Biology subjects

Zhou, J.

Publications and source records attributed to Zhou, J..

At least 289 records · Page 16Linked to original sources

bioRxiv2024

PIKfyve controls dendritic cell function and tumor immunity

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-{kappa}B pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

cancer biology↗

bioRxiv2024

Hachiman is a genome integrity sensor

Hachiman is a broad-spectrum antiphage defense system of unknown function. We show here that Hachiman comprises a heterodimeric nuclease-helicase complex, HamAB. HamA, previously a protein of unknown function, is the effector nuclease. HamB is the sensor helicase. HamB constrains HamA activity during surveillance of intact dsDNA. When the HamAB complex detects DNA damage, HamB helicase activity liberates HamA, unleashing nuclease activity. Hachiman activation degrades all DNA in the cell, creating phantom cells devoid of both phage and host DNA. We demonstrate Hachiman activation in the absence of phage by treatment with DNA-damaging agents, suggesting that Hachiman responds to aberrant DNA states. Phylogenetic similarities between the Hachiman helicase and eukaryotic enzymes suggest this bacterial immune system has been repurposed for diverse functions across all domains of life.

biochemistry↗

bioRxiv2024

The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy

Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. While the role of ubiquitin (Ub) ligase PARKIN in mitophagy has been extensively studied, increasing evidence suggests the existence of PARKIN-independent mitophagy in highly metabolically active organs such as the heart. Here, we identify a crucial role for Cullin-RING Ub ligase 5 (CRL5) in basal mitochondrial turnover in cardiomyocytes. CRL5 is a multi-subunit Ub ligase comprised by the catalytic RING box protein RBX2 (also known as SAG), scaffold protein Cullin 5 (CUL5), and a substrate-recognizing receptor. Analysis of the mitochondrial outer membrane-interacting proteome uncovered a robust association of CRLs with mitochondria. Subcellular fractionation, immunostaining, and immunogold electron microscopy established that RBX2 and Cul5, two core components of CRL5, localizes to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, and increased cell death in cardiomyocytes. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. Notably, the action of RBX2 in mitochondria is not dependent on PARKIN, and PARKIN gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria. Proteomics and biochemical analyses further revealed a global impact of RBX2 deficiency on the mitochondrial proteome and identified several mitochondrial proteins as its putative substrates. These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that controls mitophagy under physiological conditions in a PARKIN-independent, PINK1-dependent manner, thereby regulating cardiac homeostasis.

pathology↗

bioRxiv2024

Inferring Neural Communication Dynamics from Field Potentials Using Graph Diffusion Autoregression

Estimating dynamic functional connectivity (dFC) is attracting increased attention, spurred by rapid advancements in multi-site neural recording technologies and efforts to better understand cognitive processes. Yet, most studies focus on static estimates of functional connectivity that cannot capture highly dynamic neural processes, while also ignoring information about the structural organization of the brain. To address these issues, we introduce a class of network-constrained linear autoregressive models that give rise to a highly dynamic functional connectivity signal on the edges of a predefined structural connectivity graph. Furthermore, we demonstrate that adding an additional diffusion constraint improves the models performance. We successfully validated the resulting graph diffusion autoregressive (GDAR) model on simulated neural activity and recordings from subdural and intracortical micro-electrode arrays placed in macaque sensorimotor cortex demonstrating its ability to describe rapid communication dynamics induced by optogenetic stimulation, changes in resting state dFC following stroke and electrical stimulation, and neural correlates of behavior during a reach task.

neuroscience↗

bioRxiv2024

Genetic evolution analysis of hemagglutinin and neuraminidase genes of H9N2 avian influenza virus in external environment of some areas of Yunnan Province, China from 2020 to 2023

