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PubMed1975

Gene activation during spermatogenesis.

Cell differentiation during spermatogenesis in the rat has been analyzed in terms of the formation of specific "marker" enzymes. Hyaluronidase and other acrosomal enzymes are formed in spermatids according to a highly predictable time schedule which may be termed a "molecular biological clock". The acrosomal enzymes beta-galactosidase and N-acetyl-beta-glucosaminidase exist as isoenzyme forms distinct from enzymes with similar substrate specificities in the lysosomes of precursor cells. Differentiation of spermatids thus involves the loss of gene expression for lysosomal enzymes and the activation of genes for acrosomal isoenzymes. Spermatogenesis is characterized by the sequential loss of expression of many genes, as evidenced by the loss of beta-glucuronidase in the differentiation of spermatogonia to spermatocytes, and the loss of uridine diphosphatase activity in the differentiation of spermatocytes to spermatids. The apparent absence of ornithine decarboxylase activity from spermatids suggests a dependence of these cells upon Sertoli cells for the provision of putrescine and/or spermidine. Such biochemical cooperativity among germinal cells may be necessary as the genes of spermatids are repressed and late spermatids become metabolically inactive. Spermatogenesis is also characterized by changes in the cellular content and rates of synthesis and phosphorylation of specific acidic chromatin proteins. It is hypothesized that these proteins may participate in the activation or repression of genes during spermatogenesis.

Acetylglucosaminidase↗

PubMed1976

Evolutionary processes and evolutionary noise at the molecular level. II. A selectionist model for random fixations in proteins.

On account, notably, of a competition between different component functions for individual sites in polypeptide chains, each protein molecule represents a functional compromise, with some functions optimized, but the overall state of the molecule "suboptimal". The proposal is made that the selection coefficient relating to a protein molecule under given conditions can in principle be broken down into partial selection coefficients relevant to the different functions that the molecule carries out. At general-function sites, each fixation improves some function, while others deteriorate, at first nonsignificantly, and the overall adaptive state of the molecule fluctuates around its maximum. A selective mechanism is described whereby kaleidoscopic changes in primary structure at variable sites are indefinitely promoted, independently of any environmental changes and with the molecule remaining close to a state of maximal overall adaptation. The paradoxical aspect of this proposal is analyzed. The implication of specific functions in substitutions at general-function sites is noted. Further, it is shown that a certain category of changes in the internal environment of the organism can be integrated into the constant-environmental model for selection. Genetic sufficiency is considered a notion more adequate than genetic optimality for describing biological fitness and for providing a basis for the present model. On this basis selection occurs without genetic load. Multipolymorphism is one of the consequences. Several lines of evidence, in particular observations on polymorphism in deep sea organisms, seem to support the model. It is pointed out that it provides a theoretical foundation for a molecular evolutionary clock. The theoretical constancy of the clock depends on the constancy of functional density. The question of the evolution of functional density is examined. Comparisons of observed substitution frequencies with values expected on a random basis are rejected as a measure of the contribution to evolution of nondetermination. They are considered to reflect a hierarchy in the resistance of the molecules to different amino acid residues as substituents. A limited component of "true" randomness, again accompanied by selection, is on the other hand provided by the model. Most amino acid substitutions are considered evolutionary noise, even though noise compatible with selection. It is proposed that evolutionary significant substitutions may be identified by monitoring changes in functional density and weighted functional density.

Alleles↗

PubMed2026

Replicating lipid micelles: a feasible precursor to the origin of life and the earliest appearance of genomes.

The most commonly accepted scenario of early Earth includes: creation of the universe around 13.8 Ga (Giga-annus; or 109 years ago); establishment of our solar system ~ 4.60 Ga; and formation of Earth ~ 4.54 Ga. The earliest life forms on our planet so far observed to have existed, are microbes that left signals of their presence in rocks ~ 3.6 Ga - suggesting that Life forms existed within the first 940 million years after Earth's formation. However, an intriguing recent publication [1] infers that the last universal common ancestor (LUCA) likely existed by 4.2 Ga, and that the inferred LUCA had a genome of at least 2.5 Mb of DNA, encoding around 2,600 proteins; this suggests that sophisticated Life might have existed within the first 340 million years after Earth was formed. The commonly accepted geological history of early Earth suggests that the turbulent Hadean Eon lasted until 4.0 Ga, with the Late Heavy Bombardment (LHB) period occurring around 4.1 to 3.8 Ga. If Earth during the Hadean exhibited a molten surface, intense volcanic activity, and constant bombardment by asteroids and comets - how were sensitive molecules (e.g., nucleic acids, proteins) able to survive? Considering the "Lipid First" hypothesis [2], we propose that replicating lipid micelles are feasible candidates for having populated much of Earth's deep hydrothermal vents and turbulent surface within the first 340 million years of Earth's existence. These lipid micelles could therefore have provided a plausible form of "protective capsules" inside which early Life's sensitive molecules were able to evolve.

