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Huang, S.

Publications and source records attributed to Huang, S..

At least 163 records · Page 9Linked to original sources

Instruction-tuned large language models misalign with natural language comprehension in humans

Transformer-based large language models (LLMs) have significantly advanced our understanding of meaning representation in the human brain. However, increasingly large LLMs have been questioned as valid cognitive models due to their extensive training data and their ability to access context thousands of words long. In this study, we investigated whether instruction tuning, another core technique in recent LLMs beyond mere scaling, can enhance models ability to capture linguistic information in the human brain. We evaluated the self-attention of base and fine-tuned LLMs of different sizes against human eye movement and functional magnetic resonance imaging (fMRI) activity patterns during naturalistic reading. We show that scaling has a greater impact than instruction tuning on model-brain alignment, reinforcing the scaling law in brain encoding performance. These finding have significant implications for understanding the cognitive plausibility of LLMs and their role in studying naturalistic language comprehension.

neuroscience↗

Transcriptomic analysis of the functions of CSF1R-dependent macrophages in postnatal development in the rat

Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the Csf1r gene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type and Csf1rko rats at weaning and selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/c genes). Circulating C1Q was almost undetectable in Csf1rko rats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss in Csf1rko rats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks, Csf1rko rats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.

immunology↗

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↗

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the telencephalic interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic interneurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

neuroscience↗

Cognitive hyperplasticity drives insomnia

Sleep is vital for maintenance of cognitive functions and lifespan across the animal kingdom. Here, we report our surprising findings that insomniac (inc) Drosophila short sleep mutants, which lack a crucial adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited excessive olfactory memory. Through a genetic modifier screen, we find that a mild attenuation of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes of inc mutants. Surprisingly, this mild PKA signaling reduction further boosted the excessive memory in inc mutants, coupled with further exaggerated mushroom body overgrowth phenotypes. We propose that an intrinsic hyperplasticity scenario genuine to inc mutants enhances cognitive functions. Elevating PKA signaling seems to serve as a checkpoint which allows to constrain the excessive memory and mushroom body overgrowth in these animals, albeit at the sacrifice of sleep and longevity. Our data offer a mechanistic explanation for the sleep deficits of inc mutants, which challenges traditional views on the relation between sleep and memory, and suggest that behavioral hyperplasticity, e.g., prominent in autistic patients, can provoke sleep deficits.

neuroscience↗

Benchmarking algorithms for spatially variable gene identification in spatial transcriptomics

The rapid development of spatial transcriptomics has underscored the importance of identifying spatially variable genes. As a fundamental task in spatial transcriptomic data analysis, spatially variable gene identification has been extensively studied. However, the lack of comprehensive benchmark makes it difficult to validate the effectiveness of various algorithms scattered across a large number of studies with real-world datasets. In response, this article proposes a benchmark framework to evaluate algorithms for identifying spatially variable genes through the analysis of synthesized and real-world datasets, aiming to identify the best algorithms and their corresponding application scenarios. This framework can assist medical and life scientists in selecting suitable algorithms for their research, while also aid bioinformatics scientists in developing more powerful and efficient computational methods in spatial transcriptomic research.

bioinformatics↗

Enhanced purinergic signaling in the paraventricular hypothalamus induces hyperphagic obesity and insulin resistance

Body energy homeostasis is tightly regulated by hypothalamic neural circuits. However, their remodeling upon metabolic challenges remains incompletely characterized, thus complicating the development of safe medications against the surge of metabolic diseases. Oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVH) are one of the key effectors regulating energy balance. In this work, we report that high-fat diet (HFD) feeding in mice evokes spatiotemporally selective ATP release from astrocytes (Inflares) in the PVH, accompanied by the expression of hematopoietic lineage-specific ADP/ATP receptor P2Y12 on local OXT (PVHOXT) neurons. Strikingly, increased purinergic signaling leads to impaired responsiveness of PVHOXT neurons accompanied by hyperphagic obesity and insulin resistance in mice. Conversely, loss of P2Y12 in PVHOXT neurons attenuates metabolic phenotypes, illustrating that such remodeling is both necessary and sufficient to induce metabolic phenotypes. Inflares were also induced by hyperglycemia, while emergence of P2Y12 on OXT neurons of patients with diabetes mellitus suggests an evolutionary conserved purinergic response to various metabolic challenges and its potential as a drug target. Accordingly, nasal administration of clinically approved doses of P2Y12 inhibitors counteracts obesity in mice and non-human primates, paving the way for application of these compounds in patients with metabolic disorders.

neuroscience↗

Critical roles of Ikaros and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