ObjectiveTo understand the molecular characteristics and genetic variation of hemagglutinin (HA) and neuraminidase (NA) genes of H9N2 subtype avian influenza virus (AIV) in the external environment of Yunnan Province, and to provide evidence for the prevention and control of H9N2 subtype AIV in this area. ResultsThe HA and NA genes of 20 isolates belonged to Y280-like sub-branch. The nucleotide and amino acid homology of HA gene were 88.46%-99.81% and 89.08% -99.61%, respectively. The nucleotide and amino acid homology of NA gene were 88.85%-100% and 90.09%-100%, respectively. The HA protein cleavage site of 20 isolates was PSRSSRGLF, which was consistent with the molecular characteristics of low pathogenic avian influenza virus. The 226 th and 228 th positions of the receptor binding site are all L and G, which have the ability to bind to the mammalian sialic acid -2,6 sialic acid receptor; HA protein had 7-8 glycosylation sites, and the main variation was the deletion of one site at 218 and the addition of one glycosylation site at 313 and 491. The main antigenic sites were G90E, S/T145D, D/N153G, A/S/F168N/E, T200R, N/D201G/T mutations. The NA protein neck of 20 isolates lacked 3 amino acids (TEI), which had the molecular characteristics of highly pathogenic avian influenza. NA protein had 6-8 glycosylation sites. The main variation was that two isolates increased a new glycosylation site NPTQ at the 2nd position, and one isolate increased a new glycosylation site NTTI at the 67th position. All isolates lost one site at the 402nd position, and some isolates lost at the 83rd and 365th positions. The amino acids at the active site and key site of NA protease were not mutated, and the isolates did not produce resistance to neuraminidase inhibitors. ConclusionThe HA and NA genes of H9N2 subtype avian influenza virus in Yunnan Province have evolved continuously, but they still belong to the Y280 branch of the Eurasian lineage. Mutations in key sites may cause increased infectivity and transmission. The monitoring of H9N2 subtype avian influenza virus should be strengthened to prevent it from breaking the interspecies barrier and spreading to humans and lower mammals, so as to prevent the outbreak of H9N2 subtype avian influenza.

molecular biology↗

bioRxiv2024

Genetic Studies Highlight the Role of TET2 and INO80 in DNA Damage Response and Kidney Disease Pathogenesis

Genome-wide association studies (GWAS) have identified over 800 loci associated with kidney function, yet the specific genes, variants, and pathways involved remain elusive. By integrating kidney function GWAS, human kidney expression and methylation quantitative trait analyses, we identified Ten-Eleven Translocation (TET) DNA demethylase 2: TET2 as a novel kidney disease risk gene. Utilizing single-cell chromatin accessibility and CRISPR-based genome editing, we highlight GWAS variants that influence TET2 expression in kidney proximal tubule cells. Experiments using kidney-tubule-specific Tet2 knockout mice indicated its protective role in cisplatin-induced acute kidney injury, as well as chronic kidney disease and fibrosis, induced by unilateral ureteral obstruction or adenine diet. Single-cell gene profiling of kidneys from Tet2 knockout mice and TET2-knock-down tubule cells revealed the altered expression of DNA damage repair and chromosome segregation genes, notably including INO80, another kidney function GWAS target gene itself. Remarkably both TET2-null and INO80-null cells exhibited an increased accumulation of micronuclei after injury, leading to the activation of cytosolic nucleotide sensor cGAS-STING. Genetic deletion of cGAS or STING in kidney tubules or pharmacological inhibition of STING protected TET2 null mice from disease development. In conclusion, our findings highlight TET2 and INO80 as key genes in the pathogenesis of kidney diseases, indicating the importance of DNA damage repair mechanisms.

genetics↗

bioRxiv2024

Regional specialization manifests in the reliability of neural population codes

The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1-3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4-6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9 and learning from2,7,9-12 the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13-20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.

neuroscience↗

bioRxiv2024

scMeFormer: a transformer-based deep learning model for imputing DNA methylation states in single cells enhances the detection of epigenetic alterations in schizophrenia

DNA methylation (DNAm), a crucial epigenetic mark, plays a key role in gene regulation, mammalian development, and various human diseases. Single-cell technologies enable the profiling of DNAm states at cytosines within the DNA sequence of individual cells, but they often suffer from limited coverage of CpG sites. In this study, we introduce scMeFormer, a transformer-based deep learning model designed to impute DNAm states for each CpG site in single cells. Through comprehensive evaluations, we demonstrate the superior performance of scMeFormer compared to alternative models across four single-nucleus DNAm datasets generated by distinct technologies. Remarkably, scMeFormer exhibits high-fidelity imputation, even when dealing with significantly reduced coverage, as low as 10% of the original CpG sites. Furthermore, we applied scMeFormer to a single-nucleus DNAm dataset generated from the prefrontal cortex of four schizophrenia patients and four neurotypical controls. This enabled the identification of thousands of differentially methylated regions associated with schizophrenia that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia within specific cell types. Our study highlights the power of deep learning in imputing DNAm states in single cells, and we expect scMeFormer to be a valuable tool for single-cell DNAm studies.

genomics↗

bioRxiv2024

Deep learning predicts DNA methylation regulatory variants in specific brain cell types and enhances fine mapping for brain disorders