Origin of Life↗

PubMed2026

Convergent latitudinal erosion of circadian systems in a rapidly diversifying order of fishes.

Biological clocks allow organisms to anticipate cyclical environmental changes, yet in high-latitude or deep-sea habitats, the diel cues that entrain these rhythms are often seasonally diminished or absent. Fishes of the order Perciformes have rapidly diversified across these arrhythmic ecosystems, raising the question of whether changes to circadian rhythms and biological clock genetic architecture are a component of their evolutionary success. Here, we used a comparative genomic approach to investigate patterns of core biological clock gene loss across 96 perciform and five outgroup species. We found widespread and lineage-specific loss in core clock genes, particularly in the convergently evolving polar and deep-sea suborders Notothenioidei and Cottoidei. This trend of clock gene loss was significantly amplified with higher-latitude species. To determine if these genomic signatures reflect a functional loss of rhythmicity, we performed metabolic phenotyping on three notothenioid species. We found a consistent lack of circadian metabolic oscillations during the late austral fall across all notothenioids, including the sub-Antarctic sister lineage to the cryonotothenioid adaptive radiation, Eleginops maclovinus. Experimental data across Perciformes, combined with suborder-wide patterns of gene loss, suggest that a release from circadian constraints occurred early in their diversification, potentially facilitating the repeated expansion of these fishes into polar and deep-sea habitats.

Animals↗

PubMed2025

Circadian clock control of ribosome composition promotes rhythmic translation and termination fidelity.

Ribosome composition is dynamic, shifting with cell state and stress, but whether it varies with circadian time is unknown. Here, we uncover circadian clock-driven changes in ribosome composition in Neurospora crassa. Mass spectrometry of ribosomes across circadian time identified six ribosomal proteins and one associated factor under clock control. Rhythms in eL31 abundance were validated in purified ribosomes, and deletion of el31 disrupted translation rhythms in nearly half of rhythmically translated mRNAs. N. crassa eL31 promotes circadian control of translation termination and impacts elongation fidelity while maintaining Mg homeostasis, a key determinant of translational accuracy. These findings reveal that the circadian clock reprograms ribosome composition to orchestrate rhythmic translation and fidelity, temporally expanding the proteome beyond the static genome to align cellular function with time of day.

Neurospora crassa↗

PubMed2025

Multi-omic underpinnings of heterogeneous aging across multiple organ systems.

Aging is the main determinant of chronic diseases and mortality, yet organ-specific aging trajectories vary, and the molecular basis underlying this heterogeneity remains unclear. To elucidate this, we integrated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data, employing post-genome-wide association study methodologies to systematically investigate the molecular mechanisms of nine organ-specific aging clocks and four blood-based epigenetic clocks. We uncovered genetic correlations and specific phenotypic clusters among these aging-related traits, identified prioritized genetic drug targets for heterogeneous aging, and elucidated downstream proteomic and metabolomic effects mediated by heterogeneous aging. We constructed a cross-layer molecular interaction network of heterogeneous aging across multiple organ systems and characterized detectable biomarkers of this heterogeneity. Integrating these findings, we developed an R/Shiny-based framework that provides a comprehensive multi-omic molecular landscape of heterogeneous aging, thereby advancing the understanding of aging heterogeneity and informing precision medicine strategies to delay organ-specific aging and prevent or treat its associated chronic diseases.

Aging↗

PubMed2026

Mapping the regulatory architecture of circadian clock adaptation: A genome-wide eQTL analysis in Drosophila melanogaster.

The circadian clock enables organisms to align internal daily rhythms with environmental cues, with major consequences for survival and fitness. Although the molecular framework of this system in Drosophila melanogaster is well characterized through transcription translation feedback loops involving ten core clock genes, the genetic basis of natural variation in their expression remains poorly understood. Here, we used natural expression variation to identify expression quantitative trait loci (eQTLs) through genome-wide association mapping. Using the Drosophila Genetic Reference Panel, we measured relative expression of all core clock genes at a single time point two hours after light onset. We identified 109 significant SNPs and 28 indels associated with expression variation across the clock network. Expression levels varied widely, with Pdp1ε showing the greatest variation (an 86-fold difference between extreme lines) and cyc the least (11.3-fold). Only three significant SNPs were located within clock genes themselves, all in Clk, whereas most associations represented trans-eQTLs in genes with diverse molecular functions. Candidate regulators included transcription factors such as Abd-B, tai, and E5; RNA binding proteins including Pum, Bru-3, and Mbl; and several long noncoding and antisense RNAs. Variants were also detected in gbb and the BMP pathway transcription factor Mad. Consistent with this, Mad knockdown reduced vri expression. Together, these results reveal a complex regulatory architecture underlying natural variation in circadian gene expression.

