Biology subjects

Kim, H.

Publications and source records attributed to Kim, H..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

MYST acetyltransferases are a targetable therapeutic vulnerability in SETBP1-mutant leukemia

Mutations in SET binding protein 1 (SETBP1) are associated with an adverse prognosis in myeloid malignancies. These mutations stabilize SETBP1 protein, driving increased expression of a progenitor-associated gene expression program through incompletely described mechanisms. A proteomic screen revealed interactions between SETBP1 and members of the MYST acetyltransferase complexes, including the catalytic subunits--KAT6A and KAT7. Mutant SETBP1 increases the localization of MYST complexes at known SETBP1 target genes, including the Hoxa cluster, where it drives increased histone acetylation and gene expression. Treatment of SETBP1D868N-expressing myeloid progenitors with MYST inhibitors reduced target gene expression. To establish the efficacy of MYST inhibition in vivo, we treated mice harboring a syngeneic SETBP1-mutant leukemia with the clinical-grade MYST inhibitor--PF-9363. This resulted in complete hematologic control and increased survival. MYST inhibition was also highly effective against a SETBP1-mutant PDX model. These studies identify MYST acetyltransferases as promising therapeutic targets in SETBP1-mutant malignancies. Statement of SignificanceSETBP1 mutations are markers of high-risk myeloid malignancies, but we lack any targeted therapies to improve outcomes. In this study, we identify MYST acetyltransferases as key drivers of mutant SETBP1-driven transcription. MYST inhibitors are highly effective against SETBP1-mutant leukemia and represent a promising avenue for clinical translation.

cancer biology↗

bioRxiv2026

Trait anxiety is associated with idiosyncratic neural event boundaries during naturalistic movie-watching

Anxiety is associated with altered patterns of attention to images and objects, but how it influences the perception of continuous experiences remains underexplored. Here, we examined whether trait anxiety is associated with differences in how the brain segments continuous experience into events. Using a large-scale open-access dataset and data-driven methods to detect neural event boundaries, we compared neural event segmentation between healthy adults with high (N=60) and low trait-level anxiety (N=60) as they viewed a short suspenseful film. While the cortical temporal hierarchy was preserved across groups, high-anxiety individuals had more idiosyncratic event boundaries, exhibiting reduced alignment to both low-anxiety individuals and one another. This divergence was most pronounced in the dorsal attention and frontoparietal control networks, suggesting that trait anxiety is associated with idiosyncratic temporal organization in systems involved in attentional control. Furthermore, boundary variability in high-anxiety participants was greater during moments rated as more anxiety-provoking by a large language model, controlling for arousal, valence, and low-level visual features. Together, these findings suggest that anxious individuals organize continuous experience in a more individualized manner. More broadly, they offer a neurocomputational framework for investigating how trait-level variability interacts with narrative content to shape naturalistic event perception.

neuroscience↗

bioRxiv2025

Template-based RNA structure prediction advanced through a blind code competition

Automatically predicting RNA 3D structure from sequence remains an unsolved challenge in biology and biotechnology. Here, we describe a Kaggle code competition engaging over 1700 teams and 43 previously unreleased structures to tackle this challenge. The top three submitted algorithms achieved scores within statistical error of the winners of the recent CASP16 competition. Unexpectedly, the top Kaggle strategy involved a pipeline for discovering 3D templates, without the use of deep learning. We integrated this template-modeling pipeline and other Kaggle strategies to develop a single model RNAPro that retrospectively outperformed individual Kaggle models on the same test set. These results suggest a growing importance of template-based modeling in RNA structure prediction.

biophysics↗

bioRxiv2025

FAM84B facilitates tau propagation via RYR3-mediated exocytosis in response to neuroinflammation