DNA methylation (DNAm) is essential for brain development and function and potentially mediates the effects of genetic risk variants underlying brain disorders. We present INTERACT, a transformer-based deep learning model to predict regulatory variants impacting DNAm levels in specific brain cell types, leveraging existing single-nucleus DNAm data from the human brain. We show that INTERACT accurately predicts cell type-specific DNAm profiles, achieving an average area under the Receiver Operating Characteristic curve of 0.98 across cell types. Furthermore, INTERACT predicts cell type-specific DNAm regulatory variants, which reflect cellular context and enrich the heritability of brain-related traits in relevant cell types. Importantly, we demonstrate that incorporating predicted variant effects and DNAm levels of CpG sites enhances the fine mapping for three brain disorders--schizophrenia, depression, and Alzheimers disease--and facilitates mapping causal genes to particular cell types. Our study highlights the power of deep learning in identifying cell type-specific regulatory variants, which will enhance our understanding of the genetics of complex traits. TeaserDeep learning reveals genetic variations impacting brain cell type-specific DNA methylation and illuminates genetic bases of brain disorders

genetics↗

bioRxiv2024

Estrogen receptor-related receptor (Esrra) induces ribosomal protein Rplp1-mediated adaptive hepatic translation during prolonged starvation

Protein translation is an energy-intensive ribosome-driven process that is reduced during nutrient scarcity to conserve cellular resources. During prolonged starvation, cells selectively translate specific proteins to enhance their survival (adaptive translation); however, this process is poorly understood. Accordingly, we analyzed protein translation and mRNA transcription by multiple methods in vitro and in vivo to investigate adaptive hepatic translation during starvation. While acute starvation suppressed protein translation in general, proteomic analysis showed that prolonged starvation selectively induced translation of lysosome and autolysosome proteins. Significantly, the expression of the orphan nuclear receptor, estrogen-related receptor alpha (Esrra) increased during prolonged starvation and served as a master regulator of this adaptive translation by transcriptionally stimulating 60S acidic ribosomal protein P1 (Rplp1) gene expression. Overexpression or siRNA knockdown of Esrra expression in vitro or in vivo led to parallel changes in Rplp1 gene expression, lysosome/autophagy protein translation, and autophagy. Remarkably, we have found that Esrra had dual functions by not only regulating transcription but also controling adaptive translation via the Esrra/Rplp1/lysosome/autophagy pathway during prolonged starvation.

molecular biology↗

bioRxiv2024

Aberrant non-canonical NF-kappaB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-{kappa}B pathway to nurture their survival while they accumulate pro- proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-{kappa}B activation. Here, we find that sustained NF-{kappa}B/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis- regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-{kappa}B signalling potentiates transcriptional programs beneficial for multiple myeloma progression.

cancer biology↗

bioRxiv2023

Early Intervention with Electrical Stimulation Reduces Neural Damage After Stroke in Non-human Primates

Ischemic stroke is a neurological condition that results in significant mortality and long-term disability for adults, creating huge health burdens worldwide. For stroke patients, acute intervention offers the most critical therapeutic opportunity as it can reduce irreversible tissue injury and improve functional outcomes. However, currently available treatments within the acute window are highly limited. Although emerging neuromodulation therapies have been tested for chronic stroke patients, acute stimulation is rarely studied due to the risk of causing adverse effects related to ischemia-induced electrical instability. To address this gap, we combined electrophysiology and histology tools to investigate the effects of acute electrical stimulation on ischemic neural damage in non-human primates. Specifically, we induced photothrombotic lesions in the monkey sensorimotor cortex while collecting electrocorticography (ECoG) signals through a customized neural interface. Gamma activity in ECoG was used as an electrophysiological marker to track the effects of stimulation on neural activation. Meanwhile, histological analysis including Nissl, cFos, and microglial staining was performed to evaluate the tissue response to ischemic injury. Comparing stimulated monkeys to controls, we found that theta-burst stimulation administered directly adjacent to the ischemic infarct at 1 hour post-stroke briefly inhibits peri-infarct neuronal activation as reflected by decreased ECoG gamma power and cFos expression. Meanwhile, lower microglial activation and smaller lesion volumes were observed in animals receiving post-stroke stimulation. Together, these results suggest that acute electrical stimulation can be used safely and effectively as an early stroke intervention to reduce excitotoxicity and inflammation, thus mitigating neural damage and enhancing stroke outcomes.

neuroscience↗

bioRxiv2023

AVM: a manually curated database of aerosol-transmitted virus mutations, human diseases, and drugs

