Biology subjects

Li, A.

Publications and source records attributed to Li, A..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis

Copious expression of protein arginine methyltransferase 1 (PRMT1) is associated with poor survival in many types of cancers, including acute myeloid leukemia. We observed that a specific acute megakaryocytic leukemia (AMKL) cell line (6133) derived from RBM15-MKL1 knock-in mice exhibited heterogeneity in Prmt1 expression levels. Interestingly, only a subpopulation of 6133 cells expressing high levels of Prmt1 caused leukemia when transplanted into congenic mice. The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia. Seahorse analysis revealed that PRMT1 increased the extracellular acidification rate (ECAR) and decreased the oxygen consumption rate (OCR). Consistently, PRMT1 accelerated glucose consumption and led to the accumulation of lactic acid in the leukemia cells. The metabolomic analysis supported that PRMT1 stimulated the intracellular accumulation of lipids, which was further validated by FACS analysis with BODIPY 493/503. In line with fatty acid accumulation, PRMT1 downregulated the protein level of CPT1A, which is involved in the rate-limiting step of fatty acid oxidation. Furthermore, administering the glucose analogue 2-deoxy-glucose (2-DG) delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/628174v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ae96borg.highwire.dtl.DTLVardef@d27916org.highwire.dtl.DTLVardef@ba63corg.highwire.dtl.DTLVardef@cee9af_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Microbial functional guilds and genes are key to explaining soil nutrient cycling alongside soil and plant variables

Microbes play central roles in soil nutrient cycling, yet a limited range of microbial community characteristics have been used to explain ecosystem nutrient cycling rates and their importance relative to plant and abiotic factors remains unclear. In this study, we assessed which of 126 commonly measured soil fungal and bacterial community characteristics best explained soil nitrogen (N) and phosphorus (P) cycling rates in temperate forests in the Northeastern U.S., as well as the relative contributions of microbial, plant, and abiotic factors. Using boosted regression tree modeling, we identified the microbial variables with the highest contributions to models explaining nutrient cycling rates: the relative abundances of ectomycorrhizal fungi and N-decomposition genes from oligotrophic bacteria were the most important for net ammonification, the relative abundances of indicator taxa in bacterial networks, nitrifying bacteria, and copiotrophic bacteria were the most important for net nitrification, and the relative abundance of fungal P-cycling oxidoreductase genes was the most important for net soil phosphate change. Microbial variables explained more variation than plant and abiotic variables in multivariate linear models of net nitrification and net phosphate release rates, but not net ammonification rates, which were largely explained by soil edaphic factors. Leaf litter traits were also important in explaining variation in net nitrification rates, and soil temperature was important in explaining rates of net phosphate release in soil. Collectively, our findings suggest that the N-cycling capacity of microbial functional guilds and fungal community P-cycling capacity should be incorporated into ecosystem biogeochemical models to improve our predictions and understanding of nutrient cycling and related ecological processes.

ecology↗

bioRxiv2024

Structures of the human adult muscle-type nicotinic receptor in resting and desensitised states

Muscle-type nicotinic acetylcholine receptor (AChR) is the key signalling molecule in neuromuscular junctions. Here we present the structures of full-length human adult receptors in complex with Fab35 in -bungarotoxin (BuTx)-bound resting states, and in acetylcholine (ACh)-bound desensitised states. In addition to identifying the conformational changes during recovery from desensitisation, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in congenital myasthenic syndrome (CMS) patients, revealing they cause either slow- or fast-channel CMS characterised by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both AChR state transition and the pathogenic mechanisms of disease variants.

neuroscience↗

bioRxiv2024

In Search of Transcriptomic Correlates of Neuronal Firing-Rate Adaptation across Subtypes, Regions and Species: A Patch-seq Analysis