The increasing prevalence of dementia underscores the pressing need for effective therapeutic interventions. Despite extensive research into A{beta}, the limited efficacy of existing treatment modalities necessitates a paradigm shift toward tau pathology including tau propagation to slow dementia progression. Here, we identified a novel protein, FAM84B (also known as LRATD2), involved in tau propagation. Elevated FAM84B levels were detected in the postmortem cortex, cerebrospinal fluid, and induced pluripotent stem cell-derived cortical neurons of patients with tauopathy. FAM84B facilitates tau secretion through exosome assembly and RYR3-mediated exocytosis, followed by exosomal uptake into neighboring cells via clathrin-mediated endocytosis, thereby driving tau propagation. We confirmed that neuroinflammation induced by heightened STAT3 activity and cytokine treatment upregulated FAM84B expression, stimulating tau propagation, as evidenced by reduced propagation upon RYR3 inhibition. These findings provide invaluable insights into potential avenues for targeting tau propagation to ameliorate disease progression in tauopathies.

neuroscience↗

bioRxiv2025

Genome-Level Hierarchical Attention Transformer with Multi-Head Attention Weighted Sum for Broad-Spectrum Antimicrobial Resistance Prediction and Discovery of Resistance-Related Genomic Contexts

Antimicrobial resistance is a growing global health concern, requiring reliable tools for predicting resistance across a wide range of bacteria and antibiotics. In this study, we introduce a genome-level hierarchical attention transformer (GL-HAT) that integrates a pretrained genomic foundation model with hierarchical attention mechanisms to analyze the full protein sequence context of bacterial genomes. GL-HAT is designed to deliver both accurate resistance predictions and interpretable insights into the genomic features associated with resistance using specialized modules. Trained and validated on a comprehensive dataset of bacterial genomes and antimicrobial susceptibility profiles, the model outperformed traditional machine learning method, with an F1-score of 0.845 and AUROC of 0.953. Moreover, GL-HAT could demonstrate the resistance-related contexts in the genome, such as vanA operon and nearby resolvase genes in vancomycin-resistant Enterococcus and tet(M) gene adjacent to conjugation proteins in tetracycline-resistant Streptococcus pneumoniae. By combining high accuracy with interpretability, GL-HAT offers a practical approach for advancing AMR diagnostics and research, supporting more informed clinical and public health decisions.

bioinformatics↗

bioRxiv2025

Stress-induced loss of CTCF reveals an alternative, promoter-based mode of cohesin looping

Cells continually face environmental stressors that challenge homeostasis, yet how three-dimensional (3D) chromatin structure contributes to these stress responses remains unclear under hyperosmotic conditions. To investigate this, we map 3D chromatin structure, its molecular drivers, and transcriptional outcomes during sorbitol-induced hyperosmotic stress. Within 1 hour of sorbitol treatment, pre-existing loops and domains collapse, while several hundred de novo sorbitol-induced loops emerge. These loops are punctate, longer-range, and transient. 3D chromatin structure largely returns to baseline conditions by 24 hours. Loop reorganization is consistent across cell types and hyperosmotic stimuli. Sorbitol-induced loops require cohesin but not CTCF, and anchors are enriched at active promoters harboring GC-rich transcription factor motifs. Genes at these anchors show delayed activation following loop formation, consistent with loops acting upstream of transcription. Together, hyperosmotic stress triggers rapid, reversible, CTCF-independent chromatin reorganization that correlates with transcriptional adaptation.

genomics↗

bioRxiv2025

Conserved RNA helicase Vasa regulates ribonucleoprotein condensates through protein interaction and mRNA recruitment

