Biology subjects

Chen, X. J.

Publications and source records attributed to Chen, X. J..

10 recordsLinked to original sources

bioRxiv2026

The language network does not support music perception across a range of music experience

Music and language share many similarities, yet music does not elicit a response in the language brain areas in adults with typical amounts of music experience, and patients with aphasia show preserved music ability. However, this dissociation might not generalize across development or expertise: it may not yet be present in children, who have limited experience with language and music, or it may be diminished in musicians with extensive music training. To evaluate these possibilities, we here used a precision fMRI approach to examine the responses in the language areas of children (aged 4-16 years, n=80) and adult musicians (n=10) to music. We found that the results obtained previously for non-musician adults replicate in two new control samples and, critically, generalize to both of the newly tested populations: the language areas are already selective for language relative to music in young children, showing no age-related change from early to late childhood, and remain selective despite extensive music training in highly experienced musicians. Thus, it appears that the amount of music exposure and practice have little effect on how the language brain areas respond to music.

neuroscience↗

bioRxiv2025

Evidence for an Integrated Bilingual Language System from Discourse Tasks in Aphasia

BackgroundThe extent to which bilingual individuals represent and process their two languages within a shared or partially distinct neural architecture remains a topic of ongoing debate. While both parallel and divergent patterns of impairment have been reported in bilingual aphasia, such findings likely reflect a spectrum of representational overlap influenced by dominance, proficiency, and task demands. Critically, few studies have examined how breakdown manifests across multiple levels of linguistic structure using ecologically valid, discourse-based tasks. AimsThis study investigates whether Spanish-English bilinguals with aphasia exhibit parallel or dissociable patterns of impairment across their two languages, focusing on naturalistic narrative production and fine-grained analysis of error types and code-switching. Methods & ProceduresThirteen bilingual individuals with aphasia following acquired brain injury produced story retellings in both languages. Speech samples were transcribed and coded for phonological, morphological, syntactic, and semantic errors, and for the word type at which they occurred. Code-switches were also identified and categorized. Analyses included generalized linear modeling and unsupervised clustering. Outcomes & ResultsWhile participants made more errors in their non-dominant language, the structure and distribution of errors were highly similar across languages. Clustering algorithms revealed that impairments were parallel across languages and did not group by language dominance. Code-switching occurred more frequently from the non-dominant to the dominant language, consistent with activation-based lexical selection. ConclusionsFindings support an integrated bilingual language system that spans multiple levels of linguistic representation, modulated by language dominance. Naturalistic discourse tasks allow for richer characterization of bilingual language breakdown and may better inform both theoretical models and clinical management of bilingual aphasia.

neuroscience↗

bioRxiv2025

The Mitochondrial F-box protein 1 and DJ-1 homolog HSP31 support cellular proteostasis during mitochondrial protein import clogging

Mitochondrial biogenesis requires the import of [~]1,000-1,500 nuclear-encoded proteins across the Translocase of Outer Membrane (TOM) and the Translocase of Inner Membrane (TIM) 22 or 23 complexes. Protein import defects cannot only impair mitochondrial respiration but also cause mitochondrial Precursor Overaccumulation Stress (mPOS) in the cytosol. Recent studies showed that specific mutations in the nuclear-encoded Adenine Nucleotide Translocase 1 (ANT1) cause musculoskeletal and neurological diseases by clogging TOM and TIM22 and inducing mPOS. Here, we found that overexpression of MFB1, encoding the mitochondrial F-box protein 1, suppresses cell growth defect caused by a clogger allele of AAC2, the yeast homolog of Ant1. Disruption of MFB1 synergizes with a clogger allele of aac2 to inhibit cell growth. This is accompanied by increased retention of mitochondrial proteins in the cytosol, suggesting exacerbated defect in mitochondrial protein import. Proximity-dependent biotin identification (BioID) suggested that Mfb1 interacts with several mitochondrial surface proteins including Tom22, a component of the TOM complex. Loss of MFB1 under clogging conditions activates genes encoding cytosolic chaperones including HSP31. Interestingly, disruption of HSP31 creates a synthetic lethality with protein import clogging under respiring conditions. We propose that Mfb1 functions to maintain mitochondrial protein import competency under clogging conditions, whereas Hsp31 plays an important role in protecting the cytosol against mPOS. Mutations in DJ-1, the human homolog of Hsp31, and mitochondria-associated F-box proteins (eg., Fbxo7) are known to cause early-onset Parkinsons disease. Our work may help to better understand how these mutations affect cellular proteostasis and cause neurodegeneration.