Can the transcriptomic profile of a neuron predict its physiological properties? Using a Patch-seq dataset of the primary visual cortex, we addressed this question by focusing on spike rate adaptation (SRA), a well-known phenomenon that depends on small conductance calcium (Ca)-dependent potassium (SK) channels. We first show that in parvalbumin-expressing (PV) and somatostatin-expressing (SST) interneurons, expression levels of genes encoding the ion channels underlying action potential generation are correlated with the half-width (HW) of spikes. Surprisingly, the SK encoding genes are not correlated with the degree of SRA (dAdap). Instead, genes that encode proteins upstream from the SK current, as well as the low-voltage-activated Calcium channel, are correlated with dAdap. This general principle is supported by datasets from the mouse primary motor cortex and multiple macaque brain regions. Finally, we generate testable predictions by constructing a minimal model.

neuroscience↗

bioRxiv2024

ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression

Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression, and exploring the underlying molecular nature may offer significant therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis, and Aldh3a1 is an inactivation-resistant intracellular aldehyde dehydrogenase that detoxifies 4-HNE to protect eyes against UV-induced oxidative stress. We detected prominently higher levels of Aldh3a1 in mouse EOMs compared to other muscles under normal physiological conditions. In an ALS mouse model (hSOD1G93A) reaching end-stage, Aldh3a1 expression was maintained high in EOMs, substantially elevated in soleus and diaphragm, but only moderately increased in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling, as demonstrated by unparalleled upregulation of a denervation marker Ankrd1. Importantly, sciatic nerve transection in wildtype mice further confirmed induced Aldh3a1 and Ankrd1 expression in an inverse manner across muscle types in response to denervation. Mechanistically, whole-muscle RNA-Seq and pharmacological tests indicate that higher basal levels of lipid oxidation in soleus and diaphragm muscles may predispose them to stronger Nrf2 antioxidant responses under pathological stress compared to EDL, leading to more prominent Aldh3a1 upregulation. Additionally, the identification of the myoblast fusion marker Mymk as an EOM signature gene suggests that the spontaneous activation of satellite cells contributes to high levels of Aldh3a1 in EOMs. Functionally, adeno-associated virus-mediated overexpression of Aldh3a1 protected myotubes from 4-HNE-induced DNA fragmentation and plasma membrane leakage. It also restored MG53-mediated membrane repair, highlighting its potential for clinical applications.

cell biology↗

bioRxiv2024

Towards optimizing diversifying base editors for high-throughput studies of single-nucleotide variants

Determining the phenotypic effects of single nucleotide variants is critical for understanding the genome and interpreting clinical sequencing results. Base editors, including diversifying base editors that create C>N mutations, are potent tools for installing point mutations in mammalian genomes and studying their effect on cellular function. Numerous base editor options are available for such studies, but little information exists on how the composition of the editor (deaminase, recruitment method, and fusion architecture) affects editing. To address this knowledge gap, the effect of various design features, such as deaminase recruitment and delivery method (electroporation or lentiviral transduction), on editing was assessed across [~]200 synthetic target sites. The direct fusion of a hyperactive variant of activation-induced cytidine deaminase to the N-terminus of dCas9 (DivA-BE) produced the highest editing efficiency, [~]4-fold better than the previous CRISPR-X method. Additionally, DivA-BE mutagenized the DNA strand that anneals to the targeting sgRNA to create G>N mutations, which were absent when the deaminase was fused to the C-terminus of dCas9. The DivA-BE editors efficiently diversified their target sites, an ideal characteristic for discovering functional variants. These and other findings provide a comprehensive analysis of how design features influence the activity of several popular base editors.

genomics↗

bioRxiv2024

C3aR1 on β cells enhances β cell function and survival

Pancreatic {beta} cell dysfunction is critical to the development of type 2 diabetes (T2D). We show that the complement receptor C3aR1 on {beta} cells plays an essential role in maintaining {beta} cell homeostasis, especially under the metabolic duress of obesity and T2D. Mice with {beta} cell specific deletion of C3ar1 have worse glucose tolerance, lower insulin levels, and decreased {beta} cell mass. Islets from {beta} cell specific C3ar1 knockout ({beta}-C3aR1 KO) mice demonstrate impaired insulin secretion. Disruption of C3ar1 on {beta} cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and {beta} cell-derived C3aR1. Markers of {beta} cell identity were decreased while stress markers were increased in {beta}-C3aR1 KO mice. Islets from {beta}-C3aR1 KO also exhibit increased {beta} cell death to lipotoxicity. Finally, we show that C3AR1 is positively correlated with insulin secretion in human islets. These findings indicate that C3aR1 expression on {beta} cells is necessary to maintain optimal {beta} cell function and preserve {beta} cell mass in T2D.