Germlines contain ribonucleoprotein condensates known as germ granules, which concentrate proteins and mRNAs essential for animal development. Vasa, a conserved DEAD-box RNA helicase, is a core and highly concentrated constituent of germ granules. However, its roles within these structures remain poorly understood. Here, we use Drosophila germ granules as a model system to address this question. Applying in vivo and human cell systems, we found that condensation of Oskar (Osk) protein, which nucleates germ granules, occurred independently of Vasa. However, in oocytes lacking detectable Vasa protein, Osk formed aggregated condensates regardless of the eGFP tag. Furthermore, Osk-eGFP showed minimal recovery as measured by fluorescence recovery after photobleaching (FRAP) indicating that its exchange between condensates and their surroundings was greatly reduced in the absence of Vasa. Supporting this result, co-expression of Vasa increased the FRAP recovery of Osk-eGFP condensates and reduced Osk-eGFP partitioning into them in cells. This effect required the interaction between Vasa and Osk, suggesting that by binding Osk, Vasa modulates Osks phase behavior and its condensate material properties. Super-resolution microscopy further revealed that Vasa is required for germ granule mRNA localization to Osk condensates in vivo. Co-expression of Vasa with Osk-eGFP is necessary and sufficient to recruit germ granule mRNAs to condensates in cells. Although this activity depends on Vasa-Osk interaction, the interaction itself is not sufficient. Notably, localization of a conserved germ granule mRNA nanos reduced the FRAP recovery of Osk-eGFP condensates in cells, partially counteracting Vasas effect. Collectively, our findings uncovered a novel function of the DEAD-box RNA helicase Vasa in regulating the material properties of Osk condensates through coordinated protein-protein and protein-mRNA interactions. Four highlightsO_LIVasa modulates the material properties of Oskar ribonucleoprotein condensates in fly oocytes and human cells. C_LIO_LIVasa modulates condensate material properties through its interaction with Oskar. C_LIO_LImRNA localization to Oskar condensates requires Vasa and Vasa-Oskar interaction. C_LIO_LInanos mRNA localization counteracts Vasas enhancement of Oskar exchange between condensates and their surroundings. C_LI

molecular biology↗

bioRxiv2025

A Biologically Grounded Structural Causal Model Enables cfRNA Specific In-Context Learning

Cell-free RNA (cfRNA) in human plasma provides a minimally invasive readout of tissue physiology, yet its extreme sparsity, heavy-tailed abundance distributions, and weak but structured correlation patterns create major challenges for machine learning. Conventional tabular foundation models are typically trained on synthetic datasets that assume generic statistical properties, and as a result, they fail to capture the distinctive characteristics of cfRNA. These limitations become even more pronounced in settings where labeled data are scarce. We introduce cfRNA-ICL, a cfRNA-specific in-context learning model trained entirely on tasks generated from a biologically grounded structural causal model (SCM). The SCM produces realistic cfRNA-like scenarios by incorporating empirical measurements of gene-level dropout, overdispersion, tissue-mixture-driven latent factors, compositional variability, and sequencing noise. This synthetic task universe enables cfRNA-ICL to acquire inductive biases that closely reflect the geometry of real cfRNA data. Across multiple cancer classification benchmarks, cfRNA-ICL demonstrates consistently higher performance than tabular ICL models trained on generic synthetic data. The gains are most sub-stantial in few-shot settings, where the model benefits from its exposure to cfRNA-specific statistical regimes during meta-training. Representation-level analyses further show that cfRNA-ICL organizes samples into biologically coherent manifolds, preserving cancer-type identity without the use of supervised constraints. This finding indicates strong alignment between the synthetic prior and real cfRNA structure. Taken together, these results show that domain-aware generative priors can meaningfully enhance in-context learning for biological tabular data. cfRNA-ICL provides a generalizable framework for cfRNA modeling and establishes a practical path toward foundation-scale models that are intrinsically adapted to the statistical landscape of plasma cfRNA.

genomics↗

bioRxiv2025

Chlorotonils exhibit potent activity against Mycobacterium tuberculosis, while resistance is mediated by MmpR5-MmpL5

Treatment of Mycobacterium tuberculosis (Mtb) is challenging and requires administration of at least four different antibiotics. Unfortunately, multi-drug resistant Mtb strains continue to emerge, undermining the effectiveness of current treatment regimens and highlighting the urgent need for new therapeutics. In this study, we evaluated the potential of natural product-derived chlorotonils as anti-Mtb agents. We demonstrate that chlorotonils exhibit nanomolar potency against a range of attenuated and virulent Mtb strains. Mechanistic studies and resistance profiling in Mtb revealed that chlorotonils affect both lipid and energy metabolism. Through systems biology approaches, including the construction of an Mtb CRISPRi library specifically designed for chemical-genomic profiling, we identified MmpR5/MmpL5 as major driver of chlorotonil-resistance in Mtb leading also to cross-resistance with bedaquiline. Our findings highlight chlorotonils as valuable chemical tools to further dissect the role and function of the MmpS5-MmpL5 efflux pump in drug-resistant Mtb.