genetics↗

bioRxiv2025

A theoretically driven calculation for language dominance and degree of multilingualism

Bilingualism research has long been challenged by a lack of a unified approach to quantifying language dominance and degree of multilingualism. While numerous questionnaires (e.g., LHQ, BLP, LEAP-Q, and LUQ) provide valuable data on language background variables, they lack a standardized formula to compute key measures from it. We introduce two formulas that synthesize critical linguistic variables to efficiently calculate language dominance and a multilingualism score that ranges from perfect monolingualism to native-like proficiency in multiple languages. Validation across two large datasets shows our dominance measure closely aligns with more complex PCA methods while being simpler and more efficient.

neuroscience↗

bioRxiv2025

Capturing Natural Evolution in Function-guided RNA Design via Genomic Foundation Models

RNAs play critical roles in gene expression regulation, catalysis, genetic information transmission, and immune response. However, current RNA engineering approaches face limitations in designing RNA for efficient in vivo folding and functional execution. Here, we present a novel, zero-shot strategy that integrates genomic large language models (LLMs) with inverse folding models (IFMs) to generate RNA sequences that mirror natural evolutionary patterns while preserving the structural integrity of critical functional regions. Benchmarking 9 state-of-the-art genomic foundation models, we show that their unsupervised log-likelihood scores correlate strongly with RNA fitness, enabling zero-shot sequence design. Applied to fluorescent RNA aptamers, our approach yielded 20 Broccoli variants, over half of which achieved up to 155% in fluorescence and a twofold increase in binding affinity, with robust performance both in vitro and in vivo. For Pepper, two rounds of optimization produced 40 variants, 16 of which demonstrated up to 2.6 fold in fluorescence and a threefold boost in binding affinity, including five with superior in vivo brightness.This approach offers a scalable, efficient, and resource-light method for RNA design, with significant implications for RNA-based therapeutics and diagnostics. By leveraging general foundation models to facilitate RNA evolution in a zero-shot fashion, we believe our work represents a major advancement in the field of RNA engineering.

evolutionary biology↗

bioRxiv2022

Mitochondrial protein import clogging as a mechanism of disease

Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria is disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in adenine nucleotide translocase 1 (Ant1), and its yeast ortholog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of Ant1s nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/Ant1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger Ant1 variant led to an age-dependent dominant myopathy that phenocopies Ant1-induced human disease, suggesting clogging as a mechanism of disease. We propose that secondary structures of mitochondrial preproteins play an essential role in preventing clogging and disease.

biochemistry↗

bioRxiv2022

Mitochondrial protein import stress potentiates neurodegeneration in a mouse model of Parkinson disease

Several genetic and environmental risk factors for Parkinsons disease have been identified that converge on mitochondria as central elements in the disease process. However, the mechanisms by which mitochondrial dysfunction contributes to neurodegeneration remain incompletely understood. Non-bioenergetic pathways of the mitochondria are increasingly appreciated, but confounding bioenergetic defects are a major barrier to experimental validation. Here, we describe a novel bioenergetics-independent mechanism by which mild mitochondrial protein import stress augments neurodegeneration. We induced this mitochondrial protein import stress in an established mouse model of Parkinsons disease expressing the A53T mutated form of -synuclein (SNCA). Mice with import stress in addition to the A53T mutation demonstrated increased size of -synuclein aggregates, co-aggregation of mitochondrial preproteins with -synuclein, and worsened neurodegeneration. Importantly, we found no evidence of bioenergetic defects in any of the mutant mice, even with the added import stress. These data suggest that mitochondrial protein import stress contributes to neurodegeneration through cytosolic proteostatic stress and co-aggregation of mitochondrial and neuropathogenic proteins independent of bioenergetics. Given that protein import efficiency is affected by many types of mitochondrial stress, our findings add a new layer to understanding why the pathogenic mitochondrial dysfunction and cytosolic protein misfolding pathways converge in neurodegenerative diseases such as Parkinsons disease.

biochemistry↗

bioRxiv2021

Mitochondrial DNA metabolism is coupled with 20S proteasome function via regulation of deoxyribonucleotide homeostasis in Saccharomyces cerevisiae

