RESULTS: In order to enable an efficient handling of MSAs, including subsequent statistical analyses, we introduce CREMSA (Column-wise Run-length Encoding for MSAs), a new index that builds on sparse bitvector representations to compress an existing or streamed MSA, all the while allowing for an expressive set of accelerated requests to query the alignment without prior decompression. Using CREMSA, a 65 GB MSA consisting of 1.9M SARS-CoV 2 genomes could be compressed into 22 MB using less than half a gigabyte of main memory, while executing access requests in the order of 100 ns. Such a speed up enables a comprehensive analysis of covariation over this very large MSA. We further assess the impact of the sequence ordering on the compressibility of MSAs and propose a resorting strategy that, despite the proven NP-hardness of an optimal sort, induces greatly increased compression ratios at a marginal computational cost. AVAILABILITY AND IMPLEMENTATION: CREMSA is freely accessible at https://gitlab.univ-lille.fr/cremsa/cremsa. The Snakemake workflow for the benchmarks is available at: https://gitlab.univ-lille.fr/cremsa/bench. The data used in the paper is on Zenodo at https://zenodo.org/records/14698859 and https://zenodo.org/records/15100011.

SARS-CoV-2↗
PubMed2025

DiCARN-DNase: enhancing cell-to-cell Hi-C resolution using dilated cascading ResNet with self-attention and DNase-seq chromatin accessibility data.

MOTIVATION: The spatial organization of chromatin is fundamental to gene regulation and essential for proper cellular function. The Hi-C technique remains the leading method for unraveling 3D genome structures, but the limited availability of high-resolution (HR) Hi-C data poses significant challenges for comprehensive analysis. Deep learning models have been developed to predict HR Hi-C data from low-resolution counterparts. Early Convolutional Neural Network (CNN)-based models improved resolution but struggled with issues like blurring and capturing fine details. In contrast, Generative Adversarial Network (GAN)-based methods encountered difficulties in maintaining diversity and generalization. Additionally, most existing algorithms perform poorly in cross-cell line generalization, where a model trained on one cell type is used to enhance HR data in another cell type. RESULTS: In this work, we propose Dilated Cascading Residual Network (DiCARN) to overcome these challenges and improve Hi-C data resolution. DiCARN leverages dilated convolutions and cascading residuals to capture a broader context while preserving fine-grained genomic interactions. Additionally, we incorporate DNase-seq data into our model, providing a robust framework that demonstrates superior generalizability across cell lines in HR Hi-C data reconstruction. AVAILABILITY AND IMPLEMENTATION: DiCARN is publicly available at https://github.com/OluwadareLab/DiCARN.

Chromatin↗
PubMed2025

HI-FEVER: a Nextflow pipeline for the high-throughput discovery and annotation of endogenous viral elements.

SUMMARY: Endogenous viral elements (EVEs) offer valuable insights into virus and host evolution, but their detection remains computationally and biologically challenging. We present HI-FEVER, a user-friendly Nextflow pipeline for the discovery of EVEs in eukaryotic host genomes. HI-FEVER is highly parallelizable and customizable, ensuring computational efficiency while allowing researchers to fine-tune parameters to their specific needs. Its output provides a comprehensive analysis of discovered EVEs, including detailed annotations which can provide evolutionary insights. HI-FEVER scales seamlessly to handle millions of viral protein queries across multiple host genomes on both laptops and high-performance computing nodes. AVAILABILITY AND IMPLEMENTATION: The HI-FEVER source code is available on GitHub at https://github.com/PaleovirologyLab/hi-fever. Minimal reference databases, test datasets and benchmarking results are hosted on the Open Science Framework at https://osf.io/y357r. A detailed wiki is available at https://github.com/PaleovirologyLab/hi-fever/wiki, including usage instructions, parameter descriptions, and guidance on interpreting outputs. The pipeline includes a Pixi environment compatible with Conda and Apptainer containerization, and Docker images. HI-FEVER has been tested on Linux, Windows (via WSL2), and macOS (Intel and ARM64).

Software↗
PubMed2026

SEMPLR: an R package for transcription factor binding prediction.

SUMMARY: SEMPLR is an R package that predicts transcription factor binding and variant effects using SNP Effect Matrices (SEMs), providing efficient, genome-wide scoring, enrichment testing, and visualization tools for comprehensive analysis of regulatory sequences. AVAILABILITY: Available on GitHub at https://github.com/grkenney/SEMPLR and on Bioconductor at https://bioconductor.org/packages/release/bioc/html/SEMPLR.html.

Transcription Factors↗
PubMed1989

Diagnostic and prognostic values and limitations of Holter monitoring.

