Biology subjects

Schon, K.

Publications and source records attributed to Schon, K..

7 recordsLinked to original sources

bioRxiv2026

Large-scale single-cell mapping of concealed mitochondrial ageing

Mitochondrial DNA (mtDNA) mutations have been linked to ageing. We find that the mtDNA mutations detected in routine bulk sequencing are greatly outnumbered by a class of concealed mutations that, despite being in a proliferative tissue, show little negative selection. Combining new scATAC-seq experiments with existing scRNA-seq, we map mtDNA mutations across 2.7 million cells from 311 individuals, covering 11 proliferative cell types and 5 tissues. We find that low-prevalence mutations (in[≤] 1% of assayed cells), concealed from routine bulk sequencing, accumulate markedly with age, with mutations unique to single cells (cryptic) predominating. We find a near universal accumulation rate across cell types and tissues, with, by age 50, approximately 40% of cells having at least one mutation affecting 30% of cellular mtDNA or more. At a correlative level we find that human age can be predicted from these concealed mutations but there is evidence of, possibly physiological, inter-individual variation. These low-prevalence mutations (unlike mutations tracking larger clones) show limited negative selection and coincide with gene-expression changes marking dysfunction.

genomics↗

bioRxiv2025

Computationally designed stem-epitope mimetics elicit broadly reactive antibodies

Broad protection against diverse influenza viruses can be conferred by broadly neutralizing antibodies (bnAbs) targeting a conserved site on the hemagglutinin (HA) stem domain. However, the low immunogenicity of this antigenic region hinders the robust induction of such antibodies. Here, we showcase a structure-based immunogen design strategy focusing on the surface mimicry of antigenic sites. By leveraging the structural definition of a stem epitope, we apply computational protein design to develop epitope mimetics to focus the immune response against this site of viral vulnerability. The structurally complex antigenic site is displayed on heterologous protein scaffolds, retaining excellent binding towards known HA stem-specific bnAbs. Our epitope-mimetic induces stem-specific antibodies against highly divergent group 1 and 2 subtypes. The results provide a general framework for the design of novel immunogens eliciting focused immune responses which may be a valuable tool in the development of effective vaccine candidates against other variable pathogens.

biochemistry↗

bioRxiv2024

Nuclear RNAi Modulates Influenza A Virus Infectivity By Downregulating Type-I Interferon Response

The role of Argonaute (AGO) proteins and the RNA interference (RNAi) machinery in mammalian antiviral response has been debated. Therefore, we set out to investigate how mammalian RNAi impacts influenza A virus (IAV) infection. We reveal that IAV infection triggers nuclear accumulation of AGO2, which is directly facilitated by p53 activation. Mechanistically, we show that IAV induces nuclear AGO2 targeting of TRIM71, a proposed AGO2 E3 ligase, and type-I interferon-pathway genes for silencing. Accordingly, Tp53-/- mice do not accumulate nuclear AGO2 and demonstrate decreased susceptibility to IAV infection. Hence, the RNAi machinery is highjacked by the virus to evade the immune system and support viral replication. Furthermore, the FDA approved drug arsenic trioxide, which prevents p53 tetramerization and nuclear translocation, increases interferon response and decreases viral replication in vitro and in a mouse model in vivo. Our data indicates that targeting the AGO2:p53-mediated silencing of innate immunity may offer a promising strategy to mitigate viral infections.

biochemistry↗

bioRxiv2024

Personal Mastery Attenuates the Association between Greater Perceived Discrimination and Lower Amygdala and Anterior Hippocampal Volume in a Diverse Sample of Older Adults

There is limited research investigating whether perceived discrimination influences brain structures that subserve episodic memory, namely the hippocampus and amygdala. Our rationale for examining these regions build on their known sensitivity to stress and functional differences along the long-axis of the hippocampus, with the anterior hippocampus and amygdala implicated in emotional and stress regulation. We defined perceived discrimination as the unfair treatment of one group by a dominant social group without the agency to respond to the event. A potential moderator of perceived discrimination is personal mastery, which we operationally defined as personal agency. Our primary goals were to determine whether perceived discrimination correlated with amygdala and anterior hippocampal volume, and if personal mastery moderated these relationships. Using FreeSurfer 7.1.0, we processed T1-weighted images to extract bilateral amygdala and hippocampal volumes. Discrimination and personal mastery were assessed via self-report (using the Experiences of Discrimination and Sense of Control questionnaires, respectively). Using multiple regression, greater perceived discrimination correlated with lower bilateral amygdala and anterior hippocampal volume, controlling for current stress, sex, education, age, and intracranial volume. Exploratory subfield analyses showed these associations were localized to the anterior hippocampal CA1 and subiculum. As predicted, using a moderation analysis, personal mastery attenuated the relationship between perceived discrimination and amygdala and anterior hippocampal volume. Here, we extend our knowledge on perceived discrimination as a salient psychosocial stressor with a neurobiological impact on brain systems implicated in stress, memory, and emotional regulation, and provide evidence for personal mastery as a moderating factor of these relationships.

neuroscience↗

bioRxiv2023

An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants

The role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR modified cell lines and mouse models, we have identified a novel silencer element that is lost in ADLD patients and that specifically targets overexpression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving the LMNB1 and the recruitment of the PRC2 repressor complex. Loss of the silencer element in ADLD identifies a previously unknown role for silencer elements in tissue specificity and disease causation.

genetics↗

bioRxiv2023

Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer

Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori.

immunology↗

bioRxiv2021

Cardiorespiratory fitness predicts cortical thickness of medial temporal brain areas associated with spatial cognition in young but not older adults

Cardiorespiratory fitness (CRF) has been shown to have a potent effect on neurocognitive health. However, less is known about the impact of CRF on extrahippocampal neocortical regions in the medial temporal lobes (MTL). Specifically, it is unclear whether CRF modulates these MTL regions in young adulthood and if these brain areas are differentially related to CRF in young vs. older adults. The primary goal of the current study was to investigate if CRF predicted cortical thickness of MTL neocortical regions that, along with the hippocampus, are critical for spatial learning and memory. Additionally, given the established role of the MTL cortices in spatial navigation, we sought to determine if CRF and MTL cortical thickness would predict greater subjective sense of direction in both young and older adults. Cross-sectional data from 56 young adults (20-35 years) and 44 older adults (55-85 years) were included. Using hierarchical multiple regression analyses, we confirmed significant positive relationships between greater CRF and greater left entorhinal, left parahippocampal, and left perirhinal cortical thickness in young, but not older, adults. Left parahippocampal thickness interacted with age group to differentially predict sense of direction in young and older adults. Young adults displayed a positive, and older adults a negative, relationship between left parahippocampal thickness and sense of direction. Our findings extend previous work on the association between CRF and hippocampal subfield structure in young adulthood to left MTL neocortical regions. HighlightsO_LICardiorespiratory fitness assessed in young and older adults using a submaximal treadmill test. C_LIO_LISurface-based structural analysis of cortical thickness of medial temporal regions. C_LIO_LICardiorespiratory fitness predicted left medial temporal cortical thickness in young but not older adults. C_LIO_LILeft parahippocampal thickness differentially predicted sense of direction in young and older adults. C_LI

neuroscience↗