microbiology↗

bioRxiv2025

Role of Myc family proteins in transcriptional regulation of growth and oncogenic transformation in fusion-positive rhabdomyosarcoma

Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a PAX3::FOXO1 (P3F) or PAX7::FOXO1 fusion gene. After finding that MYCN is required for P3F-induced oncogenic transformation in a human myoblast model of FP-RMS, we further investigated the role of Myc family proteins in FP-RMS. Expression studies revealed that myoblast models and a subset of FP-RMS lines have predominant MYCN or MYC expression whereas other FP-RMS lines have both high MYCN and MYC expression. In myoblast models, MYCN was required for optimal P3F binding to and high-level activation of FGF8, a P3F target that is necessary and sufficient for oncogenic transformation. MYCN or MYC knockdown suppressed transformation in myoblast and FP-RMS lines with dominant MYCN or MYC expression, respectively. In FP-RMS lines with high MYCN and MYC expression, there was partial loss of transformation when one gene was targeted and complete loss when both genes were targeted. Despite the loss of oncogenic activity in lines with knockdown of a dominant Myc family member, FGF8 expression was not decreased. Transcriptomic analyses revealed that P3F target genes were not affected by MYCN or MYC knockdown, and instead a group of Myc-specific targets was down-regulated. Collectively, these results indicate that MYCN or MYC is functionally dominant in myoblast models and FP-RMS lines with dominant expression of one Myc family protein whereas MYCN and MYC are functionally redundant in FP-RMS cell lines with high expression of both. These Myc family proteins contribute to oncogenic properties by facilitating P3F activation of FGF8 and increasing expression of Myc-specific targets.

cancer biology↗

bioRxiv2025

MIR17HG Expression Is Transcriptionally Regulated by PAX3::FOXO1 and MYCN 1 and is Necessary for Oncogenic Activity in Fusion-Positive Rhabdomyosarcoma

Alveolar rhabdomyosarcoma (RMS), an aggressive pediatric soft tissue cancer, is driven by the oncogenic fusion transcription factor PAX3::FOXO1 (P3F) or PAX7::FOXO1. In a subset of fusion-positive (FP)-RMS cases, amplification of the MIR17HG locus leads to overexpression of the miR-17-92 cluster of microRNAs (miRNAs). However, miR-17-92 is also highly expressed in FP-RMS tumors lacking this amplification, suggesting alternative regulatory mechanisms. Here, we show that P3F and MYCN cooperatively drive miR-17-92 expression in FP-RMS. CRISPR/Cas9-mediated knockout of P3F or MYCN in FP-RMS cell lines substantially reduced miR-17-92 expression. Using a human myoblast line or low P3F FP-RMS variant with inducible P3F or MYCN expression, P3F or MYCN alone induces minimal to low miR-17-92 expression whereas introduction of both MYCN and P3F leads to robust activation of the miR-17-92 cluster and acquisition of oncogenic phenotypes. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed a P3F binding motif located 1.84 Mb upstream of the MIR17HG promoter. CRISPR-mediated deletion of this region in the myoblast system resulted in marked reduction of miR-17-92 expression and impaired oncogenic transformation. Functional inhibition of mature miRNAs of this cluster in FP-RMS cells using miRNA-sponge constructs suppressed proliferation and transformation. In the myoblast model system, transduction studies with exogenous miR-17-92 or miRNA-sponge expression constructs indicated that miR-17-92 is necessary but not sufficient for oncogenic transformation. Together, these findings establish a cooperative transcriptional axis in FP-RMS involving P3F and MYCN that activates MIR17HG through a distal regulatory element, thereby contributing to oncogenic behavior and uncovering a novel mechanistic vulnerability.