The value of Holter monitoring in the management of arrhythmias is mainly related to the considerable amount of data it provides regarding arrhythmias and their determinants in spontaneous conditions. The rate dependence and the adrenergic dependence of arrhythmias are the two factors that have the most important electrophysiological, prognostic and therapeutic implications. The limitations of Holter monitoring are related less to technical than to theoretical problems. Both will progressively be solved. Three-channel recordings and digitization of the signal would assist processing and help exploit information about QRS morphology. Even more fruitful might be more extensive and comprehensive analysis of the interactions between the various factors responsible for the pattern and the severity of arrhythmias, for example, the preceding rate, pauses, the coupling interval and the repetitive activity. The prognostic implications of many arrhythmias may depend on the context of myocardial functional impairment and adrenergic stimulation.

Arrhythmias, Cardiac↗
PubMed2025

Engineering of xylose metabolic pathways in Rhodotorula toruloides for sustainable biomanufacturing.

The oleaginous yeast Rhodotorula toruloides is a promising microbial cell factory for the sustainable production of biofuels and value-added chemicals from renewable carbon sources. Unlike the conventional yeast Saccharomyces cerevisiae, R. toruloides can naturally metabolize xylose, the second most abundant sugar in lignocellulosic hydrolysates. However, its native xylose metabolism is inefficient, characterized by slow xylose uptake and accumulation of D-arabitol. Moreover, despite its phenotype, research on the enzymes involved in xylose metabolism has yet to reach a consensus. Therefore, this review provides a comprehensive analysis of the non-canonical xylose metabolism in R. toruloides, focusing on the properties of key enzymes involved in xylose metabolism. Native xylose reductase and xylitol dehydrogenase exhibit broad substrate promiscuity compared to their counterparts in the xylose-fermenting Scheffersomyces stipitis. Additionally, the absence of xylulokinase expression under xylose-utilizing conditions redirects metabolism toward D-arabitol accumulation. Consequently, D-arabitol dehydrogenases and ribulokinase play essential roles in the xylose metabolism of R. toruloides. These findings highlight the fundamental differences between R. toruloides xylose metabolism and the oxidoreductase pathways observed in other xylose-fermenting yeast, providing insights for metabolic engineering strategies to improve xylose utilization and enhance bioconversion of cellulosic hydrolysates to different bioproducts by R. toruloides.

Xylose↗
PubMed2026

Post-translational modification of proteins in the human testis development pathway.

BACKGROUND: The foetal testes produce the androgens necessary to masculinise the developing embryo and support the maturation of germ cells, that will eventually develop into sperm, thus ensuring future reproductive capacity. The testes develop from the bi-potential gonads in a highly orchestrated process resulting in the differentiation of a complex tissue with multiple cellular lineages. While recent transcriptomic and chromatin-based analyses of human foetal testes have provided an unprecedented level of insight into signalling pathways activated during this process, proteomic studies of the human foetal gonads remain limited. Proteins are active molecules and post-translational modification (PTM) of proteins influences protein activity, stability and localisation. Studies have shown that PTMs regulate critical proteins in testis development, and their disruptions are implicated in congenital disorders including differences of sex development (DSD), in which sex development is atypical. Despite this, the role and regulation of protein PTM during human testis development remains poorly understood due to limited access to human foetal gonadal tissue, a paucity of large-scale proteomics studies, and a lack of robust of human gonad in vitro models. OBJECTIVE AND RATIONALE: This review aims to provide a comprehensive analysis of validated PTMs affecting proteins critical for testicular development. We discuss PTMs with evidence for a role in normal testis development, and highlight those disrupted in DSD. We review emerging techniques, including proteomic technologies and organ modelling systems that may advance our understanding of PTMs in foetal testis development. We discuss challenges that have restricted the application of these technologies and how overcoming these will significantly improve our understanding of testis development and disease, diagnostics and patient outcomes. SEARCH METHODS: We searched PubMed and the University of Melbourne library for peer-reviewed English-language studies using keywords such as phosphorylation, SUMOylation, acetylation, ubiquitination alongside each protein of interest. PTM sites in proteins involved in testis development were identified using the PhosphoSitePlus database focusing those confirmed in in vitro or animal model studies. ClinVar and the Human Gene Mutation Database were used to identify patient variants that may disrupt PTM sites. OUTCOMES: Our review finds that proteins required for human foetal testis development are subject to extensive PTM. Several PTM sites and PTM-mediated pathways [e.g. MAPK (mitogen-activated protein kinase) pathway] are disrupted in patients with DSD or related conditions. While recent advances in proteomics technologies hold considerable promise, their application to human foetal gonads has been constrained by technical, ethical, and logistical challenges. Encouragingly, emerging high-sensitivity and low-input technologies, alongside stem cell-based approaches, offer viable pathways to overcoming these barriers. WIDER IMPLICATIONS: The relationship between gene regulation, protein expression, and cellular outcome is inherently non-linear, shaped by additional regulatory layers-most notably PTMs. The contribution of PTMs to human testis development in both typical and atypical contexts is a major knowledge gap. Addressing this gap has broad clinical and biological relevance: it may help improve genetic diagnosis or shed light on how proteins or pathways critical for testis development respond to environmental signals-an increasingly pressing question as declining global fertility rates bring testicular function under greater scrutiny. REGISTRATION NUMBER: N/A.

Humans↗