physiology↗

bioRxiv2024

Prediction of context-specific regulatory programs and pathways using interpretable deep learning

Variational autoencoders (VAEs) are being widely adopted for the analysis of single-cell RNA sequencing (scRNA-seq) data. As with any non-linear models, however, they lack interpretability, which is a crucial aspect in the biomedical field where researchers want to be able to trust their model predictions. Our previously developed OntoVAE model addressed this issue by integrating biological ontologies in the decoder, which made the neuronal activations correspond to pathway activities. However, when multiple covariates are present, disentangling their relative contributions is challenging. To address this limitation, we developed COBRA, a VAE tool that combines the interpretable decoder part of OntoVAE with an adversarial approach that separates covariate effects in the latent space. In this work, we demonstrate the use of COBRA on two different scRNA-seq datasets in different contexts. We applied the tool to an interferon stimulated mouse dataset to separate the effects of celltype and treatment on transcription factors and biological pathways. We furthermore showed how COBRA can be used to predict the state of unseen celltypes.

bioinformatics↗

bioRxiv2024

m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome

Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and loss of the FMRP protein. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP is known to bind to and regulate the stability of m6A-containing transcripts. However, how loss of FMRP impacts on transcriptome-wide m6A modifications in FXS patients remains unknown. To answer this question, we generated cortical neurons differentiated from induced pluripotent stem cells (iPSC) derived from healthy subjects and FXS patients. In electrophysiology recordings, we validated that synaptic and neuronal network defects in iPSC-derived FXS neurons corresponded to the clinical EEG data of the patients from which the corresponding iPSC line was derived. In analysis of transcriptome-wide methylation, we show that FMRP deficiency led to increased translation of m6A writers, resulting in hypermethylation that primarily affecting synapse-associated transcripts and increased mRNA decay. Conversely, in the presence of an m6A writer inhibitor, synaptic defects in FXS neurons were rescued. Taken together, our findings uncover that an FMRP-dependent epi-transcriptomic mechanism contributes to FXS pathogenesis by disrupting m6A modifications in FXS, suggesting a promising avenue for m6A- targeted therapies.

neuroscience↗

bioRxiv2024

Tetanizing wakeful consolidation: ten-hertz repetitive visual stimulation enhances the offline gain of visual learning

Consolidation of encoded information is vital for learning and memory, often explored during sleep. However, the consolidation during post-encoding offline wakefulness remains largely uncharted, especially regarding its modulation and brain mechanisms. Here, we unraveled frequency-dependent modulatory effects of repetitive visual stimulation (RVS) on wakeful consolidation of visual learning and investigated the underlying neural substrates. After training on an orientation discrimination task, exposure to 10-Hz grating-form RVS enhanced, while 1-Hz RVS deteriorated, the discrimination performance in a subsequent retest. However, 10-Hz uniform-disk RVS failed to facilitate wakeful consolidation, suggesting that alpha entrainment alone was not the facilitative mechanism. Using neuroimaging of multiple modalities, we observed augmented event-related potential and heightened neural excitation in the early visual cortex after 10-Hz grating-form RVS, implying an involvement of long-term potentiation-like (LTP-like) plasticity. Collectively, we provide a new photic method for modulating the offline processing of encoded sensory information and suggest a role of sensory tetanization in the modulation.

neuroscience↗

bioRxiv2024

Putting computational models of immunity to the test - an invited challenge to predict B. pertussis vaccination outcomes

Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.

immunology↗

bioRxiv2024

Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma

PurposeAdenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental DesignWe leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-{psi} or a STING agonist. ResultsmIF demonstrated that ACC tumors are immunologically cold, with few tumor- infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-{psi} or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression. ConclusionsLow/absent HLA/B2M expression may explain ACC tumors immunologically cold status and lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.