Aerosol-transmitted viruses, with aerosol particles floating in the air to long distances, have the characteristics of strong infectivity and wide spread that is difficult to control. They cause various human diseases, posing a huge threat to human health. Some mutations can increase the transmissibility and virulence of the strain, which can reduce the protection of vaccines and weaken efficacy of antiviral drugs. Here, we established a manually curated database, AVM, to store this information. The current version of the AVM contains a total of 42,041 virus mutations, including 2613 immune escape mutations, 45 clinical information datasets, and 407 drugs, antibodies, or vaccines. In addition, we recorded 88 human diseases associated with viruses, and we found that the same virus can attack multiple target organs in the body and lead to diversified diseases. Further, the AVM database offers a straightforward user interface to expediently browse, retrieve, and download details. The AVM database is a comprehensive resource that provides timely and valuable assistance regarding the transmission, treatment, and related diseases of aerosol-transmitted viruses (http://bio-bigdata.hrbmu.edu.cn/AVM or http://www.bio-bigdata.center/AVM).

bioinformatics↗

bioRxiv2023

The ULK1 effector BAG2 regulates autophagy initiation by modulating AMBRA1 localization

Canonical autophagy is regulated by ULK1, the most proximal protein kinase specifically regulating autophagy initiation. To gain new insights into functions of the ULK1 holo-complex in autophagy regulation, we generated a deep ULK1 complex interactome by combining affinity purification- and proximity labelling-mass spectrometry of all four ULK1 complex members: ULK1, ATG13, ATG101 and RB1CC1/FIP200. Under starvation conditions, the ULK1 complex interacts with several protein and lipid kinases and phosphatases implying the formation of a signalosome. Interestingly, also several selective autophagy receptors interact with ULK1 indicating the activation of selective autophagy pathways by nutrient starvation. One effector of the ULK1 complex is the HSC/HSP70 co-chaperone BAG2, which regulates the subcellular localization of the VPS34 lipid kinase complex member AMBRA1. Depending on the nutritional status, BAG2 has opposing roles. In growth promoting conditions, the unphosphorylated form of BAG2 sequesters AMBRA1, attenuating autophagy induction. In starvation conditions, ULK1 phosphorylates BAG2 on Ser31, supporting its recruitment to the ER membrane and positively affecting autophagy flux.

cell biology↗

bioRxiv2023

Transfer of disulfide bond formation modules via yeast artificial chromosomes promotes the expression of heterologous proteins in Kluyveromyces marxianus

Kluyveromyces marxianus is a food-safe yeast with great potential for producing heterologous proteins. Improving the yield in K. marxianus remains a challenge, while incorporating large-scale functional modules poses a technical obstacle in engineering. To address these issues, linear and circular yeast artificial chromosomes of K. marxianus (KmYACs) were constructed and loaded with disulfide bond formation modules from Pichia pastoris or K. marxianus. These modules contained up to 7 genes with a maximum size of 15 kb. KmYACs carried telomeres either from K. marxianus or Tetrahymena. KmYACs were transferred successfully into K. marxianus and stably propagated without affecting the normal growth of the host, regardless of the type of telomeres and configurations of KmYACs. KmYACs increased the overall expressions of disulfide bond formation genes and significantly enhanced the yield of various heterologous proteins. In high-density fermentation, the use of KmYACs resulted in a glucoamylase yield of 16.8 g/L, the highest reported level to date in K. marxianus. Transcriptomic and metabolomic analysis of cells containing KmYACs suggested increased FAD biosynthesis, enhanced flux entering the TCA cycle and a preferred demand for lysine and arginine as features of cells overexpressing heterologous proteins. Consistently, supplementing lysine or arginine further improved the yield. Therefore, KmYAC provides a powerful platform for manipulating large modules with enormous potential for industrial applications and fundamental research. Transferring the disulfide bond formation module via YACs proves to be an efficient strategy for improving the yield of heterologous proteins, and this strategy may be applied to optimize other microbial cell factories. Impact StatementIn this study, yeast artificial chromosomes of K. marxianus (KmYACs) were constructed and successfully incorporating modules for large-scale disulfide bond formation. KmYACs were stably propagated in K. marxianus without compromising the normal growth of the host, irrespective of the selection of telomeres (either Tetrahymena or K. marxianus) and configuration (either linear or circular). KmYACs notably enhanced the expressions of various heterologous proteins, with further yield improvement by supplementing lysine or arginine in the medium. Our findings affirm KmYAC as a robust and versatile platform for transferring large-scale function modules, demonstrating immense potential for both industrial applications and fundamental research.