The IKZF1 gene encodes IKAROS - a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which Ikaros exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of Ikaros and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel Ikaros and HDAC1 functions in T-ALL: Both Ikaros and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by Ikaros is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and Ikaros-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of Ikaros and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.

bioinformatics↗

Fokker-Planck diffusion maps of multiple single cell microglial transcriptomes reveals radial differentiation into substates associated with Alzheimer's pathology

The identification of microglia subtypes is important for understanding the role of innate immunity in neu-rodegenerative diseases. Current methods of unsupervised cell type identification assume a small noise-to-signal ratio of transcriptome measurements that would produce well-separated cell clusters. However, identification of subtypes is obscured by gene expression noise, diminishing the distances in transcriptome space between distinct cell types and blurring boundaries. Here we use Fokker-Planck (FP) diffusion maps to model cellular differentiation as a stochastic process whereby cells settle into local minima, corresponding to cell subtypes, in a potential landscape constructed from transcriptome data using a nearest neighbor graph approach. By applying critical transition fields, we identify individual cells on the verge of transitioning between subtypes, revealing microglial cells in inactivated, homeostatic state before radially transitioning into various specialized subtypes. Specifically, we show that cells from Alzheimers disease patients are enriched in a microglia subtype associated to antigen presentation and T-cell recruitment.

systems biology↗

Multi-talker speech comprehension at different temporal scales in listeners with normal and impaired hearing

Comprehending speech requires deciphering a range of linguistic representations, from phonemes to narratives. Prior research suggests that in single-talker scenarios, the neural encoding of linguistic units follows a hierarchy of increasing temporal receptive windows. Shorter temporal units like phonemes and syllables are encoded by lower-level sensory brain regions, whereas longer units such as sentences and paragraphs are processed by higher-level perceptual and cognitive areas. However, the brains representation of these linguistic units under challenging listening conditions, such as a cocktail party situation, remains unclear. In this study, we recorded electroencephalogram (EEG) responses from both normal-hearing and hearing-impaired participants as they listened to individual and dual speakers narrating different parts of a story. The inclusion of hearing-impaired listeners allowed us to examine how hierarchically organized linguistic units in competing speech streams affect comprehension abilities. We leveraged a hierarchical language model to extract linguistic information at multiple levels--phoneme, syllable, word, phrase, and sentence--and aligned these model activations with the EEG data. Our findings showed distinct neural responses to dual-speaker speech between the two groups. Specifically, compared to normal-hearing listeners, hearing-impaired listeners exhibited poorer model fits at the acoustic, phoneme, and syllable levels as well as the sentence levels, but not at the word and phrase levels. These results suggest that hearing-impaired listeners experience disruptions at both shorter and longer temporal scales, while their processing at medium temporal scales remains unaffected.

neuroscience↗

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↗

Calorie Restriction Induces Degeneration of Neurons with Mitochondrial DNA Depletion by Altering ER-Mitochondria Calcium Transfer

Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model where in mtDNA depletion induced by Herpes Simplex Virus Type 1 (HSV-1) protein-UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neurons in vitro (rho-) causes epilepsy-like abnormal EEG. Caloric restriction (CR) is a strategy proven to reduce epileptic activity, however CR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating CR-induced mitochondrial calcium overload. Rho- neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho- neuron model. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that CR may not be a viable clinical intervention in patients with mtDNA depletion.

cell biology↗

A phosphorylation-controlled switch confers cell cycle-dependent protein relocalization

Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled Anchor-away/Recruiter System (MARS) comprises an engineered, 15-kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP-GFP nanobody interaction. Applications of MARS include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods.

cell biology↗

TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion

Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental disorder (NDD) with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs ("rapalogs") for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, with further modulation by MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation, comparing their impact on transcriptome-wide mRNA translation, as well as effects of inhibiting these pathways in TSC has not been explored. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we have examined transcriptome-wide changes in mRNA translation upon TSC2 loss. Our results reveal dysregulated translation in TSC2-Null NPCs, which significantly overlaps with the translatome from TSC1-Null NPCs. Interestingly, numerous non-monogenic ASD-, NDD-and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, were translationally suppressed in TSC2-Null NPCs. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TSC, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders.

molecular biology↗

The genomic and epigenomic dynamics of hemizygous genes across crops with contrasting mating systems