Journal Article↗

PubMed1977

[The biological clock: circadian organization of the cell (author's transl)].

Unicellular systems, and particularly individual cells, are advantageous in investigating the molecular mechanism of the circadian rhythm. The greeen alga Acetabularia has proven to be a uniquely suitable organism. Experiments are described which indicate that the circadian rhythm is due to a sequence of events which are casually interrelated. A model is presented which is based on a two-step mechanism, the first step of which is the synthesis of "essential polypeptides" on 80 S ribosomes. In a second step these polypeptides are consumed. The function of the "essential polypeptides" is to change a membrane component of the circadian clock. The membrane participates in a feed-back mechanism which produces a periodic alteration of the rate of synthesis of "essential polypeptides" and of photosynthesis. It is possible to draw parallels between this circadian rhythm model and other repetitive and non-repetitive types of temporal organization within the cell, e.g., the cell cycle; however, it must be stressed that in the case of the circadian rhythm, much stronger and more efficient mechanisms exist to keep the period constant. This is true particularly for temperature compensation. Such a conservatism is understandable if one recalls that during evolution, the circadian rhythm represents an adaptive advantage which permits the organism to adjust it activities in advance to periodic processes resulting from the earth's rotation.

Acetabularia↗

PubMed2025

Gene editing of clock components in Solanum lycopersicum: Effects on gene expression, development, and productivity.

The circadian clock plays a crucial role in regulating key biological processes, including growth and development. While studies in the model plant Arabidopsis thaliana have significantly advanced our understanding of circadian function, recent research has also focused on crop species for improved yield and quality. In this study, we examined the rhythmic behavior and regulatory function of circadian clock components in tomato (Solanum lycopersicum). Time course analyses of gene expression over the circadian cycle revealed robust rhythmic oscillations in tomato leaves under free-running conditions. Comparative analyses showed similar peak phases for several clock genes in Arabidopsis and tomato, suggesting functional conservation. Rhythms in tomato fruits, however, showed reduced amplitude, slight phase changes, or arrhythmia, indicating organ-specific circadian variations. By using CRISPR-Cas9 gene editing strategies (clockcrispr), we also showed that proper clock gene expression is essential for setting the phase in tomato plants. Leaf movement analyses also showed a phase change in the clockcrispr lines, correlating with shorter or longer periods. The clockcrispr lines also displayed distinct growth and developmental phenotypes that differ from those reported in the Arabidopsis clock mutant counterparts. Our transcriptomic analyses identified species-specific regulation of key target genes. The results offer mechanistic insights into the conserved and divergent molecular pathways governing circadian phenotypic variations between Arabidopsis and tomato plants.

Solanum lycopersicum↗

PubMed2026

Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation.

BACKGROUND: Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. METHODS: We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. RESULTS: Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7%]) compared with adult tumors (39 of 62 [62.9%]). After adjustment for methylation-based subgroup as well as technical and biological covariates, 2,923 CpG probes were associated with age at a false discovery rate (FDR) threshold below 0.05, and 530 also met the prespecified effect-size threshold. Global methylation summaries were similar between age groups. CNV patterns were dominated by molecular subgroup; adjusted genomic CNV load was not independently associated with pediatric age. In contrast, epiTOC2 intrinsic rate score and the methylation signature represented by the first principal component (PC1) showed age-associated effects independent of molecular subgroup. Methylation-based deconvolution suggested a limited microenvironmental signal, with neutrophil fraction showing the most consistent adjusted association. CONCLUSIONS: Adult and pediatric PTPR share the established PTPR-A/PTPR-B framework. Pediatric tumors, particularly within PTPR-B, showed age-associated DNA methylation differences and higher epigenetic mitotic-clock (epiTOC2) scores in this retrospective cohort. These tissue-level associations do not establish clinical risk or treatment implications and require prospective clinical annotation and orthogonal validation.

Humans↗

PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗

PubMed2025

Birds of a feather flock together: social context exacerbates the effects of light pollution on circadian disruption.

Artificial light at night (ALAN), a growing pervasive pollutant, disrupts physiological and behavioural rhythms across organisms. Social interactions play a significant role in shaping individual and group biological rhythms, but they are often overlooked in the context of environmental stressors, such as ALAN. We explore how dim ALAN affects zebra finches (Taeniopygia guttata) in social and isolated environments, examining behavioural, physiological and molecular rhythms. We found that social birds under ALAN had an earlier activity onset and greater disruption in hypothalamic and liver circadian gene expression than control or isolated counterparts under ALAN. Additionally, we found that activity onset correlated negatively with hypothalamic bmal1 and cry1 expression in birds exposed to ALAN. Within ALAN-exposed birds, there was a larger disassociation between central and peripheral clock gene expression for social birds than in isolated birds. However, rhythmic melatonin concentrations did not differ among treatment groups. We show that social interactions may exacerbate the effects of ALAN, which highlights the impact of social interactions on circadian regulation at a molecular level and a critical need to consider social contexts in biological studies.

