Biology subjects

Schneider, K. L.

Publications and source records attributed to Schneider, K. L..

9 recordsLinked to original sources

bioRxiv2026

Inferring organ aging, hallmark of aging and senescence scores from blood and facial photographs

Aging progresses asynchronously across organs, motivating the development of organ-resolved aging clocks. Direct assessment of organ aging in living humans, however, is largely impractical. Here, we construct tissue-specific transcriptomic aging clocks and infer organ biological age from paired whole-blood (blood-organ age) and tissue RNA sequencing data in the GTEx project. We observe high variability both in the strength of aging signatures across organs and in the ability to predict organ age and organ scores from blood. Pathway analysis shows that organ aging clocks are dominated by biological processes that differ across tissues. Age-associated multi-organ modules identified in an aging multi-organ network correlation analysis and organ age features causally mediated through organ-blood-organ transcriptomic interactions support a role for systemic signaling in coupling organ aging processes. Given the established role of cellular senescence as a driver of tissue dysfunction and its tissue-specific accumulation during aging, we extend this framework to estimate burden of organ-level senescence and hallmarks of aging. Using senescence- and hallmark-associated gene sets, we derive tissue-specific senescence and hallmark scores (organ scores) and demonstrate that these burdens across multiple organs can be inferred from blood transcriptomes (blood-organ scores). Finally, in pursuit of extending these models to other blood omics and alternative non-invasive assessments, we evaluate whether blood methylation (methylation-blood-organ age and scores) and facial photographs (facial-blood-organ age and scores) can serve as proxies for blood-organ age and blood-organ scores in independent cohorts (Edifice Health and Health and Retirement Study). The methylation- and facial-blood-organ age and scores were associated with mortality in additional testing cohorts (Framingham Heart Study and IMDB-WIKI dataset). These results establish a cross-modal framework for inferring organ-specific aging and senescence from minimally invasive data.

bioinformatics↗

bioRxiv2024

Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition

The stress-associated molecular chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing hundreds of oncoproteins and disturbing the stoichiometry of protein complexes. Most inhibitors target the key component heat-shock protein 90 (HSP90). However, although classical HSP90 inhibitors are highly tumor-selective, they fail in phase 3 clinical oncology trials. These failures are at least partly due to an interference with a negative feedback loop by HSP90 inhibition, known as heat-shock response (HSR): in response to HSP90 inhibition there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock factor 1 (HSF1). We recently identified that wildtype p53 (p53) actively reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here we test the hypothesis that in HSP90-based therapies simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. Indeed, we find that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids and patient-derived organoids (PDOs). Mechanistically, upon combination therapy human CRC cells strongly upregulate p53-associated pathways, apoptosis, and inflammatory immune pathways. Likewise, in the chemical AOM/DSS CRC model in mice, dual HSF1-HSP90 inhibition strongly represses tumor growth and remodels immune cell composition, yet displays only minor toxicities in mice and normal mucosa-derived organoids. Importantly, inhibition of the cyclin dependent kinases 4 and 6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Even more important, in p53-deficient (mutp53-harboring) CRC cells, an HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR system and reduces cancer growth. Likewise, p53-mutated PDOs strongly respond to dual HSF1-HSP90 pathway inhibition and thus, providing a strategy to target CRC independent of the p53 status. In sum, activating p53 (in p53-proficient cancer cells) or inhibiting CDK4/6 (independent of the p53 status) provide new options to improve the clinical outcome of HSP90-based therapies and to enhance colorectal cancer therapy.

cancer biology↗

bioRxiv2022

Improved Centromere Assemblies for RefGen_v4

Genome assemblies based on long read sequencing technology have revolutionized the assembly of repeat-rich centromere regions. However, because maize centromeres are highly enriched for the tandem repeat CentC and centromeric retrotransposons (CR), automated genome assembly left gaps even in the excellent B73 RefGen_v4 reference genome constructed from long-read data. Manual editing of >140 Mb spanning the ten centromeres of maize inbred B73 resulted in the closure of 127 sequence gaps and the addition of >8.4 Mb of previously unanchored sequence (unitigs and reads) containing 24 genes, 2 Mb of CR repeat and 887 kb of CentC without including any additional sequence data. The functional centromeres of five maize chromosomes were closed completely, including a 7 Mb region spanning the extremely CR2-rich CEN2. This improved assembly, B73 RefGen_v4CEN, was completed in February 2019 and has been available at https://doi.org/10.25739/7y1p-5169, both as pseudomolecules and as centromere assemblies alone. Thus, the manual editing of existing sequence data significantly improved the centromere regions of the B73 RefGen_v4 reference genome. These data were used for centromere analyses until the release of RefGen_v5.