cancer biology↗

bioRxiv2024

The KU70-SAP domain has an overlapping function with DNA-PKcs in limiting the lateral movement of KU along DNA

The non-homologous end-joining (NHEJ) pathway is critical for DNA double-strand break repair and is essential for lymphocyte development and maturation. The Ku70/Ku80 heterodimer (KU) binds to DNA ends, initiating NHEJ and recruiting additional factors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that caps the ends and pushes KU inward. The C-terminus of Ku70 in higher eukaryotes includes a flexible linker and a SAP domain, whose physiological role remains poorly understood. To investigate this, we generated a mouse model with knock-in deletion of the SAP domain (Ku70{Delta}SAP/{Delta}SAP). Ku70{Delta}SAP supports KU stability and its recruitment to DNA damage sites in vivo. In contrast to the growth retardation and immunodeficiency seen in Ku70-/- mice, Ku70{Delta}SAP/{Delta}SAP mice show no defects in lymphocyte development and maturation. Structural modeling of KU on long dsDNA, but not dsRNA suggests that the SAP domain can bind to an adjacent major groove, where it can limit KUs rotation and lateral movement along the dsDNA. Accordingly, in the absence of DNA-PKcs that caps the ends, Ku70{Delta}SAP fails to support stable DNA damage-induced KU foci. In DNA-PKcs-/- mice, Ku70{Delta}SAP abrogates the leaky T cell development and reduces both the qualitative and quantitative aspects of residual V(D)J recombination. In the absence of DNA-PKcs, purified Ku70{Delta}SAP has reduced affinity for DNA ends and dissociates more readily at lower concentration and accumulated as multimers at high concentration. These findings revealed a physiological role of the SAP domain in NHEJ by restricting KU rotation and lateral movement on DNA that is largely masked by DNA-PKcs. HighlightKu70 is a conserved non-homologous end-joining (NHEJ) factor. Using genetically engineered mouse models and biochemical analyses, our study uncovered a previously unappreciated role of the C-terminal SAP domain of Ku70 in limiting the lateral movement of KU on DNA ends and ensuring end protection. The presence of DNA-PKcs partially masks this role of the SAP domain.

genetics↗

bioRxiv2024

Compressed higher-order structures facilitate human knowledge network learning

Humans naturally seek knowledge, yet integrating vast, fragmented information remains challenging. Traditionally, knowledge acquisition has relied on random walks within network--an unguided and inefficient process. We introduce compressive learning, a framework that embeds higher-order structural features--specifically node-degree inhomogeneity--into pre-learning trajectories to scaffold more efficient learning. Across two large-scale experiments, we demonstrate that scale-free networks--due to their pronounced node-degree inhomogeneity--are more compressible and learnable than other network types, and confirm the efficacy of the compressive learning approach. Magnetoencephalography (MEG) recordings reveal that compressive pre-learning enhances structured neural representations in the dorsal anterior cingulate cortex (ACC). A hypergraph-based two-stage model further reveals that compressive learning constructs a network skeleton of hyperedge-defined substructures that more effectively accommodate new inputs. Together, our results highlight the central role of higher-order network structure in human learning and offer a strategic approach to effectively "connect the dots."

neuroscience↗

bioRxiv2024

Longevity or Well-being? A Dual-Dimension Structure of Neuroticism

The development of personality traits is often viewed as evolutionarily adaptive. Current neuroticism research, however, predominantly highlights its negative health impacts, neglecting its potential evolutionary advantages. We propose that neuroticisms inter-individual variability can be structured into two distinct geometric dimensions. One, named the Emotional Reactivity-Instability/Distress Spectrum (ERIS), correlates strongly with longevity and is associated with chronic diseases and risk-averse lifestyle. This dimension is underpinned by evolutionarily conserved subcortical brain regions and genes. The other, resembling the overall neuroticism score, is primarily linked to mental and stress-related disorders, as well as life satisfaction. It involves higher-order emotional brain regions and is genetically enriched in human-accelerated regions. Collectively, these dimensions represent a dual-strategy personality framework that optimizes survival and well-being, with the former being evolutionarily conservative and the latter potentially a unique human adaptation.