synthetic biology↗

bioRxiv2023

AP-1 regulates heterogeneous cellular dormancy in TNBC

BackgroundDormant or slow cycling cells (SSCs) pre-exist in tumor and responsible for chemo-resistant and tumor recurrence. Due to their low differentiation and dormancy characteristics, SCCs are resistant to standard chemotherapy and targeted therapy. Label-retaining is a common method used to identify and isolate live SCCs. However, it remains unclear whether different label-retaining methods yield distinct SCC subpopulations. In this study, we investigated that various label-retaining methods result in overlapping yet heterogeneous subpopulations of SCCs. Additionally, we explored the molecular mechanisms regulating dormancy in triple-negative breast cancer (TNBC). MethodsWe employed multiple label-retaining methods to simultaneously label MDA-MB-231 cells, thereby generating distinct subpopulations of SCCs. We subsequently analyzed these subpopulations for heterogeneity in cell cycle distribution, drug resistance, invasive capacity, and other characteristics using real-time PCR, flow cytometry, and Transwell assays. RNA-seq analysis was performed to characterize the gene expression profiles of the SCCs. Furthermore, we used real-time PCR, Western blotting, immunofluorescence, and luciferase assays to investigate the role of characteristic AP-1 expression in dormancy regulation. Finally, the therapeutic effects of targeting AP-1 in the treatment of TNBC were assessed using a cell-derived xenograft model. ResultsWe labeled and separated three overlapping but non-identical SCCs subpopulations. We found that all three SCCs subgroups are cell cycle arrested. Additionally, Violet enriched SCCs showed stronger drug resistance and more G1 phase arrest, while Claret enriched SCCs demonstrated enhanced migratory and invasive abilities, along with more G2/M phase arrest. Furthermore, we observed upregulation of AP-1 expression in SCCs, and the JunB subunit of AP-1 promoted the expression of CDKN1A and GADD45A, thereby maintaining cell cycle arrest. CC-930 can inhibit AP-1 transcriptional activity by suppressing JNK activity, ultimately improving the therapeutic efficacy and prognosis of TNBC when used in combination with chemotherapy drugs. ConclusionsWe obtained three subpopulations of SCCs with heterogeneous drug resistance. Our findings suggest that AP-1 plays a regulatory role in dormancy regulation in TNBC, and elucidated the molecular function of JunB subunit. Targeting AP-1 with CC-930 has the potential to improve the treatment and prognosis of TNBC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/566980v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@129ce76org.highwire.dtl.DTLVardef@1b1cfa1org.highwire.dtl.DTLVardef@b68315org.highwire.dtl.DTLVardef@57faf1_HPS_FORMAT_FIGEXP M_FIG C_FIG TNBC harbors both fast-cycling cells (FCCs) and functionally overlapping slow-cycling cell (SCC) subpopulations that manifest differential drug sensitivities and motility (A) but are commonly regulated by the JunB-containing AP1 complex (B). (A). Slow-cycling (quiescent) TNBC cells in culture (a) identified by different label-retaining approaches phenotypically overlap (b), display differential drug sensitivities (c, d) and motility (e) but share common gene expression profiles (f). (B). Schematic depicting regulation of proliferation in FCCs by the c-Jun/c-Fos AP1 complex (left) and regulation of cellular dormancy in SCCs by c-Jun/JunB AP1 complex.

cancer biology↗

bioRxiv2023

Comparing neural models using their perceptual discriminability predictions

Internal representations are not uniquely identifiable from perceptual measurements: different representations can generate identical perceptual predictions, and similar representations may predict dissimilar percepts. Here, we generalize a previous method ("Eigendistortions" - Berardino et al., 2017) to enable comparison of models based on their metric tensors, which can be verified perceptually. Metric tensors characterize sensitivity to stimulus perturbations, reflecting both the geometric and stochastic properties of the representation, and providing an explicit prediction of perceptual discriminability. Brute force comparison of model-predicted metric tensors would require estimation of human perceptual thresholds along an infeasibly large set of stimulus directions. To circumvent this "perceptual curse of dimensionality", we compute and measure discrimination capabilities for a small set of most-informative perturbations, reducing the measurement cost from thousands of hours (a conservative estimate) to a single trial. We show that this single measurement, made for a variety of different test stimuli, is sufficient to differentiate models, select models that better match human perception, or generate new models that combine the advantages of existing models. We demonstrate the power of this method in comparison of (1) two models for trichromatic color representation, with differing internal noise; and (2) two autoencoders trained with different regularizers.

neuroscience↗

bioRxiv2023

Aberrant splicing exonizes C9ORF72 repeat expansion in ALS/FTD

A nucleotide repeat expansion (NRE) in the first annotated intron of the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. C9ORF72 aberrant splicing was substantially elevated in both C9 NRE+ motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.

neuroscience↗