genomics↗

bioRxiv2022

Artificial Hsp100-mediated systems for re-localizing protein aggregates

Spatial Protein Quality Control (sPQC) sequesters misfolded proteins into specific, organelle-associated inclusions within the cell to harness their toxicity. To approach the role of sPQC in cellular fitness, neurodegenerative diseases and aging, we report on the construction of Hsp100-based systems in yeast cells, which can artificially target protein aggregates to non-canonical locations. We demonstrated that aggregates of mutant Huntingtin (mHtt), the disease-causing agent of Huntingtons disease can be artificially targeted to daughter cells as well as to eisosomes and endosomes with this approach. Removing aggregates from mother cells did not significantly affect their lifespan and targeting mHtt to multiple smaller aggregates rather than one large inclusion did not alter its toxicity. We demonstrated that this approach is able to manipulate mHtt inclusion formation also in human cells and has the potential to be a useful complementation to present therapeutic approaches aimed at alleviating age-related neurodegenerative diseases.

cell biology↗

bioRxiv2021

Comparison of endogenously expressed fluorescent protein fusions behaviour for protein quality control and cellular aging research

The yeast Hsp104 protein disaggregase is often used as a reporter for misfolded or damaged protein aggregates and protein quality control and ageing research. Observing endogenously expressed Hsp104 fusions with fluorescent proteins is a popular approach to follow post stress protein aggregation, inclusion formation and disaggregation. Overall, such protein fusions used in molecular and microbiology research are often sparsely characterised. To address this issue, we performed a comparative assessment of Hsp104 fluorescent fusions function and behaviour. We provide experimental evidence that molecular behaviour may not only be altered by introducing a fluorescent protein tag but also varies depending on the fluorophore within the fusion. Although our findings are especially applicable to protein quality control and ageing research in yeast, similar effects and points may play a role in other eukaryotic systems.

molecular biology↗

bioRxiv2021

Large Organellar Changes occur during Mild Heat Shock in Yeast

When the temperature is increased, the heat shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here, Saccharomyces cerevisiae were subjected to a mild continuous heat shock and intermittently cryo-immobilized for electron microscopy. Through measuring changes in all distinguishable organelle numbers, sizes, and morphologies in over 2400 electron micrographs a major restructuring of the cells internal architecture during the progressive heat shock was revealed. The cell grew larger but most organelles within it expanded even more. Organelles responded to heat shock at different times, both in terms of size and number, and adaptations of certain organelles morphology were observed. Multivesicular bodies grew to almost 170% in size, indicating a previously unknown involvement in the heat shock response. A previously undescribed electron translucent structure accumulated close to the plasma membrane during the entire time course. This all-encompassing approach provides a detailed chronological progression of organelle adaptation throughout the cellular stress response. Summary statementExposure to mild heat shock leads to large quantifiable changes in the cellular ultrastructure of yeast, shows involvement of MVBs in the heat shock response and the apparition of novel structures.

cell biology↗

bioRxiv2019

Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data while N=415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

pharmacology and toxicology↗

bioRxiv2019

Signals of anticipation of reward and of mean reward rates in the human brain

Theoretical models of dopamine function stemming from reinforcement learning theory have emphasized the importance of prediction errors, which signal changes in the expectation of impending rewards. Much less is known about the effects of mean reward rates, which may be of motivational significance due to their role in computing the optimal effort put into exploiting reward opportunities. Here, we used a reinforcement learning model to design three functional neuroimaging studies and disentangle the effects of changes in reward expectations and mean reward rates, showing recruitment of specific regions in the brainstem regardless of prediction errors. While changes in reward expectations activated ventral striatal areas as in previous studies, mean reward rates preferentially modulated the substantia nigra/ventral tegmental area, deep layers of the superior colliculi, and a posterior pontomesencephalic region. These brainstem structures may work together to set motivation and attentional efforts levels according to perceived reward opportunities.

neuroscience↗

bioRxiv2016

The complex sequence landscape of maize revealed by single molecule technologies

Complete and accurate reference genomes and annotations provide fundamental tools for characterization of genetic and functional variation. These resources facilitate elucidation of biological processes and support translation of research findings into improved and sustainable agricultural technologies. Many reference genomes for crop plants have been generated over the past decade, but these genomes are often fragmented and missing complex repeat regions. Here, we report the assembly and annotation of maize, a genetic and agricultural model species, using Single Molecule Real-Time (SMRT) sequencing and high-resolution optical mapping. Relative to the previous reference genome, our assembly features a 52-fold increase in contig length and significant improvements in the assembly of intergenic spaces and centromeres. Characterization of the repetitive portion of the genome revealed over 130,000 intact transposable elements (TEs), allowing us to identify TE lineage expansions unique to maize. Gene annotations were updated using 111,000 full-length transcripts obtained by SMRT sequencing. In addition, comparative optical mapping of two other inbreds revealed a prevalence of deletions in the low gene density region and maize lineage-specific genes.

genomics↗