neuroscience↗

bioRxiv2024

SlNAP2 promoted fruit ripening by directly binding the ACS2 promoter and interacting with EIL3

The ripening process of tomato fruit is affected by a variety of environmental factors and genetic regulators. NAC transcription factors (TFs) function in a multitude of biological processes, while the current knowledge on the participation of NAC TFs in the regulatory network of fruit ripening is relatively limited. In this study, we isolated a NAC TFs, NAP2, which acts as a positive transcription activator in tomato fruit ripening. We also observed a notable delay in the ripening process of SlNAP2 silenced and knockout mutant fruit. In particular, ethylene production was obviously inhibited in SlNAP2 mutant fruit. Y1H and DLR assays showed that SlNAP2 directly binds to the promoter of SlACS2 and activates its transcriptional activity. Furthermore, SlNAP2 and SlEIL3 physically interaction was demonstrated by yeast two-hybrid (Y2H), luciferase complementation (LUC), bimolecular fluorescence complementation (BiFC) and coimmunoprecipitation analysis (CoIP) assays. Meanwhile, the pigment content, firmness and the transcript levels of genes associated with carotenoid and chlorophyll metabolism and cell wall metabolism were also potentially affected by the SlNAP2 deletion; however, it has remained unclear whether these genes are also directly regulated by SlNAP2. Therefore, our findings indicate that SlNAP2 directly binds to SlACS2 promoter to activate its expression and promote ethylene generation, which in turn interacts with EIL3 to enhance the function of ethylene in tomato fruit ripening. Collectively, our data contribute to understanding the interaction of NAC TFs and ethylene in tomato fruit ripening, thereby enhancing our knowledge of the ripening regulatory network that governs tomato fruit maturation.

biochemistry↗

bioRxiv2024

The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1

INTRODUCTIONThough recognized as a potential cause of Autosomal Dominant Alzheimers Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared A{beta} production across all missense PSEN2 variants in the Alzforum database and, when possible, to corresponding PSEN1 variants. METHODSWe expressed 74 PSEN2 variants, 21 of which had homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. A{beta} production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. RESULTSA{beta}42/40 and A{beta}37/42 ratios were associated with AAO across PSEN2 variants, strongly driven by PSEN2 variants with PSEN1 homologs. PSEN2 AAO was 18.3 years later compared to PSEN1 homologs. A{beta} ratios from PSEN1/2 homologs were highly correlated, suggesting a similar mechanism of {gamma}-secretase dysfunction. DISCUSSIONThe existence of a PSEN1 homolog and patterns of A{beta} production are important considerations in assessing the pathogenicity of previously-reported and new PSEN2 variants.

neuroscience↗

bioRxiv2024

Mapping Individual Differences in the Topological Landscape of Naturalistic Brain Dynamics

Psychiatry seeks to unravel brain dysfunction and individual differences in real-world contexts. Naturalistic stimuli, like movie watching, are increasingly recognized for eliciting complex, context-dependent neural activity with high ecological validity. Yet, current methods often rely on standard paradigms that average data across time, limiting the full potential of such stimuli. Here, we present STIM, a Topological Data Analysis-based framework designed to dynamically track how individuals integrate complex contexts in real time. Applied to large-sample fMRI data from movie watching, STIM constructs a robust low-dimensional dynamical landscape that reflects group consensus while probing individual variations at both global (spanning narratives) and local (within specific narratives) levels. At the global level, individual differences emerge along a center-periphery gradient in the dynamical landscape, which significantly predicts fluid intelligence, underscoring the importance of neural adaptability and diversity. At finer scales, local geometric features correlate with context-specific psychological traits beyond cognition. STIM also captures developmental changes in the dynamical landscape and reveals abnormalities in conditions such as autism. These findings demonstrate that STIM leverages the rich information from movie stimuli and fMRI recordings as neural probes to assess individual differences in cognition and mental health.

neuroscience↗