cancer biology↗

bioRxiv2025

The Role of Pavlovian Bias in Smoking Cessation Success and Neurocognitive Alterations During Nicotine Withdrawal

BackgroundInability to manage conflicts between multiple decision-making systems is associated with various mental disorders including addiction. The imbalance between the Pavlovian and instrumental systems may contribute to smoking cessation failure and relapse, as excessive Pavlovian motivation may override goal-directed quitting attempts. However, the exact role of the Pavlovian bias in smoking cessation and its neurocognitive mechanisms remain poorly understood. MethodsEighty-six smokers participated in a smoking cessation clinic, completing the well-established orthogonalized go-nogo task before and after the intervention. We applied computational modeling and functional magnetic resonance imaging (fMRI) analyses to investigate the role of Pavlovian bias and its neural correlates in predicting smoking cessation outcomes. ResultsComputational modeling revealed that higher levels of Pavlovian bias were associated with treatment failures. Importantly, Pavlovian bias significantly moderated the relationship between clinic participation rate and the likelihood of smoking cessation, suggesting that such bias can undermine motivational effort to quit. Furthermore, individuals who successfully quit smoking exhibited increased Pavlovian bias toward reward following cessation, indicating a potential cognitive mechanism underlying the relapse cycle. Complementary fMRI analyses demonstrated that Pavlovian bias influenced valence encoding in the ventromedial prefrontal cortex (vmPFC), suggesting altered decision-making neural circuits. ConclusionsPavlovian bias can be a critical risk factor of relapse in the smoking population, while this bias can be increased in response to nicotine abstinence. Moreover, the results highlight the roles of the vmPFC in decision-making under Pavlovian-instrumental conflict, providing insights into the neural underpinnings of relapse vulnerability. Understanding these mechanisms may guide targeted interventions to enhance smoking cessation outcomes.

neuroscience↗

bioRxiv2025

Deep cerebellar tFUS engages cortical circuits via convergent local and sensory-driven mechanisms

Transcranial focused ultrasound (tFUS) enables non-invasive access to deep brain structures with high spatial precision, but its mechanisms of action remain elusive and under active investigation. The leading hypothesis posits that tFUS exerts its neuromodulatory effects through direct activation of neurons, while others attribute effects to indirect activation of auditory pathways. Here, we investigated the neuromodulatory effects of tFUS on the dentato- thalamo-cortical (DTC) pathway by targeting either the lateral cerebellar nucleus (LCN) or auditory cortex (AUD) in anesthetized rats. Electroencephalography (EEG) recordings from bilateral motor cortices and the contralateral auditory cortex revealed that tFUS reliably evoked cortical potentials, whereas sham stimulation produced no responses. Both LCN and AUD stimulation activated the auditory cortex, suggesting auditory pathway involvements. However, only LCN stimulation elicited early and significant event-related potentials and gamma-band activity in the contralateral motor cortex, consistent with DTC pathway engagement. We propose that LCN-targeted stimulation engages the DTC pathway through modulation of neuronal excitability, while concurrent auditory inputs account for global cortical activation. These results are consistent with a hybrid mechanism in which tFUS modulates neuronal dynamics, converging both direct and indirect components depending on the stimulation site. Proposed framework reconciles competing views of tFUS as either a direct or indirect modulator and clarifies how ultrasound can differentially influence cortical circuits depending on the stimulation target.