The synthesis of mitochondrial DNA (mtDNA) is not coupled with cell cycle. Previous studies have shown that the size of deoxyribonucleoside triphosphate (dNTP) pools plays an important role in regulating mtDNA replication and amplification. In yeast, dNTPs are synthesized by the cytosolic ribonucleotide reductase (RNR). It is currently poorly understood as to how RNR activity is regulated in non-dividing or quiescent cells to finely tune mtDNA metabolism to cope with different metabolic states. Here, we show that defect in the 20S proteasome drastically destabilizes mtDNA. The mtDNA instability phenotype in 20S proteasome mutants is suppressed by overexpression of RNR3 or by the deletion of SML1, encoding a minor catalytic subunit and an intrinsic inhibitor of RNR respectively. We found that Sml1 is stabilized in the 20S proteasomal mutants, suggesting that 20S affects mtDNA stability by stabilizing Sml1. Interestingly, defect in the regulatory 19S proteasomal function has only subtle effect on mtDNA stability, supporting a role of the 20S proteasome in dNTP homeostasis independent of 19S. Finally, we found that when cells are transitioned from glycolytic to oxidative growth, Sml1 level is reduced in a 20S-dependent manner. In summary, our study establishes a link between cellular proteostasis and mtDNA metabolism through the regulation of dNTP homeostasis. We propose that increased degradation of Sml1 by the 20S proteasome under respiratory conditions provides a mechanism to stimulate dNTP synthesis and promote mtDNA amplification.

genetics↗

bioRxiv2021

The chromatin organization of a chlorarachniophyte nucleomorph genome

Nucleomoprhs are remnants of secondary endosymbiotic events between two eukaryote cells wherein the endosymbiont has retained its eukaryotic nucleus. Nucleomorphs have evolved at least twice independently, in chlorarachniophytes and cryptophytes, yet they have converged on a remarkably similar genomic architecture, characterized by the most extreme compression and miniaturization among all known eukaryotic genomes. Previous computational studies have suggested that nucleomorph chromatin likely exhibits a number of divergent features. In this work, we provide the first maps of open chromatin, active transcription, and three-dimensional organization for the nucleomorph genome of the chlorarachniophyte Bigelowiella natans. We find that the B. natans nucleomorph genome exists in a highly accessible state, akin to that of ribosomal DNA in some other eukaryotes, and that it is highly transcribed over its entire length, with few signs of polymerase pausing at transcription start sites (TSSs). At the same time, most nucleomorph TSSs show very strong nucleosome positioning. Chromosome conformation (Hi-C) maps reveal that nucleomorph chromosomes interact with one other at their telomeric regions, and show the relative contact frequencies between the multiple genomic compartments of distinct origin that B. natans cells contain.

genomics↗

bioRxiv2019

Cytosolic Proteostatic Adaptation to Mitochondrial Stress Causes Progressive Muscle Wasting

Mitochondrial dysfunction causes muscle wasting (or atrophy) in many diseases and probably also during aging. The underlying mechanism is unclear. Accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient by themselves to intrinsically cause muscle wasting, raising the possibility that non-bioenergetic factors may contribute to mitochondria-induced muscle wasting. In this report, we show that chronic adaptation to mitochondria-induced proteostatic stress in the cytosol induces muscle wasting. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by a two-fold increase in the expression of the nuclear-encoded mitochondrial carrier protein, Ant1. We found that the ANT1-transgenic mice progressively lose muscle mass. Skeletal muscle is severely atrophic in older mice without affecting the overall lifespan. Mechanistically, Ant1 overloading induces aggresome-like structures and the expression of small heat shock proteins in the cytosol. The data support mitochondrial Precursor Overaccumulation Stress (mPOS), a recently discovered cellular stress mechanism caused by the toxic accumulation of unimported mitochondrial precursors/preproteins. Importantly, the ANT1-transgenic muscles have a drastically remodeled transcriptome that appears to be trying to counteract mPOS, by repressing protein synthesis, and by stimulating proteasomal function, autophagy and lysosomal amplification. These anti-mPOS responses collectively reduce protein content, which is known to decrease myofiber size and muscle mass. Our work therefore revealed that a subtle imbalance between mitochondrial protein load and import is sufficient to induce mPOS in vivo, and that anti-mPOS adaptation is a robust mechanism of muscle wasting. This finding may help improve the understanding of how mitochondria contribute to muscle wasting. It could have direct implications for several human diseases associated with ANT1 overexpression, including Facioscapulohumeral Dystrophy (FSHD). One Sentence SummaryProteostatic adaptations to proteostatic stress in the cytosol caused by unbalanced mitochondrial protein loading and import lead to progressive muscle wasting.

cell biology↗