Animals↗

PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention. FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster.

Journal Article↗

PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

Journal Article↗

PubMed2026

The circadian clock proteins PRR modulate root hair development via the RHD6/RSL module in Arabidopsis.

Root hairs, derived from trichoblasts, are critical for plant growth and environmental adaptation. Although environmental cues are known to influence root hair development, how endogenous timing systems such as the circadian clock integrate into the core transcriptional network governing root hair formation remains unclear. Here, we show that the circadian clock-associated protein PSEUDO-RESPONSE REGULATOR5 (PRR5) physically interacts with ROOT HAIR DEFECTIVE6 (RHD6) and RHD6 LIKE1 (RSL1), two basic helix-loop-helix transcription factors essential for root hair initiation. Genetic analyses suggest that PRR proteins contribute to root hair development under long-day conditions in Arabidopsis thaliana. Simultaneous disruption of PRR5, PRR7, and PRR9 results in defective root hairs, whereas PRR5 overexpression markedly increases root hair density and length. Transcriptomic and RT-qPCR analyses reveal that PRRs enhance the expression of RHD6, RSL1, and multiple downstream root hair-responsive genes, while modulating their temporal expression patterns. Furthermore, PRR5-mediated root hair promotion requires RHD6/RSL1, and PRR proteins enhance RHD6-dependent activation of the RSL4 promoter. PRRs also contribute to root hair development under phosphate-deficient and salt-stress conditions. Together, these findings establish a molecular framework in which PRR proteins regulate the RHD6/RSL network to coordinate root hair development and environmental responses.

Arabidopsis↗

PubMed1979

The role of chloroplast-membrane-protein synthesis in the circadian clock. Purification and partial characterization of a polypeptide which is suggested to be involved in the clock.

A polypeptide (polypeptide P39), which is presumed to involved in the photosynthetic circadian rhythm in the green alga Acetabularia, was purified from the EDTA-insoluble chloroplast membrane fraction by means of preparative dodecylsulfate gel electrophoresis and then partially characterized. The purity of the isolated polypeptide P39 was confirmed by a further electrophoresis on an analytical dodecylsulfate gel and further elucidated by amino-terminal analysis which shows that glycine is the only amino-terminal amino acid of the purified polypeptide material. The molecular weight of the polypeptide P39 was found to be about 39,000 on analytical gel electrophoresis and the value was further supported by those obtained from amino acid composition and peptide mapping. The amino acid composition of polypeptide P39 showed that the proportion of intermediate amino acid groups is high while the proportion of hydrophilic amino acid groups is well balanced by that of hydrophobic amino acid groups, a property characteristic of membrane proteins.

Acetabularia↗

PubMed2024

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Kidney Neoplasms↗

PubMed2024

40S Ribosomal protein S6 kinase integrates daylength perception and growth regulation in Arabidopsis thaliana.

Plant growth occurs via the interconnection of cell growth and proliferation in each organ following specific developmental and environmental cues. Therefore, different photoperiods result in distinct growth patterns due to the integration of light and circadian perception with specific Carbon (C) partitioning strategies. In addition, the TARGET OF RAPAMYCIN (TOR) kinase pathway is an ancestral signaling pathway that integrates nutrient information with translational control and growth regulation. Recent findings in Arabidopsis (Arabidopsis thaliana) have shown a mutual connection between the TOR pathway and the circadian clock. However, the mechanistical network underlying this interaction is mostly unknown. Here, we show that the conserved TOR target, the 40S ribosomal protein S6 kinase (S6K) is under circadian and photoperiod regulation both at the transcriptional and post-translational level. Total S6K (S6K1 and S6K2) and TOR-dependent phosphorylated-S6K protein levels were higher during the light period and decreased at dusk especially under short day conditions. Using chemical and genetic approaches, we found that the diel pattern of S6K accumulation results from 26S proteasome-dependent degradation and is altered in mutants lacking the circadian F-box protein ZEITLUPE (ZTL), further strengthening our hypothesis that S6K could incorporate metabolic signals via TOR, which are also under circadian regulation. Moreover, under short days when C/energy levels are limiting, changes in S6K1 protein levels affected starch, sucrose and glucose accumulation and consequently impacted root and rosette growth responses. In summary, we propose that S6K1 constitutes a missing molecular link where day-length perception, nutrient availability and TOR pathway activity converge to coordinate growth responses with environmental conditions.

Arabidopsis↗