neuroscience↗

bioRxiv2025

PROX1 loss in adult mouse Schlemm's canal causes permanent ocular hypertension

Glaucoma is associated with ocular hypertension and lowering intraocular pressure is a key objective of glaucoma therapies. Recent studies have established a role for the Schlemms canal endothelium in this pressure increase and have shown it to have a unique, lymphatic-like, hybrid phenotype. However, the role of these lymphatic phenotypes in the adult canal remains uncertain. Long-term functional studies have been limited by systemic importance of lymphatic genes and lack of Schlemms canal-specific animal models. Here, we designed and validated a strategy using 4OH-tamoxifen-loaded nanocarriers to generate targeted, Schlemms canal specific knockout mice lacking lymphatic phenotypes. Using this system, we selectively deleted Prox1, the master transcription factor governing lymphatic fate. Within four weeks, intraocular pressure significantly increased, and ocular hypertension was maintained for at least 24 weeks. Unlike lymphatic vessels, which degenerate following Prox1 deletion, Schlemms canal reverted to a less functional vein-like phenotype with no change in size or morphology. These results highlight the utility of nanocarriers for tissue-specific genetic recombination and demonstrate that changes in lymphatic phenotypes alter intraocular pressure, providing new targets for glaucoma therapy. Moreover, as we found that PROX1 was downregulated with age in human Schlemms canal, these canal-specific conditional Prox1 knockout mice are a valuable new adult-onset model of ocular hypertension that captures key features of age-related human disease.

physiology↗

bioRxiv2025

eIF2B Selectively Anchors and Activates Mutant KRAS

Much is known about how RAS oncoproteins regulate mRNA translation factors, but the reverse relationship, how translation factors influence RAS activity, has remained largely unexplored. At the plasma membrane (PM), Son of Sevenless (SOS) acts as the canonical guanine nucleotide exchange factor (GEF) for RAS proteins, yet mechanisms governing its specificity for individual RAS isoforms remain unknown. Here, we show that the translation initiation factor eIF2B, best known for its GEF function in translation initiation, forms a distinct complex with SOS and mutant KRAS at the PM, but not with other oncogenic RAS variants. Mechanistically, eIF2B acts as an allosteric regulator of SOS, selectively enhancing GDP-GTP exchange on mutant KRAS. This specificity arises from the translational activity of eIF2B, which upregulates glycosphingolipid (GSL) biosynthesis to remodel PM lipids and preferentially anchor mutant KRAS. Together, our results uncover an unexpected moonlighting function of eIF2B: acting both as a direct activator of SOS and as a regulator of GSL pathway that shapes the membrane landscape, both required for mutant KRAS activation. These insights redefine our understanding of eIF2B and mutant KRAS functions in cancer and have profound implications for KRAS-driven oncogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/686860v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1f50934org.highwire.dtl.DTLVardef@2f55b9org.highwire.dtl.DTLVardef@1a51e39org.highwire.dtl.DTLVardef@1634aac_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIeIF2B interacts with mutant KRAS and SOS at the plasma membrane (PM). C_LIO_LIThe eIF2B:SOS complex promotes the GTP-bound active state of mutant KRAS. C_LIO_LIeIF2B enhances the translation of B4GALT5 mRNA, encoding a key enzyme of glycosphingolipid (GSL) biosynthesis. C_LIO_LIUpregulation of the GSL metabolites, ganglioside GM3 and sulfatide SM4, remodels PM lipid composition to facilitate eIF2B:SOS:KRAS complex formation and mutant KRAS nanoclustering. C_LIO_LIThrough its interaction with SOS and stimulation of GSL synthesis, eIF2B selectively activates mutant KRAS at the PM among RAS isoforms. C_LIO_LIeIF2B is required for the development of mKRAS-driven lung adenocarcinoma in mice. C_LIO_LIeIF2B is a marker of poor prognosis in mutant KRAS-driven cancers. C_LI

cancer biology↗

bioRxiv2025

Brainstem enkephalinergic neural circuit underlying cold-induced pain relief in mice