Hemizygous genes, which present on only one of the two homologous chromosomes of diploid organisms, have been mainly studied in the context of sex chromosomes and sex-linked genes. However, structural variants (SVs), such as a deletion/insertion of one allele, can lead to hemizygous genes, a phenomenon largely unexplored in plants. Here, we investigated the genomic and epigenomic landscapes of hemizygous genes across 22 genomes with varying propagation histories: eleven clonal lineages, seven outcrossed samples and four inbred and putatively homozygous genomes. We identified SVs leading to genic hemizygosity. As expected, very few genes (0.01%-1.2%) were hemizygous in the homozygous genomes, representing negative controls. Hemizygosity was appreciable among outcrossed lineages, averaging 8.7% of genes, but consistently elevated for the clonal samples at 13.8% genes, likely reflecting heterozygous SVs accumulation during clonal propagation. Compared to diploid genes, hemizygous genes were more often situated in centromeric than telomeric regions and underlying weaker purifying selection. They also had reduced levels of expression, averaging [~]20% of the expression levels of diploid genes, violating the evolutionary model of dosage compensation. We also detected higher DNA methylation levels, in hemizygous genes and transposable elements, which may contribute to the reduced expression of hemizygous genes. Finally, expression profiles showed that hemizygous genes were more specifically expressed in contexts related to fruit development, organ differentiation and stress responses. Overall, hemizygous genes accumulate in clonally propagated lineages and display distinct genetic, and epigenetic features compared to diploid genes, shedding new insights on genetic studies and breeding programs of clonal crops.

plant biology↗

Amd1-skp2 cascade regulates hepatocyte proliferation during liver growth and hepatocellular carcinoma development in zebrafish

Rapid hepatocyte proliferation is a common characteristic of liver growth in early liver development and hepatocellular carcinoma (HCC). Clarifying the mechanism how liver growth is regulated in development would benefit studying HCC progress. Although many genes have been reported to be involved in liver growth during early development, the mechanism underlying liver growth is far from being elucidated. Here we found that the liver undergoes rapid growth from 2dpf to 5dpf in zebrafish. Comparing the transcriptome for different staged hepatocytes identified 813 hepatocyte enriched genes at 3 dpf. Among them, S-adenosylmethionine decarboxylase proenzyme (AMD1) had not been previously reported to be involved in liver development. Our study further confirmed that amd1 was highly enriched in hepatocytes during liver rapid growth and that amd1 mutation inhibited liver growth mainly by repressing hepatocyte proliferation. Mechanistically, amd1 loss of function downregulated the expression of skp2, and skp2 is required for amd1 to regulate hepatocyte proliferation. Furthermore, the role of Amd1-Skp2 cascade in regulating hepatocyte proliferation was also conserved in a zebrafish HCC model. In conclusion, our study systematically identified some uncharacterized genes possibly being involved in regulating liver growth during zebrafish development, and revealed the role of amd1-skp2 cascade in regulating hepatocyte proliferation during liver growth and HCC progression. This work also provided a database which would benefit elucidating the mechanism how hepatocyte proliferation is regulated during liver growth and HCC progress.

developmental biology↗

Enhanced Recognition of a Herbal Compound Epiberberine by a DNA Quadruplex-Duplex Structure

The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases, including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence Q4, resulting in a nanomolar binding affinity (KD approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures in physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer the Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5' end. Q4-ds-A is a superb EPI binder with a KD of 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI from Rhizoma coptidis (Huang Lian) extracts.

biochemistry↗

Proteomic Discovery of RNA-Protein Molecular Clamps Using a Thermal Shift Assay with ATP and RNA (TSAR)

Uncompetitive inhibition is an effective strategy for suppressing dysregulated enzymes and their substrates, but discovery of suitable ligands depends on often-unavailable structural knowledge and serendipity. Hence, despite surging interest in mass spectrometry-based target identification, proteomic studies of substrate-dependent target engagement remain sparse. Herein, we describe a strategy for the discovery of substrate-dependent ligand binding. Using proteome integral solubility alteration (PISA) assays, we show that simple biochemical additives can enable detection of RNA-protein-small molecule complexes in native cell lysates. We apply our approach to rocaglates, molecules that specifically clamp RNA to eukaryotic translation initiation factor 4A (eIF4A), DEAD-box helicase 3X (DDX3X), and potentially other members of the DEAD-box (DDX) helicase family. To identify unexpected interactions, we used a target class-specific thermal window and compared ATP analog and RNA base dependencies for key rocaglate-DDX interactions. We report and validate novel DDX targets of high-profile rocaglates - including the clinical candidate Zotatifin - using limited proteolysis-mass spectrometry and fluorescence polarization (FP) experiments. We also provide structural insight into divergent DDX3X affinities between synthetic rocaglates. Taken together, our study provides a model for screening uncompetitive inhibitors using a chemical proteomics approach and uncovers actionable DDX clamping targets, clearing a path towards characterization of novel molecular clamps and associated RNA helicases.

biochemistry↗