Application of cold or cold-mimicking chemicals to injury has long been recognized as an effective means of pain relief and is widely utilized in daily life. However, underlying neural mechanisms remain elusive. Here, we identified a cold-responsive neuronal subset within lateral parabrachial nucleus (lPBN), the thermosensory relay region in the hindbrain, that mediates cold-induced analgesia in mice. Selective activation of these neurons and their projection to ventrolateral periaqueductal gray (vlPAG) increased nociceptive threshold via opioid receptor signaling in vlPAG. Conversely, ablation of these neurons attenuated analgesia induced by cold-mimicking chemicals. We further identified that these neurons express precursor gene of enkephalin, which is released into vlPAG for pain relief. Activation of cold-responsive neurons in descending pain modulation circuitry reduced spinal cord responses to noxious stimuli, suggesting the involvement of top-down pain modulation pathway. These findings propose a central mechanism underlying cold-induced pain relief, which could be a novel therapeutic target. TeaserCold-sensitive lPBN neurons release enkephalin into vlPAG for top-down analgesic action during cold-induced pain relief

neuroscience↗

bioRxiv2025

Cell Numbers Contribute to Cell Fate During Ciona Cardiopharyngeal Mesoderm Specification

The Ciona heart cell lineage can be accurately traced back to a pair of blastomeres, the B7.5 cells, that form at the 64-cell stage. In addition to the adult heart, the B7.5 cells also contribute to two tail muscle cells in the larva, as well as the muscles that form the siphons for pumping water for feeding. Because of the simplicity of this system, we have a good understanding of how the B7.5 derivatives are specified during development. However, we know less about how the Ciona embryo precisely regulates cell numbers, as well as what effects altering cell numbers will have on development. We found that cell numbers in the B7.5 lineage are controlled by a pulse of transcription of the cell cycle inhibitor Cdkn1.b. Cdkn1.b can be repressed by the paralogues Prdm1-r.a and Prdm1-r.b that are exclusively transcribed in the B7.5 cells at the 110-cell stage. We unexpectedly found that precocious arrest of cell division in the B7.5 cell lineage resulted in a reversion to tail muscle fate, even in cells that can migrate. Our work demonstrates an unexpected connection between the control of cell numbers and cell fate in development. Significance StatementThe control of cell numbers is essential to many developmental processes, but it has been relatively understudied. A clear example of this can be seen in heart development. Hearts develop from precursor cells called cardiopharyngeal mesoderm. These cells must be able to migrate and proliferate in a precise way or heart defects will occur. We took advantage of the simplicity of embryonic development in the chordate Ciona (an invertebrate closely related to vertebrates) to investigate the consequences of disrupting cell numbers on heart development. Our finding that an early arrest in cell division results in a failure of heart development has implications for similar processes in vertebrates, including humans.

developmental biology↗

bioRxiv2025

Neuropathological Correlates of Apathy Progression in Alzheimer's Disease and Related Dementias: A Longitudinal NACC Cohort Study

ObjectiveApathy is a prevalent and disabling symptom in Alzheimers disease and related dementias, yet its progression across neuropathological subtypes remains incompletely understood. This cohort study investigates longitudinal changes in apathy and their associations with major neuropathologies using data from the National Alzheimers Coordinating Center. MethodsWe analyzed 1,488 participants with autopsy-confirmed neuropathology and at least two caregiver-reported NPI-Q assessments. Generalized linear mixed models were used to assess associations between apathy and six neuropathologies--Alzheimers disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HS), cerebrovascular disease (CVD), and cerebral amyloid angiopathy (CAA). with time modeled as years to death and including interaction terms. Sex-stratified analyses were also conducted. All models were adjusted for age at death, sex, and NPI-Q total score excluding apathy. ResultsApathy prevalence increased over time across all pathology groups. FTLD (OR = 2.11, 95% CI: 1.32-3.39) and HS (OR = 2.23, 95% CI: 1.38-3.60) were consistently associated with higher odds of apathy throughout the disease course. No significant interaction effect was observed in any of the neuropathologies. In sex-stratified analyses, FTLD (OR=2.58, 95% CI 1.40-4.77), HS (OR=2.48, 95% CI 1.29-4.77), and LBD (OR=1.64, 95% CI 1.03-2.61) were significantly associated with apathy in males, while only HS (OR=2.18, 95% CI 1.06-4.47) remained significant in females. InterpretationApathy severity varied by neuropathologies but progressed similarly over time. The elevated burden in FTLD and HS, particularly among males, underscores the importance of stratified approaches to early detection and intervention targeting apathy in ADRDs.